EXTRACELLULAR VESICLE COMPRISING A FUSION PROTEIN HAVING FC BINDING CAPACITY

Abstract

The present invention pertains to extracellular vesicle (EV) therapeutics, wherein the EVs are coated with proteins containing Fc domains (such as antibodies) for i.a. targeting and therapeutic applications. The coating of EVs is achieved through inventive protein engineering of EV polypeptides. The present invention thus relates to methods for coating of EVs, EVs per se, as well as pharmaceutical compositions and medical applications of such EVs coated with Fc containing proteins.

Description

RELATED APPLICATIONS

[0001] This application is a division of U.S. application Ser. No. 16/319,061, filed on Jan. 18, 2019, which is a U.S. National Phase Application, filed under U.S.C. .sctn. 371, of International PCT Application No. PCT/EP2017/068476, filed Jul. 21, 2017, which claims the priority benefit of GB 1612643.5, filed Jul. 21, 2016, the contents of each of which are herein incorporated by reference in their entirety.

INCORPORATE-BY-REFERENCE OF SEQUENCE LISTING

[0002] The contents of the file named "EVOX-006_D01US_SeqListing_ST25", which was created on Dec. 15, 2021, and is 313 KB in size are hereby incorporated by reference in their entirety.

TECHNICAL FIELD

[0003] The present invention pertains to extracellular vesicle (EV) therapeutics, wherein the EVs are coated with proteins comprising Fc domains (such as antibodies) for i.a. targeting and therapeutic applications.

BACKGROUND ART

[0004] Protein biologics are routinely used in the treatment and/or prevention of a wide range of diseases, including cancer, genetic disorders and autoimmune diseases. Antibodies and chimeric receptors, among which many of today's blockbuster drugs can be found, are typically administered in naked form, i.e. without any delivery vehicles. Extracellular vesicles (EVs) are nano-sized vesicles that are released by EV-producing cells into the extracellular environment. EVs and in particular exosomes have been shown to be able to transport protein biologics, such as antibodies and decoy receptors, into target cells, enabling an entirely novel form of advanced biological therapeutics harnessing the properties of EVs in combination with the specificity of recombinant proteins.

[0005] The use of EVs to deliver protein therapeutics provides a number of advantages over conventional direct administration of biologics. For example, when biotherapeutics are delivered using EVs they are protected from degradation and are more stable; EVs constitute a multivalent drug delivery modality which may lead to enhanced efficacy; EVs may improve the pharmacokinetics and the pharmacodynamics of a protein biologic; EVs can be targeted to tissues and cells of interest; EVs may have inherent therapeutic effects reflecting their cellular origin; and, EVs also enable penetration of the blood-brain-barrier and improved CNS delivery.

[0006] Despite all their advantages, loading of large and complex protein biologics into EVs for subsequent delivery to a target cell has not proved entirely straightforward. WO2013/084000 and WO2014/168548 both describe successful loading of protein-based biologics (such as antibodies and decoy receptors) into and onto EVs. WO2013/084000 discloses both so called endogenous and exogenous loading of for instance antibodies into EVs such as exosomes. Exogenous loading refers to loading of EVs via introduction of a protein cargo molecule directly into EVs after their isolation from an EV-producing cell in culture. Exogenous introduction of a protein may be carried out, as in WO2013/084000, using for instance electroporation or transfection of the polypeptide of interest post isolation from the parental cell. Endogenous loading on the other hand involves, as taught for instance by WO2014/168548, transfecting an EV-producing cell with a polynucleotide construct which encodes the therapeutic protein of interest. WO2015/058148 teaches an example of endogenous loading of proteins of interest, namely genetic engineering of NK cells with construct encoding for Fc receptors such as CD64, CD32 and CD16. However, genetic modification of e.g. NK cells to express Fc receptors is not a particularly effective way of loading proteins of interest, as it will only result in a low number of Fc receptors per EV. Thus, the approach taught by WO2015/058148 does not at all address the challenges associated with efficient loading of EVs with multiple large and complex protein biologics, especially in a controllable, predictable, scalable, and cost-efficient manner.

SUMMARY OF THE INVENTION

[0007] It is hence an object of the present invention to overcome the above-identified problems associated with the loading of EVs with protein biologics, and especially loading of antibodies and other proteins comprising Fc domains, for subsequent therapeutic application. Furthermore, the present invention aims to satisfy other existing needs within the art, for instance to enable high-affinity and high-density coating of EVs with a substantial plurality of therapeutic, targeting, or anti-clearance antibodies and other proteins comprising Fc domains (either naturally or as a result of protein engineering), to considerably enhance the therapeutic potential of EVs for therapeutic protein delivery.

[0008] The present invention achieves these and other objectives by utilizing fusion constructs comprising exosomal proteins fused to Fc binding polypeptides (herein often referred to as Fc binders) of human and/or non-human origin. The use of exosomal proteins as modalities for loading of EVs enables displaying a large number of Fc binders on the surface of EVs, which is important in order to be able to densely coat the EVs with proteins comprising Fc domains (herein often referred to as Fc containing proteins), which are bound to the EV via interaction between the Fc binders and the proteins comprising Fc domains (such Fc containing proteins may in advantageous embodiments be antibodies). Fc domains of human and/or mammalian origin that may be fused onto proteins natively lacking Fc domains may be selected from the following non-limiting list of alternatives: human IGHM (as a non-limiting example the accession number P01871), human IGHA1 (as a non-limiting example the accession number P01876), human IGHA2 (as a non-limiting example the accession number P01877), human IGKC (as a non-limiting example the accession number P01834), human IGHG1 (as a non-limiting example the accession number P01857), human IGHG2 (as a non-limiting example the accession number P01859), human IGHG3 (as a non-limiting example the accession number P01860), human IGHG4 (as a non-limiting example the accession number P01861), human IGHD (as a non-limiting example the accession number P01880), human IGHE (as a non-limiting example the accession number P01854), and any domains, derivatives, or combinations thereof. The use of non-human Fc binding polypeptides such as Protein A/G and the so called Z domain and the dimeric ZZ domain may result in higher binding affinity between the Fc binder and its interaction partner(s), i.e. the Fc domains of an Fc containing protein. Furthermore, non-human Fc binders are often smaller in size than human Fc binding proteins. On the other hand, Fc binding proteins and polypeptide domains of human and/or mammal origin, such as human FCGRI (CD64) (as a non-limiting example the SEQ ID NO 31), FCGR2A (CD32A) (as a non-limiting example the accession number P12318), FCGR2B (CD32B) (as a non-limiting example the accession number P31994), FCGR2C (CD32C) (as a non-limiting example the accession number P31995), FCGR3A (CD16A) (as a non-limiting example the accession number P0837), FCGR3B (CD16B) (as a non-limiting example the accession number O75015), FCAMR (as a non-limiting example the SEQ ID NO 28), FCERA (as a non-limiting example the SEQ ID NO 30), FCAR (as a non-limiting example the SEQ ID NO 29), or mouse FCGRI (as a non-limiting example the SEQ ID NO 79), FCGRIIB (as a non-limiting example the SEQ ID NO 80), FCGRIII (as a non-limiting example the SEQ ID NO 81), FCGRIV (as a non-limiting example the SEQ ID NO 82), FCGRn (as a non-limiting example the SEQ ID NO 83), may offer advantages as they are mammal proteins and as such may be less immunostimulatory. Regardless, it is key to engineer the EVs so as to ensure that they comprise fusion constructs of the Fc binding polypeptides as opposed to merely overexpressed proteins that bind to Fc domains, in order to ensure adequate numbers of Fc binding polypeptides being displayed on EVs and to enable controllable production.

[0009] Furthermore, the Fc binder polypeptides of the present invention may be engineered to be smaller than natively expressed Fc binding proteins, which makes it easier to direct them to EV surfaces with the aid of fusion constructs with EV proteins. Moreover, one significant difference between non-human Fc binders (which may be e.g. bacterial in origin) and human Fc binders is the fact that such non-human Fc binders can in certain instances simultaneously bind more than one Fc domain, which may lead to increased surface coating of the EVs with the protein of interest comprising an Fc domain. For instance, Protein A/G, which is a fusion protein between Protein A derived from Staphylococcus aureus and from Streptococcus dysgalactiae, has seven binding regions for the Fc domain of IgG antibodies. This multivalency can lead to multiple proteins comprising Fc domains, such as antibodies, being bound to each Fc binder (in this case Protein A/G), enabling denser coating of the EVs with Fc domain-containing proteins, such as antibodies. The denser coating of the EVs with the Fc binders importantly may also enable e.g. a higher avidity between e.g. antibodies and their corresponding antigens, meaning that the binding to the target of interest will be enhanced, which may be beneficial from a targeting and/or therapeutic standpoint.

[0010] In one aspect, the present invention relates to EVs comprising fusion proteins, wherein the fusion proteins comprise at least one polypeptide-based Fc binder fused to an exosomal polypeptide. As a result of the fusion with the EV protein, the Fc binders are efficiently displayed in high numbers on the surface of EVs, enabling dense coating of EVs with Fc domain-containing proteins such as antibodies. Coating of EVs with antibodies and other proteins comprising Fc domains (naturally or as a result of molecular biology engineering) is advantageous for several reasons: (1) antibodies or other proteins targeting a specific cell types, tissue, and/or organs represent a highly useful approach to re-directing distribution and optimizing delivery of EV-based therapeutics, (2) therapeutic antibodies or other Fc domain-containing proteins that interact with a target antigen of interest can be efficiently delivered to tissues of interest using EVs (for instance to the CNS or to the brain), (3) multiplexed antibodies or other Fc domain-containing proteins on the surface of EVs may be significantly better at binding targets, such as target antigens, (4) EVs are an advantageous modality for delivery of antibody-drug conjugates (ADCs) or receptor-drug conjugates, as multiplexing of ADCs may significantly enhance their therapeutic efficacy and their presence on EVs means they can also enter target cells, (5) EVs comprising Fc binders facilitate cellular internalization of Fc domain-containing proteins, such as antibodies, ADCs or essentially any protein comprising an Fc domain, either naturally or as a result of engineering, and (6) coating of EVs with antibodies or Fc domain-containing proteins may reduce opsonization and/or immune-mediated clearance of EVs, which may in turn be important for their therapeutic activity.

[0011] In another aspect, the present invention relates to complexes between fusion proteins as per the present invention and Fc domain-containing proteins (such as antibodies and virtually any biopharmaceutical to which an Fc domain can be fused, e.g. an intracellularly active enzyme such as NPC1 or the nuclease Cas9). As above-mentioned the fusion protein comprises an Fc-binding polypeptide fused to an exosomal polypeptide, and the Fc binder binds to the Fc domain of the Fc domain-containing protein in the complex, which Fc domain-containing protein may be any protein of interest, for instance an antibody or any other protein comprising an Fc domain, either naturally or as a result of engineering of the protein in question. As a result of the EV trafficking capabilities of EV proteins, such non-covalent complexes between fusion proteins and Fc domain-containing proteins are typically present, e.g. anchored in the membrane of EV, resulting in an EV coated with a plurality of Fc domain-containing proteins which are capable of exerting their biological effects. The complexes may additionally or alternatively reside inside an EV.

[0012] In a further aspect, the present invention pertains to pharmaceutical compositions comprising EVs and/or non-covalent complexes, such as nanoparticle complexes (i.e. EVs decorated inside, outside, and/or in the EV membrane with a plurality of at least one type of Fc containing proteins) as per the present invention, and a pharmaceutically acceptable carrier. In further aspects, the present invention thus also relates to EVs, EV-protein complexes, and/or pharmaceutical compositions comprising such EVs and EV-protein complexes for use in medicine, preferably in the treatment of diseases which would benefit from antibody- or Fc domain-containing protein-based treatment, ADC-based treatment, and/or antibody-mediated targeting.

[0013] In further aspects, the present invention pertains to methods for producing EVs capable of binding to proteins comprising an Fc domain. Such methods may comprise the steps of: (i) introducing into an EV source cell a polynucleotide construct encoding a fusion protein comprising at least one Fc binder polypeptide and at least one exosomal polypeptide, and (ii) harvesting EVs which are secreted from the EV source cell, said EVs comprising the fusion protein of interest. Additionally, the present invention relates to methods for coating EVs with at least one protein comprising an Fc domain, comprising the steps of (i) providing an EV comprising a fusion protein comprising at least one Fc binder and at least one exosomal polypeptide, and (ii) allowing the Fc binder of the fusion protein to bind the Fc domain of at least one protein comprising an Fc domain.

[0014] Finally, the present invention also relates to fusion proteins comprising at least one Fc binder and at least one exosomal polypeptide, and polynucleotide constructs encoding for such fusion proteins, as well as vectors, EVs and cells comprising such constructs.

BRIEF DESCRIPTION OF THE FIGURES

[0015] FIG. 1. Schematic illustration of an EV comprising a fusion protein comprising an exosomal protein fused to an Fc binding polypeptide (i.e. the Fc binder domain). The Fc binder is capable of binding e.g. an antibody and/or any other protein comprising an Fc domain, thereby turning the EV into a multivalent delivery vehicle for protein therapeutics.

[0016] FIG. 2. Electron microscopy pictures of EVs comprising Fc binding polypeptides (A) are decorated with nanogold labeled antibodies (i.e. Fc containing proteins), whereas control EVs (B), which lack Fc binding polypeptides, do not have any antibodies bound to their surfaces.

[0017] FIG. 3. Flow cytometry data showing that the EVs comprising Fc binding polypeptides bind Fc containing proteins of interest (human IgG). The binding is very efficient to all bead populations included in the kit, including the unspecific/Isotype/negative control bead populations

[0018] FIG. 4. Anti-HER2 antibody increases uptake of antibody-decorated EVs as compared to isotype control-decorated and wild type EVs only in HER2 high-expressing cell line MDA-MB-361, but not in HER2 low-expressing cell line MDA-MB-231.

[0019] FIG. 5. Etanercept-coated EVs protects mice from loss of body weight, as opposed to WT or control decorated-EVs, and displayed higher activity than naked etanercept, possible due to higher affinity between etanercept and TNFalpha when etanercept is multiplexed and/or when the Fc binding polypeptide binds to its Fc domain.

[0020] FIG. 6. Signals of fluorescently labelled antibodies are clearly present in cells treated with Fc-binding EVs having attached to their surfaces antibodies comprising Fc domains, while fluorescence signals are absent in untreated (1) or control EV treated (2) cells, measured by fluorescence microscopy (A) and flow cytometry (B). This demonstrates that Fc containing proteins such as antibodies can be delivered intracellularly by Fc binding EVs, and that binding to EVs dramatically increases uptake of antibodies into cells.

[0021] FIG. 7. Successful inhibition of NFkB-mediated intracellular signals when an anti-NFkB antibody is delivered into cells by Fc-binding EVs (i.e. EVs comprising at least one Fc binding polypeptide fused to at least one exosomal polypeptide).

[0022] FIG. 8. Control EVs, as well as single treatment with an anti-integrin-4a antibody display moderate protective effect from EAE development in mice, whereas zz domain EVs coated with the same anti-integrin-4a antibody almost completely abrogates EAE development in vivo.

[0023] FIG. 9. Intracellular delivery of CRISPR-Cas9 guide RNA complexes for targeted genome editing, graph showing targeted genomic cleavage after delivery of Fc Cas9 guide RNA complexes through Fc binding domain-Lamp2b engineered EVs.

[0024] FIG. 10. Intracellular delivery of the lysosomal storage disorder enzyme GBA fused to an Fc domain, and bound to HEK-derived EVs comprising an Fc binding polypeptide.

[0025] FIG. 11. Cyclin D levels following U2OS cell treatment with siRNA-loaded Ago2 attached to the surface of Lamp2b-ZZ domain EVs, resulting in significant target silencing.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention relates to various aspects and embodiments pertaining to EVs comprising fusion proteins comprising at least one Fc binder fused to an exosomal polypeptide, to enable dense coating of EVs with antibodies and other Fc domain-containing proteins that can be sequestered by the Fc binder and used for therapeutic application in the treatment of various diseases and disorders.

[0027] For convenience and clarity, certain terms employed herein are collected and described below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0028] Where features, aspects, embodiments, or alternatives of the present invention are described in terms of Markush groups, a person skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. The person skilled in the art will further recognize that the invention is also thereby described in terms of any combination of individual members or subgroups of members of Markush groups. Additionally, it should be noted that embodiments and features described in connection with one of the aspects and/or embodiments of the present invention also apply mutatis mutandis to all the other aspects and/or embodiments of the invention. For example, the Fc binding polypeptides described herein in connection with the EVs comprising fusion proteins comprising such Fc binding polypeptides are to be understood to be disclosed, relevant, and compatible with all other aspects, teachings and embodiments herein, for instance aspects and/or embodiments relating to the methods for producing or coating the EVs, or relating to the polynucleotide and polypeptide constructs described herein. Furthermore, certain embodiments described in connection with certain aspects, for instance the administration routes of the EVs comprising the fusion protein comprising the Fc binding polypeptide and the exosome polypeptide, as described in relation to aspects pertaining to treating certain medical indications, may naturally also be relevant in connection with other aspects and/or embodiment such as those pertaining to the pharmaceutical compositions and/or the Fc binding polypeptide--Fc containing protein complexes of the present invention. Furthermore, all polypeptides and proteins identified herein can be freely combined in fusion proteins using conventional strategies for fusing polypeptides. As a non-limiting example, all Fc binding polypeptides described herein may be freely combined in any combination with one or more exosomal polypeptides. Also, Fc binding polypeptides may be combined with each other to generate constructs comprising more than one Fc binding polypeptide. Moreover, any and all features (for instance any and all members of a Markush group) can be freely combined with any and all other features (for instance any and all members of any other Markush group), e.g. any Fc binding protein may be combined with any Fc containing protein such as any antibody, or any exosomal polypeptide may be combined with any Fc binding polypeptide. Furthermore, when teachings herein refer to EVs (and/or the EV-anchored fusion protein--Fc containing protein complexes) in singular and/or to EVs as discrete natural nanoparticle-like vesicles it should be understood that all such teachings are equally relevant for and applicable to a plurality of EVs and populations of EVs and the EVs coated with Fc containing proteins. As a general remark, the Fc binding polypeptides, the Fc containing proteins such as the antibodies, the EV-producing cell sources, the exosomal proteins, and all other aspects, embodiments, and alternatives in accordance with the present invention may be freely combined in any and all possible combinations without deviating from the scope and the gist of the invention. Furthermore, any polypeptide or polynucleotide or any polypeptide or polynucleotide sequences (amino acid sequences or nucleotide sequences, respectively) of the present invention may deviate considerably from the original polypeptides, polynucleotides and sequences as long as any given molecule retains the ability to carry out the desired technical effect associated therewith. As long as their biological properties are maintained the polypeptide and/or polynucleotide sequences according to the present application may deviate with as much as 50% (calculated using for instance BLAST or ClustalW) as compared to the native sequence, although a sequence identity that is as high as possible is preferable (for instance 60%, 70%, 80%, or e.g. 90% or higher). The combination (fusion) of e.g. at least one Fc binding polypeptide and at least one exosomal protein implies that certain segments of the respective polypeptides may be replaced and/or modified and/or that the sequences may be interrupted by insertion of other amino acid stretches, meaning that the deviation from the native sequence may be considerable as long as the key properties (e.g. Fc binding properties, trafficking to the surface of exosomes, therapeutic activity, etc.) are conserved. Similar reasoning thus naturally applies to the polynucleotide sequences encoding for such polypeptides. All accession numbers and SEQ ID NOs mentioned herein in connection with peptides, polypeptides and proteins shall only be seen as examples and for information only, and all peptides, polypeptides and proteins shall be given their ordinary meaning as the skilled person would understand them. Thus, as above-mentioned, the skilled person will also understand that the present invention encompasses not merely the specific SEQ ID NOs and/or accession numbers referred to herein but also variants and derivatives thereof. All accession numbers referred to herein are UniProtKB accession numbers as per the 22 Jun. 2017 version of the database, and all proteins, polypeptides, peptides, nucleotides and polynucleotides mentioned herein are to be construed according to their conventional meaning as understood by a skilled person.

[0029] The terms "extracellular vesicle" or "EV" or "exosome" are used interchangeably herein and shall be understood to relate to any type of vesicle that is obtainable from a cell in any form, for instance a microvesicle (e.g. any vesicle shed from the plasma membrane of a cell), an exosome (e.g. any vesicle derived from the endo-lysosomal pathway), an apoptotic body (e.g. obtainable from apoptotic cells), a microparticle (which may be derived from e.g. platelets), an ectosome (derivable from e.g. neutrophils and monocytes in serum), prostatosome (e.g. obtainable from prostate cancer cells), or a cardiosome (e.g. derivable from cardiac cells), etc. The sizes of EVs may vary considerably but an EV typically has a nano-sized hydrodynamic radius, i.e. a radius below 1000 nm. Clearly, EVs may be derived from any cell type, both in vivo, ex vivo, and in vitro. Furthermore, the said terms shall also be understood to relate to extracellular vesicle mimics, cell membrane-based vesicles obtained through for instance membrane extrusion, sonication, or other techniques, etc. It will be clear to the skilled artisan that when describing medical and scientific uses and applications of the EVs, the present invention normally relates to a plurality of EVs, i.e. a population of EVs which may comprise thousands, millions, billions or even trillions of EVs. As can be seen from the experimental section below, EVs may be present in concentrations such as 10.sup.5, 10.sup.8, 10.sup.10, 10.sup.11, 10.sup.12, 10.sup.13, 10.sup.14, 10.sup.15, 10.sup.18, 10.sup.25, 10.sup.30 EVs (often termed "particles") per unit of volume (for instance per ml), or any other number larger, smaller or anywhere in between. In the same vein, the term "population", which may e.g. relate to an EV comprising a certain fusion protein between an exosomal polypeptide and an Fc binding polypeptide which in turn may be bound to an Fc containing protein of interest, shall be understood to encompass a plurality of entities constituting such a population. In other words, individual EVs when present in a plurality constitute an EV population. Thus, naturally, the present invention pertains both to individual EVs and populations comprising EVs, as will be clear to the skilled person. The dosages of EVs when applied in vivo may naturally vary considerably depending on the disease to be treated, the administration route, the Fc containing protein of interest, any targeting moieties present on the EVs, the pharmaceutical formulation, etc. Furthermore, the EVs of the present invention may also comprise additional therapeutic agents, in addition to the Fc containing proteins which may be bound to the EV surfaces. In some embodiments, the additional therapeutic agent may be at least one therapeutic small molecule drug. In some embodiments, the therapeutic small molecule drug may be selected from the group consisting of DNA damaging agents, agents that inhibit DNA synthesis, microtubule and tubulin binding agents, anti-metabolites, inducers of oxidative damage, anti-angiogenics, endocrine therapies, anti-estrogens, immuno-modulators such as Toll-like receptor agonists or antagonists, histone deacetylase inhibitors, inhibitors of signal transduction such as inhibitors of kinases, inhibitors of heat shock proteins, retinoids, inhibitors of growth factor receptors, anti-mitotic compounds, anti-inflammatories, cell cycle regulators, transcription factor inhibitors, and apoptosis inducers, and any combination thereof. In further embodiments, the additional therapeutic agent may be a therapeutic nucleic acid-based agent. Such nucleic acid-based therapeutic agents may be selected from the group comprising single-stranded RNA or DNA, double-stranded RNA or DNA, oligonucleotides such as siRNA, splice-switching RNA, CRISPR guide strands, short hairpin RNA (shRNA), miRNA, antisense oligonucleotides, polynucleotides such as mRNA, plasm ids, or any other RNA or DNA vector. Of particular interest are nucleic acid-based agents which are chemically synthesized and/or which comprise chemically modified nucleotides such as 2'-O-Me, 2'-O-Allyl, 2'-O-MOE, 2'-F, 2'-CE, 2'-EA 2'-FANA, LNA, CLNA, ENA, PNA, phosphorothioates, tricyclo-DNA, etc. In yet further embodiments, the EVs as per the present invention may comprise additional therapeutic agents which may be protein and/or peptides. Such proteins and/or peptides may be present inside of the EVs, inserted into the EV membrane or in association with the EV membrane, or may be protruding from the EV into the extravesicular environment. Such therapeutic protein and/or peptide agents may be selected from a group of non-limiting examples including: antibodies, intrabodies, single chain variable fragments (scFv), affibodies, bi- and multispecific antibodies or binders, affibodies, darpins, receptors, ligands, enzymes for e.g. enzyme replacement therapy or gene editing, tumor suppressors, viral or bacterial inhibitors, cell component proteins, DNA and/or RNA binding proteins, DNA repair inhibitors, nucleases, proteinases, integrases, transcription factors, growth factors, apoptosis inhibitors and inducers, toxins (for instance pseudomonas exotoxins), structural proteins, neurotrophic factors such as NT3/4, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) and its individual subunits such as the 2.5S beta subunit, ion channels, membrane transporters, proteostasis factors, proteins involved in cellular signaling, translation- and transcription related proteins, nucleotide binding proteins, protein binding proteins, lipid binding proteins, glycosaminoglycans (GAGs) and GAG-binding proteins, metabolic proteins, cellular stress regulating proteins, inflammation and immune system regulating proteins, mitochondrial proteins, and heat shock proteins, etc. In a preferred embodiment, the therapeutic agent may be a CRISPR-associated (Cas) polypeptide (such as Cas9 (as a non-limiting example the accession number Q99ZW2)) with intact nuclease activity which is associated with (i.e. carries with it) an RNA strand that enables the Cas polypeptide to carry out its nuclease activity in a target cell once delivered by the EV. Alternatively, in another preferred embodiment, the Cas polypeptide may be catalytically inactive, to enable targeted genetic engineering. Yet another alternative may be any other type of CRISPR effector such as the single RNA-guided endonuclease Cpf1 (from species such as Acidaminococcus or Lachnospiraceae) (as non-limiting examples the accession numbers U2UMQ6 and A0Q7Q2). Additional preferred embodiments include therapeutic proteins selected from the group comprising enzymes for lysosomal storage disorders, for instance glucocerebrosidases such as imiglucerase, alpha-galactosidase, alpha-L-iduronidase, iduronate-2-sulfatase and idursulfase, arylsulfatase, galsulfase, acid-alpha glucosidase, sphingomyelinase, galactocerebrosidase, galactosylceramidase, glucosylceramidase (as a non-limiting example the accession number P04062) ceramidase, alpha-N-acetylgalactosaminidase, beta-galactosidase, lysosomal acid lipase, acid sphingomyelinase, NPC1 (as a non-limiting example the accession number O15118), NPC2 (as a non-limiting example the accession number P61916), heparan sulfamidase, N-acetylglucosaminidase, heparan-.alpha.-glucosaminide-N-acetyltransferase, N-acetylglucosamine 6-sulfatase, galactose-6-sulfate sulfatase, galactose-6-sulfate sulfatase, hyaluronidase, alpha-N-acetyl neuraminidase, GlcNAc phosphotransferase, mucolipin1, palmitoyl-protein thioesterase, tripeptidyl peptidase I, palmitoyl-protein thioesterase 1, tripeptidyl peptidase 1, battenin, linclin, alpha-D-mannosidase, beta-mannosidase, aspartylglucosaminidase, alpha-L-fucosidase, cystinosin, cathepsin K, sialin, LAMP2, and hexoaminidase. In other preferred embodiments, the therapeutic protein may be e.g. an intracellular protein that modifies inflammatory responses, for instance epigenetic proteins such as methylases and bromodomains, or an intracellular protein that modifies muscle function, e.g. transcription factors such as MyoD (as a non-limiting example the accession number P15172) or Myf5, proteins regulating muscle contractility e.g. myosin, actin, calcium/binding proteins such as troponin, or structural proteins such as dystrophin (as a non-limiting example the accession number P11532), mini dystrophin (as a non-limiting example the accession number P15172), utrophin, titin, nebulin, dystrophin-associated proteins such as dystrobrevin, syntrophin, syncoilin, desmin, sarcoglycan, dystroglycan, sarcospan, agrin, and/or fukutin. Importantly, all of the above-mentioned therapeutic proteins may be engineered to contain an Fc domain, in order to enable binding to the Fc binding polypeptide present on the EVs. Another non-limiting example is the fusion of an Fc domain onto the enzyme NPC1 for subsequent delivery into a target cell. Yet another non-limiting example which may be utilized to improve intracellular bioactivity of EV-delivered Fc containing proteins (for instance Fc-Cas9 or antibodies) is to fuse an Fc domain to an endosomal escape peptide or protein, such as HA2, cell-penetrating peptides (CPPs) such as the TAT peptide, transportan, peneratin, poly-lysine, or gp41, cholera toxin, Shiga toxin, saporin, diphtheria toxin peptides, etc. Displaying such endosomal escape domains on the surface of an EV may enhance both internalization into target cells and subsequent endosomal escape. An advantageous non-limiting example of how an Fc domain can be fused onto a protein of interest is the fusion of an Fc domain onto Cas9, Cpf1, non-cleaving Cas variants, or any other type of gene editing protein or ribonucleoprotein (RNP) for EV-mediated delivery into a target cell. In a preferred embodiment, an Fc domain is fused either N-terminally or C-terminally to Cas9, which has been pre-loaded in vitro with the single guide RNA (sgRNA) strand (Cas pre-loaded with RNA forms a so called ribonucleoprotein (RNP) complex). The resulting Fc domain-containing RNP complex thus formed is then allowed to be bound by the Fc binding polypeptides of a suitable EV to attached them to the EV surface, followed by delivery into target cells. Creation of the RNP complex can be achieved in different ways and with different RNA components, such as conventional single guide RNA, a synthetic guide RNA comprising both the crRNA and the tracrRNA optionally combined with a hairpin loop, crRNA, tracrRNA, and various combinations thereof. Repair templates for homology-directed recombination or non-homologous end-joining or any other repair or replacement mechanism may also be included in a pre-formed RNP which can then be attached to EVs using the Fc domain--Fc binding polypeptide linkage.

[0030] The terms "antibody" and "mAb" and "Ab" as described herein is to be understood to include both antibodies in their entirety (i.e. whole antibodies) and any derivatives thereof with antigen-binding properties. Conventionally, an antibody refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding-portion thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V.sub.H) and a heavy chain constant region. Each light chain is comprised of a light chain variable region (abbreviated herein as V.sub.L) and a light chain constant region. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The V.sub.H and V.sub.L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Importantly, for the purposes of the present invention an antibody of interest preferably has an Fc domain or a derivative thereof to which the Fc binding polypeptides of the present invention can bind, in order to enable coating of the EV surface. Antibodies of use in the invention may be monoclonal antibodies (mAbs) or polyclonal antibodies, preferably mAbs. Antibodies of particular utility in the invention may be chimeric antibodies, CDR-grafted antibodies, nanobodies, human or humanised antibodies or any derivative thereof as long as it can be bound by the Fc binding polypeptide, which are typically comprised in the fusion proteins as per the present invention. The production of antibodies is outside of the scope of the present invention but typically both monoclonal and polyclonal antibodies are raised experimental non-human mammals such as goat, rabbit, llama, camelids, rat or mouse, but suitable antibodies may also be the result of other production methodologies, e.g. the standard somatic cell hybridization technique of Kohler and Milstein. Hybridoma production in e.g. the mouse is a very well-established procedure and can be achieved using techniques well known in the art. An antibody of use in the invention may be a human antibody, humanized antibody, and/or any type of chimeric antibody. The term "human antibody", as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. The human antibodies of use in the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). The term "antibody derivatives" refers to any modified form of an antibody, e.g. an antibody having an amino acid sequence that is modified in any way, or a conjugate of the antibody and another agent or antibody, bispecific antibodies, multispecific antibodies, antibody domains, etc. The term "humanized antibody" refers to antibodies in which CDR sequences derived from another mammalian species, such as a mouse, camelid, llama, etc., have been grafted onto human framework sequences. Additional framework region modifications may be made within the human framework sequences. Antibodies in accordance with the present invention may include all isotypes and subtypes such as IgG (for instance IgG1, IgG2, IgG3, IgG4, IgG2a, IgG2d, and IgG2c), IgA, IgM, IgM, IgD, etc., and monomers, dimers, and oligomers thereof. Further, antibodies as per the present invention may have several functions when displayed on EVs: (1) antibodies may target specific cell types, tissues, and/or organs in order to re-direct distribution and optimize delivery of EV-based therapeutics, (2) therapeutic antibodies that interact with a target antigen of interest can be efficiently delivered to tissues of interest using EVs (for instance to the CNS or to the brain), (3) multiplexed antibodies on the surface of EVs may be significantly better at binding target antigens, (4) antibody-drug conjugates (ADCs) may be multiplexed on EVs to significantly enhance their therapeutic efficacy, (5) antibodies bound by Fc binding polypeptide may have higher affinity for the target, (6) antibodies coated onto EVs as per the present invention may be delivered intracellularly, and (7) coating of EVs with antibodies may reduce opsonization and/or immune-mediated clearance of EVs, which may in turn be important for therapeutic activity.

[0031] The terms "Fc containing protein" and "protein comprising an Fc domain" and "Fc domain-containing protein" and "Fc domain containing protein" and "Fc domain protein" and similar terms are used interchangeably herein and shall be understood to relate to any protein, polypeptide, or peptide (i.e. any molecule comprising a sequence of amino acids) which comprises at least one Fc domain, either naturally or as a result of engineering of the protein in question to introduce an Fc domain. Fc stands for "fragment crystallizable", which is the name of the tail regions of antibodies. Fc domains can however also be created and used on other proteins, not only antibodies. Non-limiting examples of such Fc domain-containing proteins include antibodies and antibody derivatives, Fc-modified decoy receptors and/or signal transducers such as interleukin decoy receptors for IL1, IL2, IL3, IL4, IL5, IL6 (such as the signal transducer gp130 (as a non-limiting example the accession number P40189)), IL7, IL8, IL9, IL10, IL11, IL12, IL13, IL14, IL15, IL17 (such as IL17R, with as a non-limiting example the accession number Q96F46), IL23 (such as IL23R, with as a non-limiting example the accession number Q5VWK5), etc., Fc domain-containing bi- and multi-specific binders, any type of Fc domain-containing receptors or ligands, Fc domain-modified enzymes for e.g. enzyme replacement therapy or gene editing, nucleases such as Cas and Cas9 onto which an Fc domain has been grafted, tumor suppressors fused to Fc domains, etc. Suitable Fc domains that may be fused with a protein of interest natively lacking an Fc domain include the following non-limiting examples: human IGHM (as a non-limiting example the accession number P01871), human IGHA1 (as a non-limiting example the accession number P01876), human IGHA2 (as a non-limiting example the accession number P01877), human IGKC (as a non-limiting example the accession number P01834), human IGHG1 (as a non-limiting example the accession number P01857), human IGHG2 (as a non-limiting example the accession number P01859), human IGHG3 (as a non-limiting example the accession number P01860), human IGHG4 (as a non-limiting example the accession number P01861), human IGHD (as a non-limiting example the accession number P01880), human IGHE (as a non-limiting example the accession number P01854), and any domains, derivatives, or combinations thereof. In essence, any protein of interest may be modified to incorporate an Fc domain. Non-limiting examples of proteins onto which an Fc domain can be introduced include for instance tumor suppressors, viral or bacterial inhibitors, cell component proteins, DNA and/or RNA binding proteins, DNA repair inhibitors, nucleases, proteinases, integrases, transcription factors, growth factors, apoptosis inhibitors and inducers, toxins (for instance pseudomonas exotoxins), structural proteins, neurotrophic factors such as NT3/4, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) and its individual subunits such as the 2.5S beta subunit, ion channels, membrane transporters, proteostasis factors, proteins involved in cellular signaling, translation- and transcription related proteins, nucleotide binding proteins, protein binding proteins, lipid binding proteins, glycosaminoglycans (GAGs) and GAG-binding proteins, metabolic proteins, cellular stress regulating proteins, inflammation and immune system regulating proteins, mitochondrial proteins, and heat shock proteins, etc. The above list of proteins of interest is not exhaustive and other proteins may also be relevant, as long as the protein either comprises an Fc domain or as long as it is possible to engineer the protein in question to comprise an Fc domain. One non-limiting example of such engineering of a protein to introduce an Fc domain includes adding an Fc domain to a decoy receptor, e.g. adding an Fc domain onto the Cas or Cas9 enzymes for bioactive delivery into target cells to enable gene editing. Another non-limiting example of such engineering of a protein to introduce an Fc domain includes adding an Fc domain onto an enzyme for enzyme replacement therapy (for instance Fc domain-glucocerebrosidase or Fc domain-.alpha.-galactosidase or Fc domain-NPC1). A well-known example of a commercially available Fc domain-modified protein is etanercept, which is a biopharmaceutical for the treatment of various autoimmune disease, comprising the Fc domain of IgG fused onto TNF receptor 2. Thus, as is clear from the above, Fc domain-containing proteins as per the present invention may be essentially any protein of interest that contains an Fc domain, either naturally or as a result of introduction thereof.

[0032] The Fc containing proteins are often described herein as being "attached to" an EV and/or to an Fc binding polypeptide. Alternatively, EVs are sometimes referred to as being "coated by" Fc containing proteins, or as having "bound to their surface" or "attached to their surface" the Fc containing proteins. These terms shall be understood in the context of the conventional interaction between an Fc binding polypeptide and an Fc domain, that is that the two polypeptides are interacting with each other in a way that results in a chemical bond (typically a non-covalent bond) forming between the Fc binder and the Fc domain. Thus, this normally means that the EV which comprises the Fc binding polypeptide therefore has attached to it, by virtue of the chemical bond, the Fc domain of the Fc containing protein. As will be understood by the skilled person, an EV may consequently have a plurality of such Fc containing proteins bound (attached) to it, resulting in a form of coating when the binding is taking place on the EV surface.

[0033] The terms "Fc binding polypeptide" and "Fc binding protein" and "Fc binder" and "Fc-binding protein" and "binder" are used interchangeably herein and shall be understood to relate to any protein, polypeptide, or peptide (i.e. any molecule comprising a sequence of amino acids) which can bind an Fc domain of any protein of interest. Typically, the Fc binding polypeptides of the present invention are derived from various sources that are either human or non-human (e.g. mammal sources, bacteria, etc.), they have high affinity for Fc domains of various antibody isotypes, subtypes, and species (for instance IgG (as non-limiting examples in the case of IgG, IgG1, IgG2, IgG3, IgG4, IgG2a, IgG2d, and/or IgG2c), IgA, IgM, IgM, IgD, etc.), and they can be fused to EV proteins. Non-limiting examples of Fc binding polypeptides in accordance with the present invention include, in addition to other Fc binding polypeptides mentioned through the present application, Protein A (as a non-limiting example the SEQ ID NO 77), Protein G (as a non-limiting example the SEQ ID NO 78), Protein A/G (as a non-limiting example the SEQ ID NO 72), Z domain (as a non-limiting example the SEQ ID NO 73), ZZ domain (two operably linked copies of as a non-limiting example the SEQ ID NO 73, i.e. as a non-limiting example the SEQ ID NO 74), human FCGRI (as a non-limiting example the SEQ ID NO 31), human FCGRIIA (as a non-limiting example the SEQ ID NO 33), human FCGRIIB (as a non-limiting example the accession number 31994), human FCGRIIC (as a non-limiting example the accession number 31995), human FCGRIIIA (as a non-limiting example the accession number P08637), human FCGR3B (as a non-limiting example the accession number O75015), human FCAMR (as a non-limiting example the SEQ ID NO 28), human FCERA, human FCAR, mouse FCGRI (as a non-limiting example the SEQ ID NO 79), mouse FCGRIIB (as a non-limiting example the SEQ ID NO 80), mouse FCGRIII (as a non-limiting example the SEQ ID NO 81), mouse FCGRIV (as a non-limiting example the SEQ ID NO 82), mouse FCGRn (as a non-limiting example the SEQ ID NO 83), and various combinations, derivatives, or alternatives thereof.

[0034] The terms "EV protein" and "EV polypeptide" and "exosomal polypeptide" and "exosomal protein" are used interchangeably herein and shall be understood to relate to any polypeptide that can be utilized to transport a polypeptide construct (which typically comprises, in addition to the EV protein, an Fc binding polypeptide) to a suitable vesicular structure, i.e. to a suitable EV. More specifically, these terms shall be understood as comprising any polypeptide that enables transporting, trafficking or shuttling of a fusion protein construct to a vesicular structure, such as an EV. Examples of such exosomal polypeptides are for instance CD9 (as a non-limiting example the SEQ ID NO 1), CD53 (as a non-limiting example the SEQ ID NO 2), CD63 (as a non-limiting example the SEQ ID NO 3), CD81 (as a non-limiting example the SEQ ID NO 4), CD54 (as a non-limiting example the SEQ ID NO 5), CD50 (as a non-limiting example the SEQ ID NO 6), FLOT1 (as a non-limiting example the SEQ ID NO 7), FLOT2 (as a non-limiting example the SEQ ID NO 8), CD49d (as a non-limiting example the SEQ ID NO 9), CD71 (also known as the transferrin receptor) (as a non-limiting example the SEQ ID NO 10) and its endosomal sorting domain, i.e. the transferrin receptor endosomal sorting domain (as a non-limiting example the SEQ ID NO 23), CD133 (as a non-limiting example the SEQ ID NO 11), CD138 (syndecan-1) (as a non-limiting example the SEQ ID NO 12), CD235a (as a non-limiting example the SEQ ID NO 13), ALIX (as a non-limiting example the SEQ ID NO 14), Syntenin-1 (as a non-limiting example the SEQ ID NO 15), Syntenin-2 (as a non-limiting example the SEQ ID NO 16), Lamp2b (as a non-limiting example the SEQ ID NO 17), syndecan-2 (as a non-limiting example the SEQ ID NO 20), syndecan-3 (as a non-limiting example the SEQ ID NO 21), syndecan-4 (as a non-limiting example the SEQ ID NO 22), TSPAN8, TSPAN14, CD37, CD82, CD151, CD231, CD102, NOTCH1, NOTCH2, NOTCH3, NOTCH4, DLL1, DLL4, JAG1, JAG2, CD49d/ITGA4, ITGB5, ITGB6, ITGB7, CD11a, CD11b, CD11c, CD18/ITGB2, CD41, CD49b, CD49c, CD49e, CD51, CD61, CD104, Fc receptors, interleukin receptors, immunoglobulins, MHC-I or MHC-II components, CD2, CD3 epsilon, CD3 zeta, CD13, CD18, CD19 (as a non-limiting example the SEQ ID NO 26), CD30 (as a non-limiting example the SEQ ID NO 27), TSG101, CD34, CD36, CD40, CD40L, CD44, CD45, CD45RA, CD47, CD86, CD110, CD111, CD115, CD117, CD125, CD135, CD184, CD200, CD279, CD273, CD274, CD362, COL6A1, AGRN, EGFR, GAPDH, GLUR2, GLUR3, HLA-DM, HSPG2, L1CAM, LAMB1, LAMC1, LFA-1, LGALS3BP, Mac-1 alpha, Mac-1 beta, MFGE8, SLIT2, STX3, TCRA, TCRB, TCRD, TCRG, VTI1A, VTI1B, other exosomal polypeptides, and any combinations thereof, but numerous other polypeptides capable of transporting a polypeptide construct to an EV are comprised within the scope of the present invention. Typically, in many embodiments of the present invention, at least one exosomal polypeptide is fused to at least one Fc binding polypeptide, in order to form a fusion protein present in an EV. Such fusion proteins may also comprise various other components to optimize their function(s), including linkers, transmembrane domains, cytosolic domains, multimerization domains, etc.

[0035] The terms "source cell" or "EV source cell" or "parental cell" or "cell source" or "EV-producing cell" or any other similar terminology shall be understood to relate to any type of cell that is capable of producing EVs under suitable conditions, for instance in suspension culture or in adherent culture or any in other type of culturing system. Source cells as per the present invention may also include cells producing exosomes in vivo. The source cells per the present invention may be select from a wide range of cells and cell lines, for instance mesenchymal stem or stromal cells or fibroblasts (obtainable from e.g. bone marrow, adipose tissue, Wharton's jelly, perinatal tissue, tooth buds, umbilical cord blood, skin tissue, etc.), amnion cells and more specifically amnion epithelial cells optionally expressing various early markers, myeloid suppressor cells, M2 polarized macrophages, adipocytes, endothelial cells, fibroblasts, etc. Cell lines of particular interest include human umbilical cord endothelial cells (HUVECs), human embryonic kidney (HEK) cells, endothelial cell lines such as microvascular or lymphatic endothelial cells, chondrocytes, MSCs of different origin, airway or alveolar epithelial cells, fibroblasts, endothelial cells, etc. Also, immune cells such as B cells, T cells, NK cells, macrophages, monocytes, dendritic cells (DCs) are also within the scope of the present invention, and essentially any type of cell which is capable of producing EVs is also encompassed herein. Generally, EVs may be derived from essentially any cell source, be it a primary cell source or an immortalized cell line. The EV source cells may be any embryonic, fetal, and adult somatic stem cell types, including induced pluripotent stem cells (iPSCs) and other stem cells derived by any method. When treating neurological diseases, one may contemplate to utilize as source cells e.g. primary neurons, astrocytes, oligodendrocytes, microglia, and neural progenitor cells. The source cell may be either allogeneic, autologous, or even xenogeneic in nature to the patient to be treated, i.e. the cells may be from the patient himself or from an unrelated, matched or unmatched donor. In certain contexts, allogeneic cells may be preferable from a medical standpoint, as they could provide immuno-modulatory effects that may not be obtainable from autologous cells of a patient suffering from a certain indication. For instance, in the context of treating systemic, peripheral and/or neurological inflammation, allogeneic MSCs may be preferable as EVs obtainable from such cells may enable immuno-modulation via e.g. macrophage and/or neutrophil phenotypic switching (from pro-inflammatory M1 or N1 phenotypes to anti-inflammatory M2 or N2 phenotypes, respectively).

[0036] In a first aspect, the present invention relates to EVs comprising fusion proteins, wherein the fusion proteins comprise at least one Fc binding polypeptide fused to an exosomal polypeptide. As a result of the fusion with the EV protein, the Fc binding polypeptide are efficiently transported to and displayed in high numbers on the surface of EVs, which enables subsequent coating of EVs with a various types of Fc containing proteins, typically therapeutic proteins endowed with an Fc domain, targeting antibodies, therapeutic antibodies, antibody-drug conjugates, and/or antibodies that are passively bound in vivo or purposely selected to reduce opsonization and recognition by immune cells (to prolong the circulation time of the EVs).

[0037] Thus, in an embodiment, an EV according to the first aspect has bound to it a plurality of Fc containing proteins through interaction between the Fc binding polypeptide and the Fc domains of the plurality of Fc containing proteins, wherein the plurality of Fc containing proteins may be the same or different. The EVs may be coated with a plurality of proteins comprising an Fc domain through the non-covalent interaction between the Fc binder and the at least one protein comprising an Fc domain. Said plurality may be at least 10, at least 20 or at least 30 proteins comprising an Fc domain.

