TREATMENT OF MOST BOTHERSOME SYMPTOM (MBS) ASSOCIATED WITH MIGRAINE USING ANTI-CGRP ANTIBODIES

Abstract

Methods for treatment of most bothersome symptom (MBS) associated with migraine are provided. Exemplary methods provide improvement in MBS associated with migraine within 1 month of administration og anti-CGRP antibodies of the invention. Also provided are methods for improvement of patient impression of change (PGIC) associated with migraine. Exemplary methods comprise administration of an anti-CGRP antagonistic antibody to a patient in need thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Appl. No. 63/005,950, filed Apr. 6, 2020, which is hereby incorporated by reference in its entirety.

SEQUENCE LISTING DISCLOSURE

[0002] The instant application contains a Sequence Listing which has been submitted in ASCII format The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 28, 2020, is named "1143257o009401.txt" and is 357,662 bytes in size.

BACKGROUND OF THE INVENTION

Field of the Invention

[0003] This invention pertains to methods of treatment of most bothersome symptom associated with migraine, using antibodies and fragments thereof (including Fab fragments) that specifically bind to human Calcitonin Gene Related Peptide (hereinafter "CGRP").

Description of Related Art

[0004] Calcitonin Gene Related Peptide (CGRP) is produced as a multifunctional neuropeptide of 37 amino acids in length. Two forms of CGRP, the CGRP-alpha and CGRP-beta forms, exist in humans and have similar activities. CGRP-alpha and CGRP-beta differ by three amino acids in humans, and are derived from different genes. CGRP is released from numerous tissues such as trigeminal nerves, which when activated release neuropeptides within the meninges, mediating neurogenic inflammation that is characterized by vasodilation, vessel leakage, and mast-cell degradation. Durham, P. L., New Eng. J. Med., 350 (11):1073-75 (2004). Biological effects of CGRP are mediated via the CGRP receptor (CGRP-R), which consists of a seven-transmembrane component, in conjunction with receptor-associated membrane protein (RAMP). CGRP-R further requires the activity of the receptor component protein (RCP), which is essential for an efficient coupling to adenylate cyclase through G proteins and the production of cAMP. Doods, H., Curr. Op. Invest. Drugs, 2(9):1261-68 (2001).

[0005] Migraines are neurovascular disorder affecting approximately 10% of the adult population in the U.S., and are typically accompanied by intense headaches. CGRP is believed to play a prominent role in the development of migraines. In fact, several companies, i.e., Amgen, Eli Lilly, Teva and Alder Biopharmaceuticals (recently acquired by Lundbeck A/S) have developed anti-CGRP and anti-CGRP-R antibodies for use in treating or preventing migraine headaches. The present assignee has previously filed patent applications related to anti-CGRP antibodies and uses thereof including published PCT Application WO/2012/162243 filed May 21, 2012 entitled "ANTI-CGRP COMPOSITIONS AND USE THEREOF", published PCT Application WO/2012/162257 filed May 21, 2012, entitled "USE OF ANTI-CGRP ANTIBODIES AND ANTIBODY FRAGMENTS TO PREVENT OR INHIBIT PHOTOPHOBIA OR LIGHT AVERSION IN SUBJECTS IN NEED THEREOF, ESPECIALLY MIGRAINE SUFFERERS" published PCT Application WO/2012/162253, filed May 21, 2012, entitled "USE OF ANTI-CGRP OR ANTI-CGRP-R ANTIBODIES OR ANTIBODY FRAGMENTS TO TREAT OR PREVENT CHRONIC AND ACUTE FORMS OF DIARRHEA" and published PCT Application WO/2015/003122, filed Jul. 3, 2014, entitled "REGULATION OF GLUCOSE METABOLISM USING ANTI-CGRP ANTIBODIES" all of which applications are incorporated by reference in their entirety.

BRIEF SUMMARY

[0006] The present disclosure provides methods of treatment of most bothersome symptom (MBS) associated with migraine in patient suffering from chronic migraine, comprising administering to a patient in need an effective amount of at least one anti-CGRP antibody or antibody fragment thereof or an anti-CGRP-R antibody or antibody fragment thereof or one or more formulations comprising said antibody or antibody fragment as disclosed herein. Said antibody treatment may be initiated in the interictal period, i.e. in between migraine attacks or in the ictal phase, i.e. during the migraine episode. Said migraine may comprise e.g. chronic migraine or episodic migraine, in a specific aspect of the present invention the patient suffers from chronic migraine. In the present invention, said anti-CGRP antibody or antibody fragment is denoted Ab6. Ab6 is an anti-CGRP antibody or antibody fragment thereof having the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively and the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208; or having the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively. Said anti-CGRP antibody may comprise the variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202. Said anti-CGRP antibody may comprise the variable light chain polypeptide encoded by SEQ ID NO: 232 and the variable heavy chain polypeptide encoded by SEQ ID NO: 212. Said anti-CGRP antibody may comprise the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. Said anti-CGRP antibody may comprise the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567. Said anti-CGRP antibody may comprise the antibody expression product isolated from recombinant cells which express nucleic acid sequences encoding the variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202, which polypeptides optionally are respectively linked to human light and heavy constant region polypeptides, e.g., human IgG1, IgG2, IgG3 or IgG4 constant regions, which constant regions optionally may be modified to alter glycosylation or proteolysis, wherein said recombinant cells optionally comprise yeast or mammalian cells, e.g., Pichia pastoris or CHO cells. Said anti-CGRP antibody may comprise the antibody expression product isolated from recombinant cells which express nucleic acid sequences encoding the light chain of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566, wherein said recombinant cells optionally comprise yeast or mammalian cells, e.g., Pichia pastoris or CHO cells, wherein the constant regions thereof optionally may be modified to alter glycosylation or proteolysis or other effector functions. Any of the aforementioned anti-CGRP antibodies or antibody fragments, preferably Ab6, may be optionally comprised in a formulation as disclosed herein, e.g., comprising histidine (L-histidine), sorbitol, polysorbate 80, such as, per 1 mL volume, about 100 mg anti-CGRP antibody, about 3.1 mg L-Histidine, about 40.5 mg Sorbitol, and about 0.15 mg Polysorbate 80, having a pH of about 5.8. The administered dosage of said antibody may be between about 100 mg and about 300 mg, such as about 100 mg, about 300 mg, 100 mg, or 300 mg. The dosage may be administered by different means, e.g., intravenously, e.g., in a saline solution such as 0.9% sodium chloride in a suitable volume, such as 100 mL

[0007] Said patient may exhibit less than 25 headache days per month, less than 20 headache days per month, less than 15 headache days per month, or less than 10 headache days per month. For example, said patient may exhibit less than 14 headache days, less than 13 headache days, less than 12 headache days, less than headache 11 days, less than 10 headache days, less than 9 headache days, less than 8 headache days, less than 7 headache days, or less than 6 headache days per month. Said patient may exhibit between 2-15 headache days, e.g., 3-14 headache days, 4-13 headache days, 5-12 headache days, 6-11 headache days, or 7-10 headache days/month.

[0008] Said patient may exhibit less than 10 migraines per month, such as between 1-9 migraines per month, such as between 2-8 migraines per month, between 3-7 migraine per month, between 4-6 migraine per month, or about 5 migraines per month. Said patient may exhibit fewer than 1 migraine per month on average, e.g., on average one migraine every 2 months, one every 3 months, one every 4 or 6 months, or intermediate values such as 2 every 3 months, etc. Said migraine may be diagnosed in accord with the ICHD-3 guidelines.

[0009] In addition to headache and associated symptoms as described in the diagnostic criteria of the International Classification of Headache Disorders (ICHD-3) for migraine with or without aura, migraine patients experience a variety of autonomic, cognitive, sensory and motor symptoms during migraine, these symptoms are experienced uniquely by individual patients. In the present invention, the patients were allowed to self-identify a specific symptom associated with chronic migraine that they considered to be most bothersome. In the present application these symptoms will be referred to at the most bothersome symptom (MBS) associated with migraine. In the present invention the patient could identify their MBS without limitation, which provides a unique patient-centered approach for identifying and measuring the efficacy of antibodies of the invention as treatment of these most bothersome migraine-associated symptoms and hence is expected to have a meaningful impact on the patients ability to function during migraine. Although nausea, vomiting, photophobia, and phonophobia are migraine-associated symptoms included in ICDH-3 diagnostic criteria, many other symptoms may be observed to occur prior to, after, and even between days with diagnosable migraine. Over the duration of a migraine attack, these can include cognitive symptoms (e.g. memory, executive function, attention deficit), affective symptoms (e.g. mood changes, depression, anxiety, irritability), other sensory symptoms (e.g. osmophobia, taste abnormalities), as well as blurry vision, nasal congestion, rhinorrhea, lacrimation, sweating, ptosis, yawning, polyuria, abdominal cramps, diarrhea, dizziness, and neck pain. The MBS associated with migraine reported by the patients enrolled in the clinical trial described in Example 2 is summarized in Table 1. Although nausea/vomiting, photophobia, and phonophobia were common in the patient population in Example 2, less than half of these patients named one of these 3 symptoms included in ICDH-3 diagnostic criteria as their patient-identified MBS.

[0010] Migraine is a complex disorder of the brain associated with multifaceted symptomatology yet expressed in a personalized unique manner. Often persisting over multiple days, the peri-ictal period of migraine can be classified into four distinct phases--prodrome/premonitory, preictal/aura, ictal/headache, postdrome/postictal--with overlapping symptoms occurring during each phase of migraine. The various types and timing of MBS across the course of the migraine is illustrated in FIG. 15. It is highly relevant to assess MBS in migraine patients during clinical trials, since it is recognized that headache pain alone is not considered sufficient to adequately eliminate the impact of migraine on the patients daily living and health status. The reduction in mean monthly migraine days (MMDs) or a similar endpoints in clinical trials do not fully capture the burden of migraine and the associated symptoms that are affected by therapeutic intervention. The inventors of the present invention found that in addition to reducing MMDs Ab6, an anti-CGRP antibody, was also effective in improving MBS in migraine patients. Improvements in these symptoms associated with treatment were correlated with improved patients' perception of disease status and indirectly with satisfaction with treatment response. It is known that migraine patients often continue to seek treatment for their migraine because of the burden of their MBS, thus supporting the clinical value of treating both the primary migraine pathology and the MBS associated with said migraine.

[0011] The present invention provides anti-CGRP antibodies or antibody fragments thereof, which are able to improve the MBS associated with migraine in patients suffering from migraine, such as chronic or episodic migraine. The MBS parameter rates the patient's assessment of change (improvement or worsening since the start of the study) in this symptom.

[0012] The present invention provides anti-CGRP antibodies or antibody fragments thereof, which are able to improve the patient global impression of change (PGIC) associated with migraine treatment in patients impacted by migraine, such as chronic or episodic migraine. The patient global impression of change (PGIC) associated with migraine parameter comprises a single question concerning the patient's impression of the overall change (improvement or worsening since the start of the study) in their disease status evaluated on a 7 point Likert scale anchored by very much improved and very much worse.

[0013] The present invention provides anti-CGRP antibodies or antibody fragments thereof, which are able to reduce MMDs as well as improve the patient's most bothersome symptom (MBS) associated with migraine in a manner that is highly corelated with positive change I the patient's global impression of change (PGIC) of migraine treatment. This dual action constitutes an improved treatment option for patient suffering from migraine, which goes beyond treating the migraine headache, and provides treatment for the collective migraine burden experienced by the patient comprising both migraine headache as well as MBS associated with migraine.

[0014] The present invention provides methods of improving most bothersome symptom (MBS) associated with migraine, comprising intravenously administering to a patient in need thereof between about 100 mg and about 300 mg of an anti-CGRP antibody, wherein said anti-CGRP antibody preferably comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or 566.

[0015] The present invention provides methods of improving patient global impression of change (PGIC), comprising intravenously administering to a patient in need thereof between about 100 mg and about 300 mg of an anti-CGRP antibody, wherein said anti-CGRP antibody preferably comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or 566.

[0016] In another aspect, the invention provides methods of improving most bothersome symptom (MBS) associated with migraine and simultaneously reduce the MMDs, comprising intravenously administering to a patient in need thereof between about 100 mg and about 300 mg of an anti-CGRP antibody, wherein said anti-CGRP antibody preferably comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or 566.

[0017] In another aspect, the invention provides methods of improving patient global impression of change (PGIC) associated with migraine and simultaneously reduce the MMDs, comprising intravenously administering to a patient in need thereof between about 100 mg and about 300 mg of an anti-CGRP antibody, wherein said anti-CGRP antibody preferably comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or 566.

[0018] In another aspect, the invention provides methods of improving most bothersome symptom (MBS) associated with migraine and patient global impression of change (PGIC) associated with migraine, comprising intravenously administering to a patient in need thereof between about 100 mg and about 300 mg of an anti-CGRP antibody, wherein said anti-CGRP antibody preferably comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or 566

[0019] In another aspect, the invention provides methods of improving most bothersome symptom (MBS) associated with migraine and/or patient global impression of change (PGIC) associated with migraine and simultaneously reduce the MMDs, comprising intravenously administering to a patient in need thereof between about 100 mg and about 300 mg of an anti-CGRP antibody, wherein said anti-CGRP antibody preferably comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or 566.

[0020] In some exemplary embodiments the dosage of said anti-CGRP antibody may be 100 mg.

[0021] In other exemplary embodiments the dosage of said anti-CGRP antibody may be 300 mg.

[0022] The method may further comprise intravenously administering 100 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks.

[0023] The method may further comprise intravenously administering 300 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks.

[0024] The antibody may be provided or administered in a formulation as disclosed herein, e.g., comprising histidine (L-histidine), sorbitol, polysorbate 80, such as, per 1 mL volume, about 100 mg anti-CGRP antibody, about 3.1 mg L-Histidine, about 40.5 mg Sorbitol, and about 0.15 mg Polysorbate 80, having a pH of about 5.8.

[0025] Prior to first dosage, the patient may exhibit between about 10 and about 22 migraine days per month, such as between about 13 and about 19 migraine days per month, such as about 16 migraine days per month.

[0026] Prior to first dosage, the patient may exhibit between about 14 and about 27 headache days per month, such as between about 17 and about 24 headache days per month, such as about 20 or about 21 headache days per month.

[0027] Said patient may have been diagnosed with migraine at least 10 years prior to said first dosage, such as at least 15 years prior to said first dosage, such as at least 18 or at least 19 years prior to said first dosage.

[0028] Said patient may have been diagnosed with chronic migraine at least 5 years prior to said first dosage, such as at least 8 years prior to said first dosage, such as at least 11 or at least 12 years prior to said first dosage.

[0029] The patient may have a headache when administered the anti-CGRP antibody or fragments thereof of the invention.

[0030] The patient may have a migraine, such as a migraine with aura, when administered anti-CGRP antibody or fragments thereof of the invention.

[0031] Said patient may have a reduction in the number of migraine days by at least 50% in the one month period after being administered said first dose relative to the baseline number of migraine days experienced by that patient prior to said first dose.

[0032] Said patient may have a reduction in the number of migraine days by at least 75% in the one month period after being administered said first dose relative to the baseline number of migraine days experienced by that patient prior to said first dose.

[0033] Said patient may have a reduction in the number of migraine days by 100% in the one month period after being administered said first dose relative to the baseline number of migraine days experienced by that patient prior to said first dose.

[0034] Said patient may have a reduction in the number of migraine days by at least 50% in the 12 week period after being administered said first dose relative to the baseline number of migraine days experienced by that patient prior to said first dose.

[0035] Said patient may have a reduction in the number of migraine days by at least 75% in the 12 week period after being administered said first dose relative to the baseline number of migraine days experienced by that patient prior to said first dose.

[0036] Said patient may have a reduction in the number of migraine days by 100% in the 12 week period after being administered said first dose relative to the baseline number of migraine days experienced by that patient prior to said first dose.

[0037] Said patient may experience an improvement in their MBS associated with migraine in the one month period after being administered said first dose measured as the change from the baseline MBS.

[0038] Said patient may experience an improvement in their MBS associated with migraine in the 3 month period after being administered said first dose measured as the change from the baseline MBS.

[0039] Said patient may experience an improvement in their MBS associated with migraine in the 6 month period after being administered said first dose measured as the change from the baseline MBS.

[0040] Said patient may experience an improvement in their PGIC associated with migraine in the one month period after being administered said first dose measured as the change from the baseline.

[0041] Said patient may experience an improvement in their PGIC associated with migraine in the 3 month period after being administered said first dose measured as the change from the baseline.

[0042] Said patient may experience an improvement in their PGIC associated with migraine in the 6 month period after being administered said first dose measured as the change from the baseline.

[0043] The method may further comprise administering, e.g., intravenously, a second dose of an anti-CGRP antibody of the invention to said patient within about 10-14 weeks, preferably 11-13 weeks, more preferably about 12 weeks or about 3 months, after said first dose.

[0044] Said first dose may comprise about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of said anti-CGRP antibody.

[0045] Prior to said administration, the patient may exhibit between about 15 and about 30 migraine days per month, such as between about 16 and about 28 migraine days per month, such as between about 17 and about 26 migraine days per month, such as about 16 migraine days per month.

[0046] Prior to said administration, the patient may exhibit between about 15 and about 27 headache days per month, such as between about 17 and about 24 headache days per month, such as about 20 or about 21 headache days per month.

[0047] Said patient may have been diagnosed with migraine at least 10 years prior to said administration, such as at least 15 years prior to said administration, such as at least 18 or at least 19 years prior to said administration.

[0048] Said patient may have been diagnosed with chronic migraine at least 5 years prior to said administration, such as at least 8 years prior to said administration, such as at least 11 or at least 12 years prior to said administration.

[0049] Said patient may have a reduction in the number of migraine days by at least 50% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration.

[0050] Said patient may have a reduction in the number of migraine days by at least 75% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration.

[0051] Said patient may have a reduction in the number of migraine days by 100% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration.

[0052] Said patient may have a reduction in the number of migraine days by at least 50% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration.

[0053] Said patient may have a reduction in the number of migraine days by at least 75% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration.

[0054] Said patient may have a reduction in the number of migraine days by 100% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration.

[0055] The method may further comprise administering, e.g., intravenously, a second dose of said anti-CGRP antibody to said patient within about 10-14 weeks, preferably 11-13 weeks, more preferably about 12 weeks or about 3 months, after said administration.

[0056] Said administration may comprise about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of said anti-CGRP antibody.

[0057] Said anti-CGRP antibody may be aglycosylated or if glycosylated only may contain only mannose residues.

[0058] Said anti-CGRP antibody may consist of the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566. Said anti-CGRP antibody may consist of the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0059] In some embodiments, said anti-human CGRP antibody or antibody fragment comprises the variable light chain of SEQ ID NO: 222 and/or the variable heavy chain of SEQ ID NO: 202. In some embodiments, said anti-human CGRP antibody or antibody fragment comprises the variable light chain encoded by SEQ ID NO: 232 and/or the variable heavy chain encoded by SEQ ID NO: 212.

[0060] In some embodiments, said anti-human CGRP antibody or antibody fragment comprises the light chain of SEQ ID NO: 221 and/or the heavy chain of SEQ ID NO: 201 or SEQ ID NO: 566. In some embodiments, said anti-human CGRP antibody or antibody fragment comprises the light chain encoded by SEQ ID NO: 231 and/or the heavy chain encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0061] In some embodiments, said anti-CGRP antibody may comprise the antibody expression product isolated from recombinant cells which express nucleic acid sequences encoding the VL polypeptide of SEQ ID NO: 222 and the VH polypeptide of SEQ ID NO: 202, which polypeptides optionally are respectively linked to human light and heavy constant region polypeptides, e.g., human IgG1, IgG2, IgG3 or IgG4 constant regions, which constant regions optionally may be modified to alter glycosylation or proteolysis, wherein said recombinant cells optionally comprise yeast or mammalian cells, e.g., Pichia pastoris or CHO cells.

[0062] In some embodiments, said anti-CGRP antibody may comprise the antibody expression product isolated from recombinant cells which express nucleic acid sequences encoding the light chain of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566, wherein said recombinant cells optionally comprise yeast or mammalian cells, e.g., Pichia pastoris or CHO cells, wherein the constant regions thereof optionally may be modified to alter glycosylation or proteolysis or other effector functions.

[0063] In some embodiments any of the aforementioned anti-CGRP antibodies or antibody fragments may be comprised in a formulation as disclosed herein, e.g., comprising histidine (L-histidine), sorbitol, polysorbate 80, such as, per 1 mL volume, about 100 mg anti-CGRP antibody, about 3.1 mg L-Histidine, about 40.5 mg Sorbitol, and about 0.15 mg Polysorbate 80, having a pH of about 5.8. The antibody or fragment may be administered by different means, e.g., intravenously, e.g., in a saline solution such as 0.9% sodium chloride in a suitable volume, such as 100 mL.

[0064] In some embodiments, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of said anti-CGRP antibody or antibody fragment is administered, e.g., intravenously.

[0065] In other embodiments, about 100 mg of said anti-CGRP antibody or antibody fragment is administered.

[0066] In other embodiments, about 300 mg of said anti-CGRP antibody or antibody fragment is administered, e.g., intravenously.

[0067] In exemplary embodiments, the anti-human CGRP antibody or antibody fragment is administered, e.g., intravenously at a frequency which is at most every 10-14 weeks, preferably every 11-13 weeks, more preferably every 3 months or every 12 weeks, wherein the antibody dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 10-14 weeks, preferably every 11-13 weeks, more preferably every 3 months or every 12 weeks. The phrase "the antibody dosage is administered in a single formulation or divided into different formulations" refers to the administration of the recited amount of antibody within a relatively short period of time, e.g., within a period of several hours, e.g., 1 to 8 hours, about one day, within about two days, or within about one week, which may be by the same or different routes (e.g., i.v., i.m., and/or s.c.), sites of administration. The term "different formulations" in this context refers to antibody dosages that are administered at different times and/or at different sites and/or different routes, irrespective of whether the dosages are the same or different with respect to the chemical composition of the pharmaceutical formulation in with each dosage is administered; for example, the concentration, excipients, carriers, pH, and the like may be the same or different between the different administered dosages.

[0068] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 8 weeks or every 2 months.

[0069] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks or every 3 months.

[0070] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 16 weeks or every 4 months.

[0071] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 20 weeks or every 5 months.

[0072] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 24 weeks or every 6 months.

[0073] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 28 weeks or every 7 months.

[0074] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 32 weeks or every 8 months.

[0075] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 36 weeks or every 9 months.

[0076] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 40 weeks or every 8 months.

[0077] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 44 weeks or every 9 months.

[0078] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 48 weeks or every 10 months.

[0079] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 52 weeks or every 11 months.

[0080] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 56 weeks or every 12 months.

[0081] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 15-18 months.

[0082] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment dosage is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 18-21 months.

[0083] In other exemplary embodiments, the anti-human CGRP antibody dosage or antibody fragment used in the afore-mentioned methods is administered in a single formulation or divided into different formulations which are administered at a frequency of approximately every 2 years.

[0084] In other exemplary embodiments, the anti-human CGRP antibody used in the afore-mentioned methods is administered systemically.

[0085] In other exemplary embodiments, the anti-human CGRP antibody or antibody fragment used in the afore-mentioned methods is administered by a mode of administration is selected from intravenous, intramuscular, intravenous, intrathecal, intracranial, topical, intranasal, and oral. In a preferred embodiment, the anti-human CGRP antibody or antibody fragment used in the afore-mentioned methods is administered intravenously.

[0086] In other exemplary embodiments, the anti-human CGRP antibody used in the afore-mentioned methods has an in vivo half-life of at least 10 days.

[0087] In other exemplary embodiments, the anti-human CGRP antibody has an in vivo half-life of at least 15 days.

[0088] In other exemplary embodiments, the anti-human CGRP antibody used in the afore-mentioned methods has an in vivo half-life of at least 20 days.

[0089] In other exemplary embodiments, the anti-human CGRP antibody used in the afore-mentioned methods has an in vivo half-life of at least 20-30 days.

[0090] In other exemplary embodiments, the anti-human CGRP antibody is administered at a dosage of between about 100 mg and about 300 mg has an in vivo half-life of 20% of at least about (284 f 44 hours).

[0091] In other exemplary embodiments, the anti-human CGRP antibody used in the afore-mentioned methods binds to human .alpha.- and .beta.-CGRP.

[0092] In other exemplary embodiments, the administered anti-human CGRP antibody dosage results in the inhibition of vasodilation induced by topically applied capsaicin at least 30 days after antibody administration.

[0093] In other exemplary embodiments, the administered anti-human CGRP antibody dosage results in the inhibition of vasodilation induced by topically applied capsaicin at least 60 days after antibody administration.

[0094] In other exemplary embodiments, the administered anti-human CGRP antibody dosage results in inhibition of vasodilation induced by topically applied capsaicin at least 90 days after antibody administration.

[0095] In other exemplary embodiments, the administered anti-human CGRP antibody dosage results in the inhibition of vasodilation induced by topically applied capsaicin at least 120 days after antibody administration.

[0096] In other exemplary embodiments, the administered anti-human CGRP antibody dosage results in the inhibition of vasodilation induced by topically applied capsaicin at least 150 days after antibody administration.

[0097] In other exemplary embodiments, the administered anti-human CGRP antibody dosage results in the inhibition of vasodilation induced by topically applied capsaicin at least 180 days after antibody administration.

[0098] In other exemplary embodiments, the administered anti-human CGRP antibody dosage results in the inhibition of vasodilation induced by topically applied capsaicin more than 180 days after antibody administration.

[0099] In other exemplary embodiments, the administered anti-human CGRP antibody dosage results in sustained pharmacodynamic (PK) activity, within 5% of the maximal response (Imax) (as compared to lower antibody doses).

[0100] In other exemplary embodiments, the administered anti-human CGRP antibody dosage results in sustained pharmacodynamic (PK) activity which is maintained for at least 2-3 months after antibody administration, wherein PK analysis of the anti-human CGRP antibody is derived from plasma concentrations.

[0101] In other exemplary embodiments, the administered anti-human CGRP antibody dosage is between about 100 mg and about 300 mg or more which is administered no more frequently than every 2 months.

[0102] The present invention is additionally directed to the use of specific antibodies and fragments thereof having binding specificity for CGRP, in particular antibodies having desired epitopic specificity, high affinity or avidity and/or functional properties. A preferred embodiment of the invention is directed to usage of chimeric or humanized antibodies and fragments thereof (including Fab fragments) capable of binding to CGRP and/or inhibiting the biological activities mediated by the binding of CGRP to the CGRP receptor ("CGRP-R") e.g., wherein such antibodies optionally are derived from recombinant cells engineered to express same, optionally yeast or mammalian cells, further optionally Pichia pastoris and CHO cells.

[0103] In another preferred embodiment of the invention, full length antibodies and Fab fragments thereof are contemplated that inhibit the CGRP-alpha-, CGRP-beta-, and rat CGRP-driven production of cAMP. In a further preferred embodiment of the invention, full length and Fab fragments thereof are contemplated that reduce vasodilation in a recipient following administration.

[0104] The invention also contemplates usage of conjugates of anti-CGRP antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates usage of chimeric or humanized anti-CGRP or anti-CGRP/CGRP-R complex antibodies and binding fragments thereof. In one embodiment, binding fragments include, but are not limited to, Fab, Fab', F(ab').sub.2, Fv, scFv fragments, SMIPs (small molecule immunopharmaceuticals), camelbodies, nanobodies, and IgNAR.

BRIEF DESCRIPTION OF THE DRAWINGS

[0105] FIG. 1 provide the polypeptide sequences of the full-length heavy chain for antibody Ab6 with framework regions (FR), complementarity determining regions (CDRs), and constant region sequences delimited.

[0106] FIG. 2 provide the polypeptide sequences of the full-length light chain for antibody Ab6 with framework regions (FR), complementarity determining regions (CDRs), and constant region sequences delimited.

[0107] FIG. 3 provide exemplary polynucleotide sequences encoding the full-length heavy chain for antibody Ab6 with framework regions (FR), complementarity determining regions (CDRs), and variable region coding sequences delimited.

[0108] FIG. 4 provide exemplary polynucleotide sequences encoding the full-length light chain for antibody Ab6 with their framework regions (FR), complementarity determining regions (CDRs), and variable region coding sequences delimited.

[0109] FIG. 5 provides the polypeptide sequence coordinates within the full-length heavy chain polypeptide sequences of antibodies Ab6 of sequence features including the variable region and complementarity determining regions (CDRs), and the SEQ ID NO of each individual feature.

[0110] FIG. 6 provides the polypeptide sequence coordinates within the full-length heavy chain polypeptide sequences of antibody Ab6 of sequence features including the framework regions (FRs) and constant region, and the SEQ ID NO of each individual feature.

[0111] FIG. 7 provides the polypeptide sequence coordinates within the full-length light chain polypeptide sequences of antibody Ab6 of sequence features including the variable region and complementarity determining regions (CDRs), and the SEQ ID NO of each individual feature.

[0112] FIG. 8 provides the polypeptide sequence coordinates within the full-length light chain polypeptide sequences of antibody Ab6 of sequence features including the framework regions (FRs) and constant region, and the SEQ ID NO of each individual feature.

[0113] FIG. 9 provides the polynucleotide sequence coordinates within the exemplary polynucleotide sequences encoding the full-length heavy chain polypeptide sequences of antibody Ab6 of sequence features including the variable region and complementarity determining regions (CDRs), and the SEQ ID NO of each individual feature.

