In-patient therapeutic biologic production from cells encapsulated in a biohybrid device

Abstract

A biohybrid device housing engineered cells expressing at least one peptide-based therapeutic agent, the biohybrid device comprises a house containing engineered cells, an oxygenator disposed inside or in adjacent to the house; each of the engineered cells comprises a vector; and the vector has at least one promoter followed by at least one peptide encoding sequence.

Description

Attorney. Docket. No.616146.100579 IN-PATIENT THERAPEUTIC BIOLOGIC PRODUCTION FROM CELLS ENCAPSULATED IN A BIOHYBRID DEVICE STATEMENT AS TO RIGHTS UNDER FEDERALLY-SPONSORED RESEARCH

[0001] This invention was made with government support grant number AY1AX000003-01awarded by the Advanced Research Projects Agency for Health and grant number FA8650-21-2- 7119 awarded by the Other Agency. The government has certain rights in the invention. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application Serial No.63 / 664,476 (Atty Doc. No.313US0), filed on June 26, 2024. The disclosure of the application is incorporated herein by reference.

[0003] This application claims priority to U.S. Provisional Patent Application Serial No.63 / 788,181 (Atty Doc. No.318US0), filed on April 14, 2025. The disclosure of the application is incorporated herein by reference.

[0004] This application claims priority to U.S. Provisional Patent Application Serial No.63 / 741, 644 (Atty Doc. No.314US0), filed on January 3, 2025. The disclosure of the application is incorporated herein by reference.

[0005] This is also a continuation-in-part of PCT application No. PCT / US2025 / 010450 (AttyDoc. No.303WO2), filed on January 6, 2025. The disclosures of each of these applications are also incorporated herein by reference.

[0006] This application is also a continuation-in-part of PCT application No.PCT / US2024 / 047927 (Atty Doc. No.297WO2), PCT / US2024 / 047934(Atty Doc. No. 297WO22), PCT / US2024 / 047943(Atty Doc. No.297WO23), PCT / US2024 / 047951(Atty Doc. No.297WO24), all of which are filed on September 23, 2024. The disclosures of each of these applications are also incorporated herein by reference.

[0007] This application is also a continuation-in-part of PCT application No.PCT / US2024 / 053241 (Atty Doc. No.276WO22) filed on October 28, 2024.

[0008] This application is also a continuation-in-part of U.S. Patent Application Serial No.18 / 287,671, U.S. Patent Application Serial No.18 / 287,684, and U.S. Patent Application Serial No.18 / 287,709, filed on October 20, 2023, which are U.S. national stage applications of PCT applications PCT / US22 / 25686 (Atty Doc. No.266WO2), PCT / US22 / 25706(Atty Doc. No. 266WO22), and PCT / US22 / 25724 (Atty Doc. No.266WO23) filed on April 21, 2022,Attorney. Docket. No.616146.100579 respectively. The disclosures of each of these applications are also incorporated herein by reference. SEQUENCE LISTING

[0009] A Sequence Listing conforming to the rules of WIPO Standard ST.26 is herebyincorporated by reference. Said Sequence Listing has been filed as an electronic document via PatentCenter encoded as XML in UTF-8 text. The electronic document, created on June 25, 2025, is entitled “1007890.100US5_ST26.xml”, and is 745,763 bytes in size. FIELD OF THE INVENTION

[0010] The present disclosure relates generally to field of biotechnology, and moreparticularly to therapeutic agents producing engineered cells which are encapsulated in and supported by a biohybrid device. BACKGROUND OF THE INVENTION

[0011] The background description provided herein is for the purpose of generally presentingthe context of the present disclosure. The subject matter discussed in the background of the invention section should not be assumed to be prior art merely as a result of its mention in the background of the invention section. Similarly, a problem mentioned in the background of the invention section or associated with the subject matter of the background of the invention section should not be assumed to have been previously recognized in the prior art. The subject matter in the background of the invention section merely represents different approaches, which in and of themselves may also be inventions.

[0012] Key challenges for biological production of therapeutic agents in a subject includeachieving effective production and controlling the production levels, which can vary due to cell health, cell metabolism, temperature and etc. Production of desired therapeutic agents by genetically engineered cells, due to the nature of the art, is hard to be precisely controlled, and therefore, its use in medical treatments is significantly undermined.

[0013] Therefore, there remains an imperative need for genetically engineered cellsproducing desired therapeutic agents whose production and delivery can be precisely controlled. SUMMARY OF THE INVENTIONAttorney. Docket. No.616146.100579

[0014] In light of the foregoing, this invention discloses a biohybrid device housingengineered cells expressing at least one peptide-based therapeutic agent. The biohybrid device comprises a house containing engineered cells, an oxygenator disposed inside or in adjacent to the house; wherein each of the engineered cells comprises a vector; wherein the vector has at least one promoter followed by at least one peptide encoding sequence.

[0015] In one embodiment, the engineered cells are ARPE-19 cells transfected by the vector.

[0016] In one embodiment, the at least one peptide encoding sequence comprises a firstpeptide encoding sequence and a second peptide encoding sequence.

[0017] In one embodiment, the vector further comprises a IRES DNA sequence or a P2Asequence locates between the first peptide encoding sequence and the second peptide encoding sequence.

[0018] In one embodiment, the at least one promoter comprises a first promoter and a secondpromoter, wherein the first promoter is followed by the first peptide encoding sequence and the second promoter is followed by the second peptide encoding sequence.

[0019] In one embodiment, the vector further comprises a selectable marker driven by aselectable marker promoter.

[0020] In one embodiment, the vector further comprises an expression enhancing componentwhich enhances the expression of the at least one peptide encoding sequence.

[0021] In one embodiment, the first peptide encoding sequence encodes one of a light chainand a heavy chain of the therapeutic agent, and the second peptide encoding sequence encodes the other of the light chain and the heavy chain of the therapeutic agent.

[0022] In one embodiment, the therapeutic agent comprises one of natalizumab, ipilimumab,pembrolizumab, PGT121, 3BNC117, GLP-1 analogs, interleukin-12, atezolizumab and any fragments thereof.

[0023] In one embodiment, the therapeutic agent comprises one of cytokines, interferongamma, and metabolic regulators.

[0024] In one embodiment, the at least one promoter comprise one of a CAG promoter, ahPGK promoter, and a CMV promoter.

[0025] In one embodiment, the engineered cells are encapsulated in an encapsulationcomprising a biocompatible material.

[0026] In one embodiment, the biocompatible material comprises hydrogel.

[0027] In one embodiment, the biocompatible material is coated with at least oneAttorney. Docket. No.616146.100579 immunomodulatory small molecule.

[0028] In another aspect of the invention, a method for treating a subject having a medicalcondition with engineered cells expressing at least one therapeutic agent, the method comprising placing a biohybrid device inside a body of the subject for a period of time.

[0029] In yet another aspect of the invention, a method for treating a subject having amedical condition with engineered cells expressing at least one therapeutic agent comprises producing engineered cells expressing at least one therapeutic agent; disposing the engineered cells into a biohybrid device; and placing the biohybrid device inside a body of the subject for a period of time.

[0030] In one embodiment, the step of producing the engineered cells comprises transfectingARPE-19 cells with vectors, wherein each of the vectors has at least one promoter followed by at least one peptide encoding sequence.

[0031] In one embodiment, the at least one peptide encoding sequence comprises a firstpeptide encoding sequence and a second peptide encoding sequence.

[0032] In one embodiment, each of the vectors further comprises a IRES DNA sequence or aP2A sequence locates between the first peptide encoding sequence and the second peptide encoding sequence.

[0033] In one embodiment, the at least one promoter comprises a first promoter and a secondpromoter, wherein the first promoter is followed by the first peptide encoding sequence and the second promoter is followed by the second peptide encoding sequence.

[0034] In one embodiment, the engineered cells comprise a first type of engineered cells anda second type of engineered cells.

[0035] In one embodiment, the first type of engineered cells is configured to express a firsttype of therapeutic agent, and the second type of engineered cells is configured to express a second type of therapeutic agent, wherein the first type of therapeutic agent is different from the second type of the therapeutic agent.

[0036] In one embodiment, the engineered cells are encapsulated in one or more capsules.

[0037] In one embodiment, the step of disposing the engineered cells into the biohybriddevice comprises disposing the one or more capsules containing the engineered cells into the biohybrid device.

[0038] In one embodiment, the one or more capsules containing the engineered cells arecryopreserved for a period of time before being thawed and disposed into the biohybrid device.Attorney. Docket. No.616146.100579

[0039] These and other aspects of the present disclosure will become apparent from thefollowing description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Illustrative embodiments of the invention will hereafter be described with reference tothe accompanying drawings, wherein like numerals denote like elements.

[0041] Fig. 1 shows a schematic view of a biohybrid device according to one embodiment ofthe present disclosure.

[0042] Fig. 2 shows a top view and a side view of a biohybrid device according to anotherembodiment of the present disclosure.

[0043] Fig. 3 shows a process for using the engineered cells to produce desired therapeuticagents in vivo.

[0044] Fig. 4 shows vector designs of a IRES system, a P2A system, and a dual promotersystem.

[0045] Fig. 5 shows a map of a vector expressing natalizumab.

[0046] Fig. 6 shows productions of 3BNC117, PGT121, Pembrolizumab, Ipilimumab, andnatalizumab by the engineered cells, as measured by ELISA.

[0047] Fig. 7 shows a chart of ELISA tests reflecting productivity of heavy chain and lightchain of 3BNC117 by the engineered ARPE-19 cells.

[0048] Fig. 8 shows a chart of ELISA tests reflecting the antigenicity of pembrolizumabproduced by the engineered ARPE-19 cells.

[0049] Fig. 9 shows a chart of ELISA tests reflecting productions of GLP-1 analogs by theengineered cells.

[0050] Fig. 10 shows a chart of ELISA tests reflecting productions of human cytokine IL-12by the engineered ARPE-19 cells.

[0051] Fig. 11 shows a chart of ELISA tests reflecting productions of atezolizumab within 24hours by the engineered ARPE-19 cells, as compared to unengineered cells.

[0052] Fig. 12 shows in vivo erythropoietin production by engineered cells disposed inside abiohybrid device which was implanted inside mice.

[0053] Fig. 13 shows a chart reflecting the fresh capsule production of Ipilimumab andAttorney. Docket. No.616146.100579 hIL12 by APRE-19 cells encapsulated at a total concentration of 100E6 cell / mL in 1.4% w / v SLG20 sodium alginate.

[0054] Fig. 14 shows a chart reflecting the cryopreserved capsule production of Ipilimumaband hIL12 by APRE-19 cells encapsulated at a total concentration of 100E6 cell / mL in 1.4% w / v SLG20 sodium alginate.

[0055] Fig. 15 shows charts reflecting oxygenation function by measuring the oxygenconcentration at two different distances. The left panel shows oxygenation concentration measured by an O2 sensing probe placed 1.5mm away from the oxygenator surface. The right panel shows oxygenation concentration measured by an O2 sensing probe placed 4mm away from the oxygenator surface. DETAILED DESCRIPTION OF THE INVENTION

[0056] The invention will now be described more fully hereinafter with reference to theaccompanying drawings, in which exemplary embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this invention will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout.

[0057] The terms used in this specification generally have their ordinary meanings in the art,within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and / or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether or not it is highlighted. It will be appreciated that same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, theAttorney. Docket. No.616146.100579 invention is not limited to various embodiments given in this specification.

[0058] One of ordinary skill in the art will appreciate that starting materials, biologicalmaterials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

[0059] Whenever a range is given in the specification, for example, a temperature range, atime range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the invention. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the claims herein. Definition

[0060] It will be understood that, as used in the description herein and throughout the claimsthat follow, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and equivalents thereof known to those skilled in the art. As well, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably.

[0061] It will be understood that when an element is referred to as being “on”, “attached” to,“connected” to, “coupled” with, “contacting”, etc., another element, it can be directly on, attached to, connected to, coupled with or contacting the other element or intervening elements may also be present. In contrast, when an element is referred to as being, for example, “directly on”, “directly attached” to, “directly connected” to, “directly coupled” with or “directly contacting” another element, there are no intervening elements present. It will also beAttorney. Docket. No.616146.100579 appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.

[0062] It will be understood that, although the terms first, second, third etc. may be usedherein to describe various elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the invention.

[0063] Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top,” maybe used herein to describe one element’s relationship to another element as illustrated in the figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation depicted in the figures. For example, if the device in one of the figures is turned over, elements described as being on the “lower” side of other elements would then be oriented on “upper” sides of the other elements. The exemplary term “lower”, can therefore, encompasses both an orientation of “lower” and “upper,” depending of the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below.

[0064] It will be further understood that the terms “comprises” and / or “comprising”, or“includes” and / or “including”, or “has” and / or “having”, or “carry” and / or “carrying”, or “contain” and / or “containing”, or “involve” and / or “involving”, “characterized by”, and the like are to be open-ended, i.e., to mean including but not limited to. When used in this disclosure, they specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0065] Unless otherwise defined, all terms (including technical and scientific terms) usedherein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the invention, and will not be interpreted inAttorney. Docket. No.616146.100579 an idealized or overly formal sense unless expressly so defined herein.

[0066] As used in the disclosure, “around”, “about”, “approximately” or “substantially” shallgenerally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “around”, “about”, “approximately” or “substantially” can be inferred if not expressly stated.

[0067] As used in the disclosure, the phrase “at least one of A, B, and C” should beconstrued to mean a logical (A or B or C), using a non-exclusive logical OR. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0068] As used in the disclosure, the term “implantable” refers to an ability of a device to bepositioned at a location within a body, such as subcutaneously, within a body cavity, or etc. Furthermore, the terms “implantation” and “implanted” refer to the positioning of a device at a location within a body, such as subcutaneously, within a body cavity, or etc.

[0069] As used in the disclosure, “biocompatible” material is a material that is compatiblewith living tissue or a living system by not being toxic or injurious and not causing immunological rejection.

[0070] As used in the disclosure, “therapeutic agent” refers to any substance that providestherapeutic effects to a medical or mental condition, as well as physiological condition or symptom related thereto. In certain embodiments, a therapeutic agent refers to a substance that provides therapeutic effects to any diseases or biological or physiological responses. The therapeutic agent may be a biological substance, such as a nucleic acid (e.g., a nucleotide, DNA, or RNA), a polypeptide, a lipid, a sugar (e.g., a monosaccharide, disaccharide, oligosaccharide, or polysaccharide), a small molecule, etc. In some embodiments, the therapeutic agent is a polypeptide.

[0071] As used in the disclosure, the term “therapy” refers to any protocol, method, and / oragent that can be used in the management, treatment, and / or amelioration of a given disease, or a symptom related thereto. In certain embodiments, the terms “therapies” and “therapy” refer to a biological therapy, supportive therapy, and / or other therapies known to one of skill in the art, such as medical personnel, useful in the management or treatment of a given disease, or symptom related thereto.

[0072] As used in the disclosure, “treat,” “treatment,” and “treating” refer to the reduction oramelioration of the progression, severity, and / or duration of a given disease resulting from theAttorney. Docket. No.616146.100579 administration of one or more therapies (including, but not limited to, the administration of microspheres disclosed herein). In certain embodiments, the terms refer to the reduction of pain associated with one or more diseases or conditions.

[0073] As used in the disclosure, “engineered cell(s)” refers herein to cells having beenengineered, e.g., by the introduction of an exogenous nucleic acid sequence or specific alteration of an endogenous gene sequence. An exogenous nucleic acid sequence that is introduced may comprise a wild type sequence of any species that may be modified. An engineered cell may comprise genetic modifications such as one or more mutations, insertions and / or deletions in an endogenous gene and / or insertion of an exogenous nucleic acid (e.g., a genetic construct) in the genome. An engineered cell may refer to a cell in isolation or in culture. Engineered cells may be “transduced cells” wherein the cells have been infected with e.g., an engineered virus. For example, a retroviral vector may be used, such as described in the examples, but other suitable viral vectors may also be contemplated such as lentiviruses. Non-viral methods may also be used, such as transfections or electroporation of DNA vectors. DNA vectors that may be used are transposon vectors. Engineered cells may thus also be “stably transfected cells” or “transiently transfected cells”. Transfection refers to non-viral methods to transfer DNA (or RNA) to cells such that a gene is expressed. Transfection methods are widely known in the art, such as calcium phosphate transfection, PEG transfection, and liposomal or lipoplex transfection of nucleic acids. Such a transfection may be transient but may also be a stable transfection wherein cells can be selected that have the gene construct integrated in their genome.

[0074] As used in the disclosure, “transgene” refers to a nucleic acid sequence (encoding, forexample, a therapeutic agent or a reporter agent) that is partly or entirely heterologous, i.e., foreign, to the host cell into which it is introduced. The transgene is inserted into an organism, host cell, or vector in a manner that ensures its function.

[0075] As used in the disclosure, “vector” or “plasmid” refers to discrete elements that areused to introduce heterologous nucleic acids or transgenes into cells for either expression of the heterologous nucleic acid or for replication of the heterologous nucleic acid. One vector may contain one or more transgenes. Selection and use of such vectors and plasmids are well within the level of skill of the art.

[0076] As used herein, “nucleic acid” refers to single-stranded and / or double-strandedpolynucleotides, such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), as well as analogs or derivatives of either RNA or DNA. Also included in the term “nucleic acid” areAttorney. Docket. No.616146.100579 analogs of nucleic acids such as peptide nucleic acid (PNA), phosphorothioate DNA, and other such analogs and derivatives. When referring to probes or primers, optionally labeled, with a detectable label, such as a fluorescent or radiolabel, single-stranded molecules are contemplated. Such molecules are typically of a length such that they are statistically unique and of low copy number (typically less than 5, preferably less than 3) for probing or priming a library. Generally a probe or primer contains at least 14, 16 or 30 contiguous nucleotides of sequence complementary to or identical to a gene of interest. Probes and primers can be 10, 20, 30, 50, 100 or more nucleotides long.

[0077] As used herein, “DNA” is meant to include all types and sizes of DNA moleculesincluding cDNA, plasmids and DNA including modified nucleotides and nucleotide analogs.

[0078] As used herein, “nucleotides” include nucleoside mono-, di-, and triphosphates.Nucleotides also include modified-nucleotides, such as, but are not limited to, phosphorothioate nucleotides and deazapurine nucleotides and other nucleotide analogs.

[0079] As used herein,” heterologous” or “foreign DNA and RNA” are used interchangeablyand refer to DNA or RNA that does not occur naturally as part of the genome in which it is present, or which is found in a location or locations and / or in amounts in a genome or cell that differ from that in which it occurs in nature. Heterologous nucleic acid is generally not endogenous to the cell into which it is introduced, but has been obtained from another cell or prepared synthetically. Generally, although not necessarily, such nucleic acid encodes RNA and proteins that are not normally produced by the cell in which it is expressed. Any DNA or RNA that one of skill in the art would recognize or consider as heterologous or foreign to the cell in which it is expressed is herein encompassed by heterologous DNA. Heterologous DNA and RNA may also encode RNA or proteins that mediate or alter expression of endogenous DNA by affecting transcription, translation, or other regulatable biochemical processes.

[0080] Examples of heterologous DNA include, but are not limited to, DNA that encodes agene product or gene product(s) of interest, introduced for purposes of modification of the endogenous genes or for production of an encoded protein. For example, a heterologous or foreign gene may be isolated from a different species than that of the host genome, or alternatively, may be isolated from the host genome but operably linked to one or more regulatory regions which differ from those found in the unaltered, native gene. Other examples of heterologous DNA include, but are not limited to, DNA that encodes traceable marker proteins, such as a protein that confers traits including, but not limited to, herbicide, insect, orAttorney. Docket. No.616146.100579 disease resistance; traits, including, but not limited to, oil quality or carbohydrate composition. Antibodies that are encoded by heterologous DNA may be secreted or expressed on the surface of the cell in which the heterologous DNA has been introduced.

[0081] As used herein, “operative linkage” or “operative association”, or grammaticalvariations thereof, of heterologous DNA to regulatory and effector sequences of nucleotides, such as promoters, enhancers, transcriptional and translational stop sites, and other signal sequences refers to the relationship between such DNA and such sequences of nucleotides. For example, operative linkage of heterologous DNA to a promoter refers to the physical relationship between the DNA and the promoter such that the transcription of such DNA is initiated from the promoter by an RNA polymerase that specifically recognizes, binds to and transcribes the DNA.

[0082] In order to optimize expression and / or in vitro transcription, it may be necessary toremove, add or alter 5′ untranslated portions of the clones to eliminate extra, potential inappropriate alternative translation initiation (i.e., start) codons or other sequences that may interfere with or reduce expression, either at the level of transcription or translation.

[0083] Alternatively, consensus ribosome binding sites (see, e.g., Kozak (1991) J. Biol.Chem.266:19867-19870) can be inserted immediately 5′ of the start codon and may enhance expression.

[0084] As used herein, a sequence complementary to at least a portion of an RNA, withreference to antisense oligonucleotides, means a sequence having sufficient complementarity to be able to hybridize with the RNA, preferably under moderate or high stringency conditions, forming a stable duplex. The ability to hybridize depends on the degree of complementarity and the length of the antisense nucleic acid. The longer the hybridizing nucleic acid, the more base mismatches it can contain and still form a stable duplex (or triplex, as the case may be). One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the melting point of the hybridized complex.

[0085] As used herein, “regulatory molecule” refers to a polymer of deoxyribonucleic acid(DNA) or ribonucleic acid (RNA) or a polypeptide that is capable of enhancing or inhibiting expression of a gene.

[0086] As used herein, a “promoter”, with respect to a region of DNA, refers to a sequenceof DNA that contains a sequence of bases that signals RNA polymerase to associate with the DNA and initiate transcription of RNA (such as poI II for mRNA) from a template strand of the DNA. A promoter thus generally regulates transcription of DNA into mRNA.Attorney. Docket. No.616146.100579

[0087] As used herein, a “light sensing protein activated promoter” refers to a promotordirectly or indirectly activated by light to regulate the transcription. Particular light sensing protein activated promoter provided herein may include NFAT-dependent promoter, PIR3_HSP70min promoter, C120 promoter, and etc.

[0088] As used herein, “expression” refers to the transcription and / or translation of nucleicacid. For example, expression can be the transcription of a gene that may be transcribed into an RNA molecule, such as a messenger RNA (mRNA) molecule. Expression may further include translation of an RNA molecule and translated into peptides, polypeptides, or proteins. If the nucleic acid is derived from genomic DNA, expression may, if an appropriate eukaryotic host cell or organism is selected, include splicing of the mRNA. With respect to an antisense construct, expression may refer to the transcription of the antisense DNA.

[0089] As used herein, “transformation / transfection” refers to the process by which nucleicacid is introduced into cells. The terms transfection and transformation refer to the taking up of exogenous nucleic acid, e.g., an expression vector, by a host cell whether or not any coding sequences are in fact expressed. Numerous methods of transfection are known to the ordinarily skilled artisan, for example, by Agrobacterium-mediated transformation, protoplast transformation (including polyethylene glycol (PEG)-mediated transformation, electroporation, protoplast fusion, and microcell fusion), lipid-mediated delivery, liposomes, electroporation, sonoporation, microinjection, particle bombardment and silicon carbide whisker-mediated transformation and combinations thereof (see, e.g., Paszkowski et al. (1984) EMBO J.3:2717- 2722; Potrykus et al. (1985) Mol. Gen. Genet.199:169-177; Reich et al. (1986) Biotechnology 4:1001-1004; Klein et al. (1987) Nature 327:70-73; U.S. Pat. No.6,143,949; Paszkowski et al. (1989) in Cell Culture and Somatic Cell Genetics of Plants, Vol.6, Molecular Biology of Plant Nuclear Genes, eds. Schell, J and Vasil, L. K. Academic Publishers, San Diego, Calif., p.52-68; and Frame et al. (1994) Plant J.6:941-948), direct uptake using calcium phosphate (CaPO4; see,e.g., Wigler et al. (1979) Proc. Natl. Acad. Sci. U.S.A.76:1373-1376), polyethylene glycol (PEG)-mediated DNA uptake, lipofection (see, e.g., Strauss (1996) Meth. Mol. Biol.54:307- 327), microcell fusion (see, EXAMPLES, see, also Lambert (1991) Proc. Natl. Acad. Sci. U.S.A. 88:5907-5911; U.S. Pat. No.5,396,767, Sawford et al. (1987) Somatic Cell Mol. Genet.13:279- 284; Dhar et al. (1984) Somatic Cell Mol. Genet.10:547-559; and McNeill-Killary et al. (1995) Meth. Enzymol.254:133-152), lipid-mediated carrier systems (see, e.g., Teifel et al. (1995) Biotechniques 19:79-80; Albrecht et al. (1996) Ann. Hematol.72:73-79; Holmen et al. (1995) InAttorney. Docket. No.616146.100579 Vitro Cell Dev. Biol. Anim.31:347-351; Remy et al. (1994) Bioconjug. Chem.5:647-654; Le Bolch et al. (1995) Tetrahedron Lett.36:6681-6684; Loeffler et al. (1993) Meth. Enzymol. 217:599-618) or other suitable method. Successful transfection is generally recognized by detection of the presence of the heterologous nucleic acid within the transfected cell, such as, for example, any visualization of the heterologous nucleic acid or any indication of the operation of a vector within the host cell.

[0090] As used herein, “substantially homologous DNA” or “equivalent DNA” refers toDNA that includes a sequence of nucleotides that is sufficiently similar to another such sequence to form stable hybrids, with each other or a reference sequence, under specified conditions.

[0091] As used herein: stringency of hybridization in determining percentage mismatchencompass the following conditions or equivalent conditions thereto: 1) high stringency: 0.1×SSPE or SSC, 0.1% SDS, 65° C. 2) medium stringency: 0.2×SSPE or SSC, 0.1% SDS, 50° C. 3) low stringency: 1.0×SSPE or SSC, 0.1% SDS, 50° C. or any combination of salt and temperature and other reagents that result in selection of the same degree of mismatch or matching. Equivalent conditions refer to conditions that select for substantially the same percentage of mismatch in the resulting hybrids. Additions of ingredients, such as formamide, Ficoll, and Denhardt's solution affect parameters such as the temperature under which the hybridization should be conducted and the rate of the reaction. Thus, hybridization in 5×SSC, in 20% formamide at 42° C. is substantially the same as the conditions recited above hybridization under conditions of low stringency. The recipes for SSPE, SSC and Denhardt's and the preparation of deionized formamide are described, for example, in Sambrook et al. (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Chapter 8; see, Sambrook et al., vol.3, p. B.13, see, also, numerous catalogs that describe commonly used laboratory solutions. It is understood that equivalent stringencies may be achieved using alternative buffers, salts and temperatures. As used herein, all assays and procedures, such as hybridization reactions and antibody-antigen reactions, unless otherwise specified, are conducted under conditions recognized by those of skill in the art as standard conditions.

[0092] As used herein, conditions under which DNA molecules form stable hybrids areconsidered substantially homologous, and a DNA or nucleic acid homolog refers to a nucleic acid that includes a preselected conserved nucleotide sequence, such as a sequence encoding aAttorney. Docket. No.616146.100579 polypeptide. By the term “substantially homologous” is meant having at least 75%, preferably 80%, preferably at least 90%, most preferably at least 95% homology therewith or a less percentage of homology or identity and conserved biological activity or function.

[0093] The terms “homology” and “identity” are often used interchangeably. In this regard,percent homology or identity may be determined, for example, by comparing sequence information using a GAP computer program. The GAP program utilizes the alignment method of Needleman and Wunsch (J. Mol. Biol.48:443 (1970), as revised by Smith and Waterman (Adv. Appl. Math.2:482 (1981). Briefly, the GAP program defines similarity as the number of aligned symbols (i.e., nucleotides or amino acids) which are similar, divided by the total number of symbols in the shorter of the two sequences. The preferred default parameters for the GAP program may include: (1) a unary comparison matrix (containing a value of 1 for identities and 0 for non-identities) and the weighted comparison matrix of Gribskov and Burgess, Nuc. Acids Res.14:6745 (1986), as described by Schwartz and Dayhoff, eds., ATLAS OF PROTEIN SEQUENCE AND STRUCTURE, National Biomedical Research Foundation, pp.353-358 (1979); (2) a penalty of 3.0 for each gap and an additional 0.10 penalty for each symbol in each gap; and (3) no penalty for end gaps.

[0094] By sequence identity, the number of conserved amino acids are determined bystandard alignment algorithms programs, and are used with default gap penalties established by each supplier. Substantially homologous nucleic acid molecules would hybridize typically at moderate stringency or at high stringency all along the length of the nucleic acid of interest. Preferably the two molecules will hybridize under conditions of high stringency. Also contemplated are nucleic acid molecules that contain degenerate codons in place of codons in the hybridizing nucleic acid molecule.

[0095] Whether any two nucleic acid molecules have nucleotide sequences that are at least75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% “identical” can be determined using known computer algorithms such as the “FAST A” program, using for example, the default parameters as in Pearson and Lipman, Proc. Natl. Acad. Sci. USA 85:2444 (1988). Alternatively the BLAST function of the National Center for Biotechnology Information database may be used to determine relative sequence identity.

[0096] In general, sequences are aligned so that the highest order match is obtained.“Identity” per se has an art-recognized meaning and can be calculated using published techniques. (See, e.g.: Computational Molecular Biology, Lesk, A. M., ed., Oxford UniversityAttorney. Docket. No.616146.100579 Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991). While there exist a number of methods to measure identity between two polynucleotide or polypeptide sequences, the term “identity” is well known to skilled artisans (Carillo, H. & Lipton, D., SIAM J Applied Math 48:1073 (1988)). Methods commonly employed to determine identity or similarity between two sequences include, but are not limited to, those disclosed in Guide to Huge Computers, Martin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo, H. & Lipton, D., SIAM J Applied Math 48:1073 (1988). Methods to determine identity and similarity are codified in computer programs. Preferred computer program methods to determine identity and similarity between two sequences include, but are not limited to, GCG program package (Devereux, J., et al., Nucleic Acids Research 12(I):387 (1984)), BLASTP, BLASTN, FASTA (Atschul, S. F., et al., J Molec Biol 215:403 (1990)).

[0097] Therefore, as used herein, the term “identity” represents a comparison between a testand a reference polypeptide or polynucleotide.

[0098] For example, a test polypeptide may be defined as any polypeptide that is 90% ormore identical to a reference polypeptide.

[0099] As used herein, the term at least “90% identical to” refers to percent identities from90 to 99.99 relative to the reference polypeptides. Identity at a level of 90% or more is indicative of the fact that, assuming for exemplification purposes a test and reference polynucleotide length of 100 amino acids are compared. No more than 10% (i.e., 10 out of 100) amino acids in the test polypeptide differs from that of the reference polypeptides. Similar comparisons may be made between a test and reference polynucleotides. Such differences may be represented as point mutations randomly distributed over the entire length of an amino acid sequence or they may be clustered in one or more locations of varying length up to the maximum allowable, e.g., 10 / 100 amino acid difference (approximately 90% identity). Differences are defined as nucleic acid or amino acid substitutions, or deletions.

