TLE3 AS A MARKER FOR CHEMOTHERAPY

Abstract

Methods of using TLE3 as a marker for predicting the likelihood that a patient's cancer will respond to chemotherapy. Methods of using TLE3 as a marker for selecting a chemotherapy for a cancer.

Description

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation of U.S. patent application Ser. No. 12/889,630, filed Sep. 24, 2010, which is a continuation of U.S. patent application Ser. No. 12/277,920, filed Nov. 25, 2008, (issued as U.S. Pat. No. 7,816,084), which claims priority to U.S. Provisional Patent Application Ser. No. 60/991,487, filed Nov. 30, 2007, each of which is hereby incorporated herein by reference in its entirety.

SEQUENCE LISTING

[0002] In accordance with 37 C.F.R. §1.52(e)(5), a Sequence Listing in the form of a text file (entitled "Sequence Listing.txt," created on Nov. 5, 2012, and 90 kilobytes) is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0003] A major challenge of cancer treatment is the selection of chemotherapies that maximize efficacy and minimize toxicity for a given patient. Assays for cell surface markers, e.g., using immunohistochemistry (IHC), have provided means for dividing certain cancers into subclasses. For example, one factor considered in prognosis and treatment decisions for breast cancer is the presence or absence of the estrogen receptor (ER). ER-positive breast cancers typically respond much more readily to hormonal therapies such as tamoxifen, which acts as an anti-estrogen in breast tissue, than ER-negative cancers. Though useful, these analyses only in part predict the clinical behavior of breast cancers. There is phenotypic diversity present in cancers that current diagnostic tools fail to detect. As a consequence, there is still much controversy over how to stratify patients amongst potential treatments in order to optimize outcome (e.g., for breast cancer see "NIH Consensus Development Conference Statement: Adjuvant Therapy for Breast Cancer, Nov. 1-3, 2000", J. Nat. Cancer Inst. Monographs, 30:5-15, 2001 and Di Leo et al., Int. J. Clin. Oncol. 7:245-253, 2002). In particular, there is currently no tool for predicting a patient's likely response to treatment with paclitaxel, a chemotherapeutic with particularly adverse side-effects. There clearly exists a need for improved methods and reagents for classifying cancers and thereby selecting therapeutic regimens that maximize efficacy and minimize toxicity for a given patient.

SUMMARY OF THE INVENTION

[0004] We have identified a correlation between the expression of TLE3 (transducin-like enhancer of split 3, Entrez Gene ID 7090) and a cancer's response to chemotherapy. This correlation has been demonstrated using TLE3 antibodies and samples from breast cancer cohorts which include both treated and untreated patients with known outcome. The inventors have also observed that binding of TLE3 antibodies in samples from treated ovarian cancer patients correlates with improved prognosis. In one aspect, the present invention therefore provides methods of using TLE3 as a marker for predicting the likelihood that a patient's cancer will respond to chemotherapy. In another aspect, the present invention provides methods of using TLE3 as a marker for deciding whether to administer chemotherapy to a cancer patient. In yet another aspect, the present invention provides methods of using TLE3 as a marker for selecting a chemotherapy for a cancer patient.

[0005] Expression of TLE3 can be detected using any known method. Thus, while the inventive methods have been exemplified by detecting TLE3 polypeptides using antibodies, in certain embodiments TLE3 polynucleotides may be detected using one or more primers as is well known in the art.

[0006] In general, TLE3 can be used in conjunction with other markers or clinical factors (e.g., stage, tumor size, node characteristics, age, etc.) to further improve the predictive power of the inventive methods.

BRIEF DESCRIPTION OF THE APPENDIX

[0007] This patent application refers to material comprising a table and data presented as Appendix A immediately after the section entitled "Exemplification" and immediately before the section entitled "Other Embodiments." Specifically, Appendix A is a table that lists a variety of markers that could be used in a panel in conjunction with the TLE3 marker in an inventive method. The table includes the antibody ID, parent gene name, Entrez Gene ID, known aliases for the parent gene, peptides that may be used in preparing antibodies and exemplary antibody titers for staining Using the parent gene name, Entrez Gene ID and/or known aliases for the parent gene, a skilled person can readily obtain the nucleotide (and corresponding amino acid) sequences for each and every one of the parent genes that are listed in Appendix A from a public database (e.g., GenBank, Swiss-Prot or any future derivative of these). The nucleotide and corresponding amino acid sequences for each and every one of the parent genes that are listed in Appendix A are hereby incorporated by reference from these public databases. Antibodies with IDs that begin with S5 or S6 may be obtained from commercial sources as indicated.

BRIEF DESCRIPTION OF THE DRAWING

[0008] FIG. 1 compares IHC images of TLE3-negative (S0643-) and TLE3-positive (S0643+) samples from breast cancer patients.

[0009] FIG. 2 shows Kaplan-Meier recurrence curves that were generated using all patients in the Huntsville Hospital (HH) breast cancer cohort after classification based on staining with an antibody raised against the TLE3 marker. Recurrence data from TLE3-positive and TLE3-negative patients were used to generate the top and bottom curves, respectively. As shown in the Figure, antibody binding to the TLE3 marker correlates with improved prognosis across this breast cancer cohort (HR=0.573, p<0.004).

[0010] FIG. 3 shows Kaplan-Meier recurrence curves that were generated using all patients in the Roswell Park Cancer Institute (RP) breast cancer cohort after classification based on staining with an antibody raised against the TLE3 marker. The selected patients in the RP cohort were all triple negative for the ER (estrogen receptor, Entrez GeneID 2099), PR (progesterone receptor, Entrez GeneID 5241) and HER-2 markers (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, Entrez GeneID 2064). Recurrence data from TLE3-positive and TLE3-negative patients were used to generate the top and bottom curves, respectively. As shown in the Figure, antibody binding to the TLE3 marker correlates with improved prognosis across this breast cancer cohort (HR=0.24, p<0.011).

[0011] FIG. 4 shows Kaplan-Meier recurrence curves that were generated using patients in the HH breast cancer cohort of FIG. 1 that did not receive chemotherapy. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, antibody binding to the TLE3 marker loses its correlation with prognosis in breast cancer patients that did not receive chemotherapy (HR=0.788, p=0.49).

[0012] FIG. 5 shows Kaplan-Meier recurrence curves that were generated using patients in the HH breast cancer cohort of FIG. 1 that did receive chemotherapy. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, the correlation between antibody binding to the TLE3 marker and prognosis was restored in patients that did receive chemotherapy (HR=0.539, p<0.013).

[0013] FIG. 6 shows Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort of FIG. 2 that did receive chemotherapy. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, antibody binding to the TLE3 marker correlates with improved prognosis across this subset of breast cancer patients (HR=0.194, p=0.010). These results parallel those obtained in FIG. 5 with the HH cohort.

[0014] FIG. 7 shows Kaplan-Meier recurrence curves that were generated using patients in the HH breast cancer cohort of FIG. 5 that received CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, antibody binding to the TLE3 marker correlates with improved prognosis across this subset of treated patients (HR=0.398, p<0.019).

[0015] FIG. 8 shows Kaplan-Meier recurrence curves that were generated using patients in the HH breast cancer cohort of FIG. 5 that received CA (cyclophosphamide and adriamycin) or CAF (cyclophosphamide, adriamycin and 5-fluorouracil) chemotherapy (with or without a taxane). Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, the correlation between antibody binding to the TLE3 marker and prognosis loses significance in this subset of treated patients (HR=0.666, p=0.22).

[0016] FIG. 9 shows Kaplan-Meier recurrence curves that were generated using patients in the HH breast cancer cohort of FIG. 8 that received CA or CAF chemotherapy only (i.e., without a taxane). Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, there is no correlation between antibody binding to the TLE3 marker and prognosis in this subset of treated patients (HR=1.03, p=0.95).

[0017] FIG. 10 shows Kaplan-Meier recurrence curves that were generated using patients in the HH breast cancer cohort of FIG. 8 that received CA or CAF in combination with a taxane. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, the correlation between antibody binding to the TLE3 marker and prognosis was restored in this subset of treated patients (HR=0.114, p=0.038).

[0018] FIG. 11 shows Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort of FIG. 6 that received CA chemotherapy only (i.e., without a taxane). Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, there is no correlation between antibody binding to the TLE3 marker and prognosis in this subset of treated patients (HR=0.759, p=0.81).

[0019] FIG. 12 shows Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort of FIG. 6 that received CA in combination with a taxane. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, antibody binding to the TLE3 marker correlates with improved prognosis across this subset of treated patients (HR=0.142, p=0.011).

[0020] FIG. 13 shows Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort of FIG. 6 that received a taxane or CMF. Some of the patients receiving a taxane also received CA. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, antibody binding to the TLE3 marker correlates with improved prognosis across this subset of treated patients (HR=0.137, p=0.011).

[0021] FIG. 14 shows Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort of FIG. 6 that received neoadjuvant chemotherapy. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. The sample size was small (N=12); however, as shown in the Figure, antibody binding to the TLE3 marker showed significant correlation with improved prognosis across this subset of treated patients when measured using the Fisher Exact Test (p=0.005).

[0022] FIGS. 15-17 show Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort of FIG. 6 that received chemotherapy. Recurrence data from TLE3-positive and TLE3-negative patients with stage II+ (FIG. 15), stage IIb+ (FIG. 16) and stage III+ (FIG. 17) cancers were used to generate the top and bottom curves, respectively. In each case, antibody binding to the TLE3 marker correlated with improved prognosis across these subsets of treated patients. The sample size was small in the subset of FIG. 17 (N=19); however significance was obtained when measured using the Fisher Exact Test (p=0.020).

[0023] FIG. 18 shows Kaplan-Meier recurrence curves that were generated using patients in the University of Alabama at Birmingham (UAB) ovarian cancer cohort. All patients received paclitaxel. Most patients also received platinum chemotherapy (carboplatin or cisplatin). Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, antibody binding to the TLE3 marker correlated with prognosis in these treated patients (HR=0.64, p<0.049).

DEFINITIONS

[0024] Binds--When an interaction partner "binds" a marker they are linked by direct non-covalent interactions.

[0025] Cancer markers--"Cancer markers" or "markers" are molecular entities that are detectable in cancer samples. Generally, markers may be polypeptides (e.g., TLE3 protein) or polynucleotides (e.g., TLE3 mRNA) that are indicative of the expression of a gene (e.g., TLE3 gene) and present within the cancer sample, e.g., within the cytoplasm or membranes of cancerous cells and/or secreted from such cells.

[0026] Cancer sample--As used herein, the term "cancer sample" or "sample" is taken broadly to include cell or tissue samples removed from a cancer patient (e.g., from a tumor, from the bloodstream, etc.), cells derived from a tumor that may be located elsewhere in the body (e.g., cells in the bloodstream or at a site of metastasis), or any material derived from such a sample. Derived material may include, for example, nucleic acids or proteins extracted from the sample, cell progeny, etc. In one embodiment, a cancer sample may be a tumor sample.

[0027] Correlation--"Correlation" refers to the degree to which one variable can be predicted from another variable, e.g., the degree to which a cancer's response to therapy can be predicted from the expression of a marker in a cancer sample. A variety of statistical methods may be used to measure correlation between two variables, e.g., without limitation the student t-test, the Fisher exact test, the Pearson correlation coefficient, the Spearman correlation coefficient, the Chi squared test, etc. Results are traditionally given as a measured correlation coefficient with a p-value that provides a measure of the likelihood that the correlation arose by chance. A correlation with a p-value that is less than 0.05 is generally considered to be statistically significant. Preferred correlations have p-values that are less than 0.01, especially less than 0.001.

[0028] Hybridized--When a primer and a marker are physically "hybridized" with one another as described herein, they are non-covalently linked by base pair interactions.

[0029] Interaction partner--An "interaction partner" is an entity that binds a polypeptide marker. For example and without limitation, an interaction partner may be an antibody or a fragment thereof that binds a marker. In general, an interaction partner is said to "bind specifically" with a marker if it binds at a detectable level with the marker and does not bind detectably with unrelated molecular entities (e.g., other markers) under similar conditions. Specific association between a marker and an interaction partner will typically be dependent upon the presence of a particular structural feature of the target marker such as an antigenic determinant or epitope recognized by the interaction partner. In general, it is to be understood that specificity need not be absolute. For example, it is well known in the art that antibodies frequently cross-react with other epitopes in addition to the target epitope. Such cross-reactivity may be acceptable depending upon the application for which the interaction partner is to be used. Thus the degree of specificity of an interaction partner will depend on the context in which it is being used. In general, an interaction partner exhibits specificity for a particular marker if it favors binding with that partner above binding with other potential partners, e.g., other markers. One of ordinary skill in the art will be able to select interaction partners having a sufficient degree of specificity to perform appropriately in any given application (e.g., for detection of a target marker, for therapeutic purposes, etc.). It is also to be understood that specificity may be evaluated in the context of additional factors such as the affinity of the interaction partner for the target marker versus the affinity of the interaction partner for other potential partners, e.g., other markers. If an interaction partner exhibits a high affinity for a target marker and low affinity for non-target molecules, the interaction partner will likely be an acceptable reagent for diagnostic purposes even if it lacks specificity.

[0030] Primer--A "primer" is an oligonucleotide entity that physically hybridizes with a polynucleotide marker. In general, a primer is said to "hybridize specifically" with a marker if it hybridizes at a detectable level with the marker and does not hybridize detectably with unrelated molecular entities (e.g., other markers) under similar conditions. Specific hybridization between a marker and a primer will typically be dependent upon the presence of a particular nucleotide sequence of the target marker which is complementary to the nucleotide sequence of the primer. In general, it is to be understood that specificity need not be absolute. The degree of specificity of a primer will depend on the context in which it is being used. In general, a primer exhibits specificity for a particular marker if it favors hybridization with that partner above hybridization with other potential partners, e.g., other markers. One of ordinary skill in the art will be able to select primers having a sufficient degree of specificity to perform appropriately in any given application. It is also to be understood that specificity may be evaluated in the context of additional factors such as the affinity of the primer for the target marker versus the affinity of the primer for other potential partners, e.g., other markers. If a primer exhibits a high affinity for a target marker and low affinity for non-target molecules, the primer will likely be an acceptable reagent for diagnostic purposes even if it lacks specificity.

[0031] Response--The "response" of a cancer to therapy may represent any detectable change, for example at the molecular, cellular, organellar, or organismal level. For instance, tumor size, patient life expectancy, recurrence, or the length of time the patient survives, etc., are all responses. Responses can be measured in any of a variety of ways, including for example non-invasive measuring of tumor size (e.g., CT scan, image-enhanced visualization, etc.), invasive measuring of tumor size (e.g., residual tumor resection, etc.), surrogate marker measurement (e.g., serum PSA, etc.), clinical course variance (e.g., measurement of patient quality of life, time to relapse, survival time, etc.).

[0032] Small molecule--A "small molecule" is a non-polymeric molecule. A small molecule can be synthesized in a laboratory (e.g., by combinatorial synthesis) or found in nature (e.g., a natural product). A small molecule is typically characterized in that it contains several carbon-carbon bonds and has a molecular weight of less than about 1500 Da, although this characterization is not intended to be limiting for the purposes of the present invention.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION

[0033] As noted above, we have identified a correlation between the expression of TLE3 (transducin-like enhancer of split 3, Entrez Gene ID 7090) in a cancer sample and a cancer's response to chemotherapy. As described in the Examples, this correlation has been demonstrated using TLE3 antibodies and samples from two breast cancer cohorts which include both treated and untreated patients with known outcome. We have also shown that this predictive model is consistent when applied to samples from a cohort of treated ovarian cancer patients. We have also demonstrated the utility of TLE3 for predicting response to specific types of chemotherapies including treatments which involve the administration of cell cycle specific chemotherapeutics, e.g., methotrexate and taxanes. Since these chemotherapeutics have known utility across different cancer types, these results suggest that the inventive methods will also be useful in predicting their efficacy across different cancer types.

Predicting Response to Chemotherapy and Selecting Chemotherapy

[0034] In one aspect, the present invention provides methods of using TLE3 as a marker for predicting the likelihood that a patient's cancer will respond to chemotherapy. In general, these methods involve providing a cancer sample from a cancer patient, determining whether TLE3 is expressed in the cancer sample, and predicting the likelihood that the patient's cancer will respond to chemotherapy based upon a result of the step of determining. In one embodiment, the step of predicting comprises predicting that the patient's cancer is likely to respond to chemotherapy based upon the presence of TLE3 expression in the cancer sample. In one embodiment, the step of predicting comprises predicting that the patient's cancer is unlikely to respond to chemotherapy based upon the absence of TLE3 expression in the cancer sample.

[0035] In certain embodiments, a negative control sample is provided and the step of determining comprises detecting a level of TLE3 expression in the cancer sample and the negative control sample and comparing the level of expression of TLE3 in the cancer sample and the negative control sample. In general, the negative control sample can be any sample that does not reproducibly express TLE3. In one embodiment, the negative control sample can be a sample that does not reproducibly bind TLE3 antibodies. In one embodiment, the negative control sample can be a sample that does not reproducibly produce a detectable level of TLE3 mRNA. In one embodiment, the negative control sample can be from a patient with a TLE3-negative cancer. In one embodiment, the negative control sample can be from a patient without cancer. In certain embodiments the negative control sample may originate from the same tissue type as the cancer in question (e.g., breast tissue when considering breast cancer). In other embodiments, the negative control sample may originate from a different tissue type or even a different organism, or a cell line.

[0036] Additionally or alternatively, in certain embodiments, a positive control sample is provided and the step of determining comprises detecting a level of TLE3 expression in the cancer sample and the positive control sample and comparing the level of expression of TLE3 in the cancer sample and the positive control sample. In general, the positive control sample can be any sample that reproducibly expresses TLE3. In one embodiment, the negative control sample can be a sample that reproducibly bind TLE3 antibodies. In one embodiment, the negative control sample can be a sample that reproducibly produces a detectable level of TLE3 mRNA. In one embodiment, the positive control sample can be from a patient with a TLE3-positive cancer. In certain embodiments the positive control sample may originate from the same tissue type as the cancer in question (e.g., breast tissue when considering breast cancer). In other embodiments, the positive control sample may originate from a different tissue type or even a different organism, or cell line.

[0037] Expression of TLE3 can be determined using any known method.

[0038] In one embodiment, TLE3 polypeptides may be detected using an interaction partner that binds a TLE3 polypeptide (e.g., TLE3 protein or an antigenic fragment thereof). For example, as described below one may use a TLE3 antibody as an interaction partner and detect TLE3 expression by contacting the cancer sample with the TLE3 antibody. In such embodiments, the inventive methods may involve providing a cancer sample from a cancer patient, contacting the cancer sample with an antibody directed to TLE3, and predicting the likelihood that the patient's cancer will respond to chemotherapy based upon binding of the antibody to the cancer sample. In one embodiment, the step of predicting may comprise predicting that the patient's cancer is likely to respond to chemotherapy based upon binding of the antibody to the cancer sample. In another embodiment, the step of predicting may comprise predicting that the patient's cancer is unlikely to respond to chemotherapy based upon lack of binding of the antibody to the cancer sample.

[0039] In another embodiment, TLE3 polynucleotides may be detected using one or more primers that hybridize with a TLE3 polynucleotide (e.g., a TLE3 mRNA, cDNA or RNA). In such embodiments, the inventive methods may involve providing a cancer sample from a cancer patient, contacting the cancer sample with one or more primers that hybridize with TLE3, and predicting the likelihood that the patient's cancer will respond to chemotherapy based upon hybridization of the one or more primers to the cancer sample. In one embodiment, the step of predicting may comprise predicting that the patient's cancer is likely to respond to chemotherapy based upon hybridization of the one or more primers to the cancer sample. In another embodiment, the step of predicting may comprise predicting that the patient's cancer is unlikely to respond to chemotherapy based upon lack of hybridization of the one or more primers to the cancer sample.

[0040] In another aspect, the present invention provides methods for deciding whether to administer chemotherapy to the cancer patient based upon the likelihood that the patient's cancer will respond to chemotherapy. In one embodiment, the step of deciding comprises deciding to administer chemotherapy to the cancer patient based upon the presence of TLE3 expression in the cancer sample. In one embodiment, the step of deciding comprises deciding not to administer chemotherapy to the cancer patient based upon the absence of TLE3 expression in the cancer sample.

[0041] In yet another aspect, the present invention provides methods for selecting a chemotherapy for a cancer patient. In general, these methods comprise providing a cancer sample from a cancer patient, determining whether TLE3 is expressed in the cancer sample, and selecting a chemotherapy for the cancer patient based upon the results of the step of determining. In one embodiment, the step of selecting comprises selecting a chemotherapy based upon the presence of TLE3 expression in the cancer sample.

[0042] As described in the Examples, we have demonstrated that TLE3 expression correlates with response to chemotherapy with methotrexate (see FIG. 7) and taxanes (see FIGS. 10, 12 and 13). Methotrexate and taxanes are thought to be cell cycle specific chemotherapeutics (e.g., see Goodman & Gilman's The Pharmacological Basis of Therapeutics, IX. Chemotherapy of Neoplastic Diseases Chapter 51. Antineoplastic Agents, 11 th Edition, Laurence L. Brunton, editor-in-chief, John S. Lazo and Keith L. Parker, Associate Editors). Cell cycle specific chemotherapeutics exhibit their mechanism of action within a specific phase of the cell cycle in contrast to non-cell cycle specific chemotherapeutics that work equally with all phases including the resting phase (GO). Other plant alkaloids besides the taxanes have also been classified in the literature as cell cycle specific chemotherapeutics as have other antimetabolites besides methotrexate. In contrast, many alkylating agents such as cisplatin and cyclophosamide have been classified as non-cell cycle specific chemotherapeutics. Our results suggest that the predictive power of TLE3 may extend to other cell cycle specific chemotherapeutics besides methotrexate and taxanes.

[0043] In some embodiments, the inventive methods may therefore be used to select, or decide whether to administer, a cell cycle specific chemotherapeutic. In one embodiment, the inventive methods may be used to select, or decide whether to administer, an antimetabolite. In one embodiment, the inventive methods may be used to select, or decide whether to administer, a plant alkaloid. In one embodiment, the inventive methods may be used to select, or decide whether to administer, methotrexate. In another embodiment, the inventive methods may be used to select, or decide whether to administer, a taxane. In one embodiment the taxane is paclitaxel. In one embodiment the taxane is docetaxel.

[0044] In each case it will be appreciated that these chemotherapeutics may be administered alone or in combination with other chemotherapeutics as is known in the art and discussed below. It will also be appreciated that the present invention encompasses methods in which the selected chemotherapeutic is a methotrexate or taxane derivative, i.e., a compound with a structure which is derived from methotrexate or a taxane. Derivatives will typically share most of the structure of the parent compound but may include different substituents, heteroatoms, ring fusions, levels of saturation, isomerism, stereoisomerism, etc. at one or more positions within the parent compound. Without limitation, the following U.S. Patents describe the preparation of exemplary methotrexate derivatives that could be employed according to an inventive method: U.S. Pat. Nos. 6,559,149 and 4,374,987. Without limitation, the following U.S. Patents describe the preparation of exemplary taxane derivatives that could be employed according to an inventive method: U.S. Pat. Nos. 7,074,945; 7,063,977; 6,906,101; 6,649,778; 6,596,880; 6,552,205; 6,531,611; 6,482,963; 6,482,850; 6,462,208; 6,455,575; 6,441,026; 6,433,180; 6,392,063; 6,369,244; 6,339,164; 6,291,690; 6,268,381; 6,239,167; 6,218,553; 6,214,863; 6,201,140; 6,191,290; 6,187,916; 6,162,920; 6,147,234; 6,136,808; 6,114,550; 6,107,332; 6,051,600; 6,025,385; 6,011,056; 5,955,489; 5,939,567; 5,912,263; 5,908,835; 5,869,680; 5,861,515; 5,821,263; 5,763,477; 5,750,561; 5,728,687; 5,726,346; 5,726,318; 5,721,268; 5,719,177; 5,714,513; 5,714,512; 5,703,117; 5,698,582; 5,686,623; 5,677,462; 5,646,176; 5,637,723; 5,621,121; 5,616,739; 5,606,083; 5,580,899; 5,476,954; 5,403,858; 5,380,916; 5,254,703; and 5,250,722. The entire contents of each of the aforementioned patents and any other reference which is cited herein is hereby incorporated by reference.

[0045] Methotrexate acts by inhibiting the metabolism of folic acid and has been approved for the treatment of bladder cancer, breast cancer, gastric cancer, choriocarcinoma, head and neck cancer, leptomeningeal cancer, leukemia (acute meningeal, acute lymphoblastic, acute lymphocytic), lymphoma (Burkitt's, childhood, non-Hodgkin's), mycosis fungoides, primary unknown cancer and lymphatic sarcoma (Methotrexate in BC Cancer Agency Cancer Drug Manual, 2007). Methotrexate has also been shown to be useful for treating esophageal cancer, lung cancer and testicular cancer (Methotrexate in UpToDate, 2007). In certain embodiments, the inventive methods comprise a step of selecting, or deciding whether to administer, methotrexate in combination with one or more additional chemotherapeutics. For example, methotrexate is commonly administered to cancer patients as a combination called CMF which also includes cyclophosphamide and 5-fluorouracil.

[0046] Taxanes are diterpenes produced by the plants of the genus Taxus. Taxanes can be obtained from natural sources or produced synthetically. Taxanes include paclitaxel (TAXOL®) and docetaxel (TAXOTERE®). Taxanes work by interfering with normal microtubule growth during cell division. In certain embodiments, the inventive methods comprise a step of selecting, or deciding whether to administer, a taxane (e.g., paclitaxel or docetaxel) in combination with one or more additional chemotherapeutics. For example, taxanes are commonly administered to cancer patients in combination with cyclophosphamide and adriamycin (doxorubicin) and optionally 5-fluorouracil (i.e., with CA or CAF).

[0047] Paclitaxel has been approved for the treatment of breast cancer, Kaposi's sarcoma, lung cancer and ovarian cancer (Paclitaxel in BC Cancer Agency Cancer Drug Manual, 2007 and Mekhail and Markman, Expert Opin. Pharmacother. 3:755-66, 2002). Paclitaxel has also been shown to be useful in treating cervical cancer (pp. 1124-34 in AHFS 2005 Drug Information. Bethesda, Md.: American Society of Health-System Pharmacists, 2005), endometrial cancer (Paclitaxel in BC Cancer Agency Cancer Drug Manual, 2007), bladder cancer (Paclitaxel in UpToDate, 2007), head and neck cancer (Paclitaxel in UpToDate, 2007), leukemia (Paclitaxel in UpToDate, 2007) and malignant melanoma (Paclitaxel in UpToDate, 2007). Side effects of paclitaxel include hypersensitivity reactions such as flushing of the face, skin rash, or shortness of breath. Patients often receive medication to prevent hypersensitivity reactions before they take paclitaxel. Paclitaxel can also cause temporary damage to the bone marrow. Bone marrow damage can cause a person to be more susceptible to infection, anemia, and bruise or bleed easily. Other side effects may include joint or muscle pain in the arms or legs; diarrhea; nausea and vomiting; numbness, burning, or tingling in the hands or feet; and loss of hair.

[0048] Docetaxel has been approved for the treatment of breast cancer (Aapro, Seminars in Oncology 25(5 Suppl 12):7-11, 1998; Nabholtz et al., Journal of Clinical Oncology 17(5):1413-24, 1999; Sjostrom et al., European Journal of Cancer 35(8):1194-201, 1999; and Burstein et al., Journal of Clinical Oncology 18(6):1212-9, 2000), non-small cell lung cancer (Fossella et al., Journal of Clinical Oncology 18(12):2354-62, 2000 and Hainsworth et al., Cancer 89(2):328-33, 2000) and ovarian cancer (Kaye et al., European Journal of Cancer 33(13):2167-70, 1997). Docetaxel has also been shown to be useful in treating esothelioma (Vorobiof et al., Proc Am Soc Clin Oncol 19:578a, 2000), prostate cancer (Picus et al., Seminars in Oncology 26(5 Suppl 17):14-8, 1999 and Petrylak et al., Journal of Clinical Oncology 17(3):958-67, 1999), urothelial transitional cell cancer (Dimopoulos et al., Annals of Oncology 10(11):1385-8, 1999 and Pectasides et al., European Journal of Cancer 36(1):74-9, 2000), head and neck cancer (Docetaxel in USP DI, 2000 and Couteau et al., British Journal of Cancer 81(3):457-62, 1999) and small cell lung cancer (Smyth et al., European Journal of Cancer 30A(8):1058-60, 1994).

[0049] Our observation that improved response to chemotherapy is observed for both breast and ovarian cancer patients that are TLE3-positive suggests that the inventive methods may be useful across different cancer types. Our observation that TLE3 expression is associated with improved response to treatment with methotrexate and taxanes further suggest that the inventive methods may be applicable across cancers that respond to these chemotherapeutics. As discussed above, this includes without limitation breast cancer, ovarian cancer, lung cancer, bladder cancer, gastric cancer, head and neck cancer, and leukemia.

[0050] In one embodiment, the inventive methods may be used with a cancer patient that has breast cancer. In one embodiment, the inventive methods may be used with a cancer patient that has ovarian cancer. In one embodiment, the inventive methods may be used with a cancer patient that has lung cancer. In one embodiment, the inventive methods may be used with a cancer patient that has bladder cancer. In one embodiment, the inventive methods may be used with a cancer patient that has gastric cancer. In one embodiment, the inventive methods may be used with a cancer patient that has head and neck cancer. In one embodiment, the inventive methods may be used with a cancer patient that has leukemia.

[0051] As demonstrated in the Examples, in one embodiment, the correlation between TLE3 expression and response to chemotherapy was observed with breast cancer patients that are triple negative for the ER (estrogen receptor, Entrez GeneID 2099), PR (progesterone receptor, Entrez GeneID 5241) and HER-2 markers (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, Entrez GeneID 2064). In certain embodiments, the inventive methods may therefore be used with breast cancer patients that belong to this class.

[0052] As demonstrated in the Examples, the correlation between TLE3 expression and response to chemotherapy was found to also exist when treatment was administered in a neoadjuvant setting. Thus, in certain embodiments, the inventive methods may be used with patients receiving chemotherapy in a neoadjuvant setting. In other embodiments, the chemotherapy may be administered in an adjuvant setting.

[0053] As demonstrated in the Examples, the correlation between TLE3 expression and response to chemotherapy was also found to be independent of stage. Thus, in certain embodiments, the inventive methods may be used with patients with a stage II+ (i.e., stage II or greater) cancer. In certain embodiments, the inventive methods may be used with patients with a stage IIb+ or a stage III+ cancer.

Detecting TLE3 Expression

[0054] As mentioned above, expression of TLE3 can be determined using any known method. In one embodiment, TLE3 expression may be determined by detecting TLE3 polypeptide markers using interaction partners (e.g., antibodies). In another embodiment, TLE3 expression may be determined by detecting TLE3 polynucleotide markers using primers.

Detecting TLE3 Polypeptide Markers

[0055] TLE3 polypeptide markers may be detected using any interaction partner that binds a TLE3 polypeptide marker (which could be a TLE3 protein or an antigenic fragment thereof). Thus, any entity that binds detectably to the TLE3 marker may be utilized as an interaction partner in accordance with the present invention, so long as it binds the marker with an appropriate combination of affinity and specificity.

[0056] Particularly preferred interaction partners are antibodies, or fragments (e.g., F(ab) fragments, F(ab')₂ fragments, Fv fragments, or sFv fragments, etc.; see, for example, Inbar et al., Proc. Nat. Acad. Sci. USA 69:2659, 1972; Hochman et al., Biochem. 15:2706, 1976; and Ehrlich et al., Biochem. 19:4091, 1980; Huston et al., Proc. Nat. Acad. Sci. USA 85:5879, 1998; U.S. Pat. Nos. 5,091,513 and 5,132,405 to Huston et al.; and U.S. Pat. No. 4,946,778 to Ladner et al., each of which is incorporated herein by reference). In certain embodiments, interaction partners may be selected from libraries of mutant antibodies (or fragments thereof). For example, collections of antibodies that each include different point mutations may be screened for their association with a marker of interest. Yet further, chimeric antibodies may be used as interaction partners, e.g., "humanized" or "veneered" antibodies as described in greater detail below.