[0114] FIG. 10 provides the polynucleotide sequence coordinates within the exemplary polynucleotide sequences encoding the full-length heavy chain polypeptide sequences of antibody Ab6 of sequence features including the framework regions (FRs) and constant region, and the SEQ ID NO of each individual feature.

[0115] FIG. 11 provides the polynucleotide sequence coordinates within the exemplary polynucleotide sequences encoding the full-length light chain polypeptide sequences of antibody Ab6 of sequence features including the variable region and complementarity determining regions (CDRs), and the SEQ ID NO of each individual feature.

[0116] FIG. 12 provides the polynucleotide sequence coordinates within the exemplary polynucleotide sequences encoding the full-length light chain polypeptide sequences of antibody Ab6 of sequence features including the framework regions (FRs) and constant region, and the SEQ ID NO of each individual feature.

[0117] FIG. 13 Study design of the clinical trial protocol as summarized in Example 2.

[0118] FIG. 14 displays the efficacy of Ab6 on Mean Monthly Migraine Days (MMDs) in the clinical trial described in Example 2.

[0119] FIG. 15 Illustrates the types and timing of Most Bothersome Symptoms (MBS) across the course of the migraine

[0120] FIG. 16 Illustrates the MBS change from baseline during the 28 day screening period of the clinical trial described in Example 2--i.e. before the first infusion of Ab6.

[0121] FIG. 17 Illustrates the MBS change from baseline 1 month after the first infusion of Ab6 in the clinical trial described in Example 2.

[0122] FIG. 18 Illustrates the PGIC from baseline 1 month after the first infusion of Ab6 in the clinical trial described in Example 2.

[0123] FIG. 19 Illustrates the MBS change from baseline 3 month after the first infusion of Ab6 in the clinical trial described in Example 2.

[0124] FIG. 20 Illustrates the PGIC from baseline 3 month after the first infusion of Ab6 in the clinical trial described in Example 2.

[0125] FIG. 21 Illustrates the MBS change from baseline 6 month after the first infusion of Ab6 in the clinical trial described in Example 2.

[0126] FIG. 22 Illustrates the PGIC from baseline 6 month after the first infusion of Ab6 in the clinical trial described in Example 2.

DETAILED DESCRIPTION

[0127] Use of anti-CGRP antibodies for treatment of MBS and/or PGIC associated with migraine, such as chronic migraine or episodic migraine is described herein. Additionally, anti-CGRP antibodies are demonstrated herein to be effective for treatment of MMDs. The treatment efficacy on both MBS and PGIC are shown to be effective in providing relief of MBS and PGIC at 1 month, 3 months and 6 months following the first infusion of an anti-CGRP antibody or fragments thereof of the invention.

Definitions

[0128] It is to be understood that this invention is not limited to the particular methodology, protocols, cell lines, animal species or genera, and reagents described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. As used herein the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the protein" includes reference to one or more proteins and equivalents thereof known to those skilled in the art, and so forth. All technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs unless clearly indicated otherwise.

[0129] As used herein, the term "most bothersome symptom associated with migraine" refers to symptoms which is identified by an individual patient to be the most bothersome symptom they associate with their migraine. In the present invention the "most bothersome symptom associated with migraine" is specified in Table 1. The "most bothersome symptom associated with migraine" of the present invention described by the patient to the study investigator who assists in medical interpretation of the patients symptom. The investigator in the clinical study was able to with the patient consultation selected from the group of known migraine symptoms consisting of: Sensitivity to light (photophobia), Nausea/vomiting, Headache, Sensitivity to sound (phonophobia), Aura, Pain with activity, Pain, Throbbing/pulsation, Cognitive disruption, Fatigue, Mood changes, Sensitivity to smell (osmophobia or olfactophobia), Visual impact, Pressure/tightness, Pain (anatomical), Eye pain, Neck pain, Dizziness, Allodynia, Inactivity, Sensory disturbance, Sleep disturbance and Speech difficulty. A patient's "most bothersome symptom associated with migraine" as used in the present invention refers to the self-identified "most bothersome symptom associated with migraine", which may be one or more of the symptoms described herein above or may be classified as "other"

[0130] As used herein, the term "improvement of" or "improving" most bothersome symptom associated with migraine refers the change in the patient's assessment of the MBS compared to baseline (i.e the MBS prior to the first dosing with anti-CGRP antibodies or fragments thereof of the invention). An improvement is characterized as .gtoreq.1 categorical change in the patients assessment of the MBS compared to baseline on the 7 point Likert scale described in Example 2.

[0131] As used herein, the term "improvement of" or "improving" patient global impression of change associated with migraine refers the change in the patient's assessment of their disease status compared to baseline (i.e the disease status prior to the first dosing with anti-CGRP antibodies or fragments thereof of the invention). An improvement is characterized as .gtoreq.1 categorical change in the patients assessment of the PGIC compared to baseline on the 7-step scale described in Example 2.

[0132] As used herein, the term "chronic migraine" refers to a condition wherein a patient exhibits, on average, at least 15 headache per month with a subset of these headache days fulling the ICHD-3 criteria for migraine with or without aura. The term "episodic migraine" refers to a condition wherein a patient exhibits, on average, less than 15 day a month of headache with typically 4-15 being a migraine phenotype meeting the ICHD-3 definition of migraine with or without aura.

[0133] As used herein, the term "diagnosed with chronic migraine" refers to a patient meeting the clinical criteria for chronic migraine, whether or not a formal diagnosis of that patient was performed.

[0134] As used herein, the term "intravenously administering" refers to a mode of administration wherein a substance, e.g., an antibody, is introduced directly into the circulation of that patient, most typically into the venous circulation. The substance may be introduced in a carrier fluid, such as an aqueous solution, e.g., normal saline. The substance may be administered in a single formulation or in multiple formulations, as long as the administration is completed over a short period of time (e.g., within 1 day, preferably within 12 hours, more preferably within 6 hours, and most preferably within 1-2 hours).

[0135] As used herein, the term "the baseline number of migraine days" refers to the number of migraine days exhibited by a patient in a specified time period, e.g., prior to treatment. For example, the baseline number of migraine days may be determined over a period of one month, or longer, e.g., by recording each day whether or not a migraine occurred.

[0136] As used herein, the term "migraine days per month" refers to the number of days per month on which a patient has a migraine, i.e., at any time during that day, the patient has symptoms that meet the clinical definition of migraine. The number of migraine days per month may be determined by recording each day whether or not a migraine occurred.

[0137] As used herein, the term "headache days per month" refers to the number of days per month on which a patient has a headache, i.e., at any time during that day, the patient has symptoms that meet the clinical definition of a headache. The number of headache days per month may be determined by recording each day whether or not a headache occurred.

[0138] Calcitonin Gene Related Peptide (CGRP): As used herein, CGRP encompasses not only the following Homo sapiens CGRP-alpha and Homo sapiens CGRP-beta amino acid sequences available from American Peptides (Sunnyvale Calif.) and Bachem (Torrance, Calif.):

[0139] CGRP-alpha: ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH.sub.2 (SEQ ID NO: 561), wherein the terminal phenylalanine is amidated;

[0140] CGRP-beta: ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF-NH.sub.2 (SEQ ID NO: 562), wherein the terminal phenylalanine is amidated; but also any membrane-bound forms of these CGRP amino acid sequences, as well as mutants (mutiens), splice variants, isoforms, orthologs, homologues and variants of this sequence.

[0141] Expression Vector: These DNA vectors contain elements that facilitate manipulation for the expression of a foreign protein within the target host cell, e.g., a yeast or mammalian cell such as Pichia pastoris or CHO cells. Conveniently, manipulation of sequences and production of DNA for transformation is first performed in a bacterial host, e.g. E. coli, and usually vectors will include sequences to facilitate such manipulations, including a bacterial origin of replication and appropriate bacterial selection marker. Selection markers encode proteins necessary for the survival or growth of transformed host cells grown in a selective culture medium. Host cells not transformed with the vector containing the selection gene will not survive in the culture medium. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media. Exemplary vectors and methods for transformation of yeast are described, for example, in Burke, D., Dawson, D., & Steams, T. (2000). Methods in yeast genetics: a Cold Spring Harbor Laboratory course manual. Plainview, N.Y.: Cold Spring Harbor Laboratory Press.

[0142] Expression vectors for use in yeast or mammalian cells will generally further include yeast or mammalian specific sequences, including a selectable auxotrophic or drug marker for identifying transformed yeast strains or transformed mammalian cells. A drug marker may further be used to amplify copy number of the vector in the host cell.

[0143] The polypeptide coding sequence of interest is operably linked to transcriptional and translational regulatory sequences that provide for expression of the polypeptide in host cells, e.g., Pichia pastoris or CHO cells. These vector components may include, but are not limited to, one or more of the following: an enhancer element, a promoter, and a transcription termination sequence. Sequences for the secretion of the polypeptide may also be included, e.g. a signal sequence, and the like. A yeast or mammalian origin of replication is optional, as expression vectors are often integrated into the host cell genome. In one embodiment of the invention, the polypeptide of interest is operably linked, or fused, to sequences providing for optimized secretion of the polypeptide from yeast diploid cells.

[0144] Nucleic acids are "operably linked" when placed into a functional relationship with another nucleic acid sequence. For example, DNA for a signal sequence is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites or alternatively via a PCR/recombination method familiar to those skilled in the art (Gateway.RTM. Technology; Invitrogen, Carlsbad Calif.). If such sites do not exist, the synthetic oligonucleotide adapters or linkers are used in accordance with conventional practice.

[0145] Promoters are untranslated sequences located upstream (5') to the start codon of a structural gene (generally within about 100 to 1000 bp) that control the transcription and translation of particular nucleic acid sequences to which they are operably linked. Such promoters fall into several classes: inducible, constitutive, and repressible promoters (that increase levels of transcription in response to absence of a repressor). Inducible promoters may initiate increased levels of transcription from DNA under their control in response to some change in culture conditions, e.g., the presence or absence of a nutrient or a change in temperature.

[0146] The promoter fragment may also serve as the site for homologous recombination and integration of the expression vector into the same site in the host genome; alternatively a selectable marker is used as the site for homologous recombination. Examples of suitable promoters from Pichia include the AOX1 and promoter (Cregg et al. (1989) Mol. Cell. Biol. 9:1316-1323); ICL1 promoter (Menendez et al. (2003) Yeast 20(13):1097-108); glyceraldehyde-3-phosphate dehydrogenase promoter (GAP) (Waterham et al. (1997) Gene 186(1):37-44); and FLD1 promoter (Shen et al. (1998) Gene 216(1):93-102). The GAP promoter is a strong constitutive promoter and the AOX and FLD1 promoters are inducible.

[0147] Other yeast promoters include ADH1, alcohol dehydrogenase II, GAL4, PHO3, PHO5, Pyk, and chimeric promoters derived therefrom. Additionally, non-yeast promoters may be used in the invention such as mammalian, insect, plant, reptile, amphibian, viral, and avian promoters. Most typically the promoter will comprise a mammalian promoter (potentially endogenous to the expressed genes) or will comprise a yeast or viral promoter that provides for efficient transcription in yeast systems.

[0148] Examples of mammalian promoters include cytomegalovirus (CMV) derived promoters, chicken 3-actin (CBM) derived promoters, adenomatous polyposis coli (APC) derived promoters, leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) promoters, CAG promoter, Beta actin promoter, elongation factor-1 (EF1) promoter, early growth response 1 (EGR-1) promoter, eukaryotic initiation factor 4A (EIF4A1) promoter, simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase promoter, among others. Combinations of two or more of the foregoing promoters may also be used. Further, inducible promoters may be used. The use of an inducible promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which it is operatively linked when such expression is desired, or turning off the expression when expression is not desired. Examples of inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter.

[0149] The polypeptides of interest may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, e.g. a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a component of the vector, or it may be a part of the polypeptide coding sequence that is inserted into the vector. The heterologous signal sequence selected preferably is one that is recognized and processed through one of the standard pathways available within the host cell. The S. cerevisiae alpha factor pre-pro signal has proven effective in the secretion of a variety of recombinant proteins from P. pastoris. Other yeast signal sequences include the alpha mating factor signal sequence, the invertase signal sequence, and signal sequences derived from other secreted yeast polypeptides. Additionally, these signal peptide sequences may be engineered to provide for enhanced secretion in diploid yeast expression systems. Secretion signals for use in mammalian as well as yeast cells include mammalian signal sequences, which may be heterologous to the protein being secreted, or may be a native sequence for the protein being secreted. Signal sequences include pre-peptide sequences, and in some instances may include propeptide sequences. Many such signal sequences are known in the art, including the signal sequences found on immunoglobulin chains, e.g., K28 preprotoxin sequence, PHA-E, FACE, human MCP-1, human serum albumin signal sequences, human Ig heavy chain, human Ig light chain, and the like. For example, see Hashimoto et. al. Protein Eng 11(2) 75 (1998); and Kobayashi et. al. Therapeutic Apheresis 2(4) 257 (1998).

[0150] Transcription may be increased by inserting a transcriptional activator sequence into the vector. These activators are cis-acting elements of DNA, usually about from 10 to 300 bp, which act on a promoter to increase its transcription. Transcriptional enhancers are relatively orientation and position independent, having been found 5' and 3' to the transcription unit, within an intron, as well as within the coding sequence itself. The enhancer may be spliced into the expression vector at a position 5' or 3' to the coding sequence, but is preferably located at a site 5' from the promoter.

[0151] Expression vectors used in eukaryotic host cells may also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from 3' to the translation termination codon, in untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA.

[0152] Construction of suitable vectors containing one or more of the above-listed components employs standard ligation techniques or PCR/recombination methods. Isolated plasmids or DNA fragments are cleaved, tailored, and re-ligated in the form desired to generate the plasmids required or via recombination methods. For analysis to confirm correct sequences in plasmids constructed, the ligation mixtures are used to transform host cells, and successful transformants selected by antibiotic resistance (e.g. ampicillin or Zeocin) where appropriate. Plasmids from the transformants are prepared, analyzed by restriction endonuclease digestion and/or sequenced.

[0153] As an alternative to restriction and ligation of fragments, recombination methods based on att sites and recombination enzymes may be used to insert DNA sequences into a vector. Such methods are described, for example, by Landy (1989) Ann.Rev.Biochem. 58:913-949; and are known to those of skill in the art. Such methods utilize intermolecular DNA recombination that is mediated by a mixture of lambda and E. coli-encoded recombination proteins. Recombination occurs between specific attachment (att) sites on the interacting DNA molecules. For a description of att sites see Weisberg and Landy (1983) Site-Specific Recombination in Phage Lambda, in Lambda II, Weisberg, ed. (Cold Spring Harbor, N.Y.: Cold Spring Harbor Press), pp. 211-250. The DNA segments flanking the recombination sites are switched, such that after recombination, the att sites are hybrid sequences comprised of sequences donated by each parental vector. The recombination can occur between DNAs of any topology.

[0154] Att sites may be introduced into a sequence of interest by ligating the sequence of interest into an appropriate vector; generating a PCR product containing att B sites through the use of specific primers; generating a cDNA library cloned into an appropriate vector containing att sites; and the like.

[0155] Folding, as used herein, refers to the three-dimensional structure of polypeptides and proteins, where interactions between amino acid residues act to stabilize the structure. Proper folding is typically the arrangement of a polypeptide that results in optimal biological activity, and in the case of antibodies can conveniently be monitored by assays for activity, e.g. antigen binding.

[0156] The expression host may be further modified by the introduction of sequences encoding one or more enzymes that enhance folding and disulfide bond formation, i.e. foldases, chaperonins, etc. Such sequences may be constitutively or inducibly expressed in the yeast host cell, using vectors, markers, etc. as known in the art. Preferably the sequences, including transcriptional regulatory elements sufficient for the desired pattern of expression, are stably integrated in the yeast genome through a targeted methodology.

[0157] For example, the eukaryotic PDI is not only an efficient catalyst of protein cysteine oxidation and disulfide bond isomerization, but also exhibits chaperone activity. Co-expression of PDI can facilitate the production of active proteins having multiple disulfide bonds. Also of interest is the expression of BIP (immunoglobulin heavy chain binding protein); cyclophilin; and the like. In one embodiment of the invention, each of the haploid parental strains expresses a distinct folding enzyme, e.g. one strain may express BIP, and the other strain may express PDI or combinations thereof.

[0158] The terms "desired protein" or "desired antibody" are used interchangeably and refer generally to a parent antibody specific to a target, i.e., CGRP or a chimeric or humanized antibody or a binding portion thereof derived therefrom as described herein. The term "antibody" is intended to include any polypeptide chain-containing molecular structure with a specific shape that fits to and recognizes an epitope, where one or more non-covalent binding interactions stabilize the complex between the molecular structure and the epitope. The archetypal antibody molecule is the immunoglobulin, and in particular IgGetc., from all sources, e.g. human, rodent, rabbit, cow, sheep, pig, dog, other mammals, chicken, other avians, etc., are considered to be "antibodies." A preferred source for producing antibodies useful as starting material according to the invention is rabbits. Numerous antibody coding sequences have been described; and others may be raised by methods well-known in the art. Examples thereof include chimeric antibodies, human antibodies and other non-human mammalian antibodies, humanized antibodies, single chain antibodies (such as scFvs), camelbodies, nanobodies, IgNAR (single-chain antibodies derived from sharks), small-modular immunopharmaceuticals (SMIPs), and antibody fragments such as Fabs, Fab', F(ab').sub.2 and the like. See Streltsov V A, et al., Structure of a shark IgNAR antibody variable domain and modeling of an early-developmental isotype, Protein Sci. 2005 November; 14(11):2901-9. Epub 2005 Sep. 30; Greenberg A S, et al., A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks, Nature. 1995 Mar. 9; 374(6518):168-73; Nuttall S D, et al., Isolation of the new antigen receptor from wobbegong sharks, and use as a scaffold for the display of protein loop libraries, Mol Immunol. 2001 August; 38(4):313-26; Hamers-Casterman C, et al., Naturally occurring antibodies devoid of light chains, Nature. 1993 Jun. 3; 363(6428):446-8; Gill D S, et al., Biopharmaceutical drug discovery using novel protein scaffolds, Curr Opin Biotechnol. 2006 December; 17(6):653-8. Epub 2006 Oct. 19.

[0159] For example, antibodies or antigen binding fragments may be produced by genetic engineering. In this technique, as with other methods, antibody-producing cells are sensitized to the desired antigen or immunogen. The messenger RNA isolated from antibody producing cells is used as a template to make cDNA using PCR amplification. A library of vectors, each containing one heavy chain gene and one light chain gene retaining the initial antigen specificity, is produced by insertion of appropriate sections of the amplified immunoglobulin cDNA into the expression vectors. A combinatorial library is constructed by combining the heavy chain gene library with the light chain gene library. This results in a library of clones which co-express a heavy and light chain (resembling the Fab fragment or antigen binding fragment of an antibody molecule). The vectors that carry these genes are co-transfected into a host cell. When antibody gene synthesis is induced in the transfected host, the heavy and light chain proteins self-assemble to produce active antibodies that can be detected by screening with the antigen or immunogen.

[0160] Antibody coding sequences of interest include those encoded by native sequences, as well as nucleic acids that, by virtue of the degeneracy of the genetic code, are not identical in sequence to the disclosed nucleic acids, and variants thereof. Variant polypeptides can include amino acid (aa) substitutions, additions or deletions. The amino acid substitutions can be conservative amino acid substitutions or substitutions to eliminate non-essential amino acids, such as to alter a glycosylation site, or to minimize misfolding by substitution or deletion of one or more cysteine residues that are not necessary for function. Variants can be designed so as to retain or have enhanced biological activity of a particular region of the protein (e.g., a functional domain, catalytic amino acid residues, etc). Variants also include fragments of the polypeptides disclosed herein, particularly biologically active fragments and/or fragments corresponding to functional domains. Techniques for in vitro mutagenesis of cloned genes are known. Also included in the subject invention are polypeptides that have been modified using ordinary molecular biological techniques so as to improve their resistance to proteolytic degradation or to optimize solubility properties or to render them more suitable as a therapeutic agent.

[0161] Chimeric antibodies may be made by recombinant means by combining the variable light and heavy chain regions (V.sub.L and V.sub.H), obtained from antibody producing cells of one species with the constant light and heavy chain regions from another. Typically chimeric antibodies utilize rodent or rabbit variable regions and human constant regions, in order to produce an antibody with predominantly human domains. The production of such chimeric antibodies is well known in the art, and may be achieved by standard means (as described, e.g., in U.S. Pat. No. 5,624,659, incorporated herein by reference in its entirety). It is further contemplated that the human constant regions of chimeric antibodies of the invention may be selected from IgG1, IgG2, IgG3, and IgG4 constant regions.

[0162] Humanized antibodies are engineered to contain even more human-like immunoglobulin domains, and incorporate only the complementarity-determining regions of the animal-derived antibody. This is accomplished by carefully examining the sequence of the hyper-variable loops of the variable regions of the monoclonal antibody, and fitting them to the structure of the human antibody chains. Although facially complex, the process is straightforward in practice. See, e.g., U.S. Pat. No. 6,187,287, incorporated fully herein by reference.

[0163] In addition to entire immunoglobulins (or their recombinant counterparts), immunoglobulin fragments comprising the epitope binding site (e.g., Fab', F(ab').sub.2, or other fragments) may be synthesized. "Fragment," or minimal immunoglobulins may be designed utilizing recombinant immunoglobulin techniques. For instance "Fv" immunoglobulins for use in the present invention may be produced by synthesizing a fused variable light chain region and a variable heavy chain region. Combinations of antibodies are also of interest, e.g. diabodies, which comprise two distinct Fv specificities. In another embodiment of the invention, SMIPs (small molecule immunopharmaceuticals), camelbodies, nanobodies, and IgNAR are encompassed by immunoglobulin fragments.

[0164] Immunoglobulins and fragments thereof may be modified post-translationally, e.g. to add effector moieties such as chemical linkers, detectable moieties, such as fluorescent dyes, enzymes, toxins, substrates, bioluminescent materials, radioactive materials, chemiluminescent moieties and the like, or specific binding moieties, such as streptavidin, avidin, or biotin, and the like may be utilized in the methods and compositions of the present invention. Examples of additional effector molecules are provided infra.

[0165] A polynucleotide sequence "corresponds" to a polypeptide sequence if translation of the polynucleotide sequence in accordance with the genetic code yields the polypeptide sequence (i.e., the polynucleotide sequence "encodes" the polypeptide sequence), one polynucleotide sequence "corresponds" to another polynucleotide sequence if the two sequences encode the same polypeptide sequence.

[0166] A "heterologous" region or domain of a DNA construct is an identifiable segment of DNA within a larger DNA molecule that is not found in association with the larger molecule in nature. Thus, when the heterologous region encodes a mammalian gene, the gene will usually be flanked by DNA that does not flank the mammalian genomic DNA in the genome of the source organism. Another example of a heterologous region is a construct where the coding sequence itself is not found in nature (e.g., a cDNA where the genomic coding sequence contains introns, or synthetic sequences having codons different than the native gene). Allelic variations or naturally-occurring mutational events do not give rise to a heterologous region of DNA as defined herein.

[0167] A "coding sequence" is an in-frame sequence of codons that (in view of the genetic code) correspond to or encode a protein or peptide sequence. Two coding sequences correspond to each other if the sequences or their complementary sequences encode the same amino acid sequences. A coding sequence in association with appropriate regulatory sequences may be transcribed and translated into a polypeptide. A polyadenylation signal and transcription termination sequence will usually be located 3' to the coding sequence. A "promoter sequence" is a DNA regulatory region capable of binding RNA polymerase in a cell and initiating transcription of a downstream (3' direction) coding sequence. Promoter sequences typically contain additional sites for binding of regulatory molecules (e.g., transcription factors) which affect the transcription of the coding sequence. A coding sequence is "under the control" of the promoter sequence or "operatively linked" to the promoter when RNA polymerase binds the promoter sequence in a cell and transcribes the coding sequence into mRNA, which is then in turn translated into the protein encoded by the coding sequence.

[0168] Vectors are used to introduce a foreign substance, such as DNA, RNA or protein, into an organism or host cell. Typical vectors include recombinant viruses (for polynucleotides) and liposomes (for polypeptides). A "DNA vector" is a replicon, such as plasmid, phage or cosmid, to which another polynucleotide segment may be attached so as to bring about the replication of the attached segment. An "expression vector" is a DNA vector which contains regulatory sequences which will direct polypeptide synthesis by an appropriate host cell. This usually means a promoter to bind RNA polymerase and initiate transcription of mRNA, as well as ribosome binding sites and initiation signals to direct translation of the mRNA into a polypeptide(s). Incorporation of a polynucleotide sequence into an expression vector at the proper site and in correct reading frame, followed by transformation of an appropriate host cell by the vector, enables the production of a polypeptide encoded by said polynucleotide sequence.

[0169] "Amplification" of polynucleotide sequences is the in vitro production of multiple copies of a particular nucleic acid sequence. The amplified sequence is usually in the form of DNA. A variety of techniques for carrying out such amplification are described in a review article by Van Brunt (1990, Bio/Technol., 8(4):291-294). Polymerase chain reaction or PCR is a prototype of nucleic acid amplification, and use of PCR herein should be considered exemplary of other suitable amplification techniques.

[0170] The general structure of antibodies in vertebrates now is well understood (Edelman, G. M., Ann. N.Y. Acad. Sci., 190: 5 (1971)). Antibodies consist of two identical light polypeptide chains of molecular weight approximately 23,000 daltons (the "light chain"), and two identical heavy chains of molecular weight 53,000-70,000 (the "heavy chain"). The four chains are joined by disulfide bonds in a "Y" configuration wherein the light chains bracket the heavy chains starting at the mouth of the "Y" configuration. The "branch" portion of the "Y" configuration is designated the F.sub.ab region; the stem portion of the "Y" configuration is designated the Fc region. The amino acid sequence orientation runs from the N-terminal end at the top of the "Y" configuration to the C-terminal end at the bottom of each chain. The N-terminal end possesses the variable region having specificity for the antigen that elicited it, and is approximately 100 amino acids in length, there being slight variations between light and heavy chain and from antibody to antibody.

[0171] The variable region is linked in each chain to a constant region that extends the remaining length of the chain and that within a particular class of antibody does not vary with the specificity of the antibody (i.e., the antigen eliciting it). There are five known major classes of constant regions that determine the class of the immunoglobulin molecule (IgG, IgM, IgA, IgD, and IgE corresponding to .gamma., .mu., .alpha., .delta., and .epsilon. (gamma, mu, alpha, delta, or epsilon) heavy chain constant regions). The constant region or class determines subsequent effector function of the antibody, including activation of complement (Kabat, E. A., Structural Concepts in Immunology and Immunochemistry, 2nd Ed., p. 413-436, Holt, Rinehart, Winston (1976)), and other cellular responses (Andrews, D. W., et al., Clinical Immunobiology, pp 1-18, W. B. Sanders (1980); Kohl, S., et al., Immunology, 48: 187 (1983)); while the variable region determines the antigen with which it will react. Light chains are classified as either .kappa. (kappa) or .lamda. (lambda). Each heavy chain class can be prepared with either kappa or lambda light chain. The light and heavy chains are covalently bonded to each other, and the "tail" portions of the two heavy chains are bonded to each other by covalent disulfide linkages when the immunoglobulins are generated either by hybridomas or by B cells.

[0172] The expression "variable region" or "VR" refers to the domains within each pair of light and heavy chains in an antibody that are involved directly in binding the antibody to the antigen. Each heavy chain has at one end a variable domain (V.sub.H) followed by a number of constant domains. Each light chain has a variable domain (V.sub.L) at one end and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.

[0173] The expressions "complementarity determining region," "hypervariable region," or "CDR" refer to one or more of the hyper-variable or complementarity determining regions (CDRs) found in the variable regions of light or heavy chains of an antibody (See Kabat, E. A. et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., (1987)). These expressions include the hypervariable regions as defined by Kabat et al. ("Sequences of Proteins of Immunological Interest," Kabat E., et al., US Dept. of Health and Human Services, 1983) or the hypervariable loops in 3-dimensional structures of antibodies (Chothia and Lesk, J Mol. Biol. 196 901-917 (1987)). The CDRs in each chain are held in close proximity by framework regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site. Within the CDRs there are select amino acids that have been described as the selectivity determining regions (SDRs) which represent the critical contact residues used by the CDR in the antibody-antigen interaction (Kashmiri, S., Methods, 36:25-34 (2005)). In the present invention when specific antibody amino acid or nucleic acid residues are referenced by number this generally refers to its position within a specified amino acid or nucleic acid sequence (i.e., particular sequence identifier) and/or in accordance with Kabat et al numbering.

[0174] The expressions "framework region" or "FR" refer to one or more of the framework regions within the variable regions of the light and heavy chains of an antibody (See Kabat, E. A. et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., (1987)). These expressions include those amino acid sequence regions interposed between the CDRs within the variable regions of the light and heavy chains of an antibody.

[0175] "Cmax" refers to the maximum (or peak) concentration that an antibody or other compound achieves in tested area (e.g., in the serum or another compartment such as cerebrospinal fluid) after the drug has been administered. For example, serum Cmax may be measured from serum, e.g., prepared by collecting a blood sample, allowing it to clot and separating solid components by centrifugation or other means to yield serum (blood containing neither blood cells nor clotting factors), and then detecting the concentration of the analyte in the serum by ELISA or other means known in the art.