[0038] In one embodiment of the invention, the Fc binders are of non-human origin, they may be obtained e.g. from bacteria, viruses, or non-human mammals. In another embodiment, the Fc binders are of human or mammal origin. In preferred embodiments, the at least one Fc binding polypeptide may be selected from the group comprising Protein A (as a non-limiting example the SEQ ID NO 77), Protein G (as a non-limiting example the SEQ ID NO 78), Protein A/G (as a non-limiting example the SEQ ID NO 72), Z domain (as a non-limiting example the SEQ ID NO 73), ZZ domain (as a non-limiting example the SEQ ID NO 74), Protein L (as a non-limiting example the pdb id no 1HEZ), Protein LG, human FCGRI (as a non-limiting example the SEQ ID NO 31), human FCGR2A (as a non-limiting example the accession number P12318), human FCGR2B (as a non-limiting example the accession number P31994), human FCGR2C (as a non-limiting example the accession number P31994), human FCGR3A (as a non-limiting example the accession number P08637), human FCGR3B (as a non-limiting example the accession number O75015), human FCGRB (as a non-limiting example the accession number Q92637) (as a non-limiting example the SEQ ID NO 32), human FCAMR (as a non-limiting example the SEQ ID NO 28), human FCERA (as a non-limiting example the SEQ ID NO 30), human FCAR (as a non-limiting example the SEQ ID NO 29), mouse FCGRI (as a non-limiting example the SEQ ID NO 79), mouse FCGRIIB (as a non-limiting example the SEQ ID NO 80), mouse FCGRIII (as a non-limiting example the SEQ ID NO 81), mouse FCGRIV (as a non-limiting example the SEQ ID NO 82), mouse FCGRn (as a non-limiting example the SEQ ID NO 83), and any combination of any of the above Fc binding polypeptides. Other suitable Fc binding polypeptides, which have been obtained from e.g. phage display screening and via bioinformatics, include the Fc binding peptides SPH (as a non-limiting example the SEQ ID NO 57), SPA (as a non-limiting example the SEQ ID NO 58), SPG2 (as a non-limiting example the SEQ ID NO 59), SpA mimic 1 (as a non-limiting example the SEQ ID NO 60), SpA mimic 2 (as a non-limiting example the SEQ ID NO 61), SpA mimic 3 (as a non-limiting example the SEQ ID NO 62), SpA mimic 4 (as a non-limiting example the SEQ ID NO 63), SpA mimic 5 (as a non-limiting example the SEQ ID NO 64), SpA mimic 6 (as a non-limiting example the SEQ ID NO 65), SpA mimic 7 (as a non-limiting example the SEQ ID NO 66), SpA mimic 8 (as a non-limiting example the SEQ ID NO 69), SpA mimic 9 (as a non-limiting example the SEQ ID NO 70), SpA mimic 10 (as a non-limiting example the SEQ ID NO 71), Fc.gamma. mimic 1 (as a non-limiting example the SEQ ID NO 67), and Fc.gamma. mimic 2 (as a non-limiting example the SEQ ID NO 68), and any combination or derivative thereof. The selection of the most suitable Fc binding polypeptide for a particular construct depends heavily on the desired binding characteristics, the affinity, the orientation of the Fc binding polypeptide when fused to an exosomal polypeptide, and various other factors.

[0039] Protein A/G is a recombinant genetically engineered protein comprised of 7 Fc-binding domains EDABC-C1C3, with the Protein A part being obtained from Staphylococcus aureus segments E, D, A, B and C, and the Protein G part from Streptococcus segments C1 and C3. Advantageously, Protein A/G (as a non-limiting example the SEQ ID NO 72) has a broader binding capacity than either Protein A (as a non-limiting example the SEQ ID NO 77) or Protein G (as a non-limiting example the SEQ ID NO 78) alone and it has a broad binding affinity for antibodies from various species. Protein A/G binds to various human, mouse and rat IgG subclasses such as the human IgG1, IgG2, IgG3, IgG4; mouse IgG2a, IgG2b, IgG3 and rat IgG2a, IgG2c. In addition, Protein A/G binds to total IgG from cow, goat, sheep, horse, rabbit, guinea pig, pig, dog and cat. Protein A/G has been engineered to remove the cell wall-binding region, the cell membrane-binding region and albumin-binding region to enable strong binding to the Fc domain of a protein of interest. Thus, in advantageous embodiments as per the present invention, the Fc binder comprises more than one Fc binding region, as is the case with Protein A, Protein G, and Protein A/G. In an alternative embodiment, the Fc binder may be multiplied in order to enable binding to more than one copy of an antibody of interest. For instance, the short Z domain Fc binder may be included in the fusion protein in more than one copy, through an operational linkage allowing for binding to more than one Fc domain. This way it is possible to multiplex antibodies and other Fc domain-containing proteins not only between separate fusion proteins but also within one single fusion protein, which thus may bind more than one antibody. For instance, when Fc binding polypeptides are introduced into EV proteins belonging to the tetraspanin family (such as CD63) it may be advantageous to insert one Fc binder on one loop and another Fc binder (which can be the same or different) on another loop of the protein. The Fc binder can be placed on inward-facing and/or outward-facing loops, depending on whether the Fc containing protein is meant to be loaded into the lumen of the EV or onto the surface of the EV. Some non-limiting examples of fusion proteins as per the present invention can be described schematically as follows (the below notation is not to be construed as illustrating any C and/or N terminal direction, it is merely meant for illustrative purposes):

[0040] Exosomal polypeptide-Fc binding polypeptide-Fc binding polypeptide

[0041] Exosomal polypeptide domain-Fc binding polypeptide-Exosomal polypeptide domain-Fc binding polypeptide

[0042] Exosomal polypeptide domain-Fc binding polypeptide A-Exosomal polypeptide domain-Fc binding polypeptide B

[0043] In some embodiments, the fusion proteins comprising the exosomal polypeptide and the Fc binding polypeptide may also contain additional polypeptides, polypeptide domains or sequences. Such additional polypeptide domains may exert various functions, for instance such domains may (i) contribute to enhancing the EV surface display of the fusion protein, (ii) lead to clustering of the fusion proteins thereby increasing the avidity of the Fc binding polypeptides, (iii) function as linkers to optimize the interaction between the exosomal polypeptides and the Fc binding polypeptide, and/or (iv) improve anchoring in the EV membrane, as well as various other functions. Two such additional polypeptides that may advantageously be included in part or as a whole in the fusion proteins of the preset invention are gp130 (as a non-limiting example the SEQ ID NO 18) and the tumor necrosis factor receptor 1 (TNFR1) (as a non-limiting example the SEQ ID NO 19). In particular, the transmembrane domains of these additional polypeptides may be highly useful to optimize the insertion into the EV membrane and the display of the Fc binding polypeptide. Overall, various transmembrane domains may be highly advantageous as additional domains in the fusion proteins. For instance, when using the exosomal protein syntenin it is highly advantageous to insert an additional polypeptide domain, such the transmembrane domain of TNFR or the transmembrane domain of gp130, between syntenin and the Fc binding polypeptide of the fusion protein. Further additional domains may include multimerization domains such as fold-on domains, leucine zipper domains and/or trimerization domains, in order to increase surface display and/or avidity. A non-limiting schematic example of this is shown below:

[0044] Syntenin-cytosolicTNRF-Foldon trimerization domain-transmembraneTNFR domain-Z domain-extracellularTNFR domain

[0045] Syndecan-leuzine zipper domain-gp130cytosolic domain-gp130 transmembrane domaine-Fc binding polypeptide-gp130 extracellular domain

[0046] In a further embodiment, the exosomal polypeptide may be selected from the group comprising CD9, CD53, CD63, CD81, CD54, CD50, FLOT1, FLOT2, CD49d, CD71, CD133, CD138, CD235a, ALIX, Syntenin-1, Syntenin-2, Lamp2b, TSPAN8, syndecan-1, syndecan-2, syndecan-3, syndecan-4, TSPAN14, CD37, CD82 (as a non-limiting example the SEQ ID NO 24), CD151, CD231, CD102, NOTCH1, NOTCH2, NOTCH3, NOTCH4, DLL1, DLL4, JAG1, JAG2, CD49d/ITGA4, ITGB5, ITGB6, ITGB7, CD11a, CD11b, CD11c, CD18/ITGB2, CD41, CD49b, CD49c, CD49e, CD51, CD61, CD104, Fc receptors, interleukin receptors, immunoglobulins, MHC-I or MHC-II components, CD2, CD3 epsilon, CD3 zeta, CD13, CD18, CD19, CD30, CD34, CD36, CD40, CD40L, CD44, CD45, CD45RA, CD47, CD86, CD110, CD111, CD115, CD117, CD125, CD135, CD184, CD200, CD279, CD273, CD274, CD362, COL6A1, AGRN, EGFR, GAPDH, GLUR2, GLUR3, HLA-DM, HSPG2, L1CAM, LAMB1, LAMC1, LFA-1, LGALS3BP, Mac-1 alpha, Mac-1 beta, MFGE8 (as a non-limiting example the SEQ ID NO 25), SLIT2, STX3, TCRA, TCRB, TCRD, TCRG, VTI1A, VTI1B, other exosomal polypeptides, and any combinations thereof.

[0047] Particularly advantageous fusion proteins as per the present invention may comprise the human exosomal proteins CD63, CD81, CD9, CD71 (transferrin receptor), Lamp2, and syntenin, fused to at least one copy of the following Fc binding polypeptides: Z domain, Protein A, Protein G, Protein A/G, FCGRI, human FCGR2A, human FCGR2B, human FCGR2C, human FCGR3A, human FCGR3B, human FCGR3C, human FCAMR, human FCAR, and human FCERA. Specifically, fusion of two Z domains to the EV protein CD63 (as a non-limiting example the SEQ ID NO 3) results in a highly potent Fc binder which is displayed in high quantities on the surface of EVs, as a consequence of the small size of the Z domain and the high EV surface expression of CD63. Display of the Fc binder on the outer surface of EVs is naturally preferable in order to enable exogenous binding of Fc domain-containing proteins of interest. In the case of CD63-ZZ domain fusion proteins, Z domains may be inserted into the first and second loop of CD63, to enable display on the outer EV surface after anchoring of CD63 into the EV membrane. Furthermore, as above-mentioned, suitable additional polypeptides and polypeptide domains and linkers may also be included in the fusion proteins, which normally comprises an exosomal polypeptide and an Fc binding polypeptide. Such additional polypeptides include domains from various cytokine receptors such as TNFR1 and TNFR2, the IL6 signal transducer gp130, and various other cytokines and cytokine-related polypeptides. In certain instances, cytokines and cytokine-related polypeptides (such as various cytokine receptors) may alone be able to transport Fc binding polypeptides to EVs. Linkers of particular utility are multiples and/or combinations of small and flexible amino acids such as glycine (G) and serine (S), typically denoted GS, for instance 2XGS or 4XGS. His tags for simplifying purification and assaying may also be added, both C terminally and N terminally, and so may various fluorescent proteins such as GFP. The following are particularly advantageous non-limiting examples of fusion proteins comprising at least one exosomal polypeptide and at least one Fc binding polypeptide, often connected via linkers and optionally including an additional polypeptide(s) or polypeptide domains:

[0048] CD81-Protein A/G CD81 Second loop (as a non-limiting example the SEQ ID NO 75)

[0049] CD9-ZZ domain CD9 Second loop (as a non-limiting example the SEQ ID NO 76)

[0050] FCAR extracellular domain-2XGGGgSlinker-Lamp2b (as a non-limiting example the SEQ ID NO 55)

[0051] FCAR extracellular domain-4XGSlinker-Lamp2b (as a non-limiting example the SEQ ID NO 54)

[0052] FCGR1A Extracellular domain-2XGGGgSlinker-Lamp2b (as a non-limiting example the SEQ ID NO 49)

[0053] FCGR1A Extracellular domain-4XGSlinker-Lamp2b (as a non-limiting example the SEQ ID NO 48)

[0054] FcRN Extracellular domain-4XGSlinker-Lamp2b (as a non-limiting example the SEQ ID NO 39)

[0055] FcRN-2XGGGgSlinker-Lamp2b (as a non-limiting example the SEQ ID NO 40).

[0056] Gp130 Extracellular domain-2XGGGGS linker-FCAR extracellular domain-Gp130 transmembrane domain-Leucine Zipper-N terminal syntenin (as a non-limiting example the SEQ ID NO 52)

[0057] Gp130 Extracellular domain-2XGGGGS linker-FCGR1A Extracellular domain-Gp130 transmembrane domain-Leucine Zipper-N terminal syntenin (as a non-limiting example the SEQ ID NO 46)

[0058] Gp130 Extracellular domain-2XGGGGS linker-FcRN Extracellular domain-Gp130 transmembrane domain-Leucine Zipper-N terminal syntenin (as a non-limiting example the SEQ ID NO 43)

[0059] Gp130 Extracellular domain-2XGGGGS linker-Z domain-Gp130 transmembrane domain-Leucine Zipper-N terminal syntenin (as a non-limiting example the SEQ ID NO 34)

[0060] Transferrin receptor-2XGGGGSlinker-FCAR extracellular domain (as a non-limiting example the SEQ ID NO 56)

[0061] Transferrin receptor-2XGGGGSlinker-FCGR1A Extracellular domain (as a non-limiting example the SEQ ID NO 50)

[0062] Transferrin receptor-2XGGGGSlinker-FcRN Extracellular domain (as a non-limiting example the SEQ ID NO 41)

[0063] Transferrin receptor-2XGGGGSlinker-Z domain (as a non-limiting example the SEQ ID NO 38)

[0064] CD63-FCAR extracellular domain CD63 First loop and CD63 Second loop (as a non-limiting example the SEQ ID NO 53)

[0065] CD63-FCGR1A Extracellular domain CD63 First loop and CD63 Second loop (as a non-limiting example the SEQ ID NO 47)

[0066] CD63-FcRN Extracellular domain CD63 First loop and CD63 Second loop (as a non-limiting example the SEQ ID NO 44)

[0067] CD63-Z domain CD63 First loop and CD63 Second loop (as a non-limiting example the SEQ ID NO 35)

[0068] TNFR Extracellular domain-2XGGGGS linker-FCAR extracellular domain-TNFR transmembrane domain-foldon-N terminal syntenin (as a non-limiting example the SEQ ID NO 51)

[0069] TNFR Extracellular domain-2XGGGGS linker-FCGR1A Extracellular domain-TNFR transmembrane domain-foldon-N terminal syntenin (as a non-limiting example the SEQ ID NO 45)

[0070] TNFR Extracellular domain-2XGGGGS linker-FcRN Extracellular domain-TNFR transmembrane domain-foldon-N terminal syntenin (as a non-limiting example the SEQ ID NO 42)

[0071] TNFR Extracellular domain-2XGGGGS linker-Z domain-TNFR transmembrane domain-foldon-N terminal syntenin (as a non-limiting example the SEQ ID NO 33)

[0072] Z domain-2XGGGgSlinker-Lamp2b (as a non-limiting example the SEQ ID NO 37)

[0073] Z domain-4XGSlinker-Lamp2b (as a non-limiting example the SEQ ID NO 36)

[0074] Transferrin receptor-Protein AG (as a non-limiting example the SEQ ID NO 10 operably fused to as a non-limiting example the SEQ ID NO 72)

[0075] The above-mentioned fusion proteins are merely examples of the many engineering possibilities the present invention allows for and as such they are merely non-limiting embodiments of the present invention. All components of the fusion proteins as per the present invention may be freely combined, e.g. the fusion proteins may contain one or several exosomal polypeptides which may be placed C terminally, N terminally, or both, or anywhere in the fusion protein. Further, the fusion proteins may also contain one or several Fc binding polypeptides, which may be placed C terminally, N terminally, or both, or on one or more of any loops of e.g. transmembrane parts, or anywhere in the fusion protein. For clarity, more than one type of exosomal polypeptide and more than one type of Fc binding polypeptide may be comprised in a single construct. Furthermore, additional stretches of amino acids such as linkers (often comprising the amino acids glycine and serine) and His tags may be included to simplify purification, assaying and visualization. Also, other peptides and polypeptide domains may also be included anywhere in the fusion protein sequence. For instance, various domains and regions from various cytokine receptors may advantageously be included, for instance various domains of TNFR1, TNFR2, IL17R, IL23R, gp130, IL6R, etc.

[0076] In a further embodiment, the Fc binding polypeptides may as above-mentioned bind to any protein comprising an Fc domain, not only antibodies but also other proteins comprising Fc domains, both naturally occurring and engineered Fc domain-containing proteins, such as the ones mentioned in several instances above. Advantageously, the present invention results in EVs coated with a plurality of proteins comprising an Fc domain, through interaction between the Fc binding polypeptide and at least one Fc containing protein. The interaction between the Fc binder and the Fc containing protein is normally based on non-covalent bonds between the Fc binding polypeptide and the Fc domain of the Fc containing protein. Naturally, one single EV may be coated with more than one type of Fc domain-containing protein. In one non-limiting example, the Fc binding EVs are coated with one antibody targeting a suitable target along the PD1 axis, whereas another antibody is targeting a suitable target along the CTLA4 axis. In another non-limiting example, the Fc binding EVs are coated with an antibody targeting a tumor cell surface receptor and Cas9 fused to an Fc domain. One single EV may also, as is typically the case, comprise a substantial plurality of one single type of Fc domain-containing protein, such as one type of monoclonal antibody. Various combinations of targeting antibodies, therapeutic antibodies, Fc containing non-antibody therapeutic proteins of interest, antibody-drug conjugates (ADCs), and antibodies for reducing opsonization and/or immune cell-mediated clearance constitute preferred embodiments of the present invention. In advantageous embodiments, the EVs according to the present invention are coated with a plurality of proteins comprising an Fc domain. For instance, when using a highly expressed EV protein such as CD63 or CD81 or syntenin one can achieve very dense coating of the surface of EVs. Thus, the present invention may be coated with at least 10 proteins comprising an Fc domain, preferably at least 20 proteins comprising an Fc domain, even more preferably at least 30 proteins comprising an Fc domain. Such proteins may be copies of the same protein (e.g. 50 etanercept molecules coating one EV, by way of example) or more than one protein (e.g. 30 etanercept molecules and 30 gp130-Fc domain fusion proteins coating one EV, by way of example). By selecting an optimal combination of EV protein and Fc binder it may be possibly to increase the display further, in certain cases it may be possible to coat an EV with more than 50 proteins comprising an Fc domain, or even more than approximately 75 proteins comprising an Fc domain.

[0077] In a further aspect, the present invention also relates to cells comprising a fusion protein between a display polypeptide and an Fc binding polypeptide. The display polypeptide may typically be a transmembrane protein. Various exosomal polypeptides can be used for this purpose, and so can regular cellular transmembrane proteins such as T cell receptor transmembrane domains, interleukin receptors, transferrin receptor, stannin, sarcolipin, phospholamban, and various other membrane proteins such as channels and symporters/importers, which can transport the Fc binding polypeptide to the cell membrane for display on the outside or on the inside of the cell membrane, depending on whether the Fc containing protein of interest is going to be present inside the cell or displayed on the surface of the cell. In a preferred embodiment, the Fc containing protein is an antibody and the cell is a cell intended for cellular therapy, such as a chimeric antigen receptor (CAR) T cell. Using this approach, a cell could be targeted to a particular tissue of interest, in the case of a CAR-T cell the tissue of interest is likely to be tumor tissue. In the case of an immune-modulatory cell such as an MSC, the tissue of interest is likely to be a site of inflammation and/or injury. All antibodies and other Fc containing proteins herein are equally suitable for being displayed on a cell for the same reasons as for the EVs.

[0078] In another aspect, the present invention relates to a complex formed between a fusion protein comprising (i) an exosomal polypeptide and (ii) an Fc binding polypeptide, and a protein comprising an Fc domain. EVs per the present invention thus typically comprise a plurality of such complexes, and typically the higher number of such complexes displayed on an EV without issues relating to for instance to steric hindrance the more potent the EV becomes from a therapeutic and/or targeting standpoint. Such fusion protein-Fc containing protein complexes are typically present in the lipid membrane of an EV, by virtue of the presence of the exosomal protein which mediates transport and anchoring into exosomal membranes. However, the complexes may also be present in other lipid membranes, for instance cell membranes or membranes of cell organelles. The EVs as per the present invention also form a type of nanoparticle complex with the Fc containing proteins. Typically, as above-mentioned, each EV comprising the Fc binding polypeptide binds to a plurality of Fc containing proteins, which results in EVs that are coated (decorated) and/or contains a plurality of the Fc containing protein of interest. An example of this is that Fc-binding EVs that are allowed to bind to antibodies through incubation with such antibodies become decorated on their surface with a plurality of antibodies, e.g. at least 10 antibodies per EV, or more frequently at least 20 or 30 antibodies per EV. Thus, this EV-antibody complex constitutes a type of nanoparticle complex with significant utility for targeting, therapy, and intracellular delivery.

[0079] Importantly, the present invention also provides for a method of loading Fc containing proteins into EVs in an endogenous fashion. Such endogenous loading methods comprise co-expression in an EV-producing cell of (i) a fusion protein comprising an exosomal polypeptide and an Fc binding polypeptide, and (ii) a protein of interest comprising an Fc domain. The exosomal polypeptide fused to the Fc binding domain enables active sorting of the fusion protein into EVs in the EV-producing cell, and the presence of the Fc binding protein enables the fusion protein to drag along (transport) the Fc containing protein into an EV. As above-mentioned, various exosomal proteins can be used to sort fusion proteins into EVs and especially in the case of endogenous loading the choice of protein is highly important. Soluble EV proteins such as Alix and syntenin may be suitable for the loading of Fc containing proteins that are meant to be soluble in the target environment, such as Cas9 which preferably is soluble inside a target cell. However, endogenous loading of Fc containing proteins can also be achieved with transmembrane and/or membrane-associated EV proteins such as CD9, CD81, CD63, etc. When utilizing membrane-bound exosomal proteins for endogenous loading the Fc binding polypeptide is instead placed on a loop on the luminal side of the EV membrane as opposed to on the extravesicular side, enabling luminal as opposed to extravesicular loading. The EVs as per the present invention thus normally comprise a plurality of such fusion protein-Fc domain-containing protein complexes ("a plurality" shall be understood to relate to multiple copies of the same Fc domain-containing protein or several different Fc domain containing proteins), either anchored in or associated with the EV membrane on the inside or on the outside, or in essentially soluble form luminally in the EV.

[0080] In a further aspect, the present invention relates to methods for producing EVs capable of binding to proteins comprising an Fc domain, such as antibodies and proteins engineered to comprise Fc domains. Such methods typically comprise the steps of (i) introducing into an EV source cell a polynucleotide construct which encodes a fusion protein comprising at least one Fc binding polypeptide and at least one exosomal polypeptide, and (ii) collecting EVs that have been secreted by the EV-producing source cells, wherein the EVs comprise the fusion protein which has been expressed from the polynucleotide construct. In a subsequent step, the EVs comprising the fusion protein may be purified using a suitable purification technique, followed by being exposed to an Fc domain-containing protein, such as an antibody, to enable binding of the Fc containing protein through interaction between the Fc binding polypeptide and the Fc domain of the protein of interest. As above-mentioned, in an alternative embodiment, step (i) may also include expressing the Fc containing protein of interest from a polynucleotide construct in the same EV source cell, thereby achieving endogenous loading of the EV. The fusion protein (between the exosomal polypeptide and the Fc binding polypeptide) and the Fc containing protein may be expressed from the same or from different polynucleotide construct, depending on the construct design.

[0081] In yet another aspect, the present invention relates to a method for attaching at least one protein comprising an Fc domain, such as an antibody, to an EV. In an embodiment, the method is for coating an EV with said at least one protein comprising an Fc domain. Such methods comprise the steps of (i) providing an EV comprising a fusion protein comprising at least one Fc binding protein fused to at least one exosomal polypeptide, and (ii) allowing the Fc binding protein of the fusion protein to bind the Fc domain of at least one protein comprising an Fc domain. The EV source cells used for production of EVs comprising the fusion proteins as per the present invention may be either stably or transiently transfected with the polynucleotide construct needed to generate the EVs carrying the fusion protein-Fc containing protein complex. Stable transfection is advantageous as it enables creation of master cell banks (MCBs) and working cell banks (WCBs). However, transient transfection is also advantageous in certain instances, for example when assessing different constructs or e.g. when rapidly creating an autologous therapy comprising EVs obtained from a patient's own EV-producing cells.

[0082] In a further aspect, the present invention relates to methods for delivery of a protein of interest into the intracellular environment of target cells, either in vitro, ex vivo or in vivo. Such methods comprise the steps of (i) providing EVs comprising at least one Fc binding polypeptide, (ii) putting the EV comprising the Fc binding polypeptide in contact with an Fc containing protein, in order to enable binding between the Fc binding polypeptide comprised in the EV and the Fc domain of the Fc containing protein, and (iii) putting the complex formed between the EV and the Fc containing protein(s) (i.e. an EV having at least one Fc containing protein attached to it through the interaction between the Fc binding polypeptide and the Fc domain) in contact with the target cell(s). In a preferred embodiment, the Fc binding polypeptide is comprised in a fusion protein together with at least an exosomal polypeptide, but optionally other polypeptides and domains as well. Due to the unique ability of EVs to internalize into target cells, the Fc containing protein will also be internalized. This is highly advantageous and opens up the intracellular space for delivery of virtually any protein-based therapeutics. As above-mentioned, the EV-mediated internalization of Fc containing proteins take place both in vivo and in vitro, and these methods may thus have significant impact for therapy development but also for research and diagnostic purposes.

[0083] In a further aspect, the present invention pertains to the use of EVs as delivery vehicles for antibodies and other Fc domain containing proteins of interest. Furthermore, the present invention also provides for the use of EVs attached to Fc containing proteins as delivery vehicles for other therapeutic agents of interest. As a non-limiting example, EVs having attached to their surface a targeting antibody may also contain additional therapeutic agents which may be present either inside the EV and/or in the EV membrane. For instance, an antibody-coated EV may be used to deliver an RNA therapeutics cargo (such as an mRNA, an siRNA, an oligonucleotide, etc.) to a target cell, tissue and/or organ. In another non-limiting example, EVs having attached to their surface an Fc containing targeting protein (such as a scFv which have been engineered to contain an Fc domain) and comprising inside the EV or in/on the EV membrane a therapeutic protein such as Cas9 for gene editing, optionally together with a CRISPR RNA guide strand.

[0084] In further aspects, the methods of the present invention may also comprise exposing the EV source cells to serum starvation, hypoxia, bafilomycin, or cytokines such as TNF-alpha and/or IFN-gamma, in order to influence the yield or properties of the resulting EVs. The EV production scale and timeline will be heavily dependent on the EV-producing cell or cell line and may thus be adapted accordingly by a person skilled in the art. The methods as per the present invention may further comprise an EV purification step, which may be carried out prior to co-incubating the EVs comprising the fusion protein with the Fc domain-containing protein (such as an antibody) to be attached to (e.g. coated on) the EVs. EVs may be purified through a procedure selected from a group of techniques comprising liquid chromatography (LC), high-performance liquid chromatography (HPLC), bead-eluate chromatography, spin filtration, tangential flow filtration (TFF), hollow fiber filtration, centrifugation, immunoprecipitation, flow field fractionation, dialysis, microfluidic-based separation, etc., or any combination thereof. In an advantageous embodiment, the purification of the EVs is carried out using a sequential combination of filtration (preferably ultrafiltration (UF), tangential flow filtration or hollow fiber filtration) and size exclusion liquid chromatography (LC) or bead-eluate chromatography. This combination of purification steps results in optimized purification, which in turn leads to superior therapeutic activity. Further, as compared to ultracentrifugation (UC), which is routinely employed for purifying exosomes, sequential filtration-chromatography is considerably faster and possible to scale to higher manufacturing volumes, which is a significant drawback of the current UC methodology that dominates the prior art. Another advantageous purification methodology is tangential flow filtration (TFF), which offers scalability and purity, and which may be combined with any other type of purification technique.

[0085] In yet another aspect, the present invention pertains to pharmaceutical compositions comprising EVs, normally in the form of populations of EVs, as per the present invention. Typically, the pharmaceutical compositions as per the present invention comprise one type of therapeutic EV (i.e. a population of EVs comprising a certain type of fusion protein and being coated by one or more types of Fc containing proteins, such as antibodies; Cas9-Fc fusion proteins and Fc-RNP fusion complexes; lysosomal storage disorder enzymes fused to Fc domains, etc.) formulated with at least one pharmaceutically acceptable excipient. However, more than one type of EV population may naturally be comprised in a single pharmaceutical composition, for instance in cases where a combinatorial antibody treatment is desirable. Naturally however, as above-mentioned, a single EV or a single population of EVs may comprise more than one Fc-containing protein (e.g. an antibody) bound to the EV surface. The at least one pharmaceutically acceptable excipient may be selected from the group comprising any pharmaceutically acceptable material, composition or vehicle, for instance a solid or liquid filler, a diluent, an excipient, a carrier, a solvent or an encapsulating material, which may be involved in e.g. suspending, maintaining the activity of or carrying or transporting the EV population from one organ, or portion of the body, to another organ, or portion of the body (e.g. from the blood to any tissue and/or organ and/or body part of interest).

[0086] The present invention also relates to cosmetic applications of EVs. Thus, the present invention may pertain to skin care products such as creams, lotions, gels, emulsions, ointments, pastes, powders, liniments, sunscreens, shampoos, etc., comprising a suitable EV, in order to improve and/or alleviate symptoms and problems such as dry skin, wrinkles, folds, ridges, and/or skin creases. In one embodiment, EVs (carrying a fusion protein bound to e.g. an antibody of interest) are obtained from a suitable EV-producing cell source with regenerative properties (for instance an MSC) are comprised in a cosmetic cream, lotion, or gel for use in the cosmetic or therapeutic alleviation of wrinkles, lines, folds, ridges and/or skin creases.

[0087] In yet another aspect, the present invention relates to EVs as per the present invention for use in medicine. Naturally, when an EV comprising a fusion protein bound to an Fc domain of a protein of interest (such as an antibody) is used in medicine, it is in fact normally a population of EVs that is being used. The dose of EVs administered to a patient will depend on the number of e.g. antibodies of interest that has been coated on the EV surface, the disease or the symptoms to be treated or alleviated, the administration route, the pharmacological action of the therapeutic protein itself, the inherent properties of the EVs, the presence of any targeting antibodies or other targeting entities, as well as various other parameters of relevance known to a skilled person.

[0088] The EVs of the present invention carrying the Fc containing proteins may be used for several different therapeutic and pharmaceutical aspects. In one embodiment, the EVs are covered with antibodies or other Fc containing proteins that target a specific cell type, tissue, and/or organ. This is a highly powerful way of targeting EVs, which may comprise other pharmaceutical agents in addition to the Fc containing protein, to tissues of interest, and could represent a step chance in targeted drug delivery. In another embodiment, therapeutic antibodies or other Fc domain-containing proteins that interact with a target antigen of interest can be efficiently delivered to tissues of interest that are typically hard to reach, using EVs with ability to cross biological barriers. This approach may for instance enable delivery of monoclonal antibodies into the central nervous system or into the brain. In yet another embodiment, coating of EVs with Fc containing proteins is a way of multiplexing the Fc containing protein of interest, in order to enhance or influence its target avidity or the conformation of its binding to a target of interest. In yet another embodiment, the EVs as per the present invention enable improved delivery and efficacy of antibody-drug conjugates (ADCs) or receptor-drug conjugates, as multiplexing of ADCs may significantly enhance their therapeutic efficacy and their presence on EVs means they can also enter target cells. In a further embodiment, the ability of EVs to enter target cells means that the EVs of the present invention opens up the entire intracellular space and make it druggable by essentially any protein comprising an Fc domain and/or any protein onto which an Fc domain can be fused (such as an enzyme for enzyme replacement therapy, nuclease such as Cas9, or a tumor suppressor such as any one of p53, pVHL, APC, CD95, ST5, YPEL3, ST7, and ST14).

[0089] The EVs and the EV populations thereof as per the present invention may thus be used for prophylactic and/or therapeutic purposes, e.g. for use in the prophylaxis and/or treatment and/or alleviation of various diseases and disorders. A non-limiting sample of diseases wherein the EVs as per the present invention may be applied comprises Crohn's disease, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, sarcoidosis, idiopathic pulmonary fibrosis, psoriasis, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), deficiency of the interleukin-1 receptor antagonist (DIRA), endometriosis, autoimmune hepatitis, scleroderma, myositis, stroke, acute spinal cord injury, vasculitis, Guillain-Barre syndrome, acute myocardial infarction, ARDS, sepsis, meningitis, encephalitis, liver failure, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), kidney failure, heart failure or any acute or chronic organ failure and the associated underlying etiology, graft-vs-host disease, Duchenne muscular dystrophy and other muscular dystrophies, lysosomal storage diseases such as Gaucher disease, Fabry's disease, MPS I, II (Hunter syndrome), and III, Niemann-Pick disease, Pompe disease, etc., neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and other trinucleotide repeat-related diseases, dementia, ALS, cancer-induced cachexia, anorexia, diabetes mellitus type 2, and various cancers. Virtually all types of cancer are relevant disease targets for the present invention, for instance, Acute lymphoblastic leukemia (ALL), Acute myeloid leukemia, Adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, Anal cancer, Appendix cancer, Astrocytoma, cerebellar or cerebral, Basal-cell carcinoma, Bile duct cancer, Bladder cancer, Bone tumor, Brainstem glioma, Brain cancer, Brain tumor (cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma), Breast cancer, Bronchial adenomas/carcinoids, Burkitt's lymphoma, Carcinoid tumor (childhood, gastrointestinal), Carcinoma of unknown primary, Central nervous system lymphoma, Cerebellar astrocytoma/Malignant glioma, Cervical cancer, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Chronic myeloproliferative disorders, Colon Cancer, Cutaneous T-cell lymphoma, Desmoplastic small round cell tumor, Endometrial cancer, Ependymoma, Esophageal cancer, Extracranial germ cell tumor, Extragonadal Germ cell tumor, Extrahepatic bile duct cancer, Eye Cancer (Intraocular melanoma, Retinoblastoma), Gallbladder cancer, Gastric (Stomach) cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal stromal tumor (GIST), Germ cell tumor (extracranial, extragonadal, or ovarian), Gestational trophoblastic tumor, Glioma (glioma of the brain stem, Cerebral Astrocytoma, Visual Pathway and Hypothalamic glioma), Gastric carcinoid, Hairy cell leukemia, Head and neck cancer, Heart cancer, Hepatocellular (liver) cancer, Hodgkin lymphoma, Hypopharyngeal cancer, Intraocular Melanoma, Islet Cell Carcinoma (Endocrine Pancreas), Kaposi sarcoma, Kidney cancer (renal cell cancer), Laryngeal Cancer, Leukemias ((acute lymphoblastic (also called acute lymphocytic leukemia), acute myeloid (also called acute myelogenous leukemia), chronic lymphocytic (also called chronic lymphocytic leukemia), chronic myelogenous (also called chronic myeloid leukemia), hairy cell leukemia)), Lip and Oral, Cavity Cancer, Liposarcoma, Liver Cancer (Primary), Lung Cancer (Non-Small Cell, Small Cell), Lymphomas, AIDS-related lymphoma, Burkitt lymphoma, cutaneous T-Cell lymphoma, Hodgkin lymphoma, Non-Hodgkin, Medulloblastoma, Merkel Cell Carcinoma, Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Mouth Cancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic/Myeloproliferative Diseases, Myelogenous Leukemia, Chronic Myeloid Leukemia (Acute, Chronic), Myeloma, Nasal cavity and paranasal sinus cancer, Nasopharyngeal carcinoma, Neuroblastoma, Oral Cancer, Oropharyngeal cancer, Osteosarcoma/malignant fibrous histiocytoma of bone, Ovarian cancer, Ovarian epithelial cancer (Surface epithelial-stromal tumor), Ovarian germ cell tumor, Ovarian low malignant potential tumor, Pancreatic cancer, Pancreatic islet cell cancer, Parathyroid cancer, Penile cancer, Pharyngeal cancer, Pheochromocytoma, Pineal astrocytoma, Pineal germinoma, Pineoblastoma and supratentorial primitive neuroectodermal tumors, Pituitary adenoma, Pleuropulmonary blastoma, Prostate cancer, Rectal cancer, Renal cell carcinoma (kidney cancer), Retinoblastoma, Rhabdomyosarcoma, Salivary gland cancer, Sarcoma (Ewing family of tumors sarcoma, Kaposi sarcoma, soft tissue sarcoma, uterine sarcoma), Sezary syndrome, Skin cancer (nonmelanoma, melanoma), Small intestine cancer, Squamous cell, Squamous neck cancer, Stomach cancer, Supratentorial primitive neuroectodermal tumor, Testicular cancer, Throat cancer, Thymoma and Thymic carcinoma, Thyroid cancer, Transitional cell cancer of the renal pelvis and ureter, Urethral cancer, Uterine cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Waldenstrom macroglobulinemia, and/or Wilm's tumor.

[0090] The EVs as per the present invention may be administered to a human or animal subject via various different administration routes, for instance auricular (otic), buccal, conjunctival, cutaneous, dental, electro-osmosis, endocervical, endosinusial, endotracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-arterial, intra-articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavernous, intracavitary, intracerebral, intracisternal, intracorneal, intracoronal (dental), intracoronary, intracorporus cavernosum, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intratumor, intratym panic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intraventricular, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric, occlusive dressing technique, ophthalmic, oral, oropharyngeal, other, parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, and/or vaginal administration, and/or any combination of the above administration routes, which typically depends on the disease to be treated and/or the characteristics of the antibody or the EV population as such.

[0091] Suitable targeting antibodies in accordance with the present invention may target antigens deriving from e.g. tumors, solid organs, bodily structures, cell or tissue types. Non-limiting examples of the origin of antigens that may be targeted by targeting antibodies include liver, lung, kidney, heart, pancreas, adrenal glands, thyroid glands, parathyroid glands, brain including all brain regions (for instance thalamus, hypothalamus, striatum, etc.), the blood-brain-barrier, the CNS, the PNS, bone marrow, the skin, the vascular system, the lymphatic system including the spleen, joints, eyes, muscle tissues, sites of inflammation, sites of injury, and cell types such as adipocytes, muscle cells (myoblasts and myotubes), satellite cells, cardiac cells, endothelial cells, fibroblasts, hepatocytes, renal cells, pericytes, neurons, glia cells, astrocytes, oligodendrocytes, macrophages, DC-cells, B-cells, T-cells, NK-cells, chrondrocytes, osteoblast, osteocytes, epithelial cells, erythrocytes, earlier progenitors such as multipotential hematopoietic stem cells/hemocytoblasts, myeloid progenitors, lymphoid progenitors, etc. Non-limiting examples of antigens relevant for targeting cancer includes adenocarcinoma antigen, alpha-fetoprotein, BAFF, C242 antigen, CA-125, carbonic anhydrase 9 (CA-IX), disialoganglioside (GD2), 4-IBB, 5T4, CD22, CD221, CD23 (IgE receptor), CD28, CD30 (TNFRSF8), CD33, CD4, CD40, CD44 v6, CD51, CD52, CD56, CD74, CD80, CEA, CNT0888, CTLA-4, DRS, EGFR, EpCAM, CD3, FAP, fibronectin extra domain-B, folate receptor 1, GD2, GD3 ganglioside, glycoprotein 75, GPNMB, HER2/neu, HGF, human scatter factor receptor kinase, IGF-1 receptor, IGF-I, IgGI, LI-CAM, IL-13, IL-6, insulin-like growth factor I receptor, integrin .alpha.5.beta.1, integrin .alpha.v.beta.3, legumain, MORAb-009, MS4A1, MUC1, mucin CanAg, C-MET, CCR4, CD 152, CD 10, CD 19, CD20, CD200, N-glycolylneuraminic acid, NPC-IC, PDGF-R a, PDL192, phosphatidylserine, tumor antigen CTAA16.88, VEGF-A, VEGFR-1, VEGFR2, vimentin, RANKL, RON, ROR1, SCH 900105, SDC1, SLAMF7, TAG-72, tenascin C, TGF beta 2, TGF-.beta., TRAIL-R1, TRAIL-R2, folic acid receptor, transferrin receptors and any combination thereof.

[0092] Antibodies or other Fc domain-containing proteins coating EVs in order to prevent or reduce opsonization and/or immune cell-mediated EV clearance in accordance with the present invention may be essentially any Fc-containing protein, such as an antibody, that is present naturally in serum or in any other body fluid. Such antibodies may thus be of any type, e.g. IgG, IgA, IgM, IgE and/or IgD, but any other protein comprising an Fc domain and having the capacity to prevent opsonization of EVs in vivo may also be used to coat the EV. Thus, coating of EVs to avoid or reduce clearance by immune may be carried out actively or passively, wherein the active coating may involve decorating the EV in question with a suitable protein comprising an Fc domain prior to application in vivo. Suitable Fc containing proteins for this purpose include Factor H and/or Factor I fused to an Fc domain. Factor H and Factor I are negative regulators of the complement system (by inhibiting C3 conversion to C3b), thereby resulting in reduced EV clearance when fused to an Fc domain and attached to the EV surface through the binding between the Fc binding polypeptide and the Fc domain of the fusion proteins. Passive coating on the other hand may entail allowing the EV in question to sequester proteins in vivo with its available non-bound Fc binders.

[0093] In a further embodiment, suitable non-limiting examples of therapeutic and/or targeting antibodies in accordance with the present invention may be any one or more of Abagovomab, Abciximab, Actoxumab, Adalimumab, Adecatumumab, Adotrastuzumab emtansine, Aducanumab, Afelimomab, Afutuzumab, Alacizumab Alemtuzumab, Alirocumab, Altumomab pentetate, Amatuximab, Anatumomab mafenatox, Anifrolumab, Anrukinzumab, Apolizumab, Arcitumomab, Aselizumab, Atezolizumab, Atinumab, Atlizumab, Atorolimuma, Avelumab, Bapineuzumab, Basiliximab, Bavituximab, Bectumomab, Belimumab, Benralizumab, Bertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab, Bimagrumab, Bivatuzumab mertansine, Blinatumomab, Blosozumab, Brentuximab vedotin, Briakinumab, Brodalumab, Canakinumab, Cantuzumab mertansine, Cantuzumab ravtansine, Caplacizumab, Capromab pendetide, Carlumab, Catumaxomab, cBR96-doxorubicin immunoconjugate, Cedelizumab, Certolizumab pegol, Cetuximab, Citatuzumab bogatox, Cixutumumab, Clazakizumab, Clenoliximab, Clivatuzumab tetraxetan, Conatumumab, Concizumab, Crenezumab, CR6261, Dacetuzumab, Daclizumab, Dalotuzumab, Daratumumab, Demcizumab, Denosumab, Detumomab, Dinutuximab, Dorlimomab aritox, Drozitumab, Duligotumab, Dupilumab, Durvalumab, Dusigitumab, Ecromeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Efungumab, Eldelumab, Elotuzumab, Elsilimomab, Enavatuzumab, Enlimomab pegol, Enokizumab, Enoticumab, Ensituximab, Epitumomab cituxetan, Epratuzumab, Erlizumab, Ertumaxomab, Etanercept, Etaracizumab, Etrolizumab, Evolocumab, Exbivirumab, Fanolesomab, Faralimomab, Farletuzumab, Fasinumab, FBTA05, Felvizumab, Fezakinumab, Ficlatuzumab, Figitumumab, Flanvotumab, Fontolizumab, Foralumab, Foravirumab, Fresolimumab, Fulranumab, Futuximab, Galiximab, Ganitumab, Gantenerumab, Gavilimomab, Gemtuzumab ozogamicin, Gevokizumab, Girentuximab, Glembatumumab vedotin, Golimumab, Gomiliximab, Guselkumab, Ibalizumab, Ibritumomab tiuxetan, Icrucumab, Igovomab, IMAB362, Imciromab, Imgatuzumab, Inclacumab, Indatuximab ravtansine, Infliximab, Intetumumab, Inolimomab, Inotuzumab ozogamicin, Ipilimumab, Iratumumab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab, Lambrolizumab, Lampalizumab, Lebrikizumab, Lemalesomab, Lerdelimumab, Lexatumumab, Libivirumab, Ligelizumab, Lintuzumab, Lirilumab, Lodelcizumab, Lorvotuzumab mertansine, Lucatumumab, Lumiliximab, Mapatumumab, Margetuximab, Maslimomab, Mavrilimumab, Matuzumab, Mepolizumab, Metelimumab, Milatuzumab, Minretumomab, Mitumomab, Mogamulizumab, Morolimumab Motavizumab, Moxetumomab pasudotox, Muromonab-CD3, Nacolomab tafenatox, Nam ilumab, Naptumomab estafenatox, Narnatumab, Natalizumab, Nebacumab, Necitumumab, Nerelimomab, Nesvacumab, Nimotuzumab, Nivolumab, Nofetumomab merpentan, Ocaratuzumab, Ocrelizumab, Odulimomab, Ofatumumab, Olaratumab, Olokizumab, Omalizumab, Onartuzumab, Ontuxizumab, Oportuzumab monatox, Oregovomab, Orticumab, Otelixizumab, Otlertuzumab, Oxelumab, Ozanezumab, Ozoralizumab, Pagibaximab, Palivizumab, Panitumumab, Pankomab, Panobacumab, Parsatuzumab, Pascolizumab, Pateclizumab, Patritumab, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab, Pexelizumab, Pidilizumab, Pinatuzumab vedotin, Pintumomab, Placulumab, Polatuzumab vedotin, Ponezumab, Priliximab, Pritoxaximab, Pritumumab, PRO 140, Quilizumab, Racotumomab, Radretumab, Rafivirumab, Ramucirumab, Ranibizumab, Raxibacumab, Regavirumab, Reslizumab, Rilotumumab, Risankizumab, Rituximab, Robatumumab, Roledumab, Romosozumab, Rontalizumab, Rovelizumab, Ruplizumab, Samalizumab, Sarilumab, Satumomab pendetide, Secukinumab, Seribantumab, Setoxaximab, Sevirumab, Sibrotuzumab, Sifalimumab, Siltuximab, Simtuzumab, Siplizumab, Sirukumab, Solanezumab, Solitomab, Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab, Suvizumab, Tabalumab, Tacatuzumab tetraxetan, Tadocizumab, Talizumab, Tanezumab, Taplitumomab paptox, Tefibazumab, Telimomab aritox, Tenatumomab, Teneliximab, Teplizumab, Teprotumumab, Ticilimumab, Tildrakizumab, Tigatuzumab, Tocilizumab, Toralizumab, Tositumomab, Bexxar, Tovetumab, Tralokinumab, Trastuzumab, Tregalizumab, Tremelimumab, Tucotuzumab celmoleukin, Tuvirumab, Ublituximab, Urelumab, Urtoxazumab, Ustekinumab, Vantictumab, Vapaliximab, Vatelizumab, Vedolizumab, Veltuzumab, Vepalimomab, Vesencumab, Visilizumab, Volociximab, Vorsetuzumab mafodotin, Votumumab, Zalutumumab, Zanolimumab, Zatuximab, Ziralimumab, Zolimomab aritox, or any combination thereof. Importantly, the present invention provides for the delivery of any antibody, regardless of whether its target is intracellular and/or extracellular. The ability of the EVs of the present invention to efficiently internalize antibodies represent a step-change in monoclonal antibody development and may enable targeting antigens and targets across the entire intracellular compartment of target cells. Importantly, antibodies and Fc containing proteins as per the present invention may advantageously be labelled for detection and imaging purposes, for instance using fluorophores, MRI agents, PET agents, radioactive agents, enzymes, nanoparticles, metals, organic and inorganic compounds, etc.

[0094] It shall be understood that the above described exemplifying aspects, embodiments, alternatives, and variants can be modified without departing from the scope of the invention. The invention will now be further exemplified with the enclosed examples, which naturally also can be modified considerably without departing from the scope and the gist of the invention.

EXPERIMENTAL PART

[0095] Materials and Methods

[0096] Construct design and cloning: Various fusion proteins comprising at least one exosomal polypeptide and at least one Fc binding polypeptide have been constructed, cloned into vectors and produced in several different EV-producing cell sources. ORFs were typically generated by synthesis and cloned into the mammalian expression vector pSF-CAG-Amp. Briefly, synthesized DNA and vector plasmid were digested with enzymes NotI and SalI as per manufacturers instruction (NEB). Restricted, purified DNA fragments were ligated together using T4 ligase as per manufacturers instruction (NEB). Successful ligation events were selected for by bacterial transformation on ampicillin-supplemented plates. Plasmid for transfection was generated by `maxi-prep`, as per manufacturers instruction.

[0097] In cases where Fc containing proteins were endogenously produced in the same EV-producing cell source that expresses the fusion protein, ORF sequences were purchased (Origene Technologies, Inc.) and amplified and cloned into the MSC A site of pIRES bicistronic expression vector (Clonetech, Laboratories Inc.) such that upon translation the exosomal polypeptide was fused to the Fc binding polypeptide in one construct, whereas the Fc containing protein of interest was translated separately (from a separate construct or from the same construct) and transported into the EV to be formed in the EV-producing cell source. Most of the cloning was performed using the NEBuilder HiFi DNA Assembly Cloning Kit (NEB, Inc.) and confirmed using Sanger sequencing (Source BioScience). The pIRES vector enables bicistronic expression of both transgenes simultaneously, ensuring EV-producing cells would express both the fusion protein and the Fc containing protein of interest simultaneously. Plasmids were transformed into the NEB 5-alpha Competent E. coli cells (NEB, Inc.) and grown overnight in a shaking incubator according to manufacturer's recommendations. Plasmids were isolated and purified using the `maxi-prep plasmid DNA purification kit` (Qiagen), as per manufacturer's instruction.

[0098] Cell Culture and Transfection

[0099] Depending on the experimental design and assays, in certain cases, non-viral transient transfection and exosome production was carried out in conventional 2D cell culture, whereas in other cases virus-mediated transduction was employed to create stable cell lines, which were typically cultured in bioreactors of different type. For conciseness, only a few examples are mentioned herein.