[0100] As used herein, “conservative amino acid substitutions”, such as those set forthbelow, are those that do not eliminate biological activity. Suitable conservative substitutions of amino acids are known to those of skill in this art and may be made generally without alteringAttorney. Docket. No.616146.100579 the biological activity of the resulting molecule. Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. Molecular Biology of the Gene, 4th Edition, 1987, The Bejacmin / Cummings Pub. co., p.224). Conservative amino acid substitutions are made, for example, in accordance with those set forth in as follows:

[0101] Conservative amino acid substitutionsOriginal residue Conservative substitution Ala (A) Gly; Ser, Abu Arg (R) Lys, orn Asn (N) Gln; His Cys (C) Ser Gln (Q) Asn Glu (E) Asp Gly (G) Ala; Pro His (H) Asn; Gln Ile (I) Leu; Val; Met; Nle; Nva Leu (L) Ile; Val; Met; Nle; Nva Lys (K) Arg; Gln; Glu Met (M) Leu; Tyr; Ile; NLe Val Ornithine Lys; Arg Phe (F) Met; Leu; Tyr Ser (S) Thr Thr (T) Ser Trp (W) Tyr Tyr (Y) Trp; Phe Val (V) Ile; Leu; Met; Nle; Nva Other substitutions also are permissible and may be determined empirically or in accord with known conservative substitutions.

[0102] As used herein, the term “equivalent protein” or “equivalent peptide” means that thetwo proteins or peptides have substantially the same amino acid sequence with only amino acid substitutions (such as, but not limited to, conservative changes) or structure and the any changesAttorney. Docket. No.616146.100579 do not substantially alter the activity or function of the protein or peptide. When equivalent refers to a property, the property does not need to be present to the same extent (e.g., two peptides can exhibit different rates of the same type of enzymatic activity), but the activities are usually substantially the same.

[0103] As used herein, the term “light sensing protein”, “light sensitive protein”, “lightactivated protein”, “protein photoreceptor” refer to proteins which react to light via photoisomerization or photoreduction, thus initiating changes of the proteins which trigger a functional effect upon irradiation with light of a selected wavelength. “Light sensing protein”, “light sensitive protein”, “light activated protein”, and “protein photoreceptor” can include: melanopsin, phytochrome, cytochrome, photopsin, rhodopsin, protein kinase C, PhyB / PIF3 & PhyB / PIF6, EL222, SOUL, CarH, LOV (light oxygen voltage sensing domain), PYP (photoactive yellow protein), OPN5, UVR8, cryptochrome, and phototropin, or any mutant variants or fragments of the aforementioned proteins having substantially the same function as to the wild type proteins.

[0104] As used herein, the term “effective amount,” “effective dose,” or “effective dosage”refers to an amount that is sufficient to achieve or at least partially achieve the desired effect, e.g., sufficient to inhibit the occurrence or ameliorate one or more symptoms of a disease or disorder. An effective amount of a therapeutic agents is administered in an “effective regime.” The term “effective regime” refers to a combination of amount of the composition being administered and dosage frequency adequate to accomplish prophylactic or therapeutic treatment of the disease or disorder.

[0105] As used herein, the term “GLP-1” or “GLP-1 molecules” refers to GLP-1 proteins,peptides, polypeptides, analogs, mimetics, derivatives, isoforms, fragments and the like which retain at least one biological activity of native GLP-1.

[0106] As used herein, the term “EGFP” refers to an enhanced green fluorescence protein,peptides, polypeptides, analogs, mimetics, derivatives, isoforms, fragments and the like which retain at least one biological activity of native EGFP.

[0107] As used herein, “IRES” refers to a region of a nucleic acid molecule, such as anmRNA molecule, that allows internal ribosome entry sufficient to initiate translation, which initiation can be detected in an assay for cap-independent translation (see, e.g., U.S. Pat. No. 6,171,821). The presence of an IRES within an mRNA molecule allows cap-independent translation of a linked protein-encoding sequence that otherwise would not be translated.Attorney. Docket. No.616146.100579

[0108] Internal ribosome entry site (IRES) elements were first identified in picornaviruses,which elements are considered the paradigm for cap-independent translation. The 5′ UTRs of all picornaviruses are long and mediate translational initiation by directly recruiting and binding ribosomes, thereby circumventing the initial cap-binding step. IRES elements are frequently found in viral mRNA, they are rare in non-viral mRNA. Among non-viral mRNA molecules that contain functional IRES elements in their respective 5′ UTRs are those encoding immunoglobulin heavy chain binding protein (BiP) (Macejak et al. (1991) Nature 353:90- 94); Drosophila Antennapedia (Oh et al. (1992) Genes Dev, 6:1643-1653); D. Ultrabithorax (Ye et al. (1997) Mol. Cell Biol.17:1714-21); fibroblast growth factor 2 (Vagner et al. (1995) Mol. Cell Biol.15:35-44); initiation factor elF4G (Gan et al. (1998) J. Biol. Chem.273:5006-5012); proto-oncogene c-myc (Nanbru et al. (1995) J. Biol. Chem.272:32061-32066; Stoneley (1998) Oncogene 16:423-428); IRESH; from the 5′UTR of NRF1 gene (Oumard et al. (2000) Mol. and Cell Biol., 20(8):2755-2759); and vascular endothelial growth factor (VEGF) (Stein et al. (1998) Mol. Cell Biol.18:3112-9).

[0109] Present system described herein features genetically engineered active cells(“engineered cells”) that produce or are capable of producing one or more therapeutic agents. The therapeutic agent may be a biological substance, such as a nucleic acid (e.g., a nucleotide, DNA, or RNA), a polypeptide, a lipid, a sugar (e.g., a monosaccharide, disaccharide, oligosaccharide, or polysaccharide), a small molecule, or a vector thereof. Therapeutic Agents

[0110] In some embodiments, a therapeutic agent is a small molecule, an siRNA, an shRNA,an antisense oligonucleotide, a miRNA, an antibody or antibody fragment, a peptide, a polypeptide, a peptide analog, a fusion peptide, a polynucleotide, a peptidomimetic, a natural product, a carbohydrate, an aptamer, an avimer, an anticalin, a speigelmer, or a site-specific nuclease.

[0111] In some embodiments, the therapeutic agent is a polypeptide, a fragment or derivativethereof that perform the full or partial function of the full polypeptide, e.g., its expression, activity, and / or function.

[0112] Each engineered cell comprises a vector which includes a promoter operably linked toa nucleotide sequence encoding the polypeptide. In such an implementation, the promoter can essentially be a nucleotide sequence. In some embodiments, the engineered cells are housed in an implantable device.Attorney. Docket. No.616146.100579

[0113] Non-limiting examples of therapeutic agents which can be produced by the platformof the present disclosure are presented in Table 1 below. Table 1 discloses the therapeutic agents and their respective polypeptide sequences, e.g. heavy chain and light chain. In some embodiments, a therapeutic agent of the present disclosure includes a full sequence of a peptide listed in Table 1 column 1. In some embodiments, the therapeutic agent of the present disclosure includes a fragment of a full sequence of a peptide, e.g. heavy chain sequence or light chain sequence.

[0114] In some embodiments, a therapeutic agent of the present disclosure includes a fusedsequence, which fuses a full or partial sequence of a peptide listed in Table 1 column 1 to one or more heterologous moieties. Non-limiting examples of heterologous moieties suitable for chemical conjugation and / or genetical fusion of the disclosure include, but are not limited to, nucleic acids, lipids, sugars, peptides, polypeptides, small molecules, polymers, etc. The heterologous moieties may be fused at the N- and / or C-terminus of the peptide. In some embodiments, the plasmid vectors are designed to express the fused peptide if the one or more heterologous moieties are peptide.

[0115] Non-limiting examples of heterologous peptides and polypeptides include, but are notlimited to, an epitope (such as FLAG) or a tag sequence (such as hexa histidine) to allow for the detection and / or isolation of a fusion protein; a polypeptide or peptide which increases stability, such as an immunoglobulin constant region (e.g., an Fc domain, derived from human IgG1, IgG2, IgG3, or IgG4.); a half-life-extending sequence comprising a combination of two or more naturally occurring or non-naturally occurring charged and / or uncharged amino acids designed to form hydrophilic or hydrophobic fusion partner for a fusion protein; a ligand or a portion thereof which binds to a transmembrane receptor protein; an enzyme or portion thereof which is catalytically active; a polypeptide or peptide which promotes oligomerization, for example, a leucine zipper domain; a transmembrane receptor protein or a portion thereof, for example, an extracellular domain or a transmembrane and intracellular domain; a functional or non-functional antibody (e.g., an antibody that is specific for dendritic cells), or a heavy or light chain thereof; and a polypeptide which has an activity, such as a therapeutic activity, different from fusion proteins of the present disclosure. In some embodiments, the one or more heterologous moieties enhances a peptide-specific immune response in a subject. In some embodiments, the one or more heterologous moieties mediates peptide delivery to a specific site within a subject.

[0116] Polynucleotide sequences, e.g. DNA or RNA, encoding these polypeptide sequencesAttorney. Docket. No.616146.100579 can be produced by a skilled artisan in the field with common knowledges.

[0117] In some embodiments, in addition to Table 1, the therapeutic agents may includeCamrelizumab, Romosozumab, Brodalumab, Reslizumab, Mepolizumab, Obinutuzumab, Raxibacumab, Catumaxomab, Eculizumab, Panitumumab, Omalizumab, Infliximab, and Palivizumab, a fragment, or a derivative thereof. In some embodiments, the therapeutic agents may include a fused peptide having one or more heterologous peptides fused to one of camrelizumab, romosozumab, brodalumab, reslizumab, mepolizumab, obinutuzumab, raxibacumab, catumaxomab, eculizumab, panitumumab, omalizumab, infliximab, palivizumab, a fragment, or a derivative thereof.

[0118] In some embodiments, these therapeutic agents are used in treatment or prevention ofdiseases in areas such as oncology, cardiovascular health, metabolic disease, infectious disease, neurology, autoimmune disease, and others. Engineered Cells

[0119] In some embodiments, the present disclosure discloses a new platform technology forthe long-term production of therapeutic agents by encapsulated cells for in-patient delivery and production. The technology of the present disclosure utilizes engineered cells that produce a wide range of therapeutic agents such as cytokines, antibodies, bispecific or multi-specific antibodies, bispecific T-cell engagers (BiTEs), enzymes, peptides, and etc. A list of therapeutic agents and their amino acid sequences that can be produced using the platform of the present disclosure are provided in Table 1 below.

[0120] In some embodiments, these engineered cells are deployed as cell factories within abiohybrid device that support the engineered cells via oxygenation, alongside biomaterials protection / modification for immunoisolation.

[0121] In some embodiments, the engineered cells are provided as a cluster or disposed in amicrocarrier. In some embodiments, the engineered cells produce or release therapeutic agents (e.g., a polypeptide) for at least 0.5 day, 1 day, 10 days, or more, when the implantable device implanted into a subject. In some embodiments, more than one therapeutic agent is produced by the engineered cells. In some embodiments, the implantable device may include one or more types of engineered cells, one type of the engineered cells may produce a therapeutic agent which is different from the therapeutic agents produced by other types of the engineered cells.

[0122] Cells suitable for encapsulation and transplantation are generally secretory ormetabolic cells (i.e., they secrete a therapeutic factor or metabolize toxins, or both) or structuralAttorney. Docket. No.616146.100579 cells (e.g., skin, muscle, blood vessel), or metabolic cells (i.e., they metabolize toxic substances). In some embodiments, the engineered cells are derived from cells are naturally secretory, such as islet cells that naturally secrete insulin, or naturally metabolic, such as hepatocytes that naturally detoxify and secrete. In some embodiments, the engineered cells are derived by genetically engineering natural cells to express a recombinant protein, such as a secreted protein or metabolic enzyme.

[0123] Depending on the cell type, the cells may be organized as single cells, cell aggregates,spheroids, or even natural or bioengineered tissue. In some embodiments, the particle comprises an epithelial cell, endothelial cell, fibroblast cell, mesenchymal stem cell, keratinocyte cell or an islet cell or a cell derived from any of the foregoing cell types. In some embodiments, the particle comprises a retinal pigment epithelial (RPE cell) or a mesenchymal stem cell (MSC). In some embodiments, the particle comprises an engineered cell (e.g., an engineered RPE cell or an engineered MSC).

[0124] In some embodiments, the disclosed compositions contain cells geneticallyengineered to produce a therapeutic protein or nucleic acid. In these embodiments, as non- limiting example, the cell can be a stem cell (e.g., pluripotent), a progenitor cell (e.g., multipotent or oligopotent), or a terminally differentiated cell (i.e., unipotent). The cell can be engineered to contain a nucleic acid encoding a therapeutic polynucleotide such miRNA or RNAi or a polynucleotide encoding a protein. The nucleic acid can be integrated into the cells genomic DNA for stable expression or can be in an expression vector (e.g., plasmid DNA). The therapeutic polynucleotide or protein can be selected based on the disease to be treated and the site of transplantation. In some embodiments, the therapeutic polynucleotide or protein is anti- neoplastic. In other embodiments, the therapeutic polynucleotide or protein is a hormone, growth factor, or enzyme.

[0125] In some embodiments, the present disclosure provides a vector comprising thepolynucleotide encoding the therapeutic agents described herein.

[0126] In order to assess the expression of a therapeutic agent described herein, apolynucleotide or vector to be introduced into a cell can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors. In other embodiments, the selectable marker may be carried on a separate piece of DNA and used in a co- transfection procedure. Both selectable markers and reporter genes may be flanked withAttorney. Docket. No.616146.100579 appropriate regulatory sequences to enable expression in the host cells. Useful selectable markers are known in the art and include, for example, antibiotic-resistance genes, such as neomycin resistance and the like.

[0127] In some embodiments, the vector is plasmid vector. Non-limiting examples of theplasmid vector include cloning vectors, expression vectors, shuttle vectors, shuttle vectors, lentiviral vectors, BAC (bacterial artificial chromosome) vectors, YAC (yeast artificial chromosome) vectors, gene knockout vectors.

[0128] In some embodiments, the vector is a viral vector. Non-limiting examples of the viralvector include adeno-associated virus (AAV) vectors, retrovirus vectors, adenovirus vectors, Sindbis virus vectors, vaccinia virus vectors, and herpes virus vectors.

[0129] In some embodiments, the expression of the protein or functional derivative orfragment thereof in the vector is controlled by a promoter selected from the group comprising fsst promoter, hDlx promoter, mDlx promoter, Synapsin promoter, CMV promoter, CAG promoter, hPGK promotor, β-actin promoter, and CamKIIa promoter. In some embodiments, the expression of the protein or functional derivative or fragment thereof in the vector is controlled by a pan-GABAergic interneuron promoter.

[0130] In another aspect, the present disclosure features a method of treating a subjectcomprising administering to the subject an implantable device housing the engineered cells producing at least one therapeutic agent. Encapsulation of cells

[0131] In some embodiments, the engineered cells are encapsulated in biocompatiblematerial such as alginate, and are injected or placed into the biohybrid device and / or crosslinked in situ.

[0132] In some embodiments, the cell-laden hydrogels are molded (before, or during) forincorporation into the biohybrid device, such that the cells are in a “slab” form within the device. In this embodiment, the electronics, described above, and the electronics housing / encapsulation (e.g. Parylene C, epoxy, or hermetic enclosure) are assembled before cells / biomaterials injection and / or incorporation. The cells / biomaterials are injected into house thereafter.

[0133] In some embodiments, the slab of biomaterial / cells is pre-molded, and theoxygenator / electronics are mated with the biomaterials, locked into place, and further modified with immunomodulating materials. In these embodiments, the total available engineered cells / therapeutic agents are dictated by the cell density, while the volume of the biohybrid deviceAttorney. Docket. No.616146.100579 devotes to the engineered cells.

[0134] In some embodiments, the freshly encapsulated engineered cells are injected / disposedinto the biohybrid device which is then implanted into a subject. In some embodiments, the capsules and the engineered cells contained therein can be pre-manufactured and cryopreserved. In such cases, the capsules containing the engineered cells are thawed and introduced into the biohybrid device prior to its implantation into the subject's body. Method of Treatment

[0135] In some embodiments, the present disclosure provides a method of preventing ortreating cancer in a subject in need thereof, comprising administering to a subject a biohybrid device containing engineered cells and / or natural cells producing one or more therapeutic agents treating the cancer, e.g. ipilimumab, pembrolizumab, IL-12, atezolizumab, described herein.

[0136] In some embodiments, the disease or condition described herein is a cancer. Cancersthat may be treated using any of the methods described herein include any types of cancers. Types of cancers to be treated with the therapeutic agent(s) as described in this application include, but are not limited to, carcinoma, blastoma, sarcoma, benign and malignant tumors, and malignancies e.g., pancreatic cancer, mesothelioma, renal cell carcinoma. Adult tumors / cancers and pediatric tumors / cancers are also included.

[0137] In some embodiments, the cancer is early stage cancer, non-metastatic cancer,primary cancer, advanced cancer, locally advanced cancer, metastatic cancer, cancer in remission, recurrent cancer, cancer in an adjuvant setting, cancer in a neoadjuvant setting, or cancer substantially refractory to a therapy.

[0138] In some embodiments, the cancer is a solid tumor.

[0139] In some embodiments, the cancer is a hemoglobin cancer.

[0140] Examples of cancers that may be treated by the methods of this application include,but are not limited to, anal cancer, astrocytoma (e.g., cerebellar and cerebral), basal cell carcinoma, bladder cancer, bone cancer (e.g., osteosarcoma and malignant fibrous histiocytoma),brain tumor (e.g., glioma, brain stem glioma, cerebellar or cerebral astrocytoma (e.g.,astrocytoma, malignant glioma, medulloblastoma, and glioblastoma), breast cancer (e.g., TNBC), cervical cancer, colon cancer, colorectal cancer, endometrial cancer (e.g., uterine cancer), esophageal cancer, eye cancer (e.g., intraocular melanoma and retinoblastoma), gastric (stomach) cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, hepatocellular (liver) cancer (e.g., hepatic carcinoma and heptoma), liver cancer, lung cancer (e.g., small cellAttorney. Docket. No.616146.100579 lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), medulloblastoma, melanoma, mesothelioma, myelodysplastic syndromes, nasopharyngeal cancer, neuroblastoma, ovarian cancer, pancreatic cancer, parathyroid cancer, cancer of the peritoneal, pituitary tumor, rectal cancer, renal cancer, renal pelvis and ureter cancer (transitional cell cancer), rhabdomyosarcoma, skin cancer (e.g., non-melanoma (e.g., squamous cell carcinoma), melanoma, and Merkel cell carcinoma), small intestine cancer, squamous cell cancer, testicular cancer, thyroid cancer, and tuberous sclerosis. Additional examples of cancers can be found in The Merck Manual of Diagnosis and Therapy, 19th Edition, § on Hematology and Oncology, published by Merck Sharp & Dohme Corp., 2011 (ISBN 978-0- 911910-19-3); The Merck Manual of Diagnosis and Therapy, 20th Edition, § on Hematology and Oncology, published by Merck Sharp & Dohme Corp., 2018 (ISBN 978-0-911-91042-1) (2018 digital online edition at internet website of Merck Manuals); and SEER Program Coding and Staging Manual 2016, each of which are incorporated by reference in their entirety for all purposes.

[0141] In some embodiments, the present disclosure provides a method of preventing ortreating autoimmune diseases in a subject in need thereof, comprising administering to a subject a biohybrid device containing engineered cells and / or natural cells producing one or more therapeutic agents treating the autoimmune diseases, e.g. natalizumab, described herein.

[0142] Non-limiting examples of autoimmune diseases include Rheumatoid Arthritis,Systemic Lupus Erythematosus (Lupus), Type 1 Diabetes, Multiple Sclerosis (MS), Celiac Disease, Graves' Disease, Hashimoto's Thyroiditis, Psoriasis, Inflammatory Bowel Disease (IBD), Ankylosing Spondylitis, Sjögren's Syndrome, Myasthenia Gravis, Scleroderma, Vasculitis.

[0143] In some embodiments, the present disclosure provides a method of preventing ortreating HIV in a subject in need thereof, comprising administering to a subject a biohybrid device containing engineered cells and / or natural cells producing one or more therapeutic agents treating HIV, e.g. PGT121 and 3BNC117, described herein.

[0144] In some embodiments, the present disclosure provides a method of preventing ortreating type 1 diabetes or obesity in a subject in need thereof, comprising administering to a subject a biohybrid device containing engineered cells and / or natural cells producing one or more therapeutic agents treating the type 1 diabetes or obesity diseases, e.g. GLP-1 analog, described herein.Attorney. Docket. No.616146.100579 Biohybrid Device and Deployment

[0145] Fig. 1 shows an implantable biohybrid device according to one embodiment of thepresent disclosure. In some embodiments, the biohybrid device is configured to be implanted into a subject’s body for treatment or prevention of diseases. In some embodiments, the biohybrid device is configured implanted into a human’s body for treatment or prevention of diseases. In some embodiments, the biohybrid device is configured implanted into a mammals’s body for treatment or prevention of diseases. In some embodiments, the biohybrid device is configured implanted into a subject’s body subcutaneously, pericardially, intracranially, or intraperitoneally. In some embodiments, the biohybrid device is configured implanted into a cavity of a subject’s body, e.g. chest or abdominal cavity. In some embodiments, the biohybrid device is configured implanted into a subject’s body for short term use, e.g. less than 1 month. In some embodiments, the biohybrid device is configured implanted into a subject’s body for long term use, e.g. more than 1 month. In some embodiments, the biohybrid device is retrievable after being implanted into a subject’s body. In some embodiments, the biohybrid device does not need to be retrieved from a subject’s body after being implanted into a subject’s body

[0146] In some embodiments, the biohybrid device 10 includes a power source 101 (i.e.batteries, or coil for wireless power transfer), a microcontroller and mm-scale electronics 103, an on-site electrochemical oxygenator 105, a wireless communication unit 107, and a house / cartridge 109. The engineered cells / biomaterials are inserted or injected into the house, so as to be in close contact with / in adjacent to the oxygenator. In some embodiments, the biomaterial (hydrogel) and modification (coatings) 104 are implemented to reduce or eliminate fibrotic capsule formation. In some embodiments, the biohybrid device comprises a cartridge in which the on-site electrochemical oxygenator and the housing are disposed. In some embodiments, the cartridge comprises a conductive scaffold 110 integrated with immunoprotective hydrogel.

[0147] In some embodiments, the conductive scaffold of the cartridge has a cylindricalshape.

[0148] In one embodiment, the biohybrid device has a diameter of about 3.5 mm. In someembodiments, the biohybrid device has a diameter between about 2-3 mm. In some embodiments, the biohybrid device has a diameter between about 3-4 mm. In some embodiments, the biohybrid device has a diameter between about 4-6 mm. In some embodiments, the biohybrid device has a diameter between about 6-8 mm. In someAttorney. Docket. No.616146.100579 embodiments, the biohybrid device has a diameter between about 8-10 mm. In some embodiments, the biohybrid device has a diameter between about 10-12 mm. Ideally, the biohybrid device has a diameter less than about 12 mm.

[0149] In one embodiment, the biohybrid device has a length as small as possible to houseenough engineered cells to produce therapeutic agents to an efficient dosage level. In some embodiments, the biohybrid device has a length between about 0.5-1 cm. In some embodiments, the biohybrid device has a length between about 1-2 cm. In some embodiments, the biohybrid device has a length between about 2-3 cm. In some embodiments, the biohybrid device has a length between about 3-4 cm. In some embodiments, the biohybrid device has a length between about 4-5 cm. In some embodiments, the biohybrid device has a length between about 5-6 cm. In some embodiments, the biohybrid device has a length between about 6-7 cm.

[0150] In some embodiments, the length of the biohybrid device is smaller than 1 cmproviding the engineered cells has a capacity to produce the therapeutic agents to an efficient dosage level within the subject’s body. In some embodiments, the length of the biohybrid device is smaller than 1 cm providing the therapeutic agents produced has a long circulation half-life so as to maintain its effective treatment.

[0151] In some embodiments, instead of one house, the biohybrid device include multiplehouses, which may contain more than one type of the engineered cells. In some embodiments, the house contains multiple compartments.

[0152] In some embodiments, the biohybrid device is capable of supporting the engineeredcells at a high cell density due to its oxygenator which is capable of producing enough oxygen for the engineered cells at a high cell density.

[0153] Fig. 2 shows an implantable biohybrid device according to another embodiment ofthe invention. The upper panel shows a side view of the biohybrid device, while the lower panel shows a top view of the biohybrid device. In some embodiments, the biohybrid device includes a house for containing the engineered cells producing the therapeutic agents, an oxygenation component disposed in adjacent to the house, and a barrier at least partially covers the house. In some embodiments, the barrier is a semi-preamble barrier.

[0154] In some embodiments, at least one side of the implantable biohybrid device arecoated or encapsulated with a permeable material / membrane which shield the implantable biohybrid device from the immune system / cells of the user.

[0155] In some embodiments, the biohybrid device includes a stimulator for triggering theAttorney. Docket. No.616146.100579 production of the therapeutic agents and are reporter agent / molecule by the engineered cells locates in the house. A sensor for sensing the reporter agent / molecule also locates in the house. Both the stimulator and the sensor locate in vicinity to the engineered cells such that they effectively stimulate the production of the therapeutic agents and the reporter agent / molecule and sensing the production of the reporter agent / molecule.

[0156] In some embodiments, the implantable device can be implanted subcutaneously,pericardially, intracranially, or intraperitoneally for delivery of the therapeutic agents, so as to customized to the subject’s needs. In one embodiment, the implantable device can be implanted in a proper location for delivering the therapeutic agents either locally or systematically.

[0157] In an illustrative embodiment, implementation of the system involves implantation ofthe subcutaneous device in a subject. The subcutaneous device can be implanted via an outpatient procedure at approximately 2 cm or less below the skin in the abdomen. This implantation location can vary and depends on the balance of comfort / adoption and systemic delivery efficacy. Additionally, in alternative embodiments, a different implantation location may be used such as omentum, fat, muscle, brain, heart, skin, hips, joints, etc. During use, the implanted device can be secured in a subcutaneous pocket to prevent movement. In some embodiments, the user is outfitted with an external hub in a harness and provided startup operation instructions via an application running on a user device in one embodiment. These instructions guide the user in how to place the external hub by monitoring a power coupling between the implant and the external hub.

[0158] In an ideal use case, the subcutaneous device can be implanted for a needed durationof time (e.g., length of a deployment, length of a project or job, etc.) and explanted via outpatient procedure once the duration of time ends. Depending on the materials used and the implementation, the system can have a 60 day lifetime, a 130 day lifetime, a lifetime measured in years, etc. For example, it is anticipated that, using the technology described herein, the system could last for years and that repeated administration would be possible. In one embodiment, the engineered cells can be developed to include a genetically inducible safety kill switch to ensure that the cell therapy can be terminated should there be an untoward event during patient use. In the event that the device needs to be rendered non-functional, kill switch activation is initiated by an FDA-approved small molecule biologic. In an illustrative embodiment, viability of cells can be tracked optically to confirm efficacy of the kill switch. Process for Testing in vivo production of the therapeutic agentsAttorney. Docket. No.616146.100579

[0159] Fig. 3 shows a process of the present disclosure for testing the engineered cells’production of desired therapeutic agents in vivo.

[0160] In Step 1, cells such as ARPE-19 are genetically modified so as to product desiredtherapeutic agents, e.g., antibodies.

[0161] In Step 2, the quality and quantity of the desired therapeutic agents are validated so asto ensure the quality of the engineered cells.

[0162] In Step 3, the validated engineered cells are encapsulated and disposed / injected intothe biohybrid device, and / or directly disposed / injected into the biohybrid device.

[0163] In Step 4, the biohybrid device is implanted into a subject such as a patient or ananimal, e.g. mouse, for in vivo testing.

[0164] In some embodiments, other type of cells can be used as replacement for ARPE-19cells for being genetically modified. Genetics of Engineered Cells and Vectors

[0165] In some embodiments, ARPE-19 cells are genetically modified to produce the desiredtherapeutic agents either continuously or upon activation, using custom designed vectors which are described below. In some embodiments, other engineerable cell chassis, e.g., HEK293T cells, are genetically modified to produce the desired therapeutic agents either continuously or upon activation, using custom designed vectors. Non-limiting examples of cells can be used as replacement for ATPE-19 or HEK293T cells includes RPE1 cells, D407 cells, hTERT-RPE1 cells, HEK293 cells, CHO cells, and etc.

[0166] A list of therapeutic agents and their amino acid sequences that can be produced usingthe platform of the present disclosure are provided in Table 1.

[0167] In some embodiments, the cells are engineered to produce the desired peptides as thetherapeutic agents using vectors such as plasmids. The vectors contain DNAs / RNAs which encode the desired peptides shown in Table 1. The sequences of DNAs / RNAs encoding the desired peptides in Table 1 can be derived from the amino acid sequences of the desired peptides in Table 1 according to the DNA and RNA codon tables commonly known by a skilled artisan in this field.

[0168] In some embodiments, the designed vectors are transfected into the cells using a lipid-based transfection method with a PiggyBac transposase for genomic integration. In some embodiments, however, the cells are engineered using other methods such as polymer-based transfection, viral transduction, or other methods commonly known and / or used in the field.Attorney. Docket. No.616146.100579

[0169] In some embodiments, the platform of the present disclosure can also be used for anyprotein-based therapeutic agents listed in Table 1.

[0170] In some embodiments, the platform of the present disclosure can also be used for anyprotein-based therapeutic agents including cytokines, interferons, tumor necrosis factors (TNF), colony stimulating factors (CSF), chemokines, growth factors, etc. Non-limiting examples of cytokines includes IL-1 to IL-38, e.g., IL-1, IL-2, IL-6, IL-10, IL-12, IL-17, IL-23. Non-limiting examples of interferons includes IFN- α, IFN-β, IFN-γ, IFN-λ, etc. Non-limiting examples of TNF include TNF-α, TNF-β. Non-limiting examples of CSF include G-CSF, GM-CSF, M-CSF. Non-limiting examples of chemokines include CCL, CXCL, etc. Non-limiting examples of growth factors includes TGF-β and VEGF.

[0171] In some embodiments, the platform of the present disclosure can also be used for anyprotein-based therapeutic agents such as interleukin-2, interleukin-12, interleukin-10, interferon gamma or metabolic regulators such as glucagon-like-peptide-1 or gastric-inhibitory- polypeptide.