[0176] "AUC" refers to the area under the concentration-time curve which is expressed in units of mg/mL*hr (or equivalently mg*hr/ml) unless otherwise specified. "AUC.sub.0-t" refers to the area under the concentration-time curve from time=0 to last quantifiable concentration. "AUC.sub.0-inf" refers to the area under the concentration-time curve from time=0 extrapolated to infinity.

[0177] "I.sub.max" refers to the maximal pharmacodynamic response elicited by an anti-CGRP antibody dosage, preferably a dosage of 350 mg or more, more typically at least 750 or 1000 mg, as compared to the response elicited by a lower anti-CGRP antibody doses, e.g., wherein such response may be detected by the inhibition of vasodilation after topical application of capsaicin.

Anti-CGRP Antibodies and Binding Fragments Thereof Having Binding Specificity for CGRP

[0178] O1801 The invention specifically includes the use of Ab6, which is a specific anti-CGRP antibody or antibody fragment, which comprises or consists of the CDR, VL, VH, CL, CH polypeptides sequences identified in FIGS. 1-12. The polypeptides comprised in the anti-CGRP antibody, Ab6 is further described below.

[0179] Antibody Ab6

[0180] In a preferred exemplary embodiment, the invention includes humanized antibodies having binding specificity to CGRP and possessing a variable light chain sequence comprising the sequence set forth below:

TABLE-US-00001 (SEQ ID NO: 222) QVLTQSPSSLSASVGDRVTINCQASQSVYHNTYLAWYQQKPGKVPKQLIY DASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCTNGDC FVFGGGTKVEIKR.

[0181] The invention also includes humanized antibodies having binding specificity to CGRP and possessing a light chain sequence comprising the sequence set forth below:

TABLE-US-00002 (SEQ ID NO: 221) QVLTQSPSSLSASVGDRVTINCQASQSVYHNTYLAWYQQKPGKVPKQLIY DASTLASGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCLGSYDCTNGDC FVFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC.

[0182] The invention further includes humanized antibodies having binding specificity to CGRP and possessing a variable heavy chain sequence comprising the sequence set forth below:

TABLE-US-00003 (SEQ ID NO: 202) EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGV IGINGATYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDI WGQGTLVTVSS.

[0183] The invention also includes humanized antibodies having binding specificity to CGRP and possessing a heavy chain sequence comprising the sequence set forth below:

TABLE-US-00004 (SEQ ID NO: 201) EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGV IGINGATYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDI WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDARVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

[0184] Alternatively, the heavy chain of Ab6 may lack the C-terminal lysine of SEQ ID NO: 201, i.e., a heavy chain sequence comprising the sequence set forth below:

TABLE-US-00005 (SEQ ID NO: 566) EVQLVESGGGLVQPGGSLRLSCAVSGIDLSGYYMNWVRQAPGKGLEWVGV IGINGATYYASWAKGRFTISRDNSKTTVYLQMNSLRAEDTAVYFCARGDI WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDARVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.

[0185] The invention further contemplates antibodies comprising one or more of the polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 222 or the light chain sequence of SEQ ID NO: 221, and/or one or more of the polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 202 or the heavy chain sequence of SEQ ID NO: 201 or SEQ ID NO: 566, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[0186] The invention also contemplates fragments of the antibody having binding specificity to CGRP. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 222 or SEQ ID NO: 221. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 202 or SEQ ID NO: 201 or SEQ ID NO: 566.

[0187] In a further embodiment of the invention, fragments of the antibody having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 222 or the light chain sequence of SEQ ID NO: 221.

[0188] In a further embodiment of the invention, fragments of the antibody having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 202 or the heavy chain sequence of SEQ ID NO: 201 or SEQ ID NO: 566.

[0189] The invention also contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 222; the variable heavy chain region of SEQ ID NO: 202; the complementarity-determining regions (SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228) of the variable light chain region of SEQ ID NO: 222; and the complementarity-determining regions (SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208) of the variable heavy chain region of SEQ ID NO: 202.

[0190] In a particularly preferred embodiment of the invention, the humanized anti-CGRP antibody is Ab6, comprising, or alternatively consisting of, SEQ ID NO: 221 and SEQ ID NO: 201 or SEQ ID NO: 566, and having at least one of the biological activities set forth herein.

[0191] In a further particularly preferred embodiment of the invention, antibody fragments comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for CGRP. With respect to antibody Ab6, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 222 and the variable heavy chain sequence of SEQ ID NO: 202. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 222 and/or SEQ ID NO: 202 in said Fab while retaining binding specificity for CGRP.

[0192] In another particularly preferred embodiment of the invention, said anti-CGRP antibody may comprise the antibody expression product isolated from recombinant cells which express nucleic acid sequences encoding the variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202, which polypeptides optionally are respectively linked to human light and heavy constant region polypeptides, e.g., human IgG1, IgG2, IgG3 or IgG4 constant regions, which constant regions optionally may be modified to alter glycosylation or proteolysis, wherein said recombinant cells optionally comprise yeast or mammalian cells, e.g., Pichia pastoris or CHO cells.

[0193] In another particularly preferred embodiment of the invention, said anti-CGRP antibody may comprise the antibody expression product isolated from recombinant cells which express nucleic acid sequences encoding the light chain of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566, wherein said recombinant cells optionally comprise yeast or mammalian cells, e.g., Pichia pastoris or CHO cells, wherein the constant regions thereof optionally may be modified to alter glycosylation or proteolysis or other effector functions.

[0194] In another particularly preferred embodiment of the invention, any of the aforementioned anti-CGRP antibodies or antibody fragments may be optionally comprised in a formulation as disclosed herein, e.g., comprising histidine (L-histidine), sorbitol, polysorbate 80, such as, per 1 mL volume, about 100 mg anti-CGRP antibody, about 3.1 mg L-Histidine, about 40.5 mg Sorbitol, and about 0.15 mg Polysorbate 80, having a pH of about 5.8.

[0195] In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab6. In another embodiment of the invention, anti-CGRP antibodies such as Ab6 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0196] In another embodiment, antibody fragments may be present in one or more of the following non-limiting forms: Fab, Fab', F(ab').sub.2, Fv and single chain Fv antibody forms. In a preferred embodiment, the anti-CGRP antibodies described herein further comprises the kappa constant light chain sequence comprising the sequence set forth below:

TABLE-US-00006 (SEQ ID NO: 563) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS FNRGEC.

[0197] In another preferred embodiment, the anti-CGRP antibodies described herein further comprises the gamma-1 constant heavy chain polypeptide sequence comprising the sequence set forth below or the same sequence lacking the carboxy terminal lysine residue (SEQ ID NO: 564 and SEQ ID NO: 565, respectively):

TABLE-US-00007 (SEQ ID NO: 564) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 565) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG.

[0198] For clarity, any antibody disclosed herein is intended to include any variant of the disclosed constant region variant sequences, e.g., Ab6 may comprise the constant region of SEQ ID NO: 564 containing the C-terminal lysine or may comprise the constant region of SEQ ID NO: 565 lacking the C-terminal lysine. Thus, every disclosure herein of the heavy chain of SEQ ID NO: 201 also includes a variant lacking the C-terminal lysine residue thereof, i.e., having the heavy chain variable region sequence of Ab6 (SEQ ID NO: 202) and the constant region sequence of SEQ ID NO: 565. For example, the sequence encoding an antibody comprising a C-terminal lysine in the heavy chain may, when expressed in cell lines such as CHO cells, produce an antibody lacking said C-terminal lysine due to proteolysis, or a mixture of heavy chains containing or lacking said C-terminal lysine.

[0199] In one embodiment of the invention, the antibodies or V.sub.H or V.sub.L polypeptides originate or are selected from one or more rabbit B cell populations prior to initiation of the humanization process referenced herein.

[0200] In another embodiment of the invention, the anti-CGRP antibodies and fragments thereof do not have binding specificity for CGRP-R. In a further embodiment of the invention, the anti-CGRP antibodies and fragments thereof inhibit the association of CGRP with CGRP-R. In another embodiment of the invention, the anti-CGRP antibodies and fragments thereof inhibit the association of CGRP with CGRP-R and/or additional proteins and/or multimers thereof, and/or antagonizes the biological effects thereof.

[0201] As stated herein, antibodies and fragments thereof may be modified post-translationally to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials.

[0202] Antibodies or fragments thereof may also be chemically modified to provide additional advantages such as increased solubility, stability and circulating time (in vivo half-life) of the polypeptide, or decreased immunogenicity (See U.S. Pat. No. 4,179,337). The chemical moieties for derivatization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The antibodies and fragments thereof may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.

[0203] The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term "about" indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog). For example, the polyethylene glycol may have an average molecular weight of about 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa. Branched polyethylene glycols are described, for example, in U.S. Pat. No. 5,643,575; Morpurgo et al., Appl. Biochem. Biotechnol. 56:59-72 (1996); Vorobjev et al., Nucleosides Nucleotides 18:2745-2750 (1999); and Caliceti et al., Bioconjug. Chem. 10:638-646 (1999), the disclosures of each of which are incorporated herein by reference.

[0204] There are a number of attachment methods available to those skilled in the art, See e.g., EP 0 401 384, herein incorporated by reference (coupling PEG to G-CSF), See also Malik et al., Exp. Hematol. 20:1028-1035 (1992) (reporting pegylation of GM-CSF using tresyl chloride). For example, polyethylene glycol may be covalently bound through amino acid residues via a reactive group, such as, a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. Preferred for therapeutic purposes is attachment at an amino group, such as attachment at the N-terminus or lysine group.

[0205] As suggested above, polyethylene glycol may be attached to proteins via linkage to any of a number of amino acid residues. For example, polyethylene glycol can be linked to polypeptides via covalent bonds to lysine, histidine, aspartic acid, glutamic acid, or cysteine residues. One or more reaction chemistries may be employed to attach polyethylene glycol to specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid, or cysteine) or to more than one type of amino acid residue (e.g., lysine, histidine, aspartic acid, glutamic acid, cysteine and combinations thereof).

[0206] Alternatively, antibodies or fragments thereof may have increased in vivo half-lives via fusion with albumin (including but not limited to recombinant human serum albumin or fragments or variants thereof (See, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998, herein incorporated by reference in their entirety)) or other circulating blood proteins such as transferrin or ferritin. In a preferred embodiment, polypeptides and/or antibodies of the present invention (including fragments or variants thereof) are fused with the mature form of human serum albumin (i.e., amino acids 1-585 of human serum albumin as shown in FIGS. 1 and 2 of EP Patent 0 322 094) which is herein incorporated by reference in its entirety. Polynucleotides encoding fusion proteins of the invention are also encompassed by the invention.

[0207] Regarding detectable moieties, further exemplary enzymes include, but are not limited to, horseradish peroxidase, acetylcholinesterase, alkaline phosphatase, beta-galactosidase and luciferase. Further exemplary fluorescent materials include, but are not limited to, rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone, dichlorotriazinylamine, phycoerythrin and dansyl chloride. Further exemplary chemiluminescent moieties include, but are not limited to, luminol. Further exemplary bioluminescent materials include, but are not limited to, luciferin and aequorin. Further exemplary radioactive materials include, but are not limited to, Iodine 125 (.sup.125I), Carbon 14 (.sup.14C), Sulfur 35 (.sup.35S), Tritium (.sup.3H) and Phosphorus 32 (.sup.32P).

[0208] Regarding functional moieties, exemplary cytotoxic agents include, but are not limited to, methotrexate, aminopterin, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine; alkylating agents such as mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (CCNU), 1-methylnitrosourea, cyclothosphamide, mechlorethamine, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin and carboplatin (paraplatin); anthracyclines include daunorubicin (formerly daunomycin), doxorubicin (adriamycin), detorubicin, carminomycin, idarubicin, epirubicin, mitoxantrone and bisantrene; antibiotics include dactinomycin (actinomycin D), bleomycin, calicheamicin, mithramycin, and anthramycin (AMC); and antimytotic agents such as the vinca alkaloids, vincristine and vinblastine. Other cytotoxic agents include paclitaxel (taxol), ricin, pseudomonas exotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide, emetine, etoposide, tenoposide, colchicin, dihydroxy anthracin dione, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, procarbazine, hydroxyurea, asparaginase, corticosteroids, mytotane (O,P'-(DDD)), interferons, and mixtures of these cytotoxic agents.

[0209] Further cytotoxic agents include, but are not limited to, chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel, gemcitabine, calicheamicin, doxorubicin, 5-fluorouracil, mitomycin C, actinomycin D, cyclophosphamide, vincristine and bleomycin. Toxic enzymes from plants and bacteria such as ricin, diphtheria toxin and Pseudomonas toxin may be conjugated to the humanized or chimeric antibodies, or binding fragments thereof, to generate cell-type-specific-killing reagents (Youle, et al., Proc. Nat'l Acad. Sci. USA 77:5483 (1980); Gilliland, et al., Proc. Nat'l Acad. Sci. USA 77:4539 (1980); Krolick, et al., Proc. Nat'l Acad Sci. USA 77:5419 (1980)).

[0210] Other cytotoxic agents include cytotoxic ribonucleases as described by Goldenberg in U.S. Pat. No. 6,653,104. Embodiments of the invention also relate to radioimmunoconjugates where a radionuclide that emits alpha or beta particles is stably coupled to the antibody, or binding fragments thereof, with or without the use of a complex-forming agent. Such radionuclides include beta-emitters such as Phosphorus-32 (.sup.32P), Scandium-47 (.sup.41Sc), Copper-67 (.sup.67Cu), Gallium-67 (.sup.61Ga), Yttrium-88 (.sup.88Y), Yttrium-90 (.sup.90Y), Iodine-125 (.sup.125I), Iodine-131 (.sup.131I), Samarium-153 (.sup.153Sm), Lutetium-177 (.sup.177Lu), Rhenium-186 (.sup.186Re) or Rhenium-188 (.sup.188Re), and alpha-emitters such as Astatine-211 (.sup.211At), Lead-212 (.sup.212Pb), Bismuth-212 (.sup.212Bi) or -213 (.sup.213Bi) or Actinium-225 (.sup.225Ac).

[0211] Methods are known in the art for conjugating an antibody or binding fragment thereof to a detectable moiety and the like, such as for example those methods described by Hunter et al, Nature 144:945 (1962); David et al, Biochemistry 13:1014 (1974); Pain et al, J. Immunol. Meth. 40:219 (1981); and Nygren, J., Histochem. and Cytochem. 30:407 (1982).

[0212] Embodiments described herein further include variants and equivalents that are substantially homologous to the antibodies, antibody fragments, diabodies, SMIPs, camelbodies, nanobodies, IgNAR, polypeptides, variable regions and CDRs set forth herein. These may contain, e.g., conservative substitution mutations, (i.e., the substitution of one or more amino acids by similar amino acids). For example, conservative substitution refers to the substitution of an amino acid with another within the same general class, e.g., one acidic amino acid with another acidic amino acid, one basic amino acid with another basic amino acid, or one neutral amino acid by another neutral amino acid. What is intended by a conservative amino acid substitution is well known in the art.

[0213] In another embodiment, the invention contemplates polypeptide sequences having at least 90% or greater sequence homology to any one or more of the polypeptide sequences of antibody fragments, variable regions and CDRs set forth herein. More preferably, the invention contemplates polypeptide sequences having at least 95% or greater sequence homology, even more preferably at least 98% or greater sequence homology, and still more preferably at least 99% or greater sequence homology to any one or more of the polypeptide sequences of antibody fragments, variable regions and CDRs set forth herein. Methods for determining homology between nucleic acid and amino acid sequences are well known to those of ordinary skill in the art.

[0214] In another embodiment, the invention further contemplates the above-recited polypeptide homologs of the antibody fragments, variable regions and CDRs set forth herein further having anti-CGRP activity. Non-limiting examples of anti-CGRP activity are set forth herein.

[0215] The invention further contemplates treatment methods wherein the one or more anti-human CGRP antibodies discussed above are aglycosylated or if glycosylated are only mannosylated; that contain an Fe region that has been modified to alter effector function, half-life, proteolysis, and/or glycosylation; are human, humanized, single chain or chimeric; and are a humanized antibody derived from a rabbit (parent) anti-human CGRP antibody. An exemplary mutation which impairs glycosylation comprises the mutation of the Asn residue at position 297 of an IgG heavy chain constant region such as IgG1 to another amino acid, such as Ala as described in U.S. Pat. No. 5,624,821, which is incorporated by reference in its entirety.

[0216] The invention further contemplates one or more anti-human CGRP antibodies wherein the framework regions (FRs) in the variable light region and the variable heavy regions of said antibody respectively are human FRs which are unmodified or which have been modified by the substitution of one or more human FR residues in the variable light or heavy chain region with the corresponding FR residues of the parent rabbit antibody, and wherein said human FRs have been derived from human variable heavy and light chain antibody sequences which have been selected from a library of human germline antibody sequences based on their high level of homology to the corresponding rabbit variable heavy or light chain regions relative to other human germline antibody sequences contained in the library.

[0217] The invention also contemplates that the treatment method may involve the administration of two or more anti-CGRP antibodies or fragments thereof and disclosed herein. If more than one antibody is administered to the patient, the multiple antibodies may be administered simultaneously or concurrently, or may be staggered in their administration. The anti-CGRP activity of the anti-CGRP antibodies of the present invention, and fragments thereof having binding specificity to CGRP, may also be described by their strength of binding or their affinity for CGRP. In one embodiment of the invention, the anti-CGRP antibodies of the present invention, and fragments thereof having binding specificity to CGRP, bind to CGRP with a dissociation constant (K.sub.D) of less than or equal to 5.times.10.sup.-7 M, 10.sup.-7 M, 5.times.10.sup.-8 M, 10.sup.-8 M, 5.times.10.sup.-9 M, 10.sup.-9 M, 5.times..sup.-10 M, 10.sup.-10 M, 5.times.10.sup.-11 M, 10.sup.-11M, 5.times.10.sup.-12 M, 10.sup.-12 M, 5.times.10.sup.-13 M, or 10.sup.-13 M. Preferably, the anti-CGRP antibodies and fragments thereof bind CGRP with a dissociation constant of less than or equal to 10.sup.-11 M, 5.times.10.sup.-12 M, or 10.sup.-12 M. In a specific embodiment of the invention the anti-CGRP antibody is Ab6 having a dissociation constant of less than or equal to 10 pM, such as 2-8 pM, such as 3-6 pM, such as less than or equal to about 5 pM when measured using surface plasmon resonance (Misura, K et al, July 2019, Poster P220LB, AHS 61.sup.st annual scientific meeting). In another embodiment of the invention, the anti-CGRP antibodies of the present invention, and fragments thereof having binding specificity to CGRP, bind to a linear or conformational CGRP epitope.

[0218] In another embodiment of the invention, the anti-CGRP activity of the anti-CGRP antibodies of the present invention, and fragments thereof having binding specificity to CGRP, bind to CGRP with an off-rate of less than or equal to 10.sup.-4 S.sup.-1, 5.times.10.sup.-5 S.sup.-1, 10.sup.-5 S.sup.-1, 5.times.10.sup.-6 S.sup.-1, 10.sup.-6 S.sup.-1, 5.times.10.sup.-7 S.sup.-1, or 10.sup.-7 S.sup.-1. In a specific embodiment of the invention the anti-CGRP antibody is Ab6 having an off-rate of less than or equal to 5.times.10.sup.-6 S.sup.-1, such as less than or equal to 4.times.10.sup.-6 S.sup.-1, such as less than or equal to 3.times.10.sup.-6 S.sup.-1, such as less than or equal to 2.times.10.sup.-6 S.sup.-1, such as less than or equal to 1.times.10.sup.-6 S.sup.-1 when measured using surface plasmon resonance.

Polynucleotides Encoding Anti-CGRP Antibody Polypeptides

[0219] As aforementioned the invention specifically includes the use of specific anti-CGRP antibody or antibody fragment referred to herein as Ab6, which comprises or consists of the CDR, VL, VH, CL, and CH polypeptides having the sequences identified in FIGS. 1-12. The nucleic acid sequences encoding the foregoing VL, VH, CL, and CH polypeptides comprised in Ab6 are also comprised in FIGS. 1-12. The nucleic acid sequences which encode the CDR, VL, VH, CL, and CH polypeptides of an especially preferred anti-CGRP antibody, Ab6, are further described below.

[0220] Polynucleotides Encoding Antibody Ab6

[0221] The invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to CGRP. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 222:

TABLE-US-00008 (SEQ ID NO: 232) CAAGTGCTGacccagtctccatcaccctgtctgcatctgtaggagacaga gtcaccatcAATtgcCAGGCCAGTCAGAGTGTTTATCATAACACCTACCT GGCCtggtatcagcagaaaccagggaaagttcctaagCAActgatctatG ATGCATCCACTCTGGCATCTggggtcccatctcgtttcagtggcagtgga tctgggacagatttcactctcaccatcagcagcctgcagcctgaagatgt tgcaacttattactgtCTGGGCAGTTATGATTGTACTAATGGTGATTGTT TTGTTttcggcggaggaaccaaggtggaaatcaaacgt.

[0222] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 221:

TABLE-US-00009 (SEQ ID NO: 231) CAAGTGCTGacccagtctccatcctccctgtctgcatctgtaggagacag agtcaccatcAATtgcCAGGCCAGTCAGAGTGTTTATCATAACACCTACC TGGCCtggtatcagcagaaaccagggaaagttcctaagCAActgatctat GATGCATCCACTCTGGCATCTggggtcccatacgtttcagtggcagtgga tctgggacagatttcactacaccatcagcagcctgcagcctgaagatgtt gcaacttattactgtCTGGGCAGTTATGATTGTACTAATGGTGATTGTTT TGTTttcggcggaggaaccaaggtggaaatcaaacgtACGGTGGCTGCAC CATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACT GCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGT ACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTG TCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTG ACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGT CACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAG.

[0223] In another embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 202:

TABLE-US-00010 (SEQ ID NO: 212) gaggtgcagctTgtggagtctgggggaggcttggtccagcctggggggtc cctgagactctcctgtgcaGTCtctggaATCGACCTCagtGGCTACTACA TGAACtgggtccgtcaggctccagggaaggggctggagtgggtcGGAGTC ATTGGTATTAATGGTGCCACATACTACGCGAGCTGGGCGAAAGGCcgatt caccatctccagagacaattccaagACCACGGTGtatatcaaatgaacag cctgagagagaggacactgctgtgtatTTCtgtGCTAGAGGGGACATCtg gggccaagggaccctcgtcaccgtcTCGAGC.

[0224] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 201:

TABLE-US-00011 (SEQ ID NO: 211) gaggtgcagctTgtggagtctgggggaggcttggtccagcctggggggtc cctgagactacctgtgcaGTCtctggaATCGACCTCagtGGCTACTACAT GAACtgggtccgtcaggctccagggaaggggctggagtgggtcGGAGTCA TTGGTATTAATGGTGCCACATACTACGCGAGCTGGGCGAAAGGCcgattc accatctccagagacaattccaagACCACGGTGtatcttcaaatgaacag cctgagagagaggacactgctgtgtatTTCtgtGCTAGAGGGGACATCtg gggccaagggaccctcgtcaccgtcTCGAGCGCCTCCACCAAGGGCCCAT CGGTCTTCCCCCTGGCAcCCTCCTCCaAGAGCACCTCTGGGGGCACAGCG GCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCC TACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC AGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAG CAACACCAAGGTGGACGCGAGAGTTGAGCCCAAATCTTGTGACAAAACTC ACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTC TTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGaTCTCCCgGACCCC TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCA AGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG CCGCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCAC CGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAA GGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATC CCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAAC TACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTA CAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCT CATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGC CTCTCCCTGTCTCCGGGTAAATGA.

[0225] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 566:

TABLE-US-00012 (SEQ ID NO: 567) gaggtgcagctTgtggagtctgggggaggcttggtccagcctggggggtc cctgagactctcctgtgcaGTCtctggaATCGACCTCagtGGCTACTACA TGAACtgggtccgtcaggctccagggaaggggctggagtgggtcGGAGTC ATTGGTATTAATGGTGCCACATACTACGCGAGCTGGGCGAAAGGCcgatt caccatctccagagacaattccaagACCACGGTGtatcttcaaatgaaca gcctgagagctgaggacactgctgtgtatTTCtgtGCTAGAGGGGACATC tggggccaagggaccctcgtcaccgtcTCGAGCGCCTCCACCAAGGGCCC ATCGGTCTTCCCCCTGGCAcCCTCCTCCaAGAGCACCTCTGGGGGCACAG CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTG TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGT CCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCT CCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC AGCAACACCAAGGTGGACGCGAGAGTTGAGCCCAAATCTTGTGACAAAAC TCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAG TCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGaTCTCCCgGACC CCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA AGCCGCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGT CTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCA AAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAG GAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA TCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACA ACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTT CTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGA GCCTCTCCCTGTCTCCGGGTTGA.

[0226] In a further embodiment of the invention, polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 222 or the light chain sequence of SEQ ID NO: 221.

[0227] In a further embodiment of the invention, polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 202 or the heavy chain sequence of SEQ ID NO: 201 or SEQ ID NO: 566.

[0228] The invention also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments having binding specificity to CGRP comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 232 encoding the light chain variable sequence of SEQ ID NO: 222; the polynucleotide SEQ ID NO: 231 encoding the light chain sequence of SEQ ID NO: 221; the polynucleotide SEQ ID NO: 212 encoding the heavy chain variable sequence of SEQ ID NO: 202; the polynucleotide SEQ ID NO: 211 encoding the heavy chain sequence of SEQ ID NO: 201; the polynucleotide SEQ ID NO: 567 encoding the heavy chain sequence of SEQ ID NO: 566; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238) of the light chain variable sequence of SEQ ID NO: 222 or the light chain sequence of SEQ ID NO: 221; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218) of the heavy chain variable sequence of SEQ ID NO: 202 or the heavy chain sequence of SEQ ID NO: 201 or SEQ ID NO: 566.

[0229] In a preferred embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for CGRP. With respect to antibody Ab6, the polynucleotides encoding the full length Ab6 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 231 encoding the light chain sequence of SEQ ID NO: 221 and the polynucleotide SEQ ID NO: 211 encoding the heavy chain sequence of SEQ ID NO: 201 or the polynucleotide SEQ ID NO: 567 encoding the heavy chain sequence of SEQ ID NO: 566.

[0230] Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab6 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-CGRP antibodies such as Ab6 or Fab fragments thereof may be produced via expression of Ab6 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[0231] Host cells and vectors comprising said polynucleotides are also contemplated.

[0232] The invention further contemplates vectors comprising the polynucleotide sequences encoding the variable heavy and light chain polypeptide sequences, as well as the individual complementarity-determining regions (CDRs, or hypervariable regions), as set forth herein, as well as host cells comprising said vector sequences. In one embodiment of the invention, the host cell is a yeast cell. In another embodiment of the invention, the yeast host cell belongs to the genus Pichia.

[0233] Methods of Producing Antibodies and Fragments Thereof

[0234] In another embodiment, the present invention contemplates methods for producing anti-CGRP antibodies and fragments thereof. Methods for producing antibodies and fragments thereof secreted from polyploidal, preferably diploid or tetraploid strains of mating competent yeast are taught, for example, in U.S. patent application publication no. US 2009/0022659 to Olson et al., and in U.S. Pat. No. 7,935,340 to Garcia-Martinez et al., the disclosures of each of which are herein incorporated by reference in their entireties. Methods for producing antibodies and fragments thereof in mammalian cells, e.g., CHO cells are further well known in the art.

[0235] Other methods of producing antibodies are also well known to those of ordinary skill in the art. For example, methods of producing chimeric antibodies are now well known in the art (See, for example, U.S. Pat. No. 4,816,567 to Cabilly et al.; Morrison et al., P.N.A.S. USA, 81:8651-55 (1984); Neuberger, M. S. et al., Nature, 314:268-270 (1985); Boulianne, G. L. et al., Nature, 312:643-46 (1984), the disclosures of each of which are herein incorporated by reference in their entireties).

[0236] Likewise, other methods of producing humanized antibodies are now well known in the art (See, for example, U.S. Pat. Nos. 5,530,101, 5,585,089, 5,693,762, and 6,180,370 to Queen et al; U.S. Pat. Nos. 5,225,539 and 6,548,640 to Winter; U.S. Pat. Nos. 6,054,297, 6,407,213 and 6,639,055 to Carter et al; U.S. Pat. No. 6,632,927 to Adair; Jones, P. T. et al, Nature, 321:522-525 (1986); Reichmann, L., et al, Nature, 332:323-327 (1988); Verhoeyen, M, et al, Science, 239:1534-36 (1988), the disclosures of each of which are herein incorporated by reference in their entireties).

[0237] The present invention further includes the use of any of the pharmaceutical formulations disclosed herein in the manufacture of a medicament for the treatment, prevention and/or amelioration of most bothersome symptom associated with migraine.

[0238] Administration

[0239] In one embodiment of the invention, the anti-CGRP antibodies described herein, or CGRP binding fragments thereof, as well as combinations of said antibodies or antibody fragments, are administered to a subject at a concentration of between about 0.1 and 100.0 mg/kg of body weight of recipient subject. In a preferred embodiment of the invention, the anti-CGRP antibodies described herein, or CGRP binding fragments thereof, as well as combinations of said antibodies or antibody fragments, are administered to a subject at a concentration of about 0.4 mg/kg of body weight of recipient subject and/or at a dosage of 100 or 300 mg. In a preferred embodiment of the invention, the anti-CGRP antibodies described herein, or CGRP binding fragments thereof, as well as combinations of said antibodies or antibody fragments, are administered to a recipient subject with a frequency of once every twenty-six weeks or six months or less, such as once every sixteen weeks or four months or less, once every eight weeks or two months or less, once every four weeks or monthly or less, once every two weeks or bimonthly or less, once every week or less, or once daily or less. In general the administration of sequential doses may vary by plus or minus a few days from the aforementioned schedule, e.g., administration every 3 months or every 12 weeks includes administration of a dose varying from the schedule day by plus or minus 1, 2, 3, 4, 5, 5, or 7 days.