[0057] When antibodies are used as interaction partners, these may be prepared by any of a variety of techniques known to those of ordinary skill in the art (e.g., see Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988, see also the Examples). For example, antibodies can be produced by cell culture techniques, including the generation of monoclonal antibodies, or via transfection of antibody genes into suitable bacterial or mammalian cell hosts, in order to allow for the production of recombinant antibodies. In one technique, an "immunogen" comprising an antigenic portion of a marker of interest (or the marker itself) is initially injected into any of a wide variety of mammals (e.g., mice, rats, rabbits, sheep or goats). In this step, a marker (or an antigenic portion thereof) may serve as the immunogen without modification. Alternatively, particularly for relatively short markers, a superior immune response may be elicited if the marker is joined to a carrier protein, such as bovine serum albumin or keyhole limpet hemocyanin (KLH). The immunogen is injected into the animal host, preferably according to a predetermined schedule incorporating one or more booster immunizations and the animals are bled periodically. Polyclonal antibodies specific for the marker may then be purified from such antisera by, for example, affinity chromatography using the marker (or an antigenic portion thereof) coupled to a suitable solid support. An exemplary method is described in the Examples.

[0058] If desired for diagnostic or therapeutic purposes, monoclonal antibodies specific for TLE3 may be prepared, for example, using the technique of Kohler and Milstein, Eur. J. Immunol. 6:511, 1976 and improvements thereto. Briefly, these methods involve the preparation of immortal cell lines capable of producing antibodies having the desired specificity (i.e., reactivity with the marker of interest). Such cell lines may be produced, for example, from spleen cells obtained from an animal immunized as described above. The spleen cells are then immortalized by, for example, fusion with a myeloma cell fusion partner, preferably one that is syngeneic with the immunized animal. A variety of fusion techniques may be employed. For example, the spleen cells and myeloma cells may be combined with a nonionic detergent for a few minutes and then plated at low density on a selective medium that supports the growth of hybrid cells, but not myeloma cells. A preferred selection technique uses HAT (hypoxanthine, aminopterin, thymidine) selection. After a sufficient time, usually about 1 to 2 weeks, colonies of hybrids are observed. Single colonies are selected and their culture supernatants tested for binding activity against the marker. Hybridomas having high reactivity and specificity are preferred.

[0059] Monoclonal antibodies may be isolated from the supernatants of growing hybridoma colonies. In addition, various techniques may be employed to enhance the yield, such as injection of the hybridoma cell line into the peritoneal cavity of a suitable vertebrate host, such as a mouse. Monoclonal antibodies may then be harvested from the ascites fluid or the blood. Contaminants may be removed from the antibodies by conventional techniques, such as chromatography, gel filtration, precipitation and extraction. TLE3 may be used in the purification process in, for example, an affinity chromatography step.

[0060] It is to be understood that the present invention is not limited to using antibodies or antibody fragments as interaction partners. In particular, the present invention also encompasses the use of synthetic interaction partners that mimic the functions of antibodies. Several approaches to designing and/or identifying antibody mimics have been proposed and demonstrated (e.g., see the reviews by Hsieh-Wilson et al., Acc. Chem. Res. 29:164, 2000 and Peczuh and Hamilton, Chem. Rev. 100:2479, 2000). For example, small molecules that bind protein surfaces in a fashion similar to that of natural proteins have been identified by screening synthetic libraries of small molecules or natural product isolates (e.g., see Gallop et al., J. Med. Chem. 37:1233, 1994; Gordon et al., J. Med. Chem. 37:1385, 1994; DeWitt et al., Proc. Natl. Acad. Sci. U.S.A. 90:6909, 1993; Bunin et al., Proc. Natl. Acad. Sci. U.S.A. 91:4708, 1994; Virgilio and Ellman, J. Am. Chem. Soc. 116:11580, 1994; Wang et al., J. Med. Chem. 38:2995, 1995; and Kick and Ellman, J. Med. Chem. 38:1427, 1995). Similarly, combinatorial approaches have been successfully applied to screen libraries of peptides and proteins for their ability to bind a range of proteins (e.g., see Cull et al., Proc. Natl. Acad. Sci. U.S.A. 89:1865, 1992; Mattheakis et al., Proc. Natl. Acad. Sci. U.S.A. 91:9022, 1994; Scott and Smith, Science 249:386, 1990; Devlin et al., Science 249:404, 1990; Corey et al., Gene 128:129, 1993; Bray et al., Tetrahedron Lett. 31:5811, 1990; Fodor et al., Science 251:767, 1991; Houghten et al., Nature 354:84, 1991; Lam et al., Nature 354:82, 1991; Blake and Litzi-Davis, Bioconjugate Chem. 3:510, 1992; Needels et al., Proc. Natl. Acad. Sci. U.S.A. 90:10700, 1993; and Ohlmeyer et al., Proc. Natl. Acad. Sci. U.S.A. 90:10922, 1993). Similar approaches have also been used to study carbohydrate-protein interactions (e.g., see Oldenburg et al., Proc. Natl. Acad. Sci. U.S.A. 89:5393, 1992) and polynucleotide-protein interactions (e.g., see Ellington and Szostak, Nature 346:818, 1990 and Tuerk and Gold, Science 249:505, 1990). These approaches have also been extended to study interactions between proteins and unnatural biopolymers such as oligocarbamates, oligoureas, oligosulfones, etc. (e.g., see Zuckermann et al., J. Am. Chem. Soc. 114:10646, 1992; Simon et al., Proc. Natl. Acad. Sci. U.S.A. 89:9367, 1992; Zuckermann et al., J. Med. Chem. 37:2678, 1994; Burgess et al., Angew. Chem., Int. Ed. Engl. 34:907, 1995; and Cho et al., Science 261:1303, 1993). Yet further, alternative protein scaffolds that are loosely based around the basic fold of antibody molecules have been suggested and may be used in the preparation of inventive interaction partners (e.g., see Ku and Schultz Proc. Natl. Acad. Sci. U.S.A. 92:6552, 1995). Antibody mimics comprising a scaffold of a small molecule such as 3-aminomethylbenzoic acid and a substituent consisting of a single peptide loop have also been constructed. The peptide loop performs the binding function in these mimics (e.g., see Smythe et al., J. Am. Chem. Soc. 116:2725, 1994). A synthetic antibody mimic comprising multiple peptide loops built around a calixarene unit has also been described (e.g., see U.S. Pat. No. 5,770,380 to Hamilton et al.).

[0061] Any available strategy or system may be utilized to detect association between an interaction partner and the TLE3 marker. In certain embodiments, association can be detected by adding a detectable label to the interaction partner. In other embodiments, association can be detected by using a labeled secondary interaction partner that binds specifically with the primary interaction partner, e.g., as is well known in the art of antigen/antibody detection. The detectable label may be directly detectable or indirectly detectable, e.g., through combined action with one or more additional members of a signal producing system. Examples of directly detectable labels include radioactive, paramagnetic, fluorescent, light scattering, absorptive and colorimetric labels. Examples of indirectly detectable include chemiluminescent labels, e.g., enzymes that are capable of converting a substrate to a chromogenic product such as alkaline phosphatase, horseradish peroxidase and the like.

[0062] Once a labeled interaction partner has bound the TLE3 marker, the complex may be visualized or detected in a variety of ways, with the particular manner of detection being chosen based on the particular detectable label, where representative detection means include, e.g., scintillation counting, autoradiography, measurement of paramagnetism, fluorescence measurement, light absorption measurement, measurement of light scattering and the like.

[0063] In general, association between an interaction partner and the TLE3 marker may be assayed by contacting the interaction partner with a cancer sample that includes the marker. Depending upon the nature of the sample, appropriate methods include, but are not limited to, immunohistochemistry (IHC), radioimmunoassay, ELISA, immunoblotting and fluorescence activates cell sorting (FACS). In the case where the protein is to be detected in a tissue sample, e.g., a biopsy sample, IHC is a particularly appropriate detection method. Techniques for obtaining tissue and cell samples and performing IHC and FACS are well known in the art.

[0064] Where large numbers of samples are to be handled (e.g., when simultaneously analyzing several samples from the same patient or samples from different patients), it may be desirable to utilize arrayed and/or automated formats. In certain embodiments, tissue arrays as described in the Examples may be used. Tissue arrays may be constructed according to a variety of techniques. According to one procedure, a commercially-available mechanical device (e.g., the manual tissue arrayer MTA1 from Beecher Instruments of Sun Prairie, Wis.) is used to remove an 0.6-micron-diameter, full thickness "core" from a paraffin block (the donor block) prepared from each patient, and to insert the core into a separate paraffin block (the recipient block) in a designated location on a grid. In preferred embodiments, cores from as many as about 400 patients (or multiple cores from the same patient) can be inserted into a single recipient block; preferably, core-to-core spacing is approximately 1 mm. The resulting tissue array may be processed into thin sections for staining with interaction partners according to standard methods applicable to paraffin embedded material.

[0065] Whatever the format, and whatever the detection strategy, identification of a discriminating titer can simplify binding studies to assess the desirability of using an interaction partner. In such studies, the interaction partner is contacted with a plurality of different samples that preferably have at least one common trait (e.g., tissue of origin), and often have multiple common traits (e.g., tissue of origin, stage, microscopic characteristics, etc.). In some cases, it will be desirable to select a group of samples with at least one common trait and at least one different trait, so that a titer is determined that distinguishes the different trait. In other cases, it will be desirable to select a group of samples with no detectable different traits, so that a titer is determined that distinguishes among previously indistinguishable samples. Those of ordinary skill in the art will understand, however, that the present invention often will allow both of these goals to be accomplished even in studies of sample collections with varying degrees of similarity and difference.

[0066] As discussed above and in the Examples, the inventors have applied these techniques to samples from breast and ovarian cancer patients. The invention also encompasses the recognition that markers that are secreted from the cells in which they are produced may be present in serum, enabling their detection through a blood test rather than requiring a biopsy specimen. An interaction partner that binds to such markers represents a particularly preferred embodiment of the invention.

[0067] In general, the results of such an assay can be presented in any of a variety of formats. The results can be presented in a qualitative fashion. For example, the test report may indicate only whether or not the TLE3 marker was detected, perhaps also with an indication of the limits of detection. Additionally the test report may indicate the subcellular location of binding, e.g., nuclear versus cytoplasmic and/or the relative levels of binding in these different subcellular locations. The results may be presented in a semi-quantitative fashion. For example, various ranges may be defined and the ranges may be assigned a score (e.g., 0 to 5) that provides a certain degree of quantitative information. Such a score may reflect various factors, e.g., the number of cells in which the marker is detected, the intensity of the signal (which may indicate the level of expression of the marker), etc. The results may be presented in a quantitative fashion, e.g., as a percentage of cells in which the marker is detected, as a concentration, etc. As will be appreciated by one of ordinary skill in the art, the type of output provided by a test will vary depending upon the technical limitations of the test and the biological significance associated with detection of the marker. For example, in certain circumstances a purely qualitative output (e.g., whether or not the marker is detected at a certain detection level) provides significant information. In other cases a more quantitative output (e.g., a ratio of the level of expression of the marker in two samples) is necessary.

Detecting TLE3 Polynucleotide Markers

[0068] Although in many cases detection of polypeptide markers using interaction partners such as antibodies may represent the most convenient means of determining whether TLE3 is expressed in a particular sample, the inventive methods also encompass the use of primers for the detection of polynucleotide markers. A variety of methods for detecting the presence of a particular polynucleotide marker are known in the art and may be used in the inventive methods. In general, these methods rely on hybridization between one or more primers and the polynucleotide marker.

[0069] Any available strategy or system may be utilized to detect hybridization between primers and the TLE3 polynucleotides (which could be a TLE3 mRNA, a cDNA produced by RT-PCR from mRNA, RNA produced from such cDNA, etc.). In certain embodiments, hybridization can be detected by simply adding a detectable label to the primer. In other embodiments, hybridization can be detected by using a labeled secondary primer that hybridizes specifically with the primary primer (e.g., a region of the primary primer that does not hybridize with the TLE3 marker). In yet other embodiments it may be advantageous to amplify the TLE3 marker within the cancer sample by PCR using a set of primers designed to amplify a region of the TLE3 gene. The resulting product can then be detected, e.g., using a labeled secondary primer that hybridizes with the amplified product. Those skilled in the art will appreciate variations on these embodiments.

[0070] Considerations for primer design are well known in the art and are described, for example, in Newton, et al. (eds.) PCR: Essential data Series, John Wiley & Sons; PCR Primer: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1995; White, et al. (eds.) PCR Protocols: Current methods and Applications, Methods in Molecular Biology, The Humana Press, Totowa, N.J., 1993. In addition, a variety of computer programs known in the art may be used to select appropriate primers.

[0071] In general, a detectable label may be directly detectable or indirectly detectable, e.g., through combined action with one or more additional members of a signal producing system. Examples of directly detectable labels include radioactive, paramagnetic, fluorescent, light scattering, absorptive and colorimetric labels. Examples of indirectly detectable include chemiluminescent labels, e.g., enzymes that are capable of converting a substrate to a chromogenic product such as alkaline phosphatase, horseradish peroxidase and the like.

[0072] Once a labeled primer has hybridized with the TLE3 marker, the complex may be visualized or detected in a variety of ways, with the particular manner of detection being chosen based on the particular detectable label, where representative detection means include, e.g., scintillation counting, autoradiography, measurement of paramagnetism, fluorescence measurement, light absorption measurement, measurement of light scattering and the like.

[0073] In general, hybridization between a primer and the TLE3 marker may be assayed by contacting the primer with a cancer sample that includes the marker. Depending upon the nature of the cancer sample, appropriate methods include, but are not limited to, microarray analysis, in situ hybridization, Northern blot, and various nucleic acid amplification techniques such as PCR, RT-PCR, quantitative PCR, the ligase chain reaction, etc.

Identification of Novel Therapies

[0074] The predictive power of TLE3 is useful according to the present invention not only to classify cancers with respect to their likely responsiveness to known therapies, but also to identify potential new therapies or therapeutic agents that could be useful in the treatment of cancer.

[0075] Indeed, TLE3 represents an attractive candidate for identification of new therapeutic agents (e.g., via screens to detect compounds or entities that bind or hybridize to the marker, preferably with at least a specified affinity and/or specificity, and/or via screens to detect compounds or entities that modulate (i.e., increase or decrease) expression, localization, modification, or activity of the marker. Thus, in one embodiment the present invention provides methods comprising steps of contacting a test compound with a cell expressing the TLE3 marker (e.g., individual engineered cells or in the context of a tissue, etc.); and determining whether the test compound modulates the expression, localization, modification, or activity of the TLE3 marker. In many instances, interaction partners or primers (e.g., antisense or RNAi primers) themselves may prove to be useful therapeutics.

[0076] Thus the present invention provides interaction partners and primers that are themselves useful therapeutic agents. For example, binding by an antibody raised against TLE3 to cancerous cells might inhibit growth of those cells. Alternatively or additionally, interaction partners defined or prepared according to the present invention could be used to deliver a therapeutic agent to a cancer cell. In particular, interaction partners (e.g., an antibody raised against TLE3) may be coupled to one or more therapeutic agents. Suitable agents in this regard include radionuclides and drugs. Preferred radionuclides include ⁹⁰Y, ¹23I, ¹²⁵I, ¹31I, ¹⁸⁶Re, ¹88Re, ²¹¹At and ²12Bi. Preferred drugs include chlorambucil, ifosphamide, meclorethamine, cyclophosphamide, carboplatin, cisplatin, procarbazine, decarbazine, carmustine, cytarabine, hydroxyurea, mercaptopurine, methotrexate, paclitaxel, docetaxel, thioguanine, 5-fluorouracil, actinomycin D, bleomycin, daunorubicin, doxorubicin, etoposide, vinblastine, vincristine, L-asparginase, adrenocorticosteroids, canciclovir triphosphate, adenine arabinonucleoside triphosphate, 5-aziridinyl-4-hydroxylamino-2-nitrobenzamide, acrolein, phosphoramide mustard, 6-methylpurine, etoposide, benzoic acid mustard, cyanide and nitrogen mustard.

[0077] According to such embodiments, the therapeutic agent may be coupled with an interaction partner by direct or indirect covalent or non-covalent interactions. A direct interaction between a therapeutic agent and an interaction partner is possible when each possesses a substituent capable of reacting with the other. For example, a nucleophilic group, such as an amino or sulfhydryl group, on one may be capable of reacting with a carbonyl-containing group, such as an anhydride or an acid halide, or with an alkyl group containing a good leaving group (e.g., a halide) on the other. Indirect interactions might involve a linker group that is itself non-covalently bound to both the therapeutic agent and the interaction partner. A linker group can function as a spacer to distance an interaction partner from an agent in order to avoid interference with association capabilities. A linker group can also serve to increase the chemical reactivity of a substituent on an agent or an interaction partner and thus increase the coupling efficiency. An increase in chemical reactivity may also facilitate the use of agents, or functional groups on agents, which otherwise would not be possible.

[0078] It will be evident to those skilled in the art that a variety of bifunctional or polyfunctional reagents, both homo- and hetero-functional (such as those described in the catalog of the Pierce Chemical Co., Rockford, Ill.), may be employed as the linker group. Coupling may be effected, for example, through amino groups, carboxyl groups, sulfydryl groups or oxidized carbohydrate residues. There are numerous references describing such methodology, e.g., U.S. Pat. No. 4,671,958, to Rodwell et al. It will further be appreciated that a therapeutic agent and an interaction partner may be coupled via non-covalent interactions, e.g., ligand/receptor type interactions. Any ligand/receptor pair with a sufficient stability and specificity to operate in the context of the invention may be employed to couple a therapeutic agent and an interaction partner. To give but an example, a therapeutic agent may be covalently linked with biotin and an interaction partner with avidin. The strong non-covalent binding of biotin to avidin would then allow for coupling of the therapeutic agent and the interaction partner. Typical ligand/receptor pairs include protein/co-factor and enzyme/substrate pairs. Besides the commonly used biotin/avidin pair, these include without limitation, biotin/streptavidin, digoxigenin/anti-digoxigenin, FK506/FK506-binding protein (FKBP), rapamycin/FKBP, cyclophilin/cyclosporin and glutathione/glutathione transferase pairs. Other suitable ligand/receptor pairs would be recognized by those skilled in the art, e.g., monoclonal antibodies paired with a epitope tag such as, without limitation, glutathione-S-transferase (GST), c-myc, FLAG® and maltose binding protein (MBP) and further those described in Kessler pp. 105-152 of Advances in Mutagenesis" Ed. by Kessler, Springer-Verlag, 1990; "Affinity Chromatography: Methods and Protocols (Methods in Molecular Biology)" Ed. by Pascal Baillon, Humana Press, 2000; and "Immobilized Affinity Ligand Techniques" by Hermanson et al., Academic Press, 1992.

[0079] Where a therapeutic agent is more potent when free from the interaction partner, it may be desirable to use a linker group which is cleavable during or upon internalization into a cell. A number of different cleavable linker groups have been described. The mechanisms for the intracellular release of an agent from these linker groups include cleavage by reduction of a disulfide bond (e.g., U.S. Pat. No. 4,489,710 to Spitler), by irradiation of a photolabile bond (e.g., U.S. Pat. No. 4,625,014 to Senter et al.), by hydrolysis of derivatized amino acid side chains (e.g., U.S. Pat. No. 4,638,045 to Kohn et al.), by serum complement-mediated hydrolysis (e.g., U.S. Pat. No. 4,671,958 to Rodwell et al.) and by acid-catalyzed hydrolysis (e.g., U.S. Pat. No. 4,569,789 to Blattler et al.).

[0080] In certain embodiments, it may be desirable to couple more than one therapeutic agent to an interaction partner. In one embodiment, multiple molecules of an agent are coupled to one interaction partner molecule. In another embodiment, more than one type of therapeutic agent may be coupled to one interaction partner molecule. Regardless of the particular embodiment, preparations with more than one agent may be prepared in a variety of ways. For example, more than one agent may be coupled directly to an interaction partner molecule, or linkers that provide multiple sites for attachment can be used.

[0081] Alternatively, a carrier can be used. A carrier may bear the agents in a variety of ways, including covalent bonding either directly or via a linker group. Suitable carriers include proteins such as albumins (e.g., U.S. Pat. No. 4,507,234 to Kato et al.), peptides, and polysaccharides such as aminodextran (e.g., U.S. Pat. No. 4,699,784 to Shih et al.). A carrier may also bear an agent by non-covalent bonding or by encapsulation, such as within a liposome vesicle (e.g., U.S. Pat. No. 4,429,008 to Martin et al. and 4,873,088 to Mayhew et al.). Carriers specific for radionuclide agents include radiohalogenated small molecules and chelating compounds. For example, U.S. Pat. No. 4,735,792 to Srivastava discloses representative radiohalogenated small molecules and their synthesis. A radionuclide chelate may be formed from chelating compounds that include those containing nitrogen and sulfur atoms as the donor atoms for binding the metal, or metal oxide, radionuclide. For example, U.S. Pat. No. 4,673,562 to Davison et al. discloses representative chelating compounds and their synthesis.

[0082] When interaction partners are themselves therapeutics, it will be understood that, in many cases, any interaction partner that binds the same marker may be so used.

[0083] In one preferred embodiment of the invention, the therapeutic agents (whether interaction partners or otherwise) are antibodies, e.g., an antibody against the TLE3 marker. As is well known in the art, when using an antibody or fragment thereof for therapeutic purposes it may prove advantageous to use a "humanized" or "veneered" version of an antibody of interest to reduce any potential immunogenic reaction. In general, "humanized" or "veneered" antibody molecules and fragments thereof minimize unwanted immunological responses toward antihuman antibody molecules which can limit the duration and effectiveness of therapeutic applications of those moieties in human recipients.

[0084] A number of "humanized" antibody molecules comprising an antigen binding portion derived from a non-human immunoglobulin have been described in the art, including chimeric antibodies having rodent variable regions and their associated complementarity-determining regions (CDRs) fused to human constant domains (e.g., see Winter et al., Nature 349:293, 1991; Lobuglio et al., Proc. Nat. Acad. Sci. USA 86:4220, 1989; Shaw et al., J. Immunol. 138:4534, 1987; and Brown et al., Cancer Res. 47:3577, 1987), rodent CDRs grafted into a human supporting framework region (FR) prior to fusion with an appropriate human antibody constant domain (e.g., see Riechmann et al., Nature 332:323, 1988; Verhoeyen et al., Science 239:1534, 1988; and Jones et al. Nature 321:522, 1986) and rodent CDRs supported by recombinantly veneered rodent FRs (e.g., see European Patent Publication No. 519,596, published Dec. 23, 1992). It is to be understood that the invention also encompasses "fully human" antibodies produced using the XenoMouse® technology (AbGenix Corp., Fremont, Calif.) according to the techniques described in U.S. Pat. No. 6,075,181.

[0085] Yet further, so-called "veneered" antibodies may be used that include "veneered FRs". The process of veneering involves selectively replacing FR residues from, e.g., a murine heavy or light chain variable region, with human FR residues in order to provide a xenogeneic molecule comprising an antigen binding portion which retains substantially all of the native FR protein folding structure. Veneering techniques are based on the understanding that the antigen binding characteristics of an antigen binding portion are determined primarily by the structure and relative disposition of the heavy and light chain CDR sets within the antigen-association surface (e.g., see Davies et al., Ann. Rev. Biochem. 59:439, 1990). Thus, antigen association specificity can be preserved in a humanized antibody only wherein the CDR structures, their interaction with each other and their interaction with the rest of the variable region domains are carefully maintained. By using veneering techniques, exterior (e.g., solvent-accessible) FR residues which are readily encountered by the immune system are selectively replaced with human residues to provide a hybrid molecule that comprises either a weakly immunogenic, or substantially non-immunogenic veneered surface.

[0086] Preferably, interaction partners suitable for use as therapeutics (or therapeutic agent carriers) exhibit high specificity for the target marker (e.g., TLE3) and low background binding to other markers. In certain embodiments, monoclonal antibodies are preferred for therapeutic purposes.

Pharmaceutical Compositions

[0087] As mentioned above, the present invention provides new therapies and methods for identifying these. In certain embodiments, an interaction partner or primer may be a useful therapeutic agent. Alternatively or additionally, interaction partners defined or prepared according to the present invention bind to markers (e.g., TLE3) that serve as targets for therapeutic agents. Also, inventive interaction partners may be used to deliver a therapeutic agent to a cancer cell. For example, interaction partners provided in accordance with the present invention may be coupled to one or more therapeutic agents.

[0088] The invention includes pharmaceutical compositions comprising these inventive therapeutic agents. In general, a pharmaceutical composition will include a therapeutic agent in addition to one or more inactive agents such as a sterile, biocompatible carrier including, but not limited to, sterile water, saline, buffered saline, or dextrose solution. The pharmaceutical compositions may be administered either alone or in combination with other therapeutic agents including other chemotherapeutic agents, hormones, vaccines and/or radiation therapy. By "in combination with", here and elsewhere in the specification, it is not intended to imply that the agents must be administered at the same time or formulated for delivery together, although these methods of delivery are within the scope of the invention. In general, each agent will be administered at a dose and on a time schedule determined for that agent. Additionally, the invention encompasses the delivery of the inventive pharmaceutical compositions in combination with agents that may improve their bioavailability, reduce or modify their metabolism, inhibit their excretion, or modify their distribution within the body. Although the pharmaceutical compositions of the present invention can be used for treatment of any subject (e.g., any animal) in need thereof, they are most preferably used in the treatment of humans.

[0089] The pharmaceutical compositions of this invention can be administered to humans and other animals by a variety of routes including oral, intravenous, intramuscular, intra-arterial, subcutaneous, intraventricular, transdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, or drops), bucal, or as an oral or nasal spray or aerosol. In general the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), the condition of the patient (e.g., whether the patient is able to tolerate oral administration), etc. At present the intravenous route is most commonly used to deliver therapeutic antibodies. However, the invention encompasses the delivery of the inventive pharmaceutical composition by any appropriate route taking into consideration likely advances in the sciences of drug delivery.

[0090] General considerations in the formulation and manufacture of pharmaceutical agents may be found, for example, in Remington's Pharmaceutical Sciences, 19^th ed., Mack Publishing Co., Easton, Pa., 1995.

EXEMPLIFICATION

Example 1

Raising Antibodies

[0091] This example describes a method that was employed to generate the TLE3 antibodies used in these Examples. Similar methods may be used to generate an antibody that binds to any marker of interest (e.g., to proteins that are or are derived from other markers listed in Appendix A). In some cases, antibodies may be obtained from commercial sources (e.g., Chemicon, Dako, Oncogene Research Products, NeoMarkers, etc.) or other publicly available sources (e.g., Imperial Cancer Research Technology, etc.).

Materials and Solutions

[0092] Anisole (Cat. No. A4405, Sigma, St. Louis, Mo.)

[0093] 2,2'-azino-di-(3-ethyl-benzthiazoline-sulfonic acid) (ABTS) (Cat. No. A6499, Molecular Probes, Eugene, Oreg.)

[0094] Activated maleimide Keyhole Limpet Hemocyanin (Cat. No. 77106, Pierce, Rockford, Ill.)

[0095] Keyhole Limpet Hemocyanin (Cat. No. 77600, Pierce, Rockford, Ill.)

[0096] Phosphoric Acid (H₃PO₄) (Cat. No. P6560, Sigma)

[0097] Glacial Acetic Acid (Cat No. BP1185-500, Fisher)

[0098] EDC (EDAC) (Cat No. 341006, Calbiochem)

[0099] 25% Glutaraldehyde (Cat No. G-5882, Sigma)

[0100] Glycine (Cat No. G-8898, Sigma)

[0101] Biotin (Cat. No. B2643, Sigma)

[0102] Boric acid (Cat. No. B0252, Sigma)

[0103] Sepharose 4B (Cat. No. 17-0120-01, LKB/Pharmacia, Uppsala, Sweden)

[0104] Bovine Serum Albumin (LP) (Cat. No. 100 350, Boehringer Mannheim, Indianapolis, Ind.)

[0105] Cyanogen bromide (Cat. No. C6388, Sigma)

[0106] Dialysis tubing Spectra/Por Membrane MWCO: 6-8,000 (Cat. No. 132 665, Spectrum Industries, Laguna Hills, Calif.)

[0107] Dimethyl formamide (DMF) (Cat. No. 22705-6, Aldrich, Milwaukee, Wis.)

[0108] DIC (Cat. No. BP 592-500, Fisher)

[0109] Ethanedithiol (Cat. No. 39,802-0, Aldrich)

[0110] Ether (Cat. No. TX 1275-3, EM Sciences)

[0111] Ethylenediaminetetraacetatic acid (EDTA) (Cat. No. BP 120-1, Fisher, Springfield, N.J.)

[0112] 1-ethyl-3-(3'dimethylaminopropyl)-carbodiimide, HCL (EDC) (Cat. no. 341-006, Calbiochem, San Diego, Calif.)

[0113] Freund's Adjuvant, complete (Cat. No. M-0638-50B, Lee Laboratories, Grayson, Ga.)

[0114] Freund's Adjuvant, incomplete (Cat. No. M-0639-50B, Lee Laboratories)

[0115] Fritted chromatography columns (Column part No. 12131011; Frit Part No. 12131029, Varian Sample Preparation Products, Harbor City, Calif.)

[0116] Gelatin from Bovine Skin (Cat. No. G9382, Sigma)

[0117] Goat anti-rabbit IgG, biotinylated (Cat. No. A 0418, Sigma)

[0118] HOBt (Cat. No. 01-62-0008, Calbiochem)

[0119] Horseradish peroxidase (HRP) (Cat. No. 814 393, Boehringer Mannheim)

[0120] HRP-Streptavidin (Cat. No. S 5512, Sigma)

[0121] Hydrochloric Acid (Cat. No. 71445-500, Fisher)

[0122] Hydrogen Peroxide 30% w/w (Cat. No. H1009, Sigma)

[0123] Methanol (Cat. No. A412-20, Fisher)

[0124] Microtiter plates, 96 well (Cat. No. 2595, Corning-Costar, Pleasanton, Calif.)

[0125] N- -Fmoc protected amino acids from Calbiochem. See '97-'98 Catalog pp. 1-45.

[0126] N- -Fmoc protected amino acids attached to Wang Resin from Calbiochem. See '97-'98 Catalog pp. 161-164.

[0127] NMP (Cat. No. CAS 872-50-4, Burdick and Jackson, Muskegon, Mich.)

[0128] Peptide (Synthesized by Research Genetics. Details given below)

[0129] Piperidine (Cat. No. 80640, Fluka, available through Sigma)

[0130] Sodium Bicarbonate (Cat. No. BP328-1, Fisher)

[0131] Sodium Borate (Cat. No. B9876, Sigma)

[0132] Sodium Carbonate (Cat. No. BP357-1, Fisher)

[0133] Sodium Chloride (Cat. No. BP 358-10, Fisher)

[0134] Sodium Hydroxide (Cat. No. SS 255-1, Fisher)

[0135] Streptavidin (Cat. No. 1 520, Boehringer Mannheim)

[0136] Thioanisole (Cat. No. T-2765, Sigma)

[0137] Trifluoroacetic acid (Cat. No. TX 1275-3, EM Sciences)

[0138] Tween-20 (Cat. No. BP 337-500, Fisher)

[0139] Wetbox (Rectangular Servin' Saver® Part No. 3862, Rubbermaid, Wooster, Ohio)

[0140] BBS--Borate Buffered Saline with EDTA dissolved in distilled water (pH 8.2 to 8.4 with HCl or NaOH), 25 mM Sodium borate (Borax), 100 mM Boric Acid, 75 mM NaCl and 5 mM EDTA.

[0141] 0.1 N HCl in saline as follows: concentrated HCl (8.3 ml/0.917 liter distilled water) and 0.154 M NaCl

[0142] Glycine (pH 2.0 and pH 3.0) dissolved in distilled water and adjusted to the desired pH, 0.1 M glycine and 0.154 M NaCl.

[0143] 5× Borate 1× Sodium Chloride dissolved in distilled water, 0.11 M NaCl, 60 mM Sodium Borate and 250 mM Boric Acid.

[0144] Substrate Buffer in distilled water adjusted to pH 4.0 with sodium hydroxide, 50 to 100 mM Citric Acid.

[0145] AA solution: HOBt is dissolved in NMP (8.8 grams HOBt to 1 liter NMP). Fmoc-N-a-amino at a concentration at 0.53 M.

[0146] DIC solution: 1 part DIC to 3 parts NMP.

[0147] Deprotecting solution: 1 part Piperidine to 3 parts DMF.

[0148] Reagent R: 2 parts anisole, 3 parts ethanedithiol, 5 parts thioanisole and 90 parts trifluoroacetic acid.

Equipment

[0148]

[0149] MRX Plate Reader (Dynatech, Chantilly, Va.)

[0150] Hamilton Eclipse (Hamilton Instruments, Reno, Nev.)