[0172] In some embodiments, the therapeutic agents contain a single unit of antibodies.

[0173] In some embodiments, the therapeutic agents contain multiple components such asantibodies or heterodimeric proteins like interleukin-12.

[0174] As shown in Fig. 4, in some embodiments, vectors includes either a 1) IRES system,2) P2A self-cleaving peptide system, or 3) a dual promoter system. Protein expression from these systems is driven using a promoter, which in some iterations is CAG, and a Kozak sequence followed by a protein encoding region such as light chain or heavy chain antibody sequences. In some embodiments, when multiple proteins or protein subunits are expressed, this can be followed by either IRES system, P2A system, or another promoter and the second coding region. This second coding region can be the remaining light or heavy chain sequence, as shown in the example of Fig.4.

[0175] More particularly, in the IRES system, the vector has a promoter, e.g., CAGpromoter, a first peptide coding region, e.g., a light chain or heavy chain of a therapeutic peptide, a IRES sequence, and a second peptide coding region, e.g., the other of the light chain or heavy chain of the therapeutic peptide.

[0176] In the P2A system, the vector has a promoter, e.g., CAG promoter, a first peptidecoding region, e.g., a light chain or heavy chain of a therapeutic peptide, a P2A sequence, and aAttorney. Docket. No.616146.100579 second peptide coding region, e.g., the other of the light chain or heavy chain of the therapeutic peptide.

[0177] In the dual promoter system, the vector has a promoter, e.g., CAG promoter, a firstpeptide coding region, e.g., a light chain or heavy chain of a therapeutic peptide, a second promoter, e.g., hPGK promoter, and a second peptide coding region, e.g., the other of the light chain or heavy chain of the therapeutic peptide.

[0178] In some embodiments, similar vectors without the IRES, P2A or second promoter canbe used to produce individual protein-based therapeutic agents having a single protein domain.

[0179] In some embodiments, the order of components shown in Fig. 4, e.g., the promoters,the coding regions, can be swapped.

[0180] The protein coding regions shown in Fig. 4, e.g., light chain and / or heavy chain, canbe replaced with other desired therapeutic agents’ light chain and heavy chain.

[0181] In some embodiments, the vectors contain a selectable marker such as resistance to anantibiotic like puromycin, or a visible marker such as green fluorescent protein.

[0182] In some embodiments, this selection marker is driven under a separate promoter suchas CMV.

[0183] In some embodiments, the vectors contain components to increase expression levelsor integrate the vectors into the genome of the engineered cell such as BGH pA, 3’ and 5’ ITR sequences, as shown in Fig.5.

[0184] In particular, Fig. 5 shows a map of a vector expressing natalizumab. Thenatalizumab vector includes a CAG promoter, a Kozak sequence followed by a protein coding region of a light chain of natalizumab, and a IRES sequence followed by a protein coding region of a heavy chain of natalizumab. The natalizumab vector also includes a selectable marker having resistance to Ampicillin driven by a CMV promoter, and 3’ and 5’ ITR sequences.

[0185] In some embodiments, the protein coding region of the light chain and heavy chain ofthe natalizumab can be replaced by sequences for other therapeutic agents.

[0186] In some embodiments, for single component therapeutic agents, the IRES and 2ndprotein encoding region may be removed.

[0187] It should be understood that the promoters in the vectors of the present disclosure canbe replaced with other promotors. Example 1 - Expression of Therapeutic Agents

[0188] Fig. 6 shows examples of protein based therapeutic agent production from engineeredAttorney. Docket. No.616146.100579 cells, as measured by ELISA. In particular, productions of 3BNC117, PGT121, Pembrolizumab, Ipilimumab, and Natalizumab by the engineered cells are shown in Fig.6.

[0189] Antibody production values are obtained using Abcam’s Human IgG ELISA Kit(ab195215). During the antibody production process, 10K engineered cells were placed into a 96-well plate and were let to rest overnight. Supernatant were harvested the 24 hours later. ELISA tests were performed for each antibody according to Abcam’s protocol.

[0190] Fig. 7 shows productivity of heavy chain and light chain of 3BNC117. In particular,the ELISA test for the heavy chain and light chain of 3BNC117 verifies the presence of full antibody. In order to verify that complete antibody was being produced, an ELISA test that captures the heavy chain of the antibody also detects via HRP-Conjugated antibody the light chain of the antibody.

[0191] Fig. 8 shows the antigenicity test of pembrolizumab produced by the engineeredARPE-19 cells. In particular, PD-1 specifically binds to pembrolizumab, and not to Ipilimumab. In order to verify the antigenicity of pembrolizumab produced by the engineered ARPE-19 cells, PD-1 were bound to a 96 well plate to capture pembrolizumab produced. Three groups of cells were tested using the PD-1 bound 96 well plate: pembrolizumab producing ARPE-19 cells, ipilimumab producing ARPE-19 cells, and unengineered cells. As shown in Fig.8, pembrolizumab were captured in the group of pembrolizumab producing ARPE-19 cells, while no peptide was captured in the other two groups.

[0192] Fig. 9 shows ELISA tests reflecting productions of GLP-1 analogs by the engineeredcells. In particular, productions of dulaglutide and exenatide were tested via ELSA tests and were shown. In one embodiment, ARPE-19 cells are used as the cells for receiving the vectors encoding the GLP-1 analogs. In one embodiment, other cells suitable for producing the therapeutic agents are used.

[0193] Fig. 10 shows ELISA tests reflecting productions of human cytokine IL-12 by theengineered ARPE-19 cells. In one embodiment, ARPE-19 cells are used as the cells for receiving the vectors encoding the human cytokine IL-12. In one embodiment, other cells suitable for producing the therapeutic agents are used.

[0194] Fig. 11 shows ELISA tests reflecting productions of atezolizumab within 24 hours bythe engineered ARPE-19 cells, as compared to unengineered cells. In one embodiment, ARPE- 19 cells are used as the cells for receiving the vectors encoding the atezolizumab. In one embodiment, other cells suitable for producing the therapeutic agents are used.Attorney. Docket. No.616146.100579

[0195] Fig. 12 shows in vivo erythropoietin production by engineered cells disposed inside abiohybrid device which was implanted inside mice. In one embodiment, ARPE-19 cells are used as the cells for receiving the vectors encoding the erythropoietin. In one embodiment, other cells suitable for producing the therapeutic agents are used.

[0196] In particular, erythropoietin levels in mice’s serum were measure. E4-6 shows theerythropoietin levels in mice which were implanted with a biohybrid device having the oxygenation component, while E1-3 shows the erythropoietin levels in mice which were implanted with a biohybrid device without the oxygenation component. As it can be seen from Fig.12, the erythropoietin levels were maintained for a longer period and at a high level, especially between day 20-40, in mice which were implanted with a biohybrid device having the oxygenation component. Immunomodulation

[0197] Long-term survival and function of cells represents a key technical challenge due toattack from the host immune response. To achieve this, in some embodiments, the biohybrid device includes a barrier (e.g., membrane, hydrogel) which is modified with antifibrotic small molecules, as shown in Table 2 below. In some embodiments, the biohybrid device incorporates immune modulating sentinel cells, which are engineered to secrete cytokines such as IL-12 or IL-10, or long-acting drug formulations for local immune suppression, such as triamcinolone hexacetonide, dexamethasone, or GW2580. Example 2 – Production of Ipilimumab and hIL12 by fresh and cryopreserved encapsulated APRE-19 cells

[0198] Fig. 13 shows a chart reflecting the fresh capsule production of Ipilimumab andhIL12 by APRE-19 cells encapsulated at a total concentration of 100E6 cell / mL in 1.4% w / v SLG20 sodium alginate. The ratio of hIL12 expressing cells to Ipilimumab expressing cells was 1:19. In-vitro productivity was measured by ELISA over a period of 7 days using 5 capsules in 1mL of complete medium with daily media changes. IgG was used to measure Ipilimumab productivity. As shown in Fig.13, Ipilimumab productivity peaked at 21 pg / cell / day while hIL12 productivity peaked at .12 pg / cell / day.

[0199] Fig. 14 shows a chart reflecting the cryopreserved capsule production of Ipilimumaband hIL12 by APRE-19 cells encapsulated at a total concentration of 100E6 cell / mL in 1.4% w / v SLG20 sodium alginate. The ratio of hIL12 expressing cells to Ipilimumab expressing cells was 1:19. Following encapsulation, capsules were stored in BamBanker HRM at volumetric ratios ofAttorney. Docket. No.616146.100579 1:10 and 1:20 and cryopreserved at -80C.

[0200] Cryopreserved capsules were thawed in a water bath at 37C. Post cryopreserved In-vitro productivity was measured by ELISA over a period of 3 days using 5 capsules in 1mL of complete medium with daily media changes. IgG was used to measure Ipilimumab productivity. Capsules cryopreserved at a 1:10 ratio demonstrated peak Ipilimumab productivity of 28.4 pg / cell / day peak hIL12 productivity .09 pg / cell / day. Capsules cryopreserved at a 1:20 ratio demonstrated peak Ipilimumab productivity of 23.8 pg / cell / day and peak hIL12 productivity .05 pg / cell / day. Example 3 – Oxygenation function

[0201] Fig. 15 shows charts reflecting oxygenation function by measuring the oxygenconcentration at two different distances. The left panel shows oxygenation concentration measured by an O2 sensing probe placed 1.5mm away from the oxygenator surface. The right panel shows oxygenation concentration measured by an O2 sensing probe placed 4mm away from the oxygenator surface.

[0202] To achieve an extreme hypoxic condition, the electrolyte within the biohybrid devicewas purged with nitrogen gas, reducing the oxygen concentration to less than 1%. The device was then positioned upright, and oxygenation levels were measured on the side of the oxygenator at two different distances, 1.5 mm and 4 mm. This was done while the device was submerged in phosphate-buffered saline (PBS) that had been bubbled with nitrogen gas to maintain the hypoxic environment. The duty cycle of the oxygenator was set to 50%, with an "on" time (TON) of 10 minutes, at 1.7V.

[0203] Oxygenation measurements were conducted with wireless control and using aPreSens Profiling Oxygen Microsensor PM-PSt7, with oxygen probe placed at various specified distances to assess the oxygen levels accurately.