[0240] Fab fragments may be administered every two weeks or less, every week or less, once daily or less, multiple times per day, and/or every few hours. In one embodiment of the invention, a patient receives Fab fragments of 0.1 mg/kg to 40 mg/kg per day given in divided doses of 1 to 6 times a day, or in a sustained release form, effective to obtain desired results.

[0241] It is to be understood that the concentration of the antibody or Fab administered to a given patient may be greater or lower than the exemplary administration concentrations set forth above.

[0242] A person of skill in the art would be able to determine an effective dosage and frequency of administration through routine experimentation, for example guided by the disclosure herein and the teachings in Goodman, L. S., Gilman, A., Brunton, L. L., Lazo, J. S., & Parker, K. L. (2006). Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill; Howland, R. D., Mycek, M. J., Harvey, R. A., Champe, P. C., & Mycek, M. J. (2006). Pharmacology. Lippincott's illustrated reviews. Philadelphia: Lippincott Williams & Wilkins; and Golan, D. E. (2008). Principles of pharmacology: the pathophysiologic basis of drug therapy. Philadelphia, Pa., [etc.]: Lippincott Williams & Wilkins.

[0243] In another embodiment of the invention, the anti-CGRP antibodies described herein, or CGRP binding fragments thereof, as well as combinations of said antibodies or antibody fragments, are administered to a subject in a pharmaceutical formulation.

[0244] A "pharmaceutical composition" refers to a chemical or biological composition suitable for administration to a mammal. Such compositions may be specifically formulated for administration via one or more of a number of routes, including but not limited to buccal, epicutaneous, epidural, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, rectally via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal, preferably intravenous. In addition, administration can occur by means of injection, powder, liquid, gel, drops, or other means of administration.

[0245] A "pharmaceutical excipient" or a "pharmaceutically acceptable excipient" is a carrier, usually a liquid, in which an active therapeutic agent is formulated. In one embodiment of the invention, the active therapeutic agent is a humanized antibody described herein, or one or more fragments thereof. The excipient generally does not provide any pharmacological activity to the formulation, though it may provide chemical and/or biological stability, and release characteristics. Exemplary formulations can be found, for example, in Remington's Pharmaceutical Sciences, 19.sup.th Ed., Grennaro, A., Ed., 1995 which is incorporated by reference.

[0246] As used herein "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, or sublingual administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0247] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. The invention contemplates that the pharmaceutical composition is present in lyophilized form. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The invention further contemplates the inclusion of a stabilizer in the pharmaceutical composition. The proper fluidity can be maintained, for example, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

[0248] In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, the alkaline polypeptide can be formulated in a time release formulation, for example in a composition which includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art.

[0249] An exemplary composition comprises, consists essentially of Ab6, an excipient such as histidine, an isotonic agent such as sorbitol, and a surfactant such as polysorbate 80 in an aqueous solution. For example, the composition may comprise, consist essentially of, or consist of histidine (L-histidine), sorbitol, polysorbate 80, such as, per 1 mL volume, about 100 mg Ab6, about 3.1 mg L-Histidine, about 40.5 mg Sorbitol, and about 0.15 mg Polysorbate 80, having a pH of about 5.8, or approximately that constitution, e.g., within 10% of those values, within 5% of those values, within 1% of those values, within 0.5% of those values, or within 0.1% of those values, and water. For example, the pH value may be within 10% of 5.8, i.e., between 5.22 and 6.38. The Ab6 antibody may comprise or consist of the variable light and heavy chain polypeptides of SEQ ID NO: 222 and SEQ ID NO: 202 respectively, or the light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 201 respectively, or the light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 566 respectively. The composition may be in the form of an aqueous solution, or a concentrate (e.g., lyophilized) which when reconstituted, e.g., by addition of water, yields the aforementioned constitution. An exemplary composition consists of, per mL, 100 mg of the light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 201 respectively, about 3.1 mg L-Histidine, about 40.5 mg Sorbitol, and about 0.15 mg Polysorbate 80, and water Q.S, or approximately that constitution, e.g., within 10% of those quantities, within 5% of those quantities, within 1% of those quantities, within 0.5% of those quantities, or within 0.1% of those quantities. Another exemplary composition consists of, per mL, 100 mg of the light and heavy chain polypeptides of SEQ ID NO: 221 and SEQ ID NO: 566 respectively, about 3.1 mg L-Histidine, about 40.5 mg Sorbitol, and about 0.15 mg Polysorbate 80, and water Q.S, or approximately that constitution, e.g., within 10% of those quantities, within 5% of those quantities, within 1% of those quantities, within 0.5% of those quantities, or within 0.1% of those quantities. The composition may be suitable for intravenous or subcutaneous administration, preferably intravenous administration. For example, the composition may be suitable for mixing with an intravenous solution (such as 0.9% sodium chloride) at an amount of between about 100 mg and about 300 mg antibody added to 100 mL of intravenous solution. Preferably the composition may be shelf-stable for at least 1, 3, 6, 12, 18, or 24 months, e.g., showing formation of aggregates of no more than 5% or no more than 10% of the antibody or fragment after storage at room temperature or when refrigerated at 4.degree. C. for the specified duration, or in an accelerated aging test that simulates storage for that duration.

[0250] For each of the recited embodiments, the compounds can be administered by a variety of dosage forms. Any biologically-acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include, without limitation, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, powders, granules, particles, microparticles, dispersible granules, cachets, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, injectables (including subcutaneous, intramuscular, intravenous, and intradermal, preferably intravenous), infusions, and combinations thereof.

[0251] The above description of various illustrated embodiments of the invention is not intended to be exhaustive or to limit the invention to the precise form disclosed. While specific embodiments of, and examples for, the invention are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the invention, as those skilled in the relevant art will recognize. The teachings provided herein of the invention can be applied to other purposes, other than the examples described above.

[0252] These and other changes can be made to the invention in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the invention to the specific embodiments disclosed in the specification and the claims. Accordingly, the invention is not limited by the disclosure, but instead the scope of the invention is to be determined entirely by the following claims.

[0253] The invention may be practiced in ways other than those particularly described in the foregoing description and examples. Numerous modifications and variations of the invention are possible in light of the above teachings and, therefore, are within the scope of the appended claims.

[0254] Certain CGRP antibody polynucleotides and polypeptides are disclosed in the sequence listing accompanying this patent application filing, and the disclosure of said sequence listing is herein incorporated by reference in its entirety.

[0255] The entire disclosure of each document cited (including patents, patent applications, journal articles, abstracts, manuals, books, or other disclosures) in the Background of the Invention, Detailed Description, and Examples is herein incorporated by reference in their entireties.

[0256] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the subject invention, and are not intended to limit the scope of what is regarded as the invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g. amounts, temperature, concentrations, etc.) but some experimental errors and deviations should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees centigrade; and pressure is at or near atmospheric.

Additional Exemplary Embodiments

[0257] Additional exemplary embodiments of the invention are provided as follows:

[0258] S1. Use of an anti-CGRP antibody for the manufacturing of a medicament for treating most bothersome symptom (MBS) associated with migraine, comprising administering to a migraine patient an anti-CGRP antibody.

[0259] S2. Use of an anti-CGRP antibody for the manufacturing of a medicament for treating most bothersome symptom (MBS) associated with migraine, comprising administering to a migraine patient an anti-CGRP antibody, wherein said migraine patient suffers from chronic migraine.

[0260] S3. Use of an anti-CGRP antibody for the manufacturing of a medicament for treating most bothersome symptom (MBS) associated with migraine, comprising administering to a migraine patient an anti-CGRP antibody, wherein said patient suffers from episodic migraine.

[0261] S4. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein the patients most bothersome symptom (MBS) associated with migraine is improved at 1-12 hours post-completion of administration or infusion, such as 1-5 hours post-completion of administration or infusion, 1-2 hours post-completion of administration or infusion, or about 2 hours post-completion of administration or infusion.

[0262] S5. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein the patients most bothersome symptom (MBS) associated with migraine is improved within 1 month from the first dosing with said anti-CGRP antibody.

[0263] S6. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein the patients most bothersome symptom (MBS) associated with migraine is improved within 3 month from the first dosing with said anti-CGRP antibody.

[0264] S7. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein the patients most bothersome symptom (MBS) associated with migraine is improved within 6 month from the first dosing with said anti-CGRP antibody.

[0265] S8. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein the improvement is sustained for at least 3 months from the first dosing with said anti-CGRP antibody.

[0266] S9. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein the improvement is sustained for at least 6 months from the first dosing with said anti-CGRP antibody.

[0267] S10. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein the MBS is selected from the group consisting of: Sensitivity to light (photophobia), Nausea/vomiting, Headache, Sensitivity to sound (phonophobia), Aura, Pain with activity, Pain, Throbbing/pulsation, Cognitive disruption, Fatigue, Mood changes, Sensitivity to smell (osmophobia or olfactophobia), Visual impact, Pressure/tightness, Pain (anatomical), Eye pain, Neck pain, Dizziness, Allodynia, Inactivity, Sensory disturbance, Sleep disturbance and Speech difficulty.

[0268] S11. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein the MBS is selected from the group consisting of: Sensitivity to light (photophobia), Nausea/vomiting, Headache, Sensitivity to sound (phonophobia), Pain with activity, Pain, Throbbing/pulsation, Cognitive disruption, Fatigue, Mood changes and Sensitivity to smell (osmophobia or olfactophobia).

[0269] S12. Use of an anti-CGRP antibody for the manufacturing of a medicament for improving patient global impression of change (PGIC) associated with migraine, comprising administering to a migraine patient an anti-CGRP antibody.

[0270] S13. Use of an anti-CGRP antibody for the manufacturing of a medicament for improving patient global impression of change (PGIC) associated with migraine, comprising administering to a migraine patient an anti-CGRP antibody, wherein said migraine patient suffers from chronic migraine.

[0271] S14. Use of an anti-CGRP antibody for the manufacturing of a medicament for improving patient global impression of change (PGIC) associated with migraine, comprising administering to a migraine patient an anti-CGRP antibody, wherein said patient suffers from episodic migraine.

[0272] S15. Use of the anti-CGRP antibody of any one of embodiments S12-S14, wherein the administration of said medicament improves patient global impression of change (PGIC) associated with migraine within 1 month from the first dosing with said anti-CGRP antibody.

[0273] S16. Use of the anti-CGRP antibody of any one of embodiments S12-S14, wherein the administration of said medicament improves patient global impression of change (PGIC) associated with migraine within 3 month from the first dosing with said anti-CGRP antibody.

[0274] S17. Use of the anti-CGRP antibody of any one of embodiments S12-S14, wherein the administration of said medicament improves patient global impression of change (PGIC) associated with migraine within 6 month from the first dosing with said anti-CGRP antibody.

[0275] S18. Use of the anti-CGRP antibody of any one of embodiments S12-S17, wherein the administration of said medicament improves patient global impression of change (PGIC) associated with migraine, and wherein the improvement is sustained for at least 3 months from the first dosing with said anti-CGRP antibody.

[0276] S19. Use of the anti-CGRP antibody of any one of embodiments S12-S18, wherein the administration of said medicament improves patient global impression of change (PGIC) associated with migraine, and wherein the improvement is sustained for at least 6 months from the first dosing with said anti-CGRP antibody.

[0277] S20. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said medicament is for intravenous or subcutaneous infusion.

[0278] S21. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said medicament is for intravenous infusion.

[0279] S22. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said patient is headache free 2 hours post-completion of administration or infusion.

[0280] S23. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises Ab6.

[0281] S24. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain complementarity-determining region (CDR) 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively.

[0282] S25. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively.

[0283] S26. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0284] S27. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0285] S28. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0286] S29. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0287] S30. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222.

[0288] S31. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232.

[0289] S32. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable heavy chain polypeptide of SEQ ID NO: 202.

[0290] S33. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0291] S34. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202.

[0292] S35. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232 and the variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0293] S36. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221.

[0294] S37. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain polypeptide encoded by SEQ ID NO: 231.

[0295] S38. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0296] S39. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0297] S40. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0298] S41. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0299] S42. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein the administered amount of said anti-CGRP antibody is between about 100 mg and about 300 mg, or is about 100 mg, or is about 300 mg.

[0300] S43. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein the administered amount of said anti-CGRP antibody is 100 mg.

[0301] S44. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said medicament is for intravenous administration in a dosage of 100 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks.

[0302] S45. Use of the anti-CGRP antibody of any one of embodiments S1-S42, wherein said medicament is for intravenous administration in a dosage of 300 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks.

[0303] S46. Use of the anti-CGRP antibody of any one of the foregoing embodiments wherein, prior to administration of said medicament, the patient exhibits between 1-10 migraine attacks per month in the month or in the 3 months prior to administration.

[0304] S47. Use of the anti-CGRP antibody of any one of the foregoing embodiments wherein, prior to administration of said medicament, the patient exhibits between 2-8 migraine attacks per month in the month or in the 3 months prior to administration.

[0305] S48. Use of the anti-CGRP antibody of any one of the foregoing embodiments wherein, prior to administration of said medicament, the patient exhibits between 3-7 migraine attacks per month in the month or in the 3 months prior to administration.

[0306] S49. Use of the anti-CGRP antibody of any one of the foregoing embodiments wherein, prior to administration of said medicament, the patient exhibits less than 25 headache days per month in the month or in the 3 months prior to administration.

[0307] S50. Use of the anti-CGRP antibody of any one of the foregoing embodiments wherein, prior to administration of said medicament, the patient exhibits less than 20 headache days per month in the month or in the 3 months prior to administration.

[0308] S51. Use of the anti-CGRP antibody of any one of the foregoing embodiments wherein, prior to administration of said medicament, the patient exhibits less than 15 headache days per month in the month or in the 3 months prior to administration.

[0309] S52. Use of the anti-CGRP antibody of any one of the foregoing embodiments wherein, prior to administration of said medicament, the patient exhibits less than 10 headache days per month in the month or in the 3 months prior to administration.

[0310] S53. Use of the anti-CGRP antibody of any one of the foregoing embodiments wherein said patient was diagnosed with migraine at least 10 years prior to administration of said medicament.

[0311] S54. Use of the anti-CGRP antibody of any one of the foregoing embodiments wherein said patient was diagnosed with migraine at least 15 years prior to administration of said medicament.

[0312] S55. Use of the anti-CGRP antibody of any one of the foregoing embodiments wherein said patient was diagnosed with migraine at least 18 or at least 19 years prior to administration of said medicament.

[0313] S56. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said patient further has a reduction in the number of migraine days by at least 50% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to administration of said medicament.

[0314] S57. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said patient further has a reduction in the number of migraine days by at least 75% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to administration of said medicament.

[0315] S58. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said patient further has a reduction in the number of migraine days by 100% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to administration of said medicament.

[0316] S59. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said patient further has a reduction in the number of migraine days by at least 50% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to administration of said medicament.

[0317] S60. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said patient further has a reduction in the number of migraine days by at least 75% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to administration of said medicament.

[0318] S61. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said patient further has a reduction in the number of migraine days by 100% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to administration of said medicament.

[0319] S62. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said medicament is further for administration in a second dose of said anti-CGRP antibody about 10-14 weeks, preferably 11-13 weeks, more preferably about 12 weeks or about 3 months after administration of said medicament.

[0320] S63. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said medicament comprises about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of said anti-CGRP antibody.

[0321] S64. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody is aglycosylated or if glycosylated only contains only mannose residues.

[0322] S65. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody consists of the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0323] S66. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody consists of the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0324] S67. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said headache or said migraine is diagnosed according to the third edition of the International Classification of Headache Disorders.

[0325] S68. Use of the anti-CGRP antibody of any of any one of the foregoing embodiments, wherein said anti-CGRP antibody is expressed in or obtained by expression in Pichia pastoris.

[0326] S69. Use of the anti-CGRP antibody of any of any one of embodiments S1-S67, wherein said anti-CGRP antibody is expressed in or obtained by expression in CHO cells.

[0327] S70. Use of the anti-CGRP antibody of any one of the foregoing embodiments, wherein said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80, and water.

[0328] S71. Use of the anti-CGRP antibody of embodiment S70, wherein said formulation comprises or consists of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-10% of said values, and having a pH of 5.8 or within +/-10% of said value.

[0329] S72. Use of the anti-CGRP antibody of embodiment S70, wherein said formulation comprises or consists of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-5% of said values, and/or having a pH of 5.8 or within +/-5% of said value.

[0330] S73. Use of the anti-CGRP antibody of embodiment S70, wherein said formulation comprises or consists of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-1% of said values, and/or having a pH of 5.8 or within +/-1% of said value.

[0331] S74. Use of the anti-CGRP antibody of embodiment S70, wherein said formulation comprises or consists of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-0.5% of said values, and/or having a pH of 5.8 or within +/-0.5% of said value.

[0332] S75. Use of the anti-CGRP antibody of embodiment S70, wherein said formulation comprises or consists of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-0.1% of said values, and/or having a pH of 5.8 or within +/-0.1% of said value.

[0333] S76. Use of the anti-CGRP antibody of any of any one of the foregoing embodiments, wherein the anti-CGRP antibody has a dissociation constant of less than or equal to 10 pM, such as 2-8 pM, such as 3-6 pM, such as less than or equal to about 5 pM.

Further Exemplary Embodiments

[0334] Further exemplary embodiments of the invention are provided as follows:

[0335] E1. An anti-CGRP antibody for use in treating most bothersome symptom (MBS) associated with migraine in a patient suffering from migraine.

[0336] E2. The anti-CGRP antibody for use of embodiment E1, wherein the patient suffers from chronic migraine.

[0337] E3. The anti-CGRP antibody for use of embodiment E1, wherein the patient suffers from episodic migraine.

[0338] E4. The anti-CGRP antibody for use according to any of the foregoing embodiments, wherein the patients most bothersome symptom (MBS) associated with migraine is improved at 1-12 hours post-completion of administration or infusion, such as 1-5 hours post-completion of administration or infusion, 1-2 hours post-completion of administration or infusion, or about 2 hours post-completion of administration or infusion.

[0339] E5. The anti-CGRP antibody for use according to any of the foregoing embodiments, wherein the patients most bothersome symptom (MBS) associated with migraine is improved within 1 month from the first dosing with said anti-CGRP antibody.

[0340] E6. The anti-CGRP antibody for use according to any of the foregoing embodiments, wherein the patients most bothersome symptom (MBS) associated with migraine is improved within 3 month from the first dosing with said anti-CGRP antibody.

[0341] E7. The anti-CGRP antibody for use according to any of the foregoing embodiments, wherein the patients most bothersome symptom (MBS) associated with migraine is improved within 6 month from the first dosing with said anti-CGRP antibody.

[0342] E8. The anti-CGRP antibody for use according to any of the foregoing embodiments, wherein the improvement is sustained for at least 3 months from the first dosing with said anti-CGRP antibody.

[0343] E9. The anti-CGRP antibody for use according to any of the foregoing embodiments, wherein the improvement is sustained for at least 6 months from the first dosing with said anti-CGRP antibody.

[0344] E10. The anti-CGRP antibody for use according to any of the foregoing embodiments, wherein the MBS is selected from the group consisting of: Sensitivity to light (photophobia), Nausea/vomiting, Headache, Sensitivity to sound (phonophobia), Aura, Pain with activity, Pain, Throbbing/pulsation, Cognitive disruption, Fatigue, Mood changes, Sensitivity to smell (osmophobia or olfactophobia), Visual impact, Pressure/tightness, Pain (anatomical), Eye pain, Neck pain, Dizziness, Allodynia, Inactivity, Sensory disturbance, Sleep disturbance and Speech difficulty.

[0345] E11. The anti-CGRP antibody for use according to any of the foregoing embodiments, wherein the MBS is selected from the group consisting of: Sensitivity to light (photophobia), Nausea/vomiting, Headache, Sensitivity to sound (phonophobia), Aura, Pain with activity, Pain, Throbbing/pulsation, Cognitive disruption, Fatigue, Mood changes and Sensitivity to smell (osmophobia or olfactophobia).

[0346] E12. An anti-CGRP antibody for use in improving patient global impression of change (PGIC) associated with migraine in a patient suffering from migraine.

[0347] E13. The anti-CGRP antibody for use of embodiment E12, wherein the patient suffers from chronic migraine.

[0348] E14. The anti-CGRP antibody for use of embodiment E12, wherein the patient suffers from episodic migraine.

[0349] E15. The anti-CGRP antibody for use according to any of embodiments E12-E14, wherein the improvement of patient global impression of change (PGIC) associated with migraine is observed within 1 month from the first dosing with said anti-CGRP antibody.

[0350] E16. The anti-CGRP antibody for use according to any of embodiments E12-E14, wherein the improvement of patient global impression of change (PGIC) associated with migraine is observed within 3 month from the first dosing with said anti-CGRP antibody.

[0351] E17. The anti-CGRP antibody for use according to any of embodiments E12-E14, wherein the improvement of patient global impression of change (PGIC) associated with migraine is observed within 6 month from the first dosing with said anti-CGRP antibody.

[0352] E18. The anti-CGRP antibody for use according to any of embodiments E12-E17, wherein the improvement of patient global impression of change (PGIC) associated with migraine is sustained for 3 months from the first dosing with said anti-CGRP antibody.

[0353] E19. The anti-CGRP antibody for use according to any of embodiments E12-E18, wherein the improvement of patient global impression of change (PGIC) associated with migraine is sustained for 6 months from the first dosing with said anti-CGRP antibody.

[0354] E20. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody is for intravenous or subcutaneous infusion.

[0355] E21. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody is for intravenous infusion.

[0356] E22. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said patient is headache free 2 hours post-completion of administration or infusion.

[0357] E23. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises Ab6.

[0358] E24. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain complementarity-determining region (CDR) 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively.

[0359] E25. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively.

[0360] E26. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0361] E27. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0362] E28. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively.

[0363] E29. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively.

[0364] E30. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222.

[0365] E31. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232.

[0366] E32. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable heavy chain polypeptide of SEQ ID NO: 202.

[0367] E33. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0368] E34. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202.

[0369] E35. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232 and the variable heavy chain polypeptide encoded by SEQ ID NO: 212.

[0370] E36. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221.

[0371] E37. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain polypeptide encoded by SEQ ID NO: 231.

[0372] E38. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0373] E39. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0374] E40. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0375] E41. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody comprises the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0376] E42. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein the administered amount of said anti-CGRP antibody is between about 100 mg and about 300 mg, or is about 100 mg, or is about 300 mg.

[0377] E43. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein the administered amount of said anti-CGRP antibody is 100 mg.

[0378] E44. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody is for intravenous administration in a dosage of 100 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks.

[0379] E45. The anti-CGRP antibody for use of any one of embodiments E1-E42, wherein said anti-CGRP antibody is for intravenous administration in a dosage of administering 300 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks.

[0380] E46. The anti-CGRP antibody for use of any one of the foregoing embodiments wherein, prior to administration of said anti-CGRP antibody, the patient exhibits between 1-10 migraine attacks per month in the month or in the 3 months prior to administration.

[0381] E47. The anti-CGRP antibody for use of any one of the foregoing embodiments wherein, prior to administration of said anti-CGRP antibody, the patient exhibits between 2-8 migraine attacks per month in the month or in the 3 months prior to administration.

[0382] E48. The anti-CGRP antibody for use of any one of the foregoing embodiments wherein, prior to administration of said anti-CGRP antibody, the patient exhibits between 3-7 migraine attacks per month in the month or in the 3 months prior to administration.

[0383] E49. The anti-CGRP antibody for use of any one of the foregoing embodiments wherein, prior to administration of said anti-CGRP antibody, the patient exhibits less than 25 headache days per month in the month or in the 3 months prior to administration.

[0384] E50. The anti-CGRP antibody for use of any one of the foregoing embodiments wherein, prior to administration of said anti-CGRP antibody, the patient exhibits less than 20 headache days per month in the month or in the 3 months prior to administration.

[0385] E51. The anti-CGRP antibody for use of any one of the foregoing embodiments wherein, prior to administration of said anti-CGRP antibody, the patient exhibits less than 15 headache days per month in the month or in the 3 months prior to administration.

[0386] E52. The anti-CGRP antibody for use of any one of the foregoing embodiments wherein, prior to administration of said anti-CGRP antibody, the patient exhibits less than 10 headache days per month in the month or in the 3 months prior to administration.

[0387] E53. The anti-CGRP antibody for use of any one of the foregoing embodiments wherein said patient was diagnosed with migraine at least 10 years prior to the administration of said anti-CGRP antibody.

[0388] E54. The anti-CGRP antibody for use of any one of the foregoing embodiments wherein said patient was diagnosed with migraine at least 15 years prior to the administration of said anti-CGRP antibody.

[0389] E55. The anti-CGRP antibody for use of any one of the foregoing embodiments wherein said patient was diagnosed with migraine at least 18 or at least 19 years prior to the administration of said anti-CGRP antibody.

[0390] E56. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said patient has a reduction in the number of migraine days by at least 50% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to the administration of said anti-CGRP antibody.

[0391] E57. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said patient has a reduction in the number of migraine days by at least 75% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to the administration of said anti-CGRP antibody.

[0392] E58. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said patient has a reduction in the number of migraine days by 100% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to the administration of said anti-CGRP antibody.

[0393] E59. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said patient has a reduction in the number of migraine days by at least 50% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to the administration of said anti-CGRP antibody.

[0394] E60. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said patient has a reduction in the number of migraine days by at least 75% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to the administration of said anti-CGRP antibody.

[0395] E61. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said patient has a reduction in the number of migraine days by 100% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to the administration of said anti-CGRP antibody.

[0396] E62. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said use comprises administering a second dose of said anti-CGRP antibody to said patient about 10-14 weeks, preferably 11-13 weeks, more preferably about 12 weeks or about 3 months after the administration of said anti-CGRP antibody.

[0397] E63. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said use comprises administering about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of said anti-CGRP antibody.

[0398] E64. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody is aglycosylated or if glycosylated only contains only mannose residues.

[0399] E65. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody consists of the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566.

[0400] E66. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody consists of the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567.

[0401] E67. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said headache or said migraine is diagnosed according to the third edition of the International Classification of Headache Disorders.

[0402] E68. The anti-CGRP antibody for use of any of any one of the foregoing embodiments, wherein said anti-CGRP antibody is expressed in or obtained by expression in Pichia pastoris.

[0403] E69. The anti-CGRP antibody for use of any of any one of embodiments E1-E67, wherein said anti-CGRP antibody is expressed in or obtained by expression in CHO cells.

[0404] E70. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80, and water.

[0405] E71. The anti-CGRP antibody for use of embodiment E70, wherein said formulation comprises or consists of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-10% of said values, and having a pH of 5.8 or within +/-10% of said value.

[0406] E72. The anti-CGRP antibody for use of embodiment E70, wherein said formulation comprises or consists of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-5% of said values, and/or having a pH of 5.8 or within +/-5% of said value.

[0407] E73. The anti-CGRP antibody for use of embodiment E70, wherein said formulation comprises or consists of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-1% of said values, and/or having a pH of 5.8 or within +/-1% of said value.

[0408] E74. The anti-CGRP antibody for use of embodiment E70, wherein said formulation comprises or consists of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-0.5% of said values, and/or having a pH of 5.8 or within +/-0.5% of said value.

[0409] E75. The anti-CGRP antibody for use of embodiment E70, wherein said formulation comprises or consists of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-0.1% of said values, and/or having a pH of 5.8 or within +/-0.1% of said value.

[0410] E76. The anti-CGRP antibody for use of any one of the foregoing embodiments, wherein the anti-CGRP antibody has a dissociation constant of less than or equal to 10 pM, such as 2-8 pM, such as 3-6 pM, such as less than or equal to about 5 pM.

EXAMPLES

[0411] The following examples are provided in order to illustrate the invention, but are not to be construed as limiting the scope of the claims in any way.

Example 1

[0412] Preparation of Antibodies that Bind CGRP

[0413] The preparation of exemplary anti-CGRP antibody Ab6 having the sequences in FIGS. 1-12 is disclosed in commonly owned PCT Application WO/2012/162243, published on Nov. 29, 2012, the contents of which are incorporated by reference herein. This application exemplifies synthesis of these antibodies in Pichia pastoris cells. The present Applicant further contemplates synthesis of anti-CGRP antibody Ab6 particularly in CHO cells.

Example 2

[0414] Human Clinical Study Evaluating the Safety and Efficacy of an Anti-CGRP Antibody in Chronic Migraine Patients

[0415] This example describes a randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of Ab6 for chronic migraine prevention. In the study, 1,072 patients were randomized to receive Ab6 (300 mg or 100 mg), or placebo administered by infusion once every 12 weeks. The study design is depicted in FIG. 13. To be eligible for the trial, patients must have experienced at least 15 headache days per month, of which at least eight met criteria for migraine. Patients that participated in the trial had an average of 16.1 migraine days per month at baseline. The primary endpoint of the present study was the change from baseline in mean monthly migraine days (MMDs) over weeks 1-12 following the first infusion of Ab6. The change from baseline in mean monthly migraine days (MMDs) following the second infusion at week 12 was also assessed and the results are shown in FIG. 14.