[0100] HEK293T cells were typically seeded into 15 cm dishes (9.times.10.sup.6 cells per dish) and left overnight in serum-containing DMEM as recommended by ATCC. The following day the cells were transiently transfected with lipoplexed DNA added directly onto cells. Briefly, DNA and polyethyleneimine (PEI) were separately incubated in OptiMEM for 5 minutes before combining together for 20 minutes at room temperature. Lipoplexed DNA and cells were co-incubated for 6 hours following which conditioned culture media was changed to OptiMEM for 48 hours. Other cells and cell lines that were evaluated in dishes, flasks and other cell culture vessels included bone marrow-derived mesenchymal stromal cells (BM-MSCs) and Wharton's jelly-derived MSCs (WJ-MSCs), amnion cells, fibroblasts, various endothelial and epithelial cells, as well as various immune cells and cell lines.

[0101] In the case of viral transduction and creation of stable cell lines for various combinations of fusion proteins and Fc containing proteins of interest, cell sources such as BM-MSCs, WJ-MSC, fibroblasts, amnion cells, fibroblasts, various endothelial and epithelial cells, were virus-transduced, typically using lentivirus (LV). Typically, 24 hours before infection, 100.000 cells (e.g. fibroblasts, MSCs, etc.) or 200.000 cells (e.g. HEK293T) are plated in a 6-well plate. 2 uL of LV and optionally Polybrene (or hexadimethrine bromide, final concentration on the well of 8 ug/mL) are added, and 24 hours post transduction the cell medium of transduced cells is changed to fresh complete media. At 72 hours post transduction, puromycin selection (4-6 .mu.g/ml) is performed, normally for 7 days followed by analysis of stable expression of the fusion protein construct comprising the exosomal polypeptide and the Fc binding polypeptide.

[0102] Stable cells were cultured in either 2D culture or in bioreactors, typically hollow-fiber bioreactors or stir-rank bioreactors, and conditioned media was subsequently harvested for exosome preparation. Various preparation and purification steps were carried out. The standard workflow comprises the steps of pre-clearing of the supernatant, filtration-based concentration, chromatography-based removal of protein contaminants, and optional formulation of the resultant exosome composition in a suitable buffer for in vitro and/or in vivo assays.

[0103] Assays and Analytics

[0104] Western blot is a highly convenient analytical method to evaluate the enrichment of fusion proteins in EVs. Briefly, SDS-PAGE was performed according to manufacturer's instruction (Invitrogen, Novex PAGE 4-12% gels), whereby 1.times.10.sup.10 exosomes and 20 ug cell lysate were loaded per well. Proteins from the SDS-PAGE gel were transferred to PVDF membrane according to manufacturer's instruction (Immobilon, Invitrogen). Membranes were blocked in Odyssey blocking buffer (Licor) and probed with antibodies against the Fc binding polypeptide and/or the exosomal protein according to supplier's instruction (Primary antibodies--Abcam, Secondary antibodies--Licor). Molecular probes visualized at 680 and 800 nm wavelengths.

[0105] For EV size determination, nanoparticle tracking analysis (NTA) was performed with a NanoSight instrument equipped with analytical software. For all recordings, we used a camera level of 13 or 15 and automatic function for all post-acquisition settings. Electron microscopy and fluorescence microscopy were frequently used to understand intracellular location and release and to quantitate and analyze EVs.

[0106] EVs were isolated and purified using a variety of methods, typically a combination of filtration such as TFF and LC, in particular bead-elute LC. Typically, EV-containing media was collected and subjected to a low speed spin at 300 g for 5 minutes, followed by 2000 g spin for 10 minutes to remove larger particles and cell debris. The supernatant was then filtered with a 0.22 .mu.m syringe filter and subjected to different purification steps. Large volumes were diafiltrated and concentrated to roughly 20 ml using the Vivaflow 50R tangential flow (TFF) device (Sartorius) with 100 kDa cutoff filters or the KR2i TFF system (Spectrum Labs) with 100 or 300 kDa cutoff hollow fibre filters. The preconcentrated medium was subsequently loaded onto the bead-eluate columns (HiScreen or HiTrap Capto Core 700 column, GE Healthcare Life Sciences), connected to an AKTAprime plus or AKTA Pure 25 chromatography system (GE Healthcare Life Sciences). Flow rate settings for column equilibration, sample loading and column cleaning in place procedure were chosen according to the manufacturer's instructions. The sample was collected according to the UV absorbance chromatogram and concentrated using an Amicon Ultra-15 10 kDa molecular weight cut-off spin-filter (Millipore) to a final volume of 100 .mu.l and stored at -80.degree. C. for further downstream analysis. To assess the protein and RNA elution profiles, media was concentrated and diafiltrated with KR2i TFF system using 100 kDa and 300 kDa hollow fibre filters and a sample analysed on a Tricorn 10/300 Sepharose 4 Fast Flow (S4FF) column (GE Healthcare Life Sciences).

EXAMPLES

Example 1: Binding of IgG to EVs Comprising Fc Binding Polypeptides (Fc-Binding EVs)

[0107] EVs were isolated from the conditioned medium from engineered HEK293T cells (control versus Fc-binding construct that stably express Gp130 Extracellular domain-2XGGGGS linker-Z domain-Gp130 transmembrane domain-Leucine Zipper-N terminal syntenin-His tag) using tangential flow filtration with 300 kd hollow fiber columns, followed by ultrafiltration using 10 kd spin filters for concentration. The binding capacity for IgG by the Fc-binding EVs were then assessed using electron microscopy and flow cytometry.

[0108] For electron microscopy, 1.times.10{circumflex over ( )}9 EVs were incubated with Rabbit anti-goat 10 nm antibody conjugated with gold Nanoparticles for 2 h at 37.degree. C. As shown in FIG. 2, Fc-binding EVs (A) are decorated with nanogold labeled antibodies (i.e. Fc containing proteins), whereas control EVs (B) do not have any antibodies bound.

[0109] For flow cytometry, 1.times.10{circumflex over ( )}8 EVs were incubated overnight on an orbital shaker at 450 rpm for 16 hours in 120 .mu.l PBS with 15 .mu.l antibody-coated capture beads from the MACSPlex Exosome Kit, human (Miltenyi Biotec, Order no 130-108-813). After washing, 3 .mu.g of AlexaFluor647-conjugated human IgG Fc fragments (Jackson Laboratories, Catalogue 009-600-008) were added to controls without EVs (A), control EVs (B), or Fc-binding EVs (Synthenin--gp130-zDomain-gp130) (C). After 1 hour incubation at room temperature, unbound Fc fragments were washed away and samples were analyzed via flow cytometry. In FIG. 3 respective left dotplots show hard-dyed capture bead populations using B1-A (Excitation: 488 nm, Emission Filter: 500-550 nm; Area) versus B2-A (Excitation: 488 nm, Emission Filter: 565-605 nm, Area) parameters. Respective right plots show R1-A (Excitation: 635 nm, Emission Filter: 655-730 nm, Area) versus B2-A parameters, demonstrating binding of AlexaFluor647 labeled Fc-Fragments to EVs which have bound to the capture beads only in (C). FIG. 3 shows that the Fc-binding EVs bind both to AlexaFluor647-labelled Fc fragments (human IgG) and very efficiently also to the Fc domains of all 39 different antibodies which are coated on all capture bead populations by the manufacturer included in the kit, including the two negative control bead populations.

Example 2: FCGR1A Lamp2B EVs for Delivery of Anti-HER2 Antibody

[0110] EVs were isolated from HEK293T cells (either stably expressing FCGR1A Extracellular domain-4XGSlinker-Lamp2b or their wild type controls) using ultrafiltration and size exclusion chromatography. EVs were labelled with PKH26 red fluorescent dye, and decorated with anti-HER2 antibody or its isotype control by co-incubating EVs and antibody for 1 h at 37.degree. C. Unbound antibody was removed by size exclusion chromatography. Uptake of antibody decorated EVs was characterized in HER2 low-expressing cell line MDA-MB-231 and in HER2 high-expressing cell line MDA-MB-361 using flow cytometry. FIG. 4 shows that anti-HER2 antibody increases uptake of decorated EVs as compared to isotype control decorated and wild type EVs only in HER2 high-expressing cell line MDA-MB-361, but not in HER2 low-expressing cell line MDA-MB-231. Similar results were obtained with EVs expressing CD63-ZZ fusion proteins.

Example 3: Etanercept Delivery by EVs Comprising CD81-Protein A/G Fusion Proteins

[0111] EVs were isolated from HEK293T cells (either stably expressing CD81-ProteinA/G CD81 Second loop fusion protein or their wild type control) using ultrafiltration and size exclusion chromatography. EVs were decorated with etanercept or a control antibody by co-incubating EVs and etanercept for 1 h at 37.degree. C. Unbound etanercept was removed by size exclusion chromatography. To study anti-inflammatory effect of the etanercept-decorated EVs, the well-studied TNBS-induced colitis mouse model was used. This model simulates the gut inflammation, cytokine storm and weight decrease associated with IBD patients. 24 mice were divided into four treatment groups, with 6 mice per group. The mice were pre-sensitized by applying 150 .mu.l of a olive oil-acetate solution with 2% TNBS, on the skin, 1 week prior to colitis induction. Colitis was then induced by giving a rectal infusion of 100 .mu.l solution containing 1.5% TNBS in 40% ethanol. Immediately post colitis induction, 10E10 EVs/g EVs in 200 .mu.l were administrated intravenously in the tail vein. FIG. 5 shows that etanercept-coated EVs protected mice from loss of body weight, as opposed to WT or control decorated-EVs, and displayed higher activity than naked etanercept, possible due to higher affinity between etanercept and TNFalpha when etanercept is multiplexed and/or when the Fc binding polypeptide binds to its Fc domain.

Example 4: Intracellular Uptake and Delivery of Antibodies Via Fc-Binding EVs

[0112] EVs were isolated from the conditioned medium of Wharton's jelly-derived MSCs (either stably expressing TNFR Extracellular domain-2XGGGGS linker-Z domain-TNFR transmembrane domain-foldon-N terminal syntenin fusion proteins or control) using ultrafiltration and size exclusion chromatography. In order to investigate whether Fc-binding EVs can be employed for intracellular delivery of Abs, 4.times.10{circumflex over ( )}11 EVs were incubated in 400 .mu.l for 16 hours (overnight) with total 3 .mu.g AlexaFluor488-labelled anti-Lamin B2 IgGs [abcam ab200426, Rabbit monocolonal EPR9701(B)]. For the uptake experiment, Huh7 cells were plated in 48 well plates at 30,000 cells per well and incubated for 16 hours before 0.675.times.10{circumflex over ( )}11 antibody-labelled EVs were added. Cells were incubated for 2 hours at 37.degree. C. and 5% CO.sub.2 in a humidified atmosphere before they were trypsinized and analyzed by fluorescence microscopy (A) and flow cytometry (B) as shown in FIG. 6; A) show green fluorescence signals merged with phase contrast images. Histograms in B) show the green fluorescence intensity on a logarithmic scale on the x-axis and the normalized frequency on the y-axis. 1: HuH7 cells not treated with any antibody or EVs. 2: HuH7 cells treated with control EVs which were incubated with anti-Lamin B2 antibodies. 3: HuH7 cells treated with Fc-binding EVs which were incubated with anti-Lamin B2 antibodies. FIG. 6 shows that signals of fluorescent antibodies are clearly present in cells treated with Fc-binding EVs plus antibody, while fluorescence signals are absent in untreated (1) or control EV treated (2). This demonstrates that antibodies can be delivered intracellularly via Fc-binding EVs, and that binding to EVs dramatically increases uptake of antibodies into cells.

[0113] To demonstrate functional intracellular delivery, anti-NFkB antibodies (anti-NFkB-Ab) were incubated with respective EVs for 1 h at 37.degree. C. A reporter cell line, HEK cells stably expressing NFkB-luciferase, were treated with 5 ng/ml hTNF-alpha and the EV-Ab-mix. After 6 hours of treatment the luciferase activity was measured. FIG. 7 shows successful inhibition when the anti-NFkB-ab is delivered by Fc-binding EVs.

Example 5: EAE Treatment Using Fc-Binding EVs Decorated with Anti-Integrin-4-Alpha-Ab

[0114] C57BL/6 mice were induced with experimental autoimmune encephalitis (EAE) by s.c. injection of 100 ul of MOG.sub.35-55-CFA emulsion and i.p. injection of 400 ng pertussis toxin on the same day and two days following immunization. EVs were isolated as described in example 1, from conditioned media of bone marrow-derived MSCs (either stably expressing CD9-ZZ (a fusion construct comprising as a non-limiting example the SEQ ID NO 1 operably linked to as a non-limiting example the SEQ ID NO 74) domain fusion proteins or their wild type controls). Anti-integrin-4-alpha antibodies (Ab) were incubated with respective EVs (zzEVs or ctrl-EVs). The EAE mice were injected with anti-integrin-4a-Ab with or without EVs at day 7. FIG. 8 shows that ctrl-EVs, as well as anti-integrin-4a-Ab display moderate protective effect from EAE development per se, whereas zzEVs incubated with anti-integrin-4a-Ab displayed almost complete inhibition of EAE development.

Example 6: Targeted Genomic Deletion by Delivering Fc-Cas9 Endonuclease Using Fc-Binding EVs

[0115] EVs were purified as stated in example 1 from cell culture medium obtained from adipocytes (stably transfected FCGR1A Extracellular domain-4XGSlinker-Lamp2b fusion protein or Lamp2b GFP as a control). Varying amounts of EVs was used (100 .mu.g, 500 .mu.g, 2.5 mg, 5 mg and 10 mg), whilst the amount of Fc (IGHG1) tagged-Cas9 Guide RNA complexes (so called RNP complexes) targeting HPRT remained at 100 .mu.g. The final weight ratios of Cas9 complex to EVs were 1:1, 1:5, 1:25, 1:50 and 1:100 respectively and incubated at 22.degree. C. for 60 minutes. Maximum loading of Cas9 on EVs was obtained with 1:5 weight ratio of Cas9 complexes to EVs, free Cas9 complexes were removed by ultrafiltration. Then Cas9 loaded Fc+Adipocytes-EVs were used to treat Huh7 cells with different concentration. After 24 hours cells were harvested and GeneArt Genomic Cleavage detection kit (Thermo scientific) was used as per manufacture protocol for preparing samples genomic cleavage assay and run on a 2% agarose gel. Indels were then quantified using Image J software. FIG. 9 shows dose-dependent gene editing in target cells. Various other pairs of Fc binding polypeptides and Fc domains fused to Cas9 were also evaluated in the same setup. Human FCAMR (IgA and IgM binding), human FCGR3A (IgG binding), and human FCGRB (IgG binding) fused to CD83 and combined with Cas9 fused to several different human Fc domains (e.g. IGHM, IGHA1, IGHG1, etc.) were also evaluated in the same setup. Overall, all construct showed gene editing activity but with lower potency than the FCGR1A Extracellular domain-4XGSlinker-Lamp2b fusion protein (data not shown).

Example 7: EV Decoration with Soluble Lysosomal Proteins Using the Human-Fc/pH-Sensing Protein G Complex

[0116] The C2 domain of Protein G fused to various exosomal proteins such as CD63, Lamp2, and the transferrin receptor were evaluated for their expression and EV display levels. To facilitate the tethering of a lysosomal protein to the surface of EVs, a human Fc domain (deriving from IgG) (hFc) was fused to either the N or C terminus of the enzyme GBA. In the case of the N-fusion construct, the hFc domain was inserted following the signal peptide native to GBA. Co-expression of both constructs led to a significant enrichment of GBA with EVs, more so than over expression of wild-type GBA. In addition to the wt C2 domain of Protein G, a pH-sensing C2 domain was also displayed on the EV surface in a manner previously described. While the pH sensing C2 domain has the capacity to effectively bind the human Fc region, the affinity for complex formation drops over a thousand-fold at pH 4. Following cellular uptake of GBA-decorated by pH-sensing C2 domain EVs, they are trafficked to the lysosomal compartment. Within the low pH of the compartment, the tethered GBA and pH-sensing c2 domain dissociate, facilitating the presence of free untethered GBA within the lumen of the lysosome.

[0117] Conditioned media isolated from Hek293T cells producing wild type exosomes, C2 domain of Protein G decorated exosomes or pH-sensing C2 domain of Protein G decorated exosomes was combined with conditioned media from Hek293T cells expressing wild type GBA or human Fc-GBA fusion for 1 hour at 37.degree. C. In addition, a co-incubation was performed in which the conditioned media was acidified to pH 4. EVs were then isolated by ultrafiltration and bead elution chromatography. To assess the levels of exosome-tethered GBA, purified vesicles were analyzed by western blot and probed for the presence of GBA. To assess the GBA activity of the GBA-carrying exosomes, patient-derived GBA deficient fibroblasts were co-incubated with GBA-enriched exosomes and analyzed for glucosylceramide levels 48 hours later. FIG. 10 shows the outcome of this experiment: WT--wildtype Hek293t exosomes; GBA--wildtype GBA; hFc-GBA--human Fc fragment-GBA fusion; PG--exosomes decorated with the C2 domain of Protein G; PGpH--exosomes decorated with the C2 domain of pH sensing Protein G. n=3. In an analogous experiment, Protein L and Protein LG were also evaluated as Fc binding polypeptides in the same setup, resulting in similar outcomes (data not shown).

Example 8: EVs Coated with siRNA-Loaded Ago2 Fused to a Human Fc Domain

[0118] EVs comprising fusion proteins between Lamp2b and the Fc binding polypeptide ZZ were generated and isolated from Hek293T cells using ultrafiltration and bead-elute chromatography. hFc-Ago2 fusion proteins were expressed in Hek293T cells and isolated by affinity chromatography, following which the fusion proteins were incubated in a molecular excess of siRNAs against cyclin D overnight. Excess siRNAs were removed by a second round of affinity purification. 5.times.10.sup.6 loaded EVs were co-incubated with 10.sup.5 U2OS cells overnight, following which after 48 hours cells were harvested and cyclin D levels assessed. For the in vivo studies, 1.times.10.sup.6 of A549 cells were mixed with 1:1 ratio of Matrigel and injected subcutaneously into NCRNU mice. Tumor-bearing mice were treated every other day with 10.sup.7 siRNA-loaded exosomes using tail-vein administration. Over the course of the study caliper measurements were used to calculate tumor volume. Cyclin D levels following U2OS cell treatment with siRNA-loaded Ago2 displayed on the surface of Lamp2b-ZZ domain EVs showed significant target silencing, as shown in FIG. 11. siCyclin D were directly transfected for the +ve control. hFc denotes exosome surface display; siCyclin--anti CyclinD siRNA; siScr--scrambled sequence. n=3.

Sequence CWU 1

1

831227PRTHomo sapiens 1Pro Val Lys Gly Gly Thr Lys Cys Ile Lys Tyr Leu Leu Phe Gly Phe1 5 10 15Asn Phe Ile Phe Trp Leu Ala Gly Ile Ala Val Leu Ala Ile Gly Leu 20 25 30Trp Leu Arg Phe Asp Ser Gln Thr Lys Ser Ile Phe Glu Gln Glu Thr 35 40 45Asn Asn Asn Asn Ser Ser Phe Tyr Thr Gly Val Tyr Ile Leu Ile Gly 50 55 60Ala Gly Ala Leu Met Met Leu Val Gly Phe Leu Gly Cys Cys Gly Ala65 70 75 80Val Gln Glu Ser Gln Cys Met Leu Gly Leu Phe Phe Gly Phe Leu Leu 85 90 95Val Ile Phe Ala Ile Glu Ile Ala Ala Ala Ile Trp Gly Tyr Ser His 100 105 110Lys Asp Glu Val Ile Lys Glu Val Gln Glu Phe Tyr Lys Asp Thr Tyr 115 120 125Asn Lys Leu Lys Thr Lys Asp Glu Pro Gln Arg Glu Thr Leu Lys Ala 130 135 140Ile His Tyr Ala Leu Asn Cys Cys Gly Leu Ala Gly Gly Val Glu Gln145 150 155 160Phe Ile Ser Asp Ile Cys Pro Lys Lys Asp Val Leu Glu Thr Phe Thr 165 170 175Val Lys Ser Cys Pro Asp Ala Ile Lys Glu Val Phe Asp Asn Lys Phe 180 185 190His Ile Ile Gly Ala Val Gly Ile Gly Ile Ala Val Val Met Ile Phe 195 200 205Gly Met Ile Phe Ser Met Ile Leu Cys Cys Ala Ile Arg Arg Asn Arg 210 215 220Glu Met Val2252219PRTHomo sapiens 2Met Gly Met Ser Ser Leu Lys Leu Leu Lys Tyr Val Leu Phe Phe Phe1 5 10 15Asn Leu Leu Phe Trp Ile Cys Gly Cys Cys Ile Leu Gly Phe Gly Ile 20 25 30Tyr Leu Leu Ile His Asn Asn Phe Gly Val Leu Phe His Asn Leu Pro 35 40 45Ser Leu Thr Leu Gly Asn Val Phe Val Ile Val Gly Ser Ile Ile Met 50 55 60Val Val Ala Phe Leu Gly Cys Met Gly Ser Ile Lys Glu Asn Lys Cys65 70 75 80Leu Leu Met Ser Phe Phe Ile Leu Leu Leu Ile Ile Leu Leu Ala Glu 85 90 95Val Thr Leu Ala Ile Leu Leu Phe Val Tyr Glu Gln Lys Leu Asn Glu 100 105 110Tyr Val Ala Lys Gly Leu Thr Asp Ser Ile His Arg Tyr His Ser Asp 115 120 125Asn Ser Thr Lys Ala Ala Trp Asp Ser Ile Gln Ser Phe Leu Gln Cys 130 135 140Cys Gly Ile Asn Gly Thr Ser Asp Trp Thr Ser Gly Pro Pro Ala Ser145 150 155 160Cys Pro Ser Asp Arg Lys Val Glu Gly Cys Tyr Ala Lys Ala Arg Leu 165 170 175Trp Phe His Ser Asn Phe Leu Tyr Ile Gly Ile Ile Thr Ile Cys Val 180 185 190Cys Val Ile Glu Val Leu Gly Met Ser Phe Ala Leu Thr Leu Asn Cys 195 200 205Gln Ile Asp Lys Thr Ser Gln Thr Ile Gly Leu 210 2153237PRTHomo sapiens 3Ala Val Glu Gly Gly Met Lys Cys Val Lys Phe Leu Leu Tyr Val Leu1 5 10 15Leu Leu Ala Phe Cys Ala Cys Ala Val Gly Leu Ile Ala Val Gly Val 20 25 30Gly Ala Gln Leu Val Leu Ser Gln Thr Ile Ile Gln Gly Ala Thr Pro 35 40 45Gly Ser Leu Leu Pro Val Val Ile Ile Ala Val Gly Val Phe Leu Phe 50 55 60Leu Val Ala Phe Val Gly Cys Cys Gly Ala Cys Lys Glu Asn Tyr Cys65 70 75 80Leu Met Ile Thr Phe Ala Ile Phe Leu Ser Leu Ile Met Leu Val Glu 85 90 95Val Ala Ala Ala Ile Ala Gly Tyr Val Phe Arg Asp Lys Val Met Ser 100 105 110Glu Phe Asn Asn Asn Phe Arg Gln Gln Met Glu Asn Tyr Pro Lys Asn 115 120 125Asn His Thr Ala Ser Ile Leu Asp Arg Met Gln Ala Asp Phe Lys Cys 130 135 140Cys Gly Ala Ala Asn Tyr Thr Asp Trp Glu Lys Ile Pro Ser Met Ser145 150 155 160Lys Asn Arg Val Pro Asp Ser Cys Cys Ile Asn Val Thr Val Gly Cys 165 170 175Gly Ile Asn Phe Asn Glu Lys Ala Ile His Lys Glu Gly Cys Val Glu 180 185 190Lys Ile Gly Gly Trp Leu Arg Lys Asn Val Leu Val Val Ala Ala Ala 195 200 205Ala Leu Gly Ile Ala Phe Val Glu Val Leu Gly Ile Val Phe Ala Cys 210 215 220Cys Leu Val Lys Ser Ile Arg Ser Gly Tyr Glu Val Met225 230 2354236PRTHomo sapiens 4Met Gly Val Glu Gly Cys Thr Lys Cys Ile Lys Tyr Leu Leu Phe Val1 5 10 15Phe Asn Phe Val Phe Trp Leu Ala Gly Gly Val Ile Leu Gly Val Ala 20 25 30Leu Trp Leu Arg His Asp Pro Gln Thr Thr Asn Leu Leu Tyr Leu Glu 35 40 45Leu Gly Asp Lys Pro Ala Pro Asn Thr Phe Tyr Val Gly Ile Tyr Ile 50 55 60Leu Ile Ala Val Gly Ala Val Met Met Phe Val Gly Phe Leu Gly Cys65 70 75 80Tyr Gly Ala Ile Gln Glu Ser Gln Cys Leu Leu Gly Thr Phe Phe Thr 85 90 95Cys Leu Val Ile Leu Phe Ala Cys Glu Val Ala Ala Gly Ile Trp Gly 100 105 110Phe Val Asn Lys Asp Gln Ile Ala Lys Asp Val Lys Gln Phe Tyr Asp 115 120 125Gln Ala Leu Gln Gln Ala Val Val Asp Asp Asp Ala Asn Asn Ala Lys 130 135 140Ala Val Val Lys Thr Phe His Glu Thr Leu Asp Cys Cys Gly Ser Ser145 150 155 160Thr Leu Thr Ala Leu Thr Thr Ser Val Leu Lys Asn Asn Leu Cys Pro 165 170 175Ser Gly Ser Asn Ile Ile Ser Asn Leu Phe Lys Glu Asp Cys His Gln 180 185 190Lys Ile Asp Asp Leu Phe Ser Gly Lys Leu Tyr Leu Ile Gly Ile Ala 195 200 205Ala Ile Val Val Ala Val Ile Met Ile Phe Glu Met Ile Leu Ser Met 210 215 220Val Leu Cys Cys Gly Ile Arg Asn Ser Ser Val Tyr225 230 2355532PRTHomo sapiens 5Met Ala Pro Ser Ser Pro Arg Pro Ala Leu Pro Ala Leu Leu Val Leu1 5 10 15Leu Gly Ala Leu Phe Pro Gly Pro Gly Asn Ala Gln Thr Ser Val Ser 20 25 30Pro Ser Lys Val Ile Leu Pro Arg Gly Gly Ser Val Leu Val Thr Cys 35 40 45Ser Thr Ser Cys Asp Gln Pro Lys Leu Leu Gly Ile Glu Thr Pro Leu 50 55 60Pro Lys Lys Glu Leu Leu Leu Pro Gly Asn Asn Arg Lys Val Tyr Glu65 70 75 80Leu Ser Asn Val Gln Glu Asp Ser Gln Pro Met Cys Tyr Ser Asn Cys 85 90 95Pro Asp Gly Gln Ser Thr Ala Lys Thr Phe Leu Thr Val Tyr Trp Thr 100 105 110Pro Glu Arg Val Glu Leu Ala Pro Leu Pro Ser Trp Gln Pro Val Gly 115 120 125Lys Asn Leu Thr Leu Arg Cys Gln Val Glu Gly Gly Ala Pro Arg Ala 130 135 140Asn Leu Thr Val Val Leu Leu Arg Gly Glu Lys Glu Leu Lys Arg Glu145 150 155 160Pro Ala Val Gly Glu Pro Ala Glu Val Thr Thr Thr Val Leu Val Arg 165 170 175Arg Asp His His Gly Ala Asn Phe Ser Cys Arg Thr Glu Leu Asp Leu 180 185 190Arg Pro Gln Gly Leu Glu Leu Phe Glu Asn Thr Ser Ala Pro Tyr Gln 195 200 205Leu Gln Thr Phe Val Leu Pro Ala Thr Pro Pro Gln Leu Val Ser Pro 210 215 220Arg Val Leu Glu Val Asp Thr Gln Gly Thr Val Val Cys Ser Leu Asp225 230 235 240Gly Leu Phe Pro Val Ser Glu Ala Gln Val His Leu Ala Leu Gly Asp 245 250 255Gln Arg Leu Asn Pro Thr Val Thr Tyr Gly Asn Asp Ser Phe Ser Ala 260 265 270Lys Ala Ser Val Ser Val Thr Ala Glu Asp Glu Gly Thr Gln Arg Leu 275 280 285Thr Cys Ala Val Ile Leu Gly Asn Gln Ser Gln Glu Thr Leu Gln Thr 290 295 300Val Thr Ile Tyr Ser Phe Pro Ala Pro Asn Val Ile Leu Thr Lys Pro305 310 315 320Glu Val Ser Glu Gly Thr Glu Val Thr Val Lys Cys Glu Ala His Pro 325 330 335Arg Ala Lys Val Thr Leu Asn Gly Val Pro Ala Gln Pro Leu Gly Pro 340 345 350Arg Ala Gln Leu Leu Leu Lys Ala Thr Pro Glu Asp Asn Gly Arg Ser 355 360 365Phe Ser Cys Ser Ala Thr Leu Glu Val Ala Gly Gln Leu Ile His Lys 370 375 380Asn Gln Thr Arg Glu Leu Arg Val Leu Tyr Gly Pro Arg Leu Asp Glu385 390 395 400Arg Asp Cys Pro Gly Asn Trp Thr Trp Pro Glu Asn Ser Gln Gln Thr 405 410 415Pro Met Cys Gln Ala Trp Gly Asn Pro Leu Pro Glu Leu Lys Cys Leu 420 425 430Lys Asp Gly Thr Phe Pro Leu Pro Ile Gly Glu Ser Val Thr Val Thr 435 440 445Arg Asp Leu Glu Gly Thr Tyr Leu Cys Arg Ala Arg Ser Thr Gln Gly 450 455 460Glu Val Thr Arg Lys Val Thr Val Asn Val Leu Ser Pro Arg Tyr Glu465 470 475 480Ile Val Ile Ile Thr Val Val Ala Ala Ala Val Ile Met Gly Thr Ala 485 490 495Gly Leu Ser Thr Tyr Leu Tyr Asn Arg Gln Arg Lys Ile Lys Lys Tyr 500 505 510Arg Leu Gln Gln Ala Gln Lys Gly Thr Pro Met Lys Pro Asn Thr Gln 515 520 525Ala Thr Pro Pro 5306547PRTHomo sapiens 6Met Ala Thr Met Val Pro Ser Val Leu Trp Pro Arg Ala Cys Trp Thr1 5 10 15Leu Leu Val Cys Cys Leu Leu Thr Pro Gly Val Gln Gly Gln Glu Phe 20 25 30Leu Leu Arg Val Glu Pro Gln Asn Pro Val Leu Ser Ala Gly Gly Ser 35 40 45Leu Phe Val Asn Cys Ser Thr Asp Cys Pro Ser Ser Glu Lys Ile Ala 50 55 60Leu Glu Thr Ser Leu Ser Lys Glu Leu Val Ala Ser Gly Met Gly Trp65 70 75 80Ala Ala Phe Asn Leu Ser Asn Val Thr Gly Asn Ser Arg Ile Leu Cys 85 90 95Ser Val Tyr Cys Asn Gly Ser Gln Ile Thr Gly Ser Ser Asn Ile Thr 100 105 110Val Tyr Arg Leu Pro Glu Arg Val Glu Leu Ala Pro Leu Pro Pro Trp 115 120 125Gln Pro Val Gly Gln Asn Phe Thr Leu Arg Cys Gln Val Glu Asp Gly 130 135 140Ser Pro Arg Thr Ser Leu Thr Val Val Leu Leu Arg Trp Glu Glu Glu145 150 155 160Leu Ser Arg Gln Pro Ala Val Glu Glu Pro Ala Glu Val Thr Ala Thr 165 170 175Val Leu Ala Ser Arg Asp Asp His Gly Ala Pro Phe Ser Cys Arg Thr 180 185 190Glu Leu Asp Met Gln Pro Gln Gly Leu Gly Leu Phe Val Asn Thr Ser 195 200 205Ala Pro Arg Gln Leu Arg Thr Phe Val Leu Pro Val Thr Pro Pro Arg 210 215 220Leu Val Ala Pro Arg Phe Leu Glu Val Glu Thr Ser Trp Pro Val Asp225 230 235 240Cys Thr Leu Asp Gly Leu Phe Pro Ala Ser Glu Ala Gln Val Tyr Leu 245 250 255Ala Leu Gly Asp Gln Met Leu Asn Ala Thr Val Met Asn His Gly Asp 260 265 270Thr Leu Thr Ala Thr Ala Thr Ala Thr Ala Arg Ala Asp Gln Glu Gly 275 280 285Ala Arg Glu Ile Val Cys Asn Val Thr Leu Gly Gly Glu Arg Arg Glu 290 295 300Ala Arg Glu Asn Leu Thr Val Phe Ser Phe Leu Gly Pro Ile Val Asn305 310 315 320Leu Ser Glu Pro Thr Ala His Glu Gly Ser Thr Val Thr Val Ser Cys 325 330 335Met Ala Gly Ala Arg Val Gln Val Thr Leu Asp Gly Val Pro Ala Ala 340 345 350Ala Pro Gly Gln Pro Ala Gln Leu Gln Leu Asn Ala Thr Glu Ser Asp 355 360 365Asp Gly Arg Ser Phe Phe Cys Ser Ala Thr Leu Glu Val Asp Gly Glu 370 375 380Phe Leu His Arg Asn Ser Ser Val Gln Leu Arg Val Leu Tyr Gly Pro385 390 395 400Lys Ile Asp Arg Ala Thr Cys Pro Gln His Leu Lys Trp Lys Asp Lys 405 410 415Thr Arg His Val Leu Gln Cys Gln Ala Arg Gly Asn Pro Tyr Pro Glu 420 425 430Leu Arg Cys Leu Lys Glu Gly Ser Ser Arg Glu Val Pro Val Gly Ile 435 440 445Pro Phe Phe Val Asn Val Thr His Asn Gly Thr Tyr Gln Cys Gln Ala 450 455 460Ser Ser Ser Arg Gly Lys Tyr Thr Leu Val Val Val Met Asp Ile Glu465 470 475 480Ala Gly Ser Ser His Phe Val Pro Val Phe Val Ala Val Leu Leu Thr 485 490 495Leu Gly Val Val Thr Ile Val Leu Ala Leu Met Tyr Val Phe Arg Glu 500 505 510His Gln Arg Ser Gly Ser Tyr His Val Arg Glu Glu Ser Thr Tyr Leu 515 520 525Pro Leu Thr Ser Met Gln Pro Thr Glu Ala Met Gly Glu Glu Pro Ser 530 535 540Arg Ala Glu5457427PRTHomo sapiens 7Met Phe Phe Thr Cys Gly Pro Asn Glu Ala Met Val Val Ser Gly Phe1 5 10 15Cys Arg Ser Pro Pro Val Met Val Ala Gly Gly Arg Val Phe Val Leu 20 25 30Pro Cys Ile Gln Gln Ile Gln Arg Ile Ser Leu Asn Thr Leu Thr Leu 35 40 45Asn Val Lys Ser Glu Lys Val Tyr Thr Arg His Gly Val Pro Ile Ser 50 55 60Val Thr Gly Ile Ala Gln Val Lys Ile Gln Gly Gln Asn Lys Glu Met65 70 75 80Leu Ala Ala Ala Cys Gln Met Phe Leu Gly Lys Thr Glu Ala Glu Ile 85 90 95Ala His Ile Ala Leu Glu Thr Leu Glu Gly His Gln Arg Ala Ile Met 100 105 110Ala His Met Thr Val Glu Glu Ile Tyr Lys Asp Arg Gln Lys Phe Ser 115 120 125Glu Gln Val Phe Lys Val Ala Ser Ser Asp Leu Val Asn Met Gly Ile 130 135 140Ser Val Val Ser Tyr Thr Leu Lys Asp Ile His Asp Asp Gln Asp Tyr145 150 155 160Leu His Ser Leu Gly Lys Ala Arg Thr Ala Gln Val Gln Lys Asp Ala 165 170 175Arg Ile Gly Glu Ala Glu Ala Lys Arg Asp Ala Gly Ile Arg Glu Ala 180 185 190Lys Ala Lys Gln Glu Lys Val Ser Ala Gln Tyr Leu Ser Glu Ile Glu 195 200 205Met Ala Lys Ala Gln Arg Asp Tyr Glu Leu Lys Lys Ala Ala Tyr Asp 210 215 220Ile Glu Val Asn Thr Arg Arg Ala Gln Ala Asp Leu Ala Tyr Gln Leu225 230 235 240Gln Val Ala Lys Thr Lys Gln Gln Ile Glu Glu Gln Arg Val Gln Val 245 250 255Gln Val Val Glu Arg Ala Gln Gln Val Ala Val Gln Glu Gln Glu Ile 260 265 270Ala Arg Arg Glu Lys Glu Leu Glu Ala Arg Val Arg Lys Pro Ala Glu 275 280 285Ala Glu Arg Tyr Lys Leu Glu Arg Leu Ala Glu Ala Glu Lys Ser Gln 290 295 300Leu Ile Met Gln Ala Glu Ala Glu Ala Ala Ser Val Arg Met Arg Gly305 310 315 320Glu Ala Glu Ala Phe Ala Ile Gly Ala Arg Ala Arg Ala Glu Ala Glu 325 330 335Gln Met Ala Lys Lys Ala Glu Ala Phe Gln Leu Tyr Gln Glu Ala Ala 340 345 350Gln Leu Asp Met Leu Leu Glu Lys Leu Pro Gln Val Ala Glu Glu Ile 355 360 365Ser Gly Pro Leu Thr Ser Ala Asn Lys Ile Thr Leu Val Ser Ser Gly 370 375 380Ser Gly Thr Met Gly Ala Ala Lys Val Thr Gly Glu Val Leu Asp Ile385 390 395 400Leu Thr Arg Leu Pro Glu Ser Val Glu Arg Leu Thr Gly Val Ser Ile 405 410 415Ser Gln Val Asn His Lys Pro Leu Arg Thr Ala 420 4258427PRTHomo sapiens 8Gly Asn Cys His Thr Val Gly Pro Asn Glu Ala Leu Val Val Ser Gly1 5 10 15Gly Cys Cys Gly Ser Asp Tyr Lys Gln Tyr Val Phe Gly Gly Trp Ala 20 25 30Trp Ala Trp Trp Cys Ile Ser Asp Thr Gln Arg Ile Ser Leu Glu Ile 35 40

45Met Thr Leu Gln Pro Arg Cys Glu Asp Val Glu Thr Ala Glu Gly Val 50 55 60Ala Leu Thr Val Thr Gly Val Ala Gln Val Lys Ile Met Thr Glu Lys65 70 75 80Glu Leu Leu Ala Val Ala Cys Glu Gln Phe Leu Gly Lys Asn Val Gln 85 90 95Asp Ile Lys Asn Val Val Leu Gln Thr Leu Glu Gly His Leu Arg Ser 100 105 110Ile Leu Gly Thr Leu Thr Val Glu Gln Ile Tyr Gln Asp Arg Asp Gln 115 120 125Phe Ala Lys Leu Val Arg Glu Val Ala Ala Pro Asp Val Gly Arg Met 130 135 140Gly Ile Glu Ile Leu Ser Phe Thr Ile Lys Asp Val Tyr Asp Lys Val145 150 155 160Asp Tyr Leu Ser Ser Leu Gly Lys Thr Gln Thr Ala Val Val Gln Arg 165 170 175Asp Ala Asp Ile Gly Val Ala Glu Ala Glu Arg Asp Ala Gly Ile Arg 180 185 190Glu Ala Glu Cys Lys Lys Glu Met Leu Asp Val Lys Phe Met Ala Asp 195 200 205Thr Lys Ile Ala Asp Ser Lys Arg Ala Phe Glu Leu Gln Lys Ser Ala 210 215 220Phe Ser Glu Glu Val Asn Ile Lys Thr Ala Glu Ala Gln Leu Ala Tyr225 230 235 240Glu Leu Gln Gly Ala Arg Glu Gln Gln Lys Ile Arg Gln Glu Glu Ile 245 250 255Glu Ile Glu Val Val Gln Arg Lys Lys Gln Ile Ala Val Glu Ala Gln 260 265 270Glu Ile Leu Arg Thr Asp Lys Glu Leu Ile Ala Thr Val Arg Arg Pro 275 280 285Ala Glu Ala Glu Ala His Arg Ile Gln Gln Ile Ala Glu Gly Glu Lys 290 295 300Val Lys Gln Val Leu Leu Ala Gln Ala Glu Ala Glu Lys Ile Arg Lys305 310 315 320Ile Gly Glu Ala Glu Ala Ala Val Ile Glu Ala Met Gly Lys Ala Glu 325 330 335Ala Glu Arg Met Lys Leu Lys Ala Glu Ala Tyr Gln Lys Tyr Gly Asp 340 345 350Ala Ala Lys Met Ala Leu Val Leu Glu Ala Leu Pro Gln Ile Ala Ala 355 360 365Lys Ile Ala Ala Pro Leu Thr Lys Val Asp Glu Ile Val Val Leu Ser 370 375 380Gly Asp Asn Ser Lys Val Thr Ser Glu Val Asn Arg Leu Leu Ala Glu385 390 395 400Leu Pro Ala Ser Val His Ala Leu Thr Gly Val Asp Leu Ser Lys Ile 405 410 415Pro Leu Ile Lys Lys Ala Thr Gly Val Gln Val 420 42591032PRTHomo sapiens 9Met Ala Trp Glu Ala Arg Arg Glu Pro Gly Pro Arg Arg Ala Ala Val1 5 10 15Arg Glu Thr Val Met Leu Leu Leu Cys Leu Gly Val Pro Thr Gly Arg 20 25 30Pro Tyr Asn Val Asp Thr Glu Ser Ala Leu Leu Tyr Gln Gly Pro His 35 40 45Asn Thr Leu Phe Gly Tyr Ser Val Val Leu His Ser His Gly Ala Asn 50 55 60Arg Trp Leu Leu Val Gly Ala Pro Thr Ala Asn Trp Leu Ala Asn Ala65 70 75 80Ser Val Ile Asn Pro Gly Ala Ile Tyr Arg Cys Arg Ile Gly Lys Asn 85 90 95Pro Gly Gln Thr Cys Glu Gln Leu Gln Leu Gly Ser Pro Asn Gly Glu 100 105 110Pro Cys Gly Lys Thr Cys Leu Glu Glu Arg Asp Asn Gln Trp Leu Gly 115 120 125Val Thr Leu Ser Arg Gln Pro Gly Glu Asn Gly Ser Ile Val Thr Cys 130 135 140Gly His Arg Trp Lys Asn Ile Phe Tyr Ile Lys Asn Glu Asn Lys Leu145 150 155 160Pro Thr Gly Gly Cys Tyr Gly Val Pro Pro Asp Leu Arg Thr Glu Leu 165 170 175Ser Lys Arg Ile Ala Pro Cys Tyr Gln Asp Tyr Val Lys Lys Phe Gly 180 185 190Glu Asn Phe Ala Ser Cys Gln Ala Gly Ile Ser Ser Phe Tyr Thr Lys 195 200 205Asp Leu Ile Val Met Gly Ala Pro Gly Ser Ser Tyr Trp Thr Gly Ser 210 215 220Leu Phe Val Tyr Asn Ile Thr Thr Asn Lys Tyr Lys Ala Phe Leu Asp225 230 235 240Lys Gln Asn Gln Val Lys Phe Gly Ser Tyr Leu Gly Tyr Ser Val Gly 245 250 255Ala Gly His Phe Arg Ser Gln His Thr Thr Glu Val Val Gly Gly Ala 260 265 270Pro Gln His Glu Gln Ile Gly Lys Ala Tyr Ile Phe Ser Ile Asp Glu 275 280 285Lys Glu Leu Asn Ile Leu His Glu Met Lys Gly Lys Lys Leu Gly Ser 290 295 300Tyr Phe Gly Ala Ser Val Cys Ala Val Asp Leu Asn Ala Asp Gly Phe305 310 315 320Ser Asp Leu Leu Val Gly Ala Pro Met Gln Ser Thr Ile Arg Glu Glu 325 330 335Gly Arg Val Phe Val Tyr Ile Asn Ser Gly Ser Gly Ala Val Met Asn 340 345 350Ala Met Glu Thr Asn Leu Val Gly Ser Asp Lys Tyr Ala Ala Arg Phe 355 360 365Gly Glu Ser Ile Val Asn Leu Gly Asp Ile Asp Asn Asp Gly Phe Glu 370 375 380Asp Val Ala Ile Gly Ala Pro Gln Glu Asp Asp Leu Gln Gly Ala Ile385 390 395 400Tyr Ile Tyr Asn Gly Arg Ala Asp Gly Ile Ser Ser Thr Phe Ser Gln 405 410 415Arg Ile Glu Gly Leu Gln Ile Ser Lys Ser Leu Ser Met Phe Gly Gln 420 425 430Ser Ile Ser Gly Gln Ile Asp Ala Asp Asn Asn Gly Tyr Val Asp Val 435 440 445Ala Val Gly Ala Phe Arg Ser Asp Ser Ala Val Leu Leu Arg Thr Arg 450 455 460Pro Val Val Ile Val Asp Ala Ser Leu Ser His Pro Glu Ser Val Asn465 470 475 480Arg Thr Lys Phe Asp Cys Val Glu Asn Gly Trp Pro Ser Val Cys Ile 485 490 495Asp Leu Thr Leu Cys Phe Ser Tyr Lys Gly Lys Glu Val Pro Gly Tyr 500 505 510Ile Val Leu Phe Tyr Asn Met Ser Leu Asp Val Asn Arg Lys Ala Glu 515 520 525Ser Pro Pro Arg Phe Tyr Phe Ser Ser Asn Gly Thr Ser Asp Val Ile 530 535 540Thr Gly Ser Ile Gln Val Ser Ser Arg Glu Ala Asn Cys Arg Thr His545 550 555 560Gln Ala Phe Met Arg Lys Asp Val Arg Asp Ile Leu Thr Pro Ile Gln 565 570 575Ile Glu Ala Ala Tyr His Leu Gly Pro His Val Ile Ser Lys Arg Ser 580 585 590Thr Glu Glu Phe Pro Pro Leu Gln Pro Ile Leu Gln Gln Lys Lys Glu 595 600 605Lys Asp Ile Met Lys Lys Thr Ile Asn Phe Ala Arg Phe Cys Ala His 610 615 620Glu Asn Cys Ser Ala Asp Leu Gln Val Ser Ala Lys Ile Gly Phe Leu625 630 635 640Lys Pro His Glu Asn Lys Thr Tyr Leu Ala Val Gly Ser Met Lys Thr 645 650 655Leu Met Leu Asn Val Ser Leu Phe Asn Ala Gly Asp Asp Ala Tyr Glu 660 665 670Thr Thr Leu His Val Lys Leu Pro Val Gly Leu Tyr Phe Ile Lys Ile 675 680 685Leu Glu Leu Glu Glu Lys Gln Ile Asn Cys Glu Val Thr Asp Asn Ser 690 695 700Gly Val Val Gln Leu Asp Cys Ser Ile Gly Tyr Ile Tyr Val Asp His705 710 715 720Leu Ser Arg Ile Asp Ile Ser Phe Leu Leu Asp Val Ser Ser Leu Ser 725 730 735Arg Ala Glu Glu Asp Leu Ser Ile Thr Val His Ala Thr Cys Glu Asn 740 745 750Glu Glu Glu Met Asp Asn Leu Lys His Ser Arg Val Thr Val Ala Ile 755 760 765Pro Leu Lys Tyr Glu Val Lys Leu Thr Val His Gly Phe Val Asn Pro 770 775 780Thr Ser Phe Val Tyr Gly Ser Asn Asp Glu Asn Glu Pro Glu Thr Cys785 790 795 800Met Val Glu Lys Met Asn Leu Thr Phe His Val Ile Asn Thr Gly Asn 805 810 815Ser Met Ala Pro Asn Val Ser Val Glu Ile Met Val Pro Asn Ser Phe 820 825 830Ser Pro Gln Thr Asp Lys Leu Phe Asn Ile Leu Asp Val Gln Thr Thr 835 840 845Thr Gly Glu Cys His Phe Glu Asn Tyr Gln Arg Val Cys Ala Leu Glu 850 855 860Gln Gln Lys Ser Ala Met Gln Thr Leu Lys Gly Ile Val Arg Phe Leu865 870 875 880Ser Lys Thr Asp Lys Arg Leu Leu Tyr Cys Ile Lys Ala Asp Pro His 885 890 895Cys Leu Asn Phe Leu Cys Asn Phe Gly Lys Met Glu Ser Gly Lys Glu 900 905 910Ala Ser Val His Ile Gln Leu Glu Gly Arg Pro Ser Ile Leu Glu Met 915 920 925Asp Glu Thr Ser Ala Leu Lys Phe Glu Ile Arg Ala Thr Gly Phe Pro 930 935 940Glu Pro Asn Pro Arg Val Ile Glu Leu Asn Lys Asp Glu Asn Val Ala945 950 955 960His Val Leu Leu Glu Gly Leu His His Gln Arg Pro Lys Arg Tyr Phe 965 970 975Thr Ile Val Ile Ile Ser Ser Ser Leu Leu Leu Gly Leu Ile Val Leu 980 985 990Leu Leu Ile Ser Tyr Val Met Trp Lys Ala Gly Phe Phe Lys Arg Gln 995 1000 1005Tyr Lys Ser Ile Leu Gln Glu Glu Asn Arg Arg Asp Ser Trp Ser 1010 1015 1020Tyr Ile Asn Ser Lys Ser Asn Asp Asp1025 103010760PRTHomo sapiens 10Met Met Asp Gln Ala Arg Ser Ala Phe Ser Asn Leu Phe Gly Gly Glu1 5 10 15Pro Leu Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln Val Asp Gly Asp 20 25 30Asn Ser His Val Glu Met Lys Leu Ala Val Asp Glu Glu Glu Asn Ala 35 40 45Asp Asn Asn Thr Lys Ala Asn Val Thr Lys Pro Lys Arg Cys Ser Gly 50 55 60Ser Ile Cys Tyr Gly Thr Ile Ala Val Ile Val Phe Phe Leu Ile Gly65 70 75 80Phe Met Ile Gly Tyr Leu Gly Tyr Cys Lys Gly Val Glu Pro Lys Thr 85 90 95Glu Cys Glu Arg Leu Ala Gly Thr Glu Ser Pro Val Arg Glu Glu Pro 100 105 110Gly Glu Asp Phe Pro Ala Ala Arg Arg Leu Tyr Trp Asp Asp Leu Lys 115 120 125Arg Lys Leu Ser Glu Lys Leu Asp Ser Thr Asp Phe Thr Gly Thr Ile 130 135 140Lys Leu Leu Asn Glu Asn Ser Tyr Val Pro Arg Glu Ala Gly Ser Gln145 150 155 160Lys Asp Glu Asn Leu Ala Leu Tyr Val Glu Asn Gln Phe Arg Glu Phe 165 170 175Lys Leu Ser Lys Val Trp Arg Asp Gln His Phe Val Lys Ile Gln Val 180 185 190Lys Asp Ser Ala Gln Asn Ser Val Ile Ile Val Asp Lys Asn Gly Arg 195 200 205Leu Val Tyr Leu Val Glu Asn Pro Gly Gly Tyr Val Ala Tyr Ser Lys 210 215 220Ala Ala Thr Val Thr Gly Lys Leu Val His Ala Asn Phe Gly Thr Lys225 230 235 240Lys Asp Phe Glu Asp Leu Tyr Thr Pro Val Asn Gly Ser Ile Val Ile 245 250 255Val Arg Ala Gly Lys Ile Thr Phe Ala Glu Lys Val Ala Asn Ala Glu 260 265 270Ser Leu Asn Ala Ile Gly Val Leu Ile Tyr Met Asp Gln Thr Lys Phe 275 280 285Pro Ile Val Asn Ala Glu Leu Ser Phe Phe Gly His Ala His Leu Gly 290 295 300Thr Gly Asp Pro Tyr Thr Pro Gly Phe Pro Ser Phe Asn His Thr Gln305 310 315 320Phe Pro Pro Ser Arg Ser Ser Gly Leu Pro Asn Ile Pro Val Gln Thr 325 330 335Ile Ser Arg Ala Ala Ala Glu Lys Leu Phe Gly Asn Met Glu Gly Asp 340 345 350Cys Pro Ser Asp Trp Lys Thr Asp Ser Thr Cys Arg Met Val Thr Ser 355 360 365Glu Ser Lys Asn Val Lys Leu Thr Val Ser Asn Val Leu Lys Glu Ile 370 375 380Lys Ile Leu Asn Ile Phe Gly Val Ile Lys Gly Phe Val Glu Pro Asp385 390 395 400His Tyr Val Val Val Gly Ala Gln Arg Asp Ala Trp Gly Pro Gly Ala 405 410 415Ala Lys Ser Gly Val Gly Thr Ala Leu Leu Leu Lys Leu Ala Gln Met 420 425 430Phe Ser Asp Met Val Leu Lys Asp Gly Phe Gln Pro Ser Arg Ser Ile 435 440 445Ile Phe Ala Ser Trp Ser Ala Gly Asp Phe Gly Ser Val Gly Ala Thr 450 455 460Glu Trp Leu Glu Gly Tyr Leu Ser Ser Leu His Leu Lys Ala Phe Thr465 470 475 480Tyr Ile Asn Leu Asp Lys Ala Val Leu Gly Thr Ser Asn Phe Lys Val 485 490 495Ser Ala Ser Pro Leu Leu Tyr Thr Leu Ile Glu Lys Thr Met Gln Asn 500 505 510Val Lys His Pro Val Thr Gly Gln Phe Leu Tyr Gln Asp Ser Asn Trp 515 520 525Ala Ser Lys Val Glu Lys Leu Thr Leu Asp Asn Ala Ala Phe Pro Phe 530 535 540Leu Ala Tyr Ser Gly Ile Pro Ala Val Ser Phe Cys Phe Cys Glu Asp545 550 555 560Thr Asp Tyr Pro Tyr Leu Gly Thr Thr Met Asp Thr Tyr Lys Glu Leu 565 570 575Ile Glu Arg Ile Pro Glu Leu Asn Lys Val Ala Arg Ala Ala Ala Glu 580 585 590Val Ala Gly Gln Phe Val Ile Lys Leu Thr His Asp Val Glu Leu Asn 595 600 605Leu Asp Tyr Glu Arg Tyr Asn Ser Gln Leu Leu Ser Phe Val Arg Asp 610 615 620Leu Asn Gln Tyr Arg Ala Asp Ile Lys Glu Met Gly Leu Ser Leu Gln625 630 635 640Trp Leu Tyr Ser Ala Arg Gly Asp Phe Phe Arg Ala Thr Ser Arg Leu 645 650 655Thr Thr Asp Phe Gly Asn Ala Glu Lys Thr Asp Arg Phe Val Met Lys 660 665 670Lys Leu Asn Asp Arg Val Met Arg Val Glu Tyr His Phe Leu Ser Pro 675 680 685Tyr Val Ser Pro Lys Glu Ser Pro Phe Arg His Val Phe Trp Gly Ser 690 695 700Gly Ser His Thr Leu Pro Ala Leu Leu Glu Asn Leu Lys Leu Arg Lys705 710 715 720Gln Asn Asn Gly Ala Phe Asn Glu Thr Leu Phe Arg Asn Gln Leu Ala 725 730 735Leu Ala Thr Trp Thr Ile Gln Gly Ala Ala Asn Ala Leu Ser Gly Asp 740 745 750Val Trp Asp Ile Asp Asn Glu Phe 755 76011865PRTHomo sapiens 11Met Ala Leu Val Leu Gly Ser Leu Leu Leu Leu Gly Leu Cys Gly Asn1 5 10 15Ser Phe Ser Gly Gly Gln Pro Ser Ser Thr Asp Ala Pro Lys Ala Trp 20 25 30Asn Tyr Glu Leu Pro Ala Thr Asn Tyr Glu Thr Gln Asp Ser His Lys 35 40 45Ala Gly Pro Ile Gly Ile Leu Phe Glu Leu Val His Ile Phe Leu Tyr 50 55 60Val Val Gln Pro Arg Asp Phe Pro Glu Asp Thr Leu Arg Lys Phe Leu65 70 75 80Gln Lys Ala Tyr Glu Ser Lys Ile Asp Tyr Asp Lys Pro Glu Thr Val 85 90 95Ile Leu Gly Leu Lys Ile Val Tyr Tyr Glu Ala Gly Ile Ile Leu Cys 100 105 110Cys Val Leu Gly Leu Leu Phe Ile Ile Leu Met Pro Leu Val Gly Tyr 115 120 125Phe Phe Cys Met Cys Arg Cys Cys Asn Lys Cys Gly Gly Glu Met His 130 135 140Gln Arg Gln Lys Glu Asn Gly Pro Phe Leu Arg Lys Cys Phe Ala Ile145 150 155 160Ser Leu Leu Val Ile Cys Ile Ile Ile Ser Ile Gly Ile Phe Tyr Gly 165 170 175Phe Val Ala Asn His Gln Val Arg Thr Arg Ile Lys Arg Ser Arg Lys 180 185 190Leu Ala Asp Ser Asn Phe Lys Asp Leu Arg Thr Leu Leu Asn Glu Thr 195 200 205Pro Glu Gln Ile Lys Tyr Ile Leu Ala Gln Tyr Asn Thr Thr Lys Asp 210 215 220Lys Ala Phe Thr Asp Leu Asn Ser Ile Asn Ser Val Leu Gly Gly Gly225 230 235 240Ile Leu Asp Arg Leu Arg Pro Asn Ile Ile Pro Val Leu Asp Glu Ile 245 250 255Lys Ser Met Ala Thr Ala Ile Lys Glu Thr Lys Glu Ala Leu Glu Asn 260 265 270Met Asn Ser Thr Leu Lys Ser Leu His Gln Gln Ser Thr Gln Leu Ser 275 280 285Ser Ser