[0204] The foregoing description of illustrative embodiments of the invention has beenpresented for purposes of illustration and of description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and modifications and variations are possible in light of the above teachings or may be acquired from practice of the invention. The embodiments were chosen and described in order to explain the principles of the invention and as practical applications of the invention to enable one skilled in the art to utilize the invention in various embodiments and with various modifications as suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims appendedAttorney. Docket. No.616146.100579 hereto and their equivalents.Attorney. Docket. No.616146.100579 Table 1. Therapuetic Agents Produced by Engineered Cells citst;tAmino Acid Heavy Chain #1 Sequence (Amino Acid Heavy Chain #2 (if applicable)) Amino Acid Light Chain #1 ueneeSequence (Amino Acid Light p ggr aaChain #2 r AesSequence, if applicable) e TaehsiT D bade si QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYIMNWVRQA PGQGLEWMGLDIQMTQSPSS LSASVGDRVT mtiINPYNGGTDY NPQFQDRVTI TADKSTSTAY MELSSLRSED TAVYY uziCARDG ITCQASEDIY SFVAWYQQKP zinatam YDDGPYTLET WGQGTLVTVS S urASTKGPSVF PLAPSSKSTS GGTAALGCLV GKAPKLLIYN AQTEAQGVPS lomeKDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSNFGTQ e D RFSGSGSGTD FTLTISSLQP mH;TYTCNVDHKP SNTKVDKTVE RKSCVECPPC PAPPVAGPSV FLFPPKPKDT EDFATYYCQH HYDSPLTFGG Nah p LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTF GTKVEIKRTV AAPSVFIFPP l a- RVVSVLTVVH QDWLNGKEYK CKVSNKGLPA PIEKTISKTK GQPREPQVYT SDEQLKSGTA SVVCLLNNFY R1LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPMLDS PREAKVQWKV DNALQSGNSQ 3- DGSFFLYSKL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSP (SEQ ID ESVTEQDSKD STYSLSSTLT LINO: 1) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1001) baci GEVQLVESGG GLVQPGGSLR LSCAASGFTF ADYTMDWVRQ APGKGLEWVGGDIQMTQSPS SLSAS mafsVGDRV ire DVNPNSGGSI YNQ tace cRFKGRFT FSVDRSKNTL YLQMNSLRAE DTAVYYCARN TITCKASQDV SIGVAWYQQK pnsacLGPSFYFDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK PGKAPKLLIY SASYRYTGVP di inab tcDYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT SRFSGSGSGT DFTLTISSLQ ZciaprtYICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP PEDFATYYCQ QYYIYPATFG otayrKDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN QGTKVEIKRT VAAPSVFIFP raailiSTYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ PSDEQLKSGT ASVVCLLNNF piB B VYVYPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV YPREAKVQWK VDNALQSGNS , deLDSDGSFALV SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG (SEQ QESVTEQDSK DSTYSLSSTL ziID NO: 2) TLSKADYEKH KVYACEVTHQ na(GDIQMTQSPS SLSASVGDRV TITCRASQDV NTAVAWYQQK PGKAPKLLIY GLSSPVTKSF NRGEC (SEQ ID mu SASFLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYCQ QHYTTPPTFG NO: 1002) H;QGTKVEIKGG SGGGSGGGSG GGSGGGSGEV QLVESGGGLV QPGGSLRLSC 2 R AASGFNIKDT YIHWVRQAPG KGLEWVARIY PTNGYTRYAD SVKGRFTISA E H DTSKNTAYLQ MNSLRAEDTA VYYCSRWGGD GFYAMDYWGQ GTLVTVSSAA EPKSSDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYVLPPSR DELTKNQVSL LCLVKGFYPS DIAVEWESNG QPENNYLTWP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G) (SEQ ID NO: 3) ba4a EVQLVESGGG LVQPGGSLRL SCAASGFTFS NFWMTWVRQA PGKGLEWVANDIQMTQSPSS LSASVGDRVT m G m a g MNQDGSEKYY VDSVKGRFTI SRDNAKSSLY LQMNSLRAED TAVYYCARDR ITCRASQSIS SYLNWYQQKP tlI ole EYCISTSCYD DFDYWGQGTL TVSSASTKG PSVFPLAPCS RSTSESTAAL GKAPKLLIYA ASSLQSGVP snaeyS o GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA LQSSGLYSL SSVVTVPSSS RFSGSGSGT v m m D FTLTISSLQP niueHlpLGTKTYTCNV DHKPSNTKVD KRVESKYGPP CPPCPA 3iPPVA GPSVFLFPPK EDFATYYCQQ SYSTPPITFG L;tlPKDTLMISRT PEVTCVVVDV SQEDPEVQFN WYVDGVEVHN AKTKPREEQF QGTRLEIKRT VAAPSVFIFP DuC NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK GLPSSIEKTI SKAK , M GQPREP PSDEQLKSGT ASVVCLLNNF A QVYTLPPSQE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP YPREAKVQWK VDNALQSGNS M VLDSDGSFFL YSRLTVDKSR WQEGNVFSCS VMHEALHNHY TQKSLSLSLG K QESVTEQDSK DSTYSLSSTL C B (SEQ ID NO: 4) TLSKADYEKH KVYACEVTHQ (EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYSMHWVRQA PGKGLEWVSG GLSSPVTKSF NRGEC (SEQ ID ISWNSGSKGY ADSVKGRFTI SRDNAKNSLY LQMNSLRAED TALYYCAKYG NO: 1004) SGYGKFYHYG LDVWGQGTTV TVSSASTKGP SVFPLAPCSR STSESTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTKTYTCNVD HKPSNTKVDK RVESKYGPPC PPCPAPPVAG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN STYRVVSVLT VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ VYTLPPSQEE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SRLTVDKSRW QEGNVFSCSV MHEALHNRFT QKSLSLSPGK) (SEQ ID NO: 5)Attorney. Docket. No.616146.100579ba4 EVTLKESGPA LVKPTQTLTL TCTFSGFSLT TYGMGVGWIR QPPGKALEWL DIQMTQSPSS LSASVGDRVTmiGesANIWWDDDKY YNPSLKNRLT ISKDTSKNQV VLTMTNMDPV DTATYYCARI ITCLASEDIY DNLAWligt I aeYQQKP siadGPIKYPTAPY RYFDFWGQGT MVTVSSASTK GPSVFPLAPC SRSTSESTAA GKAPKLLIYY ASSLQxedDGVPS t LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS RFSGSGSGTD YTLTISSL nsQP Aziaoh- SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPA usPEF LGGPSVFLFP EDFATYYCLQ DSEYPWTFGG m PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE GTKVEIKRTV AAPSVFIFPP Hus;reQFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR SDEQLKSGTA SVVCLLNNFY Rv1--tfEPQVYTLPPS QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PREAKVQWKV DNALQSGNSQ FaSrPPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LGK ESVTEQDSKD STYSLSSTLT C G (SEQ ID NO: 6) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1006)baciQVQLQESGPG LVKPSETLSL TCTVSGGSIS SYYWSWIRQP PGKCL mfireEWIGY c VYYSGTTNYN PSLKSRVTIS VDTSKNQFSL KLSSVTAADT AVYYCASIAVatcae nlpsacgTGFYFDYWGQ GTLVTVSSGG GGSGGGGSGG GGSEIVLTQS PGTLSLSPGEraibnuRVTLSCRASQ RVNNNYLAWY QQRPGQAPRL LIYGASSRAT GIPDRFSGSG TcFclSGTDF s-llTLTIS RLEPEDFAVY YCQQYDRSPL TFGCGTKLEI KSGGGGSEVQ e LVESGGGLVQ PGGSLKLSCA ASGFTFNKYA MNWVRQAPGK GLEWVARIRS vcFlclKYNNYATYYA DSVKDRFTIS R saDDSKNTAYL QMNNLKTEDT AVYYCVRHGN - m F S FGNSYISYWA YWGQGTLVTV SSGGGGSGGG GSGGGGSQTV VTQEPSLTVS v c PGGTVTLTCG SSTGAVTSGN YPNWVQQKPG QAPRGLIGGT KFLAPGTPAR s;3FSGSLLGGKA ALTLSGVQPE DEAEYYCVLW YSNRWVFGGG TKLTVLGGGG D DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED C,PEVKFNWYVD GVEVHNAKTK PCEEQYGSTY RCVSVLTVLH QDWLNGKEYK LL CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK D GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGGGGS GGGGSGGGGS GGGGSGGGGS GGGGSDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPCEEQ YGSTYRCVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GK (SEQ ID NO: 7)baya aiEVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSAQSVLTQPPSV SGAPGQRVTmlIiw ISGSGGSTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAILG SCTGScahihSSNIG AGYDVHWYQQ ptATSLSAFDIW GQGTMVTVSS ASTKGPSVFP LAPSSKSTSG GTstarpoAALGCLVK LPGTAPKLLI YGNSNRPSGVa rmDYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT PDRFSGS oeKSG TSASLAITGL MtcH YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPEAAGA PSVFLFPPKP QAEDEADYYC QSYDSSLSGS afeKDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN GVFGGGTKLT VLGQPKAAPS usSTYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VTLFPPSSEE LQANKATLVC siT VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LISDFYPGAV TVAWKADSSP LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG (SEQ VKAGVETTTP SKQSNNKYAA ID NO: 8) SSYLSLTPEQ WKSHRSYSCQ VTHEGSTVEK TVAPTECS (SEQ ID NO: 1008)ba1a XVQLLESGGG LVQPGGSLRL SCAASGFTFS KYIMQWVRQA PGKGLEWVSGQSVLTQPPSA SGTPGQRVTImiGgmIDIPTKGTVY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARAL SCSGSSSNIG RNYVYWYQcaIeQL dePRSGYLISPH YYYYALDVWG QGTTVTVSSA STKGPSVFPL APCSRSTSES PGTAPKLLIY SNNQRPSGVPdanaoirTAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV DRFSGSKamugnSGT SASLAISGLR GH aPSSSLGTKTY TCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEFLGGPSVF SEDEADYYCA AWDASLRGVF ;ay I LFPPKPKDTL MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP GGGTKLTVLG QPKA IraAPSVTL t XiREEQFNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG FPPSSEELQA NKATLVCLIS rdeotreQPREPQVYTL PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY DFYPGAVTVA WKADSSPVKA caH KTTPPVLDSD GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL GVETTTPSKQ SNNKYAASSY F SLSLG (SEQ ID NO: 9) LSLTPEQWKS HRSYSCQVTH EGSTVEKTVA PTECS (SEQ ID NO: 1009)baciQVQLQQSGPQ LVRPGTSVKI SCKASGYSFT TFWMDWVKQR PGQGLEWIGR DIVLTQSPAS LAVSmirceitLGQRAT IDPSDSESRL DQRFKDRATL TVDKSSSTVY MQLSSPTSED SAVYYCARGN ISCKASQSVD YDGDSlemipeYMKWY s DGYYGFAYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD QQKPGQPPKL LIYAASNLQSbohdliC; ec YFPEPV V5 uTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY GIPARFSGSG SGTDFTLNIH a TCNVDHKPSN TKVDKRVESK YGPPCPSCPA PEFLGGPSVF LFPPKPKDTL PVEEEDAATY YCQQSNEDPY CdntiMISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR TFGGGTKLEI KRTVAAPSVF ne2- VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL IFPPSDEQLK SGTASVVCLL m V elo C PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD NNFYPREAKV QWKVDNALQS p -S GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLGK (SEQ ID GNSQESVTEQ DSKDSTYSLS mo R A NO: 10) STLTLSKADY EKHKVYACEV C S THQGLSSPVT KSFNRGEC (SEQ ID NO: 1010)Attorney. 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No.616146.100579ba1 laQVQLQQPGAE LVRPGASVKL SCKASGYTFT SYWINWVKQR PGQGLEWIGN DIVMTQSPSS LTVTAGEKVTm GeiIYPSDSYTNY NQKFKDKATL TVDKSSSTAY MQLSSPTSED SAVYYCTRSW MSCKSSxg QSLL NSGNQKNYLT Igau RGNSFDYWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY WYQQKPGQPP KLLIYWASTtecir hpRbol eFPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI ESGVPDRFTG SGSGTomiseDFTLT CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD ISSVQAEDLA VYYCQNDYSY Z horC;ts2.aTLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST PFTFGSGTKL EIKRTVAAPS g YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY VFIFPPSDEQ LKSGTASVVC 8r1oTLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD LLNNFYPREA KVQWKVDNAL nicidrSDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ QSGNSQESVT EQD utsSKDSTYS al aID NO:11) LSSTLTLSKA DYEKHKVYAC C G EVTHQGLSSP VTKSFNRGEC (SEQ ID NO: 1011)baciEVQLV mfrESGGG LVQPGRSLRL SCVASGFTFN DYAMHWVRQA PGKGLEWVSV EIVMTQSPAT LSVSPGERAT iaclucISWNSDSIGY ADSVKGRFTI SRDNAKNSLY LQMHSLRAED TALYYCAKDN LSCRASQSVS SNLAWYQQKPatxepillHYGSGSYYYY QYGMDVWGQG TTVTVSSAST KGPSVFPLAP CSRSTSESTA GQAPRLLIYG ASTRATGIPAensi oALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS RFSGSGSGTE FTLTISSo b f,LQSrd,4 aSSLGTKTYTC NVDHKPSNTK VDKRVESKYG PPCPPCPAPP VAGPSVFLFP EDFAVYYCQH YINWPLTFGG O G m gIohPKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE GTKVEIKRTV AAPSVFIFPP na pm QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR SDEQLKSGTA SVVCLLNNFY muylHlEPQVYTLPPS QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PREAKVQWKV DNALQSGNSQ l PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LG ESVTEQDSKD STYSLSS ;eTLT 3cB (SEQ ID NO:12) (EVQLVESGGG LVQPGRSLRL SCAASGFTFD DYTMHWVRQA LSKADYEKHK VYACEVTHQG D C, eg PGKGLEWVSG ISWNSGSIGY ADSVKGRFTI SRDNAKKSLY LQMNSLRAED LSSPVTKSFN RGEC (SEQ ID NO: 02ralTALYYCAKDN SGYGHYYYGM DVWGQGTTVT VASASTKGPS VFPLAPCSRS 1012) DeTSESTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS CsuffiVVTVPSSSLG TKTYTCNVDH KPSNTKVDKR VESKYGPPCP PCPAPPVAGP D SVFLFPPKPK DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV YTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNRFTQ KSLSLSLG) (SEQ ID NO: 13)badelaQVQLVESGGG LVQPGRSLRL SCAASGFTVH SSYYMAWVRQ APGKGLEWVG DIQMTQSPSS LSASVGDRVTmizinrAIFTGSGAEY KAEWAKGRVT ISKDTSKNQV VLTMTNMDPV DTATYYCASD ITCRASQGIS SSLAWYQQKPlanvautAGYDYPTHAM HYWGQGTLVT VSSASTKPGS VFPLAPSSKS TSGGTAALGC GKAPKLLIYG ASETESGVPSormcuonLVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG RFSGSGSGTD FTLTISSLQP CH l;a5TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL RRGPKVFLFP EDFATYYCQN TKVGSSYGNT CmstyPKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE FGGGTKVEIK RTVAAPSVFI nxeo QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKG mrLPSSIEK TISKAKGQPR FPPSDEQLKS GTASVVCLLN a P EPQVYTLPPS REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT NFYPREAKVQ WKVDNALQSG elp PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVLHEALHA HYTRKELSLS P NSQESVTEQD SKDSTYSLSS mo (SEQ ID NO: 14) TLTLSKADYE KHKVYACEVT C HQGLSSPVTK SFNRGEC (SEQ ID NO: 1014)ba4 QVQLVESGGG LVKPGGSLRL SCAASGFTFS NYGMSWIRQA PGKGLEWVST DIQMTQSPSS LSASVGDm GreRVTilgcISGGGSNIYY ADSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCVSYY ITCKASQDVT TAVAWulInYQQKP nacYGIDFWGQGT SVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP GKAPKLLIYW ASTRHTGVPSpra gem EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTKTYTCN RFSGSGSGTD FTLTISSLQP S unuHllVDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP PKPKDTLMIS EDFATYYCQQ HYTIPWTFGG ;l1-ecRTPEVTCVVV DVSQEDPEVQ FNWY DlVDGVEV HNAKTKPREE QFNSTYRVVS GTKLEIKRTV AAPSVFIFPP l VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS SDEQLKSGTA SVVCLLNNFY Pam S QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF PREAKVQWKV DNALQSGNSQ FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LGK (SEQ ID NO: ESVTEQDSKD STYSLSSTLT 16) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1016)ba4 EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSG SYVLTQPPSV SVAPGQT GreARImicISGSGGFTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKPP TCGGNNIGSK SVHWYlgaInQQKPG nacRGYNYGPFDY WGQGTLVTVS SASTKGPSVF PLAPCSRSTS ESTAALGCLV QAPeaVLVVYDD SDRPSGIPERmggm KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTK FSGSNSGNTA TLTISRVEu unuAG HlllTYTCNVDHKP SNTKVDKRVE SKYGPPCPPC PAPEFLGGPS VFLFPPKPKD DEADYYCQVW DSSSDHVVFG S;1eTLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST GGTKLT LcVLGQ PKAAPSVTLF -lYRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY PPSSEELQAN KATLVCLISD DlaP ms- TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD FYPGAVTVAW KADSSPVKAG no SDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGK (SEQ VETTTPSKQS NNKYAASSYL N ID NO: 17) SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS (SEQ ID NO: 1017)Attorney. 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No.616146.100579baya aiml EVQLVESGGG LVKPGGSLRL SCAASGFTFS NYAMSWVRQT PEKRLEWVATDIVMTQTPLS LSVTPGQPAS i ISRSGSYSYF PDSVQGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARLG ISCKSSQSLL ESDGKTYLNWuwzhhictapGYDEGDAMDS WGQGTTVTVS SASTKGPSVF PLAPCSRSTS ESTAAnpoLGCLV YLQKPGQSPQ LLIYLVSILDo rmKDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTK SGVPDRFSGS GSGTDFTLKI C oetcH TYTCNVDHKP SNTKVDKRVE SKYGPPCPPC PAPEFLGGPS VFLFPPKPKD SRVEAEDVGV YYCLQATHFP afeTLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST QTFGGGTKVE IKRTVAAPSV usYRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY FIFPPSDEQL KSGTASVVCL siT TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD LNNFYPREAK VQWKVDNALQ SDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGK (SEQ SGNSQESVTE QDSKDSTYSL ID NO: 18) SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1018)ba1a EVQLVQSGAE VKKPGSSVKV SCKASGGTFS RSAISWVRQA PGQGLEWMGVNFMLTQPHSV SESPGKTVTIm Gi mIIPAFGEANY AQKFQGRVTI TADESTSTAY MELSSLRSED TAVYYCARGR SCTRSSGlge IoSID SNYVQWYQQR nbiQMFGAGIDFW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK PGSAPTTVIY EDNQRPisna cSGVP raDYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT DRFSGSIDSS SNSASLTISGo m C ucHllYICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP LKTEDEADYY CQSYDSNNRH ;1ecKDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN VIFGGGTKLT VLGQPKAAPS L- suoSTYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VTLFPPSSEE LQANKATLVC D P maVYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LISDFYPGAV TVAWKADSSP uq LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK VKAGVETTTP SKQSNNKYAA S (SEQ ID NO:19) SSYLSLTPEQ WKSHRSYSCQ VTHEGSTVEK TVAPTECS (SEQ ID NO: 1019)bade emzisQVQLVQSGAE VKKPGSSVKV SCKASGYDFT RYYINWVRQA PGQGLEWMGWDIVMTQTPLS LSVTPGQPAS a INPGSGNTKY NEKFKGRVTI TADESTSTAY MELSSLRSEnesD TAVYYCAREG ISCKSSQSLL YSRGKTYLNWe naaiITVYWGQGTT VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE LLQKPGQSPQ LLIYAVSKLnmdDo usPVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV SGVPDRFSGS GSGTDFTLKI D H ’ arNHKPSNTKVD KKVEPKSCDK THTCPPCPAP ELLGGPSVFL FPPKPKDTLM SRVEAEDVGV YYCVQGTHY teP e bmiISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV FTFGQGTKLE IKRTVAAPSV diehVSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP FIFPPSDEQL KSGTASVVCL olzly A PSRDELTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG LNNFYPREAK VQWKVDNALQ m SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPG (SEQ ID SGNSQESVTE QDSKDSTYSL A NO:20) SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1020)ba4reQVQLVQSGAE VKKPGSSVKV SCKASGGTFS SYAISWVRQA PGQGLEWMGL DIQMTQSPSS VSASVGDRVTm Gi cIIPMFDTAGY AQKFQGRVAI TVDESTSTAY MELSSLRSED TAVYYCARAE ITCRASQGIS SWLAWYQQKlgitInP acHSSTGTFDYW GQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK GKAPKLLISA ASSLQSGVPSnina gS mnuDYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT RFSGSGSGTD FTLTISSLQP u HlYTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT EDFATYYCQQ ANHLPFTFGG ;ll1-ecLMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY GTKVEIKRTV AAPSVFIFPP DllaRVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT SDEQLKSGTA SVVCLLNNFY P ms- LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS PREAKVQWKV DNALQSGNSQ n DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK (SEQ ID ESVTEQDSKD STYSLSSTLT o N NO:21) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1021)ba4 l QVTLKESGPV LVKPTETLTL TCTVSGFSLS RGKMGVSWIR QPPGKALEWL QPVLTQPPSL SVSPGQTASImiGlgec AHIFSSDEKS YRTSLKSRLT ISKDTSKNQV VLTMTNMDPV DTATYYCARI TCSGEKLGDK YAYWYQQKPGlpIm RRGGIDYWGQ GTLVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY QSPVLVMYQD KQRPSGIPEsnRoaetram FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTKTYT FSGSNSGNTA TLTIS usN HcGTQAM i CNVDHKPSNT KVDKRVESKY GPPCPPCPAP EFLGGPSVFL FPPKPKDTLM DEADYYCQAW DSSTAVF ;teGGG 2-ioISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV TKLTVLGQPK AAPSVTLFPP PpSotVSVLTVLHQD WLNGKEYKCK VSNKGLPSSI EKTISKAKG AaQ PREPQVYTLP SSEELQANKA TLVCLISDFY PSQEEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG PGAVTVAWKA DSSPVKAGVE MmeH SFFLYSRLTV DKSRWQEGNV FSCSVMHEAL HNHYTQKSLS LSLGK (SEQ ID TTTPSKQSNN KYAASSYLSL NO:22) TPEQWKSHRS YSCQVTHEGS TVEKTVAPTE CS (SEQ ID NO: 1022)Attorney. 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No.616146.100579ba4 N / AQVQLQESGPG LVKPSETLSL TCTVSGDSVS SSYWTWIRQP PGKGLEWIGY AIQMTQSPSS LSASVm GesGDRVTiIYYSGSSNYN PSLKSRATIS VDTSKNQFSL KLSSVTAADT AVYYCAREGN ITCRASQGIR NDLGWYQQKlgaePezI siVDTTMIFDYW GQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK GKAPKLLIYA ASSLQSGVPSonadP m E DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT RFAGRGSGTD FTLTISSLQP u L H P YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT EDFATYYCLQ DFNYPWTFGQ ; A 5tH LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY GTKVEIKRTV AAPSVFIFPP neC RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT SDEQLKSGTA SVVCLLNNFY m LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS PREAKVQWKV DNALQSGNSQ elp DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLG (SEQ ID ESVTEQDSKD STYSLSSTLT mo NO:23) LSKADYEKHK VYACEVTHQG C LSSPVTKSFN RGEC (SEQ ID NO: 1023)ba2a EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAIGGSGDIVMTQSPDSLAVSLGERATINCmG mag GSLPY KSSQSLFNVRSRKNYLAWYQQtaI olADIVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYWPMDIWGQad eyGTLVTVS KPGQPPKLLISWASTRnerlzim SASTKG ESGVPDRFSGSGSGTDFTLTISSL Ena elpPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG QAEDVAVYYCKQSYDLFT uiFGSG mtlLYSL TKLEIKRTVAAPSV Hu;3M SSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCEVECPECPAPPVAGPSVF FIFPPSDEQLKSGTASVVCLLNN D LFPPK FYPREAKVQWKVDNALQSGNS C,PKDTLMISRTPEVTCVVVAVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTF QESVTEQDSKDSTYSL A RVVSVL SSTLTLSKADYEKHKVYACEVT M C TVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKN HQGLSSPVTKSFNRGEC (SEQ ID B QVSLT NO: 1024) CEVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQG NVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 24)ba4s EVPLVESGGG LVQPGGSLRL SCAVSGFTFS NYGMVWVRQA PGKGLEWVAYDIQMTQSPSS LSASVGm GiDRVT g v IDSDGDNTYY RDSVKGRFTI SRDNAKSSLY LQMNSLRAED TAVYYCTTGI ITCKSSQSLV GASGKTYLYWuziI arg VRPFLYWGQG TLVTVSSAST KGPSVFPLAP CSRSTSESTA ALGCLVKDYF LFQKPGKAPK RLIYLVSTLDxidealioziPEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTKTYTC SGIPSRFSGS GSGTEFnananeTLTI h NVDHKPSNTK VDKRVESKYG PPCPPCPAPE FLGGPSVFLF PPKPKDz tTLMI SSLQPEDFAT YYCLQGTHFPomusa SRTPEVTCVV VDVSQEDPEV QFNWYVDGVE VHNAKTKPRE EQFNSTYRVV HTFGQGTKLE IKRTVAAPSV R Hy;mSVLTVLHQDW LNGKEYKCKV SNKGLPSSIE KTISKAKGQP REPQVYTLPP FIFPPSDEQL KSGTASVVCL n RcdeSQEEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPVLDSDGS FzLNNFYPREAK VQWKVDNALQ ilaFFLYSRLTVD KSRWQEGNVF SCSVMHEALH NHYTQKSLSL SLGK (SEQ ID NO: SGNSQESVTE QDSKDSTYSL ren 25) SSTLTLSKAD YEKHKVYACE e G VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1025)baciEVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKQTVVTQEPSLTVSPGGmf aTVTLTCR i m YNNYAT SSTGAVTTSNYANWVQQKPGQat ceuepolYYAASVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARHGNFGNSYVSWFAY APRGLIGGTNKRAqsieyPGTl bm WGQGTL PARFSGSLLGGKAALTLSGVQPEaT 4eGlVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH DEAEYYCALWYSNLWVFGGG gpIiT tlTFPA KLTVLGQPKAAPSVTL dueVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPA FPPSSEELQANKATLVCLISDFYP ziM naPEAA GAVTVAWKADSSPVKAGVETT m GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT TPSKQSNNKYAASSY u H KPREEQ LSLTPEQWKSHRSYSCQVTHEG ;3 FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTSKAKGQPREPQVYTL STVEKTVAPTECS (SEQ ID NO: D C PPSQE 1026) , EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLT (DIQMTQSPSSLSASVGDRVTITC D5rVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:26) KASQNVATHVGWYQQKPGKAP ot(QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYTMNWVRQAPGQGLEWMGLIN KRLIYSASYRYSGVPS pec PYNSDTNY RFSGSGSGTEFTLTISNLQPEDFA erAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARVALRVALDYWGQGTL TYYCQQYNRYPYTFGQGTKLEI delVTVSSAS KRTVAAPSVFIFPP puoTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SDEQLKSGTASVVCLLNNFYPR c- SSGL EAKVQWKVDNALQSGNSQESV nietYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGP TEQDSKDSTYSLSSTLT orSVFL LSKADYEKHKVYACEVTHQGL p FPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF SSPVTKSFNRGEC) (SEQ ID NO: G NSTYRV 1027) VSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRW QEGNV FSCSVMHEALHNHYTQKSLSLSLGK) (SEQ ID NO:27)Attorney. 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No.616146.100579ba1a EVKLVESGGG LVQPGGSLRL SCAASGFTFN TYAMNWVRQA PGKGLEWVARQAVVTQEPSF SVSPGGTVTLmGgmirIo IRSKYNNYAT YYADSVKDRF TISRDDSKSS LYLQMNNLKT EDTAMYYCVR TCRSSTGAVT TSNYANWVQQathpHGNFGNSYVS WFAYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL TPGQAFRGLI GGTNKRAPGVo dc ezim ylGCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS PARFSGSLIG DKAALTITGAp Ena lLGTQTYICNV NHKPSNTKVD KRVEPKSCDK THTCPPCPAP EFEGGPSVFL QADDESIYFC ALWYSNLWVF mluec FPPKPKDTLM ISRTPEVTCV VVAVSHEDPE VKFNWYVDGV EVHNAKTKPR GGGTKLTVLG QPKAAPSVTL hciB EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ FPPSSEELQA NKATL fi eVCLIS c g eraPREPQVYTLP PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK DFYPGAVTVA WKADSSPVKA plsTTPPVLDSDG SFLLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS GVETTTPSKQ SNNKYAASS iesY B LSPG (SEQ ID NO:28) (EVQLVESGGG LVQPDRSLRL SCAAS ;ufGFTFH LSLTPEQWKS HRSYSCQVTH 3fiDYAMHWVRQA PGKGLEWVST ISWNSGTIGY ADSVKGRFTI SRDNAKNSLY EGSTVEKTVA PTECS (SEQ ID D D C LQMNSLRAED TALYYCAKDI QYGNYYYGMD VWGQGTTVTV SSASTKGPSV NO: 1028) (EIVLTQSPAT , 02FPLAPSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ LSLSPGERAT LSCRASQSVS D SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKRV EPKSCDKTHT SYLAWYQQKP GQAPRLLIYD C CPPCPAPEFE GGPSVFLFPP KPKDTLMISR TPEVTCVVVA VSHEDPEVKF ASNRATGIPA RFSGSGSGTD NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN FTLTISSLEP EDFAVYYCQQ KALPAPIEKT ISKAKGQPRE PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS RSNWPITFGQ GTRLEIKRTV DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSRLTVDKS RWQQGNVFSC AAPSVFIFPP SDEQLKSGTA SVMHEALHNH YTQKSLSLSP G) (SEQ ID NO:29) SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC) (SEQ ID NO: 1029)ba4s QVTLRESGPA LVKPTQTLTL TCTVSGFSLS AYSVNWIRQP PGKALEWLAMDIVMTQSPDS LSVSLGERATm GigtiIWGDGKIVYN SALKSRLTIS KDTSKNQVVL TMTNMDPVDT ATYYCAGDGY INCRAzI taSKSVD SYGNSFMHWYui dm YPYAMDNWGQ GSLVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY QQKPGQPPKL LIYLASNLESkierz reFPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTKTYT GVPDRFSGSG SGTDFTLTISbienadciCNVDHKPSNT KVDKRVESKY GPPCPPCPAP EFLGGPSVFL FPPKPKDTLM SLQAEDVAVY YCQQNNEDPR L m p uoISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV TFGGGTKVEI KRTVAAPSVF ht;3A VSVLTVLHQD WLNGKEYKCK VSNKGLPSSI EKTISKAKGQ PREPQVYTLP IFPPSDEQLK SGTASVVCLL 1- PSQEEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG NNFYPREAKV QWKVDNALQS LISFFLYSRLTV DKSRWQEGNV FSCSVMHEAL HNHYTQKSLS LSLGK (SEQ ID GNSQESVTEQ DSKDSTYSLS NO: 30) STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC (SEQ ID NO: 1030)baba a QVQLVQSGAEVKKPGSSVKVSCKASGYAFSYSWINWVRQAPGQGLEWMGRIFPGDIVMTQTPLSLPVTPGEPASISCRm mo DGDTDY SSKSLLHSNGITYLYWYLQKPGatMifsshNGKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYoloCARNVFDGYWLVYWGQGT QSPQLLIYQ rpMSNLV m LVTVSSA SGVPDRFSGSGSGTDFTLKISRV GC1ylllSTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVL EAEDVGVYYCAQNLELPYTFGG G geIc- QSSG GTKVEIKRTVAAPSV 1 B + LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDGGGGSGGGGSQA FIFPPSDRKLKSGTASVVCLLNN 2ecg VVTQE FYPREAKVQWKVDNA ifraLQSGNS iclePSLTVSPGGTVTLTCGSSTGAVTTSNYANW esVQEKPGQAFRGLIGGTNKRAPGTPA QESVTEQDSKDSTYSL p RFSGS SSTLTLSKADYEKHKVYACEVT siuffiLLGGKAALTLSGAQPEDEAEYYCALWYSNLWVFGGGTKLTVLSSASTKGPSVFP HQGLSSPVTKSFNRGEC (SEQ B;D e LAPSSK ID NO: 1031) 3 STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV (EVQLLESGGGLVQPGGSLRLSC D C,PSSSL AASGFTFSTYAMNWVRQAPGK 02GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPK GLEWVSRIRSKYNNYAT D DTLMI YYADSVKGRFTISRDDSKNTLY C SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT LQMNSLRAEDTAVYYCVRHGN VLHQDW FGNSYVSWFAYWGQGTL LNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCL VTVSSASVAAPSVFIFPPSDEQL VKGFY KSGTASVVCLLNNFYPREAKVQ PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM WKVDNALQSGNSQES HEALH NHYTQKSLSLSPGK (SEQ ID NO:31) VTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTK SFNRGEC) (SEQ ID NO: 1032)Attorney. 