[0151] Beckman TJ-6 Centrifuge (Model No. TJ-6, Beckman Instruments, Fullerton, Calif.)

[0152] Chart Recorder (Recorder 1 Part No. 18-1001-40, Pharmacia LKB Biotechnology)

[0153] UV Monitor (Uvicord SII Part No. 18-1004-50, Pharmacia LKB Biotechnology)

[0154] Amicon Stirred Cell Concentrator (Model 8400, Amicon, Beverly, Mass.)

[0155] 30 kD MW cut-off filter (Cat. No. YM-30 Membranes Cat. No. 13742, Amicon)

[0156] Multi-channel Automated Pipettor (Cat. No. 4880, Corning Costar, Cambridge, Mass.)

[0157] pH Meter Corning 240 (Corning Science Products, Corning Glassworks, Corning, N.Y.)

[0158] ACT396 peptide synthesizer (Advanced ChemTech, Louisville, Ky.)

[0159] Vacuum dryer (Box from Labconco, Kansas City, Mo. and Pump from Alcatel, Laurel, Md.).

[0160] Lyophilizer (Unitop 600 sl in tandem with Freezemobile 12, both from Virtis, Gardiner, N.Y.)

Peptide Selection

[0161] Peptide or peptides against which antibodies would be raised were selected from within the protein sequence of interest using a program that uses the Hopp/Woods method (described in Hopp and Woods, Mol. Immunol. 20:483, 1983 and Hopp and Woods, Proc. Nat. Acad. Sci. U.S.A. 78:3824, 1981). The program uses a scanning window that identifies peptide sequences of 15-20 amino acids containing several putative antigenic epitopes as predicted by low solvent accessibility. This is in contrast to most implementations of the Hopp/Woods method, which identify single short (˜6 amino acids) presumptive antigenic epitopes. Occasionally the predicted solvent accessibility was further assessed by PHD prediction of loop structures (described in Rost and Sander, Proteins 20:216, 1994). Preferred peptide sequences display minimal similarity with additional known human proteins. Similarity was determined by performing BLASTP alignments, using a wordsize of 2 (described in Altschul et al., J. Mol. Biol. 215:403, 1990). All alignments given an EXPECT value less than 1000 were examined and alignments with similarities of greater than 60% or more than four residues in an exact contiguous non-gapped alignment forced those peptides to be rejected. When it was desired to target regions of proteins exposed outside the cell membrane, extracellular regions of the protein of interest were determined from the literature or as defined by predicted transmembrane domains using a hidden Markov model (described in Krogh et al., J. Mol. Biol. 305:567, 2001). When the peptide sequence was in an extracellular domain, peptides were rejected if they contained N-linked glycosylation sites. As shown in Appendix A, for the preparation of TLE3 antibodies a single peptide was used having the amino acid sequence KNHHELDHRERESSAN (SEQ ID NO. 383). Appendix A provides one to three peptide sequences that can be used in preparing antibodies against other markers.

Peptide Synthesis

[0162] The sequence of the desired peptide was provided to the peptide synthesizer. The C-terminal residue was determined and the appropriate Wang Resin was attached to the reaction vessel. The peptide or peptides were synthesized C-terminus to N-terminus by adding one amino acid at a time using a synthesis cycle. Which amino acid is added was controlled by the peptide synthesizer, which looks to the sequence of the peptide that was entered into its database. The synthesis steps were performed as follows:

[0163] Step 1--Resin Swelling: Added 2 ml DMF, incubated 30 minutes, drained DMF.

[0164] Step 2--Synthesis cycle (repeated over the length of the peptide)

[0165] 2a--Deprotection: 1 ml deprotecting solution was added to the reaction vessel and incubated for 20 minutes.

[0166] 2b--Wash Cycle

[0167] 2c--Coupling: 750 ml of amino acid solution (changed as the sequence listed in the peptide synthesizer dictated) and 250 ml of DIC solution were added to the reaction vessel. The reaction vessel was incubated for thirty minutes and washed once. The coupling step was repeated once.

[0168] 2d--Wash Cycle

[0169] Step 3--Final Deprotection: Steps 2a and 2b were performed one last time.

[0170] Resins were deswelled in methanol (rinsed twice in 5 ml methanol, incubated 5 minutes in 5 ml methanol, rinsed in 5 ml methanol) and then vacuum dried.

[0171] Peptide was removed from the resin by incubating 2 hours in reagent R and then precipitated into ether. Peptide was washed in ether and then vacuum dried. Peptide was resolubilized in diH₂O, frozen and lyophilized overnight.

Conjugation of Peptide with Keyhole Limpet Hemocyanin

[0172] Peptide (6 mg) was conjugated with Keyhole Limpet Hemocyanin (KLH). If the selected peptide includes at least one cysteine, three aliquots (2 mg) can be dissolved in PBS (2 ml) and coupled to KLH via glutaraldehyde, EDC or maleimide activated KLH (2 mg) in 2 ml of PBS for a total volume of 4 ml. When the peptide lacks cysteine (as in the TLE3 peptide), two aliquots (3 mg) can be coupled via glutaraldehyde and EDC methods.

[0173] Maleimide coupling can be accomplished by mixing 2 mg of peptide with 2 mg of maleimide-activated KLH dissolved in PBS (4 ml) and incubating 4 hr.

[0174] EDC coupling can be accomplished by mixing 2 mg of peptide, 2 mg unmodified KLH, and 20 mg of EDC in 4 ml PBS (lowered to pH 5 by the addition of phosphoric acid), and incubating for 4 hours. The reaction is then stopped by the slow addition of 1.33 ml acetic acid (pH 4.2). When using EDC to couple 3 mg of peptide, the amounts listed above are increased by a factor of 1.5.

[0175] Glutaraldehyde coupling occurs when 2 mg of peptide are mixed with 2 mg of KLH in 0.9 ml of PBS. 0.9 ml of 0.2% glutaraldehyde in PBS is added and mixed for one hour. 0.46 ml of 1 M glycine in PBS is added and mixed for one hour. When using glutaraldehyde to couple 3 mg of peptide, the above amounts are increased by a factor of 1.5.

[0176] The conjugated aliquots were subsequently repooled, mixed for two hours, dialyzed in 1 liter PBS and lyophilized.

Immunization of Rabbits

[0177] Two New Zealand White Rabbits were injected with 250 μg (total) KLH conjugated peptide in an equal volume of complete Freund's adjuvant and saline in a total volume of 1 ml. 100 μg KLH conjugated peptide in an equal volume of incomplete Freund's Adjuvant and saline were then injected into three to four subcutaneous dorsal sites for a total volume of 1 ml two, six, eight and twelve weeks after the first immunization. The immunization schedule was as follows:

TABLE-US-00001 Day 0 Pre-immune bleed, primary immunization Day 15 1st boost Day 27 1st bleed Day 44 2nd boost Day 57 2nd bleed and 3rd boost Day 69 3rd bleed Day 84 4th boost Day 98 4th bleed

Collection of Rabbit Serum

[0178] The rabbits were bled (30 to 50 ml) from the auricular artery. The blood was allowed to clot at room temperature for 15 minutes and the serum was separated from the clot using an IEC DPR-6000 centrifuge at 5000 g. Cell-free serum was decanted gently into a clean test tube and stored at -20° C. for affinity purification.

Determination of Antibody Titer

[0179] All solutions with the exception of wash solution were added by the Hamilton Eclipse, a liquid handling dispenser. The antibody titer was determined in the rabbits using an ELISA assay with peptide on the solid phase. Flexible high binding ELISA plates were passively coated with peptide diluted in BBS (100 μl, 1 μg/well) and the plate was incubated at 4° C. in a wetbox overnight (air-tight container with moistened cotton balls). The plates were emptied and then washed three times with BBS containing 0.1% Tween-20 (BBS-TW) by repeated filling and emptying using a semi-automated plate washer. The plates were blocked by completely filling each well with BBS-TW containing 1% BSA and 0.1% gelatin (BBS-TW-BG) and incubating for 2 hours at room temperature. The plates were emptied and sera of both pre- and post-immune serum were added to wells. The first well contained sera at 1:50 in BBS. The sera were then serially titrated eleven more times across the plate at a ratio of 1:1 for a final (twelfth) dilution of 1:204,800. The plates were incubated overnight at 4° C. The plates were emptied and washed three times as described.

[0180] Biotinylated goat anti-rabbit IgG (100 μl) was added to each microtiter plate test well and incubated for four hours at room temperature. The plates were emptied and washed three times. Horseradish peroxidase-conjugated Streptavidin (100 μl diluted 1:10,000 in BBS-TW-BG) was added to each well and incubated for two hours at room temperature. The plates were emptied and washed three times. The ABTS was prepared fresh from stock by combining 10 ml of citrate buffer (0.1 M at pH 4.0), 0.2 ml of the stock solution (15 mg/ml in water) and 10 μl of 30% hydrogen peroxide. The ABTS solution (100 μl) was added to each well and incubated at room temperature. The plates were read at 414 nm, 20 minutes following the addition of substrate.

Preparation of Peptide Affinity Purification Column:

[0181] The affinity column was prepared by conjugating 5 mg of peptide to 10 ml of cyanogen bromide-activated Sepharose 4B and 5 mg of peptide to hydrazine-Sepharose 4B. Briefly, 100 μl of DMF was added to peptide (5 mg) and the mixture was vortexed until the contents were completely wetted. Water was then added (900 μl) and the contents were vortexed until the peptide dissolved. Half of the dissolved peptide (500 μl) was added to separate tubes containing 10 ml of cyanogen-bromide activated Sepharose 4B in 0.1 ml of borate buffered saline at pH 8.4 (BBS) and 10 ml of hydrazine-Sepharose 4B in 0.1 M carbonate buffer adjusted to pH 4.5 using excess EDC in citrate buffer pH 6.0. The conjugation reactions were allowed to proceed overnight at room temperature. The conjugated Sepharose was pooled and loaded onto fitted columns, washed with 10 ml of BBS, blocked with 10 ml of 1 M glycine and washed with 10 ml 0.1 M glycine adjusted to pH 2.5 with HCl and re-neutralized in BBS. The column was washed with enough volume for the optical density at 280 nm to reach baseline.

Affinity Purification of Antibodies

[0182] The peptide affinity column was attached to a UV monitor and chart recorder. The titered rabbit antiserum was thawed and pooled. The serum was diluted with one volume of BBS and allowed to flow through the columns at 10 ml per minute. The non-peptide immunoglobulins and other proteins were washed from the column with excess BBS until the optical density at 280 nm reached baseline. The columns were disconnected and the affinity purified column was eluted using a stepwise pH gradient from pH 7.0 to 1.0. The elution was monitored at 280 nm and fractions containing antibody (pH 3.0 to 1.0) were collected directly into excess 0.5 M BBS. Excess buffer (0.5 M BBS) in the collection tubes served to neutralize the antibodies collected in the acidic fractions of the pH gradient.

[0183] The entire procedure was repeated with "depleted" serum to ensure maximal recovery of antibodies. The eluted material was concentrated using a stirred cell apparatus and a membrane with a molecular weight cutoff of 30 kD. The concentration of the final preparation was determined using an optical density reading at 280 nm. The concentration was determined using the following formula: mg/ml=OD₂₈₀/1.4.

[0184] It will be appreciated that in certain embodiments, additional steps may be used to purify antibodies of the invention. In particular, it may prove advantageous to repurify antibodies, e.g., against one of the peptides that was used in generating the antibodies. It is to be understood that the present invention encompasses antibodies that have been prepared with such additional purification or repurification steps. It will also be appreciated that the purification process may affect the binding between samples and the inventive antibodies.

Example 2

Preparing and Staining Tissue Arrays

[0185] This example describes a method that was employed to prepare the tissue arrays that were used in the Examples. This example also describes how the antibody staining was performed.

[0186] Tissue arrays were prepared by inserting full-thickness cores from a large number of paraffin blocks (donor blocks) that contain fragments of tissue derived from many different patients and/or different tissues or fragments of tissues from a single patient, into a virgin paraffin block (recipient block) in a grid pattern at designated locations in a grid. A standard slide of the paraffin embedded tissue (donor block) was then made which contained a thin section of the specimen amenable to H & E staining A trained pathologist, or the equivalent versed in evaluating tumor and normal tissue, designated the region of interest for sampling on the tissue array (e.g., a tumor area as opposed to stroma). A commercially available tissue arrayer from Beecher Instruments was then used to remove a core from the donor block which was then inserted into the recipient block at a designated location. The process was repeated until all donor blocks had been inserted into the recipient block. The recipient block was then thin-sectioned to yield 50-300 slides containing cores from all cases inserted into the block.

[0187] The selected antibodies were then used to perform immunohistochemical staining using the DAKO Envision+, Peroxidase IHC kit (DAKO Corp., Carpenteria, Calif.) with DAB substrate according to the manufacturer's instructions. FIG. 1 shows exemplary IHC staining images of samples that are TLE3-negative (S0643-) and TLE3-positive (S0643+).

Example 3

TLE3 Expression Correlates with Response to Chemotherapy in Cancer Patients

[0188] Tumor samples from two different breast cancer cohorts--Huntsville Hospital (HH) and Roswell Park Cancer Institute (RP)--were stained with the TLE3 antibody of Example 1. Treatment and recurrence data were available for all patients in both cohorts. FIG. 2 shows Kaplan-Meier recurrence curves that were generated using all patients in the HH cohort after classification based on staining with the TLE3 antibody. Recurrence data from TLE3-positive and TLE3-negative patients were used to generate the top and bottom curves, respectively. As shown in the Figure, antibody binding to the TLE3 marker correlates with improved prognosis across this breast cancer cohort (HR=0.573, p=0.004). FIG. 3 shows Kaplan-Meier recurrence curves that were generated in a similar fashion using all patients in the RP cohort. As with the HH cohort, antibody binding to the TLE3 marker was found to correlate with improved prognosis (HR=0.239, p=0.011).

[0189] In order to determine whether TLE3 expression is correlated with response to chemotherapy, separate Kaplan-Meier recurrence curves were generated using HH cohort patients that did or did not receive chemotherapy (FIGS. 4 and 5, respectively). As shown in FIG. 4, antibody binding to the TLE3 marker lost its correlation with prognosis in patients that did not receive chemotherapy (HR=0.788, p=0.490). However, as shown in FIG. 5, the correlation was restored in patients that did receive chemotherapy (HR=0.539, p=0.013). These results demonstrate that TLE3 expression is correlated with improved response to chemotherapy (i.e., TLE3-positive cancers are more likely to respond to chemotherapy than TLE-3 negative cancers). Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort that received chemotherapy are consistent with this prediction model (see FIG. 6, HR=0.194, p=0.010). Kaplan-Meier recurrence curves that were generated using patients in the UAB ovarian cancer cohort that received chemotherapy are also consistent with this prediction model (see FIG. 18, HR=0.64, p=0.049).

Example 4

Specific Chemotherapeutic Correlations

[0190] Since different patients in the HH and RP cohorts received different types of chemotherapy we were also able to determine whether TLE3 expression correlates with response to specific types of chemotherapy.

[0191] FIG. 7 shows Kaplan-Meier recurrence curves that were generated using patients in the HH breast cancer cohort of FIG. 5 that received CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in FIG. 7, antibody binding to the TLE3 marker correlates with improved prognosis across this subset of treated patients (HR=0.398, p=0.019). Based on the results below which demonstrated a loss of correlation for patients in the HH cohort that were treated with CA (cyclophosphamide and adriamycin, HR=1.000) or CAF (cyclophosphamide, adriamycin and 5-fluorouracil, HR=1.000) we were able to establish that the predictive correlation in FIG. 7 is between TLE3 binding and treatment with methotrexate (see also FIG. 9 which combines the CA and CAF treated subsets, HR=1.030).

[0192] FIG. 8 shows Kaplan-Meier recurrence curves that were generated using patients in the HH breast cancer cohort of FIG. 5 that received CA or CAF chemotherapy (with or without a taxane). As shown in the Figure, the correlation between antibody binding to the TLE3 marker and prognosis loses significance in this subset of treated patients (HR=0.666, p=0.22). When the curves were generated using patients that received CA or CAF chemotherapy only (i.e., without a taxane) the significance was further reduced (see FIG. 9, HR=1.030, p=0.95). However, the correlation was restored in patients that received CA or CAF in combination with a taxane (see FIG. 10, HR=0.114, p=0.038). These results demonstrate a correlation between TLE3 binding and treatment with a taxane.

[0193] FIG. 11 shows Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort of FIG. 6 that received CA chemotherapy only (i.e., without a taxane). Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, there is no correlation between antibody binding to the TLE3 marker and prognosis in this subset of treated patients (HR=0.759, p=0.81). The correlation was restored when the curves were generated using patients that received CA chemotherapy in combination with a taxane (see FIG. 12, HR=0.153, p=0.018). These results support the results of FIGS. 8 and 9 that were obtained using samples from the HH cohort.

[0194] FIG. 13 shows Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort of FIG. 6 that received a taxane or CMF. Some of the patients receiving a taxane also received CA. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. As shown in the Figure, antibody binding to the TLE3 marker correlates with improved prognosis across this subset of treated patients (HR=0.137, p=0.011).

[0195] FIG. 14 shows Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort of FIG. 6 that received neoadjuvant chemotherapy. Recurrence data from TLE3-positive and TLE3-negative patients in this subset were used to generate the top and bottom curves, respectively. The sample size was small (N=12); however, as shown in the Figure, antibody binding to the TLE3 marker showed significant correlation with improved prognosis across this subset of treated patients when measured using the Fisher Exact Test (p=0.005). In addition, of the 12 patients receiving neoadjuvant chemotherapy, two received CA (both showed recurrence) while ten received CA with a taxane (seven showed recurrence, three did not). Notably, the three patients that did not show any recurrence were the only patients with TLE3-positive samples. These results are significant since they show that the correlation between TLE3 binding and response to chemotherapy applies irrespective of whether treatment is administered in an adjuvant or neoadjuvant setting.

[0196] FIGS. 15-17 show Kaplan-Meier recurrence curves that were generated using patients in the RP breast cancer cohort of FIG. 6 that received chemotherapy. Recurrence data from TLE3-positive and TLE3-negative patients with stage II+ (FIG. 15), stage IIb+ (FIG. 16) and stage III+ (FIG. 17) cancers were used to generate the top and bottom curves, respectively. In each case, antibody binding to the TLE3 marker correlated with improved prognosis across these subsets of treated patients. The sample size was small in the subset of FIG. 17 (N=19); however significance was obtained when measured using the Fisher Exact Test (p=0.020). These results are of clinical importance since they demonstrate that the predictive power of the TLE3 marker is independent of stage and remains significant even in patients with the worst prognosis (e.g., stage III+ patients).

Example 5

Bivariate Analysis

[0197] In order to confirm that the predictive power of TLE3 is independent of other clinical factors (e.g., age, tumor size, nodes status, necrosis, etc.) we performed bivariate statistical analysis using results from the RP breast cohort. The results are summarized in Table 1 below. As shown in the Table, prediction using TLE3 remained significant in all bivariate analyses demonstrating its independence of other clinical factors.

TABLE-US-00002 TABLE 1 Bivariate Analysis HR for p for Factor 1 Factor 2 N TLE3 TLE3 HR P TLE3 -- 81 0.239 0.0110 -- -- TLE3 Age 81 0.223 0.0082 0.967 0.1200 TLE3 Tumor Size 78 0.219 0.0077 1.292 0.0002 TLE3 Nodes Met Ca¹ 79 0.252 0.0150 1.066 0.0086 TLE3 Necrosis 72 0.232 0.0100 1.903 0.2600 TLE3 Vasc. Lymph Inv.² 74 0.205 0.0071 0.412 0.0790 TLE3 Stage 80 0.284 0.0280 2.063 0.0130 TLE3 Contains Tax³ 70 0.168 0.0061 2.749 0.0980 ¹Nodes found with metastatic cancer. ²Vascular lymphatic invasion. ³Taxane containing regimens.

TABLE-US-00003 APPENDIX A ENTREZ PEPTIDE 1 PEPTIDE 2 PEPTIDE 3 AGI GENE (SEQ ID (SEQ ID (SEQ ID ID GENE NAME ID ALIASES NO.) NO.) NO.) TITER S0011 vav 3 oncogene 10451 VAV3; VAV3 ONCOGENE; TEESINDED EKRTNGL DYISKSKE 1:90- ONCOGENE VAV3; vav 3 oncogene IYKGLPDLI RRTPKQV DVKLK (3) 1:300 DE (1) D (2) S0017 WAP four-disulfide 10406 WFDC2; WAP5; dJ461P17.6; major EKTGVCPE PNDKEGS RDQCQVD 1:25- core domain 2 epididymis-specific protein E4; LQADQNCT CPQVNIN TQCPGQM 1:500 epididymal secretory protein E4; WAP QE (4) (5) K (6) four-disulfide core domain 2; WAP domain containing protein HE4-V4; epididymis-specific, whey-acidic protein type, four-disulfide core; WAP four-disulfide S0018 secretoglobin, family 4250 UGB2; MGB1; SCGB2A2; SKTINPQVS DDNATTN NQTDETL 1:300- 2A, member 2 mammaglobin 1; secretoglobin, family KTEYKELL AIDELKEC SNVEVFM 1:1000 2A, member 2 QE (7) (8) Q (9) S0020 PPAR binding protein 5469 RB18A; TRIP2; PPARGBP; PBP; SSDDGIRPL DGKSKDK NKTKKKK 1:100 CRSP1; PPARBP; CRSP200; PEYSTEKH PPKRKKA SSRLPPEK DRIP230; PPAR-BINDING KK (10) DTE (11) (12) PROTEIN; PPARG binding protein; PPAR binding protein; CRSP, 200-KD SUBUNIT; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-BINDING PROTEIN; THYROID HORMONE RECEPTOR INTERACTOR 2; RECOGN S0021 hypothetical protein 222256 FLJ23834; hypothetical protein KNKEPLTK KLTCTDL EVDYENP 1:200- FLJ23834 FLJ23834 KGETKTAE DSSPRSFR SNLAAGN 1:2500 RD (13) YS (14) KYT (15) S0022 cytochrome P450 4Z1 199974 CYP4Z1; cytochrome P450 4Z1; KTLQVFNP QHFAIIEC RKFLAPD 1:50- cytochrome P450, family 4, subfamily LRFSRENSE KVAVALT HSRPPQPV 1:500 Z, polypeptide 1 KIH (16) (17) RQ (18) S0024 RAS-like, estrogen- 85004 RERG; RAS-like, estrogen-regulated, MAKSAEV VLPLKNIL YELCREV 1:900- regulated, growth- growth-inhibitor KLAIFGRA DEIKKPK RRRRMVQ 1:2700 inhibitor GVGK (19) N (20) GKT (21) S0032 fatty acid binding 2170 MDGI; O-FABP; FABP3; FABP11; TKPTTIIEK KNTEISFK HLQKWD 1:225 protein 3, muscle and H-FABP; FATTY ACID-BINDING NGDILTLK LGVEFDE GQETTLV heart (mammary- PROTEIN, SKELETAL MUSCLE; TH (22) (23) RE (24) derived growth Fatty acid-binding protein 3, muscle; inhibitor) fatty acid binding protein 11; FATTY ACID-BINDING PROTEIN, MUSCLE AND HEART; fatty acid binding protein 3, muscle and heart (mammary-de S0036 gamma-aminobutyric 2568 GABRP; GAMMA- DGNDVEFT LQQMAA KRKISFAS 1:250- acid (GABA) A AMINOBUTYRIC ACID WLRGNDS KDRGTTK IEISSDNV 1:500 receptor, pi RECEPTOR, PI; GABA-A VRGLEH EVEEVS DYSD (27) RECEPTOR, PI POLYPEPTIDE; (25) (26) gamma-aminobutyric acid (GABA) A receptor, pi S0037 annexin A8 244 ANX8; ANXA8; annexin VIII; QRQQIAKS REIMKAY EEYEKIAN 1:30- annexin A8 FKAQFGKD EEDYGSS KSIEDSIK 1:40 LTE (28) LEEDIQ SE (30) (29) S0039 CDNA FLJ25076 fis, 134111 similar to 3110006E14Rik protein; EGGSLVPA RKAGKSK KTHEKYG 1:50- clone CBL06117 CDNA FLJ25076 fis, clone CBL06117 ARQQHCTQ KSFSRKE WVTPPVS 1:30000 VRSRR (31) AE (32) DG (33) S0040 ATP-binding cassette, 5243 P-gp; PGY1; CLCS; ABCB1; ABC20; MDLEGDR NLEDLMS RGSQAQD 1:200- sub-family B CD243; GP170; MDR1; doxorubicin NGGAKKK NITNRSDI RKLSTKE 1:400 (MDR/TAP), member resistance; colchicin sensitivity; P- N (34) NDTG (35) A (36) 1 GLYCOPROTEIN 1; multidrug resistance 1; P glycoprotein 1; ATP- binding cassette sub-family B member 1; ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 1; ATP- bin S0041 ATP-binding cassette, 5244 MDR3; PGY3; PFIC-3; ABCB4; MDLEAAK NFSFPVNF KNSQMCQ 1:60- sub-family B ABC21; MDR2/3; P- NGTAWRPT SLSLLNPG KSLDVET 1:300 (MDR/TAP), member GLYCOPROTEIN 3; MULTIDRUG SAE (37) K (38) DG (39) 4 RESISTANCE 3; P-glycoprotein- 3/multiple drug resistance-3; P glycoprotein 3/multiple drug resistance 3; ATP-binding cassette, sub-family B (MDR/TAP), member 4; ATP-binding cassette, sub S0042 ATP-binding cassette, 4363 ABCC1; MRP1; GS-X; ABC29; MALRGFCS KNWKKE DSIERRPV 1:40- sub-family C multidrug resistance protein; ADGSD (40) CAKTRKQ KDGGGTN 1:500 (CFTR/MRP), MULTIDRUG RESISTANCE- PVK (41) S (42) member 1 ASSOCIATED PROTEIN 1; multiple drug resistance-associated protein; multiple drug resistance protein 1; ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 1; ATP- binding cassette, sub-fami S0043 ATP-binding cassette, 1244 MRP2; cMRP; CMOAT; ABCC2; MLEKFCNS SILCGTFQ ENNESSN 1:50- sub-family C ABC30; DJS; MULTIDRUG TFWNSSFL FQTLIRT NPSSIAS 1:333 (CFTR/MRP), RESISTANCE-ASSOCIATED DSPE (43) (44) (45) member 2 PROTEIN 2; canalicular multispecific organic anion transporter; MULTISPECIFIC ORGANIC ANION TRANSPORTER, CANALICULAR; ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 2; ATP- binding cassette, S0044 ATP-binding cassette, 10257 MOAT-B; MRP4; MOATB; ABCC4; QEVKPNPL DEISQRNR VQDFTAF 1:20- sub-family C EST170205; MULTIDRUG QDANICSR QLPSDGK WDKASET 1:100 (CFTR/MRP), RESISTANCE-ASSOCIATED (46) K (47) PTLQ (48) member 4 PROTEIN 4; MULTISPECIFIC ORGANIC ANION TRANSPORTER B; ATP-binding cassette, sub-family C, member 4; ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 4; ATP-binding cassette, sub-family C (CFT S0045 ATP-binding cassette, 8714 MOAT-D; ABC31; MLP2; ABCC3; MDALCGSG RKQEKQT DPQSVER 1:2000 sub-family C EST90757; cMOAT2; MULTIDRUG ELGSKFWD ARHKASA KTISPG (CFTR/MRP), RESISTANCE-ASSOCIATED SN (49) A (50) (51) member 3 PROTEIN 3; canicular multispecific organic anion transporter; CANALICULAR MULTISPECIFIC ORGANIC ANION TRANSPORTER 2; ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 3; ATP- binding cas S0046 ATP-binding cassette, 10057 MOAT-C; ABCC5; MRP5; MKDIDIGK RDREDSK SKHESSD 1:100- sub-family C EST277145; ABC33; SMRP; EYIIPSPGY FRRTRPLE VNCRRLE 1:450 (CFTR/MRP), pABC11; MOATC; MULTIDRUG RS (52) CQD (53) R (54) member 5 RESISTANCE-ASSOCIATED PROTEIN 5; canalicular multispecific organic anion transporter C; ATP- binding cassette, sub-family C, member 5; ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 5; ATP-bi S0047 ATP-binding cassette, 368 MRP6; ARA; EST349056; ABCC6; MAAPAEPC DPGVVDS HTLVAEN 1:50 sub-family C MOATE; PXE; MLP1; ABC34; AGQGVWN SSSGSAA AMNAEK (CFTR/MRP), ANTHRACYCLINE RESISTANCE- QTEPE (55) GKD (56) (57) member 6 ASSOCIATED PROTEIN; MULTIDRUG RESISTANCE- ASSOCIATED PROTEIN 6; ATP- binding cassette, sub-family C, member 6; ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 6; ATP-binding cassette, S0048 ATP-binding cassette, 8647 BSEP; ABCB11; PFIC-2; SPGP; MSDSVILRS TNSSLNQ QEVLSKIQ 1:600 sub-family B PGY4; PFIC2; ABC16; SISTER OF P- IKKFGEEN NMTNGTR HGHTIIS (MDR/TAP), member GLYCOPROTEIN; bile salt export D (58) (59) (60) 11 pump; progressive familial intrahepatic cholestasis 2; ABC member 16, MDR/TAP subfamily; ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 11; ATP-binding cassette, sub-fam S0049 ATP-binding cassette, 23456 MTABC2; EST20237; MABC2; M- GADDPSSV NAVASPE KPNGIYR 1:10- sub-family B ABC2; ABCB10; MITOCHONDRIAL TAEEIQR FPPRFNT KLMNKQS 1:25 (MDR/TAP), member ABC PROTEIN 2; ATP-BINDING (61) (62) FISA (63) 10 CASSETTE, SUBFAMILY B, MEMBER 10; ATP-binding cassette, sub-family B, member 10; ATP- binding cassette, sub-family B (MDR/TAP), member 10 S0050 transporter 1, ATP- 6890 RING4; ABC17; D6S114E; ABCB2; MASSRCPA QGGSGNP EFVGDGI 1:80 binding cassette, sub- TAP1; APT1; PEPTIDE PRGCR (64) VRR (65) YNNTMG family B (MDR/TAP) TRANSPORTER PSF1; HVHS (66) TRANSPORTER, ABC, MHC, 1; ABC transporter, MHC 1; antigen peptide transporter 1; peptide supply factor 1; ABC TRANSPORTER, MHC, 1; ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 2; TRANSPORTER S0052 ATP-binding cassette, 6833 SUR1; MRP8; PHHI; ABC36; MPLAFCGS DHLGKEN EIREEQCA 1:25- sub-family C ABCC8; HRINS; sulfonylurea ENHSAAYR DVFQPKT PHEPTPQG 1:150 (CFTR/MRP), receptor (hyperinsulinemia); (67) QFLG (68) (69) member 8 SULFONYLUREA RECEPTOR, BETA-CELL HIGH-AFFINITY; ATP-binding cassette, sub-family C, member 8; ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 8; ATP-binding cassette, sub-family C S0053 ATP-binding cassette, 10060 ABCC9; ABC37; sulfonylurea MSLSFCGN QRVNETQ DEIGDDS 1:25- sub-family C receptor 2A; ATP-BINDING NISS (70) NGTNNTT WRTGESS 1:50 (CFTR/MRP), CASSETTE, SUBFAMILY C, GISE (71) LPFE (72) member 9 MEMBER 9; ATP-binding cassette, sub-family C (CFTR/MRP), member 9; ATP-binding cassette, sub-family C, member 9 isoform SUR2B; ATP- binding cassette, sub-family C, member 9 isoform S0055 integral membrane 9445 E25B; ABRI; E3-16; FBD; BRI2; MVKVTFNS QTIEENIKI HDKETYK 1:450- protein 2B BRICD2B; ITM2B; BRI GENE; ALAQKEAK FEEEEVE LQRRETIK 1:500 BRICHOS domain containing 2B; KDEPK (73) (74) GIQKRE integral membrane protein 2B (75) S0057 ankyrin 3, node of 288 ankyrin-G; ANK3; ankyrin-3, node of MAHAASQ HKKETES EGFKVKT 1:750 Ranvier (ankyrin G) Ranvier; ankyrin 3 isoform 1; ankyrin LKKNRDLE DQDDEIE KKEIRHV