[0416] Study endpoints further included patient-identified MBS as part of the predefined key secondary endpoints. At screening, patients verbally identified the MBS associated with their migraine, which was pooled across treatment arms for this analysis. The change from baseline of these symptoms were than rated by the patient every month of the study beginning from Day 0.

[0417] In the present study, patients verbally identified the most bothersome symptom (MBS) associated with their migraine at screening. The MBS associated with their migraine was then categorized by the investigator into a predefined list of 8 symptoms or an "other" option. The predefined list included the terms nausea, vomiting, sensitivity to light, sensitivity to sound, mental cloudiness, fatigue, pain with activity, and mood changes. The "other" option provided investigators the opportunity to identify any migraine-associated symptom without limitation described by the patient as most bothersome but did not easily fit into the check list of symptoms included in the work study checklist. For those patients who selected the "other" category for their MBS, their "write-in" responses were re-coded post hoc and re-classified to the predefined list or to new symptom classes. At subsequent visits, patients were asked to rate the change from the screening visit in their self-reported MBS on a 7-point scale, which is shown below:

TABLE-US-00013 Very Much Much Minimally No Minimally Much Very Much Improved Improved Improved Change Worse Worse Worse

[0418] In addition to MBS, the patients were also requested to evaluate the efficacy of the treatment on patient global impression of change (PGIC), which is a parameter comprising a single question assessing the patient's own impression of the overall change in their disease status since the start of the study. This parameter was also rated by the patients at a 7-point scale identical to the one used to assess change in MBS as displayed above and at the same time points in the study. In FIGS. 16-22 the "worse" category includes "minimally worse, "much worse", and "very much worse".

[0419] At the screening visit in, patients indicated a wide range of symptoms as their MBS, with the "other" category being the most frequent response (40%-42% across the 3 treatment groups). The patients who selected the "other" category generally provided more details and/or had more than 1 symptom as their MBS, allowing for these symptoms to be recoded. The overall list of MBS is summarized in Table 1 below.

TABLE-US-00014 TABLE 1 Summary of patient-identified MBS in the present study as described in Example 2 Eptinezumab Eptinezumab Symptom, 100 mg 300 mg Placebo Total n (%) (n = 356) (n = 350) (n = 366) (N = 1072) ICHD-3 Symptoms Sensitivity to 67 (18.8) 64 (18.3) 69 (18.9) 200 (18.7) light Nausea/ 55 (15.4) 46 (13.1 6 (16.7) 162 (15.1) vomiting Headache 45 (12.6) 43 (12.3) 32 (8.7) 120 (11.2) Sensitivity to 22 (6.2) 28 (8.0) 28 (7.7) 78 (7.3) sound Aura 4 (1.1) 1 (<1) 2 (<1) 7 (0.7) Additional Symptoms Pain with 53 (14.9) 45 (12.9) 49 (13.4) 147 (13.7) activity Pain 35 (9.8) 45 (12.9) 53 (14.5) 133 (12.4) Throbbing/ 18 (5.1) 17 (4.9) 15 (4.1) 50 (4.7) pulsation Cognitive 17 (4.8) 14 (4.0) 13 (3.6) 44 (4.1) disruption Fatigue 7 (2.0) 11 (3.1) 8 (2.2) 26 (2.4) Mood 8 (2.2) 4 (1.1) 4 (1.1) 16 (1.5) changes Sensitivity to 1 (<1) 1 (<1) 8 (2.2) 10 (0.9) smell Visual 2 (<1) 3 (<1) 3 (<1) 8 (0.7) impact Pressure/ 2 (<1) 2 (<1) 3 (<1) 7 (0.7) tightness Pain, 3 (<1) 3 (<1) 0 6 (0.6) anatomical Eye pain 4 (1.1) 1 (<1) 1 (<1) 6 (0.6) Neck pain 1 (<1) 1 (<1) 3 (<1) 5 (0.5) Dizziness 2 (<1) 2 (<1) 1 (<1) 5 (0.5) Allodynia 1 (<1) 1 (<1) 1 (<1) 3 (0.3) Inactivity 0 1 (<1) 1 (<1) 2 (0.2) Sensory 1 (<1) 0 0 1 (0.1) disturbance Sleep 0 0 1 (<1) 1 (0.1) disturbance Speech 0 0 1 (<1) 1 (0.1) difficulty Multiple* 7 (2.0) 12 (3.4) 8 (2.2) 27 (2.5) Other 1 (<1) 5 (1.4) 1 (<1) 7 (0.7) *Patient's most bothersome symptom included more than 1 symptom type. ICHD-3 = International Classification of Headache Disorders 3rd edition.

[0420] The most commonly reported symptoms were light sensitivity, nausea/vomiting, pain with activity, pain, headache, sound sensitivity, throbbing/pulsation, cognitive disruption, fatigue, mood changes, and sensitivity to smell, with each category having at least 10 patients reporting these events as their MBS. At the end of the 28-day screening period (i.e, before dosing at the baseline visit), patients were asked to rate the change in their identified MBS from very much worse to very much improved, with >90% reporting no change in their MBS, which is illustrated in FIG. 16. This suggests that the bothersomeness of patient-identified MBS was quite stable among this cohort with chronic migraine during the screening period.

[0421] Infusion of Ab6 in doses of 100 mg and 300 mg provided significantly reduction in mean MMDs across months 1-3 of the study, with further reduction after an additional infusion at week 12 of the study. This effect is shown in FIG. 14.

[0422] The efficacy of Ab6 on the MBS was demonstrated at 1 month (FIG. 17), 3 months (FIG. 19), and 6 months (FIG. 21), following the first infusion of Ab6 in doses of 100 mg and 300 mg. The efficacy of Ab6 on the PGIC was demonstrated at 1 month (FIG. 18), 3 months (FIG. 20), and 6 months (FIG. 22), following the first infusion of Ab6 in doses of 100 mg and 300 mg. The efficacy on these parameters were sustained or increased through 2 doses of Ab6 over 6 months; at Month 1, 75-82% of Ab6-treated patients indicated some level of improvement compared to 56-59% for the placebo-treated patients; at Month 3 ratings of improvement were similar to those of month 1; at Month 6, .about.80% of Ab6-treated patients indicated .gtoreq.1 categorical level of improvement in MBS and PGIC. The distribution of ratings for MBS improvement and PGIC were similar across time points, suggesting that the 2 identically rated measures in patients with chronic migraine move in parallel. These data suggest that improvements in patient-identified most bothersome migraine-associated symptoms are highly correlated with the patient's perception of an improved disease status in patients with chronic migraine.

[0423] The administered antibody, Ab6, is an anti-CGRP antibody consisting of the light chain polypeptide of SEQ ID NO: 221 and heavy chain polypeptide of SEQ ID NO: 201.

[0424] Patient characteristics are summarized in Table 2 below, with separate columns for patients receiving placebo, 100 mg of the antibody, or 300 mg of the antibody. Patients had a mean number of years from migraine diagnosis of between 17.0 and 19.0 years, a mean duration of suffering from chronic migraine of between 11.5 and 12.4 years, and between 44.3% and 45.2% of patients utilized at least one prophylactic medication. In addition, patients with a dual diagnosis of chronic migraine and medications overuse excluding opioid and butalbital over were included in this study. At baseline, in both antibody treatment groups the mean number of migraine days per month was 16.1, while for the placebo group, the mean number of migraine days per month was 16.2.

TABLE-US-00015 TABLE 2 Summarizes the characteristics of patients in each treatment group in the clinical trials described in Eptinezumab Eptinezumab 100 mg 100 mg Placebo n = 356 n = 350 n = 366 Age (years), mean 41.0 (11.72) 41.0 (10.36) 39.6 (11.28) (SD) Sex, n (%) Male 49 (13.8%) 36 (10.3%) 41 (11.2%) Female 307 (86.2%) 314 (89.7%) 325 (88.8%) Race, n (%) White 332 (93.3%) 322 (92.0%) 321 (87.7%) Black or African 21 (5.9%) 23 (6.6%) 38 (10.4%) American Other* 3 (0.8%) 5 (1.4%) 7 (1.9%) BMI (kg/m.sup.2), mean 26.4 (4.98) 26.3 (7.14) 27.0 (5.56) (SD) Age at migraine 22.8 (10.64) 22.0 (9.30) 22.6 (9.98) diagnosis (years), mean (SD) Duration of migraine 18.3 (12.22) 19.0 (11.50) 17.0 (11.63) diagnosis (years), mean (SD) Duration of chronic 11.6 (11.72) 12.3 (11.15) 11.6 (10.90) migraines (years), mean (SD) Number of migraine 16.1 (4.61) 16.1 (4.77) 16.2 (4.55) days, mean (SD) .sup..dagger. Medication-overuse 139 (39.0%) 147 (42.0%) 145 (39.6%) headache diagnosis, n (%).sup..sctn. BMI, body mass index; SD, standard deviation, *Other includes Asian, American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, multiple races, and other. .sup..dagger. As reported by the eDiary in the 28-day screening period. .sup..sctn.Based on 3rd edition of the International Classification of Headache Disorders (beta).

Example 2.

Sequence CWU 1

1

5671439PRTArtificialEngineered antibody sequence 1Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Leu Asp Leu Ser Ser Tyr Tyr 20 25 30Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45Val Ile Gly Ile Asn Asp Asn Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 50 55 60Arg Phe Thr Ile Ser Arg Ala Ser Ser Thr Thr Val Asp Leu Lys Met65 70 75 80Thr Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly 85 90 95Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 100 105 110Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 115 120 125Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 130 135 140Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His145 150 155 160Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 165 170 175Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 180 185 190Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 195 200 205Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 210 215 220Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys225 230 235 240Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 245 250 255Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 260 265 270Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 275 280 285Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 290 295 300Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu305 310 315 320Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 325 330 335Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 340 345 350Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 355 360 365Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 370 375 380Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser385 390 395 400Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 405 410 415Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 420 425 430Leu Ser Leu Ser Pro Gly Lys 4352109PRTArtificialEngineered antibody sequence 2Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Leu Asp Leu Ser Ser Tyr Tyr 20 25 30Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45Val Ile Gly Ile Asn Asp Asn Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 50 55 60Arg Phe Thr Ile Ser Arg Ala Ser Ser Thr Thr Val Asp Leu Lys Met65 70 75 80Thr Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly 85 90 95Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 100 105329PRTArtificialEngineered antibody sequence 3Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Leu Asp Leu Ser 20 2545PRTArtificialEngineered antibody sequence 4Ser Tyr Tyr Met Gln1 5514PRTArtificialEngineered antibody sequence 5Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly1 5 10616PRTArtificialEngineered antibody sequence 6Val Ile Gly Ile Asn Asp Asn Thr Tyr Tyr Ala Ser Trp Ala Lys Gly1 5 10 15731PRTArtificialEngineered antibody sequence 7Arg Phe Thr Ile Ser Arg Ala Ser Ser Thr Thr Val Asp Leu Lys Met1 5 10 15Thr Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg 20 25 3083PRTArtificialEngineered antibody sequence 8Gly Asp Ile1911PRTArtificialEngineered antibody sequence 9Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser1 5 1010330PRTArtificialEngineered antibody sequence 10Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330111320DNAArtificialEngineered antibody sequence 11cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60tgcacagtct ctggactcga cctcagtagc tactacatgc aatgggtccg ccaggctcca 120gggaaggggc tggaatggat cggagtcatt ggtattaatg ataacacata ctacgcgagc 180tgggcgaaag gccgattcac catctccaga gcctcgtcga ccacggtgga tctgaaaatg 240accagtctga caaccgagga cacggccacc tatttctgtg ccagagggga catctggggc 300ccaggcaccc tcgtcaccgt ctcgagcgcc tccaccaagg gcccatcggt cttccccctg 360gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 420tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 480accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgaccgtg 540ccctccagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 600accaaggtgg acaagagagt tgagcccaaa tcttgtgaca aaactcacac atgcccaccg 660tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 720gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 780gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 840acaaagccgc gggaggagca gtacgccagc acgtaccgtg tggtcagcgt cctcaccgtc 900ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 960ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1020tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 1080gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1140aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1200aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1260catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaatga 132012327DNAArtificialEngineered antibody sequence 12cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60tgcacagtct ctggactcga cctcagtagc tactacatgc aatgggtccg ccaggctcca 120gggaaggggc tggaatggat cggagtcatt ggtattaatg ataacacata ctacgcgagc 180tgggcgaaag gccgattcac catctccaga gcctcgtcga ccacggtgga tctgaaaatg 240accagtctga caaccgagga cacggccacc tatttctgtg ccagagggga catctggggc 300ccaggcaccc tcgtcaccgt ctcgagc 3271387DNAArtificialEngineered antibody sequence 13cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60tgcacagtct ctggactcga cctcagt 871415DNAArtificialEngineered antibody sequence 14agctactaca tgcaa 151542DNAArtificialEngineered antibody sequence 15tgggtccgcc aggctccagg gaaggggctg gaatggatcg ga 421648DNAArtificialEngineered antibody sequence 16gtcattggta ttaatgataa cacatactac gcgagctggg cgaaaggc 481793DNAArtificialEngineered antibody sequence 17cgattcacca tctccagagc ctcgtcgacc acggtggatc tgaaaatgac cagtctgaca 60accgaggaca cggccaccta tttctgtgcc aga 93189DNAArtificialEngineered antibody sequence 18ggggacatc 91933DNAArtificialEngineered antibody sequence 19tggggcccag gcaccctcgt caccgtctcg agc 3320993DNAArtificialEngineered antibody sequence 20gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 99321219PRTArtificialEngineered antibody sequence 21Gln Val Leu Thr Gln Thr Ala Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asp Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys 50 55 60Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu65 70 75 80Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Ser Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21522113PRTArtificialEngineered antibody sequence 22Gln Val Leu Thr Gln Thr Ala Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asp Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys 50 55 60Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Leu Glu65 70 75 80Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Ser Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg2322PRTArtificialEngineered antibody sequence 23Gln Val Leu Thr Gln Thr Ala Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys 202413PRTArtificialEngineered antibody sequence 24Gln Ala Ser Gln Ser Val Tyr Asp Asn Asn Tyr Leu Ala1 5 102515PRTArtificialEngineered antibody sequence 25Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu Ile Tyr1 5 10 15267PRTArtificialEngineered antibody sequence 26Ser Thr Ser Thr Leu Ala Ser1 52732PRTArtificialEngineered antibody sequence 27Gly Val Ser Ser Arg Phe Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr1 5 10 15Leu Thr Ile Ser Asp Leu Glu Cys Ala Asp Ala Ala Thr Tyr Tyr Cys 20 25 302813PRTArtificialEngineered antibody sequence 28Leu Gly Ser Tyr Asp Cys Ser Ser Gly Asp Cys Phe Val1 5 102911PRTArtificialEngineered antibody sequence 29Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg1 5 1030106PRTArtificialEngineered antibody sequence 30Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 10531660DNAArtificialEngineered antibody sequence 31caagtgctga cccagactgc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgccagg ccagtcagag tgtttatgat aacaactacc tagcctggta tcagcagaaa 120ccagggcagc ctcccaagca actgatctat tctacatcca ctctggcatc tggggtctca 180tcgcggttca aaggcagtgg atctgggaca cagttcactc tcaccatcag cgacctggag 240tgtgccgatg ctgccactta ctactgtcta ggcagttatg attgtagtag tggtgattgt 300tttgttttcg gcggagggac cgaggtggtg gtcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 66032339DNAArtificialEngineered antibody sequence 32caagtgctga cccagactgc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgccagg ccagtcagag tgtttatgat aacaactacc tagcctggta tcagcagaaa 120ccagggcagc ctcccaagca actgatctat tctacatcca ctctggcatc tggggtctca 180tcgcggttca aaggcagtgg atctgggaca cagttcactc tcaccatcag cgacctggag 240tgtgccgatg ctgccactta ctactgtcta ggcagttatg attgtagtag tggtgattgt 300tttgttttcg gcggagggac cgaggtggtg gtcaaacgt

3393366DNAArtificialEngineered antibody sequence 33caagtgctga cccagactgc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgc 663439DNAArtificialEngineered antibody sequence 34caggccagtc agagtgttta tgataacaac tacctagcc 393545DNAArtificialEngineered antibody sequence 35tggtatcagc agaaaccagg gcagcctccc aagcaactga tctat 453621DNAArtificialEngineered antibody sequence 36tctacatcca ctctggcatc t 213796DNAArtificialEngineered antibody sequence 37ggggtctcat cgcggttcaa aggcagtgga tctgggacac agttcactct caccatcagc 60gacctggagt gtgccgatgc tgccacttac tactgt 963839DNAArtificialEngineered antibody sequence 38ctaggcagtt atgattgtag tagtggtgat tgttttgtt 393933DNAArtificialEngineered antibody sequence 39ttcggcggag ggaccgaggt ggtggtcaaa cgt 3340321DNAArtificialEngineered antibody sequence 40acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 32141441PRTArtificialEngineered antibody sequence 41Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Leu Asp Leu Ser Ser Tyr 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ile Asn Asp Asn Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 115 120 125Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 130 135 140Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly145 150 155 160Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 165 170 175Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 180 185 190Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 195 200 205Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 210 215 220Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys225 230 235 240Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 260 265 270Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys305 310 315 320Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu385 390 395 400Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 405 410 415Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 44042111PRTArtificialEngineered antibody sequence 42Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Leu Asp Leu Ser Ser Tyr 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ile Asn Asp Asn Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 1104330PRTArtificialEngineered antibody sequence 43Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Leu Asp Leu Ser 20 25 30445PRTArtificialEngineered antibody sequence 44Ser Tyr Tyr Met Gln1 54514PRTArtificialEngineered antibody sequence 45Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly1 5 104616PRTArtificialEngineered antibody sequence 46Val Ile Gly Ile Asn Asp Asn Thr Tyr Tyr Ala Ser Trp Ala Lys Gly1 5 10 154732PRTArtificialEngineered antibody sequence 47Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu Gln1 5 10 15Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg 20 25 30483PRTArtificialEngineered antibody sequence 48Gly Asp Ile14911PRTArtificialEngineered antibody sequence 49Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser1 5 1050330PRTArtificialEngineered antibody sequence 50Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330511326DNAArtificialEngineered antibody sequence 51gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggact cgacctcagt agctactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtatca atgataacac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600agcaacacca aggtggacaa gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 840gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1140ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320aaatga 132652333DNAArtificialEngineered antibody sequence 52gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggact cgacctcagt agctactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtatca atgataacac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agc 3335390DNAArtificialEngineered antibody sequence 53gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggact cgacctcagt 905415DNAArtificialEngineered antibody sequence 54agctactaca tgcaa 155542DNAArtificialEngineered antibody sequence 55tgggtccgtc aggctccagg gaaggggctg gagtgggtcg ga 425648DNAArtificialEngineered antibody sequence 56gtcattggta tcaatgataa cacatactac gcgagctggg cgaaaggc 485796DNAArtificialEngineered antibody sequence 57cgattcacca tctccagaga caattccaag accacggtgt atcttcaaat gaacagcctg 60agagctgagg acactgctgt gtatttctgt gctaga 96589DNAArtificialEngineered antibody sequence 58ggggacatc 95933DNAArtificialEngineered antibody sequence 59tggggccaag ggaccctcgt caccgtctcg agc 3360993DNAArtificialEngineered antibody sequence 60gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 99361219PRTArtificialEngineered antibody sequence 61Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asp Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Ser Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21562113PRTArtificialEngineered antibody sequence 62Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asp Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Ser Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg6322PRTArtificialEngineered antibody sequence 63Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys 206413PRTArtificialEngineered antibody sequence 64Gln Ala Ser Gln Ser Val Tyr Asp Asn Asn Tyr Leu Ala1 5 106515PRTArtificialEngineered antibody sequence 65Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu Ile Tyr1 5 10 15667PRTArtificialEngineered antibody sequence 66Ser Thr Ser Thr Leu Ala Ser1 56732PRTArtificialEngineered antibody sequence 67Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys 20 25 306813PRTArtificialEngineered antibody sequence 68Leu Gly Ser Tyr Asp Cys Ser Ser Gly Asp Cys Phe Val1 5 106911PRTArtificialEngineered antibody sequence 69Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg1 5 1070106PRTArtificialEngineered antibody sequence 70Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 10571660DNAArtificialEngineered antibody sequence 71caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagag tgtttatgat aacaactacc tagcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtcta ggcagttatg attgtagtag tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 66072339DNAArtificialEngineered antibody sequence 72caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagag tgtttatgat aacaactacc tagcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtcta ggcagttatg attgtagtag tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgt 3397366DNAArtificialEngineered antibody sequence 73caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgc 667439DNAArtificialEngineered antibody sequence 74caggccagtc agagtgttta tgataacaac tacctagcc 397545DNAArtificialEngineered antibody sequence 75tggtatcagc agaaaccagg gaaagttcct aagcaactga tctat 457621DNAArtificialEngineered antibody sequence 76tctacatcca ctctggcatc t 217796DNAArtificialEngineered antibody sequence 77ggggtcccat ctcgtttcag tggcagtgga tctgggacag atttcactct caccatcagc 60agcctgcagc ctgaagatgt tgcaacttat tactgt 967839DNAArtificialEngineered antibody sequence 78ctaggcagtt atgattgtag tagtggtgat tgttttgtt 397933DNAArtificialEngineered antibody sequence 79ttcggcggag gaaccaaggt ggaaatcaaa cgt 3380321DNAArtificialEngineered antibody sequence 80acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 32181441PRTArtificialEngineered antibody sequence 81Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Leu Asp Leu Ser Ser Tyr 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ile Asn Asp Asn Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 115 120 125Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 130 135 140Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly145 150 155 160Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 165 170 175Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 180 185 190Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Ala Arg 195 200 205Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 210 215 220Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys225 230 235 240Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 260 265 270Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys305 310 315 320Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu385 390 395 400Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 405 410 415Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 44082111PRTArtificialEngineered antibody sequence 82Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Leu Asp Leu Ser Ser Tyr 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ile Asn Asp Asn Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 1108330PRTArtificialEngineered antibody sequence 83Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Leu Asp Leu Ser 20 25 30845PRTArtificialEngineered antibody sequence 84Ser Tyr Tyr Met Gln1 58514PRTArtificialEngineered antibody sequence 85Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly1 5 108616PRTArtificialEngineered antibody sequence 86Val Ile Gly Ile Asn Asp Asn Thr Tyr Tyr Ala Ser Trp Ala Lys Gly1 5 10 158732PRTArtificialEngineered antibody sequence 87Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu Gln1 5 10 15Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg 20 25 30883PRTArtificialEngineered antibody sequence 88Gly Asp Ile18911PRTArtificialEngineered antibody sequence 89Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser1 5 1090330PRTArtificialEngineered antibody sequence 90Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Ala 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330911326DNAArtificialEngineered antibody sequence 91gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggact cgacctcagt agctactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtatca atgataacac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600agcaacacca aggtggacgc gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 840gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1140ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320aaatga 132692333DNAArtificialEngineered antibody sequence 92gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggact cgacctcagt agctactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtatca atgataacac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agc 3339390DNAArtificialEngineered antibody sequence 93gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggact cgacctcagt 909415DNAArtificialEngineered antibody sequence 94agctactaca tgcaa 159542DNAArtificialEngineered antibody sequence 95tgggtccgtc aggctccagg gaaggggctg gagtgggtcg ga 429648DNAArtificialEngineered antibody sequence 96gtcattggta tcaatgataa cacatactac gcgagctggg cgaaaggc 489796DNAArtificialEngineered antibody sequence 97cgattcacca tctccagaga caattccaag accacggtgt atcttcaaat gaacagcctg 60agagctgagg acactgctgt gtatttctgt gctaga 96989DNAArtificialEngineered antibody sequence 98ggggacatc 99933DNAArtificialEngineered antibody sequence 99tggggccaag ggaccctcgt caccgtctcg agc 33100993DNAArtificialEngineered antibody sequence 100gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacgcgag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993101219PRTArtificialEngineered antibody sequence 101Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asp Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Ser Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215102113PRTArtificialEngineered antibody sequence 102Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asp Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65

70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Ser Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg10322PRTArtificialEngineered antibody sequence 103Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys 2010413PRTArtificialEngineered antibody sequence 104Gln Ala Ser Gln Ser Val Tyr Asp Asn Asn Tyr Leu Ala1 5 1010515PRTArtificialEngineered antibody sequence 105Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu Ile Tyr1 5 10 151067PRTArtificialEngineered antibody sequence 106Ser Thr Ser Thr Leu Ala Ser1 510732PRTArtificialEngineered antibody sequence 107Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys 20 25 3010813PRTArtificialEngineered antibody sequence 108Leu Gly Ser Tyr Asp Cys Ser Ser Gly Asp Cys Phe Val1 5 1010911PRTArtificialEngineered antibody sequence 109Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg1 5 10110106PRTArtificialEngineered antibody sequence 110Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105111660DNAArtificialEngineered antibody sequence 111caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagag tgtttatgat aacaactacc tagcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtcta ggcagttatg attgtagtag tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660112339DNAArtificialEngineered antibody sequence 112caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagag tgtttatgat aacaactacc tagcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtcta ggcagttatg attgtagtag tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgt 33911366DNAArtificialEngineered antibody sequence 113caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgc 6611439DNAArtificialEngineered antibody sequence 114caggccagtc agagtgttta tgataacaac tacctagcc 3911545DNAArtificialEngineered antibody sequence 115tggtatcagc agaaaccagg gaaagttcct aagcaactga tctat 4511621DNAArtificialEngineered antibody sequence 116tctacatcca ctctggcatc t 2111796DNAArtificialEngineered antibody sequence 117ggggtcccat ctcgtttcag tggcagtgga tctgggacag atttcactct caccatcagc 60agcctgcagc ctgaagatgt tgcaacttat tactgt 9611839DNAArtificialEngineered antibody sequence 118ctaggcagtt atgattgtag tagtggtgat tgttttgtt 3911933DNAArtificialEngineered antibody sequence 119ttcggcggag gaaccaaggt ggaaatcaaa cgt 33120321DNAArtificialEngineered antibody sequence 120acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 321121439PRTArtificialEngineered antibody sequence 121Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro1 5 10 15Leu Thr Leu Thr Cys Ser Val Ser Gly Ile Asp Leu Ser Gly Tyr Tyr 20 25 30Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45Val Ile Gly Ile Asn Gly Ala Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 50 55 60Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met65 70 75 80Thr Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly 85 90 95Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 100 105 110Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 115 120 125Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 130 135 140Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His145 150 155 160Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 165 170 175Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 180 185 190Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 195 200 205Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 210 215 220Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys225 230 235 240Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 245 250 255Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 260 265 270Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 275 280 285Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 290 295 300Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu305 310 315 320Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 325 330 335Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 340 345 350Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 355 360 365Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 370 375 380Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser385 390 395 400Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 405 410 415Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 420 425 430Leu Ser Leu Ser Pro Gly Lys 435122109PRTArtificialEngineered antibody sequence 122Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro1 5 10 15Leu Thr Leu Thr Cys Ser Val Ser Gly Ile Asp Leu Ser Gly Tyr Tyr 20 25 30Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45Val Ile Gly Ile Asn Gly Ala Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 50 55 60Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met65 70 75 80Thr Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly 85 90 95Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 100 10512329PRTArtificialEngineered antibody sequence 123Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro1 5 10 15Leu Thr Leu Thr Cys Ser Val Ser Gly Ile Asp Leu Ser 20 251245PRTArtificialEngineered antibody sequence 124Gly Tyr Tyr Met Asn1 512514PRTArtificialEngineered antibody sequence 125Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly1 5 1012616PRTArtificialEngineered antibody sequence 126Val Ile Gly Ile Asn Gly Ala Thr Tyr Tyr Ala Ser Trp Ala Lys Gly1 5 10 1512731PRTArtificialEngineered antibody sequence 127Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met1 5 10 15Thr Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg 20 25 301283PRTArtificialEngineered antibody sequence 128Gly Asp Ile112911PRTArtificialEngineered antibody sequence 129Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser1 5 10130330PRTArtificialEngineered antibody sequence 130Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3301311320DNAArtificialEngineered antibody sequence 131cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60tgttccgtct ctggcatcga cctcagtggc tactacatga actgggtccg ccaggctcca 120gggaaggggc tggaatggat cggagtcatt ggtattaatg gtgccacata ctacgcgagc 180tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240accagtctga caaccgagga cacggccacc tatttctgtg ccagagggga catctggggc 300ccgggcaccc tcgtcaccgt ctcgagcgcc tccaccaagg gcccatcggt cttccccctg 360gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 420tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 480accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgaccgtg 540ccctccagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 600accaaggtgg acaagagagt tgagcccaaa tcttgtgaca aaactcacac atgcccaccg 660tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 720gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 780gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 840acaaagccgc gggaggagca gtacgccagc acgtaccgtg tggtcagcgt cctcaccgtc 900ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 960ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1020tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 1080gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1140aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1200aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1260catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaatga 1320132327DNAArtificialEngineered antibody sequence 132cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60tgttccgtct ctggcatcga cctcagtggc tactacatga actgggtccg ccaggctcca 120gggaaggggc tggaatggat cggagtcatt ggtattaatg gtgccacata ctacgcgagc 180tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240accagtctga caaccgagga cacggccacc tatttctgtg ccagagggga catctggggc 300ccgggcaccc tcgtcaccgt ctcgagc 32713387DNAArtificialEngineered antibody sequence 133cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60tgttccgtct ctggcatcga cctcagt 8713415DNAArtificialEngineered antibody sequence 134ggctactaca tgaac 1513542DNAArtificialEngineered antibody sequence 135tgggtccgcc aggctccagg gaaggggctg gaatggatcg ga 4213648DNAArtificialEngineered antibody sequence 136gtcattggta ttaatggtgc cacatactac gcgagctggg cgaaaggc 4813793DNAArtificialEngineered antibody sequence 137cgattcacca tctccaaaac ctcgtcgacc acggtggatc tgaaaatgac cagtctgaca 60accgaggaca cggccaccta tttctgtgcc aga 931389DNAArtificialEngineered antibody sequence 138ggggacatc 913933DNAArtificialEngineered antibody sequence 139tggggcccgg gcaccctcgt caccgtctcg agc 33140993DNAArtificialEngineered antibody sequence 140gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993141219PRTArtificialEngineered antibody sequence 141Gln Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr His Asn Thr 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu 35 40 45Ile Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55

60Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val Gln65 70 75 80Cys Asn Asp Ala Ala Ala Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Thr 85 90 95Asn Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215142113PRTArtificialEngineered antibody sequence 142Gln Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr His Asn Thr 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu 35 40 45Ile Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val Gln65 70 75 80Cys Asn Asp Ala Ala Ala Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Thr 85 90 95Asn Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg14322PRTArtificialEngineered antibody sequence 143Gln Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys 2014413PRTArtificialEngineered antibody sequence 144Gln Ala Ser Gln Ser Val Tyr His Asn Thr Tyr Leu Ala1 5 1014515PRTArtificialEngineered antibody sequence 145Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu Ile Tyr1 5 10 151467PRTArtificialEngineered antibody sequence 146Asp Ala Ser Thr Leu Ala Ser1 514732PRTArtificialEngineered antibody sequence 147Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr1 5 10 15Leu Thr Ile Ser Gly Val Gln Cys Asn Asp Ala Ala Ala Tyr Tyr Cys 20 25 3014813PRTArtificialEngineered antibody sequence 148Leu Gly Ser Tyr Asp Cys Thr Asn Gly Asp Cys Phe Val1 5 1014911PRTArtificialEngineered antibody sequence 149Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg1 5 10150106PRTArtificialEngineered antibody sequence 150Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105151660DNAArtificialEngineered antibody sequence 151caagtgctga cccagactcc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgccagg ccagtcagag tgtttatcat aacacctacc tggcctggta tcagcagaaa 120ccagggcagc ctcccaaaca actgatctat gatgcatcca ctctggcgtc tggggtccca 180tcgcggttca gcggcagtgg atctgggaca cagttcactc tcaccatcag cggcgtgcag 240tgtaacgatg ctgccgctta ctactgtctg ggcagttatg attgtactaa tggtgattgt 300tttgttttcg gcggagggac cgaggtggtg gtcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660152339DNAArtificialEngineered antibody sequence 152caagtgctga cccagactcc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgccagg ccagtcagag tgtttatcat aacacctacc tggcctggta tcagcagaaa 120ccagggcagc ctcccaaaca actgatctat gatgcatcca ctctggcgtc tggggtccca 180tcgcggttca gcggcagtgg atctgggaca cagttcactc tcaccatcag cggcgtgcag 240tgtaacgatg ctgccgctta ctactgtctg ggcagttatg attgtactaa tggtgattgt 300tttgttttcg gcggagggac cgaggtggtg gtcaaacgt 33915366DNAArtificialEngineered antibody sequence 153caagtgctga cccagactcc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgc 6615439DNAArtificialEngineered antibody sequence 154caggccagtc agagtgttta tcataacacc tacctggcc 3915545DNAArtificialEngineered antibody sequence 155tggtatcagc agaaaccagg gcagcctccc aaacaactga tctat 4515621DNAArtificialEngineered antibody sequence 156gatgcatcca ctctggcgtc t 2115796DNAArtificialEngineered antibody sequence 157ggggtcccat cgcggttcag cggcagtgga tctgggacac agttcactct caccatcagc 60ggcgtgcagt gtaacgatgc tgccgcttac tactgt 9615839DNAArtificialEngineered antibody sequence 158ctgggcagtt atgattgtac taatggtgat tgttttgtt 3915933DNAArtificialEngineered antibody sequence 159ttcggcggag ggaccgaggt ggtggtcaaa cgt 33160321DNAArtificialEngineered antibody sequence 160acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 321161441PRTArtificialEngineered antibody sequence 161Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser Gly Tyr 20 25 30Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ile Asn Gly Ala Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 115 120 125Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 130 135 140Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly145 150 155 160Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 165 170 175Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 180 185 190Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 195 200 205Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 210 215 220Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys225 230 235 240Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 260 265 270Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys305 310 315 320Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu385 390 395 400Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 405 410 415Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440162111PRTArtificialEngineered antibody sequence 162Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser Gly Tyr 20 25 30Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ile Asn Gly Ala Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 11016330PRTArtificialEngineered antibody sequence 163Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser 20 25 301645PRTArtificialEngineered antibody sequence 164Gly Tyr Tyr Met Asn1 516514PRTArtificialEngineered antibody sequence 165Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly1 5 1016616PRTArtificialEngineered antibody sequence 166Val Ile Gly Ile Asn Gly Ala Thr Tyr Tyr Ala Ser Trp Ala Lys Gly1 5 10 1516732PRTArtificialEngineered antibody sequence 167Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu Gln1 5 10 15Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg 20 25 301683PRTArtificialEngineered antibody sequence 168Gly Asp Ile116911PRTArtificialEngineered antibody sequence 169Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser1 5 10170330PRTArtificialEngineered antibody sequence 170Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3301711326DNAArtificialEngineered antibody sequence 171gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacctcagt ggctactaca tgaactgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtatta atggtgccac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600agcaacacca aggtggacaa gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 840gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1140ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320aaatga 1326172333DNAArtificialEngineered antibody sequence 172gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacctcagt ggctactaca tgaactgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtatta atggtgccac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agc 33317390DNAArtificialEngineered antibody sequence 173gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacctcagt 9017415DNAArtificialEngineered antibody sequence 174ggctactaca tgaac 1517542DNAArtificialEngineered antibody sequence 175tgggtccgtc aggctccagg gaaggggctg gagtgggtcg ga 4217648DNAArtificialEngineered antibody sequence 176gtcattggta ttaatggtgc cacatactac gcgagctggg cgaaaggc 4817796DNAArtificialEngineered antibody sequence 177cgattcacca tctccagaga caattccaag accacggtgt atcttcaaat gaacagcctg 60agagctgagg acactgctgt gtatttctgt gctaga 961789DNAArtificialEngineered antibody sequence 178ggggacatc 917933DNAArtificialEngineered antibody sequence 179tggggccaag ggaccctcgt

caccgtctcg agc 33180993DNAArtificialEngineered antibody sequence 180gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993181219PRTArtificialEngineered antibody sequence 181Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr His Asn Thr 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Thr 85 90 95Asn Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215182113PRTArtificialEngineered antibody sequence 182Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr His Asn Thr 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Thr 85 90 95Asn Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg18322PRTArtificialEngineered antibody sequence 183Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys 2018413PRTArtificialEngineered antibody sequence 184Gln Ala Ser Gln Ser Val Tyr His Asn Thr Tyr Leu Ala1 5 1018515PRTArtificialEngineered antibody sequence 185Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu Ile Tyr1 5 10 151867PRTArtificialEngineered antibody sequence 186Asp Ala Ser Thr Leu Ala Ser1 518732PRTArtificialEngineered antibody sequence 187Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys 20 25 3018813PRTArtificialEngineered antibody sequence 188Leu Gly Ser Tyr Asp Cys Thr Asn Gly Asp Cys Phe Val1 5 1018911PRTArtificialEngineered antibody sequence 189Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg1 5 10190106PRTArtificialEngineered antibody sequence 190Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105191660DNAArtificialEngineered antibody sequence 191caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagag tgtttatcat aacacctacc tggcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat gatgcatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtactaa tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660192339DNAArtificialEngineered antibody sequence 192caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagag tgtttatcat aacacctacc tggcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat gatgcatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtactaa tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgt 33919366DNAArtificialEngineered antibody sequence 193caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgc 6619439DNAArtificialEngineered antibody sequence 194caggccagtc agagtgttta tcataacacc tacctggcc 3919545DNAArtificialEngineered antibody sequence 195tggtatcagc agaaaccagg gaaagttcct aagcaactga tctat 4519621DNAArtificialEngineered antibody sequence 196gatgcatcca ctctggcatc t 2119796DNAArtificialEngineered antibody sequence 197ggggtcccat ctcgtttcag tggcagtgga tctgggacag atttcactct caccatcagc 60agcctgcagc ctgaagatgt tgcaacttat tactgt 9619839DNAArtificialEngineered antibody sequence 198ctgggcagtt atgattgtac taatggtgat tgttttgtt 3919933DNAArtificialEngineered antibody sequence 199ttcggcggag gaaccaaggt ggaaatcaaa cgt 33200321DNAArtificialEngineered antibody sequence 200acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 321201441PRTArtificialEngineered antibody sequence 201Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser Gly Tyr 20 25 30Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ile Asn Gly Ala Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 115 120 125Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 130 135 140Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly145 150 155 160Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 165 170 175Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 180 185 190Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Ala Arg 195 200 205Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 210 215 220Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys225 230 235 240Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 260 265 270Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys305 310 315 320Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu385 390 395 400Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 405 410 415Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440202111PRTArtificialEngineered antibody sequence 202Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser Gly Tyr 20 25 30Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ile Asn Gly Ala Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 11020330PRTArtificialEngineered antibody sequence 203Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser 20 25 302045PRTArtificialEngineered antibody sequence 204Gly Tyr Tyr Met Asn1 520514PRTArtificialEngineered antibody sequence 205Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly1 5 1020616PRTArtificialEngineered antibody sequence 206Val Ile Gly Ile Asn Gly Ala Thr Tyr Tyr Ala Ser Trp Ala Lys Gly1 5 10 1520732PRTArtificialEngineered antibody sequence 207Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu Gln1 5 10 15Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg 20 25 302083PRTArtificialEngineered antibody sequence 208Gly Asp Ile120911PRTArtificialEngineered antibody sequence 209Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser1 5 10210330PRTArtificialEngineered antibody sequence 210Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Ala 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3302111326DNAArtificialEngineered antibody sequence 211gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacctcagt ggctactaca tgaactgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtatta atggtgccac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600agcaacacca aggtggacgc gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 840gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag

1140ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320aaatga 1326212333DNAArtificialEngineered antibody sequence 212gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacctcagt ggctactaca tgaactgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtatta atggtgccac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agc 33321390DNAArtificialEngineered antibody sequence 213gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacctcagt 9021415DNAArtificialEngineered antibody sequence 214ggctactaca tgaac 1521542DNAArtificialEngineered antibody sequence 215tgggtccgtc aggctccagg gaaggggctg gagtgggtcg ga 4221648DNAArtificialEngineered antibody sequence 216gtcattggta ttaatggtgc cacatactac gcgagctggg cgaaaggc 4821796DNAArtificialEngineered antibody sequence 217cgattcacca tctccagaga caattccaag accacggtgt atcttcaaat gaacagcctg 60agagctgagg acactgctgt gtatttctgt gctaga 962189DNAArtificialEngineered antibody sequence 218ggggacatc 921933DNAArtificialEngineered antibody sequence 219tggggccaag ggaccctcgt caccgtctcg agc 33220993DNAArtificialEngineered antibody sequence 220gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacgcgag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993221219PRTArtificialEngineered antibody sequence 221Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr His Asn Thr 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Thr 85 90 95Asn Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215222113PRTArtificialEngineered antibody sequence 222Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr His Asn Thr 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Asp Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Thr 85 90 95Asn Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg22322PRTArtificialEngineered antibody sequence 223Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys 2022413PRTArtificialEngineered antibody sequence 224Gln Ala Ser Gln Ser Val Tyr His Asn Thr Tyr Leu Ala1 5 1022515PRTArtificialEngineered antibody sequence 225Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu Ile Tyr1 5 10 152267PRTArtificialEngineered antibody sequence 226Asp Ala Ser Thr Leu Ala Ser1 522732PRTArtificialEngineered antibody sequence 227Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys 20 25 3022813PRTArtificialEngineered antibody sequence 228Leu Gly Ser Tyr Asp Cys Thr Asn Gly Asp Cys Phe Val1 5 1022911PRTArtificialEngineered antibody sequence 229Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg1 5 10230106PRTArtificialEngineered antibody sequence 230Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105231660DNAArtificialEngineered antibody sequence 231caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagag tgtttatcat aacacctacc tggcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat gatgcatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtactaa tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660232339DNAArtificialEngineered antibody sequence 232caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagag tgtttatcat aacacctacc tggcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat gatgcatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtactaa tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgt 33923366DNAArtificialEngineered antibody sequence 233caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgc 6623439DNAArtificialEngineered antibody sequence 234caggccagtc agagtgttta tcataacacc tacctggcc 3923545DNAArtificialEngineered antibody sequence 235tggtatcagc agaaaccagg gaaagttcct aagcaactga tctat 4523621DNAArtificialEngineered antibody sequence 236gatgcatcca ctctggcatc t 2123796DNAArtificialEngineered antibody sequence 237ggggtcccat ctcgtttcag tggcagtgga tctgggacag atttcactct caccatcagc 60agcctgcagc ctgaagatgt tgcaacttat tactgt 9623839DNAArtificialEngineered antibody sequence 238ctgggcagtt atgattgtac taatggtgat tgttttgtt 3923933DNAArtificialEngineered antibody sequence 239ttcggcggag gaaccaaggt ggaaatcaaa cgt 33240321DNAArtificialEngineered antibody sequence 240acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 321241440PRTArtificialEngineered antibody sequence 241Gln Glu Gln Leu Lys Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr1 5 10 15Ser Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Asn His 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Val Gly Ile Asn Gly Arg Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Thr Ser Ser Thr Thr Val Asp Leu Lys65 70 75 80Met Thr Arg Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Gly Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser Ala Ser 100 105 110Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 115 120 125Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 130 135 140Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val145 150 155 160His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 165 170 175Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 180 185 190Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val 195 200 205Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 210 215 220Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro225 230 235 240Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 245 250 255Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 260 265 270Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 275 280 285Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 290 295 300Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala305 310 315 320Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 325 330 335Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 340 345 350Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 355 360 365Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 370 375 380Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr385 390 395 400Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 405 410 415Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 420 425 430Ser Leu Ser Leu Ser Pro Gly Lys 435 440242110PRTArtificialEngineered antibody sequence 242Gln Glu Gln Leu Lys Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr1 5 10 15Ser Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser Asn His 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Val Gly Ile Asn Gly Arg Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Thr Ser Ser Thr Thr Val Asp Leu Lys65 70 75 80Met Thr Arg Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95Gly Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 100 105 11024330PRTArtificialEngineered antibody sequence 243Gln Glu Gln Leu Lys Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr1 5 10 15Ser Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Leu Ser 20 25 302445PRTArtificialEngineered antibody sequence 244Asn His Tyr Met Gln1 524514PRTArtificialEngineered antibody sequence 245Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly1 5 1024616PRTArtificialEngineered antibody sequence 246Val Val Gly Ile Asn Gly Arg Thr Tyr Tyr Ala Ser Trp Ala Lys Gly1 5 10 1524731PRTArtificialEngineered antibody sequence 247Arg Phe Thr Ile Ser Arg Thr Ser Ser Thr Thr Val Asp Leu Lys Met1 5 10 15Thr Arg Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg 20 25 302483PRTArtificialEngineered antibody sequence 248Gly Asp Ile124911PRTArtificialEngineered antibody sequence 249Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser1 5 10250330PRTArtificialEngineered antibody sequence 250Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260

265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3302511323DNAArtificialEngineered antibody sequence 251caggagcagc tgaaggagtc cgggggtcgc ctggtcacgc ctgggacatc cctgacactc 60acctgcaccg tctctggaat cgacctcagt aaccactaca tgcaatgggt ccgccaggct 120ccagggaagg ggctggagtg gatcggagtc gttggtatta atggtcgcac atactacgcg 180agctgggcga aaggccgatt caccatctcc agaacctcgt cgaccacggt ggatctgaaa 240atgaccaggc tgacaaccga ggacacggcc acctatttct gtgccagagg ggacatctgg 300ggcccaggca ccctggtcac cgtctcgagc gcctccacca agggcccatc ggtcttcccc 360ctggcaccct cctccaagag cacctctggg ggcacagcgg ccctgggctg cctggtcaag 420gactacttcc ccgaaccggt gacggtgtcg tggaactcag gcgccctgac cagcggcgtg 480cacaccttcc cggctgtcct acagtcctca ggactctact ccctcagcag cgtggtgacc 540gtgccctcca gcagcttggg cacccagacc tacatctgca acgtgaatca caagcccagc 600aacaccaagg tggacaagag agttgagccc aaatcttgtg acaaaactca cacatgccca 660ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 720aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 780cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 840aagacaaagc cgcgggagga gcagtacgcc agcacgtacc gtgtggtcag cgtcctcacc 900gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 960ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 1020gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 1080ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 1140gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 1200agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 1260atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1320tga 1323252330DNAArtificialEngineered antibody sequence 252caggagcagc tgaaggagtc cgggggtcgc ctggtcacgc ctgggacatc cctgacactc 60acctgcaccg tctctggaat cgacctcagt aaccactaca tgcaatgggt ccgccaggct 120ccagggaagg ggctggagtg gatcggagtc gttggtatta atggtcgcac atactacgcg 180agctgggcga aaggccgatt caccatctcc agaacctcgt cgaccacggt ggatctgaaa 240atgaccaggc tgacaaccga ggacacggcc acctatttct gtgccagagg ggacatctgg 300ggcccaggca ccctggtcac cgtctcgagc 33025390DNAArtificialEngineered antibody sequence 253caggagcagc tgaaggagtc cgggggtcgc ctggtcacgc ctgggacatc cctgacactc 60acctgcaccg tctctggaat cgacctcagt 9025415DNAArtificialEngineered antibody sequence 254aaccactaca tgcaa 1525542DNAArtificialEngineered antibody sequence 255tgggtccgcc aggctccagg gaaggggctg gagtggatcg ga 4225648DNAArtificialEngineered antibody sequence 256gtcgttggta ttaatggtcg cacatactac gcgagctggg cgaaaggc 4825793DNAArtificialEngineered antibody sequence 257cgattcacca tctccagaac ctcgtcgacc acggtggatc tgaaaatgac caggctgaca 60accgaggaca cggccaccta tttctgtgcc aga 932589DNAArtificialEngineered antibody sequence 258ggggacatc 925933DNAArtificialEngineered antibody sequence 259tggggcccag gcaccctggt caccgtctcg agc 33260993DNAArtificialEngineered antibody sequence 260gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993261219PRTArtificialEngineered antibody sequence 261Gln Val Leu Thr Gln Thr Ala Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asn Tyr Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys 50 55 60Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val Gln65 70 75 80Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Thr Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215262113PRTArtificialEngineered antibody sequence 262Gln Val Leu Thr Gln Thr Ala Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asn Tyr Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys 50 55 60Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val Gln65 70 75 80Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Thr Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg26322PRTArtificialEngineered antibody sequence 263Gln Val Leu Thr Gln Thr Ala Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys 2026413PRTArtificialEngineered antibody sequence 264Gln Ala Ser Gln Ser Val Tyr Asn Tyr Asn Tyr Leu Ala1 5 1026515PRTArtificialEngineered antibody sequence 265Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu Ile Tyr1 5 10 152667PRTArtificialEngineered antibody sequence 266Ser Thr Ser Thr Leu Ala Ser1 526732PRTArtificialEngineered antibody sequence 267Gly Val Ser Ser Arg Phe Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr1 5 10 15Leu Thr Ile Ser Asp Val Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys 20 25 3026813PRTArtificialEngineered antibody sequence 268Leu Gly Ser Tyr Asp Cys Ser Thr Gly Asp Cys Phe Val1 5 1026911PRTArtificialEngineered antibody sequence 269Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg1 5 10270106PRTArtificialEngineered antibody sequence 270Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105271660DNAArtificialEngineered antibody sequence 271caagtgctga cccagactgc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgccagg ccagtcagag tgtttataat tacaactacc ttgcctggta tcagcagaaa 120ccagggcagc ctcccaagca actgatctat tctacatcca ctctggcatc tggggtctca 180tcgcgattca aaggcagtgg atctgggaca cagttcactc tcaccatcag cgacgtgcag 240tgtgacgatg ctgccactta ctactgtcta ggcagttatg actgtagtac tggtgattgt 300tttgttttcg gcggagggac cgaggtggtg gtcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660272339DNAArtificialEngineered antibody sequence 272caagtgctga cccagactgc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgccagg ccagtcagag tgtttataat tacaactacc ttgcctggta tcagcagaaa 120ccagggcagc ctcccaagca actgatctat tctacatcca ctctggcatc tggggtctca 180tcgcgattca aaggcagtgg atctgggaca cagttcactc tcaccatcag cgacgtgcag 240tgtgacgatg ctgccactta ctactgtcta ggcagttatg actgtagtac tggtgattgt 300tttgttttcg gcggagggac cgaggtggtg gtcaaacgt 33927366DNAArtificialEngineered antibody sequence 273caagtgctga cccagactgc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgc 6627439DNAArtificialEngineered antibody sequence 274caggccagtc agagtgttta taattacaac taccttgcc 3927545DNAArtificialEngineered antibody sequence 275tggtatcagc agaaaccagg gcagcctccc aagcaactga tctat 4527621DNAArtificialEngineered antibody sequence 276tctacatcca ctctggcatc t 2127796DNAArtificialEngineered antibody sequence 277ggggtctcat cgcgattcaa aggcagtgga tctgggacac agttcactct caccatcagc 60gacgtgcagt gtgacgatgc tgccacttac tactgt 9627839DNAArtificialEngineered antibody sequence 278ctaggcagtt atgactgtag tactggtgat tgttttgtt 3927933DNAArtificialEngineered antibody sequence 279ttcggcggag ggaccgaggt ggtggtcaaa cgt 33280321DNAArtificialEngineered antibody sequence 280acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 321281441PRTArtificialEngineered antibody sequence 281Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser Asn His 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Val Gly Ile Asn Gly Arg Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 115 120 125Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 130 135 140Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly145 150 155 160Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 165 170 175Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 180 185 190Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 195 200 205Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 210 215 220Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys225 230 235 240Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 260 265 270Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys305 310 315 320Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu385 390 395 400Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 405 410 415Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440282111PRTArtificialEngineered antibody sequence 282Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser Asn His 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Val Gly Ile Asn Gly Arg Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 11028330PRTArtificialEngineered antibody sequence 283Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser 20 25 302845PRTArtificialEngineered antibody sequence 284Asn His Tyr Met Gln1 528514PRTArtificialEngineered antibody sequence 285Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly1 5 1028616PRTArtificialEngineered antibody sequence 286Val Val Gly Ile Asn Gly Arg Thr Tyr Tyr Ala Ser Trp Ala Lys Gly1 5 10 1528732PRTArtificialEngineered antibody sequence 287Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu Gln1 5 10 15Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg 20 25 302883PRTArtificialEngineered antibody sequence 288Gly Asp Ile128911PRTArtificialEngineered antibody sequence 289Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser1 5 10290330PRTArtificialEngineered antibody sequence 290Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5

10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3302911326DNAArtificialEngineered antibody sequence 291gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacctcagt aaccactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc gttggtatca atggtcgcac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600agcaacacca aggtggacaa gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 840gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1140ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320aaatga 1326292333DNAArtificialEngineered antibody sequence 292gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacctcagt aaccactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc gttggtatca atggtcgcac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agc 33329390DNAArtificialEngineered antibody sequence 293gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacctcagt 9029415DNAArtificialEngineered antibody sequence 294aaccactaca tgcaa 1529542DNAArtificialEngineered antibody sequence 295tgggtccgtc aggctccagg gaaggggctg gagtgggtcg ga 4229648DNAArtificialEngineered antibody sequence 296gtcgttggta tcaatggtcg cacatactac gcgagctggg cgaaaggc 4829796DNAArtificialEngineered antibody sequence 297cgattcacca tctccagaga caattccaag accacggtgt atcttcaaat gaacagcctg 60agagctgagg acactgctgt gtatttctgt gctaga 962989DNAArtificialEngineered antibody sequence 298ggggacatc 929933DNAArtificialEngineered antibody sequence 299tggggccaag ggaccctcgt caccgtctcg agc 33300993DNAArtificialEngineered antibody sequence 300gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993301219PRTArtificialEngineered antibody sequence 301Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asn Tyr Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Thr Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215302113PRTArtificialEngineered antibody sequence 302Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Ser Val Tyr Asn Tyr Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Thr Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg30322PRTArtificialEngineered antibody sequence 303Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys 2030413PRTArtificialEngineered antibody sequence 304Gln Ala Ser Gln Ser Val Tyr Asn Tyr Asn Tyr Leu Ala1 5 1030515PRTArtificialEngineered antibody sequence 305Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu Ile Tyr1 5 10 153067PRTArtificialEngineered antibody sequence 306Ser Thr Ser Thr Leu Ala Ser1 530732PRTArtificialEngineered antibody sequence 307Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys 20 25 3030813PRTArtificialEngineered antibody sequence 308Leu Gly Ser Tyr Asp Cys Ser Thr Gly Asp Cys Phe Val1 5 1030911PRTArtificialEngineered antibody sequence 309Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg1 5 10310106PRTArtificialEngineered antibody sequence 310Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105311660DNAArtificialEngineered antibody sequence 311caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagag tgtttacaat tacaactacc ttgcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtagtac tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660312339DNAArtificialEngineered antibody sequence 312caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagag tgtttacaat tacaactacc ttgcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtagtac tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgt 33931366DNAArtificialEngineered antibody sequence 313caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgc 6631439DNAArtificialEngineered antibody sequence 314caggccagtc agagtgttta caattacaac taccttgcc 3931545DNAArtificialEngineered antibody sequence 315tggtatcagc agaaaccagg gaaagttcct aagcaactga tctat 4531621DNAArtificialEngineered antibody sequence 316tctacatcca ctctggcatc t 2131796DNAArtificialEngineered antibody sequence 317ggggtcccat ctcgtttcag tggcagtgga tctgggacag atttcactct caccatcagc 60agcctgcagc ctgaagatgt tgcaacttat tactgt 9631839DNAArtificialEngineered antibody sequence 318ctgggcagtt atgattgtag tactggtgat tgttttgtt 3931933DNAArtificialEngineered antibody sequence 319ttcggcggag gaaccaaggt ggaaatcaaa cgt 33320321DNAArtificialEngineered antibody sequence 320acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 321321439PRTArtificialEngineered antibody sequence 321Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Gly Leu Ser Ser Tyr Tyr 20 25 30Met Gln Trp Val Arg Gln Ser Pro Gly Arg Gly Leu Glu Trp Ile Gly 35 40 45Val Ile Gly Ser Asp Gly Lys Thr Tyr Tyr Ala Thr Trp Ala Lys Gly 50 55 60Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Arg Met65 70 75 80Ala Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Thr Arg Gly 85 90 95Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 100 105 110Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 115 120 125Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 130 135 140Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His145 150 155 160Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 165 170 175Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 180 185 190Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 195 200 205Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 210 215 220Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys225 230 235 240Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 245 250 255Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 260 265 270Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 275 280 285Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 290 295 300Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu305 310 315 320Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 325 330 335Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 340 345 350Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 355 360 365Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 370 375 380Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser385 390 395 400Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 405 410 415Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 420 425 430Leu Ser Leu Ser Pro Gly Lys 435322109PRTArtificialEngineered antibody sequence 322Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Gly Leu Ser Ser Tyr Tyr 20 25