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No.616146.100579ba4s QVQLVQSGAEVKKPGSSVKVSCKASGYKFTRYVMHWVRQAPGQGLEWMGYINPDIQMTQSPSSLSASVGDRVTITCm GitgilYNDGTNY KASDHILKFLTWYQQKPGKAPKuziI odceNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARNWDTGLWGQGTTVTVS LLIYGATSLETGVPSki erizivSASTK MniG RFSGSGSGTDFTLTISSLQPEDFA ataPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG TYYCQMYWSTPFTFGGGTKVEI mreuclLYSL KRTVAAPSVFIFPP H;9U SSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVF SDEQLKSGTASVVCLLNNFYPR 1pLFPP EAKVQWKVDNALQSGNSQESV 3 2- KPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST TEQDSKDSTYSLSSTLT LIYRVVSV LSKADYEKHKVYACEVTHQGL LTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK SSPVTKSFNRGEC (SEQ ID NO: NQVSL 1033) TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSC SVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 33)ba4 QVQLQESGPGLVKPSETLSLTCTVSGFSLTSYGVHWIRQPPGKGLEWIGVIYADm GllGS DIVMTQSPDSLAVSLGERATINC gecTNYN KSSESVSNDVAWYQQKPGQPPKuzIsildPSLKSRVTISKDTSKNQVSLKLSSVTAADTAVYYCARAYGNYWYIDVWGQGTTel eu z o V LLINYAFHRFTGVPD i m TaTVSSAS RFSGSGYGTDFTLTISSLQAEDVsina uTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ AVYYCHQAYSSPYTFGQGTKLE m q uslSSGL IKRTVAAPSVFIFPP H; ae YSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGGP SDEQLKSGTASVVCLLNNFYPR 1- gahSVFL EAKVQWKVDNALQSGNSQESV D P posFPPKPKDTLMISRTPEVTCVVVAVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF TEQDSKDSTYSLSSTLT E NSTYRV LSKADYEKHKVYACEVTHQGL VSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE SSPVTKSFNRGEC (SEQ ID NO: MTKNQ 1034) VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QEGNV FSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 34)ba4,aQGQLVQSGAE VKKPGASVKV SCKASGYTFT DYEMHWVRQA PIHGLEWIGV DVVMTQSPLS LPVTLGQPASmiG IESETGGTAY NQKFKGRVTI TADKSTSTAY MELSSLRSED TAVYYCAREG ISCRSSQSlgaImo IV HSNGNTYLEWrdeniITTVATTYYW YFDVWGQGTT VTVSSASTKG PSVFPLAPCS RSTSESTAAL YLQKPGQSPQ LLIYKVSNRFpi zicrGCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS SGVPDRFSGS GSGTDFTLKIo TnaaclLGTKTYTCNV DHKPSNTKVD KRVESKYGPP CPPCPAPEFL GGPSVFLFPP SRVEAEDVGV YYCFQGSHVP muaeKPKDTLMISR TPEVTCVVVD VSQEDPEVQF NWYVDGVEVH NAKTKPREEQ LTFGQGTKLE IKRTVAAPSV H n ;yrFNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KGLPSSIEKT ISKAKGQPRE FIFPPSDEQL KSGTASVVCL 1-ahp PQVYTLPPSQ EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP LNNFYPREAK VQWKVDNALQ D PosaPVLDSDGSFF LYSRLTVDK RWQEGNVFSC SVMHEALHNH YTQKSLSLSL GK SGNSQESVTE QDSKDSTYSL N (SEQ ID NO: 35) SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1035)ba4a QVQLVQSGAE VKKPGASVKV SCKASGYSFT SYWMNWVRQA PGQGLEWIGVEIVLTQSPAT LSLSPGERATm G miIHPSDSETWL DQKFKDRVTI TVDKSTSTAY MELSSLRSED TAVYYCAREH LSCRASESVD NYGMSFMNWlg Fn IoaniYGTSPFAYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD QQKPGQPPKL LIHAASNQGSfidecrtYFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY GVPSRFSGSeziRn aacG SGTDFTLTIS l TCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEFLGGPSVF LFPPKPKDTL SLEPEDFAVY FCQQSKEVPY mleucMISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR T ;lFGGGTKVEI KRTVAAPSVF HeVVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL IFPPSDEQLK SGTA 1 k SVVCLL -rePPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD NNFYPREAKV QWKVDNALQS D P M GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLG (SEQ ID GNSQESVTEQ DSKDSTYSLS NO: 36) STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC (SEQ ID NO: 1036)ba ;sl e EVQLVESGGG LVQPGGSLRL SCSASGFTFS SFGMHWVRQA PGKGLEWVAmeirsYDVVMTQSPLS LPVTPGAPAS a ISSGSSTIYY GDTVKGRFTI SRDNAKNSLF LQMSSLRAED TAVYYCAREG ISCRSSQSIV HSNGNTYLEWnbaifesidGYYYGRSYYT MDYWGQGTTV TVSSASTKGP SVFPLAPSSK STSGGTAALG YLQKPGQSPK LLIYKVSNRFceotor sCLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL SGVPDRFSGS GSGTDFTLRI L p ’ areGTQTYICNVN HKPSNTKVDK RVEPKSCDKT HTCPPCPAPE LLGGPSVFLF SRVEAEDVGI YYCFQGSHVP temPPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE PTFGPGTKLE IKRTVAAPSV bidiehEQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP FIFPP olzlSDEQL KSGTASVVCL REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT LNNFYPREAK VQWKVDNALQ y A m TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SGNSQESVTE QDSKDSTYSL A SPGK (SEQ ID NO: 37) SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1037)Attorney. 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No.616146.100579ba1smeQVQLVQSGGG VVQPGRSLRL SCKASGYTFT RYTMHWVRQA PGKGLEWIGYtDIQMTQSPSS LSASVGDRVT GzeINPSRGYTNY NQKVKDRFTI SRDNSKNTAF LQMDSLRPED TGVYFCARYY ITCSASSSVS YMNWYQQTPGugIbildDDHYCLDYWG QGTPVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVpeaiKD KAPKRWIYDT SKLASGVPSRezidYFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY FSGSGSGTDY TFTISSLQPE Tna1epICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPEAAGGP SVFLFPPKPK DIATYYCQQW SSNPFTFGQG muytDTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS TKLQITRTVA APSVFIFPPS Hf;3otTYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV DEQLKSGTAS VVCLLNNFYP DesYTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL REAKVQWKVD NALQSGNSQE Cno DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK (SEQ SVTEQDSKDS TYSLSSTLTL yaleID NO: 38) SKADYEKHKV YACEVTHQGL D SSPVTKSFNR GEC (SEQ ID NO: 1038)ba1s QAYLQQSGAE LVRPGASVKM SCKASGYTFT SYNMHWVKQT PRQGLEWIGGQIVLSQSPAI LSASPGEKVTm Gisig IYPGNGDTSY NQKFKGKATL TVGKSSSTAY MQLSSLTSED SAVYFCARYD MTCRASSSVS YMHWYQQKP IorGxuteYNYAMDlcYWGQ GTSVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY SSPKPWIYAT SNLAiirlcSGVPAR s beFPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI FSGSGSGTSY SFTISRVEAE Umi ehlpCitCNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD DAATYYCQQW TFNPPTFGGG ;luTLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST TRLEIKRTVA APSVFIFPPS 02M YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY DEQLKSGTAS VVCLLNNFYP D TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD REAKVQWKVD NALQSGNSQE C SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ SVTEQDSKDS TYSLSSTLTL ID NO: 39) SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC (SEQ ID NO: 1039)ba1QVQLVQSGAEVKKPGSSVMVSCQASGGLLEDYIINWVRQAPGQGPEWMGGIIPVDIQMTQSPSSLSAAVm GnGDRVTITC oiiLGTVHY QASQDIVNvgI tcYLNWYQQKPGKAPesnGPKFQGRVTITADESTDTAYMELSSLRSEDTAMYYCATETALVVSETYLPHYFDN KLLIYVASNLETGri aefVPS n miWGQGT RFSGSGSGTDFSLTISSLQPEDVA N u V H LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV TYYCQQYDNLPLTFGGGTKVEI ; S R V HTFP KRTVAAPSVFIFPP S R AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP SDEQLKSGTASVVCLLNNFYPR PCPA EAKVQWKVDNALQSGNSQESV PELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN TEQDSKDSTYSLSSTLT AKTKP LSKADYEKHKVYACEVTHQGL REEQYNSTYRVVSVLTVLHQDWLEGKEYKCKVSNKALPAPIEKTISKAKGQPREP SSPVTKSFNRGEC (SEQ ID NO: QVYTL 1040) PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 40)baAr QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDIQMTQSPSSLSASm 2eVGDRVTITC c n DGSNKYY RASQSINSYLDWYQQKPGKAPKu Gmigl Iac ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPRGATLYYYYYGMD LLIYAASSLQSGVPSenareVWGQGTT RFSGSGSGTDFTLTISSLQPEDFAmerm v uil;VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVH TYYCQQYYSTPFTFGPGTKVEIK T H;ciTFPA RTVAAPSV 4-tsFIFPP a VLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCP SDEQLKSGTASVVCLLNNFYPR AlLpoAPPVA EAKVQWKVDNALQSGNSQESV TeCnitGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKP TEQDSKDSTYSLSSTLT n A REEQF LSKADYEKHKVYACEVTHQGL NSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTL SSPVTKSFNRGEC (SEQ ID NO: PPSRE 1041) EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT VDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 41)bade si QVQLVQSGAE VKKPGASVKV SCKASGYSFT SSWIHWVKQA PGQGLEWMGEQIVLTQSPGT LSLSPGERATmsiINPGNVRTNY NENFRNKVTM TVDTSISTAY MELSRLRSDD TAVYYCTVVF MTCTASSSVS SlzionasairSYFHWYQQK YGEPYFPYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD PGQAPRLWIY RTSRLASGepm osVP u p YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY DRFSGSGSGT DFTLTISRLE SHr;ralu ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPEAAGGP SVFLFPPKPK PEDAATYYCH QFHRSPLTFG ot tpsu DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS AGTKLEIKRT VAAPSVFIFP ecpTYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV PSDEQLKSGT ASVVCLLNNF erdeYTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL YPREAKVQWK VDNALQSGNS 6zi3-laDSDGSFFLYS KLTVDKSRWQ QGN LIrVFSCSVM HEALHNHYTQ KSLSLSPGK (SEQ QESVTEQDSK DSTYSLSSTL e neID NO: 42) TLSKADYEKH KVYACEVTHQ G GLSSPVTKSF NRGEC (SEQ ID NO: 1042)Attorney. 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No.616146.100579ba4a QLQLQESGPG LVKPSETLSL TCTVSGGSIS SGSYFWGWIR QPPGKGLEWISYVLTQPPSV SVAPGQTARImG mag GSIYYSGITY YNPSLKSRVT ISVDTSKNQF SLKLSSVTAA DTAVYYCARH TCGGNNIGSK SVHWYQQPPGtsI oliDGAVAGLFDY WGQGTLVTVS SASTKGPSVF PLAPCSRSTS ESTAAlcieLGCLV QAPVVVVYDD SDRPSGIPERcefi yTcem peKDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTK FSGSNSGNTA TLTISRVEAG silpbiTYTCNVDHKP SNTKVDKRVE SKYGPPCPPC PAPEAAGGPS VFLFPPKPKD DEAVYYCQVW DSSSDHVVFG tlTLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST GGTKLTVLGQ PKAAPSVTLF dueM YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY PPSSEELQAN KATLVCLISD zinaTLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD FYPGAVTVAW KGDSSPVKAG m SDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGK (SEQ VETTTPSKQS NNKYAASSYL u H ID NO: 43) (EVQLVESGGG LVQPGGSLRL SCAASGFTFN TYAMNWVRQA SLTPEQWKSH RSYSCQVTHE ;3PGKGLEWVAR IRSKYNNYAT YYAASVKGRF TISRDDSKNS LYLQMNSLKT GSTVEKTVAP TECS (SEQ ID D C EDTAVYYCAR HGNFGNSYVS WFAYWGQGTL VTVSSASTKG PSVFPLAPCS NO: 1044) (QTVVTQEPSL , A RSTSESTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL TVSPGGTVTL TCRSSTGAVT M SSVVTVPSSS LGTKTYTCNV DHKPSNTKVD KRVESKYGPP CPPCPAPEAA TSNYANWVQQ KPGQAPRGLI C B GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSQEDPEVQF NWYVDGVEVH GGTNKRAPGT PARFSGSLLG NAKTKPREEQ FNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KGLPSSIEKT GKAALTLSGV QPEDEAEYYC ISKAKGQPRE PQVYTLPPSQ EEMTKNQVSL TCLVKGFYPS DIAVEWESNG ALWYSNLWVF GGGTKLTVLG QPENNYKTTP PVLDSDGSFL LYSKLTVDKS RWQEGNVFSC SVMHEALHNH QPKAAPSVTL FPPSSEELQA YTQKSLSLSL GK) (SEQ ID NO: 44) NKATLVCLIS DFYPGAVTVA WKADSSPVKA GVETTTPSKQ SNNKYAASSY LSLTPEQWKS HRSYSCQVTH EGSTVEKTVA PTECS) (SEQ ID NO: 1043)ba1a EVQLVQSGAE VKKPGASVKV SCKASGYTFT NYYIHWVRQA PGQGLEWIGWDIVMTQSPDS LAVSLGERATmGug mIYPGDGNTKY NEKFKGRATL TADTSTSTAY LELSSLRSED TAVYYCARDS INCKSzI oSQSLL NSRTRKNYLAuhYSNYYFDYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD WYQQKPGQPP KLLIYtceif pWASTR icm YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ESGVPDRFSG SGSGTDFTLTnusey plraICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK ISSLQAEDVA VYYCTQSFILosilDTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYGS RTFGQGTKVE IKRTVAAPSV MbudeciTYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV FIFPPSDEQL KSGTASVVCL zillo naF YTLPPSREEM TKNQVSLSCA VKGFYPSDIA VEWESNGQPE NNYKTTPPVL LNNFYPREAK VQWKVDNALQ m DSDGSFFLVS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK (SEQ SGNSQESVTE QDSKDSTYSL u H ID NO: 45) (EVQLVESGGG LVQPGGSLRL SCAASGYTFT SYNMHWVRQA SSTLTLSKAD YEKHKVYACE ;3PGKGLEWVGA IYPGNGDTSY NQKFKGRFTI SVDKSKNTLY LQMNSLRAED VTHQGLSSPV TKSFNRGEC D C TAVYYCARVV YYSNSYWYFD VWGQGTLVTV SSASTKGPSV FPLAPSSKST (SEQ ID NO: 1045) (DIQMTQSPSS , 0 SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV LSASVGDRVT ITCRASSSVS 2 D VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPKSCDKTHT CPPCPAPELL YMHWYQQKPG KAPKPLIYAP C GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH SNLASGVPSR FSGSGSGTDF NAKTKPREEQ YGSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT TLTISSLQPE DFATYYCQQW ISKAKGQPRE PQVYTLPPSR EEMTKNQVSL WCLVKGFYPS DIAVEWESNG SFNPPTFGQG TKVEIKRTVA QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH APSVFIFPPS DEQLKSGTAS YTQKSLSLSP GK) (SEQ ID NO: 46) VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC) (SEQ ID NO: 1046)ba1QMQLVQSGPE VKKPGTSVKV SCKASGFTFM SSAVQWVRQA RGQRLEWIGWEIVLTQSPGT LSLSPGERATmiG9g1- IVIGSGNTNY AQKFQERVTI TRDMSTSTAY MELSSLRSED TAVYYCAAPY LSCRASQSVS SSYLAWYQQKvaIn DIaV CSSISCNDGF DIWGQGTMVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC PGQAPRLLIY GASSRATGIPglicm O LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG DRFSGSGSGT DFTLTISRLE,u CbTQTYICNVNH KPSNTKVDKR VEPKSCDKTH TCPPCPAPEF EGGPSVFLFP PEDFAVYYCQ HYGSSaH RGWTF ; 2- PKPKDTLYIT REPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE GQGTKVEIKR TVAAPSVFIFmiveV QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPASIEK TISKAKGQPR PPSDEQLKSG TASVVCLLNNgoaCxi -EPQVYTLPPS REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT FYPREAKVQW KVDNALQSGN S PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS PGK SQESVTEQDS KDSTYSLSST T R A (SEQ ID NO: 47) LTLSKADYEK HKVYACEVTH S QGLSSPVTKS FNRGEC (SEQ ID NO: 1047)Attorney. 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No.616146.100579ba4a QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHREIVLTQSPATLSLSPGERATLSCRm G miGSTNSN ASQSISSYLAWYQQKPGQAPRLlgtaIo nnalPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGT LIYDASNRATGIPAle ameM LVTVSS RFSGSGSGTDFTLTISSLEPEDFA R u H ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV VYYCQQRSNWPLTFGQGTNLEI ; 3- LQSS KRTVAAPSVFIFPP G GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG SDEQLKSGTASVVCLLNNFYPR A L GPSV EAKVQWKVDNALQSGNSQESV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ TEQDSKDSTYSLSSTLT FNSTY LSKADYEKHKVYACEVTHQGL RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ SSPVTKSFNRGEC (SEQ ID NO: EEMTK 1048) NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR WQEG NVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 48)pscAIQMTQSPSS LSASVGDRVT ITCRASQDIR NYLNWYQQKP GKAPKLLIYYAQQGEEDPQA LSuiIQEGENAffaT i m TSRLESGVPS RFSGSGSGTD YTLTISSLQP EDFATYYCQQ GNTLPWTFGQ MNCSYKTSIN NLQWYRQNSGatcneo nep GTKVEIKGGG GSGGGGSGGG GSGb si aleGGGSGGG SEVQLVESGG GLVQPGGSLR RGLVHLILIR SNEREKHSGReLSCAASGYSF TGYTMNWVRQ APGKGLEWVA LINPYKGVST YNQKFKDRFT LRVTLDTSKK S TB;m SSLLITASR 3lISVDKSKNTA YLQMNSLRAE DTAVYYCARS GYYGDSDWYF DVWGQGTLVT AADTASYFCA TDGSTPMQFG DaeCvVSSGGGGSDG GITQSPKYLF RKEGQNVTLS CEQNLNHDAM YWYRQDPGQG KGTRLSVIAN IQKPDPAVY ,uQ 0 LRLIYYSWAQ GDFQKGDIAE GYSVSREKKE SFPLTVTSAQ KNPTAFYLCA LRDSKSSDKS VCLFTDFD 0ci1tSQ patgsSSWGAPYEQY FGPGTRLTVT EDLKNVFPPE VAVFEPSEAE ISHTQKATLV TNVSQSKDSD VYITDKCVLD ateCLATGFYPDH VELSWWVNGK EVHSGVCTDP QPLKEQPALN DSRYALSSRL MRSMDFKSNS AVAWSNKSDF M RVSATFWQDP RNHFRCQVQF YGLSENDEWT QDRAKPVTQI VSAEAWGRAD ACANAFNNSI IPEDT (SEQ ID (SEQ ID NO: 49) NO: 1049)ba,a QVQLVQSGAE VKKPGASVKV SCKASGYTFT GYYMHWVRQA PGQmidE GLEWMGWDIQLTQSPSS LSASVGDRVT b M INPNSGGTNY AQKFQGRVTM TRDTSISTAY MELSRLRSDD TAVYYCARSP ITCSASQDIS NYLNWYQQKPcirm D NPYYYDSSGY YYPGAFDIWG QGTMVTVSSA SVAAPSVFIF PPSDEQLKSG GKAPKVLIYF TSSLHSaal ,GVPS F / aD TASVVCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST RFSGSGSGTD FTLTISSLQP p p M a A LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGECDKTH TCPPCPAPEA EDFATYYCQQ YSTVPWTFGQ k w 1 AGGPSVFLFP PKPKDTLMAS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV GTKVEIKRTV AAPSVFIFPP G HNAKTKPREE QYNSTYRVVS VLTVLAQDWL NGKEYKCKVS NKALGAPIEK SDEQLKSGTA SVVCLLNNFY gIdTISKAKGQPR EPQVCTLPPS RDELTKNQVS LSCAVKGFYP SDIAVEWESN PREAKVQWKV DNALQSGNSQ eziGQPENNYKTT PPVLDSDGSF FLVSKLTVDK SRWQQGNVFS CSVMHEALHN ESVTEQDSKD STYSLSSTLT naAYTQKSLSLS PGK (SEQ ID NO: 50) (EVQLVESGGG LVQPGGSLRL LSKADYEKHK VYACEVTHQG mu SCAASGYDFT HYGMNWVRQA PGKGLEWVGW INTYTGEPTY AADFKRRFTF LSSPVTKSFN RGEC (SEQ ID h / SLDTSKSTAY LQMNSLRAED TAVYYCAKYP YYYGTSHWYF DVWGQGTLVT NO: 1050) (SYVLTQPPSV naVSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SVAPGQTARI TCGGNNIGSK mu SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK SVHWYQQKPG QAPVLVVYDD H;VEPKSCDKTH TCPPCPAPEA AGGPSVFLFP PKPKDTLMAS RTPEVTCVVV SDRPSGIPER FSGSNSGNTA 2-g DVSHEDPEVK FNWYVDGVEV HNAKTKPREE QYNSTYRVVS VLTVLAQDWL TLTISRVEAG DEADYYCQVW n A NGKEYKCKVS NKALGAPIEK TISKAKGQPR EPQVYTLPPC RDELTKNQVS DSSSDHWVFG GGTKLTVLSS , A LWCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSKLTVDK ASTKGPSVFP LAPSSKSTSG -F SRWQQGNVFS CSVMHEALHN AYTQKSLSLS PGK) (SEQ ID NO: 51) GTAALGCLVK DYFPEPVTVS GE WNSGALTSGV HTFPAVLQSS V GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSC) (SEQ ID NO: 1051)ba4e EVQLVESGGG LVKPGGSLRL SCAASGFTFS NYAMSWVRQA PGKGLEWVATQIVLTQSPAT LSLSPGERATm GsigaesISSGGSHTYY LDSVKGRFTI SRDNSKNTLY LQMNSLRAED TALYYCARLF MSCTASSSVS SSYLHWYQQKlImiTGYAMDYWGQ GTLVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY PGKAPKLWIY STSNLASGVitde dPuznFPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTKTYT SRFSGSGSGT DYTLTI SinainSSLQ i CNVDHKPSNT KVDKRVESKY GPPCPPCPAP EFEGGPSVFL FPPKPKDTLM PEDFATYYCH QYYRLPPITF mtu ulgISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV GQGTKLEIKR TVAAPSVFIF H;sgaVSVLTVLHQD WLNGKEYKCK VSNKGLPSSI EKTISKAKGQ PR 1dEPQVYTLP PPSDEQLKSG TASVVCLLNN PSQEEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG FYPREAKVQW KVDNALQSGN CloC SFFLYSRLTV DKSRWQEGNV FSCSVMHEAL HNHYTQKSLS LSLGK (SEQ ID SQESVTEQDS KDSTYSLSST NO: 52) LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC (SEQ ID NO: 1052)Attorney. 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No.616146.100579ba1QVQLVQSGAE VKKPGASVKV SCKASGYPFT SYGISWVRQA PGQGLEWMGWEIVLTQSPGT LSLSPGERm G9AT 1i- ISTYQGNTNY AQKFQGRVTM TTDTSTTTGY MELRRLRSDD TAVYYCARDY LSCRASQTVS STSLAWYQQKvgI DonITRGAWFGESL IGGFDNWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA PGQAPRLLIY GASSRATGIPrt aV o ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS DRFSGSGSGT DFTLTISR S m O LE u C H SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV PEDFAVYYCQ QHDTSLTFGG ; 2- FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK GTKVEIKRTV AAPSVFIFPP V PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK SDEQLKSGTA SVVCLLNNFY o C- GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN PREAKVQWKV DNALQSGNSQ S R YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVLHE ALHSHYTQKS ESVTEQDSKD STYSLSSTLT A LSLSPGK (SEQ ID NO: 53) LSKADYEKHK VYACEVTHQG S LSSPVTKSFN RGEC (SEQ ID NO: 1053)ba1QITLKESGPT LVKPTQTLTL TCSFSGFSLS TSGVGVGWIR QPPGKALEWLELVLTQPPSV SAAPGQKVmiG9TI g1- ALIDWDDNKY HTTSLKTRLT ISKDTSKNQV VLTMTNMDPV DTATYYCARI SCSGSSSNIG NNYVSWYQQLvnI DIPGdnFLRYRNRY YYYGMDVWGQ GTTVTVSSAS TKGPSVFPLA PSSKSTSGGT PGTAPKLLIY DNNKRPSGIPaaV O AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP DRFSGSKSGT SATLGITGLQgemu C H SSSLGTQTYI CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPELLGGPS TGDEADYYCG TWDSSLSAGV R;2- VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT FGGGTELTVL GQPKAAPSVT V KPREEQYNST YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA LFPPSSEELQ ANKATLVCLI o C- KGQPREPQVY TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN SDFYPGAVTV AWKADGSPVK S R NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK AGVETTKPSK QSNNKYAASS A SLSLSPGK (SEQ ID NO: 54) YLSLTPEQWK SHRSYSCQVT S HEGSTVEKTV APTECS (SEQ ID NO: 1054)ba1QVQLVESGGG LVKPGGSLRL SCAASGFTFS DYYMSWIRQA PGKGLEWVSYDIQMTQSPSS LSASVGDRVTmiG9g1- ITYSGSTIYY ADSVKGRFTI SRDNAKSSLY LQMNSLRAED TAVYYCARDR ITCQASQDIT NYLNWYQQKPviI DrIinGTTMVPFDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK GKAPKLLIYA ASNLETGVPsaV Sam O DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT RFSGSGSGTD FTFTISGLQP C u C H YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP EDIATYYCQQ YDNLPLTFGG ; 2- KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN GTKVEIKRTV AAPSVFIFPP V STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ SDEQLKSGTA SVVCLLNNFY o C- VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV PREAKVQWKV DNALQSGNSQ S R LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ESVTEQDSKD STYSLSSTLT A (SEQ ID NO: 55) LSKADYEKHK VYACEVTHQG S LSSPVTKSFN RGEC (SEQ ID NO: 1055)ba1QVQLVESGGG VVQPGRSLRL SCAASGFTFS NYAMYWVRQA PGKGLEWVAVQSALTQPASV SGSPGQSITImiG9g1- ISYDGSNKYY ADSVKGRFTI SRDNSKNTLY LQMNSLRTED TAVYYCASGS SCTGTSSDVG GYNYVSWYQQveIn DIV DYGDYLLVYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK HPGKAPKLMI YDVSKRPSGV damIm O DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT SNRFSGSKSG NTASLTISGL u C H YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP QSEDEADYYC NSLTSISTWV ; 2- KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN FGGGTKLTVL GQPKAAPSVT V STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ LFPPSSEELQ ANKATLVCLI o C- VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV SDFYPGAVTV AWKADSSPVK S R LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK AGVETTTPSK QSNNKYAASS A (SEQ ID NO: 56) YLSLTPEQWK SHRSYSCQVT S HEGSTVEKTV APTECS (SEQ ID NO: 1056)bala a QMQLVESGGG VVQPGRSLRL SCAASGFTFR TYGMHWVRQA PGKGLEWVAVSYVLTQPPSV SVAPGQTARIm m m IWYDGSNKHY ADSVKGRFTI TRDNSKNTLN LQMNSLRAED TAVYYCARAP TCGGNNLGSK SVHWYQQKPGuloerthtsQWELVHEAFD IWGQGTMVTV SSASTKGPSV FPLAPCSRST SESTAALGCL QAPVLVVYDD SDRPSWIPERpesaezVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSNFGT FSGSNSGNTAeciT mreTLTISRGEAG y QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD DEADYYCQVW DSSSDHVVF hveG T S TLMISRTPEV TCVVVDVSHE DPEVQFNWYV DGVEVHNAKT KPREEQFNST GGTKLTVLGQ PKAAPSVTLF FRVVSVLTVV HQDWLNGKEY KCKVSNKGLP APIEKTISKT KGQPREPQVY PPSSEELQAN KATLVCLISD TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPMLD FYPGAVTVAW KADSSPVKAG SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ VETTTPSKQS NNKYAASSYL ID NO: 57) SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS (SEQ ID NO: 1057)Attorney. 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No.616146.100579ba1smnQVQLVESGGG VVQPGRSLRL SCAASGFTFS TYGMHWVRQA PGKGLEWVAVAIQLTQSPSS LSASVGDRVT GoIWDDGSYKYY GDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDG ITCRASQDIS SALVWYQQKPatgI itnaciaITMVRGVMKD YFDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSviftGGTAAL GKAPKLLIYD ASSLESGVPS i u mcemGCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS RFSGSESGTD FTLTISSLQP p n LGTQTYICNV NHKPSNTKVD KRVEPKSCDK THTCPPCPAP ELLGGPSVFL EDFATYYCQQ FNSYPLTFGG AsiobitrFPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR GTKVEIKRTV AAPSVFIFPP naesn EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ SDEQLKSGTA SVVCLLNNFY miu PREPQVYTLP PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK PREAKVQWKV DNALQSGN H02SQ ;nTTPPVLDSDG SFLLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS ESVTEQDSKD STYSLSSTLT TEoxMeLSPGK (SEQ ID NO: 58) (QVQLVQSGAE VKKPGASVKV SCETSGYTFT LSKADYEKHK VYACEVTHQG R SYGISWVRQA PGHGLEWMGW ISAYNGYTNY AQKLQGRVTM TTDTSTSTAY LSSPVTKSFN RGEC (SEQ ID c,F G MELRSLRSDD TAVYYCARDL RGTNYFDYWG QGTLVTVSSA STKGPSVFPL NO: 1058) (DIQMTQSPSS RF E APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG VSASVGDRVT ITCRASQGIS G / EwLYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP NWLAWFQHKP GKAPKLLIYA CL CPAPELLGGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY ASSLLSGVPS RFSGSGSGTD CS VDGVEVHNAK TKPREEQYNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL FTLTISSLQP EDFATYYCQQ N PAPIEKTISK AKGQPREPQV YTLPPSREEM TKNQVSLTCL VKGFYPSDIA ANSFPITFGQ GTRLEIKRTV VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ QGNVFSCSVM AAPSVFIFPP SDEQLKSGTA HEALHNHYTQ KSLSLSPGK) (SEQ ID NO: 59) SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC) (SEQ ID NO: 1059)ba1s EVQLVQSGAE VKKPGESLKI SCKGSGYIFT NYWIAWVRQM PGKGLESMGIEIVLTQSPGT LSLSPGERATm Gguso IYPGDSDIRY SPSFQGQVTI SADKSITTAY LQWSSLKASD TAMYYCARHD LSCRASQSVS SSFFAWYQQKulI toarnfi aIEGFDYWGRG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PGQAPRLLIY GASSRATGIP mePEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC DRLSGSGSGT DFTLTITRLEn m A uhtH NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APEFEGGPSV FLFPPKPKDT PEDFAVYYCQ QYDSSAITFG ; yr1eLMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY QGTRLEIKR RsT VAAPSVFIFP u ApNuRVVSVLTVLH QDWLNGKEYK CKVSNKALPA SIEKTISKAK GQPREPQVYT PSDEQLKSGT ASVVCLLNNF LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS YPREAKV FIlciQWK VDNALQSGNS m DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK (SEQ ID QESVTEQDSK DSTYSLSSTL etsNO: 60) TLSKADYEKH KVYACEVTHQ y S GLSSPVTKSF NRGEC (SEQ ID NO: 1060)ba1s EVQLVESGGG LVQPGGSLRL SCAASGFTFS DYNMAWVRQA PGKGLEWVATAIQLTQSPSS LSASVGDRVTm GigsaITYEGRNTYY RDSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCASPP ITCRADESVR TLMHWYQQKPuziI irQYYEGSIYRL WFAHWGQGTL VTVSSASTKG PSVFPLAPSSedeozsKSTSGGTAAL GKAPKLLIYL VSNSEIGVPDkP GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS RFSGSGSGTD FRLTISSLQPmiinaLGTQTYICNV NHKPSNTKVD KKVEPKSCDK THTCPPCPAP ELLGGPSVFL EDFATYYCQQ TWSDPWTFGQ B mu FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR GTKVEIKRTV AAPSVFIFPP H;EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ SDEQLKSGTA SVVCLLNNFY F,PREPQVYTLP PSRDELTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK PREAKVQWKV DNALQSGNSQ A7 1 TTPPVLDSDG SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS ESVTEQDSKD STYSLSSTLT - LILSPGK (SEQ ID NO: 61) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1061)ba4s QVQLVQSGAE VKKPGASVKV SCKASGYTFT NYGLSWVRQA PGQGLEWMGWSYVLTQPPSV SVAPGKTARIm GigtitaISANNGDTNY GQEFQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARDS TCGGNIIGSK LVHWYQQKPGunIiSSSWARWFFD LWGRGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL QAPVLVIYDD GDRPSGIPERknamrolmeVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT FSGSNSGNTA TLTISRVEAGarudcKTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP SVFLFPPKPK DEADYYCQVW DTGSDPVV THip FG ;3oDTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS GGTKLTVLGQ PKAAPSVTLF 1t-A L TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV PPSSEELQAN KATLVCLISD I YTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL FYPGAVTVAW KADSSPVKAG DSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK (SEQ VETTTPSKQS NNKYAASSYL ID NO: 62) SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS (SEQ ID NO: 1062)Attorney. 