Leu Thr Ser Val Lys Thr Ser Leu Arg Ser Ser Leu Asn Asp 290 295 300Pro Leu Cys Leu Val His Pro Ser Ser Glu Thr Cys Asn Ser Ile Arg305 310 315 320Leu Ser Leu Ser Gln Leu Asn Ser Asn Pro Glu Leu Arg Gln Leu Pro 325 330 335Pro Val Asp Ala Glu Leu Asp Asn Val Asn Asn Val Leu Arg Thr Asp 340 345 350Leu Asp Gly Leu Val Gln Gln Gly Tyr Gln Ser Leu Asn Asp Ile Pro 355 360 365Asp Arg Val Gln Arg Gln Thr Thr Thr Val Val Ala Gly Ile Lys Arg 370 375 380Val Leu Asn Ser Ile Gly Ser Asp Ile Asp Asn Val Thr Gln Arg Leu385 390 395 400Pro Ile Gln Asp Ile Leu Ser Ala Phe Ser Val Tyr Val Asn Asn Thr 405 410 415Glu Ser Tyr Ile His Arg Asn Leu Pro Thr Leu Glu Glu Tyr Asp Ser 420 425 430Tyr Trp Trp Leu Gly Gly Leu Val Ile Cys Ser Leu Leu Thr Leu Ile 435 440 445Val Ile Phe Tyr Tyr Leu Gly Leu Leu Cys Gly Val Cys Gly Tyr Asp 450 455 460Arg His Ala Thr Pro Thr Thr Arg Gly Cys Val Ser Asn Thr Gly Gly465 470 475 480Val Phe Leu Met Val Gly Val Gly Leu Ser Phe Leu Phe Cys Trp Ile 485 490 495Leu Met Ile Ile Val Val Leu Thr Phe Val Phe Gly Ala Asn Val Glu 500 505 510Lys Leu Ile Cys Glu Pro Tyr Thr Ser Lys Glu Leu Phe Arg Val Leu 515 520 525Asp Thr Pro Tyr Leu Leu Asn Glu Asp Trp Glu Tyr Tyr Leu Ser Gly 530 535 540Lys Leu Phe Asn Lys Ser Lys Met Lys Leu Thr Phe Glu Gln Val Tyr545 550 555 560Ser Asp Cys Lys Lys Asn Arg Gly Thr Tyr Gly Thr Leu His Leu Gln 565 570 575Asn Ser Phe Asn Ile Ser Glu His Leu Asn Ile Asn Glu His Thr Gly 580 585 590Ser Ile Ser Ser Glu Leu Glu Ser Leu Lys Val Asn Leu Asn Ile Phe 595 600 605Leu Leu Gly Ala Ala Gly Arg Lys Asn Leu Gln Asp Phe Ala Ala Cys 610 615 620Gly Ile Asp Arg Met Asn Tyr Asp Ser Tyr Leu Ala Gln Thr Gly Lys625 630 635 640Ser Pro Ala Gly Val Asn Leu Leu Ser Phe Ala Tyr Asp Leu Glu Ala 645 650 655Lys Ala Asn Ser Leu Pro Pro Gly Asn Leu Arg Asn Ser Leu Lys Arg 660 665 670Asp Ala Gln Thr Ile Lys Thr Ile His Gln Gln Arg Val Leu Pro Ile 675 680 685Glu Gln Ser Leu Ser Thr Leu Tyr Gln Ser Val Lys Ile Leu Gln Arg 690 695 700Thr Gly Asn Gly Leu Leu Glu Arg Val Thr Arg Ile Leu Ala Ser Leu705 710 715 720Asp Phe Ala Gln Asn Phe Ile Thr Asn Asn Thr Ser Ser Val Ile Ile 725 730 735Glu Glu Thr Lys Lys Tyr Gly Arg Thr Ile Ile Gly Tyr Phe Glu His 740 745 750Tyr Leu Gln Trp Ile Glu Phe Ser Ile Ser Glu Lys Val Ala Ser Cys 755 760 765Lys Pro Val Ala Thr Ala Leu Asp Thr Ala Val Asp Val Phe Leu Cys 770 775 780Ser Tyr Ile Ile Asp Pro Leu Asn Leu Phe Trp Phe Gly Ile Gly Lys785 790 795 800Ala Thr Val Phe Leu Leu Pro Ala Leu Ile Phe Ala Val Lys Leu Ala 805 810 815Lys Tyr Tyr Arg Arg Met Asp Ser Glu Asp Val Tyr Asp Asp Val Glu 820 825 830Thr Ile Pro Met Lys Asn Met Glu Asn Gly Asn Asn Gly Tyr His Lys 835 840 845Asp His Val Tyr Gly Ile His Asn Pro Val Met Thr Ser Pro Ser Gln 850 855 860His86512310PRTHomo sapiens 12Met Arg Arg Ala Ala Leu Trp Leu Trp Leu Cys Ala Leu Ala Leu Ser1 5 10 15Leu Gln Pro Ala Leu Pro Gln Ile Val Ala Thr Asn Leu Pro Pro Glu 20 25 30Asp Gln Asp Gly Ser Gly Asp Asp Ser Asp Asn Phe Ser Gly Ser Gly 35 40 45Ala Gly Ala Leu Gln Asp Ile Thr Leu Ser Gln Gln Thr Pro Ser Thr 50 55 60Trp Lys Asp Thr Gln Leu Leu Thr Ala Ile Pro Thr Ser Pro Glu Pro65 70 75 80Thr Gly Leu Glu Ala Thr Ala Ala Ser Thr Ser Thr Leu Pro Ala Gly 85 90 95Glu Gly Pro Lys Glu Gly Glu Ala Val Val Leu Pro Glu Val Glu Pro 100 105 110Gly Leu Thr Ala Arg Glu Gln Glu Ala Thr Pro Arg Pro Arg Glu Thr 115 120 125Thr Gln Leu Pro Thr Thr His Leu Ala Ser Thr Thr Thr Ala Thr Thr 130 135 140Ala Gln Glu Pro Ala Thr Ser His Pro His Arg Asp Met Gln Pro Gly145 150 155 160His His Glu Thr Ser Thr Pro Ala Gly Pro Ser Gln Ala Asp Leu His 165 170 175Thr Pro His Thr Glu Asp Gly Gly Pro Ser Ala Thr Glu Arg Ala Ala 180 185 190Glu Asp Gly Ala Ser Ser Gln Leu Pro Ala Ala Glu Gly Ser Gly Glu 195 200 205Gln Asp Phe Thr Phe Glu Thr Ser Gly Glu Asn Thr Ala Val Val Ala 210 215 220Val Glu Pro Asp Arg Arg Asn Gln Ser Pro Val Asp Gln Gly Ala Thr225 230 235 240Gly Ala Ser Gln Gly Leu Leu Asp Arg Lys Glu Val Leu Gly Gly Val 245 250 255Ile Ala Gly Gly Leu Val Gly Leu Ile Phe Ala Val Cys Leu Val Gly 260 265 270Phe Met Leu Tyr Arg Met Lys Lys Lys Asp Glu Gly Ser Tyr Ser Leu 275 280 285Glu Glu Pro Lys Gln Ala Asn Gly Gly Ala Tyr Gln Lys Pro Thr Lys 290 295 300Gln Glu Glu Phe Tyr Ala305 31013150PRTHomo sapiens 13Met Tyr Gly Lys Ile Ile Phe Val Leu Leu Leu Ser Glu Ile Val Ser1 5 10 15Ile Ser Ala Ser Ser Thr Thr Gly Val Ala Met His Thr Ser Thr Ser 20 25 30Ser Ser Val Thr Lys Ser Tyr Ile Ser Ser Gln Thr Asn Asp Thr His 35 40 45Lys Arg Asp Thr Tyr Ala Ala Thr Pro Arg Ala His Glu Val Ser Glu 50 55 60Ile Ser Val Arg Thr Val Tyr Pro Pro Glu Glu Glu Thr Gly Glu Arg65 70 75 80Val Gln Leu Ala His His Phe Ser Glu Pro Glu Ile Thr Leu Ile Ile 85 90 95Phe Gly Val Met Ala Gly Val Ile Gly Thr Ile Leu Leu Ile Ser Tyr 100 105 110Gly Ile Arg Arg Leu Ile Lys Lys Ser Pro Ser Asp Val Lys Pro Leu 115 120 125Pro Ser Pro Asp Thr Asp Val Pro Leu Ser Ser Val Glu Ile Glu Asn 130 135 140Pro Glu Thr Ser Asp Gln145 15014867PRTHomo sapiens 14Ala Thr Phe Ile Ser Val Gln Leu Lys Lys Thr Ser Glu Val Asp Leu1 5 10 15Ala Lys Pro Leu Val Lys Phe Ile Gln Gln Thr Tyr Pro Ser Gly Gly 20 25 30Glu Glu Gln Ala Gln Tyr Cys Arg Ala Ala Glu Glu Leu Ser Lys Leu 35 40 45Arg Arg Ala Ala Val Gly Arg Pro Leu Asp Lys His Glu Gly Ala Leu 50 55 60Glu Thr Leu Leu Arg Tyr Tyr Asp Gln Ile Cys Ser Ile Glu Pro Lys65 70 75 80Phe Pro Phe Ser Glu Asn Gln Ile Cys Leu Thr Phe Thr Trp Lys Asp 85 90 95Ala Phe Asp Lys Gly Ser Leu Phe Gly Gly Ser Val Lys Leu Ala Leu 100 105 110Ala Ser Leu Gly Tyr Glu Lys Ser Cys Val Leu Phe Asn Cys Ala Ala 115 120 125Leu Ala Ser Gln Ile Ala Ala Glu Gln Asn Leu Asp Asn Asp Glu Gly 130 135 140Leu Lys Ile Ala Ala Lys His Tyr Gln Phe Ala Ser Gly Ala Phe Leu145 150 155 160His Ile Lys Glu Thr Val Leu Ser Ala Leu Ser Arg Glu Pro Thr Val 165 170 175Asp Ile Ser Pro Asp Thr Val Gly Thr Leu Ser Leu Ile Met Leu Ala 180 185 190Gln Ala Gln Glu Val Phe Phe Leu Lys Ala Thr Arg Asp Lys Met Lys 195 200 205Asp Ala Ile Ile Ala Lys Leu Ala Asn Gln Ala Ala Asp Tyr Phe Gly 210 215 220Asp Ala Phe Lys Gln Cys Gln Tyr Lys Asp Thr Leu Pro Lys Glu Val225 230 235 240Phe Pro Val Leu Ala Ala Lys His Cys Ile Met Gln Ala Asn Ala Glu 245 250 255Tyr His Gln Ser Ile Leu Ala Lys Gln Gln Lys Lys Phe Gly Glu Glu 260 265 270Ile Ala Arg Leu Gln His Ala Ala Glu Leu Ile Lys Thr Val Ala Ser 275 280 285Arg Tyr Asp Glu Tyr Val Asn Val Lys Asp Phe Ser Asp Lys Ile Asn 290 295 300Arg Ala Leu Ala Ala Ala Lys Lys Asp Asn Asp Phe Ile Tyr His Asp305 310 315 320Arg Val Pro Asp Leu Lys Asp Leu Asp Pro Ile Gly Lys Ala Thr Leu 325 330 335Val Lys Ser Thr Pro Val Asn Val Pro Ile Ser Gln Lys Phe Thr Asp 340 345 350Leu Phe Glu Lys Met Val Pro Val Ser Val Gln Gln Ser Leu Ala Ala 355 360 365Tyr Asn Gln Arg Lys Ala Asp Leu Val Asn Arg Ser Ile Ala Gln Met 370 375 380Arg Glu Ala Thr Thr Leu Ala Asn Gly Val Leu Ala Ser Leu Asn Leu385 390 395 400Pro Ala Ala Ile Glu Asp Val Ser Gly Asp Thr Val Pro Gln Ser Ile 405 410 415Leu Thr Lys Ser Arg Ser Val Ile Glu Gln Gly Gly Ile Gln Thr Val 420 425 430Asp Gln Leu Ile Lys Glu Leu Pro Glu Leu Leu Gln Arg Asn Arg Glu 435 440 445Ile Leu Asp Glu Ser Leu Arg Leu Leu Asp Glu Glu Glu Ala Thr Asp 450 455 460Asn Asp Leu Arg Ala Lys Phe Lys Glu Arg Trp Gln Arg Thr Pro Ser465 470 475 480Asn Glu Leu Tyr Lys Pro Leu Arg Ala Glu Gly Thr Asn Phe Arg Thr 485 490 495Val Leu Asp Lys Ala Val Gln Ala Asp Gly Gln Val Lys Glu Cys Tyr 500 505 510Gln Ser His Arg Asp Thr Ile Val Leu Leu Cys Lys Pro Glu Pro Glu 515 520 525Leu Asn Ala Ala Ile Pro Ser Ala Asn Pro Ala Lys Thr Met Gln Gly 530 535 540Ser Glu Val Val Asn Val Leu Lys Ser Leu Leu Ser Asn Leu Asp Glu545 550 555 560Val Lys Lys Glu Arg Glu Gly Leu Glu Asn Asp Leu Lys Ser Val Asn 565 570 575Phe Asp Met Thr Ser Lys Phe Leu Thr Ala Leu Ala Gln Asp Gly Val 580 585 590Ile Asn Glu Glu Ala Leu Ser Val Thr Glu Leu Asp Arg Val Tyr Gly 595 600 605Gly Leu Thr Thr Lys Val Gln Glu Ser Leu Lys Lys Gln Glu Gly Leu 610 615 620Leu Lys Asn Ile Gln Val Ser His Gln Glu Phe Ser Lys Met Lys Gln625 630 635 640Ser Asn Asn Glu Ala Asn Leu Arg Glu Glu Val Leu Lys Asn Leu Ala 645 650 655Thr Ala Tyr Asp Asn Phe Val Glu Leu Val Ala Asn Leu Lys Glu Gly 660 665 670Thr Lys Phe Tyr Asn Glu Leu Thr Glu Ile Leu Val Arg Phe Gln Asn 675 680 685Lys Cys Ser Asp Ile Val Phe Ala Arg Lys Thr Glu Arg Asp Glu Leu 690 695 700Leu Lys Asp Leu Gln Gln Ser Ile Ala Arg Glu Pro Ser Ala Pro Ser705 710 715 720Ile Pro Thr Pro Ala Tyr Gln Ser Ser Pro Ala Gly Gly His Ala Pro 725 730 735Thr Pro Pro Thr Pro Ala Pro Arg Thr Met Pro Pro Thr Lys Pro Gln 740 745 750Pro Pro Ala Arg Pro Pro Pro Pro Val Leu Pro Ala Asn Arg Ala Pro 755 760 765Ser Ala Thr Ala Pro Ser Pro Val Gly Ala Gly Thr Ala Ala Pro Ala 770 775 780Pro Ser Gln Thr Pro Gly Ser Ala Pro Pro Pro Gln Ala Gln Gly Pro785 790 795 800Pro Tyr Pro Thr Tyr Pro Gly Tyr Pro Gly Tyr Cys Gln Met Pro Met 805 810 815Pro Met Gly Tyr Asn Pro Tyr Ala Tyr Gly Gln Tyr Asn Met Pro Tyr 820 825 830Pro Pro Val Tyr His Gln Ser Pro Gly Gln Ala Pro Tyr Pro Gly Pro 835 840 845Gln Gln Pro Ser Tyr Pro Phe Pro Gln Pro Pro Gln Gln Ser Tyr Tyr 850 855 860Pro Gln Gln86515297PRTHomo sapiens 15Ser Leu Tyr Pro Ser Leu Glu Asp Leu Lys Val Asp Lys Val Ile Gln1 5 10 15Ala Gln Thr Ala Phe Ser Ala Asn Pro Ala Asn Pro Ala Ile Leu Ser 20 25 30Glu Ala Ser Ala Pro Ile Pro His Asp Gly Asn Leu Tyr Pro Arg Leu 35 40 45Tyr Pro Glu Leu Ser Gln Tyr Met Gly Leu Ser Leu Asn Glu Glu Glu 50 55 60Ile Arg Ala Asn Val Ala Val Val Ser Gly Ala Pro Leu Gln Gly Gln65 70 75 80Leu Val Ala Arg Pro Ser Ser Ile Asn Tyr Met Val Ala Pro Val Thr 85 90 95Gly Asn Asp Val Gly Ile Arg Arg Ala Glu Ile Lys Gln Gly Ile Arg 100 105 110Glu Val Ile Leu Cys Lys Asp Gln Asp Gly Lys Ile Gly Leu Arg Leu 115 120 125Lys Ser Ile Asp Asn Gly Ile Phe Val Gln Leu Val Gln Ala Asn Ser 130 135 140Pro Ala Ser Leu Val Gly Leu Arg Phe Gly Asp Gln Val Leu Gln Ile145 150 155 160Asn Gly Glu Asn Cys Ala Gly Trp Ser Ser Asp Lys Ala His Lys Val 165 170 175Leu Lys Gln Ala Phe Gly Glu Lys Ile Thr Met Thr Ile Arg Asp Arg 180 185 190Pro Phe Glu Arg Thr Ile Thr Met His Lys Asp Ser Thr Gly His Val 195 200 205Gly Phe Ile Phe Lys Asn Gly Lys Ile Thr Ser Ile Val Lys Asp Ser 210 215 220Ser Ala Ala Arg Asn Gly Leu Leu Thr Glu His Asn Ile Cys Glu Ile225 230 235 240Asn Gly Gln Asn Val Ile Gly Leu Lys Asp Ser Gln Ile Ala Asp Ile 245 250 255Leu Ser Thr Ser Gly Thr Val Val Thr Ile Thr Ile Met Pro Ala Phe 260 265 270Ile Phe Glu His Ile Ile Lys Arg Met Ala Pro Ser Ile Met Lys Ser 275 280 285Leu Met Asp His Thr Ile Pro Glu Val 290 29516292PRTHomo sapiens 16Met Ser Ser Leu Tyr Pro Ser Leu Glu Asp Leu Lys Val Asp Gln Ala1 5 10 15Ile Gln Ala Gln Val Arg Ala Ser Pro Lys Met Pro Ala Leu Pro Val 20 25 30Gln Ala Thr Ala Ile Ser Pro Pro Pro Val Leu Tyr Pro Asn Leu Ala 35 40 45Glu Leu Glu Asn Tyr Met Gly Leu Ser Leu Ser Ser Gln Glu Val Gln 50 55 60Glu Ser Leu Leu Gln Ile Pro Glu Gly Asp Ser Thr Ala Val Ser Gly65 70 75 80Pro Gly Pro Gly Gln Met Val Ala Pro Val Thr Gly Tyr Ser Leu Gly 85 90 95Val Arg Arg Ala Glu Ile Lys Pro Gly Val Arg Glu Ile His Leu Cys 100 105 110Lys Asp Glu Arg Gly Lys Thr Gly Leu Arg Leu Arg Lys Val Asp Gln 115 120 125Gly Leu Phe Val Gln Leu Val Gln Ala Asn Thr Pro Ala Ser Leu Val 130 135 140Gly Leu Arg Phe Gly Asp Gln Leu Leu Gln Ile Asp Gly Arg Asp Cys145 150 155 160Ala Gly Trp Ser Ser His Lys Ala His Gln Val Val Lys Lys Ala Ser 165 170 175Gly Asp Lys Ile Val Val Val Val Arg Asp Arg Pro Phe Gln Arg Thr 180 185 190Val Thr Met His Lys Asp Ser Met Gly His Val Gly Phe Val Ile Lys 195 200 205Lys Gly Lys Ile Val Ser Leu Val Lys Gly Ser Ser Ala Ala Arg Asn 210 215 220Gly Leu Leu Thr Asn His Tyr Val Cys Glu Val Asp Gly Gln Asn Val225 230 235 240Ile Gly Leu Lys Asp Lys Lys Ile Met Glu Ile Leu Ala Thr Ala Gly 245 250 255Asn Val Val Thr Leu Thr Ile Ile Pro Ser Val Ile Tyr Glu His Met

260 265 270Val Lys Lys Leu Pro Pro Val Leu Leu His His Thr Met Asp His Ser 275 280 285Ile Pro Asp Ala 29017410PRTHomo sapiens 17Met Val Cys Phe Arg Leu Phe Pro Val Pro Gly Ser Gly Leu Val Leu1 5 10 15Val Cys Leu Val Leu Gly Ala Val Arg Ser Tyr Ala Leu Glu Leu Asn 20 25 30Leu Thr Asp Ser Glu Asn Ala Thr Cys Leu Tyr Ala Lys Trp Gln Met 35 40 45Asn Phe Thr Val Arg Tyr Glu Thr Thr Asn Lys Thr Tyr Lys Thr Val 50 55 60Thr Ile Ser Asp His Gly Thr Val Thr Tyr Asn Gly Ser Ile Cys Gly65 70 75 80Asp Asp Gln Asn Gly Pro Lys Ile Ala Val Gln Phe Gly Pro Gly Phe 85 90 95Ser Trp Ile Ala Asn Phe Thr Lys Ala Ala Ser Thr Tyr Ser Ile Asp 100 105 110Ser Val Ser Phe Ser Tyr Asn Thr Gly Asp Asn Thr Thr Phe Pro Asp 115 120 125Ala Glu Asp Lys Gly Ile Leu Thr Val Asp Glu Leu Leu Ala Ile Arg 130 135 140Ile Pro Leu Asn Asp Leu Phe Arg Cys Asn Ser Leu Ser Thr Leu Glu145 150 155 160Lys Asn Asp Val Val Gln His Tyr Trp Asp Val Leu Val Gln Ala Phe 165 170 175Val Gln Asn Gly Thr Val Ser Thr Asn Glu Phe Leu Cys Asp Lys Asp 180 185 190Lys Thr Ser Thr Val Ala Pro Thr Ile His Thr Thr Val Pro Ser Pro 195 200 205Thr Thr Thr Pro Thr Pro Lys Glu Lys Pro Glu Ala Gly Thr Tyr Ser 210 215 220Val Asn Asn Gly Asn Asp Thr Cys Leu Leu Ala Thr Met Gly Leu Gln225 230 235 240Leu Asn Ile Thr Gln Asp Lys Val Ala Ser Val Ile Asn Ile Asn Pro 245 250 255Asn Thr Thr His Ser Thr Gly Ser Cys Arg Ser His Thr Ala Leu Leu 260 265 270Arg Leu Asn Ser Ser Thr Ile Lys Tyr Leu Asp Phe Val Phe Ala Val 275 280 285Lys Asn Glu Asn Arg Phe Tyr Leu Lys Glu Val Asn Ile Ser Met Tyr 290 295 300Leu Val Asn Gly Ser Val Phe Ser Ile Ala Asn Asn Asn Leu Ser Tyr305 310 315 320Trp Asp Ala Pro Leu Gly Ser Ser Tyr Met Cys Asn Lys Glu Gln Thr 325 330 335Val Ser Val Ser Gly Ala Phe Gln Ile Asn Thr Phe Asp Leu Arg Val 340 345 350Gln Pro Phe Asn Val Thr Gln Gly Lys Tyr Ser Thr Ala Gln Asp Cys 355 360 365Ser Ala Asp Asp Asp Asn Phe Leu Val Pro Ile Ala Val Gly Ala Ala 370 375 380Leu Ala Gly Val Leu Ile Leu Val Leu Leu Ala Tyr Phe Ile Gly Leu385 390 395 400Lys His His His Ala Gly Tyr Glu Gln Phe 405 41018918PRTHomo sapiens 18Met Leu Thr Leu Gln Thr Trp Leu Val Gln Ala Leu Phe Ile Phe Leu1 5 10 15Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser 20 25 30Pro Glu Ser Pro Val Val Gln Leu His Ser Asn Phe Thr Ala Val Cys 35 40 45Val Leu Lys Glu Lys Cys Met Asp Tyr Phe His Val Asn Ala Asn Tyr 50 55 60Ile Val Trp Lys Thr Asn His Phe Thr Ile Pro Lys Glu Gln Tyr Thr65 70 75 80Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Phe Thr Asp Ile Ala Ser 85 90 95Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu 100 105 110Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys 115 120 125Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gly Lys Lys Met Arg Cys 130 135 140Glu Trp Asp Arg Gly Arg Glu Thr His Leu Glu Thr Asn Phe Thr Leu145 150 155 160Lys Ser Glu Trp Ala Thr His Lys Phe Ala Asp Cys Lys Ala Lys Arg 165 170 175Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Ser Thr Val Tyr Phe Val 180 185 190Asn Ile Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Thr 195 200 205Ser Asp His Ile Asn Phe Asp Pro Val Tyr Lys Val Lys Pro Asn Pro 210 215 220Pro His Asn Leu Ser Val Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu225 230 235 240Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Ser Val Ile Ile Leu Lys 245 250 255Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile 260 265 270Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Ser Phe Thr Val Gln Asp 275 280 285Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Cys Met Lys Glu 290 295 300Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile305 310 315 320Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile 325 330 335Asp Pro Ser His Thr Gln Gly Tyr Arg Thr Val Gln Leu Val Trp Lys 340 345 350Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val 355 360 365Thr Leu Thr Arg Trp Lys Ser His Leu Gln Asn Tyr Thr Val Asn Ala 370 375 380Thr Lys Leu Thr Val Asn Leu Thr Asn Asp Arg Tyr Val Ala Thr Leu385 390 395 400Thr Val Arg Asn Leu Val Gly Lys Ser Asp Ala Ala Val Leu Thr Ile 405 410 415Pro Ala Cys Asp Phe Gln Ala Thr His Pro Val Met Asp Leu Lys Ala 420 425 430Phe Pro Lys Asp Asn Met Leu Trp Val Glu Trp Thr Thr Pro Arg Glu 435 440 445Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys Val Leu Ser Asp Lys Ala 450 455 460Pro Cys Ile Thr Asp Trp Gln Gln Glu Asp Gly Thr Val His Arg Thr465 470 475 480Tyr Leu Arg Gly Asn Leu Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val 485 490 495Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala 500 505 510Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly Pro Thr Val Arg Thr Lys 515 520 525Lys Val Gly Lys Asn Glu Ala Val Leu Glu Trp Asp Gln Leu Pro Val 530 535 540Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr545 550 555 560Ile Ile Gly Asn Glu Thr Ala Val Asn Val Asp Ser Ser His Thr Glu 565 570 575Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr Leu Tyr Met Val Arg Met 580 585 590Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe 595 600 605Thr Thr Pro Lys Phe Ala Gln Gly Glu Ile Glu Ala Ile Val Val Pro 610 615 620Val Cys Leu Ala Phe Leu Leu Thr Thr Leu Leu Gly Val Leu Phe Cys625 630 635 640Phe Asn Lys Arg Asp Leu Ile Lys Lys His Ile Trp Pro Asn Val Pro 645 650 655Asp Pro Ser Lys Ser His Ile Ala Gln Trp Ser Pro His Thr Pro Pro 660 665 670Arg His Asn Phe Asn Ser Lys Asp Gln Met Tyr Ser Asp Gly Asn Phe 675 680 685Thr Asp Val Ser Val Val Glu Ile Glu Ala Asn Asp Lys Lys Pro Phe 690 695 700Pro Glu Asp Leu Lys Ser Leu Asp Leu Phe Lys Lys Glu Lys Ile Asn705 710 715 720Thr Glu Gly His Ser Ser Gly Ile Gly Gly Ser Ser Cys Met Ser Ser 725 730 735Ser Arg Pro Ser Ile Ser Ser Ser Asp Glu Asn Glu Ser Ser Gln Asn 740 745 750Thr Ser Ser Thr Val Gln Tyr Ser Thr Val Val His Ser Gly Tyr Arg 755 760 765His Gln Val Pro Ser Val Gln Val Phe Ser Arg Ser Glu Ser Thr Gln 770 775 780Pro Leu Leu Asp Ser Glu Glu Arg Pro Glu Asp Leu Gln Leu Val Asp785 790 795 800His Val Asp Gly Gly Asp Gly Ile Leu Pro Arg Gln Gln Tyr Phe Lys 805 810 815Gln Asn Cys Ser Gln His Glu Ser Ser Pro Asp Ile Ser His Phe Glu 820 825 830Arg Ser Lys Gln Val Ser Ser Val Asn Glu Glu Asp Phe Val Arg Leu 835 840 845Lys Gln Gln Ile Ser Asp His Ile Ser Gln Ser Cys Gly Ser Gly Gln 850 855 860Met Lys Met Phe Gln Glu Val Ser Ala Ala Asp Ala Phe Gly Pro Gly865 870 875 880Thr Glu Gly Gln Val Glu Arg Phe Glu Thr Val Gly Met Glu Ala Ala 885 890 895Thr Asp Glu Gly Met Pro Lys Ser Tyr Leu Pro Gln Thr Val Arg Gln 900 905 910Gly Gly Tyr Met Pro Gln 91519455PRTHomo sapiens 19Met Gly Leu Ser Thr Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu1 5 10 15Glu Leu Leu Val Gly Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro 20 25 30His Leu Gly Asp Arg Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys 35 40 45Tyr Ile His Pro Gln Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys 50 55 60Gly Thr Tyr Leu Tyr Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp65 70 75 80Cys Arg Glu Cys Glu Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu 85 90 95Arg His Cys Leu Ser Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val 100 105 110Glu Ile Ser Ser Cys Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg 115 120 125Lys Asn Gln Tyr Arg His Tyr Trp Ser Glu Asn Leu Phe Gln Cys Phe 130 135 140Asn Cys Ser Leu Cys Leu Asn Gly Thr Val His Leu Ser Cys Gln Glu145 150 155 160Lys Gln Asn Thr Val Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu 165 170 175Asn Glu Cys Val Ser Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr 180 185 190Lys Leu Cys Leu Pro Gln Ile Glu Asn Val Lys Gly Thr Glu Asp Ser 195 200 205Gly Thr Thr Val Leu Leu Pro Leu Val Ile Phe Phe Gly Leu Cys Leu 210 215 220Leu Ser Leu Leu Phe Ile Gly Leu Met Tyr Arg Tyr Gln Arg Trp Lys225 230 235 240Ser Lys Leu Tyr Ser Ile Val Cys Gly Lys Ser Thr Pro Glu Lys Glu 245 250 255Gly Glu Leu Glu Gly Thr Thr Thr Lys Pro Leu Ala Pro Asn Pro Ser 260 265 270Phe Ser Pro Thr Pro Gly Phe Thr Pro Thr Leu Gly Phe Ser Pro Val 275 280 285Pro Ser Ser Thr Phe Thr Ser Ser Ser Thr Tyr Thr Pro Gly Asp Cys 290 295 300Pro Asn Phe Ala Ala Pro Arg Arg Glu Val Ala Pro Pro Tyr Gln Gly305 310 315 320Ala Asp Pro Ile Leu Ala Thr Ala Leu Ala Ser Asp Pro Ile Pro Asn 325 330 335Pro Leu Gln Lys Trp Glu Asp Ser Ala His Lys Pro Gln Ser Leu Asp 340 345 350Thr Asp Asp Pro Ala Thr Leu Tyr Ala Val Val Glu Asn Val Pro Pro 355 360 365Leu Arg Trp Lys Glu Phe Val Arg Arg Leu Gly Leu Ser Asp His Glu 370 375 380Ile Asp Arg Leu Glu Leu Gln Asn Gly Arg Cys Leu Arg Glu Ala Gln385 390 395 400Tyr Ser Met Leu Ala Thr Trp Arg Arg Arg Thr Pro Arg Arg Glu Ala 405 410 415Thr Leu Glu Leu Leu Gly Arg Val Leu Arg Asp Met Asp Leu Leu Gly 420 425 430Cys Leu Glu Asp Ile Glu Glu Ala Leu Cys Gly Pro Ala Ala Leu Pro 435 440 445Pro Ala Pro Ser Leu Leu Arg 450 45520201PRTHomo sapiens 20Met Arg Arg Ala Trp Ile Leu Leu Thr Leu Gly Leu Val Ala Cys Val1 5 10 15Ser Ala Glu Ser Arg Ala Glu Leu Thr Ser Asp Lys Asp Met Tyr Leu 20 25 30Asp Asn Ser Ser Ile Glu Glu Ala Ser Gly Val Tyr Pro Ile Asp Asp 35 40 45Asp Asp Tyr Ala Ser Ala Ser Gly Ser Gly Ala Asp Glu Asp Val Glu 50 55 60Ser Pro Glu Leu Thr Thr Ser Arg Pro Leu Pro Lys Ile Leu Leu Thr65 70 75 80Ser Ala Ala Pro Lys Val Glu Thr Thr Thr Leu Asn Ile Gln Asn Lys 85 90 95Ile Pro Ala Gln Thr Lys Ser Pro Glu Glu Thr Asp Lys Glu Lys Val 100 105 110His Leu Ser Asp Ser Glu Arg Lys Met Asp Pro Ala Glu Glu Asp Thr 115 120 125Asn Val Tyr Thr Glu Lys His Ser Asp Ser Leu Phe Lys Arg Thr Glu 130 135 140Val Leu Ala Ala Val Ile Ala Gly Gly Val Ile Gly Phe Leu Phe Ala145 150 155 160Ile Phe Leu Ile Leu Leu Leu Val Tyr Arg Met Arg Lys Lys Asp Glu 165 170 175Gly Ser Tyr Asp Leu Gly Glu Arg Lys Pro Ser Ser Ala Ala Tyr Gln 180 185 190Lys Ala Pro Thr Lys Glu Phe Tyr Ala 195 20021442PRTHomo sapiens 21Met Lys Pro Gly Pro Pro His Arg Ala Gly Ala Ala His Gly Ala Gly1 5 10 15Ala Gly Ala Gly Ala Ala Ala Gly Pro Gly Ala Arg Gly Leu Leu Leu 20 25 30Pro Pro Leu Leu Leu Leu Leu Leu Ala Gly Arg Ala Ala Gly Ala Gln 35 40 45Arg Trp Arg Ser Glu Asn Phe Glu Arg Pro Val Asp Leu Glu Gly Ser 50 55 60Gly Asp Asp Asp Ser Phe Pro Asp Asp Glu Leu Asp Asp Leu Tyr Ser65 70 75 80Gly Ser Gly Ser Gly Tyr Phe Glu Gln Glu Ser Gly Ile Glu Thr Ala 85 90 95Met Arg Phe Ser Pro Asp Val Ala Leu Ala Val Ser Thr Thr Pro Ala 100 105 110Val Leu Pro Thr Thr Asn Ile Gln Pro Val Gly Thr Pro Phe Glu Glu 115 120 125Leu Pro Ser Glu Arg Pro Thr Leu Glu Pro Ala Thr Ser Pro Leu Val 130 135 140Val Thr Glu Val Pro Glu Glu Pro Ser Gln Arg Ala Thr Thr Val Ser145 150 155 160Thr Thr Met Ala Thr Thr Ala Ala Thr Ser Thr Gly Asp Pro Thr Val 165 170 175Ala Thr Val Pro Ala Thr Val Ala Thr Ala Thr Pro Ser Thr Pro Ala 180 185 190Ala Pro Pro Phe Thr Ala Thr Thr Ala Val Ile Arg Thr Thr Gly Val 195 200 205Arg Arg Leu Leu Pro Leu Pro Leu Thr Thr Val Ala Thr Ala Arg Ala 210 215 220Thr Thr Pro Glu Ala Pro Ser Pro Pro Thr Thr Ala Ala Val Leu Asp225 230 235 240Thr Glu Ala Pro Thr Pro Arg Leu Val Ser Thr Ala Thr Ser Arg Pro 245 250 255Arg Ala Leu Pro Arg Pro Ala Thr Thr Gln Glu Pro Asp Ile Pro Glu 260 265 270Arg Ser Thr Leu Pro Leu Gly Thr Thr Ala Pro Gly Pro Thr Glu Val 275 280 285Ala Gln Thr Pro Thr Pro Glu Thr Phe Leu Thr Thr Ile Arg Asp Glu 290 295 300Pro Glu Val Pro Val Ser Gly Gly Pro Ser Gly Asp Phe Glu Leu Pro305 310 315 320Glu Glu Glu Thr Thr Gln Pro Asp Thr Ala Asn Glu Val Val Ala Val 325 330 335Gly Gly Ala Ala Ala Lys Ala Ser Ser Pro Pro Gly Thr Leu Pro Lys 340 345 350Gly Ala Arg Pro Gly Pro Gly Leu Leu Asp Asn Ala Ile Asp Ser Gly 355 360 365Ser Ser Ala Ala Gln Leu Pro Gln Lys Ser Ile Leu Glu Arg Lys Glu 370 375 380Val Leu Val Ala Val Ile Val Gly Gly Val Val Gly Ala Leu Phe Ala385 390 395 400Ala Phe Leu Val Thr Leu Leu Ile Tyr Arg Met Lys Lys Lys Asp Glu 405 410 415Gly Ser Tyr Thr Leu Glu Glu Pro Lys Gln Ala Ser Val Thr Tyr Gln 420 425 430Lys Pro Asp Lys Gln Glu Glu Phe Tyr Ala 435 44022198PRTHomo sapiens 22Met Ala Pro Ala Arg Leu Phe