30Met Gln Trp Val Arg Gln Ser Pro Gly Arg Gly Leu Glu Trp Ile Gly 35 40 45Val Ile Gly Ser Asp Gly Lys Thr Tyr Tyr Ala Thr Trp Ala Lys Gly 50 55 60Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Arg Met65 70 75 80Ala Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Thr Arg Gly 85 90 95Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 100 10532329PRTArtificialEngineered antibody sequence 323Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Gly Leu Ser 20 253245PRTArtificialEngineered antibody sequence 324Ser Tyr Tyr Met Gln1 532514PRTArtificialEngineered antibody sequence 325Trp Val Arg Gln Ser Pro Gly Arg Gly Leu Glu Trp Ile Gly1 5 1032616PRTArtificialEngineered antibody sequence 326Val Ile Gly Ser Asp Gly Lys Thr Tyr Tyr Ala Thr Trp Ala Lys Gly1 5 10 1532731PRTArtificialEngineered antibody sequence 327Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Arg Met1 5 10 15Ala Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Thr Arg 20 25 303283PRTArtificialEngineered antibody sequence 328Gly Asp Ile132911PRTArtificialEngineered antibody sequence 329Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser1 5 10330330PRTArtificialEngineered antibody sequence 330Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3303311320DNAArtificialEngineered antibody sequence 331cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60tgcacagtct ctggaatcgg cctcagtagc tactacatgc agtgggtccg ccagtctcca 120gggagggggc tggaatggat cggagtcatt ggtagtgatg gtaagacata ctacgcgacc 180tgggcgaaag gccgattcac catctccaag acctcgtcga ccacggtgga tctgagaatg 240gccagtctga caaccgagga cacggccacc tatttctgta ccagagggga catctggggc 300ccggggaccc tcgtcaccgt ctcgagcgcc tccaccaagg gcccatcggt cttccccctg 360gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 420tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 480accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgaccgtg 540ccctccagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 600accaaggtgg acaagagagt tgagcccaaa tcttgtgaca aaactcacac atgcccaccg 660tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 720gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 780gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 840acaaagccgc gggaggagca gtacgccagc acgtaccgtg tggtcagcgt cctcaccgtc 900ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 960ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1020tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 1080gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1140aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1200aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1260catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaatga 1320332327DNAArtificialEngineered antibody sequence 332cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60tgcacagtct ctggaatcgg cctcagtagc tactacatgc agtgggtccg ccagtctcca 120gggagggggc tggaatggat cggagtcatt ggtagtgatg gtaagacata ctacgcgacc 180tgggcgaaag gccgattcac catctccaag acctcgtcga ccacggtgga tctgagaatg 240gccagtctga caaccgagga cacggccacc tatttctgta ccagagggga catctggggc 300ccggggaccc tcgtcaccgt ctcgagc 32733387DNAArtificialEngineered antibody sequence 333cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60tgcacagtct ctggaatcgg cctcagt 8733415DNAArtificialEngineered antibody sequence 334agctactaca tgcag 1533542DNAArtificialEngineered antibody sequence 335tgggtccgcc agtctccagg gagggggctg gaatggatcg ga 4233648DNAArtificialEngineered antibody sequence 336gtcattggta gtgatggtaa gacatactac gcgacctggg cgaaaggc 4833793DNAArtificialEngineered antibody sequence 337cgattcacca tctccaagac ctcgtcgacc acggtggatc tgagaatggc cagtctgaca 60accgaggaca cggccaccta tttctgtacc aga 933389DNAArtificialEngineered antibody sequence 338ggggacatc 933933DNAArtificialEngineered antibody sequence 339tggggcccgg ggaccctcgt caccgtctcg agc 33340993DNAArtificialEngineered antibody sequence 340gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993341219PRTArtificialEngineered antibody sequence 341Gln Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Asn Val Tyr Asn Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Arg 50 55 60Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val Gln65 70 75 80Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Arg Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215342113PRTArtificialEngineered antibody sequence 342Gln Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys Gln Ala Ser Gln Asn Val Tyr Asn Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Arg 50 55 60Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val Gln65 70 75 80Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Arg Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg34322PRTArtificialEngineered antibody sequence 343Gln Val Leu Thr Gln Thr Pro Ser Pro Val Ser Ala Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys 2034413PRTArtificialEngineered antibody sequence 344Gln Ala Ser Gln Asn Val Tyr Asn Asn Asn Tyr Leu Ala1 5 1034515PRTArtificialEngineered antibody sequence 345Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu Ile Tyr1 5 10 153467PRTArtificialEngineered antibody sequence 346Ser Thr Ser Thr Leu Ala Ser1 534732PRTArtificialEngineered antibody sequence 347Gly Val Ser Ser Arg Phe Arg Gly Ser Gly Ser Gly Thr Gln Phe Thr1 5 10 15Leu Thr Ile Ser Asp Val Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys 20 25 3034813PRTArtificialEngineered antibody sequence 348Leu Gly Ser Tyr Asp Cys Ser Arg Gly Asp Cys Phe Val1 5 1034911PRTArtificialEngineered antibody sequence 349Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg1 5 10350106PRTArtificialEngineered antibody sequence 350Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105351660DNAArtificialEngineered antibody sequence 351caagtgctga cccagactcc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgccagg ccagtcagaa tgtttataat aacaactacc tagcctggta tcagcagaaa 120ccagggcagc ctcccaagca actgatctat tctacgtcca ctctggcatc tggggtctca 180tcgcgattca gaggcagtgg atctgggaca cagttcactc tcaccatcag cgacgtgcag 240tgtgacgatg ctgccactta ctactgtcta ggcagttatg attgtagtcg tggtgattgt 300tttgttttcg gcggagggac cgaggtggtg gtcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660352339DNAArtificialEngineered antibody sequence 352caagtgctga cccagactcc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgccagg ccagtcagaa tgtttataat aacaactacc tagcctggta tcagcagaaa 120ccagggcagc ctcccaagca actgatctat tctacgtcca ctctggcatc tggggtctca 180tcgcgattca gaggcagtgg atctgggaca cagttcactc tcaccatcag cgacgtgcag 240tgtgacgatg ctgccactta ctactgtcta ggcagttatg attgtagtcg tggtgattgt 300tttgttttcg gcggagggac cgaggtggtg gtcaaacgt 33935366DNAArtificialEngineered antibody sequence 353caagtgctga cccagactcc atcccccgtg tctgcagctg tgggaagcac agtcaccatc 60aattgc 6635439DNAArtificialEngineered antibody sequence 354caggccagtc agaatgttta taataacaac tacctagcc 3935545DNAArtificialEngineered antibody sequence 355tggtatcagc agaaaccagg gcagcctccc aagcaactga tctat 4535621DNAArtificialEngineered antibody sequence 356tctacgtcca ctctggcatc t 2135796DNAArtificialEngineered antibody sequence 357ggggtctcat cgcgattcag aggcagtgga tctgggacac agttcactct caccatcagc 60gacgtgcagt gtgacgatgc tgccacttac tactgt 9635839DNAArtificialEngineered antibody sequence 358ctaggcagtt atgattgtag tcgtggtgat tgttttgtt 3935933DNAArtificialEngineered antibody sequence 359ttcggcggag ggaccgaggt ggtggtcaaa cgt 33360321DNAArtificialEngineered antibody sequence 360acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 321361441PRTArtificialEngineered antibody sequence 361Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Gly Leu Ser Ser Tyr 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ser Asp Gly Lys Thr Tyr Tyr Ala Thr Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Thr 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 115 120 125Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 130 135 140Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly145 150 155 160Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 165 170 175Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 180 185 190Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 195 200 205Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 210 215 220Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys225 230 235

240Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 260 265 270Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys305 310 315 320Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu385 390 395 400Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 405 410 415Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440362111PRTArtificialEngineered antibody sequence 362Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Gly Leu Ser Ser Tyr 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ser Asp Gly Lys Thr Tyr Tyr Ala Thr Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Thr 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 11036330PRTArtificialEngineered antibody sequence 363Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Gly Leu Ser 20 25 303645PRTArtificialEngineered antibody sequence 364Ser Tyr Tyr Met Gln1 536514PRTArtificialEngineered antibody sequence 365Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly1 5 1036616PRTArtificialEngineered antibody sequence 366Val Ile Gly Ser Asp Gly Lys Thr Tyr Tyr Ala Thr Trp Ala Lys Gly1 5 10 1536732PRTArtificialEngineered antibody sequence 367Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu Gln1 5 10 15Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Thr Arg 20 25 303683PRTArtificialEngineered antibody sequence 368Gly Asp Ile136911PRTArtificialEngineered antibody sequence 369Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser1 5 10370330PRTArtificialEngineered antibody sequence 370Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3303711326DNAArtificialEngineered antibody sequence 371gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cggcctcagt agctactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtagtg atggtaagac atactacgcg 180acctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtaccag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600agcaacacca aggtggacaa gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 840gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1140ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320aaatga 1326372333DNAArtificialEngineered antibody sequence 372gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cggcctcagt agctactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtagtg atggtaagac atactacgcg 180acctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtaccag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agc 33337390DNAArtificialEngineered antibody sequence 373gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cggcctcagt 9037415DNAArtificialEngineered antibody sequence 374agctactaca tgcaa 1537542DNAArtificialEngineered antibody sequence 375tgggtccgtc aggctccagg gaaggggctg gagtgggtcg ga 4237648DNAArtificialEngineered antibody sequence 376gtcattggta gtgatggtaa gacatactac gcgacctggg cgaaaggc 4837796DNAArtificialEngineered antibody sequence 377cgattcacca tctccagaga caattccaag accacggtgt atcttcaaat gaacagcctg 60agagctgagg acactgctgt gtatttctgt accaga 963789DNAArtificialEngineered antibody sequence 378ggggacatc 937933DNAArtificialEngineered antibody sequence 379tggggccaag ggaccctcgt caccgtctcg agc 33380993DNAArtificialEngineered antibody sequence 380gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993381219PRTArtificialEngineered antibody sequence 381Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Asn Val Tyr Asn Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Arg Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215382113PRTArtificialEngineered antibody sequence 382Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Asn Val Tyr Asn Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Arg Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg38322PRTArtificialEngineered antibody sequence 383Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys 2038413PRTArtificialEngineered antibody sequence 384Gln Ala Ser Gln Asn Val Tyr Asn Asn Asn Tyr Leu Ala1 5 1038515PRTArtificialEngineered antibody sequence 385Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu Ile Tyr1 5 10 153867PRTArtificialEngineered antibody sequence 386Ser Thr Ser Thr Leu Ala Ser1 538732PRTArtificialEngineered antibody sequence 387Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys 20 25 3038813PRTArtificialEngineered antibody sequence 388Leu Gly Ser Tyr Asp Cys Ser Arg Gly Asp Cys Phe Val1 5 1038911PRTArtificialEngineered antibody sequence 389Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg1 5 10390106PRTArtificialEngineered antibody sequence 390Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105391660DNAArtificialEngineered antibody sequence 391caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagaa tgtttacaat aacaactacc tagcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtagtcg tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660392339DNAArtificialEngineered antibody sequence 392caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagaa tgtttacaat aacaactacc tagcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtagtcg tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgt 33939366DNAArtificialEngineered antibody sequence 393caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgc 6639439DNAArtificialEngineered antibody sequence 394caggccagtc agaatgttta caataacaac tacctagcc 3939545DNAArtificialEngineered antibody sequence 395tggtatcagc agaaaccagg gaaagttcct aagcaactga tctat 4539621DNAArtificialEngineered antibody sequence 396tctacatcca ctctggcatc t 2139796DNAArtificialEngineered antibody sequence 397ggggtcccat ctcgtttcag tggcagtgga tctgggacag atttcactct caccatcagc 60agcctgcagc ctgaagatgt tgcaacttat tactgt 9639839DNAArtificialEngineered antibody sequence 398ctgggcagtt atgattgtag tcgtggtgat tgttttgtt 3939933DNAArtificialEngineered antibody sequence 399ttcggcggag gaaccaaggt ggaaatcaaa cgt 33400321DNAArtificialEngineered antibody sequence 400acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg

gagagtgtta g 321401439PRTArtificialEngineered antibody sequence 401Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Gly Ser1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Val Thr Asn Tyr Tyr 20 25 30Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45Val Ile Gly Val Asn Gly Lys Arg Tyr Tyr Ala Ser Trp Ala Lys Gly 50 55 60Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met65 70 75 80Thr Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly 85 90 95Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 100 105 110Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 115 120 125Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 130 135 140Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His145 150 155 160Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 165 170 175Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 180 185 190Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 195 200 205Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 210 215 220Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys225 230 235 240Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 245 250 255Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 260 265 270Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 275 280 285Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 290 295 300Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu305 310 315 320Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 325 330 335Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 340 345 350Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 355 360 365Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 370 375 380Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser385 390 395 400Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 405 410 415Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 420 425 430Leu Ser Leu Ser Pro Gly Lys 435402109PRTArtificialEngineered antibody sequence 402Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Gly Ser1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Val Thr Asn Tyr Tyr 20 25 30Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45Val Ile Gly Val Asn Gly Lys Arg Tyr Tyr Ala Ser Trp Ala Lys Gly 50 55 60Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met65 70 75 80Thr Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Gly 85 90 95Asp Ile Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 100 10540329PRTArtificialEngineered antibody sequence 403Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Gly Ser1 5 10 15Leu Thr Leu Thr Cys Thr Val Ser Gly Ile Asp Val Thr 20 254045PRTArtificialEngineered antibody sequence 404Asn Tyr Tyr Met Gln1 540514PRTArtificialEngineered antibody sequence 405Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly1 5 1040616PRTArtificialEngineered antibody sequence 406Val Ile Gly Val Asn Gly Lys Arg Tyr Tyr Ala Ser Trp Ala Lys Gly1 5 10 1540731PRTArtificialEngineered antibody sequence 407Arg Phe Thr Ile Ser Lys Thr Ser Ser Thr Thr Val Asp Leu Lys Met1 5 10 15Thr Ser Leu Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg 20 25 304083PRTArtificialEngineered antibody sequence 408Gly Asp Ile140911PRTArtificialEngineered antibody sequence 409Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser1 5 10410330PRTArtificialEngineered antibody sequence 410Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3304111320DNAArtificialEngineered antibody sequence 411cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg gaggatccct gacactcacc 60tgcacagtct ctggaatcga cgtcactaac tactatatgc aatgggtccg ccaggctcca 120gggaaggggc tggaatggat cggagtcatt ggtgtgaatg gtaagagata ctacgcgagc 180tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240accagtctga caaccgagga cacggccacc tatttctgtg ccagaggcga catctggggc 300ccggggaccc tcgtcaccgt ctcgagcgcc tccaccaagg gcccatcggt cttccccctg 360gcaccctcct ccaagagcac ctctgggggc acagcggccc tgggctgcct ggtcaaggac 420tacttccccg aaccggtgac ggtgtcgtgg aactcaggcg ccctgaccag cggcgtgcac 480accttcccgg ctgtcctaca gtcctcagga ctctactccc tcagcagcgt ggtgaccgtg 540ccctccagca gcttgggcac ccagacctac atctgcaacg tgaatcacaa gcccagcaac 600accaaggtgg acaagagagt tgagcccaaa tcttgtgaca aaactcacac atgcccaccg 660tgcccagcac ctgaactcct ggggggaccg tcagtcttcc tcttcccccc aaaacccaag 720gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 780gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 840acaaagccgc gggaggagca gtacgccagc acgtaccgtg tggtcagcgt cctcaccgtc 900ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 960ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 1020tacaccctgc ccccatcccg ggaggagatg accaagaacc aggtcagcct gacctgcctg 1080gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1140aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 1200aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1260catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtaaatga 1320412327DNAArtificialEngineered antibody sequence 412cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg gaggatccct gacactcacc 60tgcacagtct ctggaatcga cgtcactaac tactatatgc aatgggtccg ccaggctcca 120gggaaggggc tggaatggat cggagtcatt ggtgtgaatg gtaagagata ctacgcgagc 180tgggcgaaag gccgattcac catctccaaa acctcgtcga ccacggtgga tctgaaaatg 240accagtctga caaccgagga cacggccacc tatttctgtg ccagaggcga catctggggc 300ccggggaccc tcgtcaccgt ctcgagc 32741387DNAArtificialEngineered antibody sequence 413cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg gaggatccct gacactcacc 60tgcacagtct ctggaatcga cgtcact 8741415DNAArtificialEngineered antibody sequence 414aactactata tgcaa 1541542DNAArtificialEngineered antibody sequence 415tgggtccgcc aggctccagg gaaggggctg gaatggatcg ga 4241648DNAArtificialEngineered antibody sequence 416gtcattggtg tgaatggtaa gagatactac gcgagctggg cgaaaggc 4841793DNAArtificialEngineered antibody sequence 417cgattcacca tctccaaaac ctcgtcgacc acggtggatc tgaaaatgac cagtctgaca 60accgaggaca cggccaccta tttctgtgcc aga 934189DNAArtificialEngineered antibody sequence 418ggcgacatc 941933DNAArtificialEngineered antibody sequence 419tggggcccgg ggaccctcgt caccgtctcg agc 33420993DNAArtificialEngineered antibody sequence 420gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993421219PRTArtificialEngineered antibody sequence 421Gln Val Leu Thr Gln Thr Ala Ser Pro Val Ser Pro Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys Arg Ala Ser Gln Ser Val Tyr Tyr Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys 50 55 60Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val Gln65 70 75 80Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Asn Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215422113PRTArtificialEngineered antibody sequence 422Gln Val Leu Thr Gln Thr Ala Ser Pro Val Ser Pro Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys Arg Ala Ser Gln Ser Val Tyr Tyr Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Ser Ser Arg Phe Lys 50 55 60Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Asp Val Gln65 70 75 80Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Asn Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg42322PRTArtificialEngineered antibody sequence 423Gln Val Leu Thr Gln Thr Ala Ser Pro Val Ser Pro Ala Val Gly Ser1 5 10 15Thr Val Thr Ile Asn Cys 2042413PRTArtificialEngineered antibody sequence 424Arg Ala Ser Gln Ser Val Tyr Tyr Asn Asn Tyr Leu Ala1 5 1042515PRTArtificialEngineered antibody sequence 425Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Gln Leu Ile Tyr1 5 10 154267PRTArtificialEngineered antibody sequence 426Ser Thr Ser Thr Leu Ala Ser1 542732PRTArtificialEngineered antibody sequence 427Gly Val Ser Ser Arg Phe Lys Gly Ser Gly Ser Gly Thr Gln Phe Thr1 5 10 15Leu Thr Ile Ser Asp Val Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys 20 25 3042813PRTArtificialEngineered antibody sequence 428Leu Gly Ser Tyr Asp Cys Ser Asn Gly Asp Cys Phe Val1 5 1042911PRTArtificialEngineered antibody sequence 429Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg1 5 10430106PRTArtificialEngineered antibody sequence 430Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105431660DNAArtificialEngineered antibody sequence 431caggtgctga cccagactgc atcccccgtg tctccagctg tgggaagcac agtcaccatc 60aattgccggg ccagtcagag tgtttattat aacaactacc tagcctggta tcagcagaaa 120ccagggcagc ctcccaagca actgatctat tctacatcca ctctggcatc tggggtctca 180tcgcggttca aaggcagtgg atctgggaca cagttcactc tcaccatcag cgacgtgcag 240tgtgacgatg ctgccactta ctactgtcta ggcagttatg attgtagtaa tggtgattgt 300tttgttttcg gcggagggac cgaggtggtg gtcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660432339DNAArtificialEngineered antibody sequence 432caggtgctga cccagactgc atcccccgtg tctccagctg tgggaagcac agtcaccatc 60aattgccggg ccagtcagag tgtttattat aacaactacc tagcctggta tcagcagaaa 120ccagggcagc ctcccaagca actgatctat tctacatcca ctctggcatc tggggtctca 180tcgcggttca aaggcagtgg atctgggaca cagttcactc tcaccatcag cgacgtgcag

240tgtgacgatg ctgccactta ctactgtcta ggcagttatg attgtagtaa tggtgattgt 300tttgttttcg gcggagggac cgaggtggtg gtcaaacgt 33943366DNAArtificialEngineered antibody sequence 433caggtgctga cccagactgc atcccccgtg tctccagctg tgggaagcac agtcaccatc 60aattgc 6643439DNAArtificialEngineered antibody sequence 434cgggccagtc agagtgttta ttataacaac tacctagcc 3943545DNAArtificialEngineered antibody sequence 435tggtatcagc agaaaccagg gcagcctccc aagcaactga tctat 4543621DNAArtificialEngineered antibody sequence 436tctacatcca ctctggcatc t 2143796DNAArtificialEngineered antibody sequence 437ggggtctcat cgcggttcaa aggcagtgga tctgggacac agttcactct caccatcagc 60gacgtgcagt gtgacgatgc tgccacttac tactgt 9643839DNAArtificialEngineered antibody sequence 438ctaggcagtt atgattgtag taatggtgat tgttttgtt 3943933DNAArtificialEngineered antibody sequence 439ttcggcggag ggaccgaggt ggtggtcaaa cgt 33440321DNAArtificialEngineered antibody sequence 440acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 321441441PRTArtificialEngineered antibody sequence 441Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Val Thr Asn Tyr 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Val Asn Gly Lys Arg Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 115 120 125Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 130 135 140Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly145 150 155 160Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 165 170 175Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 180 185 190Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 195 200 205Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 210 215 220Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys225 230 235 240Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 260 265 270Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys305 310 315 320Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu385 390 395 400Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 405 410 415Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440442111PRTArtificialEngineered antibody sequence 442Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Val Thr Asn Tyr 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Val Asn Gly Lys Arg Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 11044330PRTArtificialEngineered antibody sequence 443Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Val Thr 20 25 304445PRTArtificialEngineered antibody sequence 444Asn Tyr Tyr Met Gln1 544514PRTArtificialEngineered antibody sequence 445Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly1 5 1044616PRTArtificialEngineered antibody sequence 446Val Ile Gly Val Asn Gly Lys Arg Tyr Tyr Ala Ser Trp Ala Lys Gly1 5 10 1544732PRTArtificialEngineered antibody sequence 447Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu Gln1 5 10 15Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg 20 25 304483PRTArtificialEngineered antibody sequence 448Gly Asp Ile144911PRTArtificialEngineered antibody sequence 449Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser1 5 10450330PRTArtificialEngineered antibody sequence 450Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3304511326DNAArtificialEngineered antibody sequence 451gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacgtcact aactactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtgtga atggtaagag atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgccag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600agcaacacca aggtggacaa gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 840gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1140ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320aaatga 1326452333DNAArtificialEngineered antibody sequence 452gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacgtcact aactactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtgtga atggtaagag atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgccag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agc 33345390DNAArtificialEngineered antibody sequence 453gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacgtcact 9045415DNAArtificialEngineered antibody sequence 454aactactaca tgcaa 1545542DNAArtificialEngineered antibody sequence 455tgggtccgtc aggctccagg gaaggggctg gagtgggtcg ga 4245648DNAArtificialEngineered antibody sequence 456gtcattggtg tgaatggtaa gagatactac gcgagctggg cgaaaggc 4845796DNAArtificialEngineered antibody sequence 457cgattcacca tctccagaga caattccaag accacggtgt atcttcaaat gaacagcctg 60agagctgagg acactgctgt gtatttctgt gccaga 964589DNAArtificialEngineered antibody sequence 458ggggacatc 945933DNAArtificialEngineered antibody sequence 459tggggccaag ggaccctcgt caccgtctcg agc 33460993DNAArtificialEngineered antibody sequence 460gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993461219PRTArtificialEngineered antibody sequence 461Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Arg Ala Ser Gln Ser Val Tyr Tyr Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Asn Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215462113PRTArtificialEngineered antibody sequence 462Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Arg Ala Ser Gln Ser Val Tyr Tyr Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Asn Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg46322PRTArtificialEngineered antibody sequence 463Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys 2046413PRTArtificialEngineered antibody sequence 464Arg Ala Ser Gln Ser Val Tyr Tyr Asn Asn Tyr Leu Ala1 5 1046515PRTArtificialEngineered antibody sequence 465Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu Ile Tyr1 5 10 154667PRTArtificialEngineered antibody sequence 466Ser Thr Ser Thr Leu Ala Ser1 546732PRTArtificialEngineered antibody sequence 467Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys 20 25 3046813PRTArtificialEngineered antibody sequence 468Leu Gly Ser Tyr Asp Cys Ser Asn Gly Asp Cys Phe Val1 5 1046911PRTArtificialEngineered antibody sequence 469Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg1 5 10470106PRTArtificialEngineered antibody sequence 470Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5

10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105471660DNAArtificialEngineered antibody sequence 471caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccggg ccagtcagag tgtttactat aacaactacc tagcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtagtaa tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660472339DNAArtificialEngineered antibody sequence 472caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccggg ccagtcagag tgtttactat aacaactacc tagcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtagtaa tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgt 33947366DNAArtificialEngineered antibody sequence 473caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgc 6647439DNAArtificialEngineered antibody sequence 474cgggccagtc agagtgttta ctataacaac tacctagcc 3947545DNAArtificialEngineered antibody sequence 475tggtatcagc agaaaccagg gaaagttcct aagcaactga tctat 4547621DNAArtificialEngineered antibody sequence 476tctacatcca ctctggcatc t 2147796DNAArtificialEngineered antibody sequence 477ggggtcccat ctcgtttcag tggcagtgga tctgggacag atttcactct caccatcagc 60agcctgcagc ctgaagatgt tgcaacttat tactgt 9647839DNAArtificialEngineered antibody sequence 478ctgggcagtt atgattgtag taatggtgat tgttttgtt 3947933DNAArtificialEngineered antibody sequence 479ttcggcggag gaaccaaggt ggaaatcaaa cgt 33480321DNAArtificialEngineered antibody sequence 480acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 321481441PRTArtificialEngineered antibody sequence 481Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly Ser1 5 10 15Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Asp Phe Ser Ser Asn Ala 20 25 30Met Trp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45Cys Ile Tyr Asn Gly Asp Gly Ser Thr Tyr Tyr Ala Ser Trp Val Asn 50 55 60Gly Arg Phe Ser Ile Ser Lys Thr Ser Ser Thr Thr Val Thr Leu Gln65 70 75 80Leu Asn Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg 85 90 95Asp Leu Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 115 120 125Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 130 135 140Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly145 150 155 160Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 165 170 175Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 180 185 190Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 195 200 205Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 210 215 220Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys225 230 235 240Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 260 265 270Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys305 310 315 320Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu385 390 395 400Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 405 410 415Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440482111PRTArtificialEngineered antibody sequence 482Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly Ser1 5 10 15Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Asp Phe Ser Ser Asn Ala 20 25 30Met Trp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly 35 40 45Cys Ile Tyr Asn Gly Asp Gly Ser Thr Tyr Tyr Ala Ser Trp Val Asn 50 55 60Gly Arg Phe Ser Ile Ser Lys Thr Ser Ser Thr Thr Val Thr Leu Gln65 70 75 80Leu Asn Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg 85 90 95Asp Leu Asp Leu Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 100 105 11048329PRTArtificialEngineered antibody sequence 483Gln Ser Val Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Glu Gly Ser1 5 10 15Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Asp Phe Ser 20 254845PRTArtificialEngineered antibody sequence 484Ser Asn Ala Met Trp1 548514PRTArtificialEngineered antibody sequence 485Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly1 5 1048617PRTArtificialEngineered antibody sequence 486Cys Ile Tyr Asn Gly Asp Gly Ser Thr Tyr Tyr Ala Ser Trp Val Asn1 5 10 15Gly48731PRTArtificialEngineered antibody sequence 487Arg Phe Ser Ile Ser Lys Thr Ser Ser Thr Thr Val Thr Leu Gln Leu1 5 10 15Asn Ser Leu Thr Val Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg 20 25 304884PRTArtificialEngineered antibody sequence 488Asp Leu Asp Leu148911PRTArtificialEngineered antibody sequence 489Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser1 5 10490330PRTArtificialEngineered antibody sequence 490Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3304911326DNAArtificialEngineered antibody sequence 491cagtcggtgg aggagtccgg gggaggcctg gtccagcctg agggatccct gacactcacc 60tgcacagcct ctggattcga cttcagtagc aatgcaatgt ggtgggtccg ccaggctcca 120gggaaggggc tggagtggat cggatgcatt tacaatggtg atggcagcac atactacgcg 180agctgggtga atggccgatt ctccatctcc aaaacctcgt cgaccacggt gactctgcaa 240ctgaatagtc tgacagtcgc ggacacggcc acgtattatt gtgcgagaga tcttgacttg 300tggggcccgg gcaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600agcaacacca aggtggacaa gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 840gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1140ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320aaatga 1326492333DNAArtificialEngineered antibody sequence 492cagtcggtgg aggagtccgg gggaggcctg gtccagcctg agggatccct gacactcacc 60tgcacagcct ctggattcga cttcagtagc aatgcaatgt ggtgggtccg ccaggctcca 120gggaaggggc tggagtggat cggatgcatt tacaatggtg atggcagcac atactacgcg 180agctgggtga atggccgatt ctccatctcc aaaacctcgt cgaccacggt gactctgcaa 240ctgaatagtc tgacagtcgc ggacacggcc acgtattatt gtgcgagaga tcttgacttg 300tggggcccgg gcaccctcgt caccgtctcg agc 33349387DNAArtificialEngineered antibody sequence 493cagtcggtgg aggagtccgg gggaggcctg gtccagcctg agggatccct gacactcacc 60tgcacagcct ctggattcga cttcagt 8749415DNAArtificialEngineered antibody sequence 494agcaatgcaa tgtgg 1549542DNAArtificialEngineered antibody sequence 495tgggtccgcc aggctccagg gaaggggctg gagtggatcg ga 4249651DNAArtificialEngineered antibody sequence 496tgcatttaca atggtgatgg cagcacatac tacgcgagct gggtgaatgg c 5149793DNAArtificialEngineered antibody sequence 497cgattctcca tctccaaaac ctcgtcgacc acggtgactc tgcaactgaa tagtctgaca 60gtcgcggaca cggccacgta ttattgtgcg aga 9349812DNAArtificialEngineered antibody sequence 498gatcttgact tg 1249933DNAArtificialEngineered antibody sequence 499tggggcccgg gcaccctcgt caccgtctcg agc 33500993DNAArtificialEngineered antibody sequence 500gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993501219PRTArtificialEngineered antibody sequence 501Ala Ile Val Met Thr Gln Thr Pro Ser Ser Lys Ser Val Pro Val Gly1 5 10 15Asp Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Leu Tyr Asn Asn 20 25 30Asn Ala Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Arg 35 40 45Leu Ile Tyr Asp Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe 50 55 60Ser Gly Gly Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val65 70 75 80Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Gly Gly Tyr Arg Ser Asp 85 90 95Ser Val Asp Gly Val Ala Phe Ala Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215502113PRTArtificialEngineered antibody sequence 502Ala Ile Val Met Thr Gln Thr Pro Ser Ser Lys Ser Val Pro Val Gly1 5 10 15Asp Thr Val Thr Ile Asn Cys Gln Ala Ser Glu Ser Leu Tyr Asn Asn 20 25 30Asn Ala Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Arg