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No.616146.100579banalamiEVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA DIQMTQSPST LSASVGDRVT l ISGDGGSTYY ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL ITCRASQSIR SWLAWu mcuiYQQKPaH maRNTIFGVVIP DAFDIWGQGT MVTVSSASTK GPSVFPLAPC SRSTSEni fSTAA GKAPKLLIYK ASSLESGVPS ;sLGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS RFSGSGSGTE FTLTISSLQPv 3 Eeu kio SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP DDFATYYCQQ YNSYSYTFGQ l-gynzPKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE GTKLEIKRTV AAPSVFIFPP it oeim QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR SDEQLKSGTA SVVCLLNNFY o o p EPQVYTLPPS QEEM o H TKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PREAKVQWKV DNALQSGNSQ igPPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LGK ESVTEQDSKD STYSLSSTLT n (SEQ ID NO: 63) LSKADYEKHK VYACEVTHQG A LSSPVTKSFN RGEC (SEQ ID NO: 1063)ba1e XVQLVESGGG VVQPGRSLRL SCAASGFAFS SYGMHWVRQA PGKGLEWVAVDIQMTQSPSS LSASVGDRVTm GsaIWFDGTKKYY TDSVKGRFTI SRDNSKNTLY LQMNTLRAED TAVYYCARDR ITCRASQSIS SYLNWYQQKPu gensaIncaidGIGARRGPYY MDVWGKGTTV TVSSASTKGP SVFPLAPSSK STSGGTAALG GKAPKLLIYA ASSLQSGVPSu sCLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL RFSGSGSGTD FTLTISSd m LQP u ’ AH rGTQTYICNVN HKPSNTKVDK RVEPKSCDKT HTCPPCPAPE LLGGPSVFLF EDFATYYCQQ SYSTPLTFGG ;eatPPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE GTKVEIKRTV A emiAPSVFIFPP behEQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KT dizlISKAKGQP SDEQLKSGTA SVVCLLNNFY REPQVYTLPP SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT PREAKVQWKV DNALQSGNSQ olA y TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPG ESVTEQDSKD STYSLSSTLT m (SEQ ID NO: 64) LSKADYEKHK VYACEVTHQG A LSSPVTKSFN RGEC (SEQ ID NO: 1064)ba4r EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYDMSWVRQA PGKGLEWVSTDIQLTQSPSF LSAYVGDRVTm GeciISGGGSYTYY QDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCASPY ITCKASQDlg VG TAVAWYQQKPraI ndaecYAMDYWGQGT TVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP GKAPKLLIYW ASTLHTGVPStslozi aEPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTKTY DnairTCN RFSGSGSGTE FTLTISSLQP teVDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP PKPKDTLMIS EDFATYYCQH YSSYPWTFGQ mu mo RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE QFNSTYRVVS GTKLEIKRTV AAPSVFIFPP H;dnVLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS SDEQLKSGTA SVVCLLNNFY 1- E QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF PREAKVQWKV DNALQSGNSQ D P FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LGK (SEQ ID NO: ESVTEQDSKD STYSLSSTLT 65) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1065)ba1n EVQLVESGGG LIQPGGSLRL SCAASGFALR MYDMHWVRQT IDKRLEWVSADIQMTQSPSS LSASVGDRITmiGgoiVGPSGDTTYA DSVKGRFAVS RENAKNSLSL QMNSLTAGDT AIYYCVRSDR ITCRASQAFD NYVAWYQQR ItcPvusnGVAGLFDSWG QGILVTVSSA STKGPSVFPL APSSKSnaefTSGG TAALGCLVKD GKVPKLLISA ASALHAGVPS n mialYFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY RFSGSGSGTH FTLTISSLQP A u H ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK EDVATYYCQN YNSAPLTFGG ;sobE DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS GTKVEIKRTV AAPSVFIFPP uriv TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV SDEQLKSGTA SVVCLLNNFY alYTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL PREAKVQWKV DNALQSGNSQ obDSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK (SEQ ESVTEQDSKD STYSLSSTLT E ID NO: 66) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1066)ba1reQVQLQQSGPE LVKPGASLKL SCTASGFNIK DTYIHWVKQR PEQGLEWIGRDIVMTQSHKF MSTSVGDRVSmiGgcIYPTNGYTRY DPKFQDKATI TADTSSNTAY LQVSRLTSED TAVYYCSRWG ITCKASQDVN TAVAWYQQKPxuIn cacGDGFYAMDYW GQGASVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK GHSPKLLIYS ASFRYTGVPDte igre tsDYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT RFTGSRSGTD FTFTISSVQAramaiherYICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELVGG PSVFLLPPKP EDLAVYYCQQ HYTTPPTFGG MC b; +2KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPPEEQYN GTKVEIKRTV AAPSVFIFPP 2 R R STLRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ SDEQLKSGTA SVVCLLNNFY E E VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPLV PREAKVQWKV DNALQSGNSQ H H LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ESVTEQDSKD STYSLSSTLT (SEQ ID NO: 67) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1067)Attorney. 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No.616146.100579ba1 QVQLVESGPG VVQPGRSLRI SCAVSGFSVT NYGVHWVRQP PGKGLEWLGV EIVMTQTPAT LSVSAGERVmGdT nagaIWAGGITNYN SAFMSRLTIS KDNSKNTVYL QMNSLRAEDT AMYYCASRGG ITCKASQSVS NDVTWYQQKPtiIaHYGYALDYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD GQAPRLLIYS ASNRYSGVPAxadem z otYFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY RFSGSGYGTE FTFTISSVQS Ninsaalb ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK EDFAVYFCQQ DYSSFGQGTK muorDTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS LEIKRTVAAP SVFIFPPSDE H;ueTYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV QLKSGTASVV CLLNNFYPRE 2nDksiYTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL AKVQWKVDNA LQSGNSQESV Gr- DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK (SEQ TEQDSKDSTY SLSSTLTLSK hgiID NO: 68) ADYEKHKVYA CEVTHQGLSS H PVTKSFNRGE C (SEQ ID NO: 1068)ba3QVQLVESGGG VVQPGRSLRL SCAASGFTFN NYGMHWVRQA PGMGLEWVAVmf nDIQMTQSPSS LSASVGDRITio oiIWHDGSDKYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARNW ITCRASQvitlertcSIS TYLHWYQQKP NLFDYWGQGT LotuVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP GKAPKLLIYA ASTLQSGVP tefS xinisEPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN RFSGSGSGTD FTLTISSLQP Amu ; VNHKPSNTKV DKKVEPKSCD KTHTCPPCPA PELLGGPSVF LFPPKPKDTL EDFATYYCQQ SFSTPPINFG sriuvMISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR QGTKLEIKRT VAAPSVFIFP riavlo VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYTL PS al bDEQLKSGT ASVVCLLNNF E PPSRDELTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD YPREAKVQWK VDNALQSGNS obE GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK (SEQ ID QESVTEQDSK DSTYSLSSTL NO: 69) TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC (SEQ ID NO: 1069)ba3EVQLVESGGG LVQPGGSLRL SCAASGFTSS SYAMNWVRQA PGKGLEWVSTmf nDIQMTQSPSS LSASVGDRVTio oitISGMGGSTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKRG ITCRASQSIS SFLNWYQQKPviter ce YPHSFDIWGQ GTMVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY GKAPKLLIYfaut fA ASSLQSGVPS xinisFPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI RFSGSGSGTD FTLTISSLQP Mmu ; CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD EDFAYTTCQQ SYSTLTFGQG sriuvTLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST TRLEIKRTVA APSVFIFPPS riavloal bYRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY DEQLKSGTAS VVCLLNNFYP E TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD REAKVQWKVD NALQSGNSQE obE SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ SVTEQDSKDS TYSLSSTLTL ID NO: 70) SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC (SEQ ID NO: 1070) nEVQLVESGGG LVQPGGSLRL SCAASGFTFS SYDMHWVRQA TGKGLEWVSADIVMTQSPDS LAVSLGEg3b f nRAT oeiIGTAGDTYYP GSVKGRFTIS RENAKNSLYL QMNSLRAGDT AVYYCARTWF INCKSSQSVL YSSNNKNYLA-obaertcu GELYFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY WYQQKPGQPP KLLIYWmtefASTRixvinisFPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI ESGVPDRFSG SGSGTEFTLTiusCNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD ITSLQAEDVA VYYCQQYYSSemd;sriuvTLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST PLTFGGGTKV EIKRTVAAPS Oriavloal bYRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY VFIFPPSDEQ LKSGTASVVC E LPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD LLNNFYPREA KVQWKVDNAL obE SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ QSGNSQESVT EQDSKDSTYS ID NO: 71) LSSTLTLSKA DYEKHKVYAC EVTHQGLSSP VTKSFNRGEC (SEQ ID NO: 1071)ba1 l EVQLVESGGG LVKPGGSLKL SCAASGYTFT SYVMHWVRQA PGKGLEWIGY DIVMTQSPAT LSLSPGERATmGleag INPYNDGTKY NEKFQGRVTI SSDKSISTAY MELSSLRSED TAMYYCARGT LSCRSSKSLQ NVNGNTYtiI c- LYW BsYYYGTRVFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV FQQKPGQSPQ LLIYRMSNLNadfe eazig KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ SGVPDRFSGS GSGTEFTLTI TnaralueTYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPDVFLFPPK SSLEPEDFAV YYCMQHLEYP ms;uPKDTLMISRT PEVTCVVVDV SHEDPEVQFN WYVDGVEVHN AKTKPREEQF ITFGAGTKLE IKRTVAAPSV HffNSTFRVVSVL TVVHQDWLNG KEYKCKVSNK ALPAPEEKTI SKTKGQPREP FIFPPSDEQL KSGTASVVCL 9i1D QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP LNNFYPREAK VQWKVDNALQ D C MLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K SGNSQESVTE QDSKDSTYSL (SEQ ID NO: 72) SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1072)Attorney. 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No.616146.100579ba2 d QVQLQESGPG LVKPSETLSL TCAVSGHSIS HDHAWSWVRQ PPGEGLEWIG DIQMTQSPSS LSASVGDSVTm GgnaFISYSGITNY NPSLQGRVTI SRDNSKNTLY LQMNSLRAED TAVYYCARSL ITCQASTDIS SHLNWYQQKPuzIaildARTTAMDYWG EGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVar ecitKD GKAPELLIYY GSHLLSGVPStpYFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSNFGTQTY RFSGSGSGTD FTFTISSLEAaziSnaosTCNVDHKPSN TKVDKTVERK SCVECPPCPA PPVAGPSVFL FPPKPKDTLM EDAATYYCGQ GNRLPYTFGQ muitilISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTFRV GTKVEIERTV AAPSVFIFPP H;eym VSVLTVVHQD WLNGKEYKCK VSNKGLPAPI EKTISKTKGQ PREPQVYTLP SDEQLKSGTA SVVCLLNNFY R 6-orPSQEEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPMLDSDG PREAKVQWKV DNALQSGNSQ LIueSFFLYSKLTV DKSRWQEGNV FSCSVMHEAL HAHYTQKSLS LSP (SEQ ID NO: ESVTEQDSKD STYSLSSTLT N 73) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1073)ba1 d EVQLVESGGG LVQPGGSLRL SCAASGFTFS SSWMNWVRQA PGKGLEWVGR EIVLTQSPDF QSVTPKEKVTm GnaIYPGDGDTNY NVKFKGRFTI SRDDSKNSLY LQMNSLKTED TAVYYCARSG ITCRASESVD TFGISFMNWFu gziIaFITTVRDFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV QQKPDQSPKL LIHEASlidecitNQGSbpeziKDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ GVPSRFSGSG SGTDFTLTINnInaositTYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK SLEAEDAATY YCQQSKEVPF muilPKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY TFGGGTKVEI KRTVAAPSVF H;eyNSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQP 1 m REP IFPPSDEQLK SGTASVVCLL 9oQVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP NNFYPREAKV QWKVDNALQS DrCueVLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K GNSQESVTEQ DSKDSTYSLS N (SEQ ID NO: 74) STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC (SEQ ID NO: 1074)ba1 QVELVESGGG VVQPGRSQRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAI EIVLTQSPAT LSLSPm GesGERAT a IWFDGSSTYY ADSVRGRFTI SRDNSKNTLY LQMNSLRAED TAVYFCAREL LSCRASQSVS SYLAWYQQKu g mIeP siud GRRYFDLWGR GTLVSVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY GQAPRLLIYD ASKRATGIPAtnaomey FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI RFSGSGSGTD FTLTISSLEPrpueHeCNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD EDFAVYYCQQ RSKWPPWTFG T;diRo1rTLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST QGTKVESKRT VAAPSVFIFP -yYRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY PSDEQLKSGT ASVVCLLNNF FhG T I TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD YPREAKVQWK VDNALQSGNS SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ QESVTEQDSK DSTYSLSSTL ID NO: 75) TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC (SEQ ID NO: 1075)ba1a QVQLVQSGAE VAKPGTSVKL SCKASGYTFT DYWMQWVKQR PGQGLEWIGTDIVMTQSHLS MSTSLGDPVSmiGg mx olIYPGDGDTGY AQKFQGKATL TADKSSKTVY MHLSSLASED SAVYYCARGD ITCKASQDVS TVVAWYQQKPuI eYYGSNSLDYW GQGTSVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK GQSPRRLIYS ASYRYIGVPDtacisIryem DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT RFTGSGAGTD FTFTISSVQA mi ehlpC;iYICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP EDLAVYYCQQ HYSPPYTFGG tlKDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEV 8uHNA KTKPREEQYN GTKLEIKRTV AAPSVFIFPP 3 M STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ SDEQLKSGTA SVVCLLNNFY D VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV PREAKVQWKV DNALQSGNSQ C LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK ESVTEQDSKD STYSLSSTLT (SEQ ID NO: 76) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1076)ba1 EVQLVESGGG LVQPGGSLRL SCAVSGIDLS GYYMNWVRQA PGKGLEWVGV QVLTQSPSSL SASVGDRVTIm Gnu goIGINGATYYA SWAKGRFTIS RDNSKTTVYL QMNSLRAEDT AVYFCARGDI NCQASQSVYH NTYLAWYQzeI itQK neWGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV PGKVPKQLIY DASTLASGVPndie vtz erSWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SRFSGSGSGT DFTLTpiISSLQ Enap SNTKVDARVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK PKDTLMISRT PEDVATYYCL GSYDCTNGDC meuniPEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY ASTYRVVSVL FVFGGGTKVE IKRTVAAPSV Har;gTVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRE FIFPPSDEQL KSGTASVVCL PiR M EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL LNNFYPREAK VQWKVDNALQ G C YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K (SEQ ID NO: 77) SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1077)Attorney. 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No.616146.100579ba2 QVQLVQSGAE VKKPGASVKV SCKVSGYTFT SYDINWVRQA PGKGLEWMGW DIQMTQSPSS LSASVGDRVm GesT aeIYPGDGSIKY NEKFKGRVTM TVDKSTDTAY MELSSLRSED TAVYYCARRG ITCKASQSVD YDGHSYMNWYu gziI siEYGNYEGAMD YWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL QQKPGKAPKL LIYAASNLESlndeda llVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVTSSNFGT GVPSRFSGSG SGTDFTLTIzziirnaeS c QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD SLQPEDFATY YCQQSDENPL CmeulkTLMISRTPEV TCVVVDVSHE DPEVQFNWYV DGMEVHNAKT KPREEQFNST TFGGGTKVEI KRTVAAPSVF Hc;inS FRVVSVLTVV HQDWLNGKEY KCAVSNKGLP APIEKTISKT KGQPREPQVY IFPPSDEQLK SGTASVVCLL itcTLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPMLD NNFYPREAKV QWKVDNALQS eleSDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ GNSQESVTEQ DSKDSTYSLS s- ID NO: 78) STLTLSKADY EKHKVYACEV P THQGLSSPVT KSFNRGEC (SEQ ID NO: 1078)ba1s QVQLVQSGAE VKKPGSSVKV SCKASGYTFT DQTIHWMRQA PGQGLEWIGYDIQMTQSPSS LSASVGDm GiRVT s IYPRDDSPKY NENFKGKVTI TADKSTSTAY MELSSLRSED TAVYYCAIPD ITCKASRDVA IAVAWYQQKPu gziIairo RSGYAWFIYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK GKVPKLLIYW ASTRHTGVPSkdne spaziDYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVseT VPSSSLGTQT RFSGSGSRTD FTLTISSLQPinauYICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPEAAGG PSVFLFPPKP EDVADYFCHQ YSSYPFTFGS R mqualP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN GTKLEIKRTV AAPSVFIFPP H;9STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ SDEQLKSGTA SVVCLLNNFY 1 VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV PREAKVQWKV DNALQSGNSQ p32- LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG (SEQ ESVTEQDSKD STYSLSSTLT LIID NO: 79) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1079)ba4 / l(A chain) XVQLVQSGAE VKKPGASVKV SCKASGHIFS NYWIQWVRQA DIQMTQSPSS LSASVGDRVTm 2anrPGQGLEWMGE ILPGSGHTEY TENFKDRVTM TRDTSTSTVY MELSSLRSED ITCGASENIY GALNWYQQKPu Gzig utTAVYYCARYF FGSSPNWYFD VWGQGTLVTV SSASTKGPSV FPLAPCSRST GKAPKLLIYG ATNLAlcDGVPSuIov denlSESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV RFSGSGSGTD FTLTISSLQPaRzinaaVTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS EDFATYYCQN VLNTPLTFGQ mmsVFLFPPKPKD TLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT GTKVEIKRTV AAPSVFIFPP uyxH o ;5rKPREEQFNST YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA SDEQLKSGTA SVVCLLNNFY a KGQPREPQVY TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN PREAKVQWKV DNALQSGNSQ C P NYKTTPPVLD SDGSFFLYSR LTVDKSRWQE GNVFSCSVLH EALHSHYTQK ESVTEQDSKD STYSLSSTLT SLSLSLG (SEQ ID NO: 81) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1081)ba1cEVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSA NFMLTQPHSV SESPGKTVTIm GigtISGSGGSTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKDG SCTRSSGSIA SNYVQWYQlaIycQRuoSSGWYVPHWF DPWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC PGSSPTTVIY EDNQRPSGVPpanagm maLVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG DRFSGSIDSS SNSASLTISG u h EpHoTQTYICNVNH KPSNTKVDKR VEPKSCDKTH TCPPCPAPEL LGGPSVFLFP LKTEDEADYY CQSYDGSNRW ;am PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE MFGGGTKLTV LGQPKAAPSV mehmyQYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR TLFPPSSEEL QANKATLVC arL gaEPQVYTLPP N m S REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT ISDFYPGAVT VAWKADSSPV FiPPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS PGK KAGVETTTPS KQSNNKYAAS IrP (SEQ ID NO: 82) SYLSLTPEQW KSHRSYSCQV THEGSTVEKT VAPTECS (SEQ ID NO: 1082)ba4 EVQLLESGGV LVQPGGSLRL SCAASGFTFS NFGMTWVRQA PGKGLEWVSG DIQMTQSm GllPSS LSASVGDSIT eigcISGGGRDTYF ADSVKGRFTI SRDNSKNTLY LQMNSLKGED TAVYYCVKWG ITCRASLSIN TFLNWYQpsQKPliInmauoNIYFDYWGQG TLVTVSSAST KGPSVFPLAP CSRSTSESTA ALGCLVKDYF GKAPNLLIYA ASSLHGGVPSem m PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SL C HaSSVVTVPS SSLGTKTYTC RFSGSGSGTD FTLTIRTLQP uuNVDHKPSNTK VDKRVESKYG PPCPPCPAPE FLGGPSVFLF PPKPKDTLMI EDFATYYCQQ SSNTPFTFGP ; q 1-ssDuSRTPEVTCVV VDVSQEDPEV QFNWYVDGVE VHNAKTKPRE EQFNSTYRVV GTVVDFRRTV AAPSVFIFPP SVLTVLHQDW LNGKEYKCKV SNKGLPSSIE KTISKAKGQP REPQVYTLPP SDEQLKSGTA SVVCLLNNFY PoenaSQEEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPVLDSDGS PREAKVQWKV DNALQSGNSQ tuFFLYSRLTVD KSRWQEGNVF SCSVMHEALH NHYTQKSLSL SLGK (SEQ ID NO: ESVTEQDSKD STYSLSSTLT C 83) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1083)Attorney. 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No.616146.100579ba2 EVQLVESGGG LVQPGGSLRL SCAASGFTFS NYWISWVRQA PGKGLEWVAE EIVLTQSPAT LSLSPGERAm GnoT i IRSESDASAT HYAEAVKGRF TISRDNAKNS LYLQMNSLRA EDTAVYYCLA LSCKASKRVT TYVSu gzeItWYQQKP n n YFDYGLAIQN YWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL GQAPRLLIYG ASNRYLnaevGIPAamerp VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSNFGT RFSGSGSGTD FTLTISSLEPm uerHeQTYTCNVDHK PSNTKVDKTV ERKCCVECPP CPAPPVAGPS VFLFPPKPKD EDFAVYYCSQ SYNYPYTFGQ F;PniTLMISRTPEV TCVVVDVSHE DPEVQFNWYV DGVEVHNAKT KPREEQFNST GTKLEIKRTV AAPSVFIFPP RarGgiFRVVSVLTVV HQDWLNGKEY KCKVSNKGLP SSIEKTISKT KGQPREPQVY SDEQLKSGTA SVVCLLNNFY C M TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPMLD PREAKVQWKV DNALQSGNSQ SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ ESVTEQDSKD STYSLSSTLT ID NO: 84) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1084) xa MEVQLVESGGGLVKPGGSLKLSCAASGFAFSIYDMSWVRQTPEKCLEWVAYISSGPEGGSLAALTAHQACHLPLETFTotni io xomeGGTTY RHRQPRGWEQLEQCGYPVQRLdutson YPDTVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCARHSGYGTHWGVLFAY VALYLAARLSWNQVpukuDQabmellWGQGTLV VIRNALASPGSGGDLGEAIREQPam leSAKASGGPEGGSLAALTAHQACHLPLETFTRHRQPRGWEQLEQCGYPVQRLVAL EQARLALTLAAAESERFVmio vcRQGT YIAARL GNDEAGAANGPADSG mFsyriaSWNQVDQVIRALASPGSGGDLGEAedIREQPEQARLALTLAAAESERFVRQGTGNDE DALLERNYPTGAEFLGDGGDVSut1 H AGAAN FSTRGTQNWTVERLLQAHRQLExoG g GPADSGDALLERNYPTGAEFLGDGGDVSFSTRGTQNWTVERLLQAHRQLEERGY ERGYVFVGYHGTFLEA MIen VFVGYH AQSIVFGGVRARSQDLDAIWRG iru GTFLEAAQSIVFGGVRARSQDLDAIWRGFYIAGDPALAYGYAQDQEPDARGRIRN FYIAGDPALAYGYAQDQEPDAR M;GALLR GRIRNGALLRVYVPRS 22VYVPRSSLPGFYRTSLTLAAPEAAGEVERLIGHPLPLRLDAITGPEEEGGRLETILG SLPGFYRTSLTLAAPEAAGEVER D WPL AERTWIPSAIPTDPRNVGGDLDPSSIPDKEQAISALPDYASQPGKPPREDLK LIGHPLPLRLDAITGPEEEGGRLE C (SEQ ID NO: 85) TILGWPLAERTVV (MDIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSILH IPSAIPTDPRNVGGDLDPSSIPDK SGVP SRFSGSGSGTDYSLTISNLEQEDFATYFCQQGNTLPWTFGCGTKLEIK) (SEQ EQAISALPDYASQPGKPPREDLK ID NO: 86) (SEQ ID NO: 1085)ba4 QVQLVQSGAE VKKPGSSVKV SCKASGYTFG NYWMQWVRQA PGQGLEWMGA DIQMTQSm GnoPSS LSASVGDRVT IYEGTGKTVY IQKug FADRVTI TADKSTSTAY MELSSLRSED TAVYYCARLS ITCRASKDIS KYLNWYQQzI itKP neDYVSGFGYWG QGTTVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD GKAPKLLIYY TSGYHSGVPnnaevSacmerYFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY RFSGSGSGTD FTLTISSLQPlau p HeTCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEAAGGPSVF LFPPKPKDTL EDFATYYCQQ GDALPPTFGG G;PniarMISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR GTKVEIKRTV AAPSVFIFPP R GgiVVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL SDEQLKSGTA SVVCLLNNFY C M PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD PREAKVQWKV DNALQSGNSQ GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLG (SEQ ID ESVTEQDSKD STYSLSSTLT NO: 1087) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1087)bana sm mkEVQLLESGGG LVQPGGSLRL SCAASGFTFS HYIMMWVRQA PGKGLEWVSGDIQMTQSPST LSASVGDRVT c IYSSGGITVY ADSVKGRFTI SRDNSKNTLY LQMNSl atLRAED TAVYYCAYRR ITCRASQSIS SWLAWYQQKPueutIGVPRRDEFD IWGQGTMVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL GKAPKLLIYK ASTLESGVdHa ; aPS a VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT RFSGSGSGTE FTLTISSLQPnaniLermeQTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP DDFATYYCQQ YNTYWTFGQG kidll eo KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ TKVEIKRTVA APSVFIFPPS aikagnYNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE DEQLKSGTAS VVCLLNNFYP amy PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP REAKVQWKVD NALQSGNSQE s alratiPVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G SVTEQDSKDS TYSLSSTLTL Pder(SEQ ID NO: 88) SKADYEKHKV YACEVTHQGL e SSPVTKSFNR GEC (SEQ ID NO: H 1088)ba1a EVQLVESGGD LVQPGRSLRL SCAASGFIFS NYGMSWVRQA PGKGLEWVATDVLMTQSPLS LPVTPGEPASm Gg m ISSASTYSYY PDSVKGRFTI SRDNAKNSLY LQMNSLRVED TALYYCGRHS ISCRSSRNIV HINGDTYLEWuziI odhep DGNFAFGYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD YLQKPGQSPQ LLIYKVSNRFluzim YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY SGVPDRFSGS GSGTDFTLKImangayllICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK SRVEAEDVGV YYCFQGSLomlueLP DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS WTFGQGTKVE IKR McTVAAPSV H;4TsTYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEK RuTISK AKGQPREPQV FIFPPSDEQL KSGTASVVCL o YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL LNNFYPREAK VQWKVDNALQ CeCnaDSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK (SEQ SGNSQESVTE QDSKDSTYSL tuID NO: 89) SSTLTLSKAD YEKHKVYACE C VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1089)Attorney. 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No.616146.100579ba2nmoQVQLVESGGG VVQPGRSLRL SCAASGFTFS SFGMHWVRQA PGKGLEWVAV QSVLTQPPSV SAAPGQKVTI GiISFDGSIKYS VDSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCARDR SCSGSSSNIG NNYVSugnItWYQQL neLNYYDSSGYY HYKYYGMAVW GQGTTVTVSS ASTKGPSVFP LAPCSRrnaevSTSE PGTAPKLLIY DNNKRPSGIP E merSTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT DRFSGSKSGT STTLGITGLQ u p HeVPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP APPVAGPSVF TGDEADYYCG TWDSRLS ;rnAVV i o LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVQFNWYVDG VEVHNAKTKP FGGGTKLTVL GQPKANPTVT tarpegiREEQFNSTFR VVSVLTVVHQ DWLNGKEYKC KVSNKGLPAP IEKTISKTKG LFPPSSEELQ ANKATLVCLI ceM QPREPQVYTL PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY SDFYPGAVTV AWKADGSPVK r P KTTPPMLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL AGVETTKPSK QSNNKYAASS R G SLSPGK (SEQ ID NO: 90) YLSLTPEQWK SHRSYSCQVT C HEGSTVEKTV APTECS (SEQ ID NO: 1090)ba1s QVQLVQSGAEVKKPGASVKVSCKASGYIFITYWMTWVRQAPGQGLEWMGQIFPDIQMTQSPSSLSASVGDRVTITCm GisASGSADY RTSENIYSYLAWYQQKPGKAPKu gziIaidrosNEKFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARGGGGFAYWGQGTLVT LLIYNAKTLAEGVPSkaerzip VSSASTK RFSGSGSGTDFTLTISSLQPEDFAdlina eu GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS TYYCQHHYGIPFTFGQG T mqTKVEIK ualP GLYS RTVAAPSVFIFPP H;9LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG SDEQLKSGTASVVCLLNNFYPR 1 PSVF EAKVQWKVDNALQSGNSQESV p32- LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ TEQDSKDSTYSLSSTLT LIYNSTYR LSKADYEKHKVYACEVTHQGL VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD SSPVTKSFNRGEC (SEQ ID NO: ELTKN 1091) QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 91)ba4QVQLQQSGPE VVKPGASVKM SCKASGYTFT SYVIHWVRQK PGQGLDWIGYDIVMTQSPDS LAVSLm GnGERVT goiINPYNDGTDY DEKFKGKATL TSDTSTSTAY MELSSLRSED TAVYYCAREK MNCKSSQSLL YSTNQKNYziI tcLAul efDNYATGAWFA YWGQGTLVTV SSASTKGPSV FPLAPCSRST SESTAALGCL WYQQKPGQSP KLLIYWASTRadenbIziiVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT ESGVPDRFSG SGSGTDFTLT naVIKTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP SVFLFPPKPK ISSVQAEDVA VYYCQQYYSY muH DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS RTFGGGTKLE IKRTVAAPSV H;4TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV FIFPPSDEQL KSGTASVVCL D YTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL LNNFYPREAK VQWKVDNALQ C DSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK (SEQ SGNSQESVTE QDSKDSTYSL ID NO: 92) SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1092)ba1a QVQLVQSGAE VKKPGASVKV SCKASGYTFT NHYMHWVRQA PGQGLEWMGIAIQLTQSPSS LSASVGDRVTm Gig metINPISGSTSN AQKFQGRVTM TRDTSTSTVY MELSSLRSED TAVYYCARDI ITCRASQGIS SALVWYQQKPusIoVDAFDFWGQG TMVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF GKAPKLLIYD ASSLESGVPSrnuaahmpsPEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC RFSGSGSGTD FTLTISSLQP B u HohNVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT EDFATYYCQQ FNDYFTFGPG ; p 3 LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY TKVDIKRTVA APSVFIFP 2opPS F yhRVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT DEQLKSGTAS VVCLLNNFYP G FdeLPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS REAKVQWKVD NALQSGNSQE kniDGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK (SEQ ID SVTEQDSKDS TYSLSSTLTL l- NO: 93) SKADYEKHKV YACEVTHQGL X SSPVTKSFNR GEC (SEQ ID NO: 1093)ba1r EVQLVESGGG LVQPGGSLRL SCAASGFTFS RYWMSWVRQA PGKGLEWVANEIVLTQSPGT LSLSPGERATm Ggecn IKQDGSEKYY VDSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAREG LSCRASQRVS SSYLAWYQQKulaIaGWFGELAFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV PGQAPRLLIY DASSRATGIvrnacP r u meKDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ DRFSGSGSGT DFTLTISRLE D udHdTYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPEFEG GPSVFLFPPK PEDFAVYYCQ QYGSLPWTFG ;al1 B PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY QGTKVEIKRT VAAPSVFIFP L- NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPASIEKTI SKAKGQPREP PSDEQLKSGT ASVVCLLNNF D P QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP YPREAKVQWK VDNALQSGNS VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K QESVTEQDSK DSTYSLSSTL (SEQ ID NO: 94) TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC (SEQ ID NO: 1094)Attorney. 