Ala Leu Leu Leu Phe Phe Val Gly Gly1 5 10 15Val Ala Glu Ser Ile Arg Glu Thr Glu Val Ile Asp Pro Gln Asp Leu 20 25 30Leu Glu Gly Arg Tyr Phe Ser Gly Ala Leu Pro Asp Asp Glu Asp Val 35 40 45Val Gly Pro Gly Gln Glu Ser Asp Asp Phe Glu Leu Ser Gly Ser Gly 50 55 60Asp Leu Asp Asp Leu Glu Asp Ser Met Ile Gly Pro Glu Val Val His65 70 75 80Pro Leu Val Pro Leu Asp Asn His Ile Pro Glu Arg Ala Gly Ser Gly 85 90 95Ser Gln Val Pro Thr Glu Pro Lys Lys Leu Glu Glu Asn Glu Val Ile 100 105 110Pro Lys Arg Ile Ser Pro Val Glu Glu Ser Glu Asp Val Ser Asn Lys 115 120 125Val Ser Met Ser Ser Thr Val Gln Gly Ser Asn Ile Phe Glu Arg Thr 130 135 140Glu Val Leu Ala Ala Leu Ile Val Gly Gly Ile Val Gly Ile Leu Phe145 150 155 160Ala Val Phe Leu Ile Leu Leu Leu Met Tyr Arg Met Lys Lys Lys Asp 165 170 175Glu Gly Ser Tyr Asp Leu Gly Lys Lys Pro Ile Tyr Lys Lys Ala Pro 180 185 190Thr Asn Glu Phe Tyr Ala 1952359PRTHomo sapiens 23Met Asp Gln Ala Arg Ser Ala Phe Ser Asn Leu Phe Gly Gly Glu Pro1 5 10 15Leu Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln Val Asp Gly Asp Asn 20 25 30Ser His Val Glu Met Lys Leu Ala Val Asp Glu Glu Glu Asn Ala Asp 35 40 45Asn Asn Thr Lys Ala Asn Val Thr Lys Pro Lys 50 5524267PRTHomo sapiens 24Met Gly Ser Ala Cys Ile Lys Val Thr Lys Tyr Phe Leu Phe Leu Phe1 5 10 15Asn Leu Ile Phe Phe Ile Leu Gly Ala Val Ile Leu Gly Phe Gly Val 20 25 30Trp Ile Leu Ala Asp Lys Ser Ser Phe Ile Ser Val Leu Gln Thr Ser 35 40 45Ser Ser Ser Leu Arg Met Gly Ala Tyr Val Phe Ile Gly Val Gly Ala 50 55 60Val Thr Met Leu Met Gly Phe Leu Gly Cys Ile Gly Ala Val Asn Glu65 70 75 80Val Arg Cys Leu Leu Gly Leu Tyr Phe Ala Phe Leu Leu Leu Ile Leu 85 90 95Ile Ala Gln Val Thr Ala Gly Ala Leu Phe Tyr Phe Asn Met Gly Lys 100 105 110Leu Lys Gln Glu Met Gly Gly Ile Val Thr Glu Leu Ile Arg Asp Tyr 115 120 125Asn Ser Ser Arg Glu Asp Ser Leu Gln Asp Ala Trp Asp Tyr Val Gln 130 135 140Ala Gln Val Lys Cys Cys Gly Trp Val Ser Phe Tyr Asn Trp Thr Asp145 150 155 160Asn Ala Glu Leu Met Asn Arg Pro Glu Val Thr Tyr Pro Cys Ser Cys 165 170 175Glu Val Lys Gly Glu Glu Asp Asn Ser Leu Ser Val Arg Lys Gly Phe 180 185 190Cys Glu Ala Pro Gly Asn Arg Thr Gln Ser Gly Asn His Pro Glu Asp 195 200 205Trp Pro Val Tyr Gln Glu Gly Cys Met Glu Lys Val Gln Ala Trp Leu 210 215 220Gln Glu Asn Leu Gly Ile Ile Leu Gly Val Gly Val Gly Val Ala Ile225 230 235 240Ile Glu Leu Leu Gly Met Val Leu Ser Ile Cys Leu Cys Arg His Val 245 250 255His Ser Glu Asp Tyr Ser Lys Val Pro Lys Tyr 260 26525387PRTHomo sapiens 25Met Pro Arg Pro Arg Leu Leu Ala Ala Leu Cys Gly Ala Leu Leu Cys1 5 10 15Ala Pro Ser Leu Leu Val Ala Leu Asp Ile Cys Ser Lys Asn Pro Cys 20 25 30His Asn Gly Gly Leu Cys Glu Glu Ile Ser Gln Glu Val Arg Gly Asp 35 40 45Val Phe Pro Ser Tyr Thr Cys Thr Cys Leu Lys Gly Tyr Ala Gly Asn 50 55 60His Cys Glu Thr Lys Cys Val Glu Pro Leu Gly Met Glu Asn Gly Asn65 70 75 80Ile Ala Asn Ser Gln Ile Ala Ala Ser Ser Val Arg Val Thr Phe Leu 85 90 95Gly Leu Gln His Trp Val Pro Glu Leu Ala Arg Leu Asn Arg Ala Gly 100 105 110Met Val Asn Ala Trp Thr Pro Ser Ser Asn Asp Asp Asn Pro Trp Ile 115 120 125Gln Val Asn Leu Leu Arg Arg Met Trp Val Thr Gly Val Val Thr Gln 130 135 140Gly Ala Ser Arg Leu Ala Ser His Glu Tyr Leu Lys Ala Phe Lys Val145 150 155 160Ala Tyr Ser Leu Asn Gly His Glu Phe Asp Phe Ile His Asp Val Asn 165 170 175Lys Lys His Lys Glu Phe Val Gly Asn Trp Asn Lys Asn Ala Val His 180 185 190Val Asn Leu Phe Glu Thr Pro Val Glu Ala Gln Tyr Val Arg Leu Tyr 195 200 205Pro Thr Ser Cys His Thr Ala Cys Thr Leu Arg Phe Glu Leu Leu Gly 210 215 220Cys Glu Leu Asn Gly Cys Ala Asn Pro Leu Gly Leu Lys Asn Asn Ser225 230 235 240Ile Pro Asp Lys Gln Ile Thr Ala Ser Ser Ser Tyr Lys Thr Trp Gly 245 250 255Leu His Leu Phe Ser Trp Asn Pro Ser Tyr Ala Arg Leu Asp Lys Gln 260 265 270Gly Asn Phe Asn Ala Trp Val Ala Gly Ser Tyr Gly Asn Asp Gln Trp 275 280 285Leu Gln Val Asp Leu Gly Ser Ser Lys Glu Val Thr Gly Ile Ile Thr 290 295 300Gln Gly Ala Arg Asn Phe Gly Ser Val Gln Phe Val Ala Ser Tyr Lys305 310 315 320Val Ala Tyr Ser Asn Asp Ser Ala Asn Trp Thr Glu Tyr Gln Asp Pro 325 330 335Arg Thr Gly Ser Ser Lys Ile Phe Pro Gly Asn Trp Asp Asn His Ser 340 345 350His Lys Lys Asn Leu Phe Glu Thr Pro Ile Leu Ala Arg Tyr Val Arg 355 360 365Ile Leu Pro Val Ala Trp His Asn Arg Ile Ala Leu Arg Leu Glu Leu 370 375 380Leu Gly Cys38526556PRTHomo sapiens 26Met Pro Pro Pro Arg Leu Leu Phe Phe Leu Leu Phe Leu Thr Pro Met1 5 10 15Glu Val Arg Pro Glu Glu Pro Leu Val Val Lys Val Glu Glu Gly Asp 20 25 30Asn Ala Val Leu Gln Cys Leu Lys Gly Thr Ser Asp Gly Pro Thr Gln 35 40 45Gln Leu Thr Trp Ser Arg Glu Ser Pro Leu Lys Pro Phe Leu Lys Leu 50 55 60Ser Leu Gly Leu Pro Gly Leu Gly Ile His Met Arg Pro Leu Ala Ile65 70 75 80Trp Leu Phe Ile Phe Asn Val Ser Gln Gln Met Gly Gly Phe Tyr Leu 85 90 95Cys Gln Pro Gly Pro Pro Ser Glu Lys Ala Trp Gln Pro Gly Trp Thr 100 105 110Val Asn Val Glu Gly Ser Gly Glu Leu Phe Arg Trp Asn Val Ser Asp 115 120 125Leu Gly Gly Leu Gly Cys Gly Leu Lys Asn Arg Ser Ser Glu Gly Pro 130 135 140Ser Ser Pro Ser Gly Lys Leu Met Ser Pro Lys Leu Tyr Val Trp Ala145 150 155 160Lys Asp Arg Pro Glu Ile Trp Glu Gly Glu Pro Pro Cys Leu Pro Pro 165 170 175Arg Asp Ser Leu Asn Gln Ser Leu Ser Gln Asp Leu Thr Met Ala Pro 180 185 190Gly Ser Thr Leu Trp Leu Ser Cys Gly Val Pro Pro Asp Ser Val Ser 195 200 205Arg Gly Pro Leu Ser Trp Thr His Val His Pro Lys Gly Pro Lys Ser 210 215 220Leu Leu Ser Leu Glu Leu Lys Asp Asp Arg Pro Ala Arg Asp Met Trp225 230 235 240Val Met Glu Thr Gly Leu Leu Leu Pro Arg Ala Thr Ala Gln Asp Ala 245 250 255Gly Lys Tyr Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu 260 265 270Glu Ile Thr Ala Arg Pro Val Leu Trp His Trp Leu Leu Arg Thr Gly 275 280 285Gly Trp Lys Val Ser Ala Val Thr Leu Ala Tyr Leu Ile Phe Cys Leu 290 295 300Cys Ser Leu Val Gly Ile Leu His Leu Gln Arg Ala Leu Val Leu Arg305 310 315 320Arg Lys Arg Lys Arg Met Thr Asp Pro Thr Arg Arg Phe Phe Lys Val 325 330 335Thr Pro Pro Pro Gly Ser Gly Pro Gln Asn Gln Tyr Gly Asn Val Leu 340 345 350Ser Leu Pro Thr Pro Thr Ser Gly Leu Gly Arg Ala Gln Arg Trp Ala 355 360 365Ala Gly Leu Gly Gly Thr Ala Pro Ser Tyr Gly Asn Pro Ser Ser Asp 370 375 380Val Gln Ala Asp Gly Ala Leu Gly Ser Arg Ser Pro Pro Gly Val Gly385 390 395 400Pro Glu Glu Glu Glu Gly Glu Gly Tyr Glu Glu Pro Asp Ser Glu Glu 405 410 415Asp Ser Glu Phe Tyr Glu Asn Asp Ser Asn Leu Gly Gln Asp Gln Leu 420 425 430Ser Gln Asp Gly Ser Gly Tyr Glu Asn Pro Glu Asp Glu Pro Leu Gly 435 440 445Pro Glu Asp Glu Asp Ser Phe Ser Asn Ala Glu Ser Tyr Glu Asn Glu 450 455 460Asp Glu Glu Leu Thr Gln Pro Val Ala Arg Thr Met Asp Phe Leu Ser465 470 475 480Pro His Gly Ser Ala Trp Asp Pro Ser Arg Glu Ala Thr Ser Leu Gly 485 490 495Ser Gln Ser Tyr Glu Asp Met Arg Gly Ile Leu Tyr Ala Ala Pro Gln 500 505 510Leu Arg Ser Ile Arg Gly Gln Pro Gly Pro Asn His Glu Glu Asp Ala 515 520 525Asp Ser Tyr Glu Asn Met Asp Asn Pro Asp Gly Pro Asp Pro Ala Trp 530 535 540Gly Gly Gly Gly Arg Met Gly Thr Trp Ser Thr Arg545 550 55527595PRTHomo sapiens 27Met Arg Val Leu Leu Ala Ala Leu Gly Leu Leu Phe Leu Gly Ala Leu1 5 10 15Arg Ala Phe Pro Gln Asp Arg Pro Phe Glu Asp Thr Cys His Gly Asn 20 25 30Pro Ser His Tyr Tyr Asp Lys Ala Val Arg Arg Cys Cys Tyr Arg Cys 35 40 45Pro Met Gly Leu Phe Pro Thr Gln Gln Cys Pro Gln Arg Pro Thr Asp 50 55 60Cys Arg Lys Gln Cys Glu Pro Asp Tyr Tyr Leu Asp Glu Ala Asp Arg65 70 75 80Cys Thr Ala Cys Val Thr Cys Ser Arg Asp Asp Leu Val Glu Lys Thr 85 90 95Pro Cys Ala Trp Asn Ser Ser Arg Val Cys Glu Cys Arg Pro Gly Met 100 105 110Phe Cys Ser Thr Ser Ala Val Asn Ser Cys Ala Arg Cys Phe Phe His 115 120 125Ser Val Cys Pro Ala Gly Met Ile Val Lys Phe Pro Gly Thr Ala Gln 130 135 140Lys Asn Thr Val Cys Glu Pro Ala Ser Pro Gly Val Ser Pro Ala Cys145 150 155 160Ala Ser Pro Glu Asn Cys Lys Glu Pro Ser Ser Gly Thr Ile Pro Gln 165 170 175Ala Lys Pro Thr Pro Val Ser Pro Ala Thr Ser Ser Ala Ser Thr Met 180 185 190Pro Val Arg Gly Gly Thr Arg Leu Ala Gln Glu Ala Ala Ser Lys Leu 195 200 205Thr Arg Ala Pro Asp Ser Pro Ser Ser Val Gly Arg Pro Ser Ser Asp 210 215 220Pro Gly Leu Ser Pro Thr Gln Pro Cys Pro Glu Gly Ser Gly Asp Cys225 230 235 240Arg Lys Gln Cys Glu Pro Asp Tyr Tyr Leu Asp Glu Ala Gly Arg Cys 245 250 255Thr Ala Cys Val Ser Cys Ser Arg Asp Asp Leu Val Glu Lys Thr Pro 260 265 270Cys Ala Trp Asn Ser Ser Arg Thr Cys Glu Cys Arg Pro Gly Met Ile 275 280 285Cys Ala Thr Ser Ala Thr Asn Ser Cys Ala Arg Cys Val Pro Tyr Pro 290 295 300Ile Cys Ala Ala Glu Thr Val Thr Lys Pro Gln Asp Met Ala Glu Lys305 310 315 320Asp Thr Thr Phe Glu Ala Pro Pro Leu Gly Thr Gln Pro Asp Cys Asn 325 330 335Pro Thr Pro Glu Asn Gly Glu Ala Pro Ala Ser Thr Ser Pro Thr Gln 340 345 350Ser Leu Leu Val Asp Ser Gln Ala Ser Lys Thr Leu Pro Ile Pro Thr 355 360 365Ser Ala Pro Val Ala Leu Ser Ser Thr Gly Lys Pro Val Leu Asp Ala 370 375 380Gly Pro Val Leu Phe Trp Val Ile Leu Val Leu Val Val Val Val Gly385 390 395 400Ser Ser Ala Phe Leu Leu Cys His Arg Arg Ala Cys Arg Lys Arg Ile 405 410 415Arg Gln Lys Leu His Leu Cys Tyr Pro Val Gln Thr Ser Gln Pro Lys 420 425 430Leu Glu Leu Val Asp Ser Arg Pro Arg Arg Ser Ser Thr Gln Leu Arg 435 440 445Ser Gly Ala Ser Val Thr Glu Pro Val Ala Glu Glu Arg Gly Leu Met 450 455 460Ser Gln Pro Leu Met Glu Thr Cys His Ser Val Gly Ala Ala Tyr Leu465 470 475 480Glu Ser Leu Pro Leu Gln Asp Ala Ser Pro Ala Gly Gly Pro Ser Ser 485 490 495Pro Arg Asp Leu Pro Glu Pro Arg Val Ser Thr Glu His Thr Asn Asn 500 505 510Lys Ile Glu Lys Ile Tyr Ile Met Lys Ala Asp Thr Val Ile Val Gly 515 520 525Thr Val Lys Ala Glu Leu Pro Glu Gly Arg Gly Leu Ala Gly Pro Ala 530 535 540Glu Pro Glu Leu Glu Glu Glu Leu Glu Ala Asp His Thr Pro His Tyr545 550 555 560Pro Glu Gln Glu Thr Glu Pro Pro Leu Gly Ser Cys Ser Asp Val Met 565 570 575Leu Ser Val Glu Glu Glu Gly Lys Glu Asp Pro Leu Pro Thr Ala Ala 580 585 590Ser Gly Lys 59528532PRTHomo Sapiens 28Met Pro Leu Phe Leu Ile Leu Cys Leu Leu Gln Gly Ser Ser Phe Ala1 5 10 15Leu Pro Gln Lys Arg Pro His Pro Arg Trp Leu Trp Glu Gly Ser Leu 20 25 30Pro Ser Arg Thr His Leu Arg Ala Met Gly Thr Leu Arg Pro Ser Ser 35 40 45Pro Leu Cys Trp Arg Glu Glu Ser Ser Phe Ala Ala Pro Asn Ser Leu 50 55 60Lys Gly Ser Arg Leu Val Ser Gly Glu Pro Gly Gly Ala Val Thr Ile65 70 75 80Gln Cys His Tyr Ala Pro Ser Ser Val Asn Arg His Gln Arg Lys Tyr 85 90 95Trp Cys Arg Leu Gly Pro Pro Arg Trp Ile Cys Gln Thr Ile Val Ser 100 105 110Thr Asn Gln Tyr Thr His His Arg Tyr Arg Asp Arg Val Ala Leu Thr 115 120 125Asp Phe Pro Gln Arg Gly Leu Phe Val Val Arg Leu Ser Gln Leu Ser 130 135 140Pro Asp Asp Ile Gly Cys Tyr Leu Cys Gly Ile Gly Ser Glu Asn Asn145 150 155 160Met Leu Phe Leu Ser Met Asn Leu Thr Ile Ser Ala Gly Pro Ala Ser 165 170 175Thr Leu Pro Thr Ala Thr Pro Ala Ala Gly Glu Leu Thr Met Arg Ser 180 185 190Tyr Gly Thr Ala Ser Pro Val Ala Asn Arg Trp Thr Pro Gly Thr Thr 195 200 205Gln Thr Leu Gly Gln Gly Thr Ala Trp Asp Thr Val Ala Ser Thr Pro 210 215 220Gly Thr Ser Lys Thr Thr Ala Ser Ala Glu Gly Arg Arg Thr Pro Gly225 230 235 240Ala Thr Arg Pro Ala Ala Pro Gly Thr Gly Ser Trp Ala Glu Gly Ser 245 250 255Val Lys Ala Pro Ala Pro Ile Pro Glu Ser Pro Pro Ser Lys Ser Arg 260 265 270Ser Met Ser Asn Thr Thr Glu Gly Val Trp Glu Gly Thr Arg Ser Ser 275 280 285Val Thr Asn Arg Ala Arg Ala Ser Lys Asp Arg Arg Glu Met Thr Thr 290 295 300Thr Lys Ala Asp Arg Pro Arg Glu Asp Ile Glu Gly Val Arg Ile Ala305 310 315 320Leu Asp Ala Ala Lys Lys Val Leu Gly Thr Ile Gly Pro Pro Ala Leu 325 330 335Val Ser Glu Thr Leu Ala Trp Glu Ile Leu Pro Gln Ala Thr Pro Val 340 345 350Ser Lys Gln Gln Ser Gln Gly Ser Ile Gly Glu Thr Thr Pro Ala Ala 355 360 365Gly Met Trp Thr Leu Gly Thr Pro Ala Ala Asp Val Trp Ile Leu Gly 370 375 380Thr Pro Ala Ala Asp Val Trp Thr Ser Met Glu Ala Ala Ser Gly Glu385 390 395 400Gly Ser Ala Ala Gly Asp Leu Asp Ala Ala

Thr Gly Asp Arg Gly Pro 405 410 415Gln Ala Thr Leu Ser Gln Thr Pro Ala Val Gly Pro Trp Gly Pro Pro 420 425 430Gly Lys Glu Ser Ser Val Lys Arg Thr Phe Pro Glu Asp Glu Ser Ser 435 440 445Ser Arg Thr Leu Ala Pro Val Ser Thr Met Leu Ala Leu Phe Met Leu 450 455 460Met Ala Leu Val Leu Leu Gln Arg Lys Leu Trp Arg Arg Arg Thr Ser465 470 475 480Gln Glu Ala Glu Arg Val Thr Leu Ile Gln Met Thr His Phe Leu Glu 485 490 495Val Asn Pro Gln Ala Asp Gln Leu Pro His Val Glu Arg Lys Met Leu 500 505 510Gln Asp Asp Ser Leu Pro Ala Gly Ala Ser Leu Thr Ala Pro Glu Arg 515 520 525Asn Pro Gly Pro 53029287PRTHomo Sapiens 29Met Asp Pro Lys Gln Thr Thr Leu Leu Cys Leu Val Leu Cys Leu Gly1 5 10 15Gln Arg Ile Gln Ala Gln Glu Gly Asp Phe Pro Met Pro Phe Ile Ser 20 25 30Ala Lys Ser Ser Pro Val Ile Pro Leu Asp Gly Ser Val Lys Ile Gln 35 40 45Cys Gln Ala Ile Arg Glu Ala Tyr Leu Thr Gln Leu Met Ile Ile Lys 50 55 60Asn Ser Thr Tyr Arg Glu Ile Gly Arg Arg Leu Lys Phe Trp Asn Glu65 70 75 80Thr Asp Pro Glu Phe Val Ile Asp His Met Asp Ala Asn Lys Ala Gly 85 90 95Arg Tyr Gln Cys Gln Tyr Arg Ile Gly His Tyr Arg Phe Arg Tyr Ser 100 105 110Asp Thr Leu Glu Leu Val Val Thr Gly Leu Tyr Gly Lys Pro Phe Leu 115 120 125Ser Ala Asp Arg Gly Leu Val Leu Met Pro Gly Glu Asn Ile Ser Leu 130 135 140Thr Cys Ser Ser Ala His Ile Pro Phe Asp Arg Phe Ser Leu Ala Lys145 150 155 160Glu Gly Glu Leu Ser Leu Pro Gln His Gln Ser Gly Glu His Pro Ala 165 170 175Asn Phe Ser Leu Gly Pro Val Asp Leu Asn Val Ser Gly Ile Tyr Arg 180 185 190Cys Tyr Gly Trp Tyr Asn Arg Ser Pro Tyr Leu Trp Ser Phe Pro Ser 195 200 205Asn Ala Leu Glu Leu Val Val Thr Asp Ser Ile His Gln Asp Tyr Thr 210 215 220Thr Gln Asn Leu Ile Arg Met Ala Val Ala Gly Leu Val Leu Val Ala225 230 235 240Leu Leu Ala Ile Leu Val Glu Asn Trp His Ser His Thr Ala Leu Asn 245 250 255Lys Glu Ala Ser Ala Asp Val Ala Glu Pro Ser Trp Ser Gln Gln Met 260 265 270Cys Gln Pro Gly Leu Thr Phe Ala Arg Thr Pro Ser Val Cys Lys 275 280 2853086PRTHomo Sapiens 30Met Ile Pro Ala Val Val Leu Leu Leu Leu Leu Leu Val Glu Gln Ala1 5 10 15Ala Ala Leu Gly Glu Pro Gln Leu Cys Tyr Ile Leu Asp Ala Ile Leu 20 25 30Phe Leu Tyr Gly Ile Val Leu Thr Leu Leu Tyr Cys Arg Leu Lys Ile 35 40 45Gln Val Arg Lys Ala Ala Ile Thr Ser Tyr Glu Lys Ser Asp Gly Val 50 55 60Tyr Thr Gly Leu Ser Thr Arg Asn Gln Glu Thr Tyr Glu Thr Leu Lys65 70 75 80His Glu Lys Pro Pro Gln 8531374PRTHomo Sapiens 31Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln1 5 10 15Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser 20 25 30Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu 35 40 45Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln 50 55 60Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser65 70 75 80Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile 85 90 95Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg 100 105 110Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys 115 120 125Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe 130 135 140Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile145 150 155 160Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr 165 170 175Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro Ala Pro 180 185 190Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn Leu Val 195 200 205Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly Leu Gln 210 215 220Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly Arg Asn225 230 235 240Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp Ser Gly 245 250 255Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Asn Val Leu Lys Arg 260 265 270Ser Pro Glu Leu Glu Leu Gln Val Leu Gly Leu Gln Leu Pro Thr Pro 275 280 285Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met Phe Leu 290 295 300Val Asn Thr Val Leu Trp Val Thr Ile Arg Lys Glu Leu Lys Arg Lys305 310 315 320Lys Lys Trp Asp Leu Glu Ile Ser Leu Asp Ser Gly His Glu Lys Lys 325 330 335Val Ile Ser Ser Leu Gln Glu Asp Arg His Leu Glu Glu Glu Leu Lys 340 345 350Cys Gln Glu Gln Lys Glu Glu Gln Leu Gln Glu Gly Val His Arg Lys 355 360 365Glu Pro Gln Gly Ala Thr 37032280PRTHomo Sapiens 32Met Trp Phe Leu Thr Thr Leu Leu Leu Trp Val Pro Val Asp Gly Gln1 5 10 15Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser 20 25 30Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu 35 40 45Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln 50 55 60Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser65 70 75 80Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile 85 90 95Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg 100 105 110Val Phe Met Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys 115 120 125Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe 130 135 140Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile145 150 155 160Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr 165 170 175Thr Ser Ala Gly Ile Ser Gln Tyr Thr Val Lys Gly Leu Gln Leu Pro 180 185 190Thr Pro Val Trp Phe His Val Leu Phe Tyr Leu Ala Val Gly Ile Met 195 200 205Phe Leu Val Asn Thr Val Leu Trp Val Thr Ile Arg Lys Glu Leu Lys 210 215 220Arg Lys Lys Lys Trp Asn Leu Glu Ile Ser Leu Asp Ser Gly His Glu225 230 235 240Lys Lys Val Ile Ser Ser Leu Gln Glu Asp Arg His Leu Glu Glu Glu 245 250 255Leu Lys Cys Gln Glu Gln Lys Glu Glu Gln Leu Gln Glu Gly Val His 260 265 270Arg Lys Glu Pro Gln Gly Ala Thr 275 28033416PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 33Met Gly Leu Ser Thr Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu1 5 10 15Glu Leu Leu Val Gly Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro 20 25 30His Leu Gly Asp Arg Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys 35 40 45Tyr Ile His Pro Gln Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys 50 55 60Gly Thr Tyr Leu Tyr Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp65 70 75 80Cys Arg Glu Cys Glu Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu 85 90 95Arg His Cys Leu Ser Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val 100 105 110Glu Ile Ser Ser Cys Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg 115 120 125Lys Asn Gln Tyr Arg His Tyr Trp Ser Glu Asn Leu Phe Gln Cys Phe 130 135 140Asn Cys Ser Leu Cys Leu Asn Gly Thr Val His Leu Ser Cys Gln Glu145 150 155 160Lys Gln Asn Thr Val Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu 165 170 175Asn Glu Cys Val Ser Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr 180 185 190Lys Leu Cys Leu Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 195 200 205Arg Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile 210 215 220Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln225 230 235 240Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 245 250 255Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Pro Gln Gly Thr Glu Asp 260 265 270Ser Gly Thr Thr Val Leu Leu Pro Leu Val Ile Phe Phe Gly Leu Cys 275 280 285Leu Leu Ser Leu Leu Phe Ile Gly Leu Met Tyr Arg Tyr Gln Arg Trp 290 295 300Lys Gly Thr Asn Gly Gly Gly Gly Ser Gly Arg Gly Tyr Ile Pro Glu305 310 315 320Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu Trp Val 325 330 335Phe Leu Ser Thr Phe Leu Ser Pro Ala Asn Gly Gly Gly Gly Ser Gly 340 345 350Arg Ser Leu Tyr Pro Ser Leu Glu Asp Leu Lys Val Asp Lys Val Ile 355 360 365Gln Ala Gln Thr Ala Phe Ser Ala Asn Pro Ala Asn Pro Ala Ile Leu 370 375 380Ser Glu Ala Ser Ala Pro Ile Pro His Asp Gly Asn Leu Tyr Pro Arg385 390 395 400Leu Tyr Pro Glu Leu Ser Gln Tyr Met Gly Leu Ser Leu Glu Gly Gly 405 410 41534836PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 34Met Ser Ala Pro Arg Ile Trp Leu Ala Gln Ala Leu Leu Phe Phe Leu1 5 10 15Thr Thr Glu Ser Ile Gly Gln Leu Leu Glu Pro Cys Gly Tyr Ile Tyr 20 25 30Pro Glu Phe Pro Val Val Gln Arg Gly Ser Asn Phe Thr Ala Ile Cys 35 40 45Val Leu Lys Glu Ala Cys Leu Gln His Tyr Tyr Val Asn Ala Ser Tyr 50 55 60Ile Val Trp Lys Thr Asn His Ala Ala Val Pro Arg Glu Gln Val Thr65 70 75 80Val Ile Asn Arg Thr Thr Ser Ser Val Thr Phe Thr Asp Val Val Leu 85 90 95Pro Ser Val Gln Leu Thr Cys Asn Ile Leu Ser Phe Gly Gln Ile Glu 100 105 110Gln Asn Val Tyr Gly Val Thr Met Leu Ser Gly Phe Pro Pro Asp Lys 115 120 125Pro Thr Asn Leu Thr Cys Ile Val Asn Glu Gly Lys Asn Met Leu Cys 130 135 140Gln Trp Asp Pro Gly Arg Glu Thr Tyr Leu Glu Thr Asn Tyr Thr Leu145 150 155 160Lys Ser Glu Trp Ala Thr Glu Lys Phe Pro Asp Cys Gln Ser Lys His 165 170 175Gly Thr Ser Cys Met Val Ser Tyr Met Pro Thr Tyr Tyr Val Asn Ile 180 185 190Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Ser Ser Glu 195 200 205Ser Ile Asn Phe Asp Pro Val Asp Lys Val Lys Pro Thr Pro Pro Tyr 210 215 220Asn Leu Ser Val Thr Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu225 230 235 240Ser Trp Val Ser Ser Gly Leu Gly Gly Leu Leu Asp Leu Lys Ser Asp 245 250 255Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ile Gln Val Pro Leu 260 265 270Glu Asp Thr Met Ser Pro Arg Thr Ser Phe Thr Val Gln Asp Leu Lys 275 280 285Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Ser Ile Lys Asp Ser Gly 290 295 300Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Thr Thr Tyr305 310 315 320Glu Asp Arg Pro Ser Arg Pro Pro Ser Phe Trp Tyr Lys Thr Asn Pro 325 330 335Ser His Gly Gln Glu Tyr Arg Ser Val Arg Leu Ile Trp Lys Ala Leu 340 345 350Pro Leu Ser Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Ile Leu 355 360 365Thr Gln Ser Lys Ser Val Ser Gln Thr Tyr Thr Val Thr Gly Thr Glu 370 375 380Leu Thr Val Asn Leu Thr Asn Asp Arg Tyr Val Ala Ser Leu Ala Ala385 390 395 400Arg Asn Lys Val Gly Lys Ser Ala Ala Ala Val Leu Thr Ile Pro Ser 405 410 415Pro His Val Thr Ala Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Arg 420 425 430Met Lys Gln Lys Lys Leu Val Gly Glu Arg Gly Ser Gly Ser Gly Ser 435 440 445Gly Ser Gly Ser Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe 450 455 460Tyr Glu Ile Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala465 470 475 480Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu 485 490 495Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Ala Ala Pro 500 505 510Ala Arg Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu Ala 515 520 525Val Leu Ala Trp Asp Gln Ile Pro Val Asp Asp Gln Asn Gly Phe Ile 530 535 540Arg Asn Tyr Ser Ile Ser Tyr Arg Thr Ser Val Gly Lys Glu Met Val545 550 555 560Val His Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu Ser 565 570 575Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu Gly 580 585 590Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala Gln 595 600 605Gly Glu Ile Glu Ala Ile Val Val Pro Val Cys Leu Ala Phe Leu Leu 610 615 620Thr Thr Leu Leu Gly Val Leu Phe Cys Phe Asn Lys Arg Asp Leu Ile625 630 635 640Lys Lys His Ile Trp Pro Asn Val Pro Asp Pro Ser Lys Ser His Ile 645 650 655Ala Gln Trp Ser Pro His Thr Pro Pro Arg His Asn Phe Asn Ser Lys 660 665 670Asp Gln Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Arg Met Lys Gln 675 680 685Leu Glu Asp Lys Val Glu Glu Leu Leu Ser Lys Asn Tyr His Leu Glu 690 695 700Asn Glu Val Ala Arg Leu Lys Lys Leu Val Gly Glu Arg Gly Ser Gly705 710 715 720Ser Gly Ser Gly Ser Gly Ser Ser Leu Tyr Pro Ser Leu Glu Asp Leu 725 730 735Lys Val Asp Lys Val Ile Gln Ala Gln Thr Ala Tyr Ser Ala Asn Pro 740 745 750Ala Ser Gln Ala Phe Val Leu Val Asp Ala Ser Ala Ala Leu Pro Pro 755 760 765Asp Gly Asn Leu Tyr Pro Lys Leu Tyr Pro Glu Leu Ser Gln Tyr Met 770 775 780Gly Leu Ser Leu Asn Glu Ala Glu Ile Cys Glu Ser Met Pro Met Val785 790 795 800Ser Gly Ala Pro Ala Gln Gly Gln Leu Val Ala Arg Pro Ser Ser Val 805 810 815Asn Tyr Met Val Ala Pro Val Thr Gly Asn Asp Ala Gly Ile Arg Arg 820 825 830Ala Glu Ile Lys 83535359PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 35Ala

Val Glu Gly Gly Met Lys Cys Val Lys Phe Leu Leu Tyr Val Leu1 5 10 15Leu Leu Ala Phe Cys Ala Cys Ala Val Gly Leu Ile Ala Val Gly Val 20 25 30Gly Ala Gln Leu Val Leu Ser Gln Thr Gly Thr Asp Asn Lys Phe Asn 35 40 45Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu His Leu Pro Asn Leu 50 55 60Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln Ser Leu Lys Asp Asp Pro65 70 75 80Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala 85 90 95Gln Ala Pro Lys Gly Thr Ile Ile Gln Gly Ala Thr Pro Gly Ser Leu 100 105 110Leu Pro Val Val Ile Ile Ala Val Gly Val Phe Leu Phe Leu Val Ala 115 120 125Phe Val Gly Cys Cys Gly Ala Cys Lys Glu Asn Tyr Cys Leu Met Ile 130 135 140Thr Phe Ala Ile Phe Leu Ser Leu Ile Met Leu Val Glu Val Ala Ala145 150 155 160Ala Ile Ala Gly Tyr Val Phe Arg Asp Lys Val Met Ser Glu Phe Asn 165 170 175Asn Asn Phe Arg Gln Gln Met Glu Asn Tyr Pro Lys Asn Asn His Thr 180 185 190Ala Ser Ile Leu Asp Arg Met Gln Ala Asp Phe Lys Cys Cys Gly Ala 195 200 205Gly Ser Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu 210 215 220Ile Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala Phe Ile225 230 235 240Gln Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 245 250 255Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Gly Ser Ala Asn Tyr 260 265 270Thr Asp Trp Glu Lys Ile Pro Ser Met Ser Lys Asn Arg Val Pro Asp 275 280 285Ser Cys Cys Ile Asn Val Thr Val Gly Cys Gly Ile Asn Phe Asn Glu 290 295 300Lys Ala Ile His Lys Glu Gly Cys Val Glu Lys Ile Gly Gly Trp Leu305 310 315 320Arg Lys Asn Val Leu Val Val Ala Ala Ala Ala Leu Gly Ile Ala Phe 325 330 335Val Glu Val Leu Gly Ile Val Phe Ala Cys Cys Leu Val Lys Ser Ile 340 345 350Arg Ser Gly Tyr Glu Val Met 35536532PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 36Met Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile1 5 10 15Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln 20 25 30Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 35 40 45Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Gly Ser Gly Ser Gly Gly 50 55 60Ser Gly Ser Gly Ser Val Cys Phe Arg Leu Phe Pro Val Pro Gly Ser65 70 75 80Gly Leu Val Leu Val Cys Leu Val Leu Gly Ala Val Arg Ser Tyr Ala 85 90 95Lys Ser Ser Val Gly Arg Gln Gly Ser Gly Ser Gly Ser Gly Leu Glu 100 105 110Leu Asn Leu Thr Asp Ser Glu Asn Ala Thr Cys Leu Tyr Ala Lys Trp 115 120 125Gln Met Asn Phe Thr Val Arg Tyr Glu Thr Thr Asn Lys Thr Tyr Lys 130 135 140Thr Val Thr Ile Ser Asp His Gly Thr Val Thr Tyr Asn Gly Ser Ile145 150 155 160Cys Gly Asp Asp Gln Asn Gly Pro Lys Ile Ala Val Gln Phe Gly Pro 165 170 175Gly Phe Ser Trp Ile Ala Asn Phe Thr Lys Ala Ala Ser Thr Tyr Ser 180 185 190Ile Asp Ser Val Ser Phe Ser Tyr Asn Thr Gly Asp Asn Thr Thr Phe 195 200 205Pro Asp Ala Glu Asp Lys Gly Ile Leu Thr Val Asp Glu Leu Leu Ala 210 215 220Ile Arg Ile Pro Leu Asn Asp Leu Phe Arg Cys Asn Ser Leu Ser Thr225 230 235 240Leu Glu Lys Asn Asp Val Val Gln His Tyr Trp Asp Val Leu Val Gln 245 250 255Ala Phe Val Gln Asn Gly Thr Val Ser Thr Asn Glu Phe Leu Cys Asp 260 265 270Lys Asp Lys Thr Ser Thr Val Ala Pro Thr Ile His Thr Thr Val Pro 275 280 285Ser Pro Thr Thr Thr Pro Thr Pro Lys Glu Lys Pro Glu Ala Gly Thr 290 295 300Tyr Ser Val Asn Asn Gly Asn Asp Thr Cys Leu Leu Ala Thr Met Gly305 310 315 320Leu Gln Leu Asn Ile Thr Gln Asp Lys Val Ala Ser Val Ile Asn Ile 325 330 335Asn Pro Asn Thr Thr His Ser Thr Gly Ser Cys Arg Ser His Thr Ala 340 345 350Leu Leu Arg Leu Asn Ser Ser Thr Ile Lys Tyr Leu Asp Phe Val Phe 355 360 365Ala Val Lys Asn Glu Asn Arg Phe Tyr Leu Lys Glu Val Asn Ile Ser 370 375 380Met Tyr Leu Val Asn Gly Ser Val Phe Ser Ile Ala Asn Asn Asn Leu385 390 395 400Ser Tyr Trp Asp Ala Pro Leu Gly Ser Ser Tyr Met Cys Asn Lys Glu 405 410 415Gln Thr Val Ser Val Ser Gly Ala Phe Gln Ile Asn Thr Phe Asp Leu 420 425 430Arg Val Gln Pro Phe Asn Val Thr Gln Gly Lys Tyr Ser Thr Ala Gln 435 440 445Asp Cys Ser Ala Asp Asp Asp Asn Phe Leu Val Pro Ile Ala Val Gly 450 455 460Ala Ala Leu Ala Gly Val Leu Ile Leu Val Leu Leu Ala Tyr Phe Ile465 470 475 480Gly Leu Lys His His His Ala Gly Tyr Glu Gln Phe Gly Ser Gly Ser 485 490 495Gly Ser Gly Ser Gly Ser Gly Ser Thr Gly Gly Ser Arg Thr Gly Ser 500 505 510Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Gly His His His His 515 520 525His His His His 53037514PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 37Met Val Cys Phe Arg Leu Phe Pro Val Pro Gly Ser Gly Leu Val Leu1 5 10 15Val Cys Leu Val Leu Gly Ala Val Arg Ser Tyr Ala Lys Ser Ser Val 20 25 30Gly Arg Gln Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr 35 40 45Glu Ile Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala Phe 50 55 60Ile Gln Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala65 70 75 80Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Gly Gly Gly Gly 85 90 95Ser Gly Gly Gly Gly Ser Leu Glu Leu Asn Leu Thr Asp Ser Glu Asn 100 105 110Ala Thr Cys Leu Tyr Ala Lys Trp Gln Met Asn Phe Thr Val Arg Tyr 115 120 125Glu Thr Thr Asn Lys Thr Tyr Lys Thr Val Thr Ile Ser Asp His Gly 130 135 140Thr Val Thr Tyr Asn Gly Ser Ile Cys Gly Asp Asp Gln Asn Gly Pro145 150 155 160Lys Ile Ala Val Gln Phe Gly Pro Gly Phe Ser Trp Ile Ala Asn Phe 165 170 175Thr Lys Ala Ala Ser Thr Tyr Ser Ile Asp Ser Val Ser Phe Ser Tyr 180 185 190Asn Thr Gly Asp Asn Thr Thr Phe Pro Asp Ala Glu Asp Lys Gly Ile 195 200 205Leu Thr Val Asp Glu Leu Leu Ala Ile Arg Ile Pro Leu Asn Asp Leu 210 215 220Phe Arg Cys Asn Ser Leu Ser Thr Leu Glu Lys Asn Asp Val Val Gln225 230 235 240His Tyr Trp Asp Val Leu Val Gln Ala Phe Val Gln Asn Gly Thr Val 245 250 255Ser Thr Asn Glu Phe Leu Cys Asp Lys Asp Lys Thr Ser Thr Val Ala 260 265 270Pro Thr Ile His Thr Thr Val Pro Ser Pro Thr Thr Thr Pro Thr Pro 275 280 285Lys Glu Lys Pro Glu Ala Gly Thr Tyr Ser Val Asn Asn Gly Asn Asp 290 295 300Thr Cys Leu Leu Ala Thr Met Gly Leu Gln Leu Asn Ile Thr Gln Asp305 310 315 320Lys Val Ala Ser Val Ile Asn Ile Asn Pro Asn Thr Thr His Ser Thr 325 330 335Gly Ser Cys Arg Ser His Thr Ala Leu Leu Arg Leu Asn Ser Ser Thr 340 345 350Ile Lys Tyr Leu Asp Phe Val Phe Ala Val Lys Asn Glu Asn Arg Phe 355 360 365Tyr Leu Lys Glu Val Asn Ile Ser Met Tyr Leu Val Asn Gly Ser Val 370 375 380Phe Ser Ile Ala Asn Asn Asn Leu Ser Tyr Trp Asp Ala Pro Leu Gly385 390 395 400Ser Ser Tyr Met Cys Asn Lys Glu Gln Thr Val Ser Val Ser Gly Ala 405 410 415Phe Gln Ile Asn Thr Phe Asp Leu Arg Val Gln Pro Phe Asn Val Thr 420 425 430Gln Gly Lys Tyr Ser Thr Ala Gln Asp Cys Ser Ala Asp Asp Asp Asn 435 440 445Phe Leu Val Pro Ile Ala Val Gly Ala Ala Leu Ala Gly Val Leu Ile 450 455 460Leu Val Leu Leu Ala Tyr Phe Ile Gly Leu Lys His His His Ala Gly465 470 475 480Tyr Glu Gln Phe Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 485 490 495Thr Gly Gly Ser Arg Thr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 500 505 510Gly Ser38826PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 38Met Asp Gln Ala Arg Ser Ala Phe Ser Asn Leu Phe Gly Gly Glu Pro1 5 10 15Leu Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln Val Asp Gly Asp Asn 20 25 30Ser His Val Glu Met Lys Leu Ala Val Asp Glu Glu Glu Asn Ala Asp 35 40 45Asn Asn Thr Lys Ala Asn Val Thr Lys Pro Lys Arg Cys Ser Gly Ser 50 55 60Ile Cys Tyr Gly Thr Ile Ala Val Ile Val Phe Phe Leu Ile Gly Phe65 70 75 80Met Ile Gly Tyr Leu Gly Tyr Cys Lys Gly Val Glu Pro Lys Thr Glu 85 90 95Cys Glu Arg Leu Ala Gly Thr Glu Ser Pro Val Arg Glu Glu Pro Gly 100 105 110Glu Asp Phe Pro Ala Ala Arg Arg Leu Tyr Trp Asp Asp Leu Lys Arg 115 120 125Lys Leu Ser Glu Lys Leu Asp Ser Thr Asp Phe Thr Gly Thr Ile Lys 130 135 140Leu Leu Asn Glu Asn Ser Tyr Val Pro Arg Glu Ala Gly Ser Gln Lys145 150 155 160Asp Glu Asn Leu Ala Leu Tyr Val Glu Asn Gln Phe Arg Glu Phe Lys 165 170 175Leu Ser Lys Val Trp Arg Asp Gln His Phe Val Lys Ile Gln Val Lys 180 185 190Asp Ser Ala Gln Asn Ser Val Ile Ile Val Asp Lys Asn Gly Arg Leu 195 200 205Val Tyr Leu Val Glu Asn Pro Gly Gly Tyr Val Ala Tyr Ser Lys Ala 210 215 220Ala Thr Val Thr Gly Lys Leu Val His Ala Asn Phe Gly Thr Lys Lys225 230 235 240Asp Phe Glu Asp Leu Tyr Thr Pro Val Asn Gly Ser Ile Val Ile Val 245 250 255Arg Ala Gly Lys Ile Thr Phe Ala Glu Lys Val Ala Asn Ala Glu Ser 260 265 270Leu Asn Ala Ile Gly Val Leu Ile Tyr Met Asp Gln Thr Lys Phe Pro 275 280 285Ile Val Asn Ala Glu Leu Ser Phe Phe Gly His Ala His Leu Gly Thr 290 295 300Gly Asp Pro Tyr Thr Pro Gly Phe Pro Ser Phe Asn His Thr Gln Phe305 310 315 320Pro Pro Ser Arg Ser Ser Gly Leu Pro Asn Ile Pro Val Gln Thr Ile 325 330 335Ser Arg Ala Ala Ala Glu Lys Leu Phe Gly Asn Met Glu Gly Asp Cys 340 345 350Pro Ser Asp Trp Lys Thr Asp Ser Thr Cys Arg Met Val Thr Ser Glu 355 360 365Ser Lys Asn Val Lys Leu Thr Val Ser Asn Val Leu Lys Glu Ile Lys 370 375 380Ile Leu Asn Ile Phe Gly Val Ile Lys Gly Phe Val Glu Pro Asp His385 390 395 400Tyr Val Val Val Gly Ala Gln Arg Asp Ala Trp Gly Pro Gly Ala Ala 405 410 415Lys Ser Gly Val Gly Thr Ala Leu Leu Leu Lys Leu Ala Gln Met Phe 420 425 430Ser Asp Met Val Leu Lys Asp Gly Phe Gln Pro Ser Arg Ser Ile Ile 435 440 445Phe Ala Ser Trp Ser Ala Gly Asp Phe Gly Ser Val Gly Ala Thr Glu 450 455 460Trp Leu Glu Gly Tyr Leu Ser Ser Leu His Leu Lys Ala Phe Thr Tyr465 470 475 480Ile Asn Leu Asp Lys Ala Val Leu Gly Thr Ser Asn Phe Lys Val Ser 485 490 495Ala Ser Pro Leu Leu Tyr Thr Leu Ile Glu Lys Thr Met Gln Asn Val 500 505 510Lys His Pro Val Thr Gly Gln Phe Leu Tyr Gln Asp Ser Asn Trp Ala 515 520 525Ser Lys Val Glu Lys Leu Thr Leu Asp Asn Ala Ala Phe Pro Phe Leu 530 535 540Ala Tyr Ser Gly Ile Pro Ala Val Ser Phe Cys Phe Cys Glu Asp Thr545 550 555 560Asp Tyr Pro Tyr Leu Gly Thr Thr Met Asp Thr Tyr Lys Glu Leu Ile 565 570 575Glu Arg Ile Pro Glu Leu Asn Lys Val Ala Arg Ala Ala Ala Glu Val 580 585 590Ala Gly Gln Phe Val Ile Lys Leu Thr His Asp Val Glu Leu Asn Leu 595 600 605Asp Tyr Glu Arg Tyr Asn Ser Gln Leu Leu Ser Phe Val Arg Asp Leu 610 615 620Asn Gln Tyr Arg Ala Asp Ile Lys Glu Met Gly Leu Ser Leu Gln Trp625 630 635 640Leu Tyr Ser Ala Arg Gly Asp Phe Phe Arg Ala Thr Ser Arg Leu Thr 645 650 655Thr Asp Phe Gly Asn Ala Glu Lys Thr Asp Arg Phe Val Met Lys Lys 660 665 670Leu Asn Asp Arg Val Met Arg Val Glu Tyr His Phe Leu Ser Pro Tyr 675 680 685Val Ser Pro Lys Glu Ser Pro Phe Arg His Val Phe Trp Gly Ser Gly 690 695 700Ser His Thr Leu Pro Ala Leu Leu Glu Asn Leu Lys Leu Arg Lys Gln705 710 715 720Asn Asn Gly Ala Phe Asn Glu Thr Leu Phe Arg Asn Gln Leu Ala Leu 725 730 735Ala Thr Trp Thr Ile Gln Gly Ala Ala Asn Ala Leu Ser Gly Asp Val 740 745 750Trp Asp Ile Asp Asn Glu Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly 755 760 765Ser Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile 770 775 780Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln785 790 795 800Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala 805 810 815Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys 820 82539726PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 39Met Ala Glu Ser His Leu Ser Leu Leu Tyr His Leu Thr Ala Val Ser1 5 10 15Ser Pro Ala Pro Gly Thr Pro Ala Phe Trp Val Ser Gly Trp Leu Gly 20 25 30Pro Gln Gln Tyr Leu Ser Tyr Asn Ser Leu Arg Gly Glu Ala Glu Pro 35 40 45Cys Gly Ala Trp Val Trp Glu Asn Gln Val Ser Trp Tyr Trp Glu Lys 50 55 60Glu Thr Thr Asp Leu Arg Ile Lys Glu Lys Leu Phe Leu Glu Ala Phe65 70 75 80Lys Ala Leu Gly Gly Lys Gly Pro Tyr Thr Leu Gln Gly Leu Leu Gly 85 90 95Cys Glu Leu Gly Pro Asp Asn Thr Ser Val Pro Thr Ala Lys Phe Ala 100 105 110Leu Asn Gly Glu Glu Phe Met Asn Phe Asp Leu Lys Gln Gly Thr Trp 115 120 125Gly Gly Asp Trp Pro Glu Ala Leu Ala Ile Ser Gln Arg Trp Gln Gln 130 135 140Gln Asp Lys Ala Ala Asn Lys Glu Leu Thr Phe Leu Leu Phe Ser Cys145 150 155 160Pro His Arg Leu Arg Glu His Leu Glu Arg Gly Arg Gly Asn Leu Glu