35 40 45Leu Ile Tyr Asp Ala Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe 50 55 60Ser Gly Gly Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val65 70 75 80Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys Gly Gly Tyr Arg Ser Asp 85 90 95Ser Val Asp Gly Val Ala Phe Ala Gly Gly Thr Glu Val Val Val Lys 100 105 110Arg50323PRTArtificialEngineered antibody sequence 503Ala Ile Val Met Thr Gln Thr Pro Ser Ser Lys Ser Val Pro Val Gly1 5 10 15Asp Thr Val Thr Ile Asn Cys 2050413PRTArtificialEngineered antibody sequence 504Gln Ala Ser Glu Ser Leu Tyr Asn Asn Asn Ala Leu Ala1 5 1050515PRTArtificialEngineered antibody sequence 505Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Arg Leu Ile Tyr1 5 10 155067PRTArtificialEngineered antibody sequence 506Asp Ala Ser Lys Leu Ala Ser1 550732PRTArtificialEngineered antibody sequence 507Gly Val Pro Ser Arg Phe Ser Gly Gly Gly Ser Gly Thr Gln Phe Thr1 5 10 15Leu Thr Ile Ser Gly Val Gln Cys Asp Asp Ala Ala Thr Tyr Tyr Cys 20 25 3050812PRTArtificialEngineered antibody sequence 508Gly Gly Tyr Arg Ser Asp Ser Val Asp Gly Val Ala1 5 1050911PRTArtificialEngineered antibody sequence 509Phe Ala Gly Gly Thr Glu Val Val Val Lys Arg1 5 10510106PRTArtificialEngineered antibody sequence 510Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105511660DNAArtificialEngineered antibody sequence 511gccatcgtga tgacccagac tccatcttcc aagtctgtcc ctgtgggaga cacagtcacc 60atcaattgcc aggccagtga gagtctttat aataacaacg ccttggcctg gtttcagcag 120aaaccagggc agcctcccaa gcgcctgatc tatgatgcat ccaaactggc atctggggtc 180ccatcgcggt tcagtggcgg tgggtctggg acacagttca ctctcaccat cagtggcgtg 240cagtgtgacg atgctgccac ttactactgt ggaggctaca gaagtgatag tgttgatggt 300gttgctttcg ccggagggac cgaggtggtg gtcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660512339DNAArtificialEngineered antibody sequence 512gccatcgtga tgacccagac tccatcttcc aagtctgtcc ctgtgggaga cacagtcacc 60atcaattgcc aggccagtga gagtctttat aataacaacg ccttggcctg gtttcagcag 120aaaccagggc agcctcccaa gcgcctgatc tatgatgcat ccaaactggc atctggggtc 180ccatcgcggt tcagtggcgg tgggtctggg acacagttca ctctcaccat cagtggcgtg 240cagtgtgacg atgctgccac ttactactgt ggaggctaca gaagtgatag tgttgatggt 300gttgctttcg ccggagggac cgaggtggtg gtcaaacgt 33951369DNAArtificialEngineered antibody sequence 513gccatcgtga tgacccagac tccatcttcc aagtctgtcc ctgtgggaga cacagtcacc 60atcaattgc 6951439DNAArtificialEngineered antibody sequence 514caggccagtg agagtcttta taataacaac gccttggcc 3951545DNAArtificialEngineered antibody sequence 515tggtttcagc agaaaccagg gcagcctccc aagcgcctga tctat 4551621DNAArtificialEngineered antibody sequence 516gatgcatcca aactggcatc t 2151796DNAArtificialEngineered antibody sequence 517ggggtcccat cgcggttcag tggcggtggg tctgggacac agttcactct caccatcagt 60ggcgtgcagt gtgacgatgc tgccacttac tactgt 9651836DNAArtificialEngineered antibody sequence 518ggaggctaca gaagtgatag tgttgatggt gttgct 3651933DNAArtificialEngineered antibody sequence 519ttcgccggag ggaccgaggt ggtggtcaaa cgt 33520321DNAArtificialEngineered antibody sequence 520acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 321521441PRTArtificialEngineered antibody sequence 521Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Gly Leu Ser Ser Tyr 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ser Asp Gly Lys Thr Tyr Tyr Ala Thr Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Thr 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 115 120 125Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 130 135 140Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly145 150 155 160Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 165 170 175Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 180 185 190Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Ala Arg 195 200 205Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 210 215 220Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys225 230 235 240Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 260 265 270Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys305 310 315 320Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu385 390 395 400Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 405 410 415Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440522111PRTArtificialEngineered antibody sequence 522Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Gly Leu Ser Ser Tyr 20 25 30Tyr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ser Asp Gly Lys Thr Tyr Tyr Ala Thr Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Thr 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 11052330PRTArtificialEngineered antibody sequence 523Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Gly Leu Ser 20 25 305245PRTArtificialEngineered antibody sequence 524Ser Tyr Tyr Met Gln1 552514PRTArtificialEngineered antibody sequence 525Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly1 5 1052616PRTArtificialEngineered antibody sequence 526Val Ile Gly Ser Asp Gly Lys Thr Tyr Tyr Ala Thr Trp Ala Lys Gly1 5 10 1552732PRTArtificialEngineered antibody sequence 527Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu Gln1 5 10 15Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Thr Arg 20 25 305283PRTArtificialEngineered antibody sequence 528Gly Asp Ile152911PRTArtificialEngineered antibody sequence 529Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser1 5 10530330PRTArtificialEngineered antibody sequence 530Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Ala 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 3305311326DNAArtificialEngineered antibody sequence 531gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cggcctcagt agctactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtagtg atggtaagac atactacgcg 180acctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtaccag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600agcaacacca aggtggacgc gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 840gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1140ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320aaatga 1326532333DNAArtificialEngineered antibody sequence 532gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cggcctcagt agctactaca tgcaatgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtagtg atggtaagac atactacgcg 180acctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtaccag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agc 33353390DNAArtificialEngineered antibody sequence 533gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cggcctcagt 9053415DNAArtificialEngineered antibody sequence 534agctactaca tgcaa 1553542DNAArtificialEngineered antibody sequence 535tgggtccgtc aggctccagg gaaggggctg gagtgggtcg ga 4253648DNAArtificialEngineered antibody sequence 536gtcattggta gtgatggtaa gacatactac gcgacctggg cgaaaggc 4853796DNAArtificialEngineered antibody sequence 537cgattcacca tctccagaga caattccaag accacggtgt atcttcaaat gaacagcctg 60agagctgagg acactgctgt gtatttctgt accaga 965389DNAArtificialEngineered antibody sequence 538ggggacatc 953933DNAArtificialEngineered antibody sequence 539tggggccaag ggaccctcgt caccgtctcg agc 33540993DNAArtificialEngineered antibody sequence 540gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240tacatctgca acgtgaatca caagcccagc aacaccaagg tggacgcgag agttgagccc 300aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 540agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960cagaagagcc tctccctgtc tccgggtaaa tga 993541219PRTArtificialEngineered antibody sequence 541Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5

10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Asn Val Tyr Asn Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Arg Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215542113PRTArtificialEngineered antibody sequence 542Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys Gln Ala Ser Gln Asn Val Tyr Asn Asn Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu 35 40 45Ile Tyr Ser Thr Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln65 70 75 80Pro Glu Asp Val Ala Thr Tyr Tyr Cys Leu Gly Ser Tyr Asp Cys Ser 85 90 95Arg Gly Asp Cys Phe Val Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 110Arg54322PRTArtificialEngineered antibody sequence 543Gln Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp1 5 10 15Arg Val Thr Ile Asn Cys 2054413PRTArtificialEngineered antibody sequence 544Gln Ala Ser Gln Asn Val Tyr Asn Asn Asn Tyr Leu Ala1 5 1054515PRTArtificialEngineered antibody sequence 545Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Gln Leu Ile Tyr1 5 10 155467PRTArtificialEngineered antibody sequence 546Ser Thr Ser Thr Leu Ala Ser1 554732PRTArtificialEngineered antibody sequence 547Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr1 5 10 15Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys 20 25 3054813PRTArtificialEngineered antibody sequence 548Leu Gly Ser Tyr Asp Cys Ser Arg Gly Asp Cys Phe Val1 5 1054911PRTArtificialEngineered antibody sequence 549Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg1 5 10550106PRTArtificialEngineered antibody sequence 550Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105551660DNAArtificialEngineered antibody sequence 551caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagaa tgtttacaat aacaactacc tagcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtagtcg tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgta cggtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660552339DNAArtificialEngineered antibody sequence 552caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgccagg ccagtcagaa tgtttacaat aacaactacc tagcctggta tcagcagaaa 120ccagggaaag ttcctaagca actgatctat tctacatcca ctctggcatc tggggtccca 180tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtagtcg tggtgattgt 300tttgttttcg gcggaggaac caaggtggaa atcaaacgt 33955366DNAArtificialEngineered antibody sequence 553caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60aattgc 6655439DNAArtificialEngineered antibody sequence 554caggccagtc agaatgttta caataacaac tacctagcc 3955545DNAArtificialEngineered antibody sequence 555tggtatcagc agaaaccagg gaaagttcct aagcaactga tctat 4555621DNAArtificialEngineered antibody sequence 556tctacatcca ctctggcatc t 2155796DNAArtificialEngineered antibody sequence 557ggggtcccat ctcgtttcag tggcagtgga tctgggacag atttcactct caccatcagc 60agcctgcagc ctgaagatgt tgcaacttat tactgt 9655839DNAArtificialEngineered antibody sequence 558ctgggcagtt atgattgtag tcgtggtgat tgttttgtt 3955933DNAArtificialEngineered antibody sequence 559ttcggcggag gaaccaaggt ggaaatcaaa cgt 33560321DNAArtificialEngineered antibody sequence 560acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga 60actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa agtacagtgg 120aaggtggata acgccctcca atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 180aaggacagca cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 240cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 300ttcaacaggg gagagtgtta g 32156137PRTHomo sapiensMOD_RES(37)..(37)AMIDATION 561Ala Cys Asp Thr Ala Thr Cys Val Thr His Arg Leu Ala Gly Leu Leu1 5 10 15Ser Arg Ser Gly Gly Val Val Lys Asn Asn Phe Val Pro Thr Asn Val 20 25 30Gly Ser Lys Ala Phe 3556237PRTHomo sapiensMOD_RES(37)..(37)AMIDATION 562Ala Cys Asn Thr Ala Thr Cys Val Thr His Arg Leu Ala Gly Leu Leu1 5 10 15Ser Arg Ser Gly Gly Met Val Lys Ser Asn Phe Val Pro Thr Asn Val 20 25 30Gly Ser Lys Ala Phe 35563106PRTHomo sapiens 563Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75 80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105564330PRTArtificialEngineered antibody sequence 564Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330565329PRTArtificialEngineered antibody sequence 565Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly 325566440PRTArtificialEngineered antibody sequence 566Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Ile Asp Leu Ser Gly Tyr 20 25 30Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Val Ile Gly Ile Asn Gly Ala Thr Tyr Tyr Ala Ser Trp Ala Lys 50 55 60Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Thr Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala 85 90 95Arg Gly Asp Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala 100 105 110Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 115 120 125Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 130 135 140Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly145 150 155 160Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 165 170 175Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 180 185 190Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Ala Arg 195 200 205Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 210 215 220Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys225 230 235 240Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 245 250 255Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 260 265 270Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 275 280 285Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 290 295 300Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys305 310 315 320Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 325 330 335Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 340 345 350Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 355 360 365Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 370 375 380Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu385 390 395 400Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 405 410 415Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 420 425 430Lys Ser Leu Ser Leu Ser Pro Gly 435 4405671323DNAArtificialEngineered antibody sequence 567gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60tcctgtgcag tctctggaat cgacctcagt ggctactaca tgaactgggt ccgtcaggct 120ccagggaagg ggctggagtg ggtcggagtc attggtatta atggtgccac atactacgcg 180agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300tggggccaag ggaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600agcaacacca aggtggacgc gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat

840gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1140ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320tga 1323

Claims

[0425] 1. A method for improving most bothersome symptom (MBS) associated with migraine, comprising administering to a patient in need an effective amount of an anti-CGRP antibody; wherein optionally the patient suffers from chronic migraine or episodic migraine.

2-3. (canceled)

4. The method of claim 1, comprising one or more of the following: (i) the patient's most bothersome symptom (MBS) associated with migraine is improved at 1-12 hours post-completion of administration or infusion, such as 1-5 hours post-completion of administration or infusion, 1-2 hours post-completion of administration or infusion, or about 2 hours post-completion of administration or infusion; (ii) the patient's most bothersome symptom (MBS) associated with migraine is improved within 1 month from the first dosing with said anti-CGRP antibody; (iii) the patient's most bothersome symptom (MBS) associated with migraine is improved within 6 months from the first dosing with said anti-CGRP antibody; (iv) the improvement is sustained for at least 3 months from the first dosing with said anti-CGRP antibody; (v) the improvement is sustained for at least 6 months from the first dosing with said anti-CGRP antibody; (vi) the improvement is sustained for at least 3 months from the first dosing with said anti-CGRP antibody; (vii) the improvement is sustained for at least 6 months from the first dosing with said anti-CGRP antibody; (viii) the MBS is selected from the group consisting of: Sensitivity to light (photophobia), Nausea/vomiting, Headache, Sensitivity to sound (phonophobia), Aura, Pain with activity, Pain, Throbbing/pulsation, Cognitive disruption, Fatigue, Mood changes, Sensitivity to smell (osmophobia or olfactophobia), Visual impact, Pressure/tightness, Pain (anatomical), Eye pain, Neck pain, Dizziness, Allodynia, Inactivity, Sensory disturbance, Sleep disturbance and Speech difficulty; or (ix) the MBS is selected from the group consisting of: Sensitivity to light (photophobia), Nausea/vomiting, Headache, Sensitivity to sound (phonophobia), Aura, Pain with activity, Pain, Throbbing/pulsation, Cognitive disruption, Fatigue, Mood changes and Sensitivity to smell (osmophobia or olfactophobia).

5-11. (canceled)

12. A method of improving patient global impression of change (PGIC) associated with migraine, comprising administering to a patient in need an effective amount of an anti-CGRP antibody; wherein optionally the patient suffers from chronic migraine or episodic migraine.

13-14. (canceled)

15. The method of claim 12, comprising one or more of the following: (i) the improvement of patient global impression of change (PGIC) associated with migraine is observed within 1 month from the first dosing with said anti-CGRP antibody; (ii) the improvement of patient global impression of change (PGIC) associated with migraine is observed within 3 months from the first dosing with said anti-CGRP antibody; (iii) the improvement of patient global impression of change (PGIC) associated with migraine is observed within 6 months from the first dosing with said anti-CGRP antibody; (iv) the improvement is sustained for at least 3 months from the first dosing with said anti-CGRP antibody; (v) the improvement is sustained for at least 6 months from the first dosing with said anti-CGRP antibody; (vi) said administration is done by infusion, such as intravenous or subcutaneous infusion; (vii) said administration is done by intravenous infusion; (viii) said patient is headache free 2 hours post-completion of administration or infusion; (ix) said anti-CGRP antibody comprises Ab6; (x) said anti-CGRP antibody comprises the light chain complementarity-determining region (CDR) 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively; (xi) said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively; (xii) said anti-CGRP antibody comprises the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively; (xiii) said anti-CGRP antibody comprises the heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively; (xiv) said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively; (xv) said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively; (xvi) said anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222; (xvii) said anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232; (xviii) said anti-CGRP antibody comprises the variable heavy chain polypeptide of SEQ ID NO: 202; (xix) said anti-CGRP antibody comprises the variable heavy chain polypeptide encoded by SEQ ID NO: 212; (xx) said anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202; (xxi) said anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232 and the variable heavy chain polypeptide encoded by SEQ ID NO: 212; (xxii) said anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221; (xxiii) said anti-CGRP antibody comprises the light chain polypeptide encoded by SEQ ID NO: 231; (xxiv) said anti-CGRP antibody comprises the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566; (xxv) said anti-CGRP antibody comprises the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567; (xxvi) said anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566; (xxvii) said anti-CGRP antibody comprises the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567; (xxviii) the administered amount of said anti-CGRP antibody is between about 100 mg and about 300 mg, or is about 100 mg, or is about 300 mg; (xxix) the administered amount of said anti-CGRP antibody is 100 mg; (xxx) the method further comprises intravenously administering 100 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks; (xxxi) the administered amount of said anti-CGRP antibody is 100 mg; (xxxii) the method further comprising intravenously administering 300 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks; (xxxiii) prior to said administration, the patient exhibits between 1-10 migraine attacks per month in the month or in the 3 months prior to administration; (xxxiv) prior to said administration, the patient exhibits between 2-8 migraine attacks per month in the month or in the 3 months prior to administration; (xxxv) prior to said administration, the patient exhibits between 3-7 migraine attacks per month in the month or in the 3 months prior to administration; (xxxvi) prior to said administration, the patient exhibits less than 25 headache days per month in the month or in the 3 months prior to administration; (xxxvii) prior to said administration, the patient exhibits less than 20 headache days per month in the month or in the 3 months prior to administration; (xxxviii) prior to said administration, the patient exhibits less than 15 headache days per month in the month or in the 3 months prior to administration; (xxxix) prior to said administration, the patient exhibits less than 10 headache days per month in the month or in the 3 months prior to administration; (xl) said patient was diagnosed with migraine at least 10 or at least 15 years prior to said administration; (xli) said patient was diagnosed with migraine at least 18 or at least 19 years prior to said administration; (xlii) said patient has a reduction in the number of migraine days by at least 50% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xliii) said patient has a reduction in the number of migraine days by at least 75% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xliv) said patient has a reduction in the number of migraine days by 100% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xlv) said patient has a reduction in the number of migraine days by at least 50% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xlvi) said patient has a reduction in the number of migraine days by at least 75% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xlvii) said patient has a reduction in the number of migraine days by 100% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xlvii) the method further comprises administering a second dose of said anti-CGRP antibody to said patient about 10-14 weeks, preferably 11-13 weeks, more preferably about 12 weeks or about 3 months after said administration; (xlix) said administration comprises administering about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of said anti-CGRP antibody; (l) said anti-CGRP antibody is aglycosylated or if glycosylated only contains only mannose residues; (li) said anti-CGRP antibody consists of the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566; (lii) said anti-CGRP antibody consists of the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567; (liii) said headache or said migraine is diagnosed according to the third edition of the International Classification of Headache Disorders; (liv) said anti-CGRP antibody is expressed in or obtained by expression in Pichia pastoris; (lv) said anti-CGRP antibody is expressed in or obtained by expression in CHO cells; (lvi) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80, and water; (lvii) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-10% of said values, and having a pH of 5.8 or within +/-10% of said value; (lviii) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-5% of said values, and/or having a pH of 5.8 or within +/-5% of said value; (lix) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-1% of said values, and/or having a pH of 5.8 or within +/-1% of said value; (lx) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-0.5% of said values, and/or having a pH of 5.8 or within +/-0.5% of said value; (lxi) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-0.1% of said values, and/or having a pH of 5.8 or within +/-0.1% of said value; (lxii) said anti-CGRP antibody has a dissociation constant of less than or equal to 10 pM, such as 2-8 pM, such as 3-6 pM, such as less than or equal to about 5 pM, optionally when measured by surface plasmon resonance, which is optionally carried out at 25.degree. C. or 37.degree. C.; or (lxiii) the method improves both MBS and PGIC in said patient.

16-78. (canceled)

79. The method of claim 1, comprising one or more of the following: (i) the improvement is sustained for at least 3 months from the first dosing with said anti-CGRP antibody; (ii) the improvement is sustained for at least 6 months from the first dosing with said anti-CGRP antibody; (iii) said administration is done by infusion, such as intravenous or subcutaneous infusion; (iv) said administration is done by intravenous infusion; (v) said patient is headache free 2 hours post-completion of administration or infusion; (vi) said anti-CGRP antibody comprises Ab6; (vii) said anti-CGRP antibody comprises the light chain complementarity-determining region (CDR) 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively; (viii) said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively; (ix) said anti-CGRP antibody comprises the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively; (x) said anti-CGRP antibody comprises the heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively; (xi) said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively; (xii) said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively; (xiii) said anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222; (xiv) said anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232; (xv) said anti-CGRP antibody comprises the variable heavy chain polypeptide of SEQ ID NO: 202; (xvi) said anti-CGRP antibody comprises the variable heavy chain polypeptide encoded by SEQ ID NO: 212; (xvii) said anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202; (xviii) said anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232 and the variable heavy chain polypeptide encoded by SEQ ID NO: 212; (xix) said anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221; (xx) said anti-CGRP antibody comprises the light chain polypeptide encoded by SEQ ID NO: 231; (xxi) said anti-CGRP antibody comprises the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566; (xxii) said anti-CGRP antibody comprises the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567; (xxiii) said anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566; (xxiv) said anti-CGRP antibody comprises the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567; (xxv) the administered amount of said anti-CGRP antibody is between about 100 mg and about 300 mg, or is about 100 mg, or is about 300 mg; (xxvi) the administered amount of said anti-CGRP antibody is 100 mg; (xvii) the method further comprises intravenously administering 100 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks; (xxviii) the administered amount of said anti-CGRP antibody is 100 mg; (xxix) the method further comprising intravenously administering 300 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks; (xxx) prior to said administration, the patient exhibits between 1-10 migraine attacks per month in the month or in the 3 months prior to administration; (xxxi) prior to said administration, the patient exhibits between 2-8 migraine attacks per month in the month or in the 3 months prior to administration; (xxxii) prior to said administration, the patient exhibits between 3-7 migraine attacks per month in the month or in the 3 months prior to administration; (xxxiii) prior to said administration, the patient exhibits less than 25 headache days per month in the month or in the 3 months prior to administration; (xxxiv) prior to said administration, the patient exhibits less than 20 headache days per month in the month or in the 3 months prior to administration; (xxxv) prior to said administration, the patient exhibits less than 15 headache days per month in the month or in the 3 months prior to administration; (xxxvi) prior to said administration, the patient exhibits less than 10 headache days per month in the month or in the 3 months prior to administration; (xvii) said patient was diagnosed with migraine at least 10 years or at least 15 prior to said administration; (xviii) said patient was diagnosed with migraine at least 18 or at least 19 years prior to said administration; (xxxix) said patient has a reduction in the number of migraine days by at least 50% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xl) said patient has a reduction in the number of migraine days by at least 75% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xli) said patient has a reduction in the number of migraine days by 100% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xlii) said patient has a reduction in the number of migraine days by at least 50% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xliii) said patient has a reduction in the number of migraine days by at least 75% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xliv) said patient has a reduction in the number of migraine days by 100% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xlv) the method further comprises administering a second dose of said anti-CGRP antibody to said patient about 10-14 weeks, preferably 11-13 weeks, more preferably about 12 weeks or about 3 months after said administration; (xlvi) said administration comprises administering about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of said anti-CGRP antibody; (xlvii) said anti-CGRP antibody is aglycosylated or if glycosylated only contains only mannose residues; (xlviii) said anti-CGRP antibody consists of the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566; (xlix) said anti-CGRP antibody consists of the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567; (l) said headache or said migraine is diagnosed according to the third edition of the International Classification of Headache Disorders; (li) said anti-CGRP antibody is expressed in or obtained by expression in Pichia pastoris; (lii) said anti-CGRP antibody is expressed in or obtained by expression in CHO cells; (liii) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80, and water; (liv) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-10% of said values, and having a pH of 5.8 or within +/-10% of said value; (lv) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-5% of said values, and/or having a pH of 5.8 or within +/-5% of said value; (lvi) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-1% of said values, and/or having a pH of 5.8 or within +/-1% of said value; (lvii) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-0.5% of said values, and/or having a pH of 5.8 or within +/-0.5% of said value; (lviii) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-0.1% of said values, and/or having a pH of 5.8 or within +/-0.1% of said value; (lix) said anti-CGRP antibody has a dissociation constant of less than or equal to 10 pM, such as 2-8 pM, such as 3-6 pM, such as less than or equal to about 5 pM, optionally when measured by surface plasmon resonance, which is optionally carried out at 25.degree. C. or 37.degree. C.; or (lx) the method improves both MBS and PGIC in said patient.

80. The method of claim 4, comprising one or more of the following: (i) the improvement is sustained for at least 3 months from the first dosing with said anti-CGRP antibody; (ii) the improvement is sustained for at least 6 months from the first dosing with said anti-CGRP antibody; (iii) said administration is done by infusion, such as intravenous or subcutaneous infusion; (iv) said administration is done by intravenous infusion; (v) said patient is headache free 2 hours post-completion of administration or infusion; (vi) said anti-CGRP antibody comprises Ab6; (vii) said anti-CGRP antibody comprises the light chain complementarity-determining region (CDR) 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively; (viii) said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively; (ix) said anti-CGRP antibody comprises the heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively; (x) said anti-CGRP antibody comprises the heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively; (xi) said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 224; SEQ ID NO: 226; and SEQ ID NO: 228, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences of SEQ ID NO: 204; SEQ ID NO: 206; and SEQ ID NO: 208, respectively; (xii) said anti-CGRP antibody comprises the light chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 234; SEQ ID NO: 236; and SEQ ID NO: 238, respectively and heavy chain CDR 1, 2, and 3 polypeptide sequences encoded by SEQ ID NO: 214; SEQ ID NO: 216; and SEQ ID NO: 218, respectively; (xiii) said anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222; (xiv) said anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232; (xv) said anti-CGRP antibody comprises the variable heavy chain polypeptide of SEQ ID NO: 202; (xvi) said anti-CGRP antibody comprises the variable heavy chain polypeptide encoded by SEQ ID NO: 212; (xvii) said anti-CGRP antibody comprises the variable light chain polypeptide of SEQ ID NO: 222 and the variable heavy chain polypeptide of SEQ ID NO: 202; (xviii) said anti-CGRP antibody comprises the variable light chain polypeptide encoded by SEQ ID NO: 232 and the variable heavy chain polypeptide encoded by SEQ ID NO: 212; (xix) said anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221; (xx) said anti-CGRP antibody comprises the light chain polypeptide encoded by SEQ ID NO: 231; (xxi) said anti-CGRP antibody comprises the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566; (xxii) said anti-CGRP antibody comprises the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567; (xxiii) said anti-CGRP antibody comprises the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566; (xxiv) said anti-CGRP antibody comprises the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567; (xxv) the administered amount of said anti-CGRP antibody is between about 100 mg and about 300 mg, or is about 100 mg, or is about 300 mg; (xxvi) the administered amount of said anti-CGRP antibody is 100 mg; (xvii) the method further comprises intravenously administering 100 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks; (xxviii) the administered amount of said anti-CGRP antibody is 100 mg; (xxix) the method further comprising intravenously administering 300 mg of said anti-CGRP antibody every 10-14 weeks, preferably every 11-13 weeks, more preferably every 12 weeks; (xxx) prior to said administration, the patient exhibits between 1-10 migraine attacks per month in the month or in the 3 months prior to administration; (xxxi) prior to said administration, the patient exhibits between 2-8 migraine attacks per month in the month or in the 3 months prior to administration; (xxxii) prior to said administration, the patient exhibits between 3-7 migraine attacks per month in the month or in the 3 months prior to administration; (xxxiii) prior to said administration, the patient exhibits less than 25 headache days per month in the month or in the 3 months prior to administration; (xxxiv) prior to said administration, the patient exhibits less than 20 headache days per month in the month or in the 3 months prior to administration; (xxxv) prior to said administration, the patient exhibits less than 15 headache days per month in the month or in the 3 months prior to administration; (xxxvi) prior to said administration, the patient exhibits less than 10 headache days per month in the month or in the 3 months prior to administration; (xvii) said patient was diagnosed with migraine at least 10 years or at least 15 prior to said administration; (xviii) said patient was diagnosed with migraine at least 18 or at least 19 years prior to said administration; (xxxix) said patient has a reduction in the number of migraine days by at least 50% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xl) said patient has a reduction in the number of migraine days by at least 75% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xli) said patient has a reduction in the number of migraine days by 100% in the one month period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xlii) said patient has a reduction in the number of migraine days by at least 50% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xliii) said patient has a reduction in the number of migraine days by at least 75% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xliv) said patient has a reduction in the number of migraine days by 100% in the 12 week period after being administered said antibody relative to the baseline number of migraine days experienced by that patient prior to said administration; (xlv) the method further comprises administering a second dose of said anti-CGRP antibody to said patient about 10-14 weeks, preferably 11-13 weeks, more preferably about 12 weeks or about 3 months after said administration; (xlvi) said administration comprises administering about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of said anti-CGRP antibody; (xlvii) said anti-CGRP antibody is aglycosylated or if glycosylated only contains only mannose residues; (xlviii) said anti-CGRP antibody consists of the light chain polypeptide of SEQ ID NO: 221 and the heavy chain polypeptide of SEQ ID NO: 201 or SEQ ID NO: 566; (xlix) said anti-CGRP antibody consists of the light chain polypeptide encoded by SEQ ID NO: 231 and the heavy chain polypeptide encoded by SEQ ID NO: 211 or SEQ ID NO: 567; (l) said headache or said migraine is diagnosed according to the third edition of the International Classification of Headache Disorders; (li) said anti-CGRP antibody is expressed in or obtained by expression in Pichia pastoris; (lii) said anti-CGRP antibody is expressed in or obtained by expression in CHO cells; (liii) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of histidine (L-histidine), sorbitol, polysorbate 80, and water; (liv) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-10% of said values, and having a pH of 5.8 or within +/-10% of said value; (lv) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-5% of said values, and/or having a pH of 5.8 or within +/-5% of said value; (lvi) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-1% of said values, and/or having a pH of 5.8 or within +/-1% of said value; (lvii) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-0.5% of said values, and/or having a pH of 5.8 or within +/-0.5% of said value; (lviii) said anti-CGRP antibody or anti-CGRP antibody fragment is comprised in a formulation comprising or consisting of, per 1 mL volume, 100 mg anti-CGRP antibody, 3.1 mg L-Histidine, 40.5 mg Sorbitol, and 0.15 mg Polysorbate 80, or having amounts of each constituent within +/-0.1% of said values, and/or having a pH of 5.8 or within +/-0.1% of said value; (lix) said anti-CGRP antibody has a dissociation constant of less than or equal to 10 pM, such as 2-8 pM, such as 3-6 pM, such as less than or equal to about 5 pM, optionally when measured by surface plasmon resonance, which is optionally carried out at 25.degree. C. or 37.degree. C.; or (lx) the method improves both MBS and PGIC in said patient.