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No.616146.100579baciQVQLVESGGG LVQPGGSLRL SCAASGFTFS YYDIQWVRQA PGKGLEWVSSDIQMTQSPSS LSASVGDmf ARVT a ISPSGQSTYY RREVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARRT ITCKASRNIE RQLAWYQQKPuiczie iliGREYGGGWYF DYWGQGTLVT VSSASTKGPS VFPLAPCSRS TSESTAALGC GQAPELLIYQcp hASRKESGVPDisibpoLVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG RFSGSRYGTD FTLTISSLQPm E,4meTQTYTCNVDH KPSNTKVDKR VESKYGPPCP PCPAPEFLGG PSVFLFPPKP EDIATYYCQQ YSDPPLTFGG Gg H I KDTLMISRTP EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQYN GTKVEIKRTV AAPSVFIFPP deSTYRVVSVLT VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ SDEQLKSGTA SVVCLLNNFY zin VYTLPPSQKE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV PREAKVQWKV DNALQSGNSQ a LDSDGSFFLY SKLTVDKSRW QEGNVFSCSV MHEALHNRYT QKSLSLSP (SEQ ESVTEQDSKD STYSLSSTLT mu ID NO: 1095) (QVQLVQSGSE LKKPGASVKV SCKASGYTFT DNNMDWVRQA LSKADYEKHK VYACEVTHQG H;PGQGLEWMGD INTRSGGSIY NEEFQDRVIM TVDKSTDTAY MELSSLRSED LSSPVTKSFN RGEC (SEQ ID NO: X,aTATYHCARRK SYGYYLDEWG EGTLVTVSSA STKGPSVFPL APCSRSTSES 1095) XITAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV r otPSSSLGTQTY TCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEFLGGPSVF caLFPPKPKDTL MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP F REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSKLT VDKSRWQEGN VFSCSVMHEA LHNHYTQESL SLSP) (SEQ ID NO: 96)ba1a EVQLVQSGAE VKKPGASVKV SCKASGYTFT SYVIHWVRQR PGQGLAWMGYDIQMTQSPSS LSASVGDRVTm Gg mh INPYNDGTKY NERFKGKVTI TSDRSTSTVY MELSSLRSED TAVYLCGREG ITCGTSEDII NYLNWYQQKPuzI tisldar ez A IRYYGLLGDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV GKAPKLLIYH TSRLQSGVPS KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ RFSGSGSGTD FTLTISSLQniPenaTYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK EDFATYYCQQ GYTLPYTFGQ BmuPKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY GTKVEIKRTV AAPSVFIFPP H;300 NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SDEQLKSGTA SVVCLLNNFY α R SKAKGQPREP QVYTLPPSRD ELTKNQVSLT CLVKGFYPSD IAVEWESNGQ PREAKVQWKV DNALQSGNSQ 5- L PENNYKTTPP VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY ESVTEQDSKD STYSLSSTLT I TQKSLSLSPG K (SEQ ID NO: 97) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1097)ba1s EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYPGDIQMTQSPSSLSASVGDRVTITCmGisug NGDTSY RASSSVSYMHWYQQKPGKAPKziI ordelNQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWG PLIYAPSNLASGVPSRle ecrscziQGTLVTV FSGSGSGTDFTLTISSLQPEDFAT Ona elpSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP YYCQQWSFNPPTFGQGTKVEIK miutluAVLQ RTVAAPSVFIFPPS H;M SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA DEQLKSGTASVVCLLNNFYPRE 02PELL AKVQWKVDNALQSGNSQESVT D C GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT EQDSKDSTYSLSSTLTL KPREEQ SKADYEKHKVYACEVTHQGLSS YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT PVTKSFNRGEC (SEQ ID NO: LPPSR 1098) EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 98) (EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYNMHWVRQAPGKGLEWVGAIYP GNGDTSY NQKFKGRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARVVYYSNSYWYFDVWG QGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL TVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK) (SEQ ID NO: 99)Attorney. 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No.616146.100579ba1si EVQLVQSGAE VKKPGESLKI SCKGSGYSFS NYWIGWVRQM PGKGLEWMGIQSVLTQPPSV SGAPGQRVTIm GsaIDPSNSYTRY SPSFQGQVTI SADKSISTAY LQWSSLKASD TAMYYCARWY SCTGSSSNIG SGYDVHWYQQu gklI iro YKPFDVWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF LPGTAPKLLI YGNSKRPSGVesna sp u mePEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC PDRFSGSKSG TSASLAITGL G u HuNVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT QSEDEADYYC ASWTDGLSLV ;q91alP LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY VFGGGTKLTV LGQPKAAPSV P RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT TLFPPSSEEL QANKATLVCL 3 2- LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS ISDFYPGAVT VAWKADSSPV LIDGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK (SEQ ID KAGVETTTPS KQSNNKYAAS NO: 100) SYLSLTPEQW KSHRSYSCQV THEGSTVEKT VAPTECS (SEQ ID NO: 1100)ba1s EVQLVESGGG LVQPGRSLRL SCAASRFTFD DYAMHWVRQA PGKGLEWVSGDIQMTQSPSS VSASVGDRVTm GitgirISWNSGRIGY ADSVKGRFTI SRDNAENSLF LQMNGLRAED TALYYCAKGR ITCRASQGIS SWLAWYQQKPuliIhr tDSFDIWGQGT MVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP GKAPKLLIYG Aana ra SSLESGVPS SmudiEPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN RFSGSGSGTD FTLTISSLQP H otaVNHKPSNTKV DKKVEPKSCD KTHTCPPCPA PELLGGPSVF LFPPKPKDTL EDFASYYCQQ ANSFPYTFGQ ; R m MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR GTKLEIKRTV AAPSVFIFPP 6- u VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG QPREPQVTYL SDEQLKSGTA SVVCLLNNFY IeLhR PPSRDELTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD PREAKVQWKV DNALQSGNSQ GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK (SEQ ID ESVTEQDSKD STYSLSSTLT NO: 101) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1101)ba4s EVQLVESGGG LEQPGGSLRL SCAGSGFTFR DYAMTWVRQA PGKGLEWVSSDIVMTQSPLS LPVTPGEPASm GigtitaISGSGGNTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKDR ISCRSSQSLL YSIGYNYLDWuli IpnuamrLSITIRPRYY GLDVWGQGTT VTVSSASTKG PSVFPLAPCS RSTSESTAAL YLQKSGQSPQ LLIYLGSNRA e d GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS SGVPDRFSGS GSGTDFTLKI DmuHciLGTKTYTCNV DHKPSNTKVD KRVESKYGPP CPPCPAPEFL GGPSVFLFPP SRVEAEDVGF YYCMQALQTP ; p αotKPKDTLMISR TPEVTCVVVD VSQEDPEVQF NWYVDGVEVH NAKTKPREEQ YTFGQGTKLE IKRTVAAPSV R 4- A FNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KGLPSSIEKT ISKAKGQPRE FIFPPSDEQL KSGTASVVCL LIPQVYTLPPSQ EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP LNNFYPREAK VQWKVDNALQ PVLDSDGSFF LYSRLTVDKS RWQEGNVFSC SVMHEALHNH YTQKSLSLSL G SGNSQESVTE QDSKDSTYSL (SEQ ID NO: 102) SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1102)ba1a EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYIMMWVRQA PGKGLEWVSSQSALTQPASV SGSPGQSITIm G m IYPSGGITFY ADTVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARIK SCTGTSSDVG u g GYNYVSWYQQleIo niLGTVTTVDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK HPGKAPKLMI YDVSNRPSGVvnacrA m DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT SNRFSGSKSG NTASL uacTISGL HllYICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP QAEDEADYYC SSYTSSSTRV ;e1cKDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN FGTGTKVTVL GQPKANPTVT L-lek STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ LFPPSSEELQ ANKATLVCLI D PreVYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV SDFYPGAVTV AWKADGSPVK M LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK AGVETTKPSK QSNNKYAASS (SEQ ID NO: 103) YLSLTPEQWK SHRSYSCQVT HEGSTVEKTV APTECS (SEQ ID NO: 1103)ba1r EVQLVESGGG LVQPGGSLRL SCAASGFTFS DSWIHWVRQA PGKGLEWVAWDIQMTQSPSS LSASVGDRVTm GgecznISPYGGSTYY ADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCARRH ITCRASQDVS TAVAWYQQKPu IaildoeczzirWPGGFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY GKAPKLLIYS ASFLYSGVPS e FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI RFSGSGSGTD FTLTISSLQPetnaddCNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD EDFATYYCQQ YLYHPATFGQ A malu B TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYAST GTKVEIKRTV AAPSVFIFPP H;YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY SDEQLKSGTA SVVCLLNNFY 1 L- TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD PREAKVQWKV DNALQSGNSQ D SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ ESVTEQDSKD STYSLSSTLT P ID NO: 105) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1105)Attorney. 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No.616146.100579bam EVQLVQSGAE VKKSGESLKI SCKGSGYSFT SYWIGWVRQM PGKGLEWMGI EIVLTQSPGT LSLSPGERATm u m iuiFYPGDSSTRY SPSFQGQVTI SADKSVNTAY LQWSSLKASD TAMYYCARRR LSCRASQSVS SSYLAWYQQKux dird tirtNWGNAFDIWG QGTMVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD PGQAPRLLIY GASSRATGIPotos slozlYFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY DRFSGSGSGT DFTLTISReColLE C ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK PEDFAVYYCQ QYGSSTWTFG B f onDTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS QGTKVEIKRT VAAPSVFIFP oitTYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV PSDEQLKSGT ASVVCLLNNF neYTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL YPREAKVQWK VDNALQSGNS verDSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK (SEQ QESVTEQDSK DSTYSLSSTL P ID NO: 106) TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC (SEQ ID NO: 1106)ba1a QLQLQESGPG LVKPSETLSL TCTVSGGSIN SSSYYWGWLR QSPGKGLEWIEIVLTQSPAT LSLSPGERATm G m GSFFYTGSTY YNPSLRSRLT ISVDTSKNQF SLMLSSVTAA DTAVYYCARQ LSCRASQSVS SYLAWYQQKPutgIocarrnSTYYYGSal aasGNY YGWFDRWDQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA GQAPRLLIYD ASNRATGIPA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVT Omu eVPS RFSGSGSGTD FTLTISSLEP HusSSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APELLGGPSV EDFAVYYCQQ RSNWPPAFGQ ;siαtFLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK GTKVEIKRTV AAPSVFIFPP FtfR o S PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK SDEQLKSGTA SVVCLLNNFY G GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN PREAKVQWKV DNALQSGNSQ D P YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS ESVTEQDSKD STYSLSSTLT LSLSPGK (SEQ ID NO: 107) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1107)ba .QVQLQQSGPE LKKPGASVKV SCKDSGYAFS SSWMNWVRQA PGQGLEWIGR DIQMTQSP BlaSS LSASVGDRVTm nifooiIYPGDGDTNY NGKFQGRVTI TADKSSSTAY MELSSLRSED TAVYFCARSG ITCRASQDIR NYLNWYQQKPxa tLLRYAMDYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD GKAVKLLIYY TSRLLPGVPSxne aotglaYFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY RFSGSGSGliith TD YSLTISSQEQbnaniICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLG OfGP SVFLFPPKPK EDIGTYFCQQ GNTLPWTFGQ e vioDTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS GTKVEIRRTV AAPSVFIFPP tcnoTYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV SDEQLKSGTA SVVCLLNNFY etitorneYTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL PREAKVQWKV DNALQSGNSQ P verDSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK (SEQ ESVTEQDSKD STYSLSSTLT P ID NO: 109) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1109)ba4s QVQLVQSGAE VKKPGSSVKV SCKASGYSFT DYHIHWVRQA PGQGLEWMGVDIVMTQTPLS LSVTPGQm GiPAS gsaINPMYGTTDY NQRFKGRVTI TADESTSTAY MELSSLRSED TAVYYCARYD ISCRSSRSLV HSRGNTYLHWuziI iro YFTGTGVYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD YLQKPGQSPQ LLIYKVSNRFkede sP YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY IGVPDRFSGS GSGTDFTLKIxIzinaTCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEFLGGPSVF LFPPKPKDTL SRVEAEDVGV YYCSQSTHLP mu MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR FTFGQGTKLE IKRTVAAPSV H;VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL FIFPPSDEQL KSGTASVVCL a71 PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD LNNFYPREAK VQWKVDNALQ - LIGSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLG (SEQ ID SGNSQESVTE QDSKDSTYSL NO: 110) SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1110)ba1a EVQLLESGGG LVQPGGSLRL SCAVSGFTFN SFAMSWVRQA PGKGLEWVSAEIVLTQSPAT LSLSPGERATmGug m olISGSGGGTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYFCAKDK LSCRASQSVS SYLAWYQQKPmIILWFGEPVFD YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL GQAPRLLIYD ASNRATGIPAuntaeyam m VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSa eSV VTVPSSSLGT RFSGSGSGTD FTLTISSLEPru HlpQTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP EDFAVYYCQQ RSNWPPTFGQ D;i8t3luKPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ GTKVEIKRTV AAPSVFIFPP D M YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE SDEQLKSGTA SVVCLLNNFY C PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PREAKVQWKV DNALQSGNSQ PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GK ESVTEQDSKD STYSLSSTLT (SEQ ID NO: 111) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1111)Attorney. 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No.616146.100579ba1a EVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPDDIQMTQSPSSLSASVGDRVTITCm Gg m SSTINY KASQDVGIAVAWYQQKPGKVPuzI oluAPSLKDKFIISRDNAKNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWGQGTL KLLIYWASTRHTGVPtdoeeyDlzim VTVSSA RFSGSGSGTDFTLTISSLQPEDVA Ena elpSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL TYYC uiQQYSSYPYTFGQGTKVEI mtlQSSG KRTVAAPSVFIFPP Hu;7M LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL SDEQLKSGTASVVCLLNNFYPR F LGGP EAKVQWKVDNALQSGNSQESV M SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE TEQDSKDSTYSLSSTLT AL EQYNS LSKADYEKHKVYACEVTHQGL S TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SSPVTKSFNRGEC (SEQ ID NO: SRDEL 1112) TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 112)ba1 QVQLQESGPG LVKPSQTLSL TCTVSGGSIS SGDYYWSWIR QPPGKGLm GreEWI EIVMTQSPAT LSLSPGERAT cnGYIYYSGSTD YNPSLKSRVT MSVDTSKNQF SLKVNSVTAA DTAVYYCARV LSCRASQSVS SYLAWYQQKPu gImn acSIFGVGTFDY WGQGTLVTVS SASTKGPSVL PLAPSSKSTS GGTAALGCLV GQAPRLLIYD ASNRATGIPAutai gKDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ RFSGSGSGTD FTcm LTISSLEPeunuHlTYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK EDFAVYYCHQ YGSTPLTFGG N;llRePKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKP FcREEQY GTKAEIKRTV AAPSVFIFPP l GlaNSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP SDEQLKSGTA SVVCLLNNFY E ms- QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP PREAKVQWKV DNALQSGNSQ no VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K ESVTEQDSKD STYSLSSTLT N (SEQ ID NO: 113) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1113)ba;n- QVQLQESGPG LVKPSETLSL TCTVSGFSLT SYIVDWIRQP PGKGLEWIGVDVVMTQSPLS LPVTLGQPASman IWAGGSTGYN SALRSRVSIT KDTSKNQFSL KLSSVTAADT AVYYCAurtzi aartSAAY ISCKSSQSLL YTDGKTYLYW gi agiYSYYNYDGFA YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL FLQRPGQSPR RLIYLVSKLDcurVKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT SGVPDRFSGS GSGTDFababTLKIdIDadfQTYICNVNHK PSNTKVDKKV EPKSC (SEQ ID NO: 114) SRVEAEDVGV YYCLQSTHFP ola HTFGGGTKVE IKRTVAAPSV sreFIFPPSDEQL KSGTASVVCL veLNNFYPREAK VQWKVDNALQ R SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC (SEQ ID NO: 1114)ba1loEVQLVESGGG LVQPGGSLRL SCAASGFTFN NYAMNWVRQA PGKGLDWVSTDIVMTQSPDS LAVSLGERATm GgretsISGSGGTTNY ADSVKGRFII SRDSSKHTLY LQMNSLRAED TAVYYCAKDS INCKSSQSVL YRSNNRNFLGucIoNWGNFDLWGR GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY WYQQKPGQPPNLLIYrniaelWASTRlmoFPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI ESGVPDRFSG SGSGTDFT uhLT A Hch CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD ISSLQAEDVA VYYCQQYYTT ;9giTLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST PYTFGQGTKL EIKRTVAAPS K H S YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY VFIFPPSDEQ LKSGTASVVC C P TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD LLNNFYPREA KVQWKVDNAL SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPG (SEQ ID QSGNSQESVT EQDSKDSTYS NO: 115) LSSTLTLSKA DYEKHKVYAC EVTHQGLSSP VTKSFNRGEC (SEQ ID NO: 1115)ba2loEVQLVQSGAE VKKPGASVKV SCKASGYTLT SYGISWVRQA PGQGLEWMGWESALTQPASV SGSPGQSITIm GgrectVSFYNGNTNY AQKLQGRGTM TTDPSTSTAY MELRSLRSDD TAVYYCARGY SCTGTSSDVG GYNSVSWYQQu IsoGMDVWGQGTT VTVSSASTKG PSVFPLAPCS RSTSESTAAL GCLVKDYFPE HPGKAPKLMI YEVSNlnoaelRPSGVvmoPVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSN FGTQTYTCNV SNRFSGSKSG NTASLTISG E uhL HcDHKPSNTKVD KTVERKCCVE CPPCPAPPVA GPSVFLFPPK PKDTLMISRT QAEDEADYYC NSYTSTSMVF ; h 9giPEVTCVVVDV SHEDPEVQFN WYVDGVEVHN AKTKPREEQF NSTFRVVSVL GGGTKLTVLG QPKAAPSVTL K H S TVVHQDWLNG KEYKCKVSNK GLPAPIEKTI SKTKGQPREP QVYTLPPSRE FPPSSEELQA NKATLVCLIS C P EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP MLDSDGSFFL DFYPGAVTVA WKADSSPVKA YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K (SEQ ID NO: 117) GVETTTPSKQ SNNKYAASSY LSLTPEQWKS HRSYSCQVTH EGSTVEKTVA PTECS (SEQ ID NO: 1117)Attorney. 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No.616146.100579ba1a EVQLLQSGPE LEKPGASVMI SCKASGSSFT GYNMNWVRQN IGKSLEWIGAEIVMTQSPAT LSVSPGERATm G miIDPYYGGTSY NQKFKGRATL TVDKSSSTAY MHLKSLTSED SAVYYCVSGM LSCRSSQSLV HRNGNTYLHWxgI otutcisaEYWGQGTSVT VSSASTKGPS VFPLAPSSKS TSGGTulAALGC LVKDYFPEPV YLQKPGQSPK LLIHKVSNRF rnbTVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH SGVPDRFSGS GSGTDFTi emorLKI DihuCeKPSNTKVDKR VEPKSCDKTH TCPPCPAPEL LGGPSVFLFP PKPKDTLMIS SRVEAEDLGV YFCSQSTHVP ; N RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE QYNSTYRVVS PLTFGAGTKL ELKRTVAAPS 2 D VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR EPQVYTLPPS VFIFPPSDEQ LKSGTASVVC G REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF LLNNFYPREA KVQWKVDNAL FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS PGK (SEQ ID NO: QSGNSQESVT EQDSKDSTYS 118) LSSTLTLSKA DYEKHKVYAC EVTHQGLSSP VTKSFNRGEC (SEQ ID NO: 1118)ba1s EVQLVESGGG LVQPGGSLRL SCAASGFTFS NYWMNWVRQA PGKGLEWVAAEIVLTQSPGT LSLSPGm GiERAT saINQDGSEKYY VGSVKGRFTI SRDNAKNSLY LQMNSLRVED TAVYYCVRDY LSCRASQSVS SSYLAWYQQKu gniI iro YDILTDYYIH YWYFDLWGRG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA PGQAPRLLIY GASSRATGIPk nu a sm P ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS DRFSGSGSGT DFTLTISRLEceu S H SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APELLGGPSV PEDFAVYYCQ QYGSSPCTFG ; a7FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK QGTRLEIKRT VAAPSVFIFP 1- PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK PSDEQLKSGT ASVVCLLNNF LIGQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YPREAKVQWK VDNALQSGNS YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS QESVTEQDSK DSTYSLSSTL LSLSPGK (SEQ ID NO: 119) TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC (SEQ ID NO: 1119)ba4 QVQLVESGGG VVQPGRSLRL DCKASGITFS NSGMHWVRQA PGKGLEWVAV EIVLTQSPAT LSLSPGERATm GllecIWYDGSKRYY ADSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCATND LSCRASQSVS SYLAWYQQKlg Pu IlolDYWGQGTLVT VSSASTKGPS VFPLAPCSRS TSESTAALGC LVKDYFPEPV GQAPRLLIYD Avina aSNRATGIPA m TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TKTYTCNVDH RFSGSGSGTD FTLTISSLEP N mus- H KPSNTKVDKR VESKYGPPCP PCPAPEFLGG PSVFLFPPKP KDTLMISRTP EDFAVYYCQQ SSNWPRTF ;noGQ 1n,EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN STYRVVSVLT GTKVEIKRTV AAPSVFIFPP DaP m VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ VYTLPPSQEE SDEQLKSGTA SVVCLLNNFY o naMTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY PREAKVQWKV DNALQSGNSQ leSRLTVDKSRW QEGNVFSCSV MHEALHNHYT QKSLSLSLGK (SEQ ID NO: 120) ESVTEQDSKD STYSLSSTLT M LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1120)ba a DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASmme idnmeNLVS o m k GIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIKGGtatuGGSuac eGGGGniflilicciBeSGGGGSQVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWI ptssialbbGQIWPG eoDGDTNYNGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYY nhipru m YAMDYW y GQGTTVTVSSGGGGSDIKLQQSGAELARPGASVKMSCKTSGYTFTRYTMHWVKQ Ml;3etu RPGQGL DcEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYY C A , DDHYC 91LDYWGQGTTLTVSSVEGGSGGSGGSGGSGGVDDIQLTQSPAIMSASPGEKVTMTC D C RASSS VSYMNWYQQKSGTSPKRWIYDTSKVASGVPYRFSGSGSGTSYSLTISSMEAEDAA TYYCQ QWSSNPLTFGAGTKLELKHHHHHH (SEQ ID NO: 121)ba4a QVQLVQSGVE VKKPGASVKV SCKASGYTFT NYYMYWVRQA PGQGLEWMGGEIVLTQSPAT LSLSPGERATm G mo INPSNGGTNF NEKFKNRVTL TTDSSTTTAY MELKSLQFDD TAVYYCARRD LSCRASKGVS TSGYSYLHWYugzIildoenarleYRFDMGFDYW GQGTTVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK QQKPGQAPRL LIYLASYLES DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT GVPARFSGSG SGTDFTLTISbzin MmaYTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSV FLFPPKPKDT SLEPEDFAVY YCQHSRDLPLeP mu LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTY TFGGGTKVEI KRTVAAPSVF H;RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT IFPPSDEQLK SGTASVVCLL 1 D LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS NNFYPREAKV QWKVDNALQS P DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK (SEQ ID GNSQESVTEQ DSKDSTYSLS NO: 122) STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC (SEQ ID NO: 1122)Attorney. 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No.616146.100579ba1r EVQLVQSGGG LVKPGGSLRL SCAASGFTFS SYSMNWVRQA PGKGLEWVSSDIQMTQSPSS VSASIGDRVTm GecISSSSSYIYY ADSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARVT ITCRASQGID NWLGWYQQurg KPi I nacnDAFDIWGQGT MVTVSSASTK GPSVLPLAPS SKS uacTSGGTAA LGCLVKDYFP GKAPKLLIYD ASNLDTGVPS ciEPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN RFSGSGSGTY FTLTISSLQAmamurtsVNHKPSNTKV DKRVEPKSCD KTHTCPPCPA PELLGGPSVF LFPPKPKDTL EDFAVYFCQQ AKAFPPTFGG RHa;2G MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REEQYNSTYR GTKVDIKRTV AAPSVFIFPP RF VVSVLTVLHQ DWLNGKEYKC KVSNKALPAP IEKTISKAKG QPREPQVYTL SDEQLKSGTA SVVCLLNNFY GE PPSREEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD PREAKVQWKV DNALQSGNSQ V GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA LHNHYTQKSL SLSPGK (SEQ ID ESVTEQDSKD STYSLSSTLT NO: 123) LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (SEQ ID NO: 1123)ba1 QVQLVQSGAEVKKPGASVKVSCKGSGYTFTSYWMHWVRQAPGQRLEWIGEIDPS DVVMTQSPLSLPVTPGEPASISm GesCug ESNTNY RSSQSLAKSYGNTYLSWYLQKPzI aesiilNQKFKGRVTLTVDISASTAYMELSSLRSEDTAVYYCARGGYDGWDYAIDYWGQ odedGQSPQLLIYGISNRFdezinGTLVTVS SGVPDRFSGSGSGTDFTLKISRV Vna horSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA EAEDVGVYYCLQGTHQPYTFG muC,sVLQS QGTKVEIKRTVAAPSV H;nitiilSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP FIFPPSDEQLKSGTASVVCLLNN rocELAG FYPREAKVQWKVDNALQSGNS get ev APSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP QESVTEQDSKDSTYSL ni i7taREEQY SSTLTLSKADYEKHKVYAC βrEVT e 4 NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL HQGLSSPVTKSFNRGEC (S αclEQ ID U PPSRD NO: 1124) ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 124)ba1 EVQLVESGGKLLKPGGSLKLSCAASGFTFSSFAMSWFRQSPEKRLEWVAEISSGGS QIVLIQSPAIMSASPGEKVTMTCmiGesgaeYTYY SASSSVSYMYWYQQKPGSSPRLxI suitcPDTVTGRFTISRDNAKNTLYLEMSSLRSEDTAMYYCARGLWGYYALDYWGQGT LIYliDTSNLASGVPVRir dSVTVSSA FSGSGSGTSYSLTISRMEAEDAA Senmi ahmSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP CeAVL TYYCQQWSGYPYTFGGGTKLEI ;lts6- aQSSG KRTVAAPSVFIFPPS LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL DEQLKSGTASVVCLLNNFYPRE L C I LGGP AKVQWKVDNALQSGNSQESVT SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQDSKDSTYSLSSTLTL EQYNS SKADYEKHKVYACEVTHQGLSS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP PVTKSFNRGEC (SEQ ID NO: SRDEL 1125) TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 125)ba1r EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPDIQMTQSPSSLSASVGDRVTITCm GegcznNSGGSIY KASQDVSIGVAWYQQKPGKAPu IauNQRFKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTL KLLIYSASYRYTtdreCtGVPSeziVTVSSA RFSGSGSGTDFTLTISSLQPEDFA Pn saae STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL TYYCQQYYIYPYTFGQGT mrKVEI u B QSSG KRTVAAPSVFIFPP H;2LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL SDEQLKSGTASVVCLLNNFYPR R LGGP EAKVQWKVDNALQSGNSQESV E H SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE TEQDSKDSTYSLSSTLT EQYNS LSKADYEKHKVYACEVTHQGL TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SSPVTKSFNRGEC (SEQ ID NO: SREEM 1128) TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 128)ba1s QVQLQQSGAEVKKPGSSVRVSCKASGGTFNNNAINWVRQAPGQGLEWMGGIIPMSSELTQDPAVSVALGQTVRVTCm Gguso FGTAKY QGDSLRSYYASWYQQKPGQAPuI tmil ne a aSQNFQGRVAITADESTGTASMELSSLRSEDTAVYYCARSRDLLLFPHHALSPWGR VLVIYGKNNRPSGIPDR meGTMVT FSGSSSGNTASLTITGAQAED B m EA uhtH yrVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF DYYCSSRDSSGNHWVFGGGTEL ;SePAVL TVLGQPKAAPSVTLF ysL u QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHHHHHH PPSSEELQANKATLVCLISDFYP Bpulc(SEQ ID NO: 129) GAVTVAWKADSSPVKAGVETT i m TPSKQSNNKYAASSYL etsSLTPEQWKSHRSYSCQVTHEGS y S TVEKTVAPTECS (SEQ ID NO: 1129)Attorney. 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No.616146.100579ba1a QVQLVESGGG VVQPGRSLRL SCAASGFTFS SYTMHWVRQA PGKGLEWVTFEIVLTQSPGT LSLSPGERATm GmISYDGNNKYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAIYYCARTG LSCRASQSVG SSYLAWYu g QQK IominWLGPFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY PGQAPRLLIlina aleY GAFSRATGIPpFPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI DRFSGSGSGT DFIm TLTISRLE u m HcitCNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD PEDFAVYYCQ QYGSSPWTFG ; 4-atTLMISRTPEV TCVVVDVSHE AsDPEVKFNWYV DGVEVHNAKT KPREEQYNST QGTKVEIKRT VAAPSVFIFP atYRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY PSDEQLKSGT ASVVCLLNNF LeT M TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD YPREAKVQWK VDNALQSGNS C SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (SEQ QESVTEQDSK DSTYSLSSTL ID NO: 130) TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC (SEQ ID NO: 1130)ba2 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGITGSG EIVLTQSPGTLSLSPGERATLSCRm Gssg o GSTYY ASQSVRGRYLAWYQQKPGQAPusIL onna eenADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDPGTTVIMSWFDPWGQ RLLIYGASSRATGIP o GTLVTV DRFSGSGSGTDFTLTISRLEPEDF DmuB H SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVFYCQQYGSSPRTFGQGTKVE ; L- AVLQ IKRTVAAPSVFIFP K SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA PSDEQLKSGTASVVCLLNNFYP N A PELL REAKVQWKVDNALQSGNSQES R GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT VTEQDSKDSTYSLSSTL KPREEQ TLSKADYEKHKVYACEVTHQG YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LSSPVTKSFNRGEC (SEQ ID NO: LPPSR 1131) DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 131)ba1siQVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGDIQMTQSPSSLSASVGDRVTITCm GtiITTY RASQDISSYLNWYQug QKPGKAzIrPK hiltNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSL LLIYYTSRLHSGicde ra VPS VTVSSA RFSGSGSGTDFTFTISSLQPEDIA oziTnadio STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL TYYCQQGNTLPYTFGQGTKVEI mtaum QSSG KRTVAAPSVFIFPP H;ueLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL SDEQLKSGTASVVCLLNNFYPR Rh6- R LGGP EAKVQWKVDNALQSGNSQESV LISVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE TEQDSKDSTYSLSSTLT EQYNS LSKADYEKHKVYACEVTHQGL TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SSPVTKSFNRGEC (SEQ ID NO: SREEM 1132) TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 132)ba1ciEVQLVESGGGLVQPGRSLRLSCAASGFTFNDYAMHWVRQAPGKGm gtLEWVSTISWN EIVLTQSPATLSLSPGERATLSCR G SGSIGY ASQSVSSYLAWYQQKPGQAP IycRLu m o ADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALtnYYCAKDIQYGNYYYGMDVWG LIYDASNRATGIPAuahpaQGTTVTV RFSGSGSGTDFTLTISSLEPfmu m EDFA O H SSASTKGPSVFPLAPGSSKSTSGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP VYYCQQRSNWPITFGQGTRLEI ;yl0c2inAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP (SEQ ID NO: KRTVAAPSVFIFPP Dor133) SDEQLKSGTASVVCLLNNFYPR C h C EAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGL SSPVTKSFNR (SEQ ID NO: 1133)ba1e QVQLVESGGGVVQPGRSLRLSCAASGFTFSVYGMNWVRQAPGKGLEWVAIIWYEIVLTQSPDFQSVTPKEKVTITCRmG mugoDnrGDNQYY ASQSIGSSLHWYQQKPDQSPKLiInadnADSVKGRFTISRDNSKNTLYLQMNGLRAEDTAVYYCARDLRTGPFDYWGQGTLV LIKYASQSFSGVPSkam y TVSSAS RFSGSGSGTDFTLTINSLEAEDAnausslTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ AAYYCHQSSSLPFTFGPGTKVDI C H;lβeSSGL KRTVAAPSVFIFPP 1- W-LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL SDEQLKSGTASVVCLLNNFYP IelR k cuGGPS EAKVQWKVDNALQSGNSQESV M VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE TEQDSKDSTYSLSSTLT QYNST LSKADYEKHKVYACEVTHQGL YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS SSPVTKSFNRGEC (SEQ ID NO: REEMT 1134) KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 134)Attorney. 