165 170 175Trp Lys Glu Pro Pro Ser Met Arg Leu Lys Ala Arg Pro Ser Ser Pro 180 185 190Gly Phe Ser Val Leu Thr Cys Ser Ala Phe Ser Phe Tyr Pro Pro Glu 195 200 205Leu Gln Leu Arg Phe Leu Arg Asn Gly Leu Ala Ala Gly Thr Gly Gln 210 215 220Gly Asp Phe Gly Pro Asn Ser Asp Gly Ser Phe His Ala Ser Ser Ser225 230 235 240Leu Thr Val Lys Ser Gly Asp Glu His His Tyr Cys Gly Ser Gly Ser 245 250 255Gly Gly Ser Gly Ser Gly Ser Val Cys Phe Arg Leu Phe Pro Val Pro 260 265 270Gly Ser Gly Leu Val Leu Val Cys Leu Val Leu Gly Ala Val Arg Ser 275 280 285Tyr Ala Lys Ser Ser Val Gly Arg Gln Gly Ser Gly Ser Gly Ser Gly 290 295 300Leu Glu Leu Asn Leu Thr Asp Ser Glu Asn Ala Thr Cys Leu Tyr Ala305 310 315 320Lys Trp Gln Met Asn Phe Thr Val Arg Tyr Glu Thr Thr Asn Lys Thr 325 330 335Tyr Lys Thr Val Thr Ile Ser Asp His Gly Thr Val Thr Tyr Asn Gly 340 345 350Ser Ile Cys Gly Asp Asp Gln Asn Gly Pro Lys Ile Ala Val Gln Phe 355 360 365Gly Pro Gly Phe Ser Trp Ile Ala Asn Phe Thr Lys Ala Ala Ser Thr 370 375 380Tyr Ser Ile Asp Ser Val Ser Phe Ser Tyr Asn Thr Gly Asp Asn Thr385 390 395 400Thr Phe Pro Asp Ala Glu Asp Lys Gly Ile Leu Thr Val Asp Glu Leu 405 410 415Leu Ala Ile Arg Ile Pro Leu Asn Asp Leu Phe Arg Cys Asn Ser Leu 420 425 430Ser Thr Leu Glu Lys Asn Asp Val Val Gln His Tyr Trp Asp Val Leu 435 440 445Val Gln Ala Phe Val Gln Asn Gly Thr Val Ser Thr Asn Glu Phe Leu 450 455 460Cys Asp Lys Asp Lys Thr Ser Thr Val Ala Pro Thr Ile His Thr Thr465 470 475 480Val Pro Ser Pro Thr Thr Thr Pro Thr Pro Lys Glu Lys Pro Glu Ala 485 490 495Gly Thr Tyr Ser Val Asn Asn Gly Asn Asp Thr Cys Leu Leu Ala Thr 500 505 510Met Gly Leu Gln Leu Asn Ile Thr Gln Asp Lys Val Ala Ser Val Ile 515 520 525Asn Ile Asn Pro Asn Thr Thr His Ser Thr Gly Ser Cys Arg Ser His 530 535 540Thr Ala Leu Leu Arg Leu Asn Ser Ser Thr Ile Lys Tyr Leu Asp Phe545 550 555 560Val Phe Ala Val Lys Asn Glu Asn Arg Phe Tyr Leu Lys Glu Val Asn 565 570 575Ile Ser Met Tyr Leu Val Asn Gly Ser Val Phe Ser Ile Ala Asn Asn 580 585 590Asn Leu Ser Tyr Trp Asp Ala Pro Leu Gly Ser Ser Tyr Met Cys Asn 595 600 605Lys Glu Gln Thr Val Ser Val Ser Gly Ala Phe Gln Ile Asn Thr Phe 610 615 620Asp Leu Arg Val Gln Pro Phe Asn Val Thr Gln Gly Lys Tyr Ser Thr625 630 635 640Ala Gln Asp Cys Ser Ala Asp Asp Asp Asn Phe Leu Val Pro Ile Ala 645 650 655Val Gly Ala Ala Leu Ala Gly Val Leu Ile Leu Val Leu Leu Ala Tyr 660 665 670Phe Ile Gly Leu Lys His His His Ala Gly Tyr Glu Gln Phe Gly Ser 675 680 685Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr Gly Gly Ser Arg Thr 690 695 700Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Gly His His705 710 715 720His His His His His His 72540710PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 40Met Val Cys Phe Arg Leu Phe Pro Val Pro Gly Ser Gly Leu Val Leu1 5 10 15Val Cys Leu Val Leu Gly Ala Val Arg Ser Tyr Ala Lys Ser Ser Val 20 25 30Gly Arg Gln Ala Glu Ser His Leu Ser Leu Leu Tyr His Leu Thr Ala 35 40 45Val Ser Ser Pro Ala Pro Gly Thr Pro Ala Phe Trp Val Ser Gly Trp 50 55 60Leu Gly Pro Gln Gln Tyr Leu Ser Tyr Asn Ser Leu Arg Gly Glu Ala65 70 75 80Glu Pro Cys Gly Ala Trp Val Trp Glu Asn Gln Val Ser Trp Tyr Trp 85 90 95Glu Lys Glu Thr Thr Asp Leu Arg Ile Lys Glu Lys Leu Phe Leu Glu 100 105 110Ala Phe Lys Ala Leu Gly Gly Lys Gly Pro Tyr Thr Leu Gln Gly Leu 115 120 125Leu Gly Cys Glu Leu Gly Pro Asp Asn Thr Ser Val Pro Thr Ala Lys 130 135 140Phe Ala Leu Asn Gly Glu Glu Phe Met Asn Phe Asp Leu Lys Gln Gly145 150 155 160Thr Trp Gly Gly Asp Trp Pro Glu Ala Leu Ala Ile Ser Gln Arg Trp 165 170 175Gln Gln Gln Asp Lys Ala Ala Asn Lys Glu Leu Thr Phe Leu Leu Phe 180 185 190Ser Cys Pro His Arg Leu Arg Glu His Leu Glu Arg Gly Arg Gly Asn 195 200 205Leu Glu Trp Lys Glu Pro Pro Ser Met Arg Leu Lys Ala Arg Pro Ser 210 215 220Ser Pro Gly Phe Ser Val Leu Thr Cys Ser Ala Phe Ser Phe Tyr Pro225 230 235 240Pro Glu Leu Gln Leu Arg Phe Leu Arg Asn Gly Leu Ala Ala Gly Thr 245 250 255Gly Gln Gly Asp Phe Gly Pro Asn Ser Asp Gly Ser Phe His Ala Ser 260 265 270Ser Ser Leu Thr Val Lys Ser Gly Asp Glu His His Tyr Cys Gly Gly 275 280 285Gly Gly Ser Gly Gly Gly Gly Ser Leu Glu Leu Asn Leu Thr Asp Ser 290 295 300Glu Asn Ala Thr Cys Leu Tyr Ala Lys Trp Gln Met Asn Phe Thr Val305 310 315 320Arg Tyr Glu Thr Thr Asn Lys Thr Tyr Lys Thr Val Thr Ile Ser Asp 325 330 335His Gly Thr Val Thr Tyr Asn Gly Ser Ile Cys Gly Asp Asp Gln Asn 340 345 350Gly Pro Lys Ile Ala Val Gln Phe Gly Pro Gly Phe Ser Trp Ile Ala 355 360 365Asn Phe Thr Lys Ala Ala Ser Thr Tyr Ser Ile Asp Ser Val Ser Phe 370 375 380Ser Tyr Asn Thr Gly Asp Asn Thr Thr Phe Pro Asp Ala Glu Asp Lys385 390 395 400Gly Ile Leu Thr Val Asp Glu Leu Leu Ala Ile Arg Ile Pro Leu Asn 405 410 415Asp Leu Phe Arg Cys Asn Ser Leu Ser Thr Leu Glu Lys Asn Asp Val 420 425 430Val Gln His Tyr Trp Asp Val Leu Val Gln Ala Phe Val Gln Asn Gly 435 440 445Thr Val Ser Thr Asn Glu Phe Leu Cys Asp Lys Asp Lys Thr Ser Thr 450 455 460Val Ala Pro Thr Ile His Thr Thr Val Pro Ser Pro Thr Thr Thr Pro465 470 475 480Thr Pro Lys Glu Lys Pro Glu Ala Gly Thr Tyr Ser Val Asn Asn Gly 485 490 495Asn Asp Thr Cys Leu Leu Ala Thr Met Gly Leu Gln Leu Asn Ile Thr 500 505 510Gln Asp Lys Val Ala Ser Val Ile Asn Ile Asn Pro Asn Thr Thr His 515 520 525Ser Thr Gly Ser Cys Arg Ser His Thr Ala Leu Leu Arg Leu Asn Ser 530 535 540Ser Thr Ile Lys Tyr Leu Asp Phe Val Phe Ala Val Lys Asn Glu Asn545 550 555 560Arg Phe Tyr Leu Lys Glu Val Asn Ile Ser Met Tyr Leu Val Asn Gly 565 570 575Ser Val Phe Ser Ile Ala Asn Asn Asn Leu Ser Tyr Trp Asp Ala Pro 580 585 590Leu Gly Ser Ser Tyr Met Cys Asn Lys Glu Gln Thr Val Ser Val Ser 595 600 605Gly Ala Phe Gln Ile Asn Thr Phe Asp Leu Arg Val Gln Pro Phe Asn 610 615 620Val Thr Gln Gly Lys Tyr Ser Thr Ala Gln Asp Cys Ser Ala Asp Asp625 630 635 640Asp Asn Phe Leu Val Pro Ile Ala Val Gly Ala Ala Leu Ala Gly Val 645 650 655Leu Ile Leu Val Leu Leu Ala Tyr Phe Ile Gly Leu Lys His His His 660 665 670Ala Gly Tyr Glu Gln Phe Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 675 680 685Gly Ser Thr Gly Gly Ser Arg Thr Gly Ser Gly Ser Gly Ser Gly Ser 690 695 700Gly Ser Gly Ser Pro Gly705 710411020PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 41Met Asp Gln Ala Arg Ser Ala Phe Ser Asn Leu Phe Gly Gly Glu Pro1 5 10 15Leu Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln Val Asp Gly Asp Asn 20 25 30Ser His Val Glu Met Lys Leu Ala Val Asp Glu Glu Glu Asn Ala Asp 35 40 45Asn Asn Thr Lys Ala Asn Val Thr Lys Pro Lys Arg Cys Ser Gly Ser 50 55 60Ile Cys Tyr Gly Thr Ile Ala Val Ile Val Phe Phe Leu Ile Gly Phe65 70 75 80Met Ile Gly Tyr Leu Gly Tyr Cys Lys Gly Val Glu Pro Lys Thr Glu 85 90 95Cys Glu Arg Leu Ala Gly Thr Glu Ser Pro Val Arg Glu Glu Pro Gly 100 105 110Glu Asp Phe Pro Ala Ala Arg Arg Leu Tyr Trp Asp Asp Leu Lys Arg 115 120 125Lys Leu Ser Glu Lys Leu Asp Ser Thr Asp Phe Thr Gly Thr Ile Lys 130 135 140Leu Leu Asn Glu Asn Ser Tyr Val Pro Arg Glu Ala Gly Ser Gln Lys145 150 155 160Asp Glu Asn Leu Ala Leu Tyr Val Glu Asn Gln Phe Arg Glu Phe Lys 165 170 175Leu Ser Lys Val Trp Arg Asp Gln His Phe Val Lys Ile Gln Val Lys 180 185 190Asp Ser Ala Gln Asn Ser Val Ile Ile Val Asp Lys Asn Gly Arg Leu 195 200 205Val Tyr Leu Val Glu Asn Pro Gly Gly Tyr Val Ala Tyr Ser Lys Ala 210 215 220Ala Thr Val Thr Gly Lys Leu Val His Ala Asn Phe Gly Thr Lys Lys225 230 235 240Asp Phe Glu Asp Leu Tyr Thr Pro Val Asn Gly Ser Ile Val Ile Val 245 250 255Arg Ala Gly Lys Ile Thr Phe Ala Glu Lys Val Ala Asn Ala Glu Ser 260 265 270Leu Asn Ala Ile Gly Val Leu Ile Tyr Met Asp Gln Thr Lys Phe Pro 275 280 285Ile Val Asn Ala Glu Leu Ser Phe Phe Gly His Ala His Leu Gly Thr 290 295 300Gly Asp Pro Tyr Thr Pro Gly Phe Pro Ser Phe Asn His Thr Gln Phe305 310 315 320Pro Pro Ser Arg Ser Ser Gly Leu Pro Asn Ile Pro Val Gln Thr Ile 325 330 335Ser Arg Ala Ala Ala Glu Lys Leu Phe Gly Asn Met Glu Gly Asp Cys 340 345 350Pro Ser Asp Trp Lys Thr Asp Ser Thr Cys Arg Met Val Thr Ser Glu 355 360 365Ser Lys Asn Val Lys Leu Thr Val Ser Asn Val Leu Lys Glu Ile Lys 370 375 380Ile Leu Asn Ile Phe Gly Val Ile Lys Gly Phe Val Glu Pro Asp His385 390 395 400Tyr Val Val Val Gly Ala Gln Arg Asp Ala Trp Gly Pro Gly Ala Ala 405 410 415Lys Ser Gly Val Gly Thr Ala Leu Leu Leu Lys Leu Ala Gln Met Phe 420 425 430Ser Asp Met Val Leu Lys Asp Gly Phe Gln Pro Ser Arg Ser Ile Ile 435 440 445Phe Ala Ser Trp Ser Ala Gly Asp Phe Gly Ser Val Gly Ala Thr Glu 450 455 460Trp Leu Glu Gly Tyr Leu Ser Ser Leu His Leu Lys Ala Phe Thr Tyr465 470 475 480Ile Asn Leu Asp Lys Ala Val Leu Gly Thr Ser Asn Phe Lys Val Ser 485 490 495Ala Ser Pro Leu Leu Tyr Thr Leu Ile Glu Lys Thr Met Gln Asn Val 500 505 510Lys His Pro Val Thr Gly Gln Phe Leu Tyr Gln Asp Ser Asn Trp Ala 515 520 525Ser Lys Val Glu Lys Leu Thr Leu Asp Asn Ala Ala Phe Pro Phe Leu 530 535 540Ala Tyr Ser Gly Ile Pro Ala Val Ser Phe Cys Phe Cys Glu Asp Thr545 550 555 560Asp Tyr Pro Tyr Leu Gly Thr Thr Met Asp Thr Tyr Lys Glu Leu Ile 565 570 575Glu Arg Ile Pro Glu Leu Asn Lys Val Ala Arg Ala Ala Ala Glu Val 580 585 590Ala Gly Gln Phe Val Ile Lys Leu Thr His Asp Val Glu Leu Asn Leu 595 600 605Asp Tyr Glu Arg Tyr Asn Ser Gln Leu Leu Ser Phe Val Arg Asp Leu 610 615 620Asn Gln Tyr Arg Ala Asp Ile Lys Glu Met Gly Leu Ser Leu Gln Trp625 630 635 640Leu Tyr Ser Ala Arg Gly Asp Phe Phe Arg Ala Thr Ser Arg Leu Thr 645 650 655Thr Asp Phe Gly Asn Ala Glu Lys Thr Asp Arg Phe Val Met Lys Lys 660 665 670Leu Asn Asp Arg Val Met Arg Val Glu Tyr His Phe Leu Ser Pro Tyr 675 680 685Val Ser Pro Lys Glu Ser Pro Phe Arg His Val Phe Trp Gly Ser Gly 690 695 700Ser His Thr Leu Pro Ala Leu Leu Glu Asn Leu Lys Leu Arg Lys Gln705 710 715 720Asn Asn Gly Ala Phe Asn Glu Thr Leu Phe Arg Asn Gln Leu Ala Leu 725 730 735Ala Thr Trp Thr Ile Gln Gly Ala Ala Asn Ala Leu Ser Gly Asp Val 740 745 750Trp Asp Ile Asp Asn Glu Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly 755 760 765Ser Ala Glu Ser His Leu Ser Leu Leu Tyr His Leu Thr Ala Val Ser 770 775 780Ser Pro Ala Pro Gly Thr Pro Ala Phe Trp Val Ser Gly Trp Leu Gly785 790 795 800Pro Gln Gln Tyr Leu Ser Tyr Asn Ser Leu Arg Gly Glu Ala Glu Pro 805 810 815Cys Gly Ala Trp Val Trp Glu Asn Gln Val Ser Trp Tyr Trp Glu Lys 820 825 830Glu Thr Thr Asp Leu Arg Ile Lys Glu Lys Leu Phe Leu Glu Ala Phe 835 840 845Lys Ala Leu Gly Gly Lys Gly Pro Tyr Thr Leu Gln Gly Leu Leu Gly 850 855 860Cys Glu Leu Gly Pro Asp Asn Thr Ser Val Pro Thr Ala Lys Phe Ala865 870 875 880Leu Asn Gly Glu Glu Phe Met Asn Phe Asp Leu Lys Gln Gly Thr Trp 885 890 895Gly Gly Asp Trp Pro Glu Ala Leu Ala Ile Ser Gln Arg Trp Gln Gln 900 905 910Gln Asp Lys Ala Ala Asn Lys Glu Leu Thr Phe Leu Leu Phe Ser Cys 915 920 925Pro His Arg Leu Arg Glu His Leu Glu Arg Gly Arg Gly Asn Leu Glu 930 935 940Trp Lys Glu Pro Pro Ser Met Arg Leu Lys Ala Arg Pro Ser Ser Pro945 950 955 960Gly Phe Ser Val Leu Thr Cys Ser Ala Phe Ser Phe Tyr Pro Pro Glu 965 970 975Leu Gln Leu Arg Phe Leu Arg Asn Gly Leu Ala Ala Gly Thr Gly Gln 980 985 990Gly Asp Phe Gly Pro Asn Ser Asp Gly Ser Phe His Ala Ser Ser Ser 995 1000 1005Leu Thr Val Lys Ser Gly Asp Glu His His Tyr Cys 1010 1015 102042610PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 42Met Gly Leu Ser Thr Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu1 5 10 15Glu Leu Leu Val Gly Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro 20 25 30His Leu Gly Asp Arg Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys 35 40 45Tyr Ile His Pro Gln Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys 50 55 60Gly Thr Tyr Leu Tyr Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp65 70 75 80Cys Arg Glu Cys Glu Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu 85 90 95Arg His Cys Leu Ser Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val 100 105 110Glu Ile Ser Ser Cys Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg 115 120

125Lys Asn Gln Tyr Arg His Tyr Trp Ser Glu Asn Leu Phe Gln Cys Phe 130 135 140Asn Cys Ser Leu Cys Leu Asn Gly Thr Val His Leu Ser Cys Gln Glu145 150 155 160Lys Gln Asn Thr Val Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu 165 170 175Asn Glu Cys Val Ser Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr 180 185 190Lys Leu Cys Leu Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 195 200 205Arg Ala Glu Ser His Leu Ser Leu Leu Tyr His Leu Thr Ala Val Ser 210 215 220Ser Pro Ala Pro Gly Thr Pro Ala Phe Trp Val Ser Gly Trp Leu Gly225 230 235 240Pro Gln Gln Tyr Leu Ser Tyr Asn Ser Leu Arg Gly Glu Ala Glu Pro 245 250 255Cys Gly Ala Trp Val Trp Glu Asn Gln Val Ser Trp Tyr Trp Glu Lys 260 265 270Glu Thr Thr Asp Leu Arg Ile Lys Glu Lys Leu Phe Leu Glu Ala Phe 275 280 285Lys Ala Leu Gly Gly Lys Gly Pro Tyr Thr Leu Gln Gly Leu Leu Gly 290 295 300Cys Glu Leu Gly Pro Asp Asn Thr Ser Val Pro Thr Ala Lys Phe Ala305 310 315 320Leu Asn Gly Glu Glu Phe Met Asn Phe Asp Leu Lys Gln Gly Thr Trp 325 330 335Gly Gly Asp Trp Pro Glu Ala Leu Ala Ile Ser Gln Arg Trp Gln Gln 340 345 350Gln Asp Lys Ala Ala Asn Lys Glu Leu Thr Phe Leu Leu Phe Ser Cys 355 360 365Pro His Arg Leu Arg Glu His Leu Glu Arg Gly Arg Gly Asn Leu Glu 370 375 380Trp Lys Glu Pro Pro Ser Met Arg Leu Lys Ala Arg Pro Ser Ser Pro385 390 395 400Gly Phe Ser Val Leu Thr Cys Ser Ala Phe Ser Phe Tyr Pro Pro Glu 405 410 415Leu Gln Leu Arg Phe Leu Arg Asn Gly Leu Ala Ala Gly Thr Gly Gln 420 425 430Gly Asp Phe Gly Pro Asn Ser Asp Gly Ser Phe His Ala Ser Ser Ser 435 440 445Leu Thr Val Lys Ser Gly Asp Glu His His Tyr Cys Pro Gln Gly Thr 450 455 460Glu Asp Ser Gly Thr Thr Val Leu Leu Pro Leu Val Ile Phe Phe Gly465 470 475 480Leu Cys Leu Leu Ser Leu Leu Phe Ile Gly Leu Met Tyr Arg Tyr Gln 485 490 495Arg Trp Lys Gly Thr Asn Gly Gly Gly Gly Ser Gly Arg Gly Tyr Ile 500 505 510Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu 515 520 525Trp Val Phe Leu Ser Thr Phe Leu Ser Pro Ala Asn Gly Gly Gly Gly 530 535 540Ser Gly Arg Ser Leu Tyr Pro Ser Leu Glu Asp Leu Lys Val Asp Lys545 550 555 560Val Ile Gln Ala Gln Thr Ala Phe Ser Ala Asn Pro Ala Asn Pro Ala 565 570 575Ile Leu Ser Glu Ala Ser Ala Pro Ile Pro His Asp Gly Asn Leu Tyr 580 585 590Pro Arg Leu Tyr Pro Glu Leu Ser Gln Tyr Met Gly Leu Ser Leu Glu 595 600 605Gly Gly 610431030PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 43Met Ser Ala Pro Arg Ile Trp Leu Ala Gln Ala Leu Leu Phe Phe Leu1 5 10 15Thr Thr Glu Ser Ile Gly Gln Leu Leu Glu Pro Cys Gly Tyr Ile Tyr 20 25 30Pro Glu Phe Pro Val Val Gln Arg Gly Ser Asn Phe Thr Ala Ile Cys 35 40 45Val Leu Lys Glu Ala Cys Leu Gln His Tyr Tyr Val Asn Ala Ser Tyr 50 55 60Ile Val Trp Lys Thr Asn His Ala Ala Val Pro Arg Glu Gln Val Thr65 70 75 80Val Ile Asn Arg Thr Thr Ser Ser Val Thr Phe Thr Asp Val Val Leu 85 90 95Pro Ser Val Gln Leu Thr Cys Asn Ile Leu Ser Phe Gly Gln Ile Glu 100 105 110Gln Asn Val Tyr Gly Val Thr Met Leu Ser Gly Phe Pro Pro Asp Lys 115 120 125Pro Thr Asn Leu Thr Cys Ile Val Asn Glu Gly Lys Asn Met Leu Cys 130 135 140Gln Trp Asp Pro Gly Arg Glu Thr Tyr Leu Glu Thr Asn Tyr Thr Leu145 150 155 160Lys Ser Glu Trp Ala Thr Glu Lys Phe Pro Asp Cys Gln Ser Lys His 165 170 175Gly Thr Ser Cys Met Val Ser Tyr Met Pro Thr Tyr Tyr Val Asn Ile 180 185 190Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Ser Ser Glu 195 200 205Ser Ile Asn Phe Asp Pro Val Asp Lys Val Lys Pro Thr Pro Pro Tyr 210 215 220Asn Leu Ser Val Thr Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu225 230 235 240Ser Trp Val Ser Ser Gly Leu Gly Gly Leu Leu Asp Leu Lys Ser Asp 245 250 255Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ile Gln Val Pro Leu 260 265 270Glu Asp Thr Met Ser Pro Arg Thr Ser Phe Thr Val Gln Asp Leu Lys 275 280 285Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Ser Ile Lys Asp Ser Gly 290 295 300Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Thr Thr Tyr305 310 315 320Glu Asp Arg Pro Ser Arg Pro Pro Ser Phe Trp Tyr Lys Thr Asn Pro 325 330 335Ser His Gly Gln Glu Tyr Arg Ser Val Arg Leu Ile Trp Lys Ala Leu 340 345 350Pro Leu Ser Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Ile Leu 355 360 365Thr Gln Ser Lys Ser Val Ser Gln Thr Tyr Thr Val Thr Gly Thr Glu 370 375 380Leu Thr Val Asn Leu Thr Asn Asp Arg Tyr Val Ala Ser Leu Ala Ala385 390 395 400Arg Asn Lys Val Gly Lys Ser Ala Ala Ala Val Leu Thr Ile Pro Ser 405 410 415Pro His Val Thr Ala Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Arg 420 425 430Met Lys Gln Lys Lys Leu Val Gly Glu Arg Gly Ser Gly Ser Gly Ser 435 440 445Gly Ser Gly Ser Ala Glu Ser His Leu Ser Leu Leu Tyr His Leu Thr 450 455 460Ala Val Ser Ser Pro Ala Pro Gly Thr Pro Ala Phe Trp Val Ser Gly465 470 475 480Trp Leu Gly Pro Gln Gln Tyr Leu Ser Tyr Asn Ser Leu Arg Gly Glu 485 490 495Ala Glu Pro Cys Gly Ala Trp Val Trp Glu Asn Gln Val Ser Trp Tyr 500 505 510Trp Glu Lys Glu Thr Thr Asp Leu Arg Ile Lys Glu Lys Leu Phe Leu 515 520 525Glu Ala Phe Lys Ala Leu Gly Gly Lys Gly Pro Tyr Thr Leu Gln Gly 530 535 540Leu Leu Gly Cys Glu Leu Gly Pro Asp Asn Thr Ser Val Pro Thr Ala545 550 555 560Lys Phe Ala Leu Asn Gly Glu Glu Phe Met Asn Phe Asp Leu Lys Gln 565 570 575Gly Thr Trp Gly Gly Asp Trp Pro Glu Ala Leu Ala Ile Ser Gln Arg 580 585 590Trp Gln Gln Gln Asp Lys Ala Ala Asn Lys Glu Leu Thr Phe Leu Leu 595 600 605Phe Ser Cys Pro His Arg Leu Arg Glu His Leu Glu Arg Gly Arg Gly 610 615 620Asn Leu Glu Trp Lys Glu Pro Pro Ser Met Arg Leu Lys Ala Arg Pro625 630 635 640Ser Ser Pro Gly Phe Ser Val Leu Thr Cys Ser Ala Phe Ser Phe Tyr 645 650 655Pro Pro Glu Leu Gln Leu Arg Phe Leu Arg Asn Gly Leu Ala Ala Gly 660 665 670Thr Gly Gln Gly Asp Phe Gly Pro Asn Ser Asp Gly Ser Phe His Ala 675 680 685Ser Ser Ser Leu Thr Val Lys Ser Gly Asp Glu His His Tyr Cys Ala 690 695 700Ala Pro Ala Arg Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn705 710 715 720Glu Ala Val Leu Ala Trp Asp Gln Ile Pro Val Asp Asp Gln Asn Gly 725 730 735Phe Ile Arg Asn Tyr Ser Ile Ser Tyr Arg Thr Ser Val Gly Lys Glu 740 745 750Met Val Val His Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser 755 760 765Leu Ser Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp 770 775 780Glu Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe785 790 795 800Ala Gln Gly Glu Ile Glu Ala Ile Val Val Pro Val Cys Leu Ala Phe 805 810 815Leu Leu Thr Thr Leu Leu Gly Val Leu Phe Cys Phe Asn Lys Arg Asp 820 825 830Leu Ile Lys Lys His Ile Trp Pro Asn Val Pro Asp Pro Ser Lys Ser 835 840 845His Ile Ala Gln Trp Ser Pro His Thr Pro Pro Arg His Asn Phe Asn 850 855 860Ser Lys Asp Gln Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Arg Met865 870 875 880Lys Gln Leu Glu Asp Lys Val Glu Glu Leu Leu Ser Lys Asn Tyr His 885 890 895Leu Glu Asn Glu Val Ala Arg Leu Lys Lys Leu Val Gly Glu Arg Gly 900 905 910Ser Gly Ser Gly Ser Gly Ser Gly Ser Ser Leu Tyr Pro Ser Leu Glu 915 920 925Asp Leu Lys Val Asp Lys Val Ile Gln Ala Gln Thr Ala Tyr Ser Ala 930 935 940Asn Pro Ala Ser Gln Ala Phe Val Leu Val Asp Ala Ser Ala Ala Leu945 950 955 960Pro Pro Asp Gly Asn Leu Tyr Pro Lys Leu Tyr Pro Glu Leu Ser Gln 965 970 975Tyr Met Gly Leu Ser Leu Asn Glu Ala Glu Ile Cys Glu Ser Met Pro 980 985 990Met Val Ser Gly Ala Pro Ala Gln Gly Gln Leu Val Ala Arg Pro Ser 995 1000 1005Ser Val Asn Tyr Met Val Ala Pro Val Thr Gly Asn Asp Ala Gly 1010 1015 1020Ile Arg Arg Ala Glu Ile Lys1025 103044747PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 44Ala Val Glu Gly Gly Met Lys Cys Val Lys Phe Leu Leu Tyr Val Leu1 5 10 15Leu Leu Ala Phe Cys Ala Cys Ala Val Gly Leu Ile Ala Val Gly Val 20 25 30Gly Ala Gln Leu Val Leu Ser Gln Thr Gly Thr Ala Glu Ser His Leu 35 40 45Ser Leu Leu Tyr His Leu Thr Ala Val Ser Ser Pro Ala Pro Gly Thr 50 55 60Pro Ala Phe Trp Val Ser Gly Trp Leu Gly Pro Gln Gln Tyr Leu Ser65 70 75 80Tyr Asn Ser Leu Arg Gly Glu Ala Glu Pro Cys Gly Ala Trp Val Trp 85 90 95Glu Asn Gln Val Ser Trp Tyr Trp Glu Lys Glu Thr Thr Asp Leu Arg 100 105 110Ile Lys Glu Lys Leu Phe Leu Glu Ala Phe Lys Ala Leu Gly Gly Lys 115 120 125Gly Pro Tyr Thr Leu Gln Gly Leu Leu Gly Cys Glu Leu Gly Pro Asp 130 135 140Asn Thr Ser Val Pro Thr Ala Lys Phe Ala Leu Asn Gly Glu Glu Phe145 150 155 160Met Asn Phe Asp Leu Lys Gln Gly Thr Trp Gly Gly Asp Trp Pro Glu 165 170 175Ala Leu Ala Ile Ser Gln Arg Trp Gln Gln Gln Asp Lys Ala Ala Asn 180 185 190Lys Glu Leu Thr Phe Leu Leu Phe Ser Cys Pro His Arg Leu Arg Glu 195 200 205His Leu Glu Arg Gly Arg Gly Asn Leu Glu Trp Lys Glu Pro Pro Ser 210 215 220Met Arg Leu Lys Ala Arg Pro Ser Ser Pro Gly Phe Ser Val Leu Thr225 230 235 240Cys Ser Ala Phe Ser Phe Tyr Pro Pro Glu Leu Gln Leu Arg Phe Leu 245 250 255Arg Asn Gly Leu Ala Ala Gly Thr Gly Gln Gly Asp Phe Gly Pro Asn 260 265 270Ser Asp Gly Ser Phe His Ala Ser Ser Ser Leu Thr Val Lys Ser Gly 275 280 285Asp Glu His His Tyr Cys Gly Thr Ile Ile Gln Gly Ala Thr Pro Gly 290 295 300Ser Leu Leu Pro Val Val Ile Ile Ala Val Gly Val Phe Leu Phe Leu305 310 315 320Val Ala Phe Val Gly Cys Cys Gly Ala Cys Lys Glu Asn Tyr Cys Leu 325 330 335Met Ile Thr Phe Ala Ile Phe Leu Ser Leu Ile Met Leu Val Glu Val 340 345 350Ala Ala Ala Ile Ala Gly Tyr Val Phe Arg Asp Lys Val Met Ser Glu 355 360 365Phe Asn Asn Asn Phe Arg Gln Gln Met Glu Asn Tyr Pro Lys Asn Asn 370 375 380His Thr Ala Ser Ile Leu Asp Arg Met Gln Ala Asp Phe Lys Cys Cys385 390 395 400Gly Ala Gly Ser Ala Glu Ser His Leu Ser Leu Leu Tyr His Leu Thr 405 410 415Ala Val Ser Ser Pro Ala Pro Gly Thr Pro Ala Phe Trp Val Ser Gly 420 425 430Trp Leu Gly Pro Gln Gln Tyr Leu Ser Tyr Asn Ser Leu Arg Gly Glu 435 440 445Ala Glu Pro Cys Gly Ala Trp Val Trp Glu Asn Gln Val Ser Trp Tyr 450 455 460Trp Glu Lys Glu Thr Thr Asp Leu Arg Ile Lys Glu Lys Leu Phe Leu465 470 475 480Glu Ala Phe Lys Ala Leu Gly Gly Lys Gly Pro Tyr Thr Leu Gln Gly 485 490 495Leu Leu Gly Cys Glu Leu Gly Pro Asp Asn Thr Ser Val Pro Thr Ala 500 505 510Lys Phe Ala Leu Asn Gly Glu Glu Phe Met Asn Phe Asp Leu Lys Gln 515 520 525Gly Thr Trp Gly Gly Asp Trp Pro Glu Ala Leu Ala Ile Ser Gln Arg 530 535 540Trp Gln Gln Gln Asp Lys Ala Ala Asn Lys Glu Leu Thr Phe Leu Leu545 550 555 560Phe Ser Cys Pro His Arg Leu Arg Glu His Leu Glu Arg Gly Arg Gly 565 570 575Asn Leu Glu Trp Lys Glu Pro Pro Ser Met Arg Leu Lys Ala Arg Pro 580 585 590Ser Ser Pro Gly Phe Ser Val Leu Thr Cys Ser Ala Phe Ser Phe Tyr 595 600 605Pro Pro Glu Leu Gln Leu Arg Phe Leu Arg Asn Gly Leu Ala Ala Gly 610 615 620Thr Gly Gln Gly Asp Phe Gly Pro Asn Ser Asp Gly Ser Phe His Ala625 630 635 640Ser Ser Ser Leu Thr Val Lys Ser Gly Asp Glu His His Tyr Cys Gly 645 650 655Ser Ala Asn Tyr Thr Asp Trp Glu Lys Ile Pro Ser Met Ser Lys Asn 660 665 670Arg Val Pro Asp Ser Cys Cys Ile Asn Val Thr Val Gly Cys Gly Ile 675 680 685Asn Phe Asn Glu Lys Ala Ile His Lys Glu Gly Cys Val Glu Lys Ile 690 695 700Gly Gly Trp Leu Arg Lys Asn Val Leu Val Val Ala Ala Ala Ala Leu705 710 715 720Gly Ile Ala Phe Val Glu Val Leu Gly Ile Val Phe Ala Cys Cys Leu 725 730 735Val Lys Ser Ile Arg Ser Gly Tyr Glu Val Met 740 74545610PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 45Met Gly Leu Ser Thr Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu1 5 10 15Glu Leu Leu Val Gly Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro 20 25 30His Leu Gly Asp Arg Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys 35 40 45Tyr Ile His Pro Gln Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys 50 55 60Gly Thr Tyr Leu Tyr Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp65 70 75 80Cys Arg Glu Cys Glu Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu 85 90 95Arg His Cys Leu Ser Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val 100 105 110Glu Ile Ser Ser Cys Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg 115 120 125Lys Asn Gln Tyr Arg His Tyr Trp Ser Glu Asn Leu Phe Gln Cys Phe 130 135 140Asn Cys Ser Leu Cys Leu Asn Gly Thr Val His

Leu Ser Cys Gln Glu145 150 155 160Lys Gln Asn Thr Val Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu 165 170 175Asn Glu Cys Val Ser Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr 180 185 190Lys Leu Cys Leu Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 195 200 205Arg Gln Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp 210 215 220Val Ser Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu225 230 235 240His Leu Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala 245 250 255Thr Gln Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn 260 265 270Asp Ser Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp 275 280 285Pro Ile Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser 290 295 300Ser Arg Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala305 310 315 320Trp Lys Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys 325 330 335Ala Phe Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr 340 345 350Asn Ile Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His 355 360 365Arg Tyr Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro 370 375 380Ala Pro Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn385 390 395 400Leu Val Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly 405 410 415Leu Gln Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly 420 425 430Arg Asn Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp 435 440 445Ser Gly Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Pro Gln Gly Thr 450 455 460Glu Asp Ser Gly Thr Thr Val Leu Leu Pro Leu Val Ile Phe Phe Gly465 470 475 480Leu Cys Leu Leu Ser Leu Leu Phe Ile Gly Leu Met Tyr Arg Tyr Gln 485 490 495Arg Trp Lys Gly Thr Asn Gly Gly Gly Gly Ser Gly Arg Gly Tyr Ile 500 505 510Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys Asp Gly Glu 515 520 525Trp Val Phe Leu Ser Thr Phe Leu Ser Pro Ala Asn Gly Gly Gly Gly 530 535 540Ser Gly Arg Ser Leu Tyr Pro Ser Leu Glu Asp Leu Lys Val Asp Lys545 550 555 560Val Ile Gln Ala Gln Thr Ala Phe Ser Ala Asn Pro Ala Asn Pro Ala 565 570 575Ile Leu Ser Glu Ala Ser Ala Pro Ile Pro His Asp Gly Asn Leu Tyr 580 585 590Pro Arg Leu Tyr Pro Glu Leu Ser Gln Tyr Met Gly Leu Ser Leu Glu 595 600 605Gly Gly 610461030PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 46Met Ser Ala Pro Arg Ile Trp Leu Ala Gln Ala Leu Leu Phe Phe Leu1 5 10 15Thr Thr Glu Ser Ile Gly Gln Leu Leu Glu Pro Cys Gly Tyr Ile Tyr 20 25 30Pro Glu Phe Pro Val Val Gln Arg Gly Ser Asn Phe Thr Ala Ile Cys 35 40 45Val Leu Lys Glu Ala Cys Leu Gln His Tyr Tyr Val Asn Ala Ser Tyr 50 55 60Ile Val Trp Lys Thr Asn His Ala Ala Val Pro Arg Glu Gln Val Thr65 70 75 80Val Ile Asn Arg Thr Thr Ser Ser Val Thr Phe Thr Asp Val Val Leu 85 90 95Pro Ser Val Gln Leu Thr Cys Asn Ile Leu Ser Phe Gly Gln Ile Glu 100 105 110Gln Asn Val Tyr Gly Val Thr Met Leu Ser Gly Phe Pro Pro Asp Lys 115 120 125Pro Thr Asn Leu Thr Cys Ile Val Asn Glu Gly Lys Asn Met Leu Cys 130 135 140Gln Trp Asp Pro Gly Arg Glu Thr Tyr Leu Glu Thr Asn Tyr Thr Leu145 150 155 160Lys Ser Glu Trp Ala Thr Glu Lys Phe Pro Asp Cys Gln Ser Lys His 165 170 175Gly Thr Ser Cys Met Val Ser Tyr Met Pro Thr Tyr Tyr Val Asn Ile 180 185 190Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Ser Ser Glu 195 200 205Ser Ile Asn Phe Asp Pro Val Asp Lys Val Lys Pro Thr Pro Pro Tyr 210 215 220Asn Leu Ser Val Thr Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu225 230 235 240Ser Trp Val Ser Ser Gly Leu Gly Gly Leu Leu Asp Leu Lys Ser Asp 245 250 255Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ile Gln Val Pro Leu 260 265 270Glu Asp Thr Met Ser Pro Arg Thr Ser Phe Thr Val Gln Asp Leu Lys 275 280 285Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Ser Ile Lys Asp Ser Gly 290 295 300Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Thr Thr Tyr305 310 315 320Glu Asp Arg Pro Ser Arg Pro Pro Ser Phe Trp Tyr Lys Thr Asn Pro 325 330 335Ser His Gly Gln Glu Tyr Arg Ser Val Arg Leu Ile Trp Lys Ala Leu 340 345 350Pro Leu Ser Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Ile Leu 355 360 365Thr Gln Ser Lys Ser Val Ser Gln Thr Tyr Thr Val Thr Gly Thr Glu 370 375 380Leu Thr Val Asn Leu Thr Asn Asp Arg Tyr Val Ala Ser Leu Ala Ala385 390 395 400Arg Asn Lys Val Gly Lys Ser Ala Ala Ala Val Leu Thr Ile Pro Ser 405 410 415Pro His Val Thr Ala Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Arg 420 425 430Met Lys Gln Lys Lys Leu Val Gly Glu Arg Gly Ser Gly Ser Gly Ser 435 440 445Gly Ser Gly Ser Gln Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln 450 455 460Pro Pro Trp Val Ser Val Phe Gln Glu Glu Thr Val Thr Leu His Cys465 470 475 480Glu Val Leu His Leu Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn 485 490 495Gly Thr Ala Thr Gln Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala 500 505 510Ser Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly 515 520 525Arg Ser Asp Pro Ile Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu 530 535 540Gln Val Ser Ser Arg Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg545 550 555 560Cys His Ala Trp Lys Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg 565 570 575Asn Gly Lys Ala Phe Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile 580 585 590Leu Lys Thr Asn Ile Ser His Asn Gly Thr Tyr His Cys Ser Gly Met 595 600 605Gly Lys His Arg Tyr Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu 610 615 620Leu Phe Pro Ala Pro Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu625 630 635 640Glu Gly Asn Leu Val Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln 645 650 655Arg Pro Gly Leu Gln Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr 660 665 670Leu Arg Gly Arg Asn Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg 675 680 685Arg Glu Asp Ser Gly Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Ala 690 695 700Ala Pro Ala Arg Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn705 710 715 720Glu Ala Val Leu Ala Trp Asp Gln Ile Pro Val Asp Asp Gln Asn Gly 725 730 735Phe Ile Arg Asn Tyr Ser Ile Ser Tyr Arg Thr Ser Val Gly Lys Glu 740 745 750Met Val Val His Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser 755 760 765Leu Ser Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp 770 775 780Glu Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe785 790 795 800Ala Gln Gly Glu Ile Glu Ala Ile Val Val Pro Val Cys Leu Ala Phe 805 810 815Leu Leu Thr Thr Leu Leu Gly Val Leu Phe Cys Phe Asn Lys Arg Asp 820 825 830Leu Ile Lys Lys His Ile Trp Pro Asn Val Pro Asp Pro Ser Lys Ser 835 840 845His Ile Ala Gln Trp Ser Pro His Thr Pro Pro Arg His Asn Phe Asn 850 855 860Ser Lys Asp Gln Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Arg Met865 870 875 880Lys Gln Leu Glu Asp Lys Val Glu Glu Leu Leu Ser Lys Asn Tyr His 885 890 895Leu Glu Asn Glu Val Ala Arg Leu Lys Lys Leu Val Gly Glu Arg Gly 900 905 910Ser Gly Ser Gly Ser Gly Ser Gly Ser Ser Leu Tyr Pro Ser Leu Glu 915 920 925Asp Leu Lys Val Asp Lys Val Ile Gln Ala Gln Thr Ala Tyr Ser Ala 930 935 940Asn Pro Ala Ser Gln Ala Phe Val Leu Val Asp Ala Ser Ala Ala Leu945 950 955 960Pro Pro Asp Gly Asn Leu Tyr Pro Lys Leu Tyr Pro Glu Leu Ser Gln 965 970 975Tyr Met Gly Leu Ser Leu Asn Glu Ala Glu Ile Cys Glu Ser Met Pro 980 985 990Met Val Ser Gly Ala Pro Ala Gln Gly Gln Leu Val Ala Arg Pro Ser 995 1000 1005Ser Val Asn Tyr Met Val Ala Pro Val Thr Gly Asn Asp Ala Gly 1010 1015 1020Ile Arg Arg Ala Glu Ile Lys1025 103047747PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 47Ala Val Glu Gly Gly Met Lys Cys Val Lys Phe Leu Leu Tyr Val Leu1 5 10 15Leu Leu Ala Phe Cys Ala Cys Ala Val Gly Leu Ile Ala Val Gly Val 20 25 30Gly Ala Gln Leu Val Leu Ser Gln Thr Gly Thr Gln Val Asp Thr Thr 35 40 45Lys Ala Val Ile Thr Leu Gln Pro Pro Trp Val Ser Val Phe Gln Glu 50 55 60Glu Thr Val Thr Leu His Cys Glu Val Leu His Leu Pro Gly Ser Ser65 70 75 80Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala Thr Gln Thr Ser Thr Pro 85 90 95Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn Asp Ser Gly Glu Tyr Arg 100 105 110Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp Pro Ile Gln Leu Glu Ile 115 120 125His Arg Gly Trp Leu Leu Leu Gln Val Ser Ser Arg Val Phe Thr Glu 130 135 140Gly Glu Pro Leu Ala Leu Arg Cys His Ala Trp Lys Asp Lys Leu Val145 150 155 160Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys Ala Phe Lys Phe Phe His 165 170 175Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr Asn Ile Ser His Asn Gly 180 185 190Thr Tyr His Cys Ser Gly Met Gly Lys His Arg Tyr Thr Ser Ala Gly 195 200 205Ile Ser Val Thr Val Lys Glu Leu Phe Pro Ala Pro Val Leu Asn Ala 210 215 220Ser Val Thr Ser Pro Leu Leu Glu Gly Asn Leu Val Thr Leu Ser Cys225 230 235 240Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu Tyr Phe Ser 245 250 255Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly Arg Asn Thr Ser Ser Glu 260 265 270Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp Ser Gly Leu Tyr Trp Cys 275 280 285Glu Ala Ala Thr Glu Asp Gly Thr Ile Ile Gln Gly Ala Thr Pro Gly 290 295 300Ser Leu Leu Pro Val Val Ile Ile Ala Val Gly Val Phe Leu Phe Leu305 310 315 320Val Ala Phe Val Gly Cys Cys Gly Ala Cys Lys Glu Asn Tyr Cys Leu 325 330 335Met Ile Thr Phe Ala Ile Phe Leu Ser Leu Ile Met Leu Val Glu Val 340 345 350Ala Ala Ala Ile Ala Gly Tyr Val Phe Arg Asp Lys Val Met Ser Glu 355 360 365Phe Asn Asn Asn Phe Arg Gln Gln Met Glu Asn Tyr Pro Lys Asn Asn 370 375 380His Thr Ala Ser Ile Leu Asp Arg Met Gln Ala Asp Phe Lys Cys Cys385 390 395 400Gly Ala Gly Ser Gln Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln 405 410 415Pro Pro Trp Val Ser Val Phe Gln Glu Glu Thr Val Thr Leu His Cys 420 425 430Glu Val Leu His Leu Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn 435 440 445Gly Thr Ala Thr Gln Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala 450 455 460Ser Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly465 470 475 480Arg Ser Asp Pro Ile Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu 485 490 495Gln Val Ser Ser Arg Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg 500 505 510Cys His Ala Trp Lys Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg 515 520 525Asn Gly Lys Ala Phe Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile 530 535 540Leu Lys Thr Asn Ile Ser His Asn Gly Thr Tyr His Cys Ser Gly Met545 550 555 560Gly Lys His Arg Tyr Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu 565 570 575Leu Phe Pro Ala Pro Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu 580 585 590Glu Gly Asn Leu Val Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln 595 600 605Arg Pro Gly Leu Gln Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr 610 615 620Leu Arg Gly Arg Asn Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg625 630 635 640Arg Glu Asp Ser Gly Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly 645 650 655Ser Ala Asn Tyr Thr Asp Trp Glu Lys Ile Pro Ser Met Ser Lys Asn 660 665 670Arg Val Pro Asp Ser Cys Cys Ile Asn Val Thr Val Gly Cys Gly Ile 675 680 685Asn Phe Asn Glu Lys Ala Ile His Lys Glu Gly Cys Val Glu Lys Ile 690 695 700Gly Gly Trp Leu Arg Lys Asn Val Leu Val Val Ala Ala Ala Ala Leu705 710 715 720Gly Ile Ala Phe Val Glu Val Leu Gly Ile Val Phe Ala Cys Cys Leu 725 730 735Val Lys Ser Ile Arg Ser Gly Tyr Glu Val Met 740 74548726PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 48Met Gln Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp1 5 10 15Val Ser Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu 20 25 30His Leu Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala 35 40 45Thr Gln Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn 50 55 60Asp Ser Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp65 70 75 80Pro Ile Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser 85 90 95Ser Arg Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala 100 105 110Trp Lys Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys 115 120 125Ala Phe Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr 130 135 140Asn Ile Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His145 150 155 160Arg Tyr Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro

165 170 175Ala Pro Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn 180 185 190Leu Val Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly 195 200 205Leu Gln Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly 210 215 220Arg Asn Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp225 230 235 240Ser Gly Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Ser Gly Ser 245 250 255Gly Gly Ser Gly Ser Gly Ser Val Cys Phe Arg Leu Phe Pro Val Pro 260 265 270Gly Ser Gly Leu Val Leu Val Cys Leu Val Leu Gly Ala Val Arg Ser 275 280 285Tyr Ala Lys Ser Ser Val Gly Arg Gln Gly Ser Gly Ser Gly Ser Gly 290 295 300Leu Glu Leu Asn Leu Thr Asp Ser Glu Asn Ala Thr Cys Leu Tyr Ala305 310 315 320Lys Trp Gln Met Asn Phe Thr Val Arg Tyr Glu Thr Thr Asn Lys Thr 325 330 335Tyr Lys Thr Val Thr Ile Ser Asp His Gly Thr Val Thr Tyr Asn Gly 340 345 350Ser Ile Cys Gly Asp Asp Gln Asn Gly Pro Lys Ile Ala Val Gln Phe 355 360 365Gly Pro Gly Phe Ser Trp Ile Ala Asn Phe Thr Lys Ala Ala Ser Thr 370 375 380Tyr Ser Ile Asp Ser Val Ser Phe Ser Tyr Asn Thr Gly Asp Asn Thr385 390 395 400Thr Phe Pro Asp Ala Glu Asp Lys Gly Ile Leu Thr Val Asp Glu Leu 405 410 415Leu Ala Ile Arg Ile Pro Leu Asn Asp Leu Phe Arg Cys Asn Ser Leu 420 425 430Ser Thr Leu Glu Lys Asn Asp Val Val Gln His Tyr Trp Asp Val Leu 435 440 445Val Gln Ala Phe Val Gln Asn Gly Thr Val Ser Thr Asn Glu Phe Leu 450 455 460Cys Asp Lys Asp Lys Thr Ser Thr Val Ala Pro Thr Ile His Thr Thr465 470 475 480Val Pro Ser Pro Thr Thr Thr Pro Thr Pro Lys Glu Lys Pro Glu Ala 485 490 495Gly Thr Tyr Ser Val Asn Asn Gly Asn Asp Thr Cys Leu Leu Ala Thr 500 505 510Met Gly Leu Gln Leu Asn Ile Thr Gln Asp Lys Val Ala Ser Val Ile 515 520 525Asn Ile Asn Pro Asn Thr Thr His Ser Thr Gly Ser Cys Arg Ser His 530 535 540Thr Ala Leu Leu Arg Leu Asn Ser Ser Thr Ile Lys Tyr Leu Asp Phe545 550 555 560Val Phe Ala Val Lys Asn Glu Asn Arg Phe Tyr Leu Lys Glu Val Asn 565 570 575Ile Ser Met Tyr Leu Val Asn Gly Ser Val Phe Ser Ile Ala Asn Asn 580 585 590Asn Leu Ser Tyr Trp Asp Ala Pro Leu Gly Ser Ser Tyr Met Cys Asn 595 600 605Lys Glu Gln Thr Val Ser Val Ser Gly Ala Phe Gln Ile Asn Thr Phe 610 615 620Asp Leu Arg Val Gln Pro Phe Asn Val Thr Gln Gly Lys Tyr Ser Thr625 630 635 640Ala Gln Asp Cys Ser Ala Asp Asp Asp Asn Phe Leu Val Pro Ile Ala 645 650 655Val Gly Ala Ala Leu Ala Gly Val Leu Ile Leu Val Leu Leu Ala Tyr 660 665 670Phe Ile Gly Leu Lys His His His Ala Gly Tyr Glu Gln Phe Gly Ser 675 680 685Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr Gly Gly Ser Arg Thr 690 695 700Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Gly His His705 710 715 720His His His His His His 72549710PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 49Met Val Cys Phe Arg Leu Phe Pro Val Pro Gly Ser Gly Leu Val Leu1 5 10 15Val Cys Leu Val Leu Gly Ala Val Arg Ser Tyr Ala Lys Ser Ser Val 20 25 30Gly Arg Gln Gln Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro 35 40 45Pro Trp Val Ser Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu 50 55 60Val Leu His Leu Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly65 70 75 80Thr Ala Thr Gln Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser 85 90 95Val Asn Asp Ser Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg 100 105 110Ser Asp Pro Ile Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln 115 120 125Val Ser Ser Arg Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys 130 135 140His Ala Trp Lys Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn145 150 155 160Gly Lys Ala Phe Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu 165 170 175Lys Thr Asn Ile Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly 180 185 190Lys His Arg Tyr Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu 195 200 205Phe Pro Ala Pro Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu 210 215 220Gly Asn Leu Val Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg225 230 235 240Pro Gly Leu Gln Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu 245 250 255Arg Gly Arg Asn Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg 260 265 270Glu Asp Ser Gly Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp Gly Gly 275 280 285Gly Gly Ser Gly Gly Gly Gly Ser Leu Glu Leu Asn Leu Thr Asp Ser 290 295 300Glu Asn Ala Thr Cys Leu Tyr Ala Lys Trp Gln Met Asn Phe Thr Val305 310 315 320Arg Tyr Glu Thr Thr Asn Lys Thr Tyr Lys Thr Val Thr Ile Ser Asp 325 330 335His Gly Thr Val Thr Tyr Asn Gly Ser Ile Cys Gly Asp Asp Gln Asn 340 345 350Gly Pro Lys Ile Ala Val Gln Phe Gly Pro Gly Phe Ser Trp Ile Ala 355 360 365Asn Phe Thr Lys Ala Ala Ser Thr Tyr Ser Ile Asp Ser Val Ser Phe 370 375 380Ser Tyr Asn Thr Gly Asp Asn Thr Thr Phe Pro Asp Ala Glu Asp Lys385 390 395 400Gly Ile Leu Thr Val Asp Glu Leu Leu Ala Ile Arg Ile Pro Leu Asn 405 410 415Asp Leu Phe Arg Cys Asn Ser Leu Ser Thr Leu Glu Lys Asn Asp Val 420 425 430Val Gln His Tyr Trp Asp Val Leu Val Gln Ala Phe Val Gln Asn Gly 435 440 445Thr Val Ser Thr Asn Glu Phe Leu Cys Asp Lys Asp Lys Thr Ser Thr 450 455 460Val Ala Pro Thr Ile His Thr Thr Val Pro Ser Pro Thr Thr Thr Pro465 470 475 480Thr Pro Lys Glu Lys Pro Glu Ala Gly Thr Tyr Ser Val Asn Asn Gly 485 490 495Asn Asp Thr Cys Leu Leu Ala Thr Met Gly Leu Gln Leu Asn Ile Thr 500 505 510Gln Asp Lys Val Ala Ser Val Ile Asn Ile Asn Pro Asn Thr Thr His 515 520 525Ser Thr Gly Ser Cys Arg Ser His Thr Ala Leu Leu Arg Leu Asn Ser 530 535 540Ser Thr Ile Lys Tyr Leu Asp Phe Val Phe Ala Val Lys Asn Glu Asn545 550 555 560Arg Phe Tyr Leu Lys Glu Val Asn Ile Ser Met Tyr Leu Val Asn Gly 565 570 575Ser Val Phe Ser Ile Ala Asn Asn Asn Leu Ser Tyr Trp Asp Ala Pro 580 585 590Leu Gly Ser Ser Tyr Met Cys Asn Lys Glu Gln Thr Val Ser Val Ser 595 600 605Gly Ala Phe Gln Ile Asn Thr Phe Asp Leu Arg Val Gln Pro Phe Asn 610 615 620Val Thr Gln Gly Lys Tyr Ser Thr Ala Gln Asp Cys Ser Ala Asp Asp625 630 635 640Asp Asn Phe Leu Val Pro Ile Ala Val Gly Ala Ala Leu Ala Gly Val 645 650 655Leu Ile Leu Val Leu Leu Ala Tyr Phe Ile Gly Leu Lys His His His 660 665 670Ala Gly Tyr Glu Gln Phe Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 675 680 685Gly Ser Thr Gly Gly Ser Arg Thr Gly Ser Gly Ser Gly Ser Gly Ser 690 695 700Gly Ser Gly Ser Pro Gly705 710501020PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 50Met Asp Gln Ala Arg Ser Ala Phe Ser Asn Leu Phe Gly Gly Glu Pro1 5 10 15Leu Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln Val Asp Gly Asp Asn 20 25 30Ser His Val Glu Met Lys Leu Ala Val Asp Glu Glu Glu Asn Ala Asp 35 40 45Asn Asn Thr Lys Ala Asn Val Thr Lys Pro Lys Arg Cys Ser Gly Ser 50 55 60Ile Cys Tyr Gly Thr Ile Ala Val Ile Val Phe Phe Leu Ile Gly Phe65 70 75 80Met Ile Gly Tyr Leu Gly Tyr Cys Lys Gly Val Glu Pro Lys Thr Glu 85 90 95Cys Glu Arg Leu Ala Gly Thr Glu Ser Pro Val Arg Glu Glu Pro Gly 100 105 110Glu Asp Phe Pro Ala Ala Arg Arg Leu Tyr Trp Asp Asp Leu Lys Arg 115 120 125Lys Leu Ser Glu Lys Leu Asp Ser Thr Asp Phe Thr Gly Thr Ile Lys 130 135 140Leu Leu Asn Glu Asn Ser Tyr Val Pro Arg Glu Ala Gly Ser Gln Lys145 150 155 160Asp Glu Asn Leu Ala Leu Tyr Val Glu Asn Gln Phe Arg Glu Phe Lys 165 170 175Leu Ser Lys Val Trp Arg Asp Gln His Phe Val Lys Ile Gln Val Lys 180 185 190Asp Ser Ala Gln Asn Ser Val Ile Ile Val Asp Lys Asn Gly Arg Leu 195 200 205Val Tyr Leu Val Glu Asn Pro Gly Gly Tyr Val Ala Tyr Ser Lys Ala 210 215 220Ala Thr Val Thr Gly Lys Leu Val His Ala Asn Phe Gly Thr Lys Lys225 230 235 240Asp Phe Glu Asp Leu Tyr Thr Pro Val Asn Gly Ser Ile Val Ile Val 245 250 255Arg Ala Gly Lys Ile Thr Phe Ala Glu Lys Val Ala Asn Ala Glu Ser 260 265 270Leu Asn Ala Ile Gly Val Leu Ile Tyr Met Asp Gln Thr Lys Phe Pro 275 280 285Ile Val Asn Ala Glu Leu Ser Phe Phe Gly His Ala His Leu Gly Thr 290 295 300Gly Asp Pro Tyr Thr Pro Gly Phe Pro Ser Phe Asn His Thr Gln Phe305 310 315 320Pro Pro Ser Arg Ser Ser Gly Leu Pro Asn Ile Pro Val Gln Thr Ile 325 330 335Ser Arg Ala Ala Ala Glu Lys Leu Phe Gly Asn Met Glu Gly Asp Cys 340 345 350Pro Ser Asp Trp Lys Thr Asp Ser Thr Cys Arg Met Val Thr Ser Glu 355 360 365Ser Lys Asn Val Lys Leu Thr Val Ser Asn Val Leu Lys Glu Ile Lys 370 375 380Ile Leu Asn Ile Phe Gly Val Ile Lys Gly Phe Val Glu Pro Asp His385 390 395 400Tyr Val Val Val Gly Ala Gln Arg Asp Ala Trp Gly Pro Gly Ala Ala 405 410 415Lys Ser Gly Val Gly Thr Ala Leu Leu Leu Lys Leu Ala Gln Met Phe 420 425 430Ser Asp Met Val Leu Lys Asp Gly Phe Gln Pro Ser Arg Ser Ile Ile 435 440 445Phe Ala Ser Trp Ser Ala Gly Asp Phe Gly Ser Val Gly Ala Thr Glu 450 455 460Trp Leu Glu Gly Tyr Leu Ser Ser Leu His Leu Lys Ala Phe Thr Tyr465 470 475 480Ile Asn Leu Asp Lys Ala Val Leu Gly Thr Ser Asn Phe Lys Val Ser 485 490 495Ala Ser Pro Leu Leu Tyr Thr Leu Ile Glu Lys Thr Met Gln Asn Val 500 505 510Lys His Pro Val Thr Gly Gln Phe Leu Tyr Gln Asp Ser Asn Trp Ala 515 520 525Ser Lys Val Glu Lys Leu Thr Leu Asp Asn Ala Ala Phe Pro Phe Leu 530 535 540Ala Tyr Ser Gly Ile Pro Ala Val Ser Phe Cys Phe Cys Glu Asp Thr545 550 555 560Asp Tyr Pro Tyr Leu Gly Thr Thr Met Asp Thr Tyr Lys Glu Leu Ile 565 570 575Glu Arg Ile Pro Glu Leu Asn Lys Val Ala Arg Ala Ala Ala Glu Val 580 585 590Ala Gly Gln Phe Val Ile Lys Leu Thr His Asp Val Glu Leu Asn Leu 595 600 605Asp Tyr Glu Arg Tyr Asn Ser Gln Leu Leu Ser Phe Val Arg Asp Leu 610 615 620Asn Gln Tyr Arg Ala Asp Ile Lys Glu Met Gly Leu Ser Leu Gln Trp625 630 635 640Leu Tyr Ser Ala Arg Gly Asp Phe Phe Arg Ala Thr Ser Arg Leu Thr 645 650 655Thr Asp Phe Gly Asn Ala Glu Lys Thr Asp Arg Phe Val Met Lys Lys 660 665 670Leu Asn Asp Arg Val Met Arg Val Glu Tyr His Phe Leu Ser Pro Tyr 675 680 685Val Ser Pro Lys Glu Ser Pro Phe Arg His Val Phe Trp Gly Ser Gly 690 695 700Ser His Thr Leu Pro Ala Leu Leu Glu Asn Leu Lys Leu Arg Lys Gln705 710 715 720Asn Asn Gly Ala Phe Asn Glu Thr Leu Phe Arg Asn Gln Leu Ala Leu 725 730 735Ala Thr Trp Thr Ile Gln Gly Ala Ala Asn Ala Leu Ser Gly Asp Val 740 745 750Trp Asp Ile Asp Asn Glu Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly 755 760 765Ser Gln Val Asp Thr Thr Lys Ala Val Ile Thr Leu Gln Pro Pro Trp 770 775 780Val Ser Val Phe Gln Glu Glu Thr Val Thr Leu His Cys Glu Val Leu785 790 795 800His Leu Pro Gly Ser Ser Ser Thr Gln Trp Phe Leu Asn Gly Thr Ala 805 810 815Thr Gln Thr Ser Thr Pro Ser Tyr Arg Ile Thr Ser Ala Ser Val Asn 820 825 830Asp Ser Gly Glu Tyr Arg Cys Gln Arg Gly Leu Ser Gly Arg Ser Asp 835 840 845Pro Ile Gln Leu Glu Ile His Arg Gly Trp Leu Leu Leu Gln Val Ser 850 855 860Ser Arg Val Phe Thr Glu Gly Glu Pro Leu Ala Leu Arg Cys His Ala865 870 875 880Trp Lys Asp Lys Leu Val Tyr Asn Val Leu Tyr Tyr Arg Asn Gly Lys 885 890 895Ala Phe Lys Phe Phe His Trp Asn Ser Asn Leu Thr Ile Leu Lys Thr 900 905 910Asn Ile Ser His Asn Gly Thr Tyr His Cys Ser Gly Met Gly Lys His 915 920 925Arg Tyr Thr Ser Ala Gly Ile Ser Val Thr Val Lys Glu Leu Phe Pro 930 935 940Ala Pro Val Leu Asn Ala Ser Val Thr Ser Pro Leu Leu Glu Gly Asn945 950 955 960Leu Val Thr Leu Ser Cys Glu Thr Lys Leu Leu Leu Gln Arg Pro Gly 965 970 975Leu Gln Leu Tyr Phe Ser Phe Tyr Met Gly Ser Lys Thr Leu Arg Gly 980 985 990Arg Asn Thr Ser Ser Glu Tyr Gln Ile Leu Thr Ala Arg Arg Glu Asp 995 1000 1005Ser Gly Leu Tyr Trp Cys Glu Ala Ala Thr Glu Asp 1010 1015 102051565PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 51Met Gly Leu Ser Thr Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu1 5 10 15Glu Leu Leu Val Gly Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro 20 25 30His Leu Gly Asp Arg Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys 35 40 45Tyr Ile His Pro Gln Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys 50 55 60Gly Thr Tyr Leu Tyr Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp65 70 75 80Cys Arg Glu Cys Glu Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu 85 90 95Arg His Cys Leu Ser Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val 100 105 110Glu Ile Ser Ser Cys Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg 115 120 125Lys Asn Gln Tyr Arg His Tyr

Trp Ser Glu Asn Leu Phe Gln Cys Phe 130 135 140Asn Cys Ser Leu Cys Leu Asn Gly Thr Val His Leu Ser Cys Gln Glu145 150 155 160Lys Gln Asn Thr Val Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu 165 170 175Asn Glu Cys Val Ser Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr 180 185 190Lys Leu Cys Leu Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 195 200 205Arg Gln Glu Gly Asp Phe Pro Met Pro Phe Ile Ser Ala Lys Ser Ser 210 215 220Pro Val Ile Pro Leu Asp Gly Ser Val Lys Ile Gln Cys Gln Ala Ile225 230 235 240Arg Glu Ala Tyr Leu Thr Gln Leu Met Ile Ile Lys Asn Ser Thr Tyr 245 250 255Arg Glu Ile Gly Arg Arg Leu Lys Phe Trp Asn Glu Thr Asp Pro Glu 260 265 270Phe Val Ile Asp His Met Asp Ala Asn Lys Ala Gly Arg Tyr Gln Cys 275 280 285Gln Tyr Arg Ile Gly His Tyr Arg Phe Arg Tyr Ser Asp Thr Leu Glu 290 295 300Leu Val Val Thr Gly Leu Tyr Gly Lys Pro Phe Leu Ser Ala Asp Arg305 310 315 320Gly Leu Val Leu Met Pro Gly Glu Asn Ile Ser Leu Thr Cys Ser Ser 325 330 335Ala His Ile Pro Phe Asp Arg Phe Ser Leu Ala Lys Glu Gly Glu Leu 340 345 350Ser Leu Pro Gln His Gln Ser Gly Glu His Pro Ala Asn Phe Ser Leu 355 360 365Gly Pro Val Asp Leu Asn Val Ser Gly Ile Tyr Arg Cys Tyr Gly Trp 370 375 380Tyr Asn Arg Ser Pro Tyr Leu Trp Ser Phe Pro Ser Asn Ala Leu Glu385 390 395 400Leu Val Val Thr Asp Ser Ile His Gln Asp Tyr Thr Thr Gln Asn Pro 405 410 415Gln Gly Thr Glu Asp Ser Gly Thr Thr Val Leu Leu Pro Leu Val Ile 420 425 430Phe Phe Gly Leu Cys Leu Leu Ser Leu Leu Phe Ile Gly Leu Met Tyr 435 440 445Arg Tyr Gln Arg Trp Lys Gly Thr Asn Gly Gly Gly Gly Ser Gly Arg 450 455 460Gly Tyr Ile Pro Glu Ala Pro Arg Asp Gly Gln Ala Tyr Val Arg Lys465 470 475 480Asp Gly Glu Trp Val Phe Leu Ser Thr Phe Leu Ser Pro Ala Asn Gly 485 490 495Gly Gly Gly Ser Gly Arg Ser Leu Tyr Pro Ser Leu Glu Asp Leu Lys 500 505 510Val Asp Lys Val Ile Gln Ala Gln Thr Ala Phe Ser Ala Asn Pro Ala 515 520 525Asn Pro Ala Ile Leu Ser Glu Ala Ser Ala Pro Ile Pro His Asp Gly 530 535 540Asn Leu Tyr Pro Arg Leu Tyr Pro Glu Leu Ser Gln Tyr Met Gly Leu545 550 555 560Ser Leu Glu Gly Gly 56552985PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 52Met Ser Ala Pro Arg Ile Trp Leu Ala Gln Ala Leu Leu Phe Phe Leu1 5 10 15Thr Thr Glu Ser Ile Gly Gln Leu Leu Glu Pro Cys Gly Tyr Ile Tyr 20 25 30Pro Glu Phe Pro Val Val Gln Arg Gly Ser Asn Phe Thr Ala Ile Cys 35 40 45Val Leu Lys Glu Ala Cys Leu Gln His Tyr Tyr Val Asn Ala Ser Tyr 50 55 60Ile Val Trp Lys Thr Asn His Ala Ala Val Pro Arg Glu Gln Val Thr65 70 75 80Val Ile Asn Arg Thr Thr Ser Ser Val Thr Phe Thr Asp Val Val Leu 85 90 95Pro Ser Val Gln Leu Thr Cys Asn Ile Leu Ser Phe Gly Gln Ile Glu 100 105 110Gln Asn Val Tyr Gly Val Thr Met Leu Ser Gly Phe Pro Pro Asp Lys 115 120 125Pro Thr Asn Leu Thr Cys Ile Val Asn Glu Gly Lys Asn Met Leu Cys 130 135 140Gln Trp Asp Pro Gly Arg Glu Thr Tyr Leu Glu Thr Asn Tyr Thr Leu145 150 155 160Lys Ser Glu Trp Ala Thr Glu Lys Phe Pro Asp Cys Gln Ser Lys His 165 170 175Gly Thr Ser Cys Met Val Ser Tyr Met Pro Thr Tyr Tyr Val Asn Ile 180 185 190Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Ser Ser Glu 195 200 205Ser Ile Asn Phe Asp Pro Val Asp Lys Val Lys Pro Thr Pro Pro Tyr 210 215 220Asn Leu Ser Val Thr Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu225 230 235 240Ser Trp Val Ser Ser Gly Leu Gly Gly Leu Leu Asp Leu Lys Ser Asp 245 250 255Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ile Gln Val Pro Leu 260 265 270Glu Asp Thr Met Ser Pro Arg Thr Ser Phe Thr Val Gln Asp Leu Lys 275 280 285Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Ser Ile Lys Asp Ser Gly 290 295 300Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Thr Thr Tyr305 310 315 320Glu Asp Arg Pro Ser Arg Pro Pro Ser Phe Trp Tyr Lys Thr Asn Pro 325 330 335Ser His Gly Gln Glu Tyr Arg Ser Val Arg Leu Ile Trp Lys Ala Leu 340 345 350Pro Leu Ser Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Ile Leu 355 360 365Thr Gln Ser Lys Ser Val Ser Gln Thr Tyr Thr Val Thr Gly Thr Glu 370 375 380Leu Thr Val Asn Leu Thr Asn Asp Arg Tyr Val Ala Ser Leu Ala Ala385 390 395 400Arg Asn Lys Val Gly Lys Ser Ala Ala Ala Val Leu Thr Ile Pro Ser 405 410 415Pro His Val Thr Ala Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Arg 420 425 430Met Lys Gln Lys Lys Leu Val Gly Glu Arg Gly Ser Gly Ser Gly Ser 435 440 445Gly Ser Gly Ser Gln Glu Gly Asp Phe Pro Met Pro Phe Ile Ser Ala 450 455 460Lys Ser Ser Pro Val Ile Pro Leu Asp Gly Ser Val Lys Ile Gln Cys465 470 475 480Gln Ala Ile Arg Glu Ala Tyr Leu Thr Gln Leu Met Ile Ile Lys Asn 485 490 495Ser Thr Tyr Arg Glu Ile Gly Arg Arg Leu Lys Phe Trp Asn Glu Thr 500 505 510Asp Pro Glu Phe Val Ile Asp His Met Asp Ala Asn Lys Ala Gly Arg 515 520 525Tyr Gln Cys Gln Tyr Arg Ile Gly His Tyr Arg Phe Arg Tyr Ser Asp 530 535 540Thr Leu Glu Leu Val Val Thr Gly Leu Tyr Gly Lys Pro Phe Leu Ser545 550 555 560Ala Asp Arg Gly Leu Val Leu Met Pro Gly Glu Asn Ile Ser Leu Thr 565 570 575Cys Ser Ser Ala His Ile Pro Phe Asp Arg Phe Ser Leu Ala Lys Glu 580 585 590Gly Glu Leu Ser Leu Pro Gln His Gln Ser Gly Glu His Pro Ala Asn 595 600 605Phe Ser Leu Gly Pro Val Asp Leu Asn Val Ser Gly Ile Tyr Arg Cys 610 615 620Tyr Gly Trp Tyr Asn Arg Ser Pro Tyr Leu Trp Ser Phe Pro Ser Asn625 630 635 640Ala Leu Glu Leu Val Val Thr Asp Ser Ile His Gln Asp Tyr Thr Thr 645 650 655Gln Asn Ala Ala Pro Ala Arg Gly Pro Thr Val Arg Thr Lys Lys Val 660 665 670Gly Lys Asn Glu Ala Val Leu Ala Trp Asp Gln Ile Pro Val Asp Asp 675 680 685Gln Asn Gly Phe Ile Arg Asn Tyr Ser Ile Ser Tyr Arg Thr Ser Val 690 695 700Gly Lys Glu Met Val Val His Val Asp Ser Ser His Thr Glu Tyr Thr705 710 715 720Leu Ser Ser Leu Ser Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala 725 730 735Tyr Thr Asp Glu Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr 740 745 750Pro Lys Phe Ala Gln Gly Glu Ile Glu Ala Ile Val Val Pro Val Cys 755 760 765Leu Ala Phe Leu Leu Thr Thr Leu Leu Gly Val Leu Phe Cys Phe Asn 770 775 780Lys Arg Asp Leu Ile Lys Lys His Ile Trp Pro Asn Val Pro Asp Pro785 790 795 800Ser Lys Ser His Ile Ala Gln Trp Ser Pro His Thr Pro Pro Arg His 805 810 815Asn Phe Asn Ser Lys Asp Gln Gly Ser Gly Ser Gly Ser Gly Ser Gly 820 825 830Ser Arg Met Lys Gln Leu Glu Asp Lys Val Glu Glu Leu Leu Ser Lys 835 840 845Asn Tyr His Leu Glu Asn Glu Val Ala Arg Leu Lys Lys Leu Val Gly 850 855 860Glu Arg Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Ser Leu Tyr Pro865 870 875 880Ser Leu Glu Asp Leu Lys Val Asp Lys Val Ile Gln Ala Gln Thr Ala 885 890 895Tyr Ser Ala Asn Pro Ala Ser Gln Ala Phe Val Leu Val Asp Ala Ser 900 905 910Ala Ala Leu Pro Pro Asp Gly Asn Leu Tyr Pro Lys Leu Tyr Pro Glu 915 920 925Leu Ser Gln Tyr Met Gly Leu Ser Leu Asn Glu Ala Glu Ile Cys Glu 930 935 940Ser Met Pro Met Val Ser Gly Ala Pro Ala Gln Gly Gln Leu Val Ala945 950 955 960Arg Pro Ser Ser Val Asn Tyr Met Val Ala Pro Val Thr Gly Asn Asp 965 970 975Ala Gly Ile Arg Arg Ala Glu Ile Lys 980 98553657PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 53Ala Val Glu Gly Gly Met Lys Cys Val Lys Phe Leu Leu Tyr Val Leu1 5 10 15Leu Leu Ala Phe Cys Ala Cys Ala Val Gly Leu Ile Ala Val Gly Val 20 25 30Gly Ala Gln Leu Val Leu Ser Gln Thr Gly Thr Gln Glu Gly Asp Phe 35 40 45Pro Met Pro Phe Ile Ser Ala Lys Ser Ser Pro Val Ile Pro Leu Asp 50 55 60Gly Ser Val Lys Ile Gln Cys Gln Ala Ile Arg Glu Ala Tyr Leu Thr65 70 75 80Gln Leu Met Ile Ile Lys Asn Ser Thr Tyr Arg Glu Ile Gly Arg Arg 85 90 95Leu Lys Phe Trp Asn Glu Thr Asp Pro Glu Phe Val Ile Asp His Met 100 105 110Asp Ala Asn Lys Ala Gly Arg Tyr Gln Cys Gln Tyr Arg Ile Gly His 115 120 125Tyr Arg Phe Arg Tyr Ser Asp Thr Leu Glu Leu Val Val Thr Gly Leu 130 135 140Tyr Gly Lys Pro Phe Leu Ser Ala Asp Arg Gly Leu Val Leu Met Pro145 150 155 160Gly Glu Asn Ile Ser Leu Thr Cys Ser Ser Ala His Ile Pro Phe Asp 165 170 175Arg Phe Ser Leu Ala Lys Glu Gly Glu Leu Ser Leu Pro Gln His Gln 180 185 190Ser Gly Glu His Pro Ala Asn Phe Ser Leu Gly Pro Val Asp Leu Asn 195 200 205Val Ser Gly Ile Tyr Arg Cys Tyr Gly Trp Tyr Asn Arg Ser Pro Tyr 210 215 220Leu Trp Ser Phe Pro Ser Asn Ala Leu Glu Leu Val Val Thr Asp Ser225 230 235 240Ile His Gln Asp Tyr Thr Thr Gln Asn Gly Thr Ile Ile Gln Gly Ala 245 250 255Thr Pro Gly Ser Leu Leu Pro Val Val Ile Ile Ala Val Gly Val Phe 260 265 270Leu Phe Leu Val Ala Phe Val Gly Cys Cys Gly Ala Cys Lys Glu Asn 275 280 285Tyr Cys Leu Met Ile Thr Phe Ala Ile Phe Leu Ser Leu Ile Met Leu 290 295 300Val Glu Val Ala Ala Ala Ile Ala Gly Tyr Val Phe Arg Asp Lys Val305 310 315 320Met Ser Glu Phe Asn Asn Asn Phe Arg Gln Gln Met Glu Asn Tyr Pro 325 330 335Lys Asn Asn His Thr Ala Ser Ile Leu Asp Arg Met Gln Ala Asp Phe 340 345 350Lys Cys Cys Gly Ala Gly Ser Gln Glu Gly Asp Phe Pro Met Pro Phe 355 360 365Ile Ser Ala Lys Ser Ser Pro Val Ile Pro Leu Asp Gly Ser Val Lys 370 375 380Ile Gln Cys Gln Ala Ile Arg Glu Ala Tyr Leu Thr Gln Leu Met Ile385 390 395 400Ile Lys Asn Ser Thr Tyr Arg Glu Ile Gly Arg Arg Leu Lys Phe Trp 405 410 415Asn Glu Thr Asp Pro Glu Phe Val Ile Asp His Met Asp Ala Asn Lys 420 425 430Ala Gly Arg Tyr Gln Cys Gln Tyr Arg Ile Gly His Tyr Arg Phe Arg 435 440 445Tyr Ser Asp Thr Leu Glu Leu Val Val Thr Gly Leu Tyr Gly Lys Pro 450 455 460Phe Leu Ser Ala Asp Arg Gly Leu Val Leu Met Pro Gly Glu Asn Ile465 470 475 480Ser Leu Thr Cys Ser Ser Ala His Ile Pro Phe Asp Arg Phe Ser Leu 485 490 495Ala Lys Glu Gly Glu Leu Ser Leu Pro Gln His Gln Ser Gly Glu His 500 505 510Pro Ala Asn Phe Ser Leu Gly Pro Val Asp Leu Asn Val Ser Gly Ile 515 520 525Tyr Arg Cys Tyr Gly Trp Tyr Asn Arg Ser Pro Tyr Leu Trp Ser Phe 530 535 540Pro Ser Asn Ala Leu Glu Leu Val Val Thr Asp Ser Ile His Gln Asp545 550 555 560Tyr Thr Thr Gln Asn Gly Ser Ala Asn Tyr Thr Asp Trp Glu Lys Ile 565 570 575Pro Ser Met Ser Lys Asn Arg Val Pro Asp Ser Cys Cys Ile Asn Val 580 585 590Thr Val Gly Cys Gly Ile Asn Phe Asn Glu Lys Ala Ile His Lys Glu 595 600 605Gly Cys Val Glu Lys Ile Gly Gly Trp Leu Arg Lys Asn Val Leu Val 610 615 620Val Ala Ala Ala Ala Leu Gly Ile Ala Phe Val Glu Val Leu Gly Ile625 630 635 640Val Phe Ala Cys Cys Leu Val Lys Ser Ile Arg Ser Gly Tyr Glu Val 645 650 655Met54681PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 54Met Gln Glu Gly Asp Phe Pro Met Pro Phe Ile Ser Ala Lys Ser Ser1 5 10 15Pro Val Ile Pro Leu Asp Gly Ser Val Lys Ile Gln Cys Gln Ala Ile 20 25 30Arg Glu Ala Tyr Leu Thr Gln Leu Met Ile Ile Lys Asn Ser Thr Tyr 35 40 45Arg Glu Ile Gly Arg Arg Leu Lys Phe Trp Asn Glu Thr Asp Pro Glu 50 55 60Phe Val Ile Asp His Met Asp Ala Asn Lys Ala Gly Arg Tyr Gln Cys65 70 75 80Gln Tyr Arg Ile Gly His Tyr Arg Phe Arg Tyr Ser Asp Thr Leu Glu 85 90 95Leu Val Val Thr Gly Leu Tyr Gly Lys Pro Phe Leu Ser Ala Asp Arg 100 105 110Gly Leu Val Leu Met Pro Gly Glu Asn Ile Ser Leu Thr Cys Ser Ser 115 120 125Ala His Ile Pro Phe Asp Arg Phe Ser Leu Ala Lys Glu Gly Glu Leu 130 135 140Ser Leu Pro Gln His Gln Ser Gly Glu His Pro Ala Asn Phe Ser Leu145 150 155 160Gly Pro Val Asp Leu Asn Val Ser Gly Ile Tyr Arg Cys Tyr Gly Trp 165 170 175Tyr Asn Arg Ser Pro Tyr Leu Trp Ser Phe Pro Ser Asn Ala Leu Glu 180 185 190Leu Val Val Thr Asp Ser Ile His Gln Asp Tyr Thr Thr Gln Asn Gly 195 200 205Ser Gly Ser Gly Gly Ser Gly Ser Gly Ser Val Cys Phe Arg Leu Phe 210 215 220Pro Val Pro Gly Ser Gly Leu Val Leu Val Cys Leu Val Leu Gly Ala225 230 235 240Val Arg Ser Tyr Ala Lys Ser Ser Val Gly Arg Gln Gly Ser Gly Ser 245 250 255Gly Ser Gly Leu Glu Leu Asn Leu Thr Asp Ser Glu Asn Ala Thr Cys 260 265 270Leu Tyr Ala Lys Trp Gln Met Asn Phe Thr Val Arg Tyr Glu Thr Thr 275 280 285Asn Lys Thr Tyr Lys Thr Val Thr Ile Ser Asp His Gly Thr Val Thr 290 295 300Tyr Asn Gly Ser Ile Cys Gly Asp Asp Gln Asn Gly Pro Lys Ile Ala305 310 315 320Val Gln Phe Gly Pro Gly Phe Ser Trp Ile Ala Asn Phe Thr Lys Ala 325 330 335Ala Ser Thr Tyr

Ser Ile Asp Ser Val Ser Phe Ser Tyr Asn Thr Gly 340 345 350Asp Asn Thr Thr Phe Pro Asp Ala Glu Asp Lys Gly Ile Leu Thr Val 355 360 365Asp Glu Leu Leu Ala Ile Arg Ile Pro Leu Asn Asp Leu Phe Arg Cys 370 375 380Asn Ser Leu Ser Thr Leu Glu Lys Asn Asp Val Val Gln His Tyr Trp385 390 395 400Asp Val Leu Val Gln Ala Phe Val Gln Asn Gly Thr Val Ser Thr Asn 405 410 415Glu Phe Leu Cys Asp Lys Asp Lys Thr Ser Thr Val Ala Pro Thr Ile 420 425 430His Thr Thr Val Pro Ser Pro Thr Thr Thr Pro Thr Pro Lys Glu Lys 435 440 445Pro Glu Ala Gly Thr Tyr Ser Val Asn Asn Gly Asn Asp Thr Cys Leu 450 455 460Leu Ala Thr Met Gly Leu Gln Leu Asn Ile Thr Gln Asp Lys Val Ala465 470 475 480Ser Val Ile Asn Ile Asn Pro Asn Thr Thr His Ser Thr Gly Ser Cys 485 490 495Arg Ser His Thr Ala Leu Leu Arg Leu Asn Ser Ser Thr Ile Lys Tyr 500 505 510Leu Asp Phe Val Phe Ala Val Lys Asn Glu Asn Arg Phe Tyr Leu Lys 515 520 525Glu Val Asn Ile Ser Met Tyr Leu Val Asn Gly Ser Val Phe Ser Ile 530 535 540Ala Asn Asn Asn Leu Ser Tyr Trp Asp Ala Pro Leu Gly Ser Ser Tyr545 550 555 560Met Cys Asn Lys Glu Gln Thr Val Ser Val Ser Gly Ala Phe Gln Ile 565 570 575Asn Thr Phe Asp Leu Arg Val Gln Pro Phe Asn Val Thr Gln Gly Lys 580 585 590Tyr Ser Thr Ala Gln Asp Cys Ser Ala Asp Asp Asp Asn Phe Leu Val 595 600 605Pro Ile Ala Val Gly Ala Ala Leu Ala Gly Val Leu Ile Leu Val Leu 610 615 620Leu Ala Tyr Phe Ile Gly Leu Lys His His His Ala Gly Tyr Glu Gln625 630 635 640Phe Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr Gly Gly 645 650 655Ser Arg Thr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro 660 665 670Gly His His His His His His His His 675 68055665PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 55Met Val Cys Phe Arg Leu Phe Pro Val Pro Gly Ser Gly Leu Val Leu1 5 10 15Val Cys Leu Val Leu Gly Ala Val Arg Ser Tyr Ala Lys Ser Ser Val 20 25 30Gly Arg Gln Gln Glu Gly Asp Phe Pro Met Pro Phe Ile Ser Ala Lys 35 40 45Ser Ser Pro Val Ile Pro Leu Asp Gly Ser Val Lys Ile Gln Cys Gln 50 55 60Ala Ile Arg Glu Ala Tyr Leu Thr Gln Leu Met Ile Ile Lys Asn Ser65 70 75 80Thr Tyr Arg Glu Ile Gly Arg Arg Leu Lys Phe Trp Asn Glu Thr Asp 85 90 95Pro Glu Phe Val Ile Asp His Met Asp Ala Asn Lys Ala Gly Arg Tyr 100 105 110Gln Cys Gln Tyr Arg Ile Gly His Tyr Arg Phe Arg Tyr Ser Asp Thr 115 120 125Leu Glu Leu Val Val Thr Gly Leu Tyr Gly Lys Pro Phe Leu Ser Ala 130 135 140Asp Arg Gly Leu Val Leu Met Pro Gly Glu Asn Ile Ser Leu Thr Cys145 150 155 160Ser Ser Ala His Ile Pro Phe Asp Arg Phe Ser Leu Ala Lys Glu Gly 165 170 175Glu Leu Ser Leu Pro Gln His Gln Ser Gly Glu His Pro Ala Asn Phe 180 185 190Ser Leu Gly Pro Val Asp Leu Asn Val Ser Gly Ile Tyr Arg Cys Tyr 195 200 205Gly Trp Tyr Asn Arg Ser Pro Tyr Leu Trp Ser Phe Pro Ser Asn Ala 210 215 220Leu Glu Leu Val Val Thr Asp Ser Ile His Gln Asp Tyr Thr Thr Gln225 230 235 240Asn Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Glu Leu Asn Leu 245 250 255Thr Asp Ser Glu Asn Ala Thr Cys Leu Tyr Ala Lys Trp Gln Met Asn 260 265 270Phe Thr Val Arg Tyr Glu Thr Thr Asn Lys Thr Tyr Lys Thr Val Thr 275 280 285Ile Ser Asp His Gly Thr Val Thr Tyr Asn Gly Ser Ile Cys Gly Asp 290 295 300Asp Gln Asn Gly Pro Lys Ile Ala Val Gln Phe Gly Pro Gly Phe Ser305 310 315 320Trp Ile Ala Asn Phe Thr Lys Ala Ala Ser Thr Tyr Ser Ile Asp Ser 325 330 335Val Ser Phe Ser Tyr Asn Thr Gly Asp Asn Thr Thr Phe Pro Asp Ala 340 345 350Glu Asp Lys Gly Ile Leu Thr Val Asp Glu Leu Leu Ala Ile Arg Ile 355 360 365Pro Leu Asn Asp Leu Phe Arg Cys Asn Ser Leu Ser Thr Leu Glu Lys 370 375 380Asn Asp Val Val Gln His Tyr Trp Asp Val Leu Val Gln Ala Phe Val385 390 395 400Gln Asn Gly Thr Val Ser Thr Asn Glu Phe Leu Cys Asp Lys Asp Lys 405 410 415Thr Ser Thr Val Ala Pro Thr Ile His Thr Thr Val Pro Ser Pro Thr 420 425 430Thr Thr Pro Thr Pro Lys Glu Lys Pro Glu Ala Gly Thr Tyr Ser Val 435 440 445Asn Asn Gly Asn Asp Thr Cys Leu Leu Ala Thr Met Gly Leu Gln Leu 450 455 460Asn Ile Thr Gln Asp Lys Val Ala Ser Val Ile Asn Ile Asn Pro Asn465 470 475 480Thr Thr His Ser Thr Gly Ser Cys Arg Ser His Thr Ala Leu Leu Arg 485 490 495Leu Asn Ser Ser Thr Ile Lys Tyr Leu Asp Phe Val Phe Ala Val Lys 500 505 510Asn Glu Asn Arg Phe Tyr Leu Lys Glu Val Asn Ile Ser Met Tyr Leu 515 520 525Val Asn Gly Ser Val Phe Ser Ile Ala Asn Asn Asn Leu Ser Tyr Trp 530 535 540Asp Ala Pro Leu Gly Ser Ser Tyr Met Cys Asn Lys Glu Gln Thr Val545 550 555 560Ser Val Ser Gly Ala Phe Gln Ile Asn Thr Phe Asp Leu Arg Val Gln 565 570 575Pro Phe Asn Val Thr Gln Gly Lys Tyr Ser Thr Ala Gln Asp Cys Ser 580 585 590Ala Asp Asp Asp Asn Phe Leu Val Pro Ile Ala Val Gly Ala Ala Leu 595 600 605Ala Gly Val Leu Ile Leu Val Leu Leu Ala Tyr Phe Ile Gly Leu Lys 610 615 620His His His Ala Gly Tyr Glu Gln Phe Gly Ser Gly Ser Gly Ser Gly625 630 635 640Ser Gly Ser Gly Ser Thr Gly Gly Ser Arg Thr Gly Ser Gly Ser Gly 645 650 655Ser Gly Ser Gly Ser Gly Ser Pro Gly 660 66556975PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 56Met Asp Gln Ala Arg Ser Ala Phe Ser Asn Leu Phe Gly Gly Glu Pro1 5 10 15Leu Ser Tyr Thr Arg Phe Ser Leu Ala Arg Gln Val Asp Gly Asp Asn 20 25 30Ser His Val Glu Met Lys Leu Ala Val Asp Glu Glu Glu Asn Ala Asp 35 40 45Asn Asn Thr Lys Ala Asn Val Thr Lys Pro Lys Arg Cys Ser Gly Ser 50 55 60Ile Cys Tyr Gly Thr Ile Ala Val Ile Val Phe Phe Leu Ile Gly Phe65 70 75 80Met Ile Gly Tyr Leu Gly Tyr Cys Lys Gly Val Glu Pro Lys Thr Glu 85 90 95Cys Glu Arg Leu Ala Gly Thr Glu Ser Pro Val Arg Glu Glu Pro Gly 100 105 110Glu Asp Phe Pro Ala Ala Arg Arg Leu Tyr Trp Asp Asp Leu Lys Arg 115 120 125Lys Leu Ser Glu Lys Leu Asp Ser Thr Asp Phe Thr Gly Thr Ile Lys 130 135 140Leu Leu Asn Glu Asn Ser Tyr Val Pro Arg Glu Ala Gly Ser Gln Lys145 150 155 160Asp Glu Asn Leu Ala Leu Tyr Val Glu Asn Gln Phe Arg Glu Phe Lys 165 170 175Leu Ser Lys Val Trp Arg Asp Gln His Phe Val Lys Ile Gln Val Lys 180 185 190Asp Ser Ala Gln Asn Ser Val Ile Ile Val Asp Lys Asn Gly Arg Leu 195 200 205Val Tyr Leu Val Glu Asn Pro Gly Gly Tyr Val Ala Tyr Ser Lys Ala 210 215 220Ala Thr Val Thr Gly Lys Leu Val His Ala Asn Phe Gly Thr Lys Lys225 230 235 240Asp Phe Glu Asp Leu Tyr Thr Pro Val Asn Gly Ser Ile Val Ile Val 245 250 255Arg Ala Gly Lys Ile Thr Phe Ala Glu Lys Val Ala Asn Ala Glu Ser 260 265 270Leu Asn Ala Ile Gly Val Leu Ile Tyr Met Asp Gln Thr Lys Phe Pro 275 280 285Ile Val Asn Ala Glu Leu Ser Phe Phe Gly His Ala His Leu Gly Thr 290 295 300Gly Asp Pro Tyr Thr Pro Gly Phe Pro Ser Phe Asn His Thr Gln Phe305 310 315 320Pro Pro Ser Arg Ser Ser Gly Leu Pro Asn Ile Pro Val Gln Thr Ile 325 330 335Ser Arg Ala Ala Ala Glu Lys Leu Phe Gly Asn Met Glu Gly Asp Cys 340 345 350Pro Ser Asp Trp Lys Thr Asp Ser Thr Cys Arg Met Val Thr Ser Glu 355 360 365Ser Lys Asn Val Lys Leu Thr Val Ser Asn Val Leu Lys Glu Ile Lys 370 375 380Ile Leu Asn Ile Phe Gly Val Ile Lys Gly Phe Val Glu Pro Asp His385 390 395 400Tyr Val Val Val Gly Ala Gln Arg Asp Ala Trp Gly Pro Gly Ala Ala 405 410 415Lys Ser Gly Val Gly Thr Ala Leu Leu Leu Lys Leu Ala Gln Met Phe 420 425 430Ser Asp Met Val Leu Lys Asp Gly Phe Gln Pro Ser Arg Ser Ile Ile 435 440 445Phe Ala Ser Trp Ser Ala Gly Asp Phe Gly Ser Val Gly Ala Thr Glu 450 455 460Trp Leu Glu Gly Tyr Leu Ser Ser Leu His Leu Lys Ala Phe Thr Tyr465 470 475 480Ile Asn Leu Asp Lys Ala Val Leu Gly Thr Ser Asn Phe Lys Val Ser 485 490 495Ala Ser Pro Leu Leu Tyr Thr Leu Ile Glu Lys Thr Met Gln Asn Val 500 505 510Lys His Pro Val Thr Gly Gln Phe Leu Tyr Gln Asp Ser Asn Trp Ala 515 520 525Ser Lys Val Glu Lys Leu Thr Leu Asp Asn Ala Ala Phe Pro Phe Leu 530 535 540Ala Tyr Ser Gly Ile Pro Ala Val Ser Phe Cys Phe Cys Glu Asp Thr545 550 555 560Asp Tyr Pro Tyr Leu Gly Thr Thr Met Asp Thr Tyr Lys Glu Leu Ile 565 570 575Glu Arg Ile Pro Glu Leu Asn Lys Val Ala Arg Ala Ala Ala Glu Val 580 585 590Ala Gly Gln Phe Val Ile Lys Leu Thr His Asp Val Glu Leu Asn Leu 595 600 605Asp Tyr Glu Arg Tyr Asn Ser Gln Leu Leu Ser Phe Val Arg Asp Leu 610 615 620Asn Gln Tyr Arg Ala Asp Ile Lys Glu Met Gly Leu Ser Leu Gln Trp625 630 635 640Leu Tyr Ser Ala Arg Gly Asp Phe Phe Arg Ala Thr Ser Arg Leu Thr 645 650 655Thr Asp Phe Gly Asn Ala Glu Lys Thr Asp Arg Phe Val Met Lys Lys 660 665 670Leu Asn Asp Arg Val Met Arg Val Glu Tyr His Phe Leu Ser Pro Tyr 675 680 685Val Ser Pro Lys Glu Ser Pro Phe Arg His Val Phe Trp Gly Ser Gly 690 695 700Ser His Thr Leu Pro Ala Leu Leu Glu Asn Leu Lys Leu Arg Lys Gln705 710 715 720Asn Asn Gly Ala Phe Asn Glu Thr Leu Phe Arg Asn Gln Leu Ala Leu 725 730 735Ala Thr Trp Thr Ile Gln Gly Ala Ala Asn Ala Leu Ser Gly Asp Val 740 745 750Trp Asp Ile Asp Asn Glu Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly 755 760 765Ser Gln Glu Gly Asp Phe Pro Met Pro Phe Ile Ser Ala Lys Ser Ser 770 775 780Pro Val Ile Pro Leu Asp Gly Ser Val Lys Ile Gln Cys Gln Ala Ile785 790 795 800Arg Glu Ala Tyr Leu Thr Gln Leu Met Ile Ile Lys Asn Ser Thr Tyr 805 810 815Arg Glu Ile Gly Arg Arg Leu Lys Phe Trp Asn Glu Thr Asp Pro Glu 820 825 830Phe Val Ile Asp His Met Asp Ala Asn Lys Ala Gly Arg Tyr Gln Cys 835 840 845Gln Tyr Arg Ile Gly His Tyr Arg Phe Arg Tyr Ser Asp Thr Leu Glu 850 855 860Leu Val Val Thr Gly Leu Tyr Gly Lys Pro Phe Leu Ser Ala Asp Arg865 870 875 880Gly Leu Val Leu Met Pro Gly Glu Asn Ile Ser Leu Thr Cys Ser Ser 885 890 895Ala His Ile Pro Phe Asp Arg Phe Ser Leu Ala Lys Glu Gly Glu Leu 900 905 910Ser Leu Pro Gln His Gln Ser Gly Glu His Pro Ala Asn Phe Ser Leu 915 920 925Gly Pro Val Asp Leu Asn Val Ser Gly Ile Tyr Arg Cys Tyr Gly Trp 930 935 940Tyr Asn Arg Ser Pro Tyr Leu Trp Ser Phe Pro Ser Asn Ala Leu Glu945 950 955 960Leu Val Val Thr Asp Ser Ile His Gln Asp Tyr Thr Thr Gln Asn 965 970 97557376PRTStreptococcus pyogenes 57Met Thr Arg Gln Gln Thr Lys Lys Asn Tyr Ser Leu Arg Lys Leu Lys1 5 10 15Thr Gly Thr Ala Ser Val Ala Val Ala Leu Thr Val Leu Gly Ala Gly 20 25 30Phe Ala Asn Gln Thr Thr Val Lys Ala Glu Gly Ala Lys Ile Asp Trp 35 40 45Gln Glu Glu Tyr Lys Lys Leu Asp Glu Asp Asn Ala Lys Leu Val Glu 50 55 60Val Val Glu Thr Thr Ser Leu Glu Asn Glu Lys Leu Lys Ser Glu Asn65 70 75 80Glu Glu Asn Lys Lys Asn Leu Asp Lys Leu Ser Lys Glu Asn Gln Gly 85 90 95Lys Leu Glu Lys Leu Glu Leu Asp Tyr Leu Lys Lys Leu Asp His Glu 100 105 110His Lys Glu His Gln Lys Glu Gln Gln Glu Gln Glu Glu Arg Gln Lys 115 120 125Asn Gln Glu Gln Leu Glu Arg Lys Tyr Gln Arg Glu Val Glu Lys Arg 130 135 140Tyr Gln Glu Gln Leu Gln Lys Gln Gln Gln Leu Glu Thr Glu Lys Gln145 150 155 160Ile Ser Glu Ala Ser Arg Lys Ser Leu Ser Arg Asp Leu Glu Ala Ser 165 170 175Arg Ala Ala Lys Lys Asp Leu Glu Ala Glu His Gln Lys Leu Glu Ala 180 185 190Glu His Gln Lys Leu Lys Glu Asp Lys Gln Ile Ser Asp Ala Ser Arg 195 200 205Gln Gly Leu Ser Arg Asp Leu Glu Ala Ser Arg Ala Ala Lys Lys Glu 210 215 220Leu Glu Ala Asn His Gln Lys Leu Glu Ala Glu His Gln Lys Leu Lys225 230 235 240Glu Asp Lys Gln Ile Ser Asp Ala Ser Arg Gln Gly Leu Ser Arg Asp 245 250 255Leu Glu Ala Ser Arg Ala Ala Lys Lys Glu Leu Glu Ala Asn His Gln 260 265 270Lys Leu Glu Ala Glu Ala Lys Ala Leu Lys Glu Gln Leu Ala Lys Gln 275 280 285Ala Glu Glu Leu Ala Lys Leu Arg Ala Gly Lys Ala Ser Asp Ser Gln 290 295 300Thr Pro Asp Thr Lys Pro Gly Asn Lys Ala Val Pro Gly Lys Gly Gln305 310 315 320Ala Pro Gln Ala Gly Thr Lys Pro Asn Gln Asn Lys Ala Pro Met Lys 325 330 335Glu Thr Lys Arg Gln Leu Pro Ser Thr Gly Glu Thr Ala Asn Pro Phe 340 345 350Phe Thr Ala Ala Ala Leu Thr Val Met Ala Thr Ala Gly Val Ala Ala 355 360 365Val Val Lys Arg Lys Glu Glu Asn 370 37558450PRTStaphylococcus aureus 58Met Lys Lys Lys Asn Ile Tyr Ser Ile Arg Lys Leu Gly Val Gly Ile1 5 10 15Ala Ser Val Thr Leu Gly Thr Leu Leu Ile Ser Gly Gly Val Thr Pro 20 25 30Ala Ala Asn Ala Ala Gln His Asp Glu Ala Gln Gln Asn Ala Phe Tyr 35 40 45Gln Val Leu Asn Met Pro Asn Leu Asn Ala Asp Gln Arg Asn Gly Phe 50 55