3 isoform 2; ankyrin 3, node of INAEE (76) KTDRRQ EKKSHS Ranvier (ankyrin G) (77) (78) S0058 hypothetical protein 80004 FLJ21918; hypothetical protein ERALAAAQ TAGMKDL DPPRTVL 1:20 FLJ21918 FLJ21918 RCHKKVM LSVFQAY QAPKEWV KER (79) Q (80) CL (81) S0059 tripartite motif- 23650 ATDC; TRIM29; tripartite motif- MEAADASR ELHLKPH EGEGLGQ 1:50- containing 29 containing 29; ataxia-telangiectasia SNGSSPEA LEGAAFR SLGNFKD 1:3000 group D-associated protein; tripartite RDAR (82) DHQ (83) DLLN (84) motif protein TRIM29 isoform alpha; tripartite motif protein TRIM29 isoform beta S0059 tripartite motif- 23650 ATDC; TRIM29; tripartite motif- ELHLKPHL N/A N/A 1:30- P2 containing 29 containing 29; ataxia-telangiectasia EGAAFRDH 1:90 group D-associated protein; tripartite Q (85) motif protein TRIM29 isoform alpha; tripartite motif protein TRIM29 isoform beta S0063 iroquois homeobox 79191 IRX3; iroquois homeobox protein 3 GSEERGAG KIWSLAE KKLLKTA 1:200- protein 3 RGSSGGRE TATSPDNP FQPVPRRP 1:1200 E (86) RRS (87) QNHLD (88) S0068 RAS-like, estrogen- 85004 RERG; RAS-like, estrogen-regulated, RRSSTTHV N/A N/A 1:500- regulated, growth- growth-inhibitor KQAINKML 1:40000 inhibitor TKISS (89) S0070 G protein-coupled 26996 GPCR150; GPR160; putative G MRRKNTC NETILYFP KVQIPAYI 1:10- receptor 160 protein-coupled receptor; G protein- QNFMEYFC FSSHSSYT EMNIPLVI 1:100 coupled receptor 160 ISLAF (90) VRSKK LCQ (92) (91) S0072 S100 calcium binding 6279 CP-10; L1Ag; CALPROTECTIN; MLTELEKA RDDLKKL KMGVAA 1:6500- protein A8 60B8AG; S100A8; MIF; CAGA; NIF; LNSIIDVYH LETECPQ HKKSHEE 1:10000 (calgranulin A) MRP8; MA387; CFAG; CGLA K (93) YIRKKGA SHKE (95) S100A8/S100A9 COMPLEX; cystic D (94) fibrosis antigen; S100 calcium-binding protein A8; S100 calcium binding protein A8 (calgranulin A) S0073 forkhead box A1 3169 HNF3A; MGC33105; TCF3A; PESRKDPS HGLAPHE EQQHKLD 1:100- FOXA1; forkhead box A1; GASNPSAD SQLHLKG FKAYEQA 1:2700 HEPATOCYTE NUCLEAR FACTOR S (96) D (97) LQYS (98) 3-ALPHA; hepatocyte nuclear factor 3, alpha S0073 forkhead box A1 3169 HNF3A; MGC33105; TCF3A; HGLAPHES N/A N/A 1:50- P2 FOXA1; forkhead box A1; QLHLKGD 1:450 HEPATOCYTE NUCLEAR FACTOR (99) 3-ALPHA; hepatocyte nuclear factor 3, alpha S0074 trefoil factor 3 7033 TFF3; trefoil factor 3 (intestinal); EEYVGLSA RVDCGYP VPWCFKP 1:2500- (intestinal) trefoil factor 3, HITF, human intestinal NQCAVPAK HVTPKEC LQEAECT 1:30000 trefoil factor DRVD (100) N (101) F (102) S0074 trefoil factor 3 7033 TFF3; trefoil factor 3 (intestinal); VPWCFKPL N/A N/A 1:400- P3 (intestinal) trefoil factor 3, HITF, human intestinal QEAECTF 1:810 trefoil factor (103) S0076 keratin 17 3872 PC2; PCHC1; KRT17; K17; KKEPVTTR QDGKVISS SSSIKGSS 1:200 x1 CYTOKERATIN 17; keratin 17 QVRTIVEE REQVHQT GLGGGSS (104) TR (105) (106) S0078 kynureninase (L- 8942 3.7.1.3; XANTHURENICACIDURIA; DEEDKLRH KPREGEE EERGCQL 1:180- kynurenine hydrolase) KYNU; FRECFYIPK TLRIEDIL TITFSVPN 1:200 HYDROXYKYNURENINURIA; IQD (107) EVIEKE KDVFQE KYNURENINASE DEFICIENCY; (108) (109) XANTHURENIC ACIDURIA; kynureninase (L-kynurenine hydrolase) S0079 solute carrier family 25800 SLC39A6; LIV-1 protein, estrogen DHNHAASG EEPAMEM QRYSREE 1:200- 39 (zinc transporter), regulated; solute carrier family 39 KNKRKALC KRGPLFS LKDAGVA 1:800 member 6 (zinc transporter), member 6; solute PDHD (110) HLSSQNI TL (112) carrier family 39 (metal ion (111) transporter), member 6 S0081 N-acetyltransferase 1 9 AAC1; 2.3.1.5; NAT1; arylamine N- MDIEAYLE QMWQPLE FNISLQRK 1:10- (arylamine N- acetyltransferase-1; ACETYL- RIGYKKSR LISGKDQP LVPKHGD 1:240 acetyltransferase) CoA:ARYLAMINE N- NKLDLE QVPCVFR RFFTI ACETYLTRANSFERASE; (113) (114) (115) ARYLAMINE N- ACETYLTRANSFERASE 1; N- acetyltransferase 1 (arylamine N- acetyltransferase); arylamide acetylase 1 (N-acetyltransferase 1) S0086 X-box binding protein 7494 XBP2; TREB5; XBP1; X-box-binding RQRLTHLS EKTHGLV QPPFLCQ 1:180- 1 protein-1; X BOX-BINDING PEEKALRR VENQELR WGRHQPS 1:400 PROTEIN 1; X BOX-BINDING KLKNR QRLGMD WKPLMN PROTEIN 2; X-box binding protein 1 (116) (117) (118) S0088 claudin 10 9071 CPETRL3; OSP-L; CLDN10; claudin NKITTEFFD FSISDNNK EDFKTTN 1:333- 10; claudin 10 isoform a; claudin 10 PLFVEQK TPRYTYN PSKQFDK 1:1000 isoform b (119) GAT (120) NAYV (121) S0090 sparc/osteonectin, 9806 KIAA0275; testican-2; SPOCK2; EGDAKGLK EWCFCFW EEEGEAG 1:100- cwcv and kazal-like TESTICAN 2; EGETPGNF REKPPCL EADDGGY 1:800 domains proteoglycan SPARC/OSTEONECTIN, CWCV, MEDE (122) AELER IW (124) (testican) 2 AND KAZAL-LIKE DOMAINS (123) PROTEOGLYCAN 2; sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican) 2 S0091 lipocalin 2 (oncogene 3934 UTEROCALIN; NGAL; LCN2; DKDPQKM KKCDYWI ENFIRFSK 1:100 24p3) NEUTROPHIL GELATINASE- YATIYE RTFVPGC YLGLPEN ASSOCIATED LIPOCALIN; (125) Q (126) (127) ONCOGENIC LIPOCALIN 24P3; lipocalin 2 (oncogene 24p3) S0092 paired box gene 8 7849 PAX8; paired box gene 8; paired box DDSDQDSC RQHYPEA NTPLGRN 1:30- gene 8 isoform PAX8C; paired box RLSIDSQ YASPSHT LSTHQTY 1:100 gene 8 isoform PAX8D; paired box (128) K (129) PVVAD gene 8 isoform PAX8E; paired box (130) gene 8 isoform PAX8A; paired box gene 8 isoform PAX8B; PAIRED DOMAIN GENE 8 PAX8/PPARG FUSION GENE S0093 mesothelin 10232 CAK1; SMR; MSLN; mesothelin; RLVSCPGP KMSPEDIR SPEELSSV 1:500 MEGAKARYOCYTE- LDQDQQE KWNVTSL PPSSIWAV POTENTIATING FACTOR; (131) ETLK (132) RPQD (133) SOLUBLE MPF/MESOTHELIN- RELATED PROTEIN; mesothelin isoform 2 precursor; mesothelin isoform 1 precursor; megakaryocyte potentiating factor precursor; ANTIGEN RECOGNIZED BY MONOCLONAL ANTIBODY S0094 kallikrein 6 (neurosin, 5653 Bssp; PRSS18; KLK6; Klk7; SP59; EEQNKLVH ELIQPLPL GKTADGD 1:150- zyme) PRSS9; MGC9355; protease M; GGPCDKTS ERDCSAN FPDTIQC 1:300 kallikrein 6 preproprotein; protease, H (134) T (135) (136) serine, 18; protease, serine, 9; kallikrein 6 (neurosin, zyme) S0095 Rap guanine 10411 bcm910; MGC21410; REQWPERR KVNSAGD QQLKVID 1:250- nucleotide exchange 9330170P05Rik; EPAC; RAPGEF3; RCHRLENG AIGLQPD NQRELSR 1:1000 factor (GEF) 3 cAMP-GEFI; RAP guanine- CGNA (137) AR (139) LSRELE nucleotide-exchange factor 3; (140) EXCHANGE PROTEIN ACTIVATED BY cAMP; RAP guanine-nucleotide-exchange factor (GEF) 3; cAMP-REGULATED GUANINE NUCLEOTIDE EXCHANGE FACTOR I; RAP GUANINE NUCLE S0096 ATPase, H+ 525 Vma2; VPP3; ATP6V1B1; RTA1B; REHMQAV KKSKAVL DEFYSRE 1:100- transporting, 3.6.3.14; VATB; ATP6B1; V-ATPase TRNYITHPR DYHDDN GRLQDLA 1:800 lysosomal 56/58 kDa, B1 subunit; H+-ATPase beta 1 (141) (142) PDTAL V1 subunit B, isoform subunit; H(+)-transporting two-sector (143) 1 (Renal tubular ATPase, 58 kD subunit; vacuolar acidosis with proton pump, subunit 3; deafness) endomembrane proton pump 58 kDa subunit; ATPase, H+ transporting, lysos S0097 frizzled homolog 8 8325 FZ-8; hFZ8; FZD8; frizzled 8; frizzled KQQDGPTK ELRVLSK RRGGEGG 1:100- (Drosophila) homolog 8 (Drosophila); FRIZZLED, THKLEKLM ANAIVPG EENPSAA 1:500 DROSOPHILA, HOMOLOG OF, 8 IR (144) LSGGE KGHLMG (145) (146) S0099 histone 1, H2ba 255626 HIST1H2BA; histone 1, H2ba MPEVSSKG GFKKAVV KEGKKRK 1:333- ATISKK KTQK RTRKE 1:500 (147) (148) (149) S0110 hypothetical protein 84259 MGC2714; hypothetical protein RYAFDFAR SVFYQYL EDGAWPV 1:500- MGC2714 MGC2714 DKDQRSLD EQSKYRV LLDEFVE 1:2500 ID (150) MNKDQ WQKVRQ (151) TS (152) S0117 reproduction 8 7993 D8S2298E; REP8; reproduction 8; SFKSPQVY RKKQQEA EDIGITVD 1:200- Reproduction/chromosome 8 LKEEEEKN QGEKASR TVLILEEK 1:375 EKR (153) YIE (154) EQTN (155) S0119 slit homolog 1 6585 SLIT3; MEGF4; SLIL1; Slit-1; SLIT1; KAFRGATD DFRCEEG DGTSFAE 1:900 (Drosophila) slit homolog 1 (Drosophila); SLIT, LKNLRLDK QEEGGCL EVEKPTK DROSOPHILA, HOMOLOG OF, 1; NQ (156) PRPQ (157) CGCALCA MULTIPLE EPIDERMAL GROWTH (158) FACTOR-LIKE DOMAINS 4 S0122 leucyl-tRNA 23395 6.1.1.4; MGC26121; KIAA0028; QRIKEQAS HAKTKEK KSPQPQLL 1:150 synthetase 2, LEURS; LARS2; leucine translase; KISEADKS LEVTWEK SNKEKAE mitochondrial leucine-tRNA ligase; LEUCYL-tRNA KPKF (159) MSKSKHN ARK (161) SYNTHETASE, MITOCHONDRIAL; (160) leucyl-tRNA synthetase 2, mitochondrial; leucyl-tRNA synthetase 2, mitochondrial precursor S0123 homeo box D4 3233 HOX4B; HOXD4; HHO.C13; HOX- MLFEQGQQ KDQKAKG HSSQGRL 1:100- 5.1; HOMEOBOX D4; HOMEOBOX ALELPECT ILHSPASQ PEAPKLT 1:500 4B; HOMEOBOX X; homeo box D4; (162) SPERS HL (164) homeobox protein Hox-D4; Hox-4.2, (163) mouse, homolog of homeo box X S0124 sphingosine-1- 8879 KIAA1252; SPL; SGPL1; KRGARRGG KIVRVPLT QFLKDIRE 1:990- phosphate lyase 1 sphingosine-1-phosphate lyase 1 WKRKMPS KMMEVD SVTQIMK 1:1500 TDL (165) VR (166) NPKA (167)

S0126 HBxAg transactivated 55789 XTP1; HBxAg transactivated protein 1 SKQGVVIL VQTFSRCI LKKPFQPF 1:450- protein 1 DDKSKELP LCSKDEV QRTRSFR 1:1600 HW (168) DLDEL M (170) (169) S0132 SRY (sex determining 6662 SRA1; CMD1; CMPD1; SOX9; SRY- MNLLDPFM NTFPKGEP KNGQAEA 1:100- region Y)-box 9 BOX 9; transcription factor SOX9; KMTDEQEK DLKKESE EEATEQT 1:500 (campomelic SRY-RELATED HMG-BOX GENE GLS (171) EDK (172) HISPN dysplasia, autosomal 9; SEX REVERSAL, AUTOSOMAL, (173) sex-reversal) 1; SRY (sex-determining region Y)- box 9 protein; SRY (sex-determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal); SRY ( S0137 cadherin, EGF LAG 1952 Flamingo1; CELSR2; EGFL2; QASSLRLEP ELKGFAE RSGKSQPS 1:1800- seven-pass G-type KIAA0279; MEGF3; CDHF10; EGF- GRANDGD RLQRNES YIPFLLRE 1:5000 receptor 2 (flamingo like-domain, multiple 2; epidermal WH (174) GLDSGR E (176) homolog, Drosophila) growth factor-like 2; multiple (175) epidermal growth factor-like domains 3; cadherin EGF LAG seven-pass G- type receptor 2; cadherin, EGF LAG seven-pass G-type receptor 2 S0139 gamma-glutamyl 8836 3.4.19.9; GGH; gamma-glutamyl RRSDYAKV KNFTMNE EFFVNEA 1:2500- hydrolase (conjugase, hydrolase precursor; gamma-glutamyl AKIFYNLSI KLKKFFN RKNNHHF 1:30000 folylpolygammagluta hydrolase (conjugase, QSFDD VLTTN KSESEE myl hydrolase) folylpolygammaglutamyl hydrolase) (177) (178) (179) S0140 bullous pemphigoid 667 BP240; FLJ13425; FLJ32235; KNTQAAEA QENQPEN KQMEKDL 1:250- antigen 1, FLJ21489; FLJ30627; CATX-15; LVKLYETK SKTLATQ AFQKQVA 1:20000 230/240 kDa KIAA0728; BPAG1; dystonin; LCE (180) LNQ (181) EKQLK hemidesmosomal plaque protein; (182) bullous pemphigoid antigen 1, 230/240 kDa; bullous pemphigoid antigen 1 (230/240 kD); bullous pemphigoid antigen 1 isoform 1 eA precursor; bullo S0143 fatty acid synthase 2194 2.3.1.85; OA-519; FASN; MGC14367; EFVEQLRK DRHPQAL REVRQLT 1:5000- MGC15706; fatty acid synthase EGVFAKEV EAAQAEL LRKLQEL 1:30000 R (183) QQHD SSKADE (184) (185) S0143 fatty acid synthase 2194 2.3.1.85; OA-519; FASN; MGC14367; REVRQLTL N/A N/A 1:200- P3 MGC15706; fatty acid synthase RKLQELSS 1:630 KADE (186) S0144 matrix 4323 MMP-X1; 3.4.24.-; MMP14; AYIREGHE DEASLEP RGSFMGS 1:500- metalloproteinase 14 MTMMP1; MT1-MMP ; membrane- KQADIMIFF GYPKHIK DEVFTYF 1:20000 (membrane-inserted) type-1 matrix metalloproteinase; AE (187) ELGR (188) YK (189) matrix metalloproteinase 14 preproprotein; MATRIX METALLOPROTEINASE 14, MEMBRANE-TYPE; matrix metalloproteinase 14 (membrane- inserted); membrane-type matrix metalloprotein S0147 cystatin A (stefin A) 1475 STF1; CSTA; STFA; cystatin AS; MIPGGLSE NETYGKL DLVLTGY 1:100- cystatin A (stefin A) AKPATPEIQ EAVQYKT QVDKNKD 1:5000 EIV (190) Q (191) DELTGF (192) S0149 transient receptor 55503 TRPV6; ECAC2; CAT1; CATL; RQEHCMSE QGHKWG RACGKRV 1:400- potential cation CALCIUM TRANSPORTER 1; HFKNRPAC ESPSQGTQ SEGDRNG 1:20000 channel, subfamily V, CALCIUM TRANSPORTER-LIKE LGAR (193) AGAGK SGGGKW member 6 PROTEIN; EPITHELIAL CALCIUM (194) G (195) CHANNEL 2; transient receptor potential cation channel, subfamily V, member 6 S0156 fatty acid binding 2173 B-FABP; FABP7; FABPB; MRG; MVEAFCAT QVGNVTK KVVIRTLS 1:100- protein 7, brain mammary-derived growth inhibitor- WKLTNSQN PTVIISQE TFKNTE 1:20000 related; FATTY ACID-BINDING (196) (197) (198) PROTEIN 7; FATTY ACID- BINDING PROTEIN, BRAIN; fatty acid binding protein 7, brain S0158 cadherin 3, type 1, P- 1001 CDHP; HJMD; PCAD; CDH3; RAVFREAE QEPALFST QKYEAHV 1:150- cadherin (placental) placental cadherin; CADHERIN, VTLEAGGA DNDDFTV PENAVGH 1:2000 PLACENTAL; cadherin 3, P-cadherin EQE (199) RN (200) E (201) (placental); calcium-dependent adhesion protein, placental; cadherin 3, type 1 preproprotein; cadherin 3, type 1, P-cadherin (placental) S0165 chemokine (C-X-C 2919 MGSA-a; NAP-3; CXCL1; SCYB1; KKIIEKML N/A N/A 1:100- motif) ligand 1 GROa; GRO1, FORMERLY; GRO NSDKSN 1:500 (melanoma growth PROTEIN, ALPHA; GRO1 (202) stimulating activity, ONCOGENE, FORMERLY; alpha) MELANOMA GROWTH STIMULATORY ACTIVITY, ALPHA; GRO1 oncogene (melanoma growth-stimulating activity); CHEMOKINE, CXC MOTIF, LIGAND 1; GRO1 oncogene (melanoma grow S0171 baculoviral IAP null BIRC5; baculoviral IAP repeat- GKPGNQNS QAEAPLV NCFLTER 1:22500- repeat-containing 5 containing 5 (survivin) KNEPPKKR PLSRQNK KAQPDE 1:30000 (survivin) ERER (203) (204) (205) S0193 procollagen-lysine, 2- 5352 PLOD2; LYSYL HYDROXYLASE 2; EFDTVDLS NKEVYHE KQVDLEN 1:20000 oxoglutarate 5- LYSINE HYDROXYLASE 2; AVDVHPN KDIKVFFD VWLDFIR dioxygenase (lysine PROCOLLAGEN-LYSINE, 2- (206) KAK (207) E (208) hydroxylase) 2 OXOGLUTARATE 5- DIOXYGENASE 2; procollagen- lysine, 2-oxoglutarate 5-dioxygenase (lysine hydroxylase) 2; procollagen- lysine, 2-oxoglutarate 5-dioxygenase (lysine hydroxylase) 2 isoform S0202 PTK7 protein tyrosine 5754 PTK7; CCK4; protein-tyrosine kinase LKKPQDSQ KAKRLQK KDRPSFSE 1:500- kinase 7 PTK7; colon carcinoma kinase-4; LEEGKPGY QPEGEEPE IASALGDS 1:800 PTK7 protein tyrosine kinase 7; PTK7 LD (209) ME (210) TVDSKP protein tyrosine kinase 7 isoform e (211) precursor; PTK7 protein tyrosine kinase 7 isoform a precursor; PTK7 protein tyrosine kinase 7 isoform d precursor; S0211 cytochrome P450, 1549 CYPIIA7; P450-IIA4; 1.14.14.1; KRGIEERIQ DRVIGKN NPQHFLD 1:500- family 2, subfamily A, CPA7; CYP2A7; CPAD; EESGFLIE RQPKFED DKGQFKK 1:2500 polypeptide 7 CYTOCHROME P450, SUBFAMILY (212) RTK (213) SD (214) IIA, POLYPEPTIDE 7; cytochrome P450, subfamily IIA (phenobarbital- inducible), polypeptide 7; cytochrome P450, family 2, subfamily A, polypeptide 7; cytochrome P450, family 2, su S0218 solute carrier family 222962 SLC29A4; solute carrier family 29 RHCILGEW KQRELAG RNAHGSC 1:20- 29 (nucleoside (nucleoside transporters), member 4 LPILIMAVF NTMTVSY LHASTAN 1:50 transporters), member N (215) MS (216) GSILAGL 4 (217) S0221 solute carrier family 9153 HCNT2; SLC28A2; HsT17153; ELMEKEVE KARSFCK KNKRLSG 1:500- 28 (sodium-coupled SPNT1; CONCENTRATIVE PEGSKRTD THARLFK MEEWIEG 1:1200 nucleoside NUCLEOSIDE TRANSPORTER 2; (218) K (219) EK (220) transporter), member SODIUM-DEPENDENT PURINE 2 NUCLEOSIDE TRANSPORTER 1; solute carrier family 28 (sodium- coupled nucleoside transporter), member 2 S0223 angiopoietin-like 4 51129 HFARP; FIAF; ANGPTL4; PGAR; EGSTDLPL KVAQQQR DHKHLDH 1:30- angiopoietin-like 4; FASTING- APESRVDP HLEKQHL EVAKPAR 1:10000 INDUCED ADIPOSE FACTOR; E (221) R (222) RKRLPE PPARG ANGIOPOIETIN-RELATED (223) PROTEIN; HEPATIC FIBRINOGEN/ANGIOPOIETIN- RELATED PROTEIN S0235 carcinoembryonic 1048 CEACAM5; CD66e; KLTIESTPF KSDLVNE KPVEDKD 1:500- antigen-related cell carcinoembryonic antigen-related cell NVAEGKEC EATGQFR AVAFTCE 1:4500 adhesion molecule 5 adhesion molecule 5 (224) VYPELPK PEAQ (226) (225) S0237 podocalyxin-like 5420 podocalyxin-like; Gp200; PCLP; DEKLISLIC KDKWDEL DSWIVPL 1:1000- PODXL; PODOCALYXIN-LIKE RAVKATFN KEAGVSD DNLTKDD 1:2000 PROTEIN; podocalyxin-like precursor PAQDK MKLGD LDEEEDT (227) (228) HL (229) S0238 xenotropic and 9213 X3; XPR1; X RECEPTOR; SYG1, EAVVTNEL RRYRDTK KARDTKV 1:100- polytropic retrovirus YEAST, HOMOLOG OF; xenotropic EDGDRQKA RAFPHLV LIEDTDDE 1:500 receptor and polytropic retrovirus receptor MKRLR NAGK ANT (232) (230) (231) S0241 glycyl-tRNA 2617 GlyRS; GARS; CMT2D; 6.1.1.14; RKRVLEAK RHGVSHK EARYPLFE 1:500- synthetase SMAD1; GLYCYL-tRNA ELALQPKD VDDSSGSI GQETGKK 1:7500 SYNTHETASE; glycine tRNA ligase; DIVD (233) GRRYAR ETIEE Charcot-Marie-Tooth neuropathy, (234) (235) neuronal type, D S0244 dachshund homolog 1 1602 DACH1; FLJ10138; dachshund DLAGHDM EKQVQLE EADRSGG 1:100- (Drosophila) homolog (Drosophila); GHESKRMH KTELKMD RTDAERTI 1:3000 DACHSHUND, DROSOPHILA, IEKDE (236) FLRERE QDGR HOMOLOG OF; dachshund homolog (237) (238) 1 (Drosophila); dachshund homolog 1 isoform a; dachshund homolog 1 isoform b; dachshund homolog 1 isoform c S0251 transcription factor 29841 TFCP2L2; LBP-32; MGR; GRHL1; EALYPQRR DYYKVPR DKYDVPH 1:5400 CP2-like 2 mammalian grainyhead; LBP protein SYTSEDEA ERRSSTA DKIGKIFK 32; transcription factor CP2-like 2; WK (239) KPEVE KCKK leader-binding protein 32 isoform 2; (240) (241) leader-binding protein 32 isoform 1 S0253 lysosomal associated 55353 LAPTM4B; lysosomal associated DPDQYNFS EYIRQLPP DTTVLLPP 1:500- protein protein transmembrane 4 beta SSELGGDF NFPYRDD YDDATVN 1:2000 transmembrane 4 beta EFMDD (243) GAAKE (242) (244) S0255 cyclin E2 9134 CYCE2; CCNE2; cyclin E2; G1/S- RREEVTKK KESRYVH DFFDRFM 1:1000- specific cyclin E2; cyclin E2 isoform HQYEIR DKHFEVL LTQKDIN 1:2000 2; cyclin E2 isoform 3; cyclin E2 (245) HSDLE K (247) isoform 1 (246) S0260 nicastrin 23385 KIAA0253; nicastrin; NCSTN; APH2; ESKHFTRD ETDRLPR ESRWKDI 1:2400- ANTERIOR PHARYNX LMEKLKGR CVRSTAR RARIFLIA 1:5400 DEFECTIVE 2, C. ELEGANS, TSR (248) LAR (249) SKELE HOMOLOG OF (250) S0265 FXYD domain 5349 MAT-8; MAT8; PLML; FXYD3; KVTLGLLV SEWRSSG KCKCKFG