60Ile Gln Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Val Leu Gly65 70 75 80Glu Ala Gln Lys Leu Asn Asp Ser Gln Ala Pro Lys Ala Asp Ala Gln 85 90 95Gln Asn Asn Phe Asn Lys Asp Gln Gln Ser Ala Phe Tyr Glu Ile Leu 100 105 110Asn Met Pro Asn Leu Asn Glu Ala Gln Arg Asn Gly Phe Ile Gln Ser 115 120 125Leu Lys Asp Asp Pro Ser Gln Ser Thr Asn Val Leu Gly Glu Ala Lys 130 135 140Lys Leu Asn Glu Ser Gln Ala Pro Lys Ala Asp Asn Asn Phe Asn Lys145 150 155 160Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu Asn Met Pro Asn Leu Asn 165 170 175Glu Glu Gln Arg Asn Gly Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser 180 185 190Gln Ser Ala Asn Leu Leu Ser Glu Ala Lys Lys Leu Asn Glu Ser Gln 195 200 205Ala Pro Lys Ala Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe 210 215 220Tyr Glu Ile Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Gly225 230 235 240Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser Val Ser Lys Glu Ile Leu 245 250 255Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Glu Glu Asp 260 265 270Asn Lys Lys Pro Gly Lys Glu Asp Gly Asn Lys Pro Gly Lys Glu Asp 275 280 285Gly Asn Lys Pro Gly Lys Glu Asp Asn Lys Lys Pro Gly Lys Glu Asp 290 295 300Gly Asn Lys Pro Gly Lys Glu Asp Asn Asn Lys Pro Gly Lys Glu Asp305 310 315 320Gly Asn Lys Pro Gly Lys Glu Asp Asn Asn Lys Pro Gly Lys Glu Asp 325 330 335Gly Asn Lys Pro Gly Lys Glu Asp Gly Asn Lys Pro Gly Lys Glu Asp 340 345 350Gly Asn Gly Val His Val Val Lys Pro Gly Asp Thr Val Asn Asp Ile 355 360 365Ala Lys Ala Asn Gly Thr Thr Ala Asp Lys Ile Ala Ala Asp Asn Lys 370 375 380Leu Ala Asp Lys Asn Met Ile Lys Pro Gly Gln Glu Leu Val Val Asp385 390 395 400Lys Lys Gln Pro Ala Asn His Ala Asp Ala Asn Lys Ala Gln Ala Leu 405 410 415Pro Glu Thr Gly Glu Glu Asn Pro Phe Ile Gly Thr Thr Val Phe Gly 420 425 430Gly Leu Ser Leu Ala Leu Gly Ala Ala Leu Leu Ala Gly Arg Arg Arg 435 440 445Glu Leu 45059593PRTStreptococcus sp 59Met Glu Lys Glu Lys Lys Val Lys Tyr Phe Leu Arg Lys Ser Ala Phe1 5 10 15Gly Leu Ala Ser Val Ser Ala Ala Phe Leu Val Gly Ser Thr Val Phe 20 25 30Ala Val Asp Ser Pro Ile Glu Asp Thr Pro Ile Ile Arg Asn Gly Gly 35 40 45Glu Leu Thr Asn Leu Leu Gly Asn Ser Glu Thr Thr Leu Ala Leu Arg 50 55 60Asn Glu Glu Ser Ala Thr Ala Asp Leu Thr Ala Ala Ala Val Ala Asp65 70 75 80Thr Val Ala Ala Ala Ala Ala Glu Asn Ala Gly Ala Ala Ala Trp Glu 85 90 95Ala Ala Ala Ala Ala Asp Ala Leu Ala Lys Ala Lys Ala Asp Ala Leu 100 105 110Lys Glu Phe Asn Lys Tyr Gly Val Ser Asp Tyr Tyr Lys Asn Leu Ile 115 120 125Asn Asn Ala Lys Thr Val Glu Gly Val Lys Asp Leu Gln Ala Gln Val 130 135 140Val Glu Ser Ala Lys Lys Ala Arg Ile Ser Glu Ala Thr Asp Gly Leu145 150 155 160Ser Asp Phe Leu Lys Ser Gln Thr Pro Ala Glu Asp Thr Val Lys Ser 165 170 175Ile Glu Leu Ala Glu Ala Lys Val Leu Ala Asn Arg Glu Leu Asp Lys 180 185 190Tyr Gly Val Ser Asp Tyr His Lys Asn Leu Ile Asn Asn Ala Lys Thr 195 200 205Val Glu Gly Val Lys Asp Leu Gln Ala Gln Val Val Glu Ser Ala Lys 210 215 220Lys Ala Arg Ile Ser Glu Ala Thr Asp Gly Leu Ser Asp Phe Leu Lys225 230 235 240Ser Gln Thr Pro Ala Glu Asp Thr Val Lys Ser Ile Glu Leu Ala Glu 245 250 255Ala Lys Val Leu Ala Asn Arg Glu Leu Asp Lys Tyr Gly Val Ser Asp 260 265 270Tyr Tyr Lys Asn Leu Ile Asn Asn Ala Lys Thr Val Glu Gly Val Lys 275 280 285Ala Leu Ile Asp Glu Ile Leu Ala Ala Leu Pro Lys Thr Asp Thr Tyr 290 295 300Lys Leu Ile Leu Asn Gly Lys Thr Leu Lys Gly Glu Thr Thr Thr Glu305 310 315 320Ala Val Asp Ala Ala Thr Ala Glu Lys Val Phe Lys Gln Tyr Ala Asn 325 330 335Asp Asn Gly Val Asp Gly Glu Trp Thr Tyr Asp Asp Ala Thr Lys Thr 340 345 350Phe Thr Val Thr Glu Lys Pro Glu Val Ile Asp Ala Ser Glu Leu Thr 355 360 365Pro Ala Val Thr Thr Tyr Lys Leu Val Ile Asn Gly Lys Thr Leu Lys 370 375 380Gly Glu Thr Thr Thr Glu Ala Val Asp Ala Ala Thr Ala Glu Lys Val385 390 395 400Phe Lys Gln Tyr Ala Asn Asp Asn Gly Val Asp Gly Glu Trp Thr Tyr 405 410 415Asp Asp Ala Thr Lys Thr Phe Thr Val Thr Glu Lys Pro Glu Val Ile 420 425 430Asp Ala Ser Glu Leu Thr Pro Ala Val Thr Thr Tyr Lys Leu Val Ile 435 440 445Asn Gly Lys Thr Leu Lys Gly Glu Thr Thr Thr Lys Ala Val Asp Ala 450 455 460Glu Thr Ala Glu Lys Ala Phe Lys Gln Tyr Ala Asn Asp Asn Gly Val465 470 475 480Asp Gly Val Trp Thr Tyr Asp Asp Ala Thr Lys Thr Phe Thr Val Thr 485 490 495Glu Met Val Thr Glu Val Pro Gly Asp Ala Pro Thr Glu Pro Glu Lys 500 505 510Pro Glu Ala Ser Ile Pro Leu Val Pro Leu Thr Pro Ala Thr Pro Ile 515 520 525Ala Lys Asp Asp Ala Lys Lys Asp Asp Thr Lys Lys Glu Asp Ala Lys 530 535 540Lys Pro Glu Ala Lys Lys Glu Asp Ala Lys Lys Ala Glu Thr Leu Pro545 550 555 560Thr Thr Gly Glu Gly Ser Asn Pro Phe Phe Thr Ala Ala Ala Leu Ala 565 570 575Val Met Ala Gly Ala Gly Ala Leu Ala Val Ala Ser Lys Arg Lys Glu 580 585 590Asp6010PRTArtificial sequenceFc binding peptide known as SpA mimic 1 60Thr Trp Lys Thr Ser Arg Ile Ser Ile Phe1 5 106113PRTArtificial sequenceFc binding peptide known as SpA mimic 2 61Asp Cys Ala Trp His Leu Gly Glu Leu Val Trp Cys Thr1 5 106210PRTArtificial sequenceFc binding peptide known as SpA mimic 3 62Phe Gly Arg Leu Val Ser Ser Ile Arg Tyr1 5 106312PRTArtificial sequenceFc binding peptide known as SpA mimic 4 63Glu Pro Ile His Arg Ser Thr Leu Thr Ala Leu Leu1 5 10646PRTArtificial sequenceFc binding peptide known as SpA mimic 5 64His Trp Arg Gly Trp Val1 5656PRTArtificial sequenceFc binding peptide known as SpA mimic 6 65His Tyr Phe Lys Phe Asp1 5666PRTArtificial sequenceFc binding peptide known as SpA mimic 7 66His Phe Arg Arg His Leu1 5678PRTArtificial sequenceFc binding peptide known as Fcgamma mimic 1 67Asn Lys Phe Arg Gly Lys Tyr Lys1 5688PRTArtificial sequenceFc binding peptide known as Fcgamma mimic 2 68Asn Ala Arg Lys Phe Tyr Lys Gly1 5698PRTArtificial sequenceFc binding peptide known as SpA mimic 8 69Phe Tyr Trp His Cys Leu Asp Glu1 5708PRTArtificial sequenceFc binding peptide known as SpA mimic 9 70Phe Tyr Cys His Trp Ala Leu Glu1 5718PRTArtificial sequenceFc binding peptide known as SpA mimic 10 71Phe Tyr Cys His Thr Ile Asp Glu1 572429PRTArtificial sequenceFc binding polypeptide known as protein A/G 72Asn Ala Ala Gln His Asp Glu Ala Gln Gln Asn Ala Phe Tyr Gln Val1 5 10 15Leu Asn Met Pro Asn Leu Asn Ala Asp Gln Arg Asn Gly Phe Ile Gln 20 25 30Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Val Leu Gly Glu Ala 35 40 45Gln Lys Leu Asn Asp Ser Gln Ala Pro Lys Ala Asp Ala Gln Gln Asn 50 55 60Asn Phe Asn Lys Asp Gln Gln Ser Ala Phe Tyr Glu Ile Leu Asn Met65 70 75 80Pro Asn Leu Asn Glu Ala Gln Arg Asn Gly Phe Ile Gln Ser Leu Lys 85 90 95Asp Asp Pro Ser Gln Ser Thr Asn Val Leu Gly Glu Ala Lys Lys Leu 100 105 110Asn Glu Ser Gln Ala Pro Lys Ala Asp Asn Asn Phe Asn Lys Glu Gln 115 120 125Gln Asn Ala Phe Tyr Glu Ile Leu Asn Met Pro Asn Leu Asn Glu Glu 130 135 140Gln Arg Asn Gly Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser Gln Ser145 150 155 160Ala Asn Leu Leu Ser Glu Ala Lys Lys Leu Asn Glu Ser Gln Ala Pro 165 170 175Lys Ala Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu 180 185 190Ile Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Gly Phe Ile 195 200 205Gln Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 210 215 220Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Ala Asp Asn Lys Phe225 230 235 240Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu His Leu Pro Asn 245 250 255Leu Thr Glu Glu Gln Arg Asn Gly Phe Ile Gln Ser Leu Lys Asp Asp 260 265 270Pro Ser Val Ser Lys Glu Ile Leu Ala Glu Ala Lys Lys Leu Asn Asp 275 280 285Ala Gln Ala Pro Lys Glu Glu Asp Ser Leu Glu Gly Ser Gly Ser Gly 290 295 300Thr Tyr Lys Leu Ile Leu Asn Gly Lys Thr Leu Lys Gly Glu Thr Thr305 310 315 320Thr Glu Ala Val Asp Ala Ala Thr Ala Glu Lys Val Phe Lys Gln Tyr 325 330 335Ala Asn Asp Asn Gly Val Asp Gly Glu Trp Thr Tyr Asp Asp Ala Thr 340 345 350Lys Thr Phe Thr Val Thr Glu Lys Pro Glu Val Ile Asp Ala Ser Glu 355 360 365Leu Thr Pro Ala Val Thr Thr Tyr Lys Leu Val Ile Asn Gly Lys Thr 370 375 380Leu Lys Gly Glu Thr Thr Thr Lys Ala Val Asp Ala Glu Thr Ala Glu385 390 395 400Lys Ala Phe Lys Gln Tyr Ala Asn Asp Asn Gly Val Asp Gly Val Trp 405 410 415Thr Tyr Asp Asp Ala Thr Lys Thr Phe Thr Val Thr Glu 420 4257357PRTArtificial sequenceFc binding polypeptide known as Z domain 73Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu1 5 10 15His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln Ser 20 25 30Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala Lys 35 40 45Lys Leu Asn Asp Ala Gln Ala Pro Lys 50 5574114PRTArtificial sequenceFc binding polypeptide known as ZZ domain 74Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu1 5 10 15His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln Ser 20 25 30Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala Lys 35 40 45Lys Leu Asn Asp Ala Gln Ala Pro Lys Asp Asn Lys Phe Asn Lys Glu 50 55 60Gln Gln Asn Ala Phe Tyr Glu Ile Leu His Leu Pro Asn Leu Asn Glu65 70 75 80Glu Gln Arg Asn Ala Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser Gln 85 90 95Ser Ala Asn Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala 100 105 110Pro Lys75665PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 75Met Gly Val Glu Gly Cys Thr Lys Cys Ile Lys Tyr Leu Leu Phe Val1 5 10 15Phe Asn Phe Val Phe Trp Leu Ala Gly Gly Val Ile Leu Gly Val Ala 20 25 30Leu Trp Leu Arg His Asp Pro Gln Thr Thr Asn Leu Leu Tyr Leu Glu 35 40 45Leu Gly Asp Lys Pro Ala Pro Asn Thr Phe Tyr Val Gly Ile Tyr Ile 50 55 60Leu Ile Ala Val Gly Ala Val Met Met Phe Val Gly Phe Leu Gly Cys65 70 75 80Tyr Gly Ala Ile Gln Glu Ser Gln Cys Leu Leu Gly Thr Phe Phe Thr 85 90 95Cys Leu Val Ile Leu Phe Ala Cys Glu Val Ala Ala Gly Ile Trp Gly 100 105 110Phe Val Asn Lys Asp Gln Ile Ala Lys Asp Val Lys Gln Phe Tyr Asp 115 120 125Gln Ala Leu Gln Gln Ala Val Val Asp Asp Asp Ala Asn Asn Ala Lys 130 135 140Ala Val Val Lys Thr Phe His Glu Thr Leu Asp Cys Cys Gly Ser Ser145 150 155 160Thr Leu Thr Ala Leu Thr Thr Ser Asn Ala Ala Gln His Asp Glu Ala 165 170 175Gln Gln Asn Ala Phe Tyr Gln Val Leu Asn Met Pro Asn Leu Asn Ala 180 185 190Asp Gln Arg Asn Gly Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser Gln 195 200 205Ser Ala Asn Val Leu Gly Glu Ala Gln Lys Leu Asn Asp Ser Gln Ala 210 215 220Pro Lys Ala Asp Ala Gln Gln Asn Asn Phe Asn Lys Asp Gln Gln Ser225 230 235 240Ala Phe Tyr Glu Ile Leu Asn Met Pro Asn Leu Asn Glu Ala Gln Arg 245 250 255Asn Gly Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser Gln Ser Thr Asn 260 265 270Val Leu Gly Glu Ala Lys Lys Leu Asn Glu Ser Gln Ala Pro Lys Ala 275 280 285Asp Asn Asn Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu 290 295 300Asn Met Pro Asn Leu Asn Glu Glu Gln Arg Asn Gly Phe Ile Gln Ser305 310 315 320Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ser Glu Ala Lys 325 330 335Lys Leu Asn Glu Ser Gln Ala Pro Lys Ala Asp Asn Lys Phe Asn Lys 340 345 350Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu His Leu Pro Asn Leu Asn 355 360 365Glu Glu Gln Arg Asn Gly Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser 370 375 380Gln Ser Ala Asn Leu Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln385 390 395 400Ala Pro Lys Ala Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe 405 410 415Tyr Glu Ile Leu His Leu Pro Asn Leu Thr Glu Glu Gln Arg Asn Gly 420 425 430Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser Val Ser Lys Glu Ile Leu 435 440 445Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Glu Glu Asp 450 455 460Ser Leu Glu Gly Ser Gly Ser Gly Thr Tyr Lys Leu Ile Leu Asn Gly465 470 475 480Lys Thr Leu Lys Gly Glu Thr Thr Thr Glu Ala Val Asp Ala Ala Thr 485 490 495Ala Glu Lys Val Phe Lys Gln Tyr Ala Asn Asp Asn Gly Val Asp Gly 500 505 510Glu Trp Thr Tyr Asp Asp Ala Thr Lys Thr Phe Thr Val Thr Glu Lys 515 520 525Pro Glu Val Ile Asp Ala Ser Glu Leu Thr Pro Ala Val Thr Thr Tyr 530 535 540Lys Leu Val Ile Asn Gly Lys Thr Leu Lys Gly Glu Thr Thr Thr Lys545 550 555 560Ala Val Asp Ala Glu Thr Ala Glu Lys Ala Phe Lys Gln Tyr Ala Asn 565 570 575Asp Asn Gly Val Asp Gly Val Trp Thr Tyr Asp Asp Ala Thr Lys Thr 580 585 590Phe Thr Val Thr Glu Val Leu Lys Asn Asn Leu Cys Pro Ser Gly Ser 595 600 605Asn Ile Ile Ser Asn Leu Phe Lys Glu Asp Cys His Gln Lys Ile Asp 610 615 620Asp Leu Phe Ser Gly Lys Leu Tyr Leu Ile Gly Ile Ala Ala Ile Val625 630 635

640Val Ala Val Ile Met Ile Phe Glu Met Ile Leu Ser Met Val Leu Cys 645 650 655Cys Gly Ile Arg Asn Ser Ser Val Tyr 660 66576342PRTArtificial sequenceArtificial sequence comprising at least one exosomal polypeptide and at least one Fc binding polypeptide 76Met Pro Val Lys Gly Gly Thr Lys Cys Ile Lys Tyr Leu Leu Phe Gly1 5 10 15Phe Asn Phe Ile Phe Trp Leu Ala Gly Ile Ala Val Leu Ala Ile Gly 20 25 30Leu Trp Leu Arg Phe Asp Ser Gln Thr Lys Ser Ile Phe Glu Gln Glu 35 40 45Thr Asn Asn Asn Asn Ser Ser Phe Tyr Thr Gly Val Tyr Ile Leu Ile 50 55 60Gly Ala Gly Ala Leu Met Met Leu Val Gly Phe Leu Gly Cys Cys Gly65 70 75 80Ala Val Gln Glu Ser Gln Cys Met Leu Gly Leu Phe Phe Gly Phe Leu 85 90 95Leu Val Ile Phe Ala Ile Glu Ile Ala Ala Ala Ile Trp Gly Tyr Ser 100 105 110His Lys Asp Glu Val Ile Lys Glu Val Gln Glu Phe Tyr Lys Asp Thr 115 120 125Tyr Asn Lys Leu Lys Thr Lys Asp Glu Pro Gln Arg Glu Thr Leu Lys 130 135 140Ala Ile His Tyr Ala Leu Asn Cys Cys Gly Leu Ala Gly Gly Val Glu145 150 155 160Gln Phe Ile Ser Asp Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala 165 170 175Phe Tyr Glu Ile Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn 180 185 190Ala Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu 195 200 205Leu Ala Glu Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Asp Asn 210 215 220Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu His Leu225 230 235 240Pro Asn Leu Asn Glu Glu Gln Arg Asn Ala Phe Ile Gln Ser Leu Lys 245 250 255Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu Ala Lys Lys Leu 260 265 270Asn Asp Ala Gln Ala Pro Lys Ile Cys Pro Lys Lys Asp Val Leu Glu 275 280 285Thr Phe Thr Val Lys Ser Cys Pro Asp Ala Ile Lys Glu Val Phe Asp 290 295 300Asn Lys Phe His Ile Ile Gly Ala Val Gly Ile Gly Ile Ala Val Val305 310 315 320Met Ile Phe Gly Met Ile Phe Ser Met Ile Leu Cys Cys Ala Ile Arg 325 330 335Arg Asn Arg Glu Met Val 34077296PRTStaphylococcus aureus 77Asn Ala Ala Gln His Asp Glu Ala Gln Gln Asn Ala Phe Tyr Gln Val1 5 10 15Leu Asn Met Pro Asn Leu Asn Ala Asp Gln Arg Asn Gly Phe Ile Gln 20 25 30Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Val Leu Gly Glu Ala 35 40 45Gln Lys Leu Asn Asp Ser Gln Ala Pro Lys Ala Asp Ala Gln Gln Asn 50 55 60Asn Phe Asn Lys Asp Gln Gln Ser Ala Phe Tyr Glu Ile Leu Asn Met65 70 75 80Pro Asn Leu Asn Glu Ala Gln Arg Asn Gly Phe Ile Gln Ser Leu Lys 85 90 95Asp Asp Pro Ser Gln Ser Thr Asn Val Leu Gly Glu Ala Lys Lys Leu 100 105 110Asn Glu Ser Gln Ala Pro Lys Ala Asp Asn Asn Phe Asn Lys Glu Gln 115 120 125Gln Asn Ala Phe Tyr Glu Ile Leu Asn Met Pro Asn Leu Asn Glu Glu 130 135 140Gln Arg Asn Gly Phe Ile Gln Ser Leu Lys Asp Asp Pro Ser Gln Ser145 150 155 160Ala Asn Leu Leu Ser Glu Ala Lys Lys Leu Asn Glu Ser Gln Ala Pro 165 170 175Lys Ala Asp Asn Lys Phe Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu 180 185 190Ile Leu His Leu Pro Asn Leu Asn Glu Glu Gln Arg Asn Gly Phe Ile 195 200 205Gln Ser Leu Lys Asp Asp Pro Ser Gln Ser Ala Asn Leu Leu Ala Glu 210 215 220Ala Lys Lys Leu Asn Asp Ala Gln Ala Pro Lys Ala Asp Asn Lys Phe225 230 235 240Asn Lys Glu Gln Gln Asn Ala Phe Tyr Glu Ile Leu His Leu Pro Asn 245 250 255Leu Thr Glu Glu Gln Arg Asn Gly Phe Ile Gln Ser Leu Lys Asp Asp 260 265 270Pro Ser Val Ser Lys Glu Ile Leu Ala Glu Ala Lys Lys Leu Asn Asp 275 280 285Ala Gln Ala Pro Lys Glu Glu Asp 290 29578125PRTStreptococcus dysgalactiae 78Thr Tyr Lys Leu Ile Leu Asn Gly Lys Thr Leu Lys Gly Glu Thr Thr1 5 10 15Thr Glu Ala Val Asp Ala Ala Thr Ala Glu Lys Val Phe Lys Gln Tyr 20 25 30Ala Asn Asp Asn Gly Val Asp Gly Glu Trp Thr Tyr Asp Asp Ala Thr 35 40 45Lys Thr Phe Thr Val Thr Glu Lys Pro Glu Val Ile Asp Ala Ser Glu 50 55 60Leu Thr Pro Ala Val Thr Thr Tyr Lys Leu Val Ile Asn Gly Lys Thr65 70 75 80Leu Lys Gly Glu Thr Thr Thr Lys Ala Val Asp Ala Glu Thr Ala Glu 85 90 95Lys Ala Phe Lys Gln Tyr Ala Asn Asp Asn Gly Val Asp Gly Val Trp 100 105 110Thr Tyr Asp Asp Ala Thr Lys Thr Phe Thr Val Thr Glu 115 120 12579404PRTMus musculus 79Met Ile Leu Thr Ser Phe Gly Asp Asp Met Trp Leu Leu Thr Thr Leu1 5 10 15Leu Leu Trp Val Pro Val Gly Gly Glu Val Val Asn Ala Thr Lys Ala 20 25 30Val Ile Thr Leu Gln Pro Pro Trp Val Ser Ile Phe Gln Lys Glu Asn 35 40 45Val Thr Leu Trp Cys Glu Gly Pro His Leu Pro Gly Asp Ser Ser Thr 50 55 60Gln Trp Phe Ile Asn Gly Thr Ala Val Gln Ile Ser Thr Pro Ser Tyr65 70 75 80Ser Ile Pro Glu Ala Ser Phe Gln Asp Ser Gly Glu Tyr Arg Cys Gln 85 90 95Ile Gly Ser Ser Met Pro Ser Asp Pro Val Gln Leu Gln Ile His Asn 100 105 110Asp Trp Leu Leu Leu Gln Ala Ser Arg Arg Val Leu Thr Glu Gly Glu 115 120 125Pro Leu Ala Leu Arg Cys His Gly Trp Lys Asn Lys Leu Val Tyr Asn 130 135 140Val Val Phe Tyr Arg Asn Gly Lys Ser Phe Gln Phe Ser Ser Asp Ser145 150 155 160Glu Val Ala Ile Leu Lys Thr Asn Leu Ser His Ser Gly Ile Tyr His 165 170 175Cys Ser Gly Thr Gly Arg His Arg Tyr Thr Ser Ala Gly Val Ser Ile 180 185 190Thr Val Lys Glu Leu Phe Thr Thr Pro Val Leu Arg Ala Ser Val Ser 195 200 205Ser Pro Phe Pro Glu Gly Ser Leu Val Thr Leu Asn Cys Glu Thr Asn 210 215 220Leu Leu Leu Gln Arg Pro Gly Leu Gln Leu His Phe Ser Phe Tyr Val225 230 235 240Gly Ser Lys Ile Leu Glu Tyr Arg Asn Thr Ser Ser Glu Tyr His Ile 245 250 255Ala Arg Ala Glu Arg Glu Asp Ala Gly Phe Tyr Trp Cys Glu Val Ala 260 265 270Thr Glu Asp Ser Ser Val Leu Lys Arg Ser Pro Glu Leu Glu Leu Gln 275 280 285Val Leu Gly Pro Gln Ser Ser Ala Pro Val Trp Phe His Ile Leu Phe 290 295 300Tyr Leu Ser Val Gly Ile Met Phe Ser Leu Asn Thr Val Leu Tyr Val305 310 315 320Lys Ile His Arg Leu Gln Arg Glu Lys Lys Tyr Asn Leu Glu Val Pro 325 330 335Leu Val Ser Glu Gln Gly Lys Lys Ala Asn Ser Phe Gln Gln Val Arg 340 345 350Ser Asp Gly Val Tyr Glu Glu Val Thr Ala Thr Ala Ser Gln Thr Thr 355 360 365Pro Lys Glu Ala Pro Asp Gly Pro Arg Ser Ser Val Gly Asp Cys Gly 370 375 380Pro Glu Gln Pro Glu Pro Leu Pro Pro Ser Asp Ser Thr Gly Ala Gln385 390 395 400Thr Ser Gln Ser80330PRTMus musculus 80Met Glu Ser Asn Trp Thr Val His Val Phe Ser Arg Thr Leu Cys His1 5 10 15Met Leu Leu Trp Thr Ala Val Leu Asn Leu Ala Ala Gly Thr His Asp 20 25 30Leu Pro Lys Ala Val Val Lys Leu Glu Pro Pro Trp Ile Gln Val Leu 35 40 45Lys Glu Asp Thr Val Thr Leu Thr Cys Glu Gly Thr His Asn Pro Gly 50 55 60Asn Ser Ser Thr Gln Trp Phe His Asn Gly Arg Ser Ile Arg Ser Gln65 70 75 80Val Gln Ala Ser Tyr Thr Phe Lys Ala Thr Val Asn Asp Ser Gly Glu 85 90 95Tyr Arg Cys Gln Met Glu Gln Thr Arg Leu Ser Asp Pro Val Asp Leu 100 105 110Gly Val Ile Ser Asp Trp Leu Leu Leu Gln Thr Pro Gln Leu Val Phe 115 120 125Leu Glu Gly Glu Thr Ile Thr Leu Arg Cys His Ser Trp Arg Asn Lys 130 135 140Leu Leu Asn Arg Ile Ser Phe Phe His Asn Glu Lys Ser Val Arg Tyr145 150 155 160His His Tyr Ser Ser Asn Phe Ser Ile Pro Lys Ala Asn His Ser His 165 170 175Ser Gly Asp Tyr Tyr Cys Lys Gly Ser Leu Gly Arg Thr Leu His Gln 180 185 190Ser Lys Pro Val Thr Ile Thr Val Gln Gly Pro Lys Ser Ser Arg Ser 195 200 205Leu Pro Val Leu Thr Ile Val Ala Ala Val Thr Gly Ile Ala Val Ala 210 215 220Ala Ile Val Ile Ile Leu Val Ser Leu Val Tyr Leu Lys Lys Lys Gln225 230 235 240Val Pro Ala Leu Pro Gly Asn Pro Asp His Arg Glu Met Gly Glu Thr 245 250 255Leu Pro Glu Glu Val Gly Glu Tyr Arg Gln Pro Ser Gly Gly Ser Val 260 265 270Pro Val Ser Pro Gly Pro Pro Ser Gly Leu Glu Pro Thr Ser Ser Ser 275 280 285Pro Tyr Asn Pro Pro Asp Leu Glu Glu Ala Ala Lys Thr Glu Ala Glu 290 295 300Asn Thr Ile Thr Tyr Ser Leu Leu Lys His Pro Glu Ala Leu Asp Glu305 310 315 320Glu Thr Glu His Asp Tyr Gln Asn His Ile 325 33081261PRTMus musculus 81Met Phe Gln Asn Ala His Ser Gly Ser Gln Trp Leu Leu Pro Pro Leu1 5 10 15Thr Ile Leu Leu Leu Phe Ala Phe Ala Asp Arg Gln Ser Ala Ala Leu 20 25 30Pro Lys Ala Val Val Lys Leu Asp Pro Pro Trp Ile Gln Val Leu Lys 35 40 45Glu Asp Met Val Thr Leu Met Cys Glu Gly Thr His Asn Pro Gly Asn 50 55 60Ser Ser Thr Gln Trp Phe His Asn Gly Arg Ser Ile Arg Ser Gln Val65 70 75 80Gln Ala Ser Tyr Thr Phe Lys Ala Thr Val Asn Asp Ser Gly Glu Tyr 85 90 95Arg Cys Gln Met Glu Gln Thr Arg Leu Ser Asp Pro Val Asp Leu Gly 100 105 110Val Ile Ser Asp Trp Leu Leu Leu Gln Thr Pro Gln Arg Val Phe Leu 115 120 125Glu Gly Glu Thr Ile Thr Leu Arg Cys His Ser Trp Arg Asn Lys Leu 130 135 140Leu Asn Arg Ile Ser Phe Phe His Asn Glu Lys Ser Val Arg Tyr His145 150 155 160His Tyr Lys Ser Asn Phe Ser Ile Pro Lys Ala Asn His Ser His Ser 165 170 175Gly Asp Tyr Tyr Cys Lys Gly Ser Leu Gly Ser Thr Gln His Gln Ser 180 185 190Lys Pro Val Thr Ile Thr Val Gln Asp Pro Ala Thr Thr Ser Ser Ile 195 200 205Ser Leu Val Trp Tyr His Thr Ala Phe Ser Leu Val Met Cys Leu Leu 210 215 220Phe Ala Val Asp Thr Gly Leu Tyr Phe Tyr Val Arg Arg Asn Leu Gln225 230 235 240Thr Pro Arg Glu Tyr Trp Arg Lys Ser Leu Ser Ile Arg Lys His Gln 245 250 255Ala Pro Gln Asp Lys 26082249PRTMus musculus 82Met Trp Gln Leu Leu Leu Pro Thr Ala Leu Val Leu Thr Ala Phe Ser1 5 10 15Gly Ile Gln Ala Gly Leu Gln Lys Ala Val Val Asn Leu Asp Pro Lys 20 25 30Trp Val Arg Val Leu Glu Glu Asp Ser Val Thr Leu Arg Cys Gln Gly 35 40 45Thr Phe Ser Pro Glu Asp Asn Ser Ile Lys Trp Phe His Asn Glu Ser 50 55 60Leu Ile Pro His Gln Asp Ala Asn Tyr Val Ile Gln Ser Ala Arg Val65 70 75 80Lys Asp Ser Gly Met Tyr Arg Cys Gln Thr Ala Leu Ser Thr Ile Ser 85 90 95Asp Pro Val Gln Leu Glu Val His Met Gly Trp Leu Leu Leu Gln Thr 100 105 110Thr Lys Trp Leu Phe Gln Glu Gly Asp Pro Ile His Leu Arg Cys His 115 120 125Ser Trp Gln Asn Arg Pro Val Arg Lys Val Thr Tyr Leu Gln Asn Gly 130 135 140Lys Gly Lys Lys Tyr Phe His Glu Asn Ser Glu Leu Leu Ile Pro Lys145 150 155 160Ala Thr His Asn Asp Ser Gly Ser Tyr Phe Cys Arg Gly Leu Ile Gly 165 170 175His Asn Asn Lys Ser Ser Ala Ser Phe Arg Ile Ser Leu Gly Asp Pro 180 185 190Gly Ser Pro Ser Met Phe Pro Pro Trp His Gln Ile Thr Phe Cys Leu 195 200 205Leu Ile Gly Leu Leu Phe Ala Ile Asp Thr Val Leu Tyr Phe Ser Val 210 215 220Arg Arg Gly Leu Gln Ser Pro Val Ala Asp Tyr Glu Glu Pro Lys Ile225 230 235 240Gln Trp Ser Lys Glu Pro Gln Asp Lys 24583365PRTMus musculus 83Met Gly Met Pro Leu Pro Trp Ala Leu Ser Leu Leu Leu Val Leu Leu1 5 10 15Pro Gln Thr Trp Gly Ser Glu Thr Arg Pro Pro Leu Met Tyr His Leu 20 25 30Thr Ala Val Ser Asn Pro Ser Thr Gly Leu Pro Ser Phe Trp Ala Thr 35 40 45Gly Trp Leu Gly Pro Gln Gln Tyr Leu Thr Tyr Asn Ser Leu Arg Gln 50 55 60Glu Ala Asp Pro Cys Gly Ala Trp Met Trp Glu Asn Gln Val Ser Trp65 70 75 80Tyr Trp Glu Lys Glu Thr Thr Asp Leu Lys Ser Lys Glu Gln Leu Phe 85 90 95Leu Glu Ala Leu Lys Thr Leu Glu Lys Ile Leu Asn Gly Thr Tyr Thr 100 105 110Leu Gln Gly Leu Leu Gly Cys Glu Leu Ala Ser Asp Asn Ser Ser Val 115 120 125Pro Thr Ala Val Phe Ala Leu Asn Gly Glu Glu Phe Met Lys Phe Asn 130 135 140Pro Arg Ile Gly Asn Trp Thr Gly Glu Trp Pro Glu Thr Glu Ile Val145 150 155 160Ala Asn Leu Trp Met Lys Gln Pro Asp Ala Ala Arg Lys Glu Ser Glu 165 170 175Phe Leu Leu Asn Ser Cys Pro Glu Arg Leu Leu Gly His Leu Glu Arg 180 185 190Gly Arg Arg Asn Leu Glu Trp Lys Glu Pro Pro Ser Met Arg Leu Lys 195 200 205Ala Arg Pro Gly Asn Ser Gly Ser Ser Val Leu Thr Cys Ala Ala Phe 210 215 220Ser Phe Tyr Pro Pro Glu Leu Lys Phe Arg Phe Leu Arg Asn Gly Leu225 230 235 240Ala Ser Gly Ser Gly Asn Cys Ser Thr Gly Pro Asn Gly Asp Gly Ser 245 250 255Phe His Ala Trp Ser Leu Leu Glu Val Lys Arg Gly Asp Glu His His 260 265 270Tyr Gln Cys Gln Val Glu His Glu Gly Leu Ala Gln Pro Leu Thr Val 275 280 285Asp Leu Asp Ser Ser Ala Arg Ser Ser Val Pro Val Val Gly Ile Val 290 295 300Leu Gly Leu Leu Leu Val Val Val Ala Ile Ala Gly Gly Val Leu Leu305 310 315 320Trp Gly Arg Met Arg Ser Gly Leu Pro Ala Pro Trp Leu Ser Leu Ser 325 330 335Gly Asp Asp Ser Gly Asp Leu Leu Pro Gly Gly Asn Leu Pro Pro Glu 340 345 350Ala Glu Pro Gln Gly Ala Asn Ala Phe Pro Ala Thr Ser 355 360 365

Claims

1. An EV comprising at least one fusion protein, wherein the at least one fusion protein comprises at least one Fc binding polypeptide fused to at least one exosomal polypeptide.

2. The EV according to claim 1, wherein the at least one Fc binding polypeptide is selected from the group comprising Protein A, Protein G, Protein A/G, Protein L, Protein LG, Z domain, ZZ domain, human FCGRI, human FCGR2A, human FCGR2B, human FCGR2C, human FCGR3A, human FCGR3B, human FCGRB, human FCAMR, human FCERA, human FCAR, mouse FCGRI, mouse FCGRIIB, mouse FCGRIII, mouse FCGRIV, mouse FCGRn, SPH peptide, SPA peptide, SPG2, SpA mimic 1, SpA mimic 2, SpA mimic 3, SpA mimic 4, SpA mimic 5, SpA mimic 6, SpA mimic 7, SpA mimic 8, SpA mimic 9, SpA mimic 10, Fc.gamma. mimic 1, Fc.gamma. mimic 2, and any combination thereof.

3. The EV according to any one of the preceding claims, wherein the at least one Fc binding polypeptide comprises more than one Fc binding region.

4. The EV according to any one of the preceding claims, wherein the at least one exosomal polypeptide is selected from the group comprising CD9, CD53, CD63, CD81, CD54, CD50, FLOT1, FLOT2, CD49d, CD71, CD133, CD138, CD235a, ALIX, Syntenin-1, Syntenin-2, Lamp2b, TSPAN8, TSPAN14, CD37, CD82, CD151, CD231, CD102, NOTCH1, NOTCH2, NOTCH3, NOTCH4, DLL1, DLL4, JAG1, JAG2, CD49d/ITGA4, ITGB5, ITGB6, ITGB7, CD11a, CD11b, CD11c, CD18/ITGB2, CD41, CD49b, CD49c, CD49e, CD51, CD61, CD104, Fc receptors, interleukin receptors, immunoglobulins, CD2, CD3 epsilon, CD3 zeta, CD13, CD18, CD19, CD30, CD34, CD36, CD40, CD40L, CD44, CD45, CD45RA, CD47, CD86, CD110, CD111, CD115, CD117, CD125, CD135, CD184, CD200, CD279, CD273, CD274, CD362, COL6A1, AGRN, EGFR, GAPDH, GLUR2, GLUR3, HLA-DM, HSPG2, L1CAM, LAMB1, LAMC1, LFA-1, LGALS3BP, Mac-1 alpha, Mac-1 beta, MFGE8, SLIT2, STX3, TCRA, TCRB, TCRD, TCRG, VTI1A, VTI1B, other exosomal polypeptides, and any combinations thereof.

5. The EV according to any one of the preceding claims, wherein the at least one Fc binding polypeptide is displayed on the outer surface of the EV.

6. The EV according to any one of the preceding claims, wherein the at least one Fc binding polypeptide is bound to at least one Fc containing protein.

7. The EV according to any one of the preceding claims, wherein the EV has bound to it a plurality of Fc containing proteins through interaction between the Fc binding polypeptide and the Fc domains of the plurality of Fc containing proteins, wherein the plurality of Fc containing proteins may be the same or different.

8. The EV according to any one of the preceding claims, wherein the at least one Fc containing protein is an antibody and/or a protein engineered to comprise an Fc domain.

9. The EV according to claim 8, wherein the antibody is a targeting antibody, a therapeutic antibody, an antibody-drug conjugate (ADC), or an antibody for reducing opsonization and/or immune cell-mediated clearance.

10. The EV according to any one of claims 6 to 9, wherein the EV having bound to it at least one Fc containing protein is having bound to it at least 10, preferably at least 20, even more preferably at least 30 Fc containing proteins.

11. The EV as claimed in any one of claims 6-10, wherein the at least one Fc containing protein is present inside the EV, in the lipid membrane of the EV and/or attached to the outer surface of the EV.

12. A non-covalent complex between (i) a fusion protein, and (ii) an Fc containing protein, characterized in that the fusion protein comprises at least one Fc binding polypeptide fused to at least one exosomal polypeptide, wherein the Fc binding polypeptide binds to the Fc containing protein.

13. The non-covalent complex according to claim 12, wherein the non-covalent complex is present in the lipid membrane of an EV and/or inside an EV.

14. A pharmaceutical composition comprising EVs according to any one of claims 1 to 11, and/or the non-covalent complexes according to any one of claims 12 to 13, and optionally a pharmaceutically acceptable carrier.

15. The EVs according to any one of claims 1 to 11, and/or the non-covalent complexes according to any one of claims 12 to 13, and/or the pharmaceutical composition according to claim 14, for use in medicine.

16. A method for attaching to an extracellular vesicle (EV) at least one Fc containing protein, comprising the steps of: (i) providing an EV comprising a fusion protein comprising at least one Fc binding polypeptide and at least one exosomal polypeptide; (ii) allowing the Fc binding polypeptide of the fusion protein to bind the Fc domain of at least one Fc containing protein.

17. A polypeptide construct comprising a fusion protein comprising at least one Fc binding polypeptide and at least one exosomal polypeptide.

18. A polynucleotide construct encoding for at least one polypeptide construct of claim 17.

19. A cell comprising at least one polypeptide construct according to claim 17, at least one polynucleotide construct according to claim 18, at least one EV according to any one of claims 1-11 and/or at least one non-covalent complex according to any one of claims 12-13.

20. A method for delivery of at least one Fc containing protein to a target cell, comprising (i) attaching the Fc domain of the at least one Fc containing protein to an Fc binding polypeptide comprised in an EV, and (ii) contacting the EV, having attached to it the at least one Fc containing protein, with the target cell.

21. The method according to claim 20, wherein the method is carried out in vitro, in vivo, and/or ex vivo.

22. The method according to any one of claims 20-21, wherein the Fc binding polypeptide of the EV is part of a fusion protein with at least one exosomal polypeptide.

23. The method according to any one of claims 20-22, wherein the Fc containing protein is delivered into a target cell.

24. A method of treating a disease or disorder comprising administering to a subject a therapeutically effective amount of an EV according to claim 1 and a pharmaceutically acceptable excipient.

25. A method of treating a disease or disorder comprising administering to a subject a therapeutically effective amount of a non-covalent complex according to claim 12 and a pharmaceutically acceptable excipient.

26. A method of treating a disease or disorder comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition according to claim 14 and a pharmaceutically acceptable excipient.

27. A cell comprising at least one polynucleotide construct according to claim 18.

28. A cell comprising at least one EV according to claim 1.

29. A cell comprising at least one non-covalent complex according claim 12.