1:400- containing ion phospholemman-like protein; FLAGFPVL EQAGR QKSGHHP 1:1200 transport regulator 3 MAMMARY TUMOR, 8-KD; FXYD DANDLED (252) GE (253) domain-containing ion transport (251) regulator 3; FXYD domain containing ion transport regulator 3; FXYD domain containing ion transport regulator 3 isoform 2 precursor; FXYD domai S0267 immunoglobulin 3321 EWI-3; V8; IGSF3; immunoglobin KVAKESDS EREKTVT KRAEDTA 1:200- superfamily, member superfamily, member 3; VFVLKIYH GEFIDKES GQTALTV 1:250 3 immunoglobulin superfamily, member LRQED KRPK (255) MRPD 3 (254) (256) S0270 signal transducing 10254 STAM2B; STAM2; DKFZp564C047; KVARKVR ETEVAAV EIKKSEPE 1:1000- adaptor molecule Hbp; STAM2A; SIGNAL- ALYDFEAV DKLNVID PVYIDED 1:9000 (SH3 domain and TRANSDUCING ADAPTOR EDNE (257) DDVE KMDR ITAM motif) 2 MOLECULE 2; signal transducing (258) (259) adaptor molecule 2; STAM-like protein containing SH3 and ITAM domains 2; signal transducing adaptor molecule (SH3 domain and ITAM motif) 2 S0273 dickkopf homolog 1 22943 DKK1; DKK-1; SK; dickkopf-1 like; DEECGTDE RGEIEETI N/A 1:400- (Xenopus laevis) dickkopf (Xenopus laevis) homolog 1; YCASPTRG TESFGND 1:500 dickkopf homolog 1 (Xenopus laevis); GD (260) HSTLD DICKKOPF, XENOPUS, HOMOLOG (261) OF, 1 S0280 solute carrier family 65010 SLC26A6; solute carrier family 26, MDLRRRD DTDIYRD EFYSDAL 1:1800- 26, member 6 member 6 YHMERPLL VAEYSEA KQRCGVD 1:2400 NQEHLEE KE (263) VDFLISQK (262) KK (264) S0286 WNT inhibitory factor 11197 WIF1; WIF-1; WNT inhibitory factor DAHQARVL ERRICECP KRYEASLI 1:90 1 1; Wnt inhibitory factor-1 precursor IGFEEDILIV DGFHGPH HALRPAG SE (265) CEK (266) AQLR (267) S0288 preferentially 23532 MADE; PRAME; OPA- KRKVDGLS KEGACDE DIKMILK 1:1200 expressed antigen in INTERACTING PROTEIN 4; Opa- TEAEQPFIP LFSYLIEK MVQLDSI melanoma interacting protein OIP4; preferentially VE (268) VKRKK EDLE (270) expressed antigen in melanoma; (269) melanoma antigen preferentially expressed in tumors S0295 prostaglandin E 9536 PGES; TP53112; MGST1L1; PP1294; RLRKKAFA RSDPDVE RVAHTVA 1:100- synthase PP102; PTGES; MGC10317; PIG12; NPEDALR RCLRAHR YLGKLRA 1:2400 MGST1-L1; MGST-IV; MGST1-like (271) ND (272) PIR (273) 1; p53-INDUCED GENE 12; prostaglandin E synthase; p53-induced apoptosis protein 12; prostaglandin E synthase isoform 2; prostaglandin E synthase isoform 1; micros S0296 solute carrier family 7 8140 SLC7A5; MPE16; D16S469E; CD98; KRRALAAP EAREKML MIWLRHR 1:300- (cationic amino acid LAT1; 4F2 light chain; Membrane AAEEKEEA AAKSADG KPELERPI 1:5000 transporter, y+ protein E16; L-TYPE AMINO ACID R (274) SAPAGE K (276) system), member 5 TRANSPORTER 1; Solute carrier (275) family 7, member 5; solute carrier family 7 (cationic amino acid transporter, y+ system), member 5 S0296 solute carrier family 7 8140 SLC7A5; MPE16; D16S469E; CD98; KRRALAAP N/A N/A 1:225- P1 (cationic amino acid LAT1; 4F2 light chain; Membrane AAEEKEEA 1:3150 transporter, y+ protein E16; L-TYPE AMINO ACID R (277) system), member 5 TRANSPORTER 1; Solute carrier family 7, member 5; solute carrier family 7 (cationic amino acid transporter, y+ system), member 5 S0297 v-maf 7975 FLJ32205; NFE2U; MAFK; NFE2, KPNKALKV KRVTQKE RLELDAL 1:333- musculoaponeurotic 18-KD SUBUNIT; nuclear factor KKEAGE ELERQRV RSKYE 1:800 fibrosarcoma erythroid-2, ubiquitous (p18); (278) ELQQEVE (280) oncogene homolog K NUCLEAR FACTOR ERYTHROID K (279) (avian) 2, UBIQUITOUS SUBUNIT; v-maf musculoaponeurotic fibrosarcoma oncogene homolog K (avian); v-maf avian musculoaponeurotic fibrosarcoma oncogen S0301 signal peptide, CUB 57758 SCUBE2; signal peptide, CUB KMHTDGRS KKGFKLL KRTEKRL 1:3500- domain, EGF-like 2 domain, EGF-like 2 CLEREDTV TDEKSCQ RKAIRTLR 1:5400 LEVTE (281) DVDE KAVHRE (282) (283) S0303 gamma-aminobutyric 2564 GABRE; GABA-A RECEPTOR, RVEGPQTE EETKSTET KWENFKL 1:300- acid (GABA) A EPSILON POLYPEPTIDE; GAMMA- SKNEASSR ETGSRVG EINEKNS 1:500 receptor, epsilon AMINOBUTYRIC ACID D (284) KLPE (285) WKLFQFD RECEPTOR, EPSILON; gamma- (286) aminobutyric acid (GABA) A receptor, epsilon; gamma-aminobutyric acid (GABA) A receptor, epsilon isoform 2; gamma-aminobutyric acid (GABA) A receptor, epsilon is S0305 S100 calcium binding 6281 CAL1L; GP11; p10; 42C; S100A10; DKGYLTKE KDPLAVD N/A 1:8332- protein A10 (annexin ANX2LG; CLP11; Ca[1]; DLRVLMEK KIMKDLD 1:24996 II ligand, calpactin I, CALPACTIN I, p11 SUBUNIT; E (287) QCRDGK light polypeptide ANNEXIN II, LIGHT CHAIN; (288) (p 11)) CALPACTIN I, LIGHT CHAIN; S100 calcium-binding protein A10 (annexin II ligand, calpactin I, light polypeptide (p11)); S100 calcium binding protein A10 S0311 v-myb myeloblastosis 4605 MYBL2; MGC15600; MYB- MSRRTRCE EEDLKEV RRSPIKKV 1:750- viral oncogene RELATED GENE BMYB; MYB- DLDELHYQ LRSEAGIE RKSLALDI 1:5000 homolog (avian)-like related protein B; v-myb DTDSD LIIEDDIR VDED 2 myeloblastosis viral oncogene (289) (290) (291) homolog (avian)-like 2; V-MYB AVIAN MYELOBLASTOSIS VIRAL ONCOGENE HOMOLOG-LIKE 2 S0312 nucleoside 4860 NP; 2.4.2.1; nucleoside phosphorylase; EDYKNTAE DERFGDR KVIMDYE 1:1000- phosphorylase PURINE- WLLSHTKH FPAMSDA SLEKANH 1:3600 NUCLEOSIDE:ORTHOPHOSPHATE R (292) YDRTMRQ EE (294) RIBOSYLTRANSFERASE; purine R (293) nucleoside phosphorylase; PNP NUCLEOSIDE PHOSPHORYLASE DEFICIENCY; ATAXIA WITH DEFICIENT CELLULAR IMMUNITY S0314 chaperonin containing 22948 KIAA0098; CCT5; chaperonin DQDRKSRL KGVIVDK RMILKIDD 1:6000- TCP1, subunit 5 containing TCP1, subunit 5 (epsilon) MGLEALKS DFSHPQM IRKPGESE 1:30000 (epsilon) HIMAAK PKKVED E (297) (295) (296) S0315 non-metastatic cells 1, 4830 GAAD; NME1; NDPKA; 2.7.4.6; RLQPEFKP KFMQASE DSVESAE 1:9000- protein (NM23A) NM23-H1; AWD NM23H1B; GZMA- KQLEGTMA DLLKEHY KEIGLWF 1:18000 expressed in ACTIVATED DNase; NUCLEOSIDE NCER (298) VDLKDR HPEELVD DIPHOSPHATE KINASE-A; AWD, (299) (300) DROSOPHILA, HOMOLOG OF; METASTASIS INHIBITION FACTOR NM23; nucleoside- diphosphate kinase 1 isoform b; NONMETASTATIC PROTEIN 23, HOMOLOG 1; nucleo S0316 squalene epoxidase 6713 SQLE; 1.14.99.7; squalene epoxidase; KSPPESENK RDGRKVT DHLKEPF 1:1000- squalene monooxygenase EQLEARRR VIERDLKE LEATDNS 1:10000 R (301) PDR (302) HLR (303) S0319 pregnancy-induced 29948 OKL38; pregnancy-induced growth DLEVKDW EYHKVHQ RHQLLCF 1:900 growth inhibitor inhibitor; PREGNANCY-INDUCED MQKKRRG MMREQSI KEDCQAV GROWTH INHIBITOR OKL38 LRNSR (304) LSPSPYEG FQDLEGV YR (305) EK (306) S0326 mal, T-cell 114569 MAL2; mal, T-cell differentiation GPDILRTYS CSLGLAL N/A 1:120- differentiation protein 2 protein 2 GAFVCLE RRWRP 1:1200 (307) (308) S0330 aldo-keto reductase 1645 1.1.1.213; 2-ALPHA-HSD; 1.3.1.20; RYLTLDIFA N/A N/A 1:2500- family 1, member 20-ALPHA-HSD; MGC8954; H-37; GPPNYPFS 1:75000 C1/2 (dihydrodiol HAKRC; MBAB; C9; DDH1; DEY (309) dehydrogenase 1; 20- AKR1C1; trans-1,2-dihydrobenzene- alpha (3-alpha)- 1,2-diol dehydrogenase; chlordecone hydroxysteroid reductase homolog; aldo-keto dehydrogenase) reductase C; 20 alpha-hydroxysteroid dehydrogenase; hepatic dihydrodiol S0330- aldo-keto reductase 1645 1.1.1.213; 2-ALPHA-HSD; 1.3.1.20; RYLTLDIFA N/A N/A 1:600 x1 family 1, member 20-ALPHA-HSD; MGC8954; H-37; GPPNYPFS C1/2 (dihydrodiol HAKRC; MBAB; C9; DDH1; DEY (310) dehydrogenase 1; 20- AKR1C1; trans-1,2-dihydrobenzene- alpha (3-alpha)- 1,2-diol dehydrogenase; chlordecone hydroxysteroid reductase homolog; aldo-keto dehydrogenase) reductase C; 20 alpha-hydroxysteroid dehydrogenase; hepatic dihydrodiol S0331 aldo-keto reductase 8644 HA1753; 1.1.1.188; DD3; hluPGFS; HYFNSDSF N/A N/A 1:300- family 1, member C3 HSD17B5; 1.3.1.20; 1.1.1.213; ASHPNYPY 1:999 (3-alpha AKR1C3; KIAA0119; HAKRB; SDEY (311) hydroxysteroid HAKRe; trans-1,2-dihydrobenzene- dehydrogenase, type 1,2-diol dehydrogenase; chlordecone II) reductase homolog; dihydrodiol dehydrogenase 3; prostaglandin F synthase; ALDO-KETO REDUCTASE B; 3- S0331- aldo-keto reductase 8644 HA1753; 1.1.1.188; DD3; hluPGFS; HYFNSDSF N/A N/A 1:150- x1 family 1, member C3 HSD17B5; 1.3.1.20; 1.1.1.213; ASHPNYPY 1:300 (3-alpha AKR1C3; KIAA0119; HAKRB; SDEY (312) hydroxysteroid HAKRe; trans-1,2-dihydrobenzene- dehydrogenase, type 1,2-diol dehydrogenase; chlordecone II) reductase homolog; dihydrodiol dehydrogenase 3; prostaglandin F synthase; ALDO-KETO REDUCTASE B; 3- S0332 aldo-keto reductase 1645 1.1.1.213; 2-ALPHA-HSD; 1.3.1.20; RYVVMDFL N/A N/A 1:300- family 1, member C4 20-ALPHA-HSD; MGC8954; H-37; MDHPDYPF 1:400 (dihydrodiol HAKRC; MBAB; C9; DDH1; SDEY (313) dehydrogenase 1; 20- AKR1C1; trans-1,2-dihydrobenzene- alpha (3-alpha)- 1,2-diol dehydrogenase; chlordecone hydroxysteroid reductase homolog; aldo-keto dehydrogenase) reductase C; 20 alpha-hydroxysteroid dehydrogenase; hepatic dihydrodiol S0332- aldo-keto reductase 1645 1.1.1.213; 2-ALPHA-HSD; 1.3.1.20; RYVVMDFL N/A N/A 1:75- x1 family 1, member C4 20-ALPHA-HSD; MGC8954; H-37; MDHPDYPF 1:150 (dihydrodiol HAKRC; MBAB; C9; DDH1; SDEY (314) dehydrogenase 1; 20- AKR1C1; trans-1,2-dihydrobenzene- alpha (3-alpha)- 1,2-diol dehydrogenase; chlordecone hydroxysteroid reductase homolog; aldo-keto dehydrogenase) reductase C; 20 alpha-hydroxysteroid dehydrogenase; hepatic dihydrodiol S0336 chromosome 20 open 140809 C20orf139; chromosome 20 open DPAKVQSL RETIPAKL N/A 1:1600-

reading frame 139 reading frame 139 VDTIREDP VQSTLSD 1:2400 D (315) LR (316) S0342 solute carrier family 2154091 SLC2A12; solute carrier family 2 SDTTEELT N/A N/A 1:400- (facilitated glucose (facilitated glucose transporter), VIKSSLKDE 1:1250 transporter), member 12 member 12 (317) S0343 solute carrier family 2154091 SLC2A12; solute carrier family 2 HSRSSLMP N/A N/A 1:50- (facilitated glucose (facilitated glucose transporter), LRNDVDKR 1:125 transporter), member 12 member 12 (318) S0357 HTPAP protein 84513 HTPAP; HTPAP protein YRNPYVEA N/A N/A 1:100- EYFPTKPM 1:300 FVIA (319) S0364 KIAA0746 protein 23231 KIAA0746; KIAA0746 protein KKFPRFRN N/A N/A 1:200- RELEATRR 1:300 QRMD (320) S0367 peroxisomal acyl-CoA 122970 PTE2B; peroxisomal acyl-CoA SGNTAINY N/A N/A 1:200- thioesterase 2B thioesterase 2B KHSSIP 1:600 (321) S0374 chloride intracellular 53405 CLIC5; chloride intracellular channel 5 DANTCGED N/A N/A 1:5000- channel 5 KGSRRKFL 1:9000 DGDE (322) S0380 keratinocyte 200634 KRTCAP3; keratinocyte associated QLEEMTEL N/A N/A 1:2000- associated protein 3 protein 3 ESPKCKRQ 1:9000 ENEQ (323) S0384 FERM, RhoGEF 10160 p63RhoGEF; CDEP; FARP1; QADGAASA N/A N/A 1:100 (ARHGEF) and chondrocyte-derived ezrin-like protein; PTEEEEEV pleckstrin domain FERM, RhoGEF, and pleckstrin VKDR (324) protein 1 domain protein 1; FERM, ARHGEF, (chondrocyte-derived) AND PLECKSTRIN DOMAIN- CONTAINING PROTEIN 1; FERM, RhoGEF (ARHGEF) and pleckstrin domain protein 1 (chondrocyte- derived) S0388 trichorhinophalangeal 7227 GC79; TRPS1; TRPS1 GENE; SGDSLETK N/A N/A 1:600 syndrome I trichorhinophalangeal syndrome I; zinc EDQKMSPK finger transcription factor TRPS1 ATEE (325) S0396 cytochrome P450, 1576 1.14.14.1; HLP; CYP3A3; CYP3A4; RKSVKRM N/A N/A 1:15 family 3, subfamily A, P450C3; NF-25; CP33; CP34; P450- KESRLEDT polypeptide 4 III, STEROID-INDUCIBLE; QKHRV nifedipine oxidase; glucocorticoid- (326) inducible P450; CYTOCHROME P450PCN1; P450, FAMILY III; P450- III, steroid inducible; cytochrome P450, subfamily IIIA, polypeptide 4; S0398 FAT tumor suppressor 2195 CDHF7; FAT; cadherin ME5; FAT KIRLPEREK N/A N/A 1:45- homolog 1 tumor suppressor precursor; cadherin- PDRERNAR 1:200 (Drosophila) related tumor suppressor homolog REP (327) precursor; cadherin family member 7 precursor; homolog of Drosophila Fat protein precursor; FAT tumor suppressor homolog 1 (Drosophila); FAT TUMOR SUPPRESS S0401 granulin 2896 ACROGRANIN; PROEPITHELIN; RGTKCLRR N/A N/A 1:600- PROGRANULIN; PEPI; PCDGF; EAPRWDAP 1:3000 granulin; GRN; EPITHELIN LRDP (328) PRECURSOR S0404 N-myc downstream 10397 HMSNL; TARG1; CMT4D; RTP; GTRSRSHT N/A N/A 1:100- regulated gene 1 PROXY1; NDRG1; GC4; NMSL; SEGTRSRS 1:900 TDD5; RIT42; NDR1; differentiation- HTSE (329) related gene 1 protein; nickel-specific induction protein Cap43; protein regulated by oxygen-1; NMYC DOWNSTREAM-REGULATED GENE 1; reducing agents and tunicamycin-respon S0411 fatty acid binding 2171 PAFABP; EFABP; E-FABP; FABP5; EETTADGR N/A N/A 1:1800 protein 5 (psoriasis- PA-FABP; FATTY ACID-BINDING KTQTVCNF associated) PROTEIN, EPIDERMAL; FATTY TD (330) ACID-BINDING PROTEIN 5; FATTY ACID-BINDING PROTEIN, PSORIASIS-ASSOCIATED; fatty acid binding protein 5 (psoriasis- associated) S0413 cyclin-dependent 1028 WBS; p57(KIP2); BWCR; CDKN1C; AKRKRSAP N/A N/A 1:2700 kinase inhibitor 1C BWS; Beckwith-Wiedemann EKSSGDVP (p57, Kip2) syndrome; cyclin-dependent kinase (331) inhibitor 1C (p57, Kip2) S0414 alpha-methylacyl- 23600 AMACR; 5.1.99.4; ALPHA- RVDRPGSR N/A N/A 1:100 CoA racemase METHYLACYL-CoA RACEMASE; YDVSRLGR AMACR DEFICIENCY; AMACR GKRS (332) ALPHA-METHYLACYL-CoA RACEMASE DEFICIENCY; alpha- methylacyl-CoA racemase isoform 1; alpha-methylacyl-CoA racemase isoform 2 S0415 gamma-aminobutyric 2562 MGC9051; GABRB3; GABA-A ETVDKLLK N/A N/A 1:600- acid (GABA) A RECEPTOR, BETA-3 GYDIRLRP 1:1800 receptor, beta 3 POLYPEPTIDE; GAMMA- D (333) AMINOBUTYRIC ACID RECEPTOR, BETA-3; gamma- aminobutyric acid (GABA) A receptor, beta 3; gamma-aminobutyric acid (GABA) A receptor, beta 3 isoform 2 precursor; gamma-aminobutyric acid (GABA) A rece S0417 HSV-1 stimulation- 22879 HSRG1; KIAA0872; HSV-1 APGGAEDL N/A N/A 1:9000 related gene 1 stimulation-related 1; HSV-1 EDTQFPSEE stimulation-related gene 1 ARE (334) S0425 tumor necrosis factor 27242 TNFRSF21; DR6; BM-018; TNFR- RKSSRTLK N/A N/A 1:9000 receptor superfamily, related death receptor 6; tumor KGPRQDPS member 21 necrosis factor receptor superfamily, AIVE (335) member 21; tumor necrosis factor receptor superfamily, member 21 precursor S0429 jumonji domain 221037 JMJD1C; TRIP8; jumonji domain GSESGDSD N/A N/A 1:1200 containing 1C containing 1C; THYROID ESESKSEQR HORMONE RECEPTOR TKR (336) INTERACTOR 8 S0432 chromosome 9 open null C9orf140; chromosome 9 open reading EADSGDAR N/A N/A 1:90- reading frame 140 frame 140 RLPRARGE 1:300 RRRH (337) S0440 cell division cycle 994 3.1.3.48; CDC25B; cell division cycle RLERPQDR N/A N/A 1:350- 25B 25B; cell division cycle 25B isoform 4; DTPVQNKR 1:3600 cell division cycle 25B isoform 5; cell RRS (338) division cycle 25B isoform 1; cell division cycle 25B isoform 2; cell division cycle 25B isoform 3 S0445 laminin, beta 1 3912 LAMB1; LAMININ, BETA-1; CUTIS DRVEDVM N/A N/A 1:600- LAXA-MARFANOID SYNDROME; MERESQFK 1:1800 laminin, beta 1; laminin, beta 1 EKQE (339) precursor; LAMB1 NEONATAL CUTIS LAXA WITH MARFANOID PHENOTYPE S0447 papillary renal cell 5546 TPRC; MGC17178; MGC4723; DEAFKRLQ N/A N/A 1:4000- carcinoma PRCC; proline-rich protein PRCC; GKRNRGRE 1:6000 (translocation- RCCP1 PRCC/TFE3 FUSION GENE; E (340) associated) papillary renal cell carcinoma (translocation-associated); RENAL CELL CARCINOMA, PAPILLARY, 1 GENE; papillary renal cell carcinoma translocation-associated gene product S0455 tumor necrosis factor 8743 APO2L; TL2; Apo-2L; TNFSF10; RFQEEIKEN N/A N/A 1:900 (ligand) superfamily, Apo-2 ligand; APO2 LIGAND; TNF- TKNDKQ member 10 RELATED APOPTOSIS-INDUCING (341) LIGAND; TNF-related apoptosis inducing ligand TRAIL; tumor necrosis factor (ligand) superfamily, member 10; TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 10 S0459 titin 7273 connectin; TMD; titin; CMD1G; KRDKEGVR N/A N/A 1:2700- CMPD4; TTN; FLJ32040; CMH9, WTKCNKK 1:8100 included; titin isoform N2-A; titin TLTD (342) isoform N2-B; titin isoform novex-1; titin isoform novex-2; titin isoform novex-3; cardiomyopathy, dilated 1G (autosomal dominant); TTN CARDIOMYOPATHY, FAMILIAL S0469 DNA fragmentation 1676 DFF45; DFF1; DFFA; ICAD; DFF-45; KEGSLLSK N/A N/A 1:600 factor, 45 kDa, alpha INHIBITOR OF CASPASE- QEESKAAF polypeptide ACTIVATED DNase; DNA GEE (343) FRAGMENTATION FACTOR, 45- KD, ALPHA SUBUNIT; DNA fragmentation factor, 45 kDa, alpha polypeptide; DNA fragmentation factor, 45 kD, alpha subunit; DNA fragmentation factor, 45 kD, alp S0494 caspase 2, apoptosis- 835 ICH-1L/1S; CASP2; ICH1; CASP-2; ESDAGKEK N/A N/A 1:2000 related cysteine ICH-1 protease; caspase 2 isoform 3; LPKMRLPT protease (neural caspase 2 isoform 4; NEDD2 apoptosis RSD (344) precursor cell regulatory gene; caspase 2 isoform 2 expressed, precursor; caspase 2 isoform 1 developmentally preproprotein; NEURAL down-regulated 2) PRECURSOR CELL EXPRESSED, DEVELOPMENTALLY DOWNREGULATED 2; S0501 G1 to S phase 2935 GSPT1; eRF3a; ETF3A; GST1, ERDKGKTV N/A N/A 1:15000 transition 1 YEAST, HOMOLOG OF; PEPTIDE EVGRAYFE CHAIN RELEASE FACTOR 3A; G1- TEK (345) TO S-PHASE TRANSITION 1; G1 to S phase transition 1 S0502 GCN5 general control 2648 hGCN5; GCN5L2; GCN5 (general EKFRVEKD N/A N/A 1:9000 of amino-acid control of amino-acid synthesis, yeast, KLVPEKR synthesis 5-like 2 homolog)-like 2; GCN5 general (346) (yeast) control of amino-acid synthesis 5-like 2 (yeast); General control of amino acid synthesis, yeast, homolog-like 2 S0503 geminin, DNA 51053 GMNN; geminin, DNA replication EVAEKRRK N/A N/A 1:333 replication inhibitor inhibitor ALYEALKE NEK (347) S0507 ADP-ribosylation 64225 ARL6IP2; ADP-ribosylation factor- ENYEDDDL N/A N/A 1:8000- factor-like 6 like 6 interacting protein 2 VNSDEVM 1:9000 interacting protein 2 KKP (348) 50511 DNA replication 51659 Pfs2; DNA replication complex GINS PKADEIRTL N/A N/A 1:2000 complex GINS protein PSF2 VKDMWDT protein PSF2 R (349)

S0524 ankyrin repeat domain 10 55608 ANKRD10; ankyrin repeat domain 10 RKRCLEDS N/A N/A 1:4500 EDFGVKKA RTE (350) S0527 potassium channel null KCTD2; potassium channel EPKSFLCRL N/A N/A 1:900- tetramerisation tetramerisation domain containing 2 CCQEDPEL 1:1500 domain containing 2 DS (351) S0528 rabconnectin-3 23312 RC3; KIAA0856; rabconnectin-3 EEYDRESK N/A N/A 1:350- SSDDVDYR 1:1200 GS (352) S0538 acidic (leucine-rich) 81611 ANP32E; acidic (leucine-rich) nuclear CVNGEIEG N/A N/A 1:1200 nuclear phosphoprotein 32 family, member E LNDTFKEL phosphoprotein 32 EF (353) family, member E S0544 chromosome 9 open 84904 C9orf100; chromosome 9 open reading EQRARWER N/A N/A 1:40- reading frame 100 frame 100 KRACTARE 1:240 (354) S0545 HpaII tiny fragments 27037 D22S1733E; HTF9C; HpaII tiny ERKQLECE N/A N/A 1:900- locus 9C fragments locus 9C; HpaII tiny QVLQKLAK 1:5400 fragments locus 9C isoform2; HpaII E (355) tiny fragments locus 9C isoform 1 S0546 cell division cycle 157313 CDCA2; cell division cycle associated 2 RNSETKVR N/A N/A 1:1200 associated 2 RSTRLQKD LEN (356) S0553 mitotic 129401 MP44; NUP35; LOC129401; SDYQVISD N/A N/A 1:3000- phosphoprotein 44 NUCLEOPORIN, 35-KD; mitotic RQTPKKDE 1:5400 phosphoprotein 44 (357) S0557 SMC4 structural 10051 SMC4L1; CAPC; hCAP-C; DIEGKLPQT N/A N/A 1:200 maintenance of chromosome-associated polypeptide C; EQELKE chromosomes 4-like 1 SMC4 (structural maintenance of (358) (yeast) chromosomes 4, yeast)-like 1; SMC4 structural maintenance of chromosomes 4-like 1 (yeast); structural maintenance of chromosomes (SMC) family member, chromosome-ass S0564 phosphatidylserine 9791 KIAA0024; PSSA; PTDSS1; DDVNYKM N/A N/A 1:1000- synthase 1 phosphatidylserine synthase 1 HFRMINEQ 1:8000 QVED (359) S0565 polo-like kinase 1 5347 2.7.1.-; PLK1; STPK13; polo-like ENPLPERPR N/A N/A 1:10- (Drosophila) kinase (Drosophila); polo (Drosophia)- EKEEPVVR 1:100 like kinase; SERINE/THREONINE (360) PROTEIN KINASE 13; polo-like kinase 1 (Drosophila) S0567 Pirin 8544 Pirin; PIR REQSEGVG N/A N/A 1:240 ARVRRSIG RPE (361) S0578 ATP-binding cassette, 21 ABCA3; ABC3; LBM180; ABC-C; PRAVAGKE N/A N/A 1:1500 sub-family A (ABC1), EST111653; ABC transporter 3; ATP- EEDSDPEK member 3 binding cassette 3; ATP-BINDING ALR (362) CASSETTE TRANSPORTER 3; ATP-BINDING CASSETTE, SUBFAMILY A, MEMBER 3; ATP- binding cassette, sub-family A member 3; ATP-binding cassette, sub-family A (ABC1), memb S0579 ATP-binding cassette, 10347 ABCX; ABCA7; ABCA-SSN; EKADTDME N/A N/A 1:300- sub-family A (ABC1), autoantigen SS-N; macrophage ABC GSVDTRQE 1:400 member 7 transporter; SJOGREN SYNDROME K (363) ANTIGEN SS-N; ATP-BINDING CASSETTE, SUBFAMILY A, MEMBER 7; ATP-binding cassette, sub-family A (ABC1), member 7; ATP-binding cassette, sub-family A, member 7 isoform a; A S0581 ATP-binding cassette, 22 ABCB7; Atm1p; ASAT; ABC7; RVQNHDNP N/A N/A 1:4000- sub-family B EST140535; ABC TRANSPORTER 7; KWEAKKE 1:10000 (MDR/TAP), member ATP-binding cassette 7; ATP- NISK (364) 7 BINDING CASSETTE TRANSPORTER 7; Anemia, sideroblastic, with spinocerebellar ataxia; ATP-BINDING CASSETTE, SUBFAMILY B, MEMBER 7; ATP- binding cassette, sub-family B, member S0585 ATP-binding cassette, 94160 MRP9; ABCC12; MULTIDRUG RSPPAKGA N/A N/A 1:500 sub-family C RESISTANCE-ASSOCIATED TGPEEQSD (CFTR/MRP), PROTEIN 9; ATP-BINDING SLK (365) member 12 CASSETTE, SUBFAMILY C, MEMBER 12; ATP-binding cassette, sub-family C (CFTR/MRP), member 12 S0586 ATP-binding cassette, 9429 ABC15; MXR1; ABCP; EST157481; REEDFKAT N/A N/A 1:333- sub-family G MRX; ABCG2; BCRP1; BMDP; EIIEPSKQD 1:400 (WHITE), member 2 MITOXANTRONE-RESISTANCE KP (366) PROTEIN; mitoxantrone resistance protein; placenta specific MDR protein; ATP-BINDING CASSETTE TRANSPORTER, PLACENTA- SPECIFIC; breast cancer resistance protein; ATP-BINDING CASS S0593 solute carrier organic 28234 OATP1B3; SLC21A8; OATP8; DKTCMKW N/A N/A 1:500- anion transporter SLCO1B3; ORGANIC ANION STNSCGAQ 1:2400 family, member 1B3 TRANSPORTER 8; solute carrier (367) organic anion transporter family, member 1B3; SOLUTE CARRIER FAMILY 21, MEMBER 8 (ORGANIC ANION TRANSPORTER); solute carrier family 21 (organic anion transporter), member 8 S0597 solute carrier family 9356 ROAT1; MGC45260; HOAT1; PAHT; DANLSKNG N/A N/A 1:3000 22 (organic anion SLC22A6; PAH TRANSPORTER; GLEVWL transporter), member para-aminohippurate transporter; renal (368) 6 organic anion transporter 1; solute carrier family 22 member 6 isoform b; solute carrier family 22 member 6 isoform c; solute carrier family 22 member 6 isoform S0604 solute carrier family 7355 UGT2; UGTL; UGAT; SLC35A2; EPFLPKLLT N/A N/A 1:2400 35 (UDP-galactose UGT1; UDP-galactose translocator; K (369) transporter), member UDP-GALACTOSE A2 TRANSPORTER, ISOFORM 2; UGALT UDP-GALACTOSE TRANSPORTER, ISOFORM 1; solute carrier family 35 (UDP-galactose transporter), member A2; solute carrier family 35 (UDP-galactose transpo S0607 cell division cycle 994 3.1.3.48; CDC25B; cell division cycle RKSEAGSG N/A N/A 1:1800 25B 25B; cell division cycle 25B isoform 4; AASSSGED cell division cycle 25B isoform 5; cell KEN (370) division cycle 25B isoform 1; cell division cycle 25B isoform 2; cell division cycle 25B isoform 3 S0609 stearoyl-CoA 6319 SCD; acyl-CoA desaturase; stearoyl- DDIYDPTY N/A N/A 1:2000- desaturase (delta-9- CoA desaturase (delta-9-desaturase); KDKEGPSP 1:5000 desaturase) fatty acid desaturase KVE (371) S0611 mitogen-activated 6300 SAPK3; p38gamma; SAPK-3; p38- QSDEAKNN N/A N/A 1:100 protein kinase 12 GAMMA; PRKM12; MAPK12; MKGLPELE ERK3; ERK6; EXTRACELLULAR KKD (372) SIGNAL-REGULATED KINASE 6; mitogen-activated protein kinase 3; stress-activated protein kinase 3; mitogen-activated protein kinase 12 S0612 nuclear factor of 4791 LYT-10; LYT10; NFKB2; SRPQGLTE N/A N/A 1:4500 kappa light ONCOGENE LYT 10; AEQRELEQ polypeptide gene TRANSCRIPTION FACTOR NFKB2; EAK (373) enhancer in B-cells 2 NFKB, p52/p100 SUBUNIT; (p49/p100) LYMPHOCYTE TRANSLOCATION CHROMOSOME 10; NUCLEAR FACTOR KAPPA-B, SUBUNIT 2; Nuclear factor of kappa light chain gene enhancer in B-cells 2; nuclear factor of kappa 1 S0613 tumor necrosis factor 958 Bp50; TNFRSF5; MGC9013; RVQQKGTS N/A N/A 1:250- receptor superfamily, CDW40; CD40 antigen; CD40L ETDTIC 1:270 member 5 receptor; B CELL-ASSOCIATED (374) MOLECULE CD40; CD40 type II isoform; B cell surface antigen CD40; nerve growth factor receptor-related B- lymphocyte activation molecule; tumor necrosis factor receptor superfam S0614 Epstein-Barr virus 10148 EBI3; IL27, EBI3 SUBUNIT; VRLSPLAE N/A N/A 1:1200- induced gene 3 EPSTEIN-BARR VIRUS-INDUCED RQLQVQW 1:3000 GENE 3; INTERLEUKIN 27, EBI3 E (375) SUBUNIT; Epstein-Barr virus induced gene 3; Epstein-Barr virus induced gene 3 precursor S0616 zinc finger protein 58495 ZNF339; zinc finger protein 339 RRSLGVSV N/A N/A 1:2500 339 RSWDELPD EKR (376) S0617 DAB2 interacting 153090 DAB2IP; DAB2 interacting protein DEGLGPDP N/A N/A 1:600 protein PHRDRLRS K (377) S0618 protein tyrosine 8500 MGC26800; LIP1; PPFIA1; LIP.1; SGKRSSDG N/A N/A 1:150 phosphatase, receptor LAR-interacting protein 1; PTPRF SLSHEEDL type, f polypeptide interacting protein alpha 1 isoform a; AK (378) (PTPRF), interacting PTPRF interacting protein alpha 1 protein (liprin), alpha isoform b; protein tyrosine 1 phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin), alpha 1 S0631 RGM domain family, 56963 RGMA; REPULSIVE GUIDANCE SQERSDSPE N/A N/A 1:600 member A MOLECULE; RGM domain family, ICHYEKSFH member A K (379) S0633 hypothetical protein 144347 LOC144347; hypothetical protein KVNPEPTH N/A N/A 1:100- LOC144347 LOC144347 EIRCNSEVK 1:200 (380) S0639 tetratricopeptide 57217 TTC7; tetratricopeptide repeat domain 7 RELREVLR N/A N/A 1:2000- repeat domain 7 TVETKATQ 1:3000 N (381) S0640 protein C (inactivator 5624 PROC; 3.4.21.69; PROC RDTEDQED N/A N/A 1:1000- of coagulation factors DEFICIENCY PROTEIN C; QVDPRLID 1:1800 Va and VIIIa) THROMBOPHILIA, HEREDITARY, GK (382) DUE TO PC DEFICIENCY; PROTEIN C DEFICIENCY, CONGENITAL THROMBOTIC DISEASE DUE TO; protein C (inactivator of coagulation factors Va

and VIIIa) S0643 transducin-like 7090 HsT18976; KIAA1547; ESG3; TLE3; KNHHELDH N/A N/A 1:200- enhancer of split 3 transducin-like enhancer protein 3; RERESSAN 1:1440 (E(sp1) homolog, enhancer of split groucho 3; (383) Drosophila) transducin-like enhancer of split 3 (E(sp1) homolog, Drosophila) S0645 frizzled homolog 7 8324 FzE3; FZD7; frizzled 7; frizzled SDGRGRPA N/A N/A 1:900 (Drosophila) homolog 7 (Drosophila); Frizzled, FPFSCPRQ drosophila, homolog of, 7 (384) S0646 solute carrier family 3 6520 MDU1; 4T2HC; SLC3A2; NACAE; GSKEDFDS N/A N/A 1:3600- (activators of dibasic 4F2HC; 4F2 HEAVY CHAIN; CD98 LLQSAKK 1:5400 and neutral amino HEAVY CHAIN; CD98 (385) acid transport), MONOCLONAL ANTIBODY 44D7; member 2 ANTIGEN DEFINED BY MONOCLONAL ANTIBODY 4F2, HEAVY CHAIN; antigen identified by monoclonal antibodies 4F2, TRA1.10, TROP4, and T43; SOLUTE CARRIER FAMILY 3 S0648 KIAA0738 gene 9747 KIAA0738; KIAA0738 gene product EYRNQTNL N/A N/A 1:200 product PTENVDK (386) S0651 phospholipase A2 22925 PLA2IR; PLA2-R; PLA2R1; QKEEKTW N/A N/A 1:3600 receptor 1, 180 kDa PLA2G1R; PHOSPHOLIPASE A2 HEALRSCQ RECEPTOR, 180-KD; phospholipase ADN (387) A2 receptor 1, 180 kDa S0654 KIAA0182 protein 23199 KIAA0182; KIAA0182 protein EKAEEGPR N/A N/A 1:400 KREPAPLD K (388) S0659 thymidine kinase 2, 7084 TK2; THYMIDINE KINASE, EQNRDRIL N/A N/A 1:300 mitochondrial MITOCHONDRIAL; thymidine TPENRK kinase 2, mitochondrial (389) S0663 chromosome 14 open 64430 C14orf135; chromosome 14 open RDWYIGLV N/A N/A 1:900 reading frame 135 reading frame 135 SDEKWK (390) S0665 KIAA1007 protein 23019 KIAA1007; KIAA1007 protein; DSYLKTRS N/A N/A 1:1500- adrenal gland protein AD-005; PVTFLSDLR 1:3000 KIAA1007 protein isoform a; (391) KIAA1007 protein isoform b S0670 DKFZP56601646 25936 DC8; DKFZP56601646 protein KCRGETVA N/A N/A 1:900 protein KEISEAMK S (392) S0672 B-cell 605 BCL7A; B-cell CLL/lymphoma-7; B- QRGSQIGR N/A N/A 1:800 CLL/lymphoma 7A cell CLL/lymphoma 7A EPIGLSGD (393) S0673 likely ortholog of 28987 ART-4; NOB1P; adenocarcinoma KPPQETEK N/A N/A 1:50 mouse nin one antigen recognized by T lymphocytes GHSACEPE binding protein 4; likely ortholog of mouse nin one N (394) binding protein S0676 guanine nucleotide 2768 RMP; NNX3; GNA12; GUANINE ERRAGSGA N/A N/A 1:1200- binding protein (G NUCLEOTIDE-BINDING PROTEIN, RDAERE 1:2400 protein) alpha 12 ALPHA-12; guanine nucleotide (395) binding protein (G protein) alpha 12 S0677 GrpE-like 1, 80273 HMGE; GRPEL1; HUMAN SEQKADPP N/A N/A 1:500- mitochondrial (E. MITOCHONDRIAL GrpE PROTEIN; ATEKTLLE 1:1000 coli) GrpE-like 1, mitochondrial (E. coli); (396) GrpE, E. COLI, HOMOLOG OF, 1 S0684 hypothetical protein 91607 FLJ34922; hypothetical protein EAEWSQGV N/A N/A 1:8100 FLJ34922 FLJ34922 QGTLRIKK YLT (397) S0687 hypothetical protein 54942 FLJ20457; hypothetical protein EESKSITEG N/A N/A 1:600- FLJ20457 FLJ20457 LLTQKQYE 1:1260 (398) S0691 solute carrier family 23657 CCBR1; SLC7A11; xCT; QNFKDAFS N/A N/A 1:1000- 7, (cationic amino cystine/glutamate transporter; GRDSSITR 1:1575 acid transporter, y+ SYSTEM Xc(-) TRANSPORTER- (399) system) member 11 RELATED PROTEIN; SOLUTE CARRIER FAMILY 7, MEMBER 11; solute carrier family 7, (cationic amino acid transporter, y+ system) member 11 S0692 glutamate-cysteine 2729 GLCLC; GCLC; 6.3.2.2; GCS; EKIHLDDA N/A N/A 1:100- ligase, catalytic GAMMA-GLUTAMYLCYSTEINE NESDHFEN 1:400 subunit SYNTHETASE, CATALYTIC (400) SUBUNIT; glutamate-cysteine ligase, catalytic subunit S0695 integrin, beta 4 3691 ITGB4; INTEGRIN, BETA-4; TEDVDEFR N/A N/A 1:2700- integrin, beta 4 NKLQGER 1:4050 (401) S0702 solute carrier family 7 8140 SLC7A5; MPE16; D16S469E; CD98; KGDVSNLD N/A N/A 1:21160- (cationic amino acid LAT1; 4F2 light chain; Membrane PNFSFEGTK 1:178200 transporter, y+ protein E16; L-TYPE AMINO ACID LDV (402) system), member 5 TRANSPORTER 1; Solute carrier family 7, member 5; solute carrier family 7 (cationic amino acid transporter, y+ system), member 5 S0705 breast cancer 25855 DKFZp564A063; BRMS1; breast KARAAVSP N/A N/A 1:1000- metastasis suppressor cancer metastasis-suppressor 1; breast QKRKSDGP 1:2000 1 cancer metastasis suppressor 1 (403) S0706 KiSS-1 metastasis- 3814 MGC39258; KISS1; KiSS-1 RQIPAPQG N/A N/A 1:180 suppressor metastasis-suppressor; KISS1 AVLVQREK METASTIN; malignant melanoma D (404) metastasis-suppressor; KISS1 METASTASIS SUPPRESSOR S0708 cofactor required for 9439 DKFZp434H0117; CRSP133; SUR2; SVKEQVEK N/A N/A 1:2430 Sp1 transcriptional DRIP130; CRSP3; mediator; IICNLKPAL activation, subunit 3, transcriptional co-activator CRSP130; K (138) 130 kDa CRSP, 130-KD SUBUNIT; CRSP 130-kD subunit; 133 kDa transcriptional co-activator; 130 kDa transcriptional co-activator; vitamin D3 receptor interacting protein; c S5002 keratin 14 3861 CK; KRT14; K14; EBS4; EBS3; Antibody obtained from Chemicon 1:50 (epidermolysis bullosa cytokeratin 14; CK 14; KERATIN, simplex, Dowling- TYPE I CYTOSKELETAL 14; keratin Meara, Koebner) 14 (epidermolysis bullosa simplex, Dowling-Meara, Koebner) S5003 keratin 17 3872 PCHC1; PC; PC2; 39.1; KRT17; K17; Antibody obtained from Dako 1:10- CYTOKERATIN 17; VERSION 1; 1:25 CK 17; KERATIN, TYPE I CYTOSKELETAL 17 S5004 keratin 18 3875 K18; CYK18; KRT18; Antibody obtained from Dako 1:200- CYTOKERATIN 18; CK 18; 1:400 KERATIN, TYPE I CYTOSKELETAL 18 S5005 keratin 18 3875 K18; CYK18; KRT18; Antibody obtained from Becton Dickinson 1:50- CYTOKERATIN 18; CK 18; 1:100 KERATIN, TYPE I CYTOSKELETAL 18 S5012 tumor-associated 4072 TROP1; LY74; Ep-CAM; GA733-2; Antibody obtained from Oncogene 1:40 calcium signal EGP40; MK-1; CO17-1A; EPCAM; Research Products (Calbiochem) transducer 1 M4S1; KSA; TACSTD1; EGP; MK-1 antigen; EPITHELIAL CELLULAR ADHESION MOLECULE; GASTROINTESTINAL TUMOR- ASSOCIATED ANTIGEN 2, 35-KD GLYCOPROTEIN; tumor-associated calcium signal transducer 1 precurso S5014 estrogen receptor 2 2100 ER-BETA; ESR-BETA; ESR2; Erb; Antibody obtained from Oncogene 1:2500 (ER beta) ESRB; NR3A2; ESTROGEN Research Products (Calbiochem) RECEPTOR, BETA; estrogen receptor 2 (ER beta) S5038 mucin 1, 4582 PEMT; MUC1; episialin; EMA; PUM; Antibody obtained from Imperial Cancer 1:1 transmembrane H23AG; CD227; PEM; Research Technology (ICRT) CARCINOMA-ASSOCIATED MUCIN; H23 antigen; TUMOR- ASSOCIATED MUCIN; DF3 antigen; peanut-reactive urinary mucin; mucin 1, transmembrane; polymorphic epithelial mucin; MUCIN 1, URINARY; MUCIN, TUMOR- ASSOCIATE S5044 transferrin receptor 7037 P90; TR; TFRC; TFR; CD71; T9; Antibody obtained from NeoMarkers 1:20 (p90, CD71) TRFR; ANTIGEN CD71; TRANSFERRIN RECEPTOR PROTEIN; transferrin receptor (p90, CD71) S5045 v-erb-b2 2064 HER-2; ERBB2; NGL; P185ERBB2; Antibody obtained from NeoMarkers 1:600 erythroblastic HER2; C-ERBB-2; NEU; MLN 19; leukemia viral EC 2.7.1.112; TKR1 HERSTATIN; oncogene homolog 2, NEU PROTO-ONCOGENE; neuro/glioblastoma ONCOGENE ERBB2; RECEPTOR derived oncogene PROTEIN-TYROSINE KINASE homolog (avian) ERBB-2 PRECURSOR; ONCOGENE NGL, NEUROBLASTOMA- OR GLIOBLASTOMA-DERIVED; TYROSINE KINASE-TYPE CELL S5047 major vault protein 9961 MVP; LRP; VAULT1; LUNG Antibody obtained from NeoMarkers 1:300 RESISTANCE-RELATED PROTEIN; MAJOR VAULT PROTEIN, RAT, HOMOLOG OF S5064 tumor protein p73-like 8626 LMS; TP73L; KET; SHFM4; p73H; Antibody obtained from Dako 1:50 EEC3; TP63; p51; TUMOR PROTEIN p63; TUMOR PROTEIN p73-LIKE; p53-RELATED PROTEIN p63; tumor protein 63 kDa with strong homology to p53 S5065 estrogen receptor 1 2099 ER; NR3A1; ESR1; Era; ESR; ER- Antibody obtained from Dako 1:20 ALPHA; ESRA; ESTRADIOL RECEPTOR; ESTROGEN RECEPTOR, ALPHA; estrogen receptor 1 (alpha) S5066 v-erb-b2 2064 HER-2; ERBB2; NGL; P185ERBB2; Antibody obtained from Dako 1:300 erythroblastic HER2; C-ERBB-2; NEU; MLN 19; leukemia viral EC 2.7.1.112; TKR1 HERSTATIN; oncogene homolog 2, NEU PROTO-ONCOGENE; neuro/glioblastoma ONCOGENE ERBB2; RECEPTOR

derived oncogene PROTEIN-TYROSINE KINASE homolog (avian) ERBB-2 PRECURSOR; ONCOGENE NGL, NEUROBLASTOMA- OR GLIOBLASTOMA-DERIVED; TYROSINE KINASE-TYPE CELL S5067 cathepsin D 1509 CTSD; MGC2311; CPSD; EC Antibody obtained from Dako 1:20- (lysosomal aspartyl 3.4.23.5; cathepsin D preproprotein; 1:50 protease) Cathepsin D precursor; cathepsin D (lysosomal aspartyl protease); S5069 CA 125 n/a Antibody obtained from Dako 1:20 S5070 CA 15-3 n/a Antibody obtained from Dako 1:50 S5071 CA 19-9 n/a Antibody obtained from Dako 1:50 S5072 v-myc 4609 c-Myc; MYC; ONCOGENE MYC; Antibody obtained from Dako 1:50 myelocytomatosis Myc proto-oncogene protein; viral oncogene PROTOONCOGENE homolog (avian) HOMOLOGOUS TO MYELOCYTOMATOSIS VIRUS; v- myc myelocytomatosis viral oncogene homolog (avian); v-myc avian myelocytomatosis viral oncogene homolog; Avian myelocytomatosis viral (v-myc) onco S5073 cadherin 1, type 1, E- 999 CDH1; Cadherin-1; Arc-1; ECAD; Antibody obtained from Dako 1:100- cadherin (epithelial) CDHE; Uvomorulin; LCAM; 1:150 Epithelial-cadherin precursor; cell- CAM 120/80; CADHERIN, EPITHELIAL; calcium-dependent adhesion protein, epithelial; cadherin 1, E-cadherin (epithelial); cadherin 1, type 1 preproprotein; cadherin 1, S5074 glutathione S- 2950 GSTP1; DFN7; GSTP1-1; GST3; Antibody obtained from Dako 1:50 transferase pi GSTPP; GST class-pi; glutathione transferase; EC 2.5.1.18; glutathione S-transferase pi; GST, CLASS PI; deafness, X-linked 7; GLUTATHIONE S-TRANSFERASE 3; GLUTATHIONE S- TRANSFERASE, PI; FAEES3 GLUTATHIONE S-TRANSFERASE PI PSEUD S5075 tumor protein p53 (Li- 7157 p53; TP53; TRP53; Antibody obtained from Dako 1:50 Fraumeni syndrome) PHOSPHOPROTEIN P53; TRANSFORMATION-RELATED PROTEIN 53; TUMOR SUPPRESSOR P53; CELLULAR TUMOR ANTIGEN P53; tumor protein p53 (Li-Fraumeni syndrome) S5076 progesterone receptor 5241 NR3C3; PR; PGR; PROGESTERONE Antibody obtained from Dako 1:50 RESISTANCE; PSEUDOCORPUS LUTEUM INSUFFICIENCY PROGESTERONE RECEPTOR S5077 trefoil factor 1 (breast 7031 Antibody obtained from Dako 1:50- cancer, estrogen- 1:100 inducible sequence expressed in) S5079 enolase 2, (gamma, 2026 NSE; ENO2; 2-phospho-D-glycerate Antibody obtained from Dako 1:400 neuronal) hydro-lyase; ENOLASE, GAMMA; neurone-specific enolase; ENOLASE, NEURON-SPECIFIC; 2-phospho-D- glycerate hydrolyase; EC 4.2.1.11; Neural enolase; enolase-2, gamma, neuronal; neuron specific gamma enolase; enolase 2, (gamma, S5080 B-cell 596 BCL2; FOLLICULAR LYMPHOMA; Antibody obtained from Dako 1:50 CLL/lymphoma 2 APOPTOSIS REGULATOR BCL-2; B-cell CLL/lymphoma 2; B-cell lymphoma protein 2 alpha; B-cell lymphoma protein 2 beta; ONCOGENE B-CELL LEUKEMIA 2 LEUKEMIA, CHRONIC LYMPHATIC, TYPE 2 S5081 retinoblastoma 1 5925 p105-Rb; PP110; Retinoblastoma-1; Antibody obtained from Dako 1:20 (including RB; RB1; RETINOBLASTOMA- osteosarcoma) ASSOCIATED PROTEIN; RB OSTEOSARCOMA, RETINOBLASTOMA-RELATED; retinoblastoma 1 (including osteosarcoma) S5082 synaptophysin 6855 SYP; Synaptophysin; Major synaptic Antibody obtained from Dako 1:50 vesicle protein P38 S5083 BCL2-associated X 581 BAX; BCL2-associated X protein; Antibody obtained from Dako 1:500 protein APOPTOSIS REGULATOR BAX, MEMBRANE ISOFORM ALPHA S5086 estrogen receptor 2 2100 ER-BETA; ESR-BETA; ESR2; Erb; Antibody obtained from Abcam 1:200 (ER beta) ESRB; NR3A2; ESTROGEN RECEPTOR, BETA; estrogen receptor 2 (ER beta) S5087 mucin 1, 4582 PEMT; MUC1; episialin; EMA; PUM; Antibody obtained from Zymed 1:200- transmembrane H23AG; CD227; PEM; 1:1600 CARCINOMA-ASSOCIATED MUCIN; H23 antigen; TUMOR- ASSOCIATED MUCIN; DF3 antigen; peanut-reactive urinary mucin; mucin 1, transmembrane; polymorphic epithelial mucin; MUCIN 1, URINARY; MUCIN, TUMOR- ASSOCIATE S6001 estrogen receptor 1 2099 ER; NR3A1; ESR1; Era; ESR; ER- Antibody obtained from US Labs 1:1 ALPHA; ESRA; ESTRADIOL RECEPTOR; ESTROGEN RECEPTOR, ALPHA; estrogen receptor 1 (alpha) S6002 progesterone receptor 5241 NR3C3; PR; PGR; PROGESTERONE Antibody obtained from US Labs 1:1 RESISTANCE; PSEUDOCORPUS LUTEUM INSUFFICIENCY PROGESTERONE RECEPTOR S6003 v-erb-b2 2064 HER-2; ERBB2; NGL; P185ERBB2; Antibody obtained from US Labs 1:1 erythroblastic HER2; C-ERBB-2; NEU; MLN 19; leukemia viral EC 2.7.1.112; TKR1 HERSTATIN; oncogene homolog 2, NEU PROTO-ONCOGENE; neuro/glioblastoma ONCOGENE ERBB2; RECEPTOR derived oncogene PROTEIN-TYROSINE KINASE homolog (avian) ERBB-2 PRECURSOR; ONCOGENE NGL, NEUROBLASTOMA- OR GLIOBLASTOMA-DERIVED; TYROSINE KINASE-TYPE CELL S6004 B-cell 596 BCL2; FOLLICULAR LYMPHOMA; Antibody obtained from US Labs 1:1 CLL/lymphoma 2 APOPTOSIS REGULATOR BCL-2; B-cell CLL/lymphoma 2; B-cell lymphoma protein 2 alpha; B-cell lymphoma protein 2 beta; ONCOGENE B-CELL LEUKEMIA 2 LEUKEMIA, CHRONIC LYMPHATIC, TYPE 2 S6005 keratin 5 3852 KRT5; EBS2; Keratin-5; K5; Antibody obtained from US Labs 1:1 (epidermolysis bullosa CYTOKERATIN 5; CK 5; 58 KDA simplex, Dowling- CYTOKERATIN; KERATIN, TYPE Meara/Kobner/Weber- II CYTOSKELETAL 5; keratin 5 Cockayne types) (epidermolysis bullosa simplex, Dowling-Meara/Kobner/Weber- Cockayne types) S6006 tumor protein p53 (Li- 7157 p53; TP53; TRP53; Antibody obtained from US Labs 1:1 Fraumeni syndrome) PHOSPHOPROTEIN P53; TRANSFORMATION-RELATED PROTEIN 53; TUMOR SUPPRESSOR P53; CELLULAR TUMOR ANTIGEN P53; tumor protein p53 (Li-Fraumeni syndrome) S6007 KI67 n/a Antibody obtained from US Labs 1:1 S6008 epidermal growth 1956 S7; EGFR; 2.7.1.112; ERBB; Antibody obtained from US Labs 1:1 factor receptor ONCOGENE ERBB; ERBB1 (erythroblastic SPECIES ANTIGEN 7; V-ERB-B leukemia viral (v-erb- AVIAN ERYTHROBLASTIC b) oncogene homolog, LEUKEMIA VIRAL ONCOGENE avian) HOMOLOG; epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog) S6011 enolase 2, (gamma, 2026 NSE; ENO2; 2-phospho-D-glycerate Antibody obtained from US Labs 1:1 neuronal) hydro-lyase; ENOLASE, GAMMA; neurone-specific enolase; ENOLASE, NEURON-SPECIFIC; 2-phospho-D- glycerate hydrolyase; EC 4.2.1.11; Neural enolase; enolase-2, gamma, neuronal; neuron specific gamma enolase; enolase 2, (gamma, S6012 thyroid transcription 7080 benign chorea; chorea, hereditary Antibody obtained from US Labs 1:1 factor 1 benign; NK-2 (Drosophila) homolog A (thyroid nuclear factor); Thyroid transcription factor 1 (NK-2, Drosophila, homolog of, A); BCH; BHC; TEBP; TTF1; NKX2A; TTF-1; NKX2.1 S6013 v-erb-b2 2064 HER-2; ERBB2; NGL; P185ERBB2; Antibody obtained from US Labs 1:1 erythroblastic HER2; C-ERBB-2; NEU; MLN 19; leukemia viral EC 2.7.1.112; TKR1 HERSTATIN; oncogene homolog 2, NEU PROTO-ONCOGENE; neuro/glioblastoma ONCOGENE ERBB2; RECEPTOR derived oncogene PROTEIN-TYROSINE KINASE homolog (avian) ERBB-2 PRECURSOR; ONCOGENE NGL, NEUROBLASTOMA- OR GLIOBLASTOMA-DERIVED; TYROSINE KINASE-TYPE CELL

OTHER EMBODIMENTS

[0198] Other embodiments of the invention will be apparent to those skilled in the art from a consideration of the specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope of the invention being indicated by the following claims.

Sequence CWU 1

1

404120PRTHomo sapiens 1Thr Glu Glu Ser Ile Asn Asp Glu Asp Ile Tyr Lys Gly Leu Pro Asp 1 5 10 15 Leu Ile Asp Glu 20 215PRTHomo sapiens 2Glu Lys Arg Thr Asn Gly Leu Arg Arg Thr Pro Lys Gln Val Asp 1 5 10 15 313PRTHomo sapiens 3Asp Tyr Ile Ser Lys Ser Lys Glu Asp Val Lys Leu Lys 1 5 10 418PRTHomo sapiens 4Glu Lys Thr Gly Val Cys Pro Glu Leu Gln Ala Asp Gln Asn Cys Thr 1 5 10 15 Gln Glu 514PRTHomo sapiens 5Pro Asn Asp Lys Glu Gly Ser Cys Pro Gln Val Asn Ile Asn 1 5 10 615PRTHomo sapiens 6Arg Asp Gln Cys Gln Val Asp Thr Gln Cys Pro Gly Gln Met Lys 1 5 10 15 719PRTHomo sapiens 7Ser Lys Thr Ile Asn Pro Gln Val Ser Lys Thr Glu Tyr Lys Glu Leu 1 5 10 15 Leu Gln Glu 815PRTHomo sapiens 8Asp Asp Asn Ala Thr Thr Asn Ala Ile Asp Glu Leu Lys Glu Cys 1 5 10 15 915PRTHomo sapiens 9Asn Gln Thr Asp Glu Thr Leu Ser Asn Val Glu Val Phe Met Gln 1 5 10 15 1019PRTHomo sapiens 10Ser Ser Asp Asp Gly Ile Arg Pro Leu Pro Glu Tyr Ser Thr Glu Lys 1 5 10 15 His Lys Lys 1117PRTHomo sapiens 11Asp Gly Lys Ser Lys Asp Lys Pro Pro Lys Arg Lys Lys Ala Asp Thr 1 5 10 15 Glu 1215PRTHomo sapiens 12Asn Lys Thr Lys Lys Lys Lys Ser Ser Arg Leu Pro Pro Glu Lys 1 5 10 15 1318PRTHomo sapiens 13Lys Asn Lys Glu Pro Leu Thr Lys Lys Gly Glu Thr Lys Thr Ala Glu 1 5 10 15 Arg Asp 1417PRTHomo sapiens 14Lys Leu Thr Cys Thr Asp Leu Asp Ser Ser Pro Arg Ser Phe Arg Tyr 1 5 10 15 Ser 1517PRTHomo sapiens 15Glu Val Asp Tyr Glu Asn Pro Ser Asn Leu Ala Ala Gly Asn Lys Tyr 1 5 10 15 Thr 1620PRTHomo sapiens 16Lys Thr Leu Gln Val Phe Asn Pro Leu Arg Phe Ser Arg Glu Asn Ser 1 5 10 15 Glu Lys Ile His 20 1715PRTHomo sapiens 17Gln His Phe Ala Ile Ile Glu Cys Lys Val Ala Val Ala Leu Thr 1 5 10 15 1817PRTHomo sapiens 18Arg Lys Phe Leu Ala Pro Asp His Ser Arg Pro Pro Gln Pro Val Arg 1 5 10 15 Gln 1918PRTHomo sapiens 19Met Ala Lys Ala Glu Val Lys Leu Ala Ile Phe Gly Arg Ala Gly Val 1 5 10 15 Gly Lys 2016PRTHomo sapiens 20Val Leu Pro Leu Lys Asn Ile Leu Asp Glu Ile Lys Lys Pro Lys Asn 1 5 10 15 2117PRTHomo sapiens 21Tyr Glu Leu Cys Arg Glu Val Arg Arg Arg Arg Met Val Gln Gly Lys 1 5 10 15 Thr 2219PRTHomo sapiens 22Thr Lys Pro Thr Thr Ile Ile Glu Lys Asn Gly Asp Ile Leu Thr Leu 1 5 10 15 Lys Thr His 2315PRTHomo sapiens 23Lys Asn Thr Glu Ile Ser Phe Lys Leu Gly Val Glu Phe Asp Glu 1 5 10 15 2415PRTHomo sapiens 24His Leu Gln Lys Trp Asp Gly Gln Glu Thr Thr Leu Val Arg Glu 1 5 10 15 2521PRTHomo sapiens 25Asp Gly Asn Asp Val Glu Phe Thr Trp Leu Arg Gly Asn Asp Ser Val 1 5 10 15 Arg Gly Leu Glu His 20 2619PRTHomo sapiens 26Leu Gln Gln Met Ala Ala Lys Asp Arg Gly Thr Thr Lys Glu Val Glu 1 5 10 15 Glu Val Ser 2720PRTHomo sapiens 27Lys Arg Lys Ile Ser Phe Ala Ser Ile Glu Ile Ser Ser Asp Asn Val 1 5 10 15 Asp Tyr Ser Asp 20 2819PRTHomo sapiens 28Gln Arg Gln Gln Ile Ala Lys Ser Phe Lys Ala Gln Phe Gly Lys Asp 1 5 10 15 Leu Thr Glu 2920PRTHomo sapiens 29Arg Glu Ile Met Lys Ala Tyr Glu Glu Asp Tyr Gly Ser Ser Leu Glu 1 5 10 15 Glu Asp Ile Gln 20 3018PRTHomo sapiens 30Glu Glu Tyr Glu Lys Ile Ala Asn Lys Ser Ile Glu Asp Ser Ile Lys 1 5 10 15 Ser Glu 3121PRTHomo sapiens 31Glu Gly Gly Ser Leu Val Pro Ala Ala Arg Gln Gln His Cys Thr Gln 1 5 10 15 Val Arg Ser Arg Arg 20 3215PRTHomo sapiens 32Arg Lys Ala Gly Lys Ser Lys Lys Ser Ser Arg Lys Glu Ala Glu 1 5 10 15 3316PRTHomo sapiens 33Lys Thr His Glu Lys Tyr Gly Trp Val Thr Pro Pro Val Ser Asp Gly 1 5 10 15 3415PRTHomo sapiens 34Met Asp Leu Glu Gly Asp Arg Asn Gly Gly Ala Lys Lys Lys Asn 1 5 10 15 3519PRTHomo sapiens 35Asn Leu Glu Asp Leu Met Ser Asn Ile Thr Asn Arg Ser Asp Ile Asn 1 5 10 15 Asp Thr Gly 3615PRTHomo sapiens 36Arg Gly Ser Gln Ala Gln Asp Arg Lys Leu Ser Thr Lys Glu Ala 1 5 10 15 3718PRTHomo sapiens 37Met Asp Leu Glu Ala Ala Lys Asn Gly Thr Ala Trp Arg Pro Thr Ser 1 5 10 15 Ala Glu 3817PRTHomo sapiens 38Asn Phe Ser Phe Pro Val Asn Phe Ser Leu Ser Leu Leu Asn Pro Gly 1 5 10 15 Lys 3916PRTHomo sapiens 39Lys Asn Ser Gln Met Cys Gln Lys Ser Leu Asp Val Glu Thr Asp Gly 1 5 10 15 4013PRTHomo sapiens 40Met Ala Leu Arg Gly Phe Cys Ser Ala Asp Gly Ser Asp 1 5 10 4116PRTHomo sapiens 41Lys Asn Trp Lys Lys Glu Cys Ala Lys Thr Arg Lys Gln Pro Val Lys 1 5 10 15 4216PRTHomo sapiens 42Asp Ser Ile Glu Arg Arg Pro Val Lys Asp Gly Gly Gly Thr Asn Ser 1 5 10 15 4320PRTHomo sapiens 43Met Leu Glu Lys Phe Cys Asn Ser Thr Phe Trp Asn Ser Ser Phe Leu 1 5 10 15 Asp Ser Pro Glu 20 4415PRTHomo sapiens 44Ser Ile Leu Cys Gly Thr Phe Gln Phe Gln Thr Leu Ile Arg Thr 1 5 10 15 4514PRTHomo sapiens 45Glu Asn Asn Glu Ser Ser Asn Asn Pro Ser Ser Ile Ala Ser 1 5 10 4616PRTHomo sapiens 46Gln Glu Val Lys Pro Asn Pro Leu Gln Asp Ala Asn Ile Cys Ser Arg 1 5 10 15 4716PRTHomo sapiens 47Asp Glu Ile Ser Gln Arg Asn Arg Gln Leu Pro Ser Asp Gly Lys Lys 1 5 10 15 4818PRTHomo sapiens 48Val Gln Asp Phe Thr Ala Phe Trp Asp Lys Ala Ser Glu Thr Pro Thr 1 5 10 15 Leu Gln 4918PRTHomo sapiens 49Met Asp Ala Leu Cys Gly Ser Gly Glu Leu Gly Ser Lys Phe Trp Asp 1 5 10 15 Ser Asn 5015PRTHomo sapiens 50Arg Lys Gln Glu Lys Gln Thr Ala Arg His Lys Ala Ser Ala Ala 1 5 10 15 5113PRTHomo sapiens 51Asp Pro Gln Ser Val Glu Arg Lys Thr Ile Ser Pro Gly 1 5 10 5219PRTHomo sapiens 52Met Lys Asp Ile Asp Ile Gly Lys Glu Tyr Ile Ile Pro Ser Pro Gly 1 5 10 15 Tyr Arg Ser 5318PRTHomo sapiens 53Arg Asp Arg Glu Asp Ser Lys Phe Arg Arg Thr Arg Pro Leu Glu Cys 1 5 10 15 Gln Asp 5415PRTHomo sapiens 54Ser Lys His Glu Ser Ser Asp Val Asn Cys Arg Arg Leu Glu Arg 1 5 10 15 5520PRTHomo sapiens 55Met Ala Ala Pro Ala Glu Pro Cys Ala Gly Gln Gly Val Trp Asn Gln 1 5 10 15 Thr Glu Pro Glu 20 5617PRTHomo sapiens 56Asp Pro Gly Val Val Asp Ser Ser Ser Ser Gly Ser Ala Ala Gly Lys 1 5 10 15 Ser 5713PRTHomo sapiens 57His Thr Leu Val Ala Glu Asn Ala Met Asn Ala Glu Lys 1 5 10 5818PRTHomo sapiens 58Met Ser Asp Ser Val Ile Leu Arg Ser Ile Lys Lys Phe Gly Glu Glu 1 5 10 15 Asn Asp 5914PRTHomo sapiens 59Thr Asn Ser Ser Leu Asn Gln Asn Met Thr Asn Gly Thr Arg 1 5 10 6015PRTHomo sapiens 60Gln Glu Val Leu Ser Lys Ile Gln His Gly His Thr Ile Ile Ser 1 5 10 15 6115PRTHomo sapiens 61Gly Ala Asp Asp Pro Ser Ser Val Thr Ala Glu Glu Ile Gln Arg 1 5 10 15 6214PRTHomo sapiens 62Asn Ala Val Ala Ser Pro Glu Phe Pro Pro Arg Phe Asn Thr 1 5 10 6318PRTHomo sapiens 63Lys Pro Asn Gly Ile Tyr Arg Lys Leu Met Asn Lys Gln Ser Phe Ile 1 5 10 15 Ser Ala 6413PRTHomo sapiens 64Met Ala Ser Ser Arg Cys Pro Ala Pro Arg Gly Cys Arg 1 5 10 6510PRTHomo sapiens 65Gln Gly Gly Ser Gly Asn Pro Val Arg Arg 1 5 10 6617PRTHomo sapiens 66Glu Phe Val Gly Asp Gly Ile Tyr Asn Asn Thr Met Gly His Val His 1 5 10 15 Ser 6716PRTHomo sapiens 67Met Pro Leu Ala Phe Cys Gly Ser Glu Asn His Ser Ala Ala Tyr Arg 1 5 10 15 6818PRTHomo sapiens 68Asp His Leu Gly Lys Glu Asn Asp Val Phe Gln Pro Lys Thr Gln Phe 1 5 10 15 Leu Gly 6916PRTHomo sapiens 69Glu Ile Arg Glu Glu Gln Cys Ala Pro His Glu Pro Thr Pro Gln Gly 1 5 10 15 7012PRTHomo sapiens 70Met Ser Leu Ser Phe Cys Gly Asn Asn Ile Ser Ser 1 5 10 7118PRTHomo sapiens 71Gln Arg Val Asn Glu Thr Gln Asn Gly Thr Asn Asn Thr Thr Gly Ile 1 5 10 15 Ser Glu 7219PRTHomo sapiens 72Asp Glu Ile Gly Asp Asp Ser Trp Arg Thr Gly Glu Ser Ser Leu Pro 1 5 10 15 Phe Glu Ser 7321PRTHomo sapiens 73Met Val Lys Val Thr Phe Asn Ser Ala Leu Ala Gln Lys Glu Ala Lys 1 5 10 15 Lys Asp Glu Pro Lys 20 7416PRTHomo sapiens 74Gln Thr Ile Glu Glu Asn Ile Lys Ile Phe Glu Glu Glu Glu Val Glu 1 5 10 15 7521PRTHomo sapiens 75His Asp Lys Glu Thr Tyr Lys Leu Gln Arg Arg Glu Thr Ile Lys Gly 1 5 10 15 Ile Gln Lys Arg Glu 20 7620PRTHomo sapiens 76Met Ala His Ala Ala Ser Gln Leu Lys Lys Asn Arg Asp Leu Glu Ile 1 5 10 15 Asn Ala Glu Glu 20 7720PRTHomo sapiens 77His Lys Lys Glu Thr Glu Ser Asp Gln Asp Asp Glu Ile Glu Lys Thr 1 5 10 15 Asp Arg Arg Gln 20 7820PRTHomo sapiens 78Glu Gly Phe Lys Val Lys Thr Lys Lys Glu Ile Arg His Val Glu Lys 1 5 10 15 Lys Ser His Ser 20 7918PRTHomo sapiens 79Glu Arg Ala Leu Ala Ala Ala Gln Arg Cys His Lys Lys Val Met Lys 1 5 10 15 Glu Arg 8015PRTHomo sapiens 80Thr Ala Gly Met Lys Asp Leu Leu Ser Val Phe Gln Ala Tyr Gln 1 5 10 15 8116PRTHomo sapiens 81Asp Pro Pro Arg Thr Val Leu Gln Ala Pro Lys Glu Trp Val Cys Leu 1 5 10 15 8220PRTHomo sapiens 82Met Glu Ala Ala Asp Ala Ser Arg Ser Asn Gly Ser Ser Pro Glu Ala 1 5 10 15 Arg Asp Ala Arg 20 8317PRTHomo sapiens 83Glu Leu His Leu Lys Pro His Leu Glu Gly Ala Ala Phe Arg Asp His 1 5 10 15 Gln 8418PRTHomo sapiens 84Glu Gly Glu Gly Leu Gly Gln Ser Leu Gly Asn Phe Lys Asp Asp Leu 1 5 10 15 Leu Asn 8517PRTHomo sapiens 85Glu Leu His Leu Lys Pro His Leu Glu Gly Ala Ala Phe Arg Asp His 1 5 10 15 Gln 8617PRTHomo sapiens 86Gly Ser Glu Glu Arg Gly Ala Gly Arg Gly Ser Ser Gly Gly Arg Glu 1 5 10 15 Glu 8718PRTHomo sapiens 87Lys Ile Trp Ser Leu Ala Glu Thr Ala Thr Ser Pro Asp Asn Pro Arg 1 5 10 15 Arg Ser 8820PRTHomo sapiens 88Lys Lys Leu Leu Lys Thr Ala Phe Gln Pro Val Pro Arg Arg Pro Gln 1 5 10 15 Asn His Leu Asp 20 8921PRTHomo sapiens 89Arg Arg Ser Ser Thr Thr His Val Lys Gln Ala Ile Asn Lys Met Leu 1 5 10 15 Thr Lys Ile Ser Ser 20 9020PRTHomo sapiens 90Met Arg Arg Lys Asn Thr Cys Gln Asn Phe Met Glu Tyr Phe Cys Ile 1 5 10 15 Ser Leu Ala Phe 20 9121PRTHomo sapiens 91Asn Glu Thr Ile Leu Tyr Phe Pro Phe Ser Ser His Ser Ser Tyr Thr 1 5 10 15 Val Arg Ser Lys Lys 20 9219PRTHomo sapiens 92Lys Val Gln Ile Pro Ala Tyr Ile Glu Met Asn Ile Pro Leu Val Ile 1 5 10 15 Leu Cys Gln 9318PRTHomo sapiens 93Met Leu Thr Glu Leu Glu Lys Ala Leu Asn Ser Ile Ile Asp Val Tyr 1 5 10 15 His Lys 9422PRTHomo sapiens 94Arg Asp Asp Leu Lys Lys Leu Leu Glu Thr Glu Cys Pro Gln Tyr Ile 1 5 10 15 Arg Lys Lys Gly Ala Asp 20 9517PRTHomo sapiens 95Lys Met Gly Val Ala Ala His Lys Lys Ser His Glu Glu Ser His Lys 1 5 10 15 Glu 9617PRTHomo sapiens 96Pro Glu Ser Arg Lys Asp Pro Ser Gly Ala Ser Asn Pro Ser Ala Asp 1 5 10 15 Ser 9715PRTHomo sapiens 97His Gly Leu Ala Pro His Glu Ser Gln Leu His Leu Lys Gly Asp 1 5 10 15 9818PRTHomo sapiens 98Glu Gln Gln His Lys Leu Asp Phe Lys Ala Tyr Glu Gln Ala Leu Gln 1 5 10 15 Tyr Ser 9915PRTHomo sapiens 99His Gly Leu Ala Pro His Glu Ser Gln Leu His Leu Lys Gly Asp 1 5 10 15 10020PRTHomo sapiens 100Glu Glu Tyr Val Gly Leu Ser Ala Asn Gln Cys Ala Val Pro Ala Lys 1 5 10 15 Asp Arg Val Asp 20 10115PRTHomo sapiens 101Arg Val Asp Cys Gly Tyr Pro His Val Thr Pro Lys Glu Cys Asn 1 5 10 15 10215PRTHomo sapiens 102Val Pro Trp Cys Phe Lys Pro Leu Gln Glu Ala Glu Cys Thr Phe 1 5 10 15 10315PRTHomo sapiens 103Val Pro Trp Cys Phe Lys Pro Leu Gln Glu Ala Glu Cys Thr Phe 1 5 10 15 10416PRTHomo sapiens 104Lys Lys Glu Pro Val Thr Thr Arg Gln Val Arg Thr Ile Val Glu Glu 1 5 10 15 10517PRTHomo sapiens 105Gln Asp Gly Lys Val Ile Ser Ser Arg Glu Gln Val His Gln Thr Thr 1 5 10 15 Arg 10615PRTHomo sapiens 106Ser Ser Ser Ile Lys Gly Ser Ser Gly Leu Gly Gly Gly Ser Ser 1 5 10 15 10720PRTHomo sapiens 107Asp Glu Glu Asp Lys Leu Arg His Phe Arg Glu Cys Phe Tyr Ile Pro 1 5 10 15 Lys Ile Gln Asp 20 10821PRTHomo sapiens 108Lys Pro Arg Glu Gly Glu Glu Thr Leu Arg Ile Glu Asp Ile Leu Glu 1 5 10 15 Val Ile Glu Lys Glu 20 10921PRTHomo sapiens 109Glu Glu Arg Gly Cys Gln Leu Thr Ile Thr Phe Ser Val Pro Asn Lys 1 5 10 15 Asp Val Phe Gln Glu 20 11020PRTHomo sapiens 110Asp His Asn His Ala Ala Ser Gly Lys Asn Lys Arg Lys Ala Leu Cys 1 5 10 15 Pro Asp His Asp 20 11121PRTHomo sapiens 111Glu Glu Pro Ala Met Glu Met Lys Arg Gly Pro Leu Phe Ser His Leu 1 5 10 15 Ser Ser Gln Asn Ile 20 11216PRTHomo sapiens 112Gln Arg Tyr Ser Arg Glu Glu Leu Lys Asp Ala Gly Val Ala Thr Leu 1 5 10 15 11322PRTHomo sapiens 113Met Asp Ile Glu Ala Tyr Leu Glu Arg Ile Gly Tyr Lys Lys Ser Arg 1 5 10 15 Asn Lys Leu Asp Leu Glu 20 11422PRTHomo sapiens 114Gln Met Trp Gln Pro Leu Glu Leu Ile Ser Gly Lys Asp Gln Pro Gln 1 5 10 15 Val Pro Cys Val Phe Arg 20 11520PRTHomo sapiens 115Phe Asn Ile Ser Leu Gln Arg Lys Leu Val Pro Lys His Gly Asp Arg 1 5 10 15 Phe Phe Thr Ile 20 11621PRTHomo sapiens 116Arg Gln Arg Leu Thr His Leu Ser Pro Glu Glu Lys Ala Leu Arg Arg 1 5 10

15 Lys Leu Lys Asn Arg 20 11720PRTHomo sapiens 117Glu Lys Thr His Gly Leu Val Val Glu Asn Gln Glu Leu Arg Gln Arg 1 5 10 15 Leu Gly Met Asp 20 11820PRTHomo sapiens 118Gln Pro Pro Phe Leu Cys Gln Trp Gly Arg His Gln Pro Ser Trp Lys 1 5 10 15 Pro Leu Met Asn 20 11916PRTHomo sapiens 119Asn Lys Ile Thr Thr Glu Phe Phe Asp Pro Leu Phe Val Glu Gln Lys 1 5 10 15 12018PRTHomo sapiens 120Phe Ser Ile Ser Asp Asn Asn Lys Thr Pro Arg Tyr Thr Tyr Asn Gly 1 5 10 15 Ala Thr 12118PRTHomo sapiens 121Glu Asp Phe Lys Thr Thr Asn Pro Ser Lys Gln Phe Asp Lys Asn Ala 1 5 10 15 Tyr Val 12220PRTHomo sapiens 122Glu Gly Asp Ala Lys Gly Leu Lys Glu Gly Glu Thr Pro Gly Asn Phe 1 5 10 15 Met Glu Asp Glu 20 12319PRTHomo sapiens 123Glu Trp Cys Phe Cys Phe Trp Arg Glu Lys Pro Pro Cys Leu Ala Glu 1 5 10 15 Leu Glu Arg 12416PRTHomo sapiens 124Glu Glu Glu Gly Glu Ala Gly Glu Ala Asp Asp Gly Gly Tyr Ile Trp 1 5 10 15 12513PRTHomo sapiens 125Asp Lys Asp Pro Gln Lys Met Tyr Ala Thr Ile Tyr Glu 1 5 10 12615PRTHomo sapiens 126Lys Lys Cys Asp Tyr Trp Ile Arg Thr Phe Val Pro Gly Cys Gln 1 5 10 15 12715PRTHomo sapiens 127Glu Asn Phe Ile Arg Phe Ser Lys Tyr Leu Gly Leu Pro Glu Asn 1 5 10 15 12815PRTHomo sapiens 128Asp Asp Ser Asp Gln Asp Ser Cys Arg Leu Ser Ile Asp Ser Gln 1 5 10 15 12915PRTHomo sapiens 129Arg Gln His Tyr Pro Glu Ala Tyr Ala Ser Pro Ser His Thr Lys 1 5 10 15 13019PRTHomo sapiens 130Asn Thr Pro Leu Gly Arg Asn Leu Ser Thr His Gln Thr Tyr Pro Val 1 5 10 15 Val Ala Asp 13115PRTHomo sapiens 131Arg Leu Val Ser Cys Pro Gly Pro Leu Asp Gln Asp Gln Gln Glu 1 5 10 15 13219PRTHomo sapiens 132Lys Met Ser Pro Glu Asp Ile Arg Lys Trp Asn Val Thr Ser Leu Glu 1 5 10 15 Thr Leu Lys 13320PRTHomo sapiens 133Ser Pro Glu Glu Leu Ser Ser Val Pro Pro Ser Ser Ile Trp Ala Val 1 5 10 15 Arg Pro Gln Asp 20 13417PRTHomo sapiens 134Glu Glu Gln Asn Lys Leu Val His Gly Gly Pro Cys Asp Lys Thr Ser 1 5 10 15 His 13516PRTHomo sapiens 135Glu Leu Ile Gln Pro Leu Pro Leu Glu Arg Asp Cys Ser Ala Asn Thr 1 5 10 15 13614PRTHomo sapiens 136Gly Lys Thr Ala Asp Gly Asp Phe Pro Asp Thr Ile Gln Cys 1 5 10 13720PRTHomo sapiens 137Arg Glu Gln Trp Pro Glu Arg Arg Arg Cys His Arg Leu Glu Asn Gly 1 5 10 15 Cys Gly Asn Ala 20 13818PRTHomo sapiens 138Ser Val Lys Glu Gln Val Glu Lys Ile Ile Cys Asn Leu Lys Pro Ala 1 5 10 15 Leu Lys 13916PRTHomo sapiens 139Lys Val Asn Ser Ala Gly Asp Ala Ile Gly Leu Gln Pro Asp Ala Arg 1 5 10 15 14020PRTHomo sapiens 140Gln Gln Leu Lys Val Ile Asp Asn Gln Arg Glu Leu Ser Arg Leu Ser 1 5 10 15 Arg Glu Leu Glu 20 14116PRTHomo sapiens 141Arg Glu His Met Gln Ala Val Thr Arg Asn Tyr Ile Thr His Pro Arg 1 5 10 15 14213PRTHomo sapiens 142Lys Lys Ser Lys Ala Val Leu Asp Tyr His Asp Asp Asn 1 5 10 14319PRTHomo sapiens 143Asp Glu Phe Tyr Ser Arg Glu Gly Arg Leu Gln Asp Leu Ala Pro Asp 1 5 10 15 Thr Ala Leu 14418PRTHomo sapiens 144Lys Gln Gln Asp Gly Pro Thr Lys Thr His Lys Leu Glu Lys Leu Met 1 5 10 15 Ile Arg 14519PRTHomo sapiens 145Glu Leu Arg Val Leu Ser Lys Ala Asn Ala Ile Val Pro Gly Leu Ser 1 5 10 15 Gly Gly Glu 14620PRTHomo sapiens 146Arg Arg Gly Gly Glu Gly Gly Glu Glu Asn Pro Ser Ala Ala Lys Gly 1 5 10 15 His Leu Met Gly 20 14714PRTHomo sapiens 147Met Pro Glu Val Ser Ser Lys Gly Ala Thr Ile Ser Lys Lys 1 5 10 14811PRTHomo sapiens 148Gly Phe Lys Lys Ala Val Val Lys Thr Gln Lys 1 5 10 14912PRTHomo sapiens 149Lys Glu Gly Lys Lys Arg Lys Arg Thr Arg Lys Glu 1 5 10 15018PRTHomo sapiens 150Arg Tyr Ala Phe Asp Phe Ala Arg Asp Lys Asp Gln Arg Ser Leu Asp 1 5 10 15 Ile Asp 15119PRTHomo sapiens 151Ser Val Phe Tyr Gln Tyr Leu Glu Gln Ser Lys Tyr Arg Val Met Asn 1 5 10 15 Lys Asp Gln 15222PRTHomo sapiens 152Glu Asp Gly Ala Trp Pro Val Leu Leu Asp Glu Phe Val Glu Trp Gln 1 5 10 15 Lys Val Arg Gln Thr Ser 20 15319PRTHomo sapiens 153Ser Phe Lys Ser Pro Gln Val Tyr Leu Lys Glu Glu Glu Glu Lys Asn 1 5 10 15 Glu Lys Arg 15417PRTHomo sapiens 154Arg Lys Lys Gln Gln Glu Ala Gln Gly Glu Lys Ala Ser Arg Tyr Ile 1 5 10 15 Glu 15520PRTHomo sapiens 155Glu Asp Ile Gly Ile Thr Val Asp Thr Val Leu Ile Leu Glu Glu Lys 1 5 10 15 Glu Gln Thr Asn 20 15618PRTHomo sapiens 156Lys Ala Phe Arg Gly Ala Thr Asp Leu Lys Asn Leu Arg Leu Asp Lys 1 5 10 15 Asn Gln 15718PRTHomo sapiens 157Asp Phe Arg Cys Glu Glu Gly Gln Glu Glu Gly Gly Cys Leu Pro Arg 1 5 10 15 Pro Gln 15821PRTHomo sapiens 158Asp Gly Thr Ser Phe Ala Glu Glu Val Glu Lys Pro Thr Lys Cys Gly 1 5 10 15 Cys Ala Leu Cys Ala 20 15920PRTHomo sapiens 159Gln Arg Ile Lys Glu Gln Ala Ser Lys Ile Ser Glu Ala Asp Lys Ser 1 5 10 15 Lys Pro Lys Phe 20 16021PRTHomo sapiens 160His Ala Lys Thr Lys Glu Lys Leu Glu Val Thr Trp Glu Lys Met Ser 1 5 10 15 Lys Ser Lys His Asn 20 16118PRTHomo sapiens 161Lys Ser Pro Gln Pro Gln Leu Leu Ser Asn Lys Glu Lys Ala Glu Ala 1 5 10 15 Arg Lys 16216PRTHomo sapiens 162Met Leu Phe Glu Gln Gly Gln Gln Ala Leu Glu Leu Pro Glu Cys Thr 1 5 10 15 16320PRTHomo sapiens 163Lys Asp Gln Lys Ala Lys Gly Ile Leu His Ser Pro Ala Ser Gln Ser 1 5 10 15 Pro Glu Arg Ser 20 16416PRTHomo sapiens 164His Ser Ser Gln Gly Arg Leu Pro Glu Ala Pro Lys Leu Thr His Leu 1 5 10 15 16518PRTHomo sapiens 165Lys Arg Gly Ala Arg Arg Gly Gly Trp Lys Arg Lys Met Pro Ser Thr 1 5 10 15 Asp Leu 16616PRTHomo sapiens 166Lys Ile Val Arg Val Pro Leu Thr Lys Met Met Glu Val Asp Val Arg 1 5 10 15 16719PRTHomo sapiens 167Gln Phe Leu Lys Asp Ile Arg Glu Ser Val Thr Gln Ile Met Lys Asn 1 5 10 15 Pro Lys Ala 16818PRTHomo sapiens 168Ser Lys Gln Gly Val Val Ile Leu Asp Asp Lys Ser Lys Glu Leu Pro 1 5 10 15 His Trp 16920PRTHomo sapiens 169Val Gln Thr Phe Ser Arg Cys Ile Leu Cys Ser Lys Asp Glu Val Asp 1 5 10 15 Leu Asp Glu Leu 20 17016PRTHomo sapiens 170Leu Lys Lys Pro Phe Gln Pro Phe Gln Arg Thr Arg Ser Phe Arg Met 1 5 10 15 17119PRTHomo sapiens 171Met Asn Leu Leu Asp Pro Phe Met Lys Met Thr Asp Glu Gln Glu Lys 1 5 10 15 Gly Leu Ser 17218PRTHomo sapiens 172Asn Thr Phe Pro Lys Gly Glu Pro Asp Leu Lys Lys Glu Ser Glu Glu 1 5 10 15 Asp Lys 17319PRTHomo sapiens 173Lys Asn Gly Gln Ala Glu Ala Glu Glu Ala Thr Glu Gln Thr His Ile 1 5 10 15 Ser Pro Asn 17418PRTHomo sapiens 174Gln Ala Ser Ser Leu Arg Leu Glu Pro Gly Arg Ala Asn Asp Gly Asp 1 5 10 15 Trp His 17520PRTHomo sapiens 175Glu Leu Lys Gly Phe Ala Glu Arg Leu Gln Arg Asn Glu Ser Gly Leu 1 5 10 15 Asp Ser Gly Arg 20 17617PRTHomo sapiens 176Arg Ser Gly Lys Ser Gln Pro Ser Tyr Ile Pro Phe Leu Leu Arg Glu 1 5 10 15 Glu 17722PRTHomo sapiens 177Arg Arg Ser Asp Tyr Ala Lys Val Ala Lys Ile Phe Tyr Asn Leu Ser 1 5 10 15 Ile Gln Ser Phe Asp Asp 20 17819PRTHomo sapiens 178Lys Asn Phe Thr Met Asn Glu Lys Leu Lys Lys Phe Phe Asn Val Leu 1 5 10 15 Thr Thr Asn 17920PRTHomo sapiens 179Glu Phe Phe Val Asn Glu Ala Arg Lys Asn Asn His His Phe Lys Ser 1 5 10 15 Glu Ser Glu Glu 20 18019PRTHomo sapiens 180Lys Asn Thr Gln Ala Ala Glu Ala Leu Val Lys Leu Tyr Glu Thr Lys 1 5 10 15 Leu Cys Glu 18117PRTHomo sapiens 181Gln Glu Asn Gln Pro Glu Asn Ser Lys Thr Leu Ala Thr Gln Leu Asn 1 5 10 15 Gln 18219PRTHomo sapiens 182Lys Gln Met Glu Lys Asp Leu Ala Phe Gln Lys Gln Val Ala Glu Lys 1 5 10 15 Gln Leu Lys 18317PRTHomo sapiens 183Glu Phe Val Glu Gln Leu Arg Lys Glu Gly Val Phe Ala Lys Glu Val 1 5 10 15 Arg 18418PRTHomo sapiens 184Asp Arg His Pro Gln Ala Leu Glu Ala Ala Gln Ala Glu Leu Gln Gln 1 5 10 15 His Asp 18520PRTHomo sapiens 185Arg Glu Val Arg Gln Leu Thr Leu Arg Lys Leu Gln Glu Leu Ser Ser 1 5 10 15 Lys Ala Asp Glu 20 18620PRTHomo sapiens 186Arg Glu Val Arg Gln Leu Thr Leu Arg Lys Leu Gln Glu Leu Ser Ser 1 5 10 15 Lys Ala Asp Glu 20 18719PRTHomo sapiens 187Ala Tyr Ile Arg Glu Gly His Glu Lys Gln Ala Asp Ile Met Ile Phe 1 5 10 15 Phe Ala Glu 18818PRTHomo sapiens 188Asp Glu Ala Ser Leu Glu Pro Gly Tyr Pro Lys His Ile Lys Glu Leu 1 5 10 15 Gly Arg 18916PRTHomo sapiens 189Arg Gly Ser Phe Met Gly Ser Asp Glu Val Phe Thr Tyr Phe Tyr Lys 1 5 10 15 19020PRTHomo sapiens 190Met Ile Pro Gly Gly Leu Ser Glu Ala Lys Pro Ala Thr Pro Glu Ile 1 5 10 15 Gln Glu Ile Val 20 19115PRTHomo sapiens 191Asn Glu Thr Tyr Gly Lys Leu Glu Ala Val Gln Tyr Lys Thr Gln 1 5 10 15 19220PRTHomo sapiens 192Asp Leu Val Leu Thr Gly Tyr Gln Val Asp Lys Asn Lys Asp Asp Glu 1 5 10 15 Leu Thr Gly Phe 20 19320PRTHomo sapiens 193Arg Gln Glu His Cys Met Ser Glu His Phe Lys Asn Arg Pro Ala Cys 1 5 10 15 Leu Gly Ala Arg 20 19419PRTHomo sapiens 194Gln Gly His Lys Trp Gly Glu Ser Pro Ser Gln Gly Thr Gln Ala Gly 1 5 10 15 Ala Gly Lys 19521PRTHomo sapiens 195Arg Ala Cys Gly Lys Arg Val Ser Glu Gly Asp Arg Asn Gly Ser Gly 1 5 10 15 Gly Gly Lys Trp Gly 20 19616PRTHomo sapiens 196Met Val Glu Ala Phe Cys Ala Thr Trp Lys Leu Thr Asn Ser Gln Asn 1 5 10 15 19715PRTHomo sapiens 197Gln Val Gly Asn Val Thr Lys Pro Thr Val Ile Ile Ser Gln Glu 1 5 10 15 19814PRTHomo sapiens 198Lys Val Val Ile Arg Thr Leu Ser Thr Phe Lys Asn Thr Glu 1 5 10 19919PRTHomo sapiens 199Arg Ala Val Phe Arg Glu Ala Glu Val Thr Leu Glu Ala Gly Gly Ala 1 5 10 15 Glu Gln Glu 20017PRTHomo sapiens 200Gln Glu Pro Ala Leu Phe Ser Thr Asp Asn Asp Asp Phe Thr Val Arg 1 5 10 15 Asn 20115PRTHomo sapiens 201Gln Lys Tyr Glu Ala His Val Pro Glu Asn Ala Val Gly His Glu 1 5 10 15 20214PRTHomo sapiens 202Lys Lys Ile Ile Glu Lys Met Leu Asn Ser Asp Lys Ser Asn 1 5 10 20320PRTHomo sapiens 203Gly Lys Pro Gly Asn Gln Asn Ser Lys Asn Glu Pro Pro Lys Lys Arg 1 5 10 15 Glu Arg Glu Arg 20 20414PRTHomo sapiens 204Gln Ala Glu Ala Pro Leu Val Pro Leu Ser Arg Gln Asn Lys 1 5 10 20513PRTHomo sapiens 205Asn Cys Phe Leu Thr Glu Arg Lys Ala Gln Pro Asp Glu 1 5 10 20615PRTHomo sapiens 206Glu Phe Asp Thr Val Asp Leu Ser Ala Val Asp Val His Pro Asn 1 5 10 15 20718PRTHomo sapiens 207Asn Lys Glu Val Tyr His Glu Lys Asp Ile Lys Val Phe Phe Asp Lys 1 5 10 15 Ala Lys 20815PRTHomo sapiens 208Lys Gln Val Asp Leu Glu Asn Val Trp Leu Asp Phe Ile Arg Glu 1 5 10 15 20918PRTHomo sapiens 209Leu Lys Lys Pro Gln Asp Ser Gln Leu Glu Glu Gly Lys Pro Gly Tyr 1 5 10 15 Leu Asp 21017PRTHomo sapiens 210Lys Ala Lys Arg Leu Gln Lys Gln Pro Glu Gly Glu Glu Pro Glu Met 1 5 10 15 Glu 21122PRTHomo sapiens 211Lys Asp Arg Pro Ser Phe Ser Glu Ile Ala Ser Ala Leu Gly Asp Ser 1 5 10 15 Thr Val Asp Ser Lys Pro 20 21217PRTHomo sapiens 212Lys Arg Gly Ile Glu Glu Arg Ile Gln Glu Glu Ser Gly Phe Leu Ile 1 5 10 15 Glu 21317PRTHomo sapiens 213Asp Arg Val Ile Gly Lys Asn Arg Gln Pro Lys Phe Glu Asp Arg Thr 1 5 10 15 Lys 21416PRTHomo sapiens 214Asn Pro Gln His Phe Leu Asp Asp Lys Gly Gln Phe Lys Lys Ser Asp 1 5 10 15 21518PRTHomo sapiens 215Arg His Cys Ile Leu Gly Glu Trp Leu Pro Ile Leu Ile Met Ala Val 1 5 10 15 Phe Asn 21616PRTHomo sapiens 216Lys Gln Arg Glu Leu Ala Gly Asn Thr Met Thr Val Ser Tyr Met Ser 1 5 10 15 21721PRTHomo sapiens 217Arg Asn Ala His Gly Ser Cys Leu His Ala Ser Thr Ala Asn Gly Ser 1 5 10 15 Ile Leu Ala Gly Leu 20 21816PRTHomo sapiens 218Glu Leu Met Glu Lys Glu Val Glu Pro Glu Gly Ser Lys Arg Thr Asp 1 5 10 15 21915PRTHomo sapiens 219Lys Ala Arg Ser Phe Cys Lys Thr His Ala Arg Leu Phe Lys Lys 1 5 10 15 22016PRTHomo sapiens 220Lys Asn Lys Arg Leu Ser Gly Met Glu Glu Trp Ile Glu Gly Glu Lys 1 5 10 15 22117PRTHomo sapiens 221Glu Gly Ser Thr Asp Leu Pro Leu Ala Pro Glu Ser Arg Val Asp Pro 1 5 10 15 Glu 22215PRTHomo sapiens 222Lys Val Ala Gln Gln Gln Arg His Leu Glu Lys Gln His Leu Arg 1 5 10 15 22320PRTHomo sapiens 223Asp His Lys His Leu Asp His Glu Val Ala Lys Pro Ala Arg Arg Lys 1 5 10 15 Arg Leu Pro Glu 20 22417PRTHomo sapiens 224Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala Glu Gly Lys Glu 1 5 10 15 Cys 22521PRTHomo sapiens 225Lys Ser Asp Leu Val Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr 1 5 10 15 Pro Glu Leu Pro Lys 20 22618PRTHomo sapiens 226Lys Pro Val Glu Asp Lys Asp Ala Val Ala Phe Thr Cys Glu Pro Glu 1 5 10 15 Ala Gln 22722PRTHomo sapiens 227Asp Glu Lys Leu Ile Ser Leu Ile Cys Arg Ala Val Lys Ala Thr Phe 1 5 10 15 Asn Pro Ala Gln Asp Lys 20 22819PRTHomo sapiens 228Lys Asp Lys Trp Asp Glu Leu Lys Glu Ala Gly Val Ser Asp Met Lys 1 5 10 15 Leu Gly Asp 22923PRTHomo sapiens

229Asp Ser Trp Ile Val Pro Leu Asp Asn Leu Thr Lys Asp Asp Leu Asp 1 5 10 15 Glu Glu Glu Asp Thr His Leu 20 23021PRTHomo sapiens 230Glu Ala Val Val Thr Asn Glu Leu Glu Asp Gly Asp Arg Gln Lys Ala 1 5 10 15 Met Lys Arg Leu Arg 20 23118PRTHomo sapiens 231Arg Arg Tyr Arg Asp Thr Lys Arg Ala Phe Pro His Leu Val Asn Ala 1 5 10 15 Gly Lys 23218PRTHomo sapiens 232Lys Ala Arg Asp Thr Lys Val Leu Ile Glu Asp Thr Asp Asp Glu Ala 1 5 10 15 Asn Thr 23320PRTHomo sapiens 233Arg Lys Arg Val Leu Glu Ala Lys Glu Leu Ala Leu Gln Pro Lys Asp 1 5 10 15 Asp Ile Val Asp 20 23421PRTHomo sapiens 234Arg His Gly Val Ser His Lys Val Asp Asp Ser Ser Gly Ser Ile Gly 1 5 10 15 Arg Arg Tyr Ala Arg 20 23520PRTHomo sapiens 235Glu Ala Arg Tyr Pro Leu Phe Glu Gly Gln Glu Thr Gly Lys Lys Glu 1 5 10 15 Thr Ile Glu Glu 20 23620PRTHomo sapiens 236Asp Leu Ala Gly His Asp Met Gly His Glu Ser Lys Arg Met His Ile 1 5 10 15 Glu Lys Asp Glu 20 23720PRTHomo sapiens 237Glu Lys Gln Val Gln Leu Glu Lys Thr Glu Leu Lys Met Asp Phe Leu 1 5 10 15 Arg Glu Arg Glu 20 23819PRTHomo sapiens 238Glu Ala Asp Arg Ser Gly Gly Arg Thr Asp Ala Glu Arg Thr Ile Gln 1 5 10 15 Asp Gly Arg 23918PRTHomo sapiens 239Glu Ala Leu Tyr Pro Gln Arg Arg Ser Tyr Thr Ser Glu Asp Glu Ala 1 5 10 15 Trp Lys 24019PRTHomo sapiens 240Asp Tyr Tyr Lys Val Pro Arg Glu Arg Arg Ser Ser Thr Ala Lys Pro 1 5 10 15 Glu Val Glu 24119PRTHomo sapiens 241Asp Lys Tyr Asp Val Pro His Asp Lys Ile Gly Lys Ile Phe Lys Lys 1 5 10 15 Cys Lys Lys 24221PRTHomo sapiens 242Asp Pro Asp Gln Tyr Asn Phe Ser Ser Ser Glu Leu Gly Gly Asp Phe 1 5 10 15 Glu Phe Met Asp Asp 20 24315PRTHomo sapiens 243Glu Tyr Ile Arg Gln Leu Pro Pro Asn Phe Pro Tyr Arg Asp Asp 1 5 10 15 24420PRTHomo sapiens 244Asp Thr Thr Val Leu Leu Pro Pro Tyr Asp Asp Ala Thr Val Asn Gly 1 5 10 15 Ala Ala Lys Glu 20 24514PRTHomo sapiens 245Arg Arg Glu Glu Val Thr Lys Lys His Gln Tyr Glu Ile Arg 1 5 10 24619PRTHomo sapiens 246Lys Glu Ser Arg Tyr Val His Asp Lys His Phe Glu Val Leu His Ser 1 5 10 15 Asp Leu Glu 24715PRTHomo sapiens 247Asp Phe Phe Asp Arg Phe Met Leu Thr Gln Lys Asp Ile Asn Lys 1 5 10 15 24819PRTHomo sapiens 248Glu Ser Lys His Phe Thr Arg Asp Leu Met Glu Lys Leu Lys Gly Arg 1 5 10 15 Thr Ser Arg 24917PRTHomo sapiens 249Glu Thr Asp Arg Leu Pro Arg Cys Val Arg Ser Thr Ala Arg Leu Ala 1 5 10 15 Arg 25020PRTHomo sapiens 250Glu Ser Arg Trp Lys Asp Ile Arg Ala Arg Ile Phe Leu Ile Ala Ser 1 5 10 15 Lys Glu Leu Glu 20 25123PRTHomo sapiens 251Lys Val Thr Leu Gly Leu Leu Val Phe Leu Ala Gly Phe Pro Val Leu 1 5 10 15 Asp Ala Asn Asp Leu Glu Asp 20 25212PRTHomo sapiens 252Ser Glu Trp Arg Ser Ser Gly Glu Gln Ala Gly Arg 1 5 10 25316PRTHomo sapiens 253Lys Cys Lys Cys Lys Phe Gly Gln Lys Ser Gly His His Pro Gly Glu 1 5 10 15 25421PRTHomo sapiens 254Lys Val Ala Lys Glu Ser Asp Ser Val Phe Val Leu Lys Ile Tyr His 1 5 10 15 Leu Arg Gln Glu Asp 20 25519PRTHomo sapiens 255Glu Arg Glu Lys Thr Val Thr Gly Glu Phe Ile Asp Lys Glu Ser Lys 1 5 10 15 Arg Pro Lys 25618PRTHomo sapiens 256Lys Arg Ala Glu Asp Thr Ala Gly Gln Thr Ala Leu Thr Val Met Arg 1 5 10 15 Pro Asp 25719PRTHomo sapiens 257Lys Val Ala Arg Lys Val Arg Ala Leu Tyr Asp Phe Glu Ala Val Glu 1 5 10 15 Asp Asn Glu 25818PRTHomo sapiens 258Glu Thr Glu Val Ala Ala Val Asp Lys Leu Asn Val Ile Asp Asp Asp 1 5 10 15 Val Glu 25919PRTHomo sapiens 259Glu Ile Lys Lys Ser Glu Pro Glu Pro Val Tyr Ile Asp Glu Asp Lys 1 5 10 15 Met Asp Arg 26018PRTHomo sapiens 260Asp Glu Glu Cys Gly Thr Asp Glu Tyr Cys Ala Ser Pro Thr Arg Gly 1 5 10 15 Gly Asp 26120PRTHomo sapiens 261Arg Gly Glu Ile Glu Glu Thr Ile Thr Glu Ser Phe Gly Asn Asp His 1 5 10 15 Ser Thr Leu Asp 20 26222PRTHomo sapiens 262Met Asp Leu Arg Arg Arg Asp Tyr His Met Glu Arg Pro Leu Leu Asn 1 5 10 15 Gln Glu His Leu Glu Glu 20 26316PRTHomo sapiens 263Asp Thr Asp Ile Tyr Arg Asp Val Ala Glu Tyr Ser Glu Ala Lys Glu 1 5 10 15 26424PRTHomo sapiens 264Glu Phe Tyr Ser Asp Ala Leu Lys Gln Arg Cys Gly Val Asp Val Asp 1 5 10 15 Phe Leu Ile Ser Gln Lys Lys Lys 20 26520PRTHomo sapiens 265Asp Ala His Gln Ala Arg Val Leu Ile Gly Phe Glu Glu Asp Ile Leu 1 5 10 15 Ile Val Ser Glu 20 26618PRTHomo sapiens 266Glu Arg Arg Ile Cys Glu Cys Pro Asp Gly Phe His Gly Pro His Cys 1 5 10 15 Glu Lys 26719PRTHomo sapiens 267Lys Arg Tyr Glu Ala Ser Leu Ile His Ala Leu Arg Pro Ala Gly Ala 1 5 10 15 Gln Leu Arg 26819PRTHomo sapiens 268Lys Arg Lys Val Asp Gly Leu Ser Thr Glu Ala Glu Gln Pro Phe Ile 1 5 10 15 Pro Val Glu 26920PRTHomo sapiens 269Lys Glu Gly Ala Cys Asp Glu Leu Phe Ser Tyr Leu Ile Glu Lys Val 1 5 10 15 Lys Arg Lys Lys 20 27018PRTHomo sapiens 270Asp Ile Lys Met Ile Leu Lys Met Val Gln Leu Asp Ser Ile Glu Asp 1 5 10 15 Leu Glu 27115PRTHomo sapiens 271Arg Leu Arg Lys Lys Ala Phe Ala Asn Pro Glu Asp Ala Leu Arg 1 5 10 15 27216PRTHomo sapiens 272Arg Ser Asp Pro Asp Val Glu Arg Cys Leu Arg Ala His Arg Asn Asp 1 5 10 15 27317PRTHomo sapiens 273Arg Val Ala His Thr Val Ala Tyr Leu Gly Lys Leu Arg Ala Pro Ile 1 5 10 15 Arg 27413PRTHomo sapiens 274Lys Arg Arg Ala Leu Ala Ala Pro Ala Ala Glu Glu Lys 1 5 10 27520PRTHomo sapiens 275Glu Ala Arg Glu Lys Met Leu Ala Ala Lys Ser Ala Asp Gly Ser Ala 1 5 10 15 Pro Ala Gly Glu 20 27616PRTHomo sapiens 276Met Ile Trp Leu Arg His Arg Lys Pro Glu Leu Glu Arg Pro Ile Lys 1 5 10 15 27713PRTHomo sapiens 277Lys Arg Arg Ala Leu Ala Ala Pro Ala Ala Glu Glu Lys 1 5 10 27814PRTHomo sapiens 278Lys Pro Asn Lys Ala Leu Lys Val Lys Lys Glu Ala Gly Glu 1 5 10 27922PRTHomo sapiens 279Lys Arg Val Thr Gln Lys Glu Glu Leu Glu Arg Gln Arg Val Glu Leu 1 5 10 15 Gln Gln Glu Val Glu Lys 20 28012PRTHomo sapiens 280Arg Leu Glu Leu Asp Ala Leu Arg Ser Lys Tyr Glu 1 5 10 28121PRTHomo sapiens 281Lys Met His Thr Asp Gly Arg Ser Cys Leu Glu Arg Glu Asp Thr Val 1 5 10 15 Leu Glu Val Thr Glu 20 28218PRTHomo sapiens 282Lys Lys Gly Phe Lys Leu Leu Thr Asp Glu Lys Ser Cys Gln Asp Val 1 5 10 15 Asp Glu 28321PRTHomo sapiens 283Lys Arg Thr Glu Lys Arg Leu Arg Lys Ala Ile Arg Thr Leu Arg Lys 1 5 10 15 Ala Val His Arg Glu 20 28417PRTHomo sapiens 284Arg Val Glu Gly Pro Gln Thr Glu Ser Lys Asn Glu Ala Ser Ser Arg 1 5 10 15 Asp 28519PRTHomo sapiens 285Glu Glu Thr Lys Ser Thr Glu Thr Glu Thr Gly Ser Arg Val Gly Lys 1 5 10 15 Leu Pro Glu 28621PRTHomo sapiens 286Lys Trp Glu Asn Phe Lys Leu Glu Ile Asn Glu Lys Asn Ser Trp Lys 1 5 10 15 Leu Phe Gln Phe Asp 20 28717PRTHomo sapiens 287Asp Lys Gly Tyr Leu Thr Lys Glu Asp Leu Arg Val Leu Met Glu Lys 1 5 10 15 Glu 28820PRTHomo sapiens 288Lys Asp Pro Leu Ala Val Asp Lys Ile Met Lys Asp Leu Asp Gln Cys 1 5 10 15 Arg Asp Gly Lys 20 28921PRTHomo sapiens 289Met Ser Arg Arg Thr Arg Cys Glu Asp Leu Asp Glu Leu His Tyr Gln 1 5 10 15 Asp Thr Asp Ser Asp 20 29023PRTHomo sapiens 290Glu Glu Asp Leu Lys Glu Val Leu Arg Ser Glu Ala Gly Ile Glu Leu 1 5 10 15 Ile Ile Glu Asp Asp Ile Arg 20 29120PRTHomo sapiens 291Arg Arg Ser Pro Ile Lys Lys Val Arg Lys Ser Leu Ala Leu Asp Ile 1 5 10 15 Val Asp Glu Asp 20 29217PRTHomo sapiens 292Glu Asp Tyr Lys Asn Thr Ala Glu Trp Leu Leu Ser His Thr Lys His 1 5 10 15 Arg 29322PRTHomo sapiens 293Asp Glu Arg Phe Gly Asp Arg Phe Pro Ala Met Ser Asp Ala Tyr Asp 1 5 10 15 Arg Thr Met Arg Gln Arg 20 29416PRTHomo sapiens 294Lys Val Ile Met Asp Tyr Glu Ser Leu Glu Lys Ala Asn His Glu Glu 1 5 10 15 29522PRTHomo sapiens 295Asp Gln Asp Arg Lys Ser Arg Leu Met Gly Leu Glu Ala Leu Lys Ser 1 5 10 15 His Ile Met Ala Ala Lys 20 29620PRTHomo sapiens 296Lys Gly Val Ile Val Asp Lys Asp Phe Ser His Pro Gln Met Pro Lys 1 5 10 15 Lys Val Glu Asp 20 29717PRTHomo sapiens 297Arg Met Ile Leu Lys Ile Asp Asp Ile Arg Lys Pro Gly Glu Ser Glu 1 5 10 15 Glu 29820PRTHomo sapiens 298Arg Leu Gln Pro Glu Phe Lys Pro Lys Gln Leu Glu Gly Thr Met Ala 1 5 10 15 Asn Cys Glu Arg 20 29920PRTHomo sapiens 299Lys Phe Met Gln Ala Ser Glu Asp Leu Leu Lys Glu His Tyr Val Asp 1 5 10 15 Leu Lys Asp Arg 20 30021PRTHomo sapiens 300Asp Ser Val Glu Ser Ala Glu Lys Glu Ile Gly Leu Trp Phe His Pro 1 5 10 15 Glu Glu Leu Val Asp 20 30118PRTHomo sapiens 301Lys Ser Pro Pro Glu Ser Glu Asn Lys Glu Gln Leu Glu Ala Arg Arg 1 5 10 15 Arg Arg 30218PRTHomo sapiens 302Arg Asp Gly Arg Lys Val Thr Val Ile Glu Arg Asp Leu Lys Glu Pro 1 5 10 15 Asp Arg 30317PRTHomo sapiens 303Asp His Leu Lys Glu Pro Phe Leu Glu Ala Thr Asp Asn Ser His Leu 1 5 10 15 Arg 30419PRTHomo sapiens 304Asp Leu Glu Val Lys Asp Trp Met Gln Lys Lys Arg Arg Gly Leu Arg 1 5 10 15 Asn Ser Arg 30524PRTHomo sapiens 305Glu Tyr His Lys Val His Gln Met Met Arg Glu Gln Ser Ile Leu Ser 1 5 10 15 Pro Ser Pro Tyr Glu Gly Tyr Arg 20 30623PRTHomo sapiens 306Arg His Gln Leu Leu Cys Phe Lys Glu Asp Cys Gln Ala Val Phe Gln 1 5 10 15 Asp Leu Glu Gly Val Glu Lys 20 30716PRTHomo sapiens 307Gly Pro Asp Ile Leu Arg Thr Tyr Ser Gly Ala Phe Val Cys Leu Glu 1 5 10 15 30812PRTHomo sapiens 308Cys Ser Leu Gly Leu Ala Leu Arg Arg Trp Arg Pro 1 5 10 30920PRTHomo sapiens 309Arg Tyr Leu Thr Leu Asp Ile Phe Ala Gly Pro Pro Asn Tyr Pro Phe 1 5 10 15 Ser Asp Glu Tyr 20 31020PRTHomo sapiens 310Arg Tyr Leu Thr Leu Asp Ile Phe Ala Gly Pro Pro Asn Tyr Pro Phe 1 5 10 15 Ser Asp Glu Tyr 20 31120PRTHomo sapiens 311His Tyr Phe Asn Ser Asp Ser Phe Ala Ser His Pro Asn Tyr Pro Tyr 1 5 10 15 Ser Asp Glu Tyr 20 31220PRTHomo sapiens 312His Tyr Phe Asn Ser Asp Ser Phe Ala Ser His Pro Asn Tyr Pro Tyr 1 5 10 15 Ser Asp Glu Tyr 20 31320PRTHomo sapiens 313Arg Tyr Val Val Met Asp Phe Leu Met Asp His Pro Asp Tyr Pro Phe 1 5 10 15 Ser Asp Glu Tyr 20 31420PRTHomo sapiens 314Arg Tyr Val Val Met Asp Phe Leu Met Asp His Pro Asp Tyr Pro Phe 1 5 10 15 Ser Asp Glu Tyr 20 31517PRTHomo sapiens 315Asp Pro Ala Lys Val Gln Ser Leu Val Asp Thr Ile Arg Glu Asp Pro 1 5 10 15 Asp 31617PRTHomo sapiens 316Arg Glu Thr Ile Pro Ala Lys Leu Val Gln Ser Thr Leu Ser Asp Leu 1 5 10 15 Arg 31717PRTHomo sapiens 317Ser Asp Thr Thr Glu Glu Leu Thr Val Ile Lys Ser Ser Leu Lys Asp 1 5 10 15 Glu 31816PRTHomo sapiens 318His Ser Arg Ser Ser Leu Met Pro Leu Arg Asn Asp Val Asp Lys Arg 1 5 10 15 31920PRTHomo sapiens 319Tyr Arg Asn Pro Tyr Val Glu Ala Glu Tyr Phe Pro Thr Lys Pro Met 1 5 10 15 Phe Val Ile Ala 20 32020PRTHomo sapiens 320Lys Lys Phe Pro Arg Phe Arg Asn Arg Glu Leu Glu Ala Thr Arg Arg 1 5 10 15 Gln Arg Met Asp 20 32114PRTHomo sapiens 321Ser Gly Asn Thr Ala Ile Asn Tyr Lys His Ser Ser Ile Pro 1 5 10 32220PRTHomo sapiens 322Asp Ala Asn Thr Cys Gly Glu Asp Lys Gly Ser Arg Arg Lys Phe Leu 1 5 10 15 Asp Gly Asp Glu 20 32320PRTHomo sapiens 323Gln Leu Glu Glu Met Thr Glu Leu Glu Ser Pro Lys Cys Lys Arg Gln 1 5 10 15 Glu Asn Glu Gln 20 32420PRTHomo sapiens 324Gln Ala Asp Gly Ala Ala Ser Ala Pro Thr Glu Glu Glu Glu Glu Val 1 5 10 15 Val Lys Asp Arg 20 32520PRTHomo sapiens 325Ser Gly Asp Ser Leu Glu Thr Lys Glu Asp Gln Lys Met Ser Pro Lys 1 5 10 15 Ala Thr Glu Glu 20 32620PRTHomo sapiens 326Arg Lys Ser Val Lys Arg Met Lys Glu Ser Arg Leu Glu Asp Thr Gln 1 5 10 15 Lys His Arg Val 20 32720PRTHomo sapiens 327Lys Ile Arg Leu Pro Glu Arg Glu Lys Pro Asp Arg Glu Arg Asn Ala 1 5 10 15 Arg Arg Glu Pro 20 32820PRTHomo sapiens 328Arg Gly Thr Lys Cys Leu Arg Arg Glu Ala Pro Arg Trp Asp Ala Pro 1 5 10 15 Leu Arg Asp Pro 20 32920PRTHomo sapiens 329Gly Thr Arg Ser Arg Ser His Thr Ser Glu Gly Arg Thr Ser Arg Ser 1 5 10 15 His Thr Ser Glu 20 33018PRTHomo sapiens 330Glu Glu Thr Thr Ala Asp Gly Arg Lys Thr Gln Thr Val Cys Asn Phe 1 5 10 15 Thr Asp 33116PRTHomo sapiens 331Ala Lys Arg Lys Arg Ser Ala Pro Glu Lys Ser Ser Gly Asp Val Pro 1 5 10 15 33220PRTHomo sapiens 332Arg Val Asp Arg Pro Gly Ser Arg Tyr Asp Val Ser Arg Leu Gly Arg 1 5 10 15 Gly Lys Arg Ser 20 33317PRTHomo sapiens 333Glu Thr Val Asp Lys Leu Leu Lys Gly Tyr Asp Ile Arg Leu Arg Pro 1 5 10 15 Asp 33420PRTHomo sapiens 334Ala Pro Gly Gly Ala Glu Asp Leu Glu Asp Thr Gln Phe Pro Ser Glu 1 5 10 15 Glu Ala Arg Glu 20 33520PRTHomo sapiens 335Arg Lys Ser Ser Arg Thr Leu Lys Lys Gly Pro Arg Gln Asp Pro Ser 1 5

10 15 Ala Ile Val Glu 20 33620PRTHomo sapiens 336Gly Ser Glu Ser Gly Asp Ser Asp Glu Ser Glu Ser Lys Ser Glu Gln 1 5 10 15 Arg Thr Lys Arg 20 33720PRTHomo sapiens 337Glu Ala Asp Ser Gly Asp Ala Arg Arg Leu Pro Arg Ala Arg Gly Glu 1 5 10 15 Arg Arg Arg His 20 33819PRTHomo sapiens 338Arg Leu Glu Arg Pro Gln Asp Arg Asp Thr Pro Val Gln Asn Lys Arg 1 5 10 15 Arg Arg Ser 33919PRTHomo sapiens 339Asp Arg Val Glu Asp Val Met Met Glu Arg Glu Ser Gln Phe Lys Glu 1 5 10 15 Lys Gln Glu 34017PRTHomo sapiens 340Asp Glu Ala Phe Lys Arg Leu Gln Gly Lys Arg Asn Arg Gly Arg Glu 1 5 10 15 Glu 34115PRTHomo sapiens 341Arg Phe Gln Glu Glu Ile Lys Glu Asn Thr Lys Asn Asp Lys Gln 1 5 10 15 34219PRTHomo sapiens 342Lys Arg Asp Lys Glu Gly Val Arg Trp Thr Lys Cys Asn Lys Lys Thr 1 5 10 15 Leu Thr Asp 34319PRTHomo sapiens 343Lys Glu Gly Ser Leu Leu Ser Lys Gln Glu Glu Ser Lys Ala Ala Phe 1 5 10 15 Gly Glu Glu 34419PRTHomo sapiens 344Glu Ser Asp Ala Gly Lys Glu Lys Leu Pro Lys Met Arg Leu Pro Thr 1 5 10 15 Arg Ser Asp 34519PRTHomo sapiens 345Glu Arg Asp Lys Gly Lys Thr Val Glu Val Gly Arg Ala Tyr Phe Glu 1 5 10 15 Thr Glu Lys 34615PRTHomo sapiens 346Glu Lys Phe Arg Val Glu Lys Asp Lys Leu Val Pro Glu Lys Arg 1 5 10 15 34719PRTHomo sapiens 347Glu Val Ala Glu Lys Arg Arg Lys Ala Leu Tyr Glu Ala Leu Lys Glu 1 5 10 15 Asn Glu Lys 34818PRTHomo sapiens 348Glu Asn Tyr Glu Asp Asp Asp Leu Val Asn Ser Asp Glu Val Met Lys 1 5 10 15 Lys Pro 34917PRTHomo sapiens 349Pro Lys Ala Asp Glu Ile Arg Thr Leu Val Lys Asp Met Trp Asp Thr 1 5 10 15 Arg 35019PRTHomo sapiens 350Arg Lys Arg Cys Leu Glu Asp Ser Glu Asp Phe Gly Val Lys Lys Ala 1 5 10 15 Arg Thr Glu 35119PRTHomo sapiens 351Glu Pro Lys Ser Phe Leu Cys Arg Leu Cys Cys Gln Glu Asp Pro Glu 1 5 10 15 Leu Asp Ser 35218PRTHomo sapiens 352Glu Glu Tyr Asp Arg Glu Ser Lys Ser Ser Asp Asp Val Asp Tyr Arg 1 5 10 15 Gly Ser 35318PRTHomo sapiens 353Cys Val Asn Gly Glu Ile Glu Gly Leu Asn Asp Thr Phe Lys Glu Leu 1 5 10 15 Glu Phe 35416PRTHomo sapiens 354Glu Gln Arg Ala Arg Trp Glu Arg Lys Arg Ala Cys Thr Ala Arg Glu 1 5 10 15 35517PRTHomo sapiens 355Glu Arg Lys Gln Leu Glu Cys Glu Gln Val Leu Gln Lys Leu Ala Lys 1 5 10 15 Glu 35619PRTHomo sapiens 356Arg Asn Ser Glu Thr Lys Val Arg Arg Ser Thr Arg Leu Gln Lys Asp 1 5 10 15 Leu Glu Asn 35716PRTHomo sapiens 357Ser Asp Tyr Gln Val Ile Ser Asp Arg Gln Thr Pro Lys Lys Asp Glu 1 5 10 15 35815PRTHomo sapiens 358Asp Ile Glu Gly Lys Leu Pro Gln Thr Glu Gln Glu Leu Lys Glu 1 5 10 15 35919PRTHomo sapiens 359Asp Asp Val Asn Tyr Lys Met His Phe Arg Met Ile Asn Glu Gln Gln 1 5 10 15 Val Glu Asp 36017PRTHomo sapiens 360Glu Asn Pro Leu Pro Glu Arg Pro Arg Glu Lys Glu Glu Pro Val Val 1 5 10 15 Arg 36119PRTHomo sapiens 361Arg Glu Gln Ser Glu Gly Val Gly Ala Arg Val Arg Arg Ser Ile Gly 1 5 10 15 Arg Pro Glu 36219PRTHomo sapiens 362Pro Arg Ala Val Ala Gly Lys Glu Glu Glu Asp Ser Asp Pro Glu Lys 1 5 10 15 Ala Leu Arg 36317PRTHomo sapiens 363Glu Lys Ala Asp Thr Asp Met Glu Gly Ser Val Asp Thr Arg Gln Glu 1 5 10 15 Lys 36419PRTHomo sapiens 364Arg Val Gln Asn His Asp Asn Pro Lys Trp Glu Ala Lys Lys Glu Asn 1 5 10 15 Ile Ser Lys 36519PRTHomo sapiens 365Arg Ser Pro Pro Ala Lys Gly Ala Thr Gly Pro Glu Glu Gln Ser Asp 1 5 10 15 Ser Leu Lys 36619PRTHomo sapiens 366Arg Glu Glu Asp Phe Lys Ala Thr Glu Ile Ile Glu Pro Ser Lys Gln 1 5 10 15 Asp Lys Pro 36715PRTHomo sapiens 367Asp Lys Thr Cys Met Lys Trp Ser Thr Asn Ser Cys Gly Ala Gln 1 5 10 15 36814PRTHomo sapiens 368Asp Ala Asn Leu Ser Lys Asn Gly Gly Leu Glu Val Trp Leu 1 5 10 36910PRTHomo sapiens 369Glu Pro Phe Leu Pro Lys Leu Leu Thr Lys 1 5 10 37019PRTHomo sapiens 370Arg Lys Ser Glu Ala Gly Ser Gly Ala Ala Ser Ser Ser Gly Glu Asp 1 5 10 15 Lys Glu Asn 37119PRTHomo sapiens 371Asp Asp Ile Tyr Asp Pro Thr Tyr Lys Asp Lys Glu Gly Pro Ser Pro 1 5 10 15 Lys Val Glu 37219PRTHomo sapiens 372Gln Ser Asp Glu Ala Lys Asn Asn Met Lys Gly Leu Pro Glu Leu Glu 1 5 10 15 Lys Lys Asp 37319PRTHomo sapiens 373Ser Arg Pro Gln Gly Leu Thr Glu Ala Glu Gln Arg Glu Leu Glu Gln 1 5 10 15 Glu Ala Lys 37414PRTHomo sapiens 374Arg Val Gln Gln Lys Gly Thr Ser Glu Thr Asp Thr Ile Cys 1 5 10 37516PRTHomo sapiens 375Val Arg Leu Ser Pro Leu Ala Glu Arg Gln Leu Gln Val Gln Trp Glu 1 5 10 15 37619PRTHomo sapiens 376Arg Arg Ser Leu Gly Val Ser Val Arg Ser Trp Asp Glu Leu Pro Asp 1 5 10 15 Glu Lys Arg 37717PRTHomo sapiens 377Asp Glu Gly Leu Gly Pro Asp Pro Pro His Arg Asp Arg Leu Arg Ser 1 5 10 15 Lys 37818PRTHomo sapiens 378Ser Gly Lys Arg Ser Ser Asp Gly Ser Leu Ser His Glu Glu Asp Leu 1 5 10 15 Ala Lys 37919PRTHomo sapiens 379Ser Gln Glu Arg Ser Asp Ser Pro Glu Ile Cys His Tyr Glu Lys Ser 1 5 10 15 Phe His Lys 38017PRTHomo sapiens 380Lys Val Asn Pro Glu Pro Thr His Glu Ile Arg Cys Asn Ser Glu Val 1 5 10 15 Lys 38117PRTHomo sapiens 381Arg Glu Leu Arg Glu Val Leu Arg Thr Val Glu Thr Lys Ala Thr Gln 1 5 10 15 Asn 38218PRTHomo sapiens 382Arg Asp Thr Glu Asp Gln Glu Asp Gln Val Asp Pro Arg Leu Ile Asp 1 5 10 15 Gly Lys 38316PRTHomo sapiens 383Lys Asn His His Glu Leu Asp His Arg Glu Arg Glu Ser Ser Ala Asn 1 5 10 15 38416PRTHomo sapiens 384Ser Asp Gly Arg Gly Arg Pro Ala Phe Pro Phe Ser Cys Pro Arg Gln 1 5 10 15 38515PRTHomo sapiens 385Gly Ser Lys Glu Asp Phe Asp Ser Leu Leu Gln Ser Ala Lys Lys 1 5 10 15 38615PRTHomo sapiens 386Glu Tyr Arg Asn Gln Thr Asn Leu Pro Thr Glu Asn Val Asp Lys 1 5 10 15 38718PRTHomo sapiens 387Gln Lys Glu Glu Lys Thr Trp His Glu Ala Leu Arg Ser Cys Gln Ala 1 5 10 15 Asp Asn 38817PRTHomo sapiens 388Glu Lys Ala Glu Glu Gly Pro Arg Lys Arg Glu Pro Ala Pro Leu Asp 1 5 10 15 Lys 38914PRTHomo sapiens 389Glu Gln Asn Arg Asp Arg Ile Leu Thr Pro Glu Asn Arg Lys 1 5 10 39014PRTHomo sapiens 390Arg Asp Trp Tyr Ile Gly Leu Val Ser Asp Glu Lys Trp Lys 1 5 10 39117PRTHomo sapiens 391Asp Ser Tyr Leu Lys Thr Arg Ser Pro Val Thr Phe Leu Ser Asp Leu 1 5 10 15 Arg 39217PRTHomo sapiens 392Lys Cys Arg Gly Glu Thr Val Ala Lys Glu Ile Ser Glu Ala Met Lys 1 5 10 15 Ser 39316PRTHomo sapiens 393Gln Arg Gly Ser Gln Ile Gly Arg Glu Pro Ile Gly Leu Ser Gly Asp 1 5 10 15 39417PRTHomo sapiens 394Lys Pro Pro Gln Glu Thr Glu Lys Gly His Ser Ala Cys Glu Pro Glu 1 5 10 15 Asn 39514PRTHomo sapiens 395Glu Arg Arg Ala Gly Ser Gly Ala Arg Asp Ala Glu Arg Glu 1 5 10 39616PRTHomo sapiens 396Ser Glu Gln Lys Ala Asp Pro Pro Ala Thr Glu Lys Thr Leu Leu Glu 1 5 10 15 39719PRTHomo sapiens 397Glu Ala Glu Trp Ser Gln Gly Val Gln Gly Thr Leu Arg Ile Lys Lys 1 5 10 15 Tyr Leu Thr 39817PRTHomo sapiens 398Glu Glu Ser Lys Ser Ile Thr Glu Gly Leu Leu Thr Gln Lys Gln Tyr 1 5 10 15 Glu 39916PRTHomo sapiens 399Gln Asn Phe Lys Asp Ala Phe Ser Gly Arg Asp Ser Ser Ile Thr Arg 1 5 10 15 40016PRTHomo sapiens 400Glu Lys Ile His Leu Asp Asp Ala Asn Glu Ser Asp His Phe Glu Asn 1 5 10 15 40115PRTHomo sapiens 401Thr Glu Asp Val Asp Glu Phe Arg Asn Lys Leu Gln Gly Glu Arg 1 5 10 15 40220PRTHomo sapiens 402Lys Gly Asp Val Ser Asn Leu Asp Pro Asn Phe Ser Phe Glu Gly Thr 1 5 10 15 Lys Leu Asp Val 20 40316PRTHomo sapiens 403Lys Ala Arg Ala Ala Val Ser Pro Gln Lys Arg Lys Ser Asp Gly Pro 1 5 10 15 40417PRTHomo sapiens 404Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys 1 5 10 15 Asp

Claims

1. (canceled)

2. A method of identifying a breast cancer that will not respond favorably to a chemotherapy treatment that includes a taxane or taxane derivative, the method comprising: (a) performing immunohistochemical staining for TLE3 polypeptide on a cancer sample obtained from a breast cancer patient, wherein the breast cancer patient is triple negative for estrogen receptor, progesterone receptor, and HER-2 markers; (b) detecting a percentage and/or intensity of immunohistochemical staining for TLE3 polypeptide in the cancer sample, wherein the detected percentage and/or intensity is lower than a reference; and (c) identifying the patient's breast cancer as one that will not respond favorably to a chemotherapy treatment that includes a taxane or taxane derivative, wherein the step of performing immunohistochemical staining comprises contacting the cancer sample with an antibody that binds TLE3 polypeptide thereby forming a complex comprising the antibody and TLE3 polypeptide, and the step of detecting comprises detecting the complex in the cancer sample.

3. The method of claim 2, wherein the step of detecting comprises quantifying a percentage of cells in which immunohistochemical staining for TLE3 polypeptide is detected.

4. The method of claim 2, wherein the step of detecting comprises quantifying an intensity of immunohistochemical staining for TLE3 polypeptide in the cancer sample.

5. The method of claim 2, wherein the step of identifying comprises identifying the patient's breast cancer as one that will not respond favorably to a chemotherapy treatment that includes a taxane.

6. The method of claim 5, wherein the taxane is paclitaxel or docetaxel.

7. The method of claim 2, further comprising administering a chemotherapy treatment that does not include a taxane or taxane derivative to the breast cancer patient.

8. A method of identifying a breast cancer that will not respond favorably to a chemotherapy treatment that includes a taxane or taxane derivative, the method comprising: (a) performing immunohistochemical staining for TLE3 polypeptide on a cancer sample obtained from a breast cancer patient, wherein the breast cancer patient is triple negative for estrogen receptor, progesterone receptor, and HER-2 markers; (b) detecting a percentage and/or intensity of immunohistochemical staining for TLE3 polypeptide in the cancer sample, wherein the detected percentage and/or intensity is lower than a reference; and (c) identifying the patient's breast cancer as one that will not respond favorably to a chemotherapy treatment that includes a taxane or taxane derivative, wherein the step of performing immunohistochemical staining comprises contacting the cancer sample with a primary antibody that binds TLE3 polypeptide and a labeled secondary antibody that binds the primary antibody thereby forming a complex comprising the primary antibody, secondary antibody and TLE3 polypeptide, and the step of detecting comprises detecting the complex in the cancer sample.

9. The method of claim 8, wherein the step of detecting comprises quantifying a percentage of cells in which immunohistochemical staining for TLE3 polypeptide is detected.

10. The method of claim 8, wherein the step of detecting comprises quantifying an intensity of immunohistochemical staining for TLE3 polypeptide in the cancer sample.

11. The method of claim 8, wherein the step of identifying comprises identifying the patient's breast cancer as one that will not respond favorably to a chemotherapy treatment that includes a taxane.

12. The method of claim 11, wherein the taxane is paclitaxel or docetaxel.

13. The method of claim 8, further comprising administering a chemotherapy treatment that does not include a taxane or taxane derivative to the breast cancer patient.

14. A method of predicting the likelihood that a breast cancer will not respond to a chemotherapy treatment that includes a taxane or taxane derivative, the method comprising: (a) performing immunohistochemical staining for TLE3 polypeptide on a cancer sample obtained from a breast cancer patient, wherein the breast cancer patient is triple negative for estrogen receptor, progesterone receptor, and HER-2 markers; (b) detecting a percentage and/or intensity of immunohistochemical staining for TLE3 polypeptide in the cancer sample, wherein the detected percentage and/or intensity is lower than a reference; and (c) predicting that the patient's breast cancer will likely not respond favorably to a chemotherapy treatment that includes a taxane or taxane derivative, wherein the step of performing immunohistochemical staining comprises contacting the cancer sample with an antibody that binds TLE3 polypeptide thereby forming a complex comprising the antibody and TLE3 polypeptide, and the step of detecting comprises detecting the complex in the cancer sample.

15. The method of claim 14, wherein the step of detecting comprises quantifying a percentage of cells in which immunohistochemical staining for TLE3 polypeptide is detected.

16. The method of claim 14, wherein the step of detecting comprises quantifying an intensity of immunohistochemical staining for TLE3 polypeptide in the cancer sample.

17. The method of claim 14, wherein the step of predicting comprises predicting that the patient's breast cancer will likely not respond to a chemotherapy treatment that includes a taxane.

18. The method of claim 17, wherein the taxane is paclitaxel.

19. The method of claim 17, wherein the taxane is docetaxel.

20. The method of claim 14, further comprising administering a chemotherapy treatment that does not include a taxane or taxane derivative to the breast cancer patient.

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