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No.616146.100579ba1si EVQLVQSGAEVKKPGESLKISCKGSGYSFTTYWLGWVRQMPGKGLDWIGIMSPVDIQMTQSPSSLSASVGDRVTITCm GsaDSDIRY RASQGISSWLAWYQQKPEKAPKu gniI iro SPSFQGQVTMSVDKSITTAYLQWNSLKASDTAMYYCARRRPGQGYFDFWGQGTL SLIYAASSLQSGVPSkena sPtm VTVSSS RFSGSGSGTDFTLTISSLQPEDFAsu U H STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL TYYCQQYNIYPYTFGQGTKLEIK ; 32QSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH (SEQ ID RTVAAPSVFIFPP / 2NO: 136) SDEQLKSGTASVVCLLNNFYPR 1- EAKVQWKVDNALQSGNSQESV LITEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC (SEQ ID NO: 1136)baba n EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTDIQLTQSPSSLSASVGDRVTITCSmF oiYTGEPTY ASQDISNYLNWYQQKPGKAPKuzi1tareAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVW VLIYFTSSLHSGVPSbiGgnn IeGQGTLVT RFSGSGSGTDFTLTISSLQPEDFAaRdegez VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF TYYCQQYSTVPWTFGQGTKVEI idnaralPAVL QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHL KRTVAAPSVFIFPP mu(SEQ ID NO: 139) SDEQLKSGTASVVCLLNNFYPR ucaH EAKVQWKVDNALQSGNSQESV ; M F TEQDSKDSTYSLSSTLT GE LSKADYEKHKVYACEVTHQGL V SSPVTKSFNRGEC (SEQ ID NO: 1139)ba4siQVQLVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQRLEWMGRIDPADIQMTQSPSSLSASVGDRVTITCm GgsorNGYTKY KTSQDINKYMAWYQQTPGKAPuziId eDPKFQGRVTITADTSASTAYMELSSLRSEDTAVYYCAREGYYGNYGVYAte lMDYW RLLIHYTSALQPGIPSlacsaziGQGTLVT RFSGSGSGRDYTFTI Nna eSSLQPEDIA lpVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF TYYCLQYDNLWTFGQGTKVEIK miutlPAVL RTVAAPSVFIFPPS Hu;nM QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPE DEQLKSGTASVVCLLNNFYPRE irFLGG AKVQWKVDNALQSGNSQESVT getPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPR EQDSKDSTYSLSSTLTL niEEQFN SKADYEKHKVYACEVTHQGLSS 4aSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PVTKSFNRGEC (SEQ ID NO: PSQEE 1141) MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRW QEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 141)ba1r EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTDIQMTQSPSSLSASVGDRVTITCm GegcYTGEPTY SASQDISNYLNWYQQKPGKAPKuziI ndaecAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVW VLIYFTSSLHSGVPScazilatcGQGTLVT RFSGSGSGTDFTLTISSLQPEDFAvenBaVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF TYYCQQYSTVPWTFGQGTKVEI meru oloPAVL KRTVAAPSVFIFPP H;C QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP SDEQLKSGTASVVCLLNNFYPR F G APEL EAKVQWKVDNALQSGNSQESV E V LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT TEQDSKDSTYSLSSTLT KPREE LSKADYEKHKVYACEVTHQGL QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV SSPVTKSFNRGEC (SEQ ID NO: YTLPPS 1142) REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 142)ba1reQVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGDILLTQSPVILSVSPGERVSFSCRmiGgcn NTDYN ASQSIGTNIHWYQQRTNGSPRLLxuIcaicTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLV IKYASESISGIPSterelatcTVSAA RFSGSGSGTDFTLSINSVESEDIA CmiherSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL DYYCQQNNNWPTTFGAGTKLE C o ;loQSSG LKRTVAAPSVFIFPP R C F LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL SDEQLKSGTASVVCLLNNFYPR G LGGP EAKVQWKVDNALQSGNSQESV E SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE TEQDSKDSTYSLSSTLT EQYNS LSKADYEKHKVYACEVTHQGL TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SSPVTKSFNRGEC (SEQ ID NO: SRDEL 1143) TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 143)Attorney. 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No.616146.100579ba;a si EVQLVESGGGLVQPGGSLRLSCAASGYSFTGHWMNWVRQAPGKGLEWVGIMIHDIQMTQSPSSLSASVGDRVTITCm1 sPSDSETR RASKTISKYLAWXQQKPu1 aGKAPKzilDirYNQKFKDIRFTISVDKSKNTLYLQMNSLRAEDTAVYYCARIGIYFYGTTYFDaCosYIW LLIYSGSTLQSGVPSfP GQGTL VTVSS (SEQ ID NO: 144) RFSGSGSGTDFTLTISSLQPEDFA E TYYCQQHNEYPLTFGQGTKVEI KR (SEQ ID NO: 1144)1QAYLQQSGAELVRPGASVKMSCKASGYTFTSYNMHWVKQTPRQGLEWIGAIYPGQIVLSQSPAIL3a12aSASPGEKVTMTCIm - G o NGDTSY RASSSVSYMHWYQQKPGSSPKPbagImehpNQKFKGKATLTVDKSSSTAYMQLSSLTSEDSAVYFCARVVYYSNSYWYFDVWG WIYAPSNLASGVPARonirmy TGTTVTV FSGSGSGTSYSLTISRVEAEDAAm ulSGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS TYYCQQWSFNPPTFGAGTKLEuntiLiMks ;g SGLY KRTVAAPSVFIFPPSo0T2doSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLG DEQLKSGTASVVCLLNNFYPRE D CH-n GPSV AKVQWKVDNALQSGNSQESVT o N FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ EQDSKDSTYSLSSTLTL YNSTY SKADYEKHKVYACEVTHQGLSS RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR PVTKSFNR (SEQ ID NO: 1147) DELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 147)na1a QAYLQQSGAELVRPGASVKMSCKASGYTFTSYNMHWVKQTPRQGLEWIGAIYPGQIVLSQSPAILSASPGEKVTMTCteG g mo NGDTSY RASSSVSYMHWYQQKPGSSPKPxuIihNQKFKGKATLTVDKSSSTAYMQLSSLTSEDSAVYFCARVVYYSNSYWYFDVWG WIYAPSNLASGVPAte pR nbairm TGTTVTV FSGSGSGTSYSLTISRVEAEDAA u y mlSAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQS TYYCQQWSFNPPTFm;n GAGTKLELo Mit0k2g DLYT KRADAAPTVFIFPPSuirDdoLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGP DEQLKSGTASVVCLLNNFYPREbICH-n SV AKVQWKVDNALQSGNSQESVT oFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDY EQDSKDSTYSLSSTLTL N NSTL SKADYEKHKVYACEVTHQGLSS RVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEE PVTKSFN (SEQ ID NO: 1148) EMTK KQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEK KNWVER NSYSCSVVHEGLHNHHTTKSFSR (SEQ ID NO: 148)ba1s EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSAITWDIQMTQSPSSLSASVGDRVTITCm GitiNSGHIDY RASQGIRNYLAWYQu grQKPGKAP I hmitADSVEGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAl na a ra KVSYLSTASSLDYWGQG KLLIYAASTLQSGVPS TLVTVS RFSGSGSGTDFTLTISSLQPEDVA dmAudiH otaSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA TYYCQRYNRAPYTFGQGTKVEI ;F m VLQS KRTVAAPSVFIFPP N u TehSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP SDEQLKSGTASVVCLLNNFYPR R ELLG EAKVQWKVDNALQSGNSQESV GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP TEQDSKDSTYSLSSTLT REEQY LSKADYEKHKVYACEVTHQGL NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL SSPVTKSFNRGEC (SEQ ID NO: PPSRD 1149) ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 149)ba1eQVQLQESGPGLVRPSQTLSLTCTVSGFTFTDFYMNWVRQPPGRGLEWIGFIRDKA DIQMTQSPSSLSASVGDRVTITCm GlpKGYTT KASQNIDKYLNWYQQKPGKAPugzI itluuEYNPSVKGRVTMLVDTSKNQFSLRLSSVTAADTAVYYCAREGHTAAPFDYWGQ KLLIYNTNNLQTGVPStdem mz;GSLVTVS RFSGSGSGTDFTFTISSLQPEDIAeilna#aiSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA TYYCLQHISRPRTFGQGTKVEIK A mumeVLQS RTVAAPSVFIFPP H;k SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP SDEQLKSGTASVVCLLNNFYPR 25ueldELLG EAKVQWKVDNALQSGNSQESV DiColGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP TEQDSKDSTYSLSSTLT eyREEQY LSKADYEKHKVYACEVTHQGL mcNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL SSPVTKSFNR (SEQ ID NO: 1150) ino PPSRD rh ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV C DKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 150)Attorney. 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No.616146.100579ba1 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTN DIQMTQSPSSLSASm GreVGDRVTITC c GYTRY RASQDVNTAVAWYQQKugzInPGKAP a ucADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQ KLLIYSASFLYStsde tGVPSa sGTLVTVSS RFSGSRSGTDFTLTISSLQPEDFArziTnaaerB ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV TYYCQQHYTTPPTFGQGTKVEI mu LQSS KRTVAAPSVFIFPP H;2GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE SDEQLKSGTASVVCLLNNFYPR R LLGG EAKVQWKVDNALQSGNSQESV E H PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR TEQDSKDSTYSLSSTLT EEQYN LSKADYEKHKVYACEVTHQGL STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP SSPVTKSFNRGEC (SEQ ID NO: PSREE 1152) MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 152)ba1 t QLQQSGTVLARPGASVKMSCKASGYSFTRYWMHWIKQRPGQGLEWIGAIYPGNS QIVSTQSPAIMSASPGEKVTMTCmiGgnaDTSYNQ SASSSRSYMQWYQQKPGTSxiI lpPKRlic sKFEGKAKLTAVTSASTAYMELSSLTHEDSsiAVYYCSRDYGYYFDFWGQGTTLTVS WIYDTSKLASGVParnAR earSASTKG FSGSGSGTSYSLTISSMEAEDAA B mtihyePSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG TYYCHQRSSYTFGGGTKLEIKRT C n ;diLYSL VAAPSVFIFPPSDE R k 2 SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPPKSCDKTHTCPPCPAPELLGG QLKSGTASVVCLLNNFYP -fREAK LIonPSVF VQWKVDNALQSGNSQESVTEQ oitLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ DSKDSTYSLSSTLTLSK neYNSTYR ADYEKHKVYACEVTHQGLSSPV verVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD TKSFNRGE (SEQ ID NO: 1155) P ELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGN VFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 155)ba1 t QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYRMHWVRQAPGQGLEWIGYINPS DIQMTQSPSTLSASVGDRVTITCm GnaTGYTEY SASSSISYMHWYQQKPGKAPKLugzI lpild sce nNQKFKDKATITADESTNTAYMELSSLRSEDTAVYYCARGGGVFDYWGQGTTLTV LIYTTSNLASGVPARaziarSSGPSV FSGSGSGTEFTLTISSLQPDDFAT DnatyeFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS YYCHQRSTYPLTFGSGTKVEVK mun diLSSV RTVAAPSVFIFPPS H;k VTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAPELLGGPSVF DEQLKSGTASVVCLLNNFYPRE Rf2-oInLFPP AKVQWKVDNALQSGNSQESVT LoitKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST EQDSKDSTYSLSSTLTL neYRVVSV SKADYEKHKVYACEVTHQGLSS verLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK PVTKSFNR (SEQ ID NO: 1156) P NQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSC SVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 156)ba1a QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPQIVLSQSPAILSASPGEKVTMTCmiGg m GNGDTSY RASSSVSYIHWFQQKPGSSPKxuIo P h NQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGA WIYATSNLASGtpVPVRicirm ReGTTVTVS FSGSGSGTSYSLTISRVEAEDAA m y ilh n AASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA TYYCQQWTS CiNPPTFGGGTKLEI ;kg VLQS KRTVAAPSVFIFPPS 02doSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKAEPKSCDKTHTCPPCPAP DEQLKSGTASVVCLLNNFYPRE DH-n ELLG AKVQWKVDNALQSGNSQESVT C o GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP EQDSKDSTYSLSSTLTL N REEQY SKADYEKHKVYACEVTHQGLSS NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PVTKSFNRGEC (SEQ ID NO: PPSRD 1157) ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 157)ba;af EVQLQQSGTVLARPGASVKMSCEASGYTFTNYWMHWVKQRPGQGLEWIGAIYP mIiIoGNSDTSxI / icbnoY i IQKFKGKAKLTAVTSTTSVYMELSSLTNEDSAVYYCTLYD bII tPnGYYVFAYWGQGTLV ev TVSAAS A GerP TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 158)Attorney. 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No.616146.100579 3 atQVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPS QIVLTQSPAIMSASPGEKVTMTCD 2nC- GalRGYTNY SASSSVSYMNWYQQKSGTSPKRb gpsa INQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGT WIYDTSKLASGVPAHneonniamrrtTLTVSSA FRGSGSGTSYSLTISGMEAEDAAouyKTTAPSVYPLAPVCGGTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVL TYYCQQWSSNPFTFGSGTKLEINruM e;nM3diQSDL RADTAPTVSIFPPS D k YTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRPKSCDKTHTCPPCPAPEL SEQLTSGGASVVCFLNNFYPKD CfI olLGG NVKWKIDGSERQNGVLNSWTD asrePSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR QDSKDSTYSMSSTLTL veEEQYN TKDEYERHNSYTCEATHKTSTS R STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PIVKSFNRNEC (SEQ ID NO: PSRDE 1159) LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 159)31nAAGGILHLELLVAVGPDVFQAHQEDTERYVLTNLNIGAELLRDPSLGShr P AQFRVHLVT KMVIL Tk-TcMtnTEPEGAPNITANLTSSLLSVCGWSQTINPEDDTDPGHADLVLYITRFDLELPDGNR AanQVRG DiAbVTQLGGACSPTWSCLITEDTGFDLGVTIAHEIGHSFGLEHDGAPGSGCGnm PSGHVMtAa oSDGAn ciberAPRAGLAWSPCSRRQLLSLLSAGRARCVWDPPRPQPGSAGHPPDAQPGLYYSAN m EQCRVA oceFGPKAVACTFAREHLDMCQALSCHTDPLDQSSCSRLLVPLLDGTECGVEKWCSKrGRCRSLnaVELTPIAAVHGRWSSWGPRSPCSRSCGGGVVTRRRQCNNPRPAFGGRACVGADL mu QAEMCN H TQACEKTQLEFMSQQCARTDGQPLRSSPGGASFYHWGAAVPHSQGDALCRHMC RAIGESF IMKRGDSFLDGTRCMPSGPREDGTLSLCVSGSCRTFGCDGRMDSQQVWDRCQVC GGDNST CSPRKGSFTAGRAREYVTFLTVTPNLTSVYIANHRPLFTHLAVRIGGRYVVAGKM SISPN TTYPSLLEDGRVEYRVALTEDRLPRLEEIRIWGPLQEDADIQVYRRYGEEYGNLTR PDIT FTYFQPKPRQAWVWAAVRGPCSVSCGAGLRWVNYSCLDQARKELVETVQCQGS QQPPAWP EACVLEPCPPYWAVGDFGPCSASCGGGLRERPVRCVEAQGSLLKTLPPARCRAGA QQPAV ALETCNPQPCPARWEVSEPSSCTSAGGAGLALENETCVPGADGLEAPVTEGPGSV DEKLP APEPCVGMSCPPGWGHLDATSAGEKAPSPWGSIRTGAQAAHVWTPAAGSCSVSC GRGLME LRFLCMDSALRVPVQEELCGLASKPGSRREVCQAVPCPARWQYKLAACSVSCGR GVVRRI LYCARAHGEDDGEEILLDTQCQGLPRPEPQEACSLEPCPPRWKVMSLGPCSASCG LGTAR RSVACVQLDQGQDVEVDEAACAALVRPEASVPCLIADCTYRWHVGTWMECSVS CGDGIQR RRDTCLGPQAQAPVPADFCQHLPKPVTVRGCWAGPCVGQGTPSLVPHEEAAAPG RTTATP AGASLEWSQARGLLFSPAPQPRRLLPGPQENSVQSSACGRQHLEPTGTIDMRGPG QADCA VAIGRPLGEVVTLRVLESSLNCSAGDMLLLWGRLTWRKMCRKLLDMTFSSKTNT LVVRQR CGRPGGGVLLRYGSQLAPETFYRECDMQLFGPWGEIVSPSLSPATSNAGGCRLFIN VAPH ARIAIHALATNMGAGTEGANASYILIRDTHSLRTTAFHGQQVLYWESESSQAEME FSEGF LKAQASLRGQYWTLQSWVPEMQDPQSWKGKEGT (SEQ ID NO: 160) roEDPQGDAAQKTDTSHHDQDHPTFNKITPNLAEFAFSLYRQLAHQSNSTNIFFSPVSItniibsip ATA hynrFAMLSLGTKADTHDEILEGLNFNLTEIPEAQIHEGFQELLRTLNQPDSQitiLQLTTGNetnGLFLsaA- 1 SEGLKLVDKFLEDVKKLYHSEAFTVNFGDTEEAKKQINDYVEKGTQGKIVDLVKEniet ah LDRDTorplVFALVNYIFFKGKWERPFEVKDTEEEDFHVDQVTTVKVPMMKRLGMFNIQHCKKP- A1LSSWVLah LMKYLGNATAIFFLPDEGKLQHLENELTHDIITKFLENEDRRSASLHLPKLSITGTYplA DLK SVLGQLGITKVFSNGADLSGVTEEAPLKLSKAVHKAVLTIDEKGTEAAGAMFLEA IPMSI PPEVKFNKPFVFLMIEQNTKSPLFMGKVVNPTQK (SEQ ID NO: 161)Attorney. 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No.616146.100579esMKRKCLSKRLMLAITMATIFTVNSTLPIYAAVDKNNATAAVQNESKRYTVSYLKTanLNYYDegLVDLLVKTEIENLPDLFQYSSDAKEFYGNKTRMSFIMDEIGRRAPQYTEIDHKGIPTalloLVE C VVRAGFYLGFHNKELNEINKRSFKERVIPSILAIQKNPNFKLGTEVQDKIVSATGLL AGN ETAPPEVVNNFTPILQDCIKNIDRYALDDLKSKALFNVLAAPTYDITEYLRATKEKP ENT PWYGKIDGFINELKKLALYGKINDNNSWIIDNGIYHIAPLGKLHSNNKIGIETLTEV MKV YPYLSMQHLQSADQIKRHYDSKDAEGNKIPLDKFKKEGKEKYCPKTYTFDDGKVI IKAGA RVEEEKVKRLYWASKEVNSQFFRVYGIDKPLEEGNPDDILTMVIYNSPEEYKLNS VLYGY DTNNGGMYIEPEGTFFTYEREAQESTYTLEELFRHEYTHYLQGRYAVPGQWGRT KLYDND RLTWYEEGGAELFAGSTRTSGILPRKSIVSNIHNTTRNNRYKLSDTVHSKYGASFE FYNY ACMFMDYMYNKDMGILNKLNDLAKNNDVDGYDNYIRDLSSNYALNDKYQDHM QERIDNYE NLTVPFVADDYLVRHAYKNPNEIYSEISEVAKLKDAKSEVKKSQYFSTFTLRGSYT GGAS KGKLEDQKAMNKFIDDSLKKLDTYSWSGYKTLTAYFTNYKVDSSNRVTYDVVF HGYLPNE GDSKNSLPYGKINGTYKGTEKEKIKFSSEGSFDPDGKIVSYEWDFGDGNKSNEENP EHSY DKVGTYTVKLKVTDDKGESSVSTTTAEIKDLSENKLPVIYMHVPKSGALNQKVVF YGKGT YDPDGSIAGYQWDFGDGSDFSSEQNPSHVYTKKGEYTVTLRVMDSSGQMSEKTM KIKITD PVYPIGTEKEPNNSKETASGPIVPGIPVSGTIENTSDQDYFYFDVITPGEVKIDINKL GY GGATWVVYDENNNAVSYATDDGQNLSGKFKADKPGRYYIHLYMFNGSYMPYRI NIEGSVG R (SEQ ID NO: 163)esMEFFKKTALAALVMGFSGAALALPNITILATGGTIAGGGDSATKSNYTVGKVGVEaniNLVNAgaVPQLKDIANVKGEQVVNIGSQDMNDNVWLTLAKKINTDCDKTDGFVITHGTDTMrapEETAYFsA LDLTVKCDKPVVMVGAMRPSTSMSADGPFNLYNAVVTAADKASANRGVLVVM NDTVLDGR DVTKTNTTDVATFKSVNYGPLGYIHNGKIDYQRTPARKHTSDTPFDVSKLNELPK VGIVY NYANASDLPAKALVDAGYDGIVSAGVGNGNLYKSVFDTLATAAKTGTAVVRSSR VPTGAT TQDAEVDDAKYGFVASGTLNPQKARVLLQLALTQTKDPQQIQQIFNQY (SEQ ID NO: 164))eSYQVICRDEKTQMIYQQHQSWLRPVLRSNRVEYCWCNSGRAQCHSVPVKSCSEPsalRCFNGGpetlTCQQALYFSDFVCQCPEGFAGKCCEIDTRATCYEDQGISYRGTWSTAESGAECTNA(WNSSAaLAQKPYSGRRPDAIRLGLGNHNYCRNPDRDSKPWCYVFKAGKYSSEFCSTPACSEPtGNSDC YFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQALGLGKHNYCRNP DGDAK PWCHVLKNRRLTWEYCDVPSCSTCGLRQYSQPQFRIKGGLFADIASHPWQAAIFA KHRRS PGERFLCGGILISSCWILSAAHCFQERFPPHHLTVILGRTYRVVPGEEEQKFEVEKYI VH KEFDDDTYDNDIALLQLKSDSSRCAQESSVVRTVCLPPADLQLPDWTECELSGYG KHEAL SPFYSERLKEAHVRLYPSSRCTSQHLLNRTVTDNMLCAGDTRSGGPQANLHDACQ GDSGG PLVCLNDGRMTLVGIISWGLGCGQKDVPGVYTKVTNYLDWIRDNMRP (SEQ ID NO: 166)Attorney. 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No.616146.100579enMAQTPAFNKPKVELHVHLDGAIKPETILYYGRKRGIALPADTPEELQNIIGMDKPLiv SLPEobFLAKFDYYMPAIAGCREAVKRIAYEFVEMKAKDGVVYVEVRYSPHLLANSKVEPIesaPWNQAmeEGDLTPDEVVSLVNQGLQEGERDFGVKVRSILCCMRHQPSWSSEVVELCKKYREdaQTVVAIgeDLAGDETIEGSSLFPGHVKAYAEAVKSGVHRTVHAGEVGSANVVKEAVDTLKTE P RLGHGY HTLEDATLYNRLRQENMHFEVCPWSSYLTGAWKPDTEHPVVRFKNDQVNYSLN TDDPLIF KSTLDTDYQMTKNEMGFTEEEFKRLNINAAKSSFLPEDEKKELLDLLYKAYGMPS PASAE QCL (SEQ ID NO: 167)esARPCIPKSFGYSSVVCVCNATYCDSFDPPTFPALGTFSRYESTRSGRRMELSMGPIQarANHeculTGTGLLLTLQPEQKFQKVKGFGGAMTDAAALNILALSPPAQNLLLKSYFSEEGIGYgiNIIRmI,VPMASCDFSIRTYTYADTPDDFQLHNFSLPEEDTKLKIPLIHRALQLAQRPVSLLASesPWTareSPTWLKTNGAVNGKGSLKGQPGDIYHQTWARYFVKFLDAYAEHKLQFWAVTAEculNEPSAGLglLSGYPFQCLGFTPEHQRDFIARDLGPTLANSTHHNVRLLMLDDQRLLLPHWAKVV A LTDPE AAKYVHGIAVHWYLDFLAPAKATLGETHRLFPNTMLFASEACVGSKFWEQSVRL GSWDRG MQYSHSIITNLLYHVVGWTDWNLALNPEGGPNWVRNFVDSPIIVDITKDTFYKQP MFYHL GHFSKFIPEGSQRVGLVASQKNDLDAVALMHPDGSAVVVVLNRSSKDVPLTIKDP AVGFL ETISPGYSIHTYLWRRQ (SEQ ID NO: 168)XIYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPrCLNGGotcaSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGY F RLAEN QKSCEPAVPFPCGRVSVSQTSKLTRAEAVFPDVDYVNSTEAETILDNITQSTQSFN DFTR VVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVA GEHNIEE TEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNI FL KFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLRSTKFTIYNNMFCAGFH EGGRDS CQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT (SEQ ID NO: 169)esLKIAAFNIQTFGETKMSNATLVSYIVQILSRYDIALVQEVRDSHLTAVGKLLDNLNan QDAP D DTYHYVVSEPLGRNSYKERYLFVYRPDQVSAVDSYYYDDGCEPCGNDTFNREPAI VRFFS RFTEVREFAIVPLHAAPGDAVAEIDALYDVYLDVQEKWGLEDVMLMGDFNAGCS YVRPSQ WSSIRLWTSPTFQWLIPDSADTTATPTHCAYDRIVVAGMLLRGAVVPDSALPFNF QAAYG LSDQLAQAISDHYPVEVMLK (SEQ ID NO: 170)esSMTNETSDRP LVHFTPNKGW MNDPNGLWYD EKDAKWHLYF QYNPNDTVWGadTPLFWGHATS DDLTNWEDQP IAIAPKRNDS GAFSGSMVVD YNNTSGFFNDisorTIDPRQRCVA IWTYNTPESE EQYISYSLDG GYTFTEYQKN PVLAANSTQFcaRDPKVFWYEP SQKWIMTAAK SQDYKIEIYS SDDLKSWKLE SAFANEGFLG S YQYECPGLIE VPTEQDPSKS YWVMFISINP GAPAGGSFNQ YFVGSFNGTH FEAFDNQSRV VDFGKDYYAL QTFFNTDPTY GSALGIAWAS NWEYSAFVPT NPWRSSMSLV RKFSLNTEYQ ANPETELINL KAEPILNISN AGPWSRFATN TTLTKANSYN VDLSNSTGTL EFELVYAVNT TQTISKSVFA DLSLWFKGLE DPEEYLRMGF EVSASSFFLD RGNSKVKFVK ENPYFTNRMS VNNQPFKSEN DLSYYKVYGL LDQNILELYF NDGDVVSTNT YFMTTGNALG SVNMTTGVDN LFYIDKFQVR EVK (SEQ ID NO: 172)Attorney. 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No.616146.100579 -nfSYQGNSDCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQALoo aaGLGn KHNY( 7572C d 5 RNPDGDAKPWCHVLKNRRLTWEYCDVPSCSTCGLRQYSQPQFRIKGGLFADIASHet3,acA PWQAA Pnut)IFAKHRRSPGERFLCGGILISSCWILSAAHCFQERFPPHHLTVILGRTYrtd RVVPGEEEQ etKF alysEVEKYIVHKEFDDDTYDNDIALLQLKSDSSRCAQESSVVRTVCLPPADLQLPDWT ocECELS ylg GYGKHEALSPFYSERLKEAHVRLYPSSRCTSQHLLNRTVTDNMLCAGDTRSGGPQ ANLHD ACQGDSGGPLVCLNDGRMTLVGIISWGLGCGQKDVPGVYTKVTNYLDWIRDNM RP (SEQ ID NO: 173),atANAFLEELRPGSLERECKEEQCSFEEAREIFKDAERTKLFWISYSDGDQCASSPCQII nanNGGS VribCKDQLQSYICFCLPAFEGRNCETHKDDQLICVNENGGCEQYCSDHTGTKRSCRCHotcmaoFcEGYSL e LADGVSCTPTVEYPCGKIPILEKRNASKPQGRIVGGKVCPKGECPWQVLLLVNnrGAoitQLCGGalTLINTIWVVSAAHCFDKIKNWRNLIAVLGEHDLSEHDGDEQSRRVAQVIIPSTYVPugaGTTNocHDIALLRLHQPVVLTDHVVPLCLPERTFSERTLAFVRFSLVSGWGQLLDRGATALE LMVL NVPRLMTQDCLQQSRKVGDSPNITEYMFCAGYSDGSKDSCKGDSGGPHATHYRG TWYLTG IVSWGQGCATVGHFGVYTRVSQYIEWLQKLMRSEPRPGVLLRAPFP (SEQ ID NO: 174)tnSYQVICRDEKTQMIYQQHQSWLRPVLRSNRVEYCWCNSGRAQCHSVPVKSCSEPairRCFNGGavrTCQQALYFSDFVCQCPEGFAGKCCEIDTRATCYEDQGISYRGNWSTAESGAECTNotWQSSAaviLAQKPYSGRRPDAIRLGLGNHNYCRNPDRDSKPWCYVFKAGKYSSEFCSTPACSEtcaGNSDCneYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQALGLGKHNYCRNPgoDGDAKniPWCHVLKNRRLTWEYCDVPSCSTCGLRQYSQPQFRIKGGLFADIASHPWQAAIFAmsalAAAAS P PGERFLCGGILISSCWILSAAHCFQERFPPHHLTVILGRTYRVVPGEEEQKFEVEKYIeusVHsitKEFDDDTYDNDIALLQLKSDSSRCAQESSVVRTVCLPPADLQLPDWTECELSGYG KHEAL SPFYSERLKEAHVRLYPSSRCTSQHLLNRTVTDNMLCAGDTRSGGPQANLHDACQ GDSGG PLVCLNDGRMTLVGIISWGLGCGQKDVPGVYTKVTNYLDWIRDNMRP (SEQ ID NO: 175)su) Sl s AVKAARYGKDNVRVYKVHKDEKTGVQTVYEMTVCVLLEGEIETSYTKADNSVIliu VATDSI gvraelfKNTIYITAKQNPVTPPELFGSILGTHFIEKYNHIHAAHVNIVCHRWTRMDIDGKPHPpsHSF A(IRDSEEKRNVQVDVVEGKGIDIKSSLSGLTVLKSTNSQFWGFLRDEYTTLKETWDesaRILSTcirDVDATWQWKNFSGLQEVRSHVPKFDATWATAREVTLKTFAEDNSASVQATMYK U MAEQILA RQQLIETVEYSLPNKHYFEIDLSWHKGLQNTGKNAEVFAPQSDPNGLIKCTVGRSS LKSK L (SEQ ID NO: 176)Attorney. 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No.616146.100579roATRRYYLGAVELSWDYMQSDLGELPVDARFPPRVPKSFPFNTSVVYKKTLFVEFTtcaDHLFNfciIAKPRPPWMGLLGPTIQAEVYDTVVITLKNMASHPVSLHAVGVSYWKASEGAEYliDDQTSQ hpoREKEDDKVFPGGSHTYVWQVLKENGPMASDPLCLTYSYLSHVDLVKDLNSGLIGmeALLVCRhitEGSLAKEKTQTLHKFILLFAVFDEGKSWHSETKNSLMQDRDAASARAWPKMHTVn A NGYVNR SLPGLIGCHRKSVYWHVIGMGTTPEVHSIFLEGHTFLVRNHRQASLEISPITFLTAQ TLL MDLGQFLLFCHISSHQHDGMEAYVKVDSCPEEPQLRMKNNEEAEDYDDDLTDSE MDVVRF DDDNSPSFIQIRSVAKKHPKTWVHYIAAEEEDWDYAPLVLAPDDRSYKSQYLNNG PQRIG RKYKKVRFMAYTDETFKTREAIQHESGILGPLLYGEVGDTLLIIFKNQASRPYNIYP HGI TDVRPLYSRRLPKGVKHLKDFPILPGEIFKYKWTVTVEDGPTKSDPRCLTRYYSSF VNME RDLASGLIGPLLICYKESVDQRGNQIMSDKRNVILFSVFDENRSWYLTENIQRFLPN PAG VQLEDPEFQASNIMHSINGYVFDSLQLSVCLHEVAYWYILSIGAQTDFLSVFFSGY TFKH KMVYEDTLTLFPFSGETVFMSMENPGLWILGCHNSDFRNRGMTALLKVSSCDKN TGDYYE DSYEDISAYLLSKNNAIEPRSFSQNSRHPSTRQKQFNATTIPENDIEKTDPWFAHRT PMP KIQNVSSSDLLMLLRQSPTPHGLSLSDLQEAKYETFSDDPSPGAIDSNNSLSEMTHF RPQ LHHSGDMVFTPESGLQLRLNEKLGTTAATELKKLDFKVSSTSNNLISTIPSDNLAA GTDN TSSLGPPSMPVHYDSQLDTTLFGKKSSPLTESGGPLSLSEENNDSKLLESGLMNSQ ESSW GKNVSSTESGRLFKGKRAHGPALLTKDNALFKVSISLLKTNKTSNNSATNRKTHID GPSL LIENSPSVWQNILESDTEFKKVTPLIHDRMLMDKNATALRLNHMSNKTTSSKNME MVQQK KEGPIPPDAQNPDMSFFKMLFLPESARWIQRTHGKNSLNSGQGPSPKQLVSLGPEK SVEG QNFLSEKNKVVVGKGEFTKDVGLKEMVFPSSRNLFLTNLDNLHENNTHNQEKKI QEEIEK KETLIQENVVLPQIHTVTGTKNFMKNLFLLSTRQNVEGSYDGAYAPVLQDFRSLN DSTNR TKKHTAHFSKKGEEENLEGLGNQTKQIVEKYACTTRISPNTSQQNFVTQRSKRAL KQFRL PLEETELEKRIIVDDTSTQWSKNMKHLTPSTLTQIDYNEKEKGAITQSPLSDCLTRS HSI PQANRSPLPIAKVSSFPSIRPIYLTRVLFQDNSSHLPAASYRKKDSGVQESSHFLQG AKK NNLSLAILTLEMTGDQREVGSLGTSATNSVTYKKVENTVLPKPDLPKTSGKVELLP KVHI YQKDLFPTETSNGSPGHLDLVEGSLLQGTEGAIKWNEANRPGKVPFLRVATESSA KTPSK LLDPLAWDNHYGTQIPKEEWKSQEKSPEKTAFKKKDTILSLNACESNHAIAAINEG QNKP EIEVTWAKQGRTERLCSQNPPVLKRHQREITRTTLQSDQEEIDYDDTISVEMKKED FDIY DEDENQSPRSFQKKTRHYFIAAVERLWDYGMSSSPHVLRNRAQSGSVPQFKKVV FQEFTD GSFTQPLYRGELNEHLGLLGPYIRAEVEDNIMVTFRNQASRPYSFYSSLISYEEDQR QGA EPRKNFVKPNETKTYFWKVQHHMAPTKDEFDCKAWAYFSDVDLEKDVHSGLIGP LLVCHT NTLNPAHGRQVTVQEFALFFTIFDETKSWYFTENMERNCRAPCNIQMEDPTFKEN YRFHA INGYIMDTLPGLVMAQDQRIRWYLLSMGSNENIHSIHFSGHVFTVRKKEEYKMAL YNLYP GVFETVEMLPSKAGIWRVECLIGEHLHAGMSTLFLVYSNKCQTPLGMASGHIRDF QITAS GQYGQWAPKLARLHYSGSINAWSTKEPFSWIKVDLLAPMIIHGIKTQGARQKFSS LYISQAttorney. Docket. No.616146.100579 FIIMYSLDGKKWQTYRGNSTGTLMVFFGNVDSSGIKHNIFNPPIIARYIRLHPTHYSI RS TLRMELMGCDLNSCSMPLGMESKAISDAQITASSYFTNMFATWSPSKARLHLQGR SNAWR PQVNNPKEWLQVDFQKTMKVTGVTTQGVKSLLTSMYVKEFLISSSQDGHQWTLF FQNGKV KVFQGNQDSFTPVVNSLDPPLLTRYLRIHPQSWVHQIALRMEVLGCEAQDLY (SEQ ID NO: 177)esAPHLVQVDAARALWPLRRFWRSTGFCPPLPHSQADQYVLSWDQQLNLAYVGAVadiPHRGIKQnoVRTHWLLELVTTRGSTGRGLSYNFTHLDGYLDLLRENQLLPGFELMGSASGHFTDraFEDKQ L QVFEWKDLVSSLARRYIGRYGLAHVSKWNFETWNEPDHHDFDNVSMTMQGFLN YYDACSE GLRAASPALRLGGPGDSFHTPPRSPLSWGLLRHCHDGTNFFTGEAGVRLDYISLHR KGAR SSISILEQEKVVAQQIRQLFPKFADTPIYNDEADPLVGWSLPQPWRADVTYAAMV VKVIA QHQNLLLANTTSAFPYALLSNDNAFLSYHPHPFAQRTLTARFQVNNTRPPHVQLL RKPVL TAMGLLALLDEEQLWAEVSQAGTVLDSNHTVGVLASAHRPQGPADAWRAAVLI YASDDTR AHPNRSVAVTLRLRGVPPGPGLVYVTRYLDNGLCSPDGEWRRLGRPVFPTAEQFR RMRAA EDPVAAAPRPLPAGGRLTLRPALRLPSLLLVHVCARPEKPPGQVTRLRALPLTQGQ LVLV WSDEHVGSKCLWTYEIQFSQDGKAYTPVSRKPSTFNLFVFSPDTGAVSGSYRVRA LDYWA RPGPFSDPVPYLEVPVPRGPPSPGNP (SEQ ID NO: 178)Attorney. Docket. No.616146.100579at LDNGLARTPTMGWLHWERFMCNLDCQEEPDSCISEKLFMEMAELMVSEGWKDAebGYEYLCIesaDDCWMAPQRDSEGRLQADPQRFPHGIRQLANYVHSKGLKLGIYADVGNKTCAGF disPGSFGYlaYDIDAQTFADWGVDLLKFDGCYCDSLENLADGYKHMSLALNRTGRSIVYSCEWP g A LYMWPF QKPNYTEIRQYCNHWRNFADIDDSWKSIKSILDWTSFNQERIVDVAGPGGWNDPD MLVIG NFGLSWNQQVTQMALWAIMAAPLFMSNDLRHISPQAKALLQDKDVIAINQDPLG KQGYQL RQGDNFEVWERPLSGLAWAVAMINRQEIGGPRSYTIAVASLGKGVACNPACFITQ LLPVK RKLGFYEWTSRLRSHINPTGTVLLQLENTMQMSLKDLL (SEQ ID NO: 179))eMWTGLGPAVTLALVLVVAWATELKPTAPPIFTGRPFVVAWDVPTQDCGPRHKMPniLDPKDMvo(KAFDVQASPNEGFVNQNITIFYRDRLGMYPHFNSVGGSVHGGVPQNGSLWVHLEesMLKGHVadiEHYIRTQEPAGLAVIDWEDWRPVWVRNWQDKDVYRRLSRQLVASHHPDWPPERnorIVKEAQY ulaEFEFAARQFMLETLRFVKAFRPRHLWGFYLFPDCYNHDYVQNWETYTGRCPDVE y VSRNDQ H LSWLWAESTALFPSVYLEETLASSTHGRNFVSFRVQEALRVADVHHANHALPVY VFTRPT YSRGLTGLSEMDLISTIGESAALGAAGVILWGDAGFTTSNETCRRLKDYLTRSLVP YVVN VSWAAQYCSWAQCHGHGRCVRRDPNAHTFLHLSASSFRLVPSHAPDEPRLRPEG ELSWAD RNHLQTHFRCQCYLGWGGEQCQWDRRRAAGGASGAWAGFHLTGLLAVAVLAF TWTS (SEQ ID NO: 180)esSGAGASRPPHLVFLLADDLGWNDVGFHGSRIRTPHLDALAAGGVLLDNYYTQPLaflCTPSRSuslQLLTGRYQIRTGLQHQIIWPCQPSCVPLDEKLLPQLLKEAGYTTHMVGKWHLGMaG YRKECL PTRRGFDTYFGYLLGSEDYYSHERCTLIDALNVTRCALDFRDGEEVATGYKNMYS TNIFT KRAIALITNHPPEKPLFLYLALQSVHEPLQVPEEYLKPYDFIQDKNRHHYAGMVSL MDEA VGNVTAALKSSGLWNNTVFIFSTDNGGQTLAGGNNWPLRGRKWSLWEGGVRGV GFVASPL LKQKGVKNRELIHISDWLPTLVKLARGHTNGTKPLDGFDVWKTISEGSPSPRIELL HNID PNFVDSSPCPRNSMAPAKDDSSLPEYSAFNTSVHAAIRHGNWKLLTGYPGCGYWF PPPSQ YNVSEIPSSDPPTKTLWLFDIDRDPEERHDLSREYPHIVTKLLSRLQFYHKHSVPVY FPA QDPRCDPKATGVWGPWM (SEQ ID NO: 182))nLNFRAPPVIP NVPFLWAWNA PSEFCLGKFD EPLDMSLFSF IGSPRINATGam QGVTIFYVDR LGYYPYIDSI TGVTVNGGIP QKISLQDHLD KAKKDITFYM u PVDNLGMAVI DWEEWRPTWA RNWKPKDVYK NRSIELVQQQ NVQLSLTEAT H(eEKAKQEFEKA GKDFLVETIK LGKLLRPNHL WGYYLFPDCY NHHYKKPGYNsadGSCFNVEIKR NDDLSWLWNE STALYPSIYL NTQQSPVAAT LYVRNRVREAinIRVSKIPDAK SPLPVFAYTR IVFTDQVLKF LSQDELVYTF GETVALGASGoru IVIWGTLSIM RSMKSCLLLD NYMETILNPY IINVTLAAKM CSQVLCQEQGlaVCIRKNWNSS DYLHLNPDNF AIQLEKGGKF TVRGKPTLED LEQFSEKFYC y H SCYSTLSCKE KADVKDTDAV DVCIADGVCI DAFLKPPMET EEPQIFY (SEQ ID NO: 183)esSETQANSTTDALNVLLIIVDDLRPSLGCYGDKLVRSPNIDQLASHSLLFQNAFAQQNPRELIAYSQYPRPSDIPQWNSDaflAVCA KPSLKDIKIMGYSIRTIDYRYTVusrPSRVSFLTGRRPDTTRLYDFNSYWRVHAGNFSTIPQYFKENGYVTMSVGKVFHPG WVGFNPDEFLANFSudIISSNH DIHAGELYFVDSDPLQDHNMYN TDDSPYSWSFPPYHPSSEKYENTKTCRGPDGELHANLLCPVDVLDVPEGTLPDKQ DSQGGDLFQLLMP (SEQ ID NO: STEQA 1184) IQLLEKMKTSASPFFLAVGYHKPHIPFRYPKEFQKLYPLENITLAPDPEVPDGLPPV AYN PWMDIRQREDVQALNISVPYGPIPVDFQRKIRQSYFASVSYLDTQVGRLLSALDDL QLAN STIIAFTSDHGWALGEHGEWAKYSNFDVATHVPLIFYVPGRTASLPEAGEKLFPYL DPFD SASQLMEPGRQSMDLVELVSLFPTLAGLAGLQVPPRCPVPSFHVELCREGKNLLK HFRFR DLEEDPYLPG (SEQ ID NO: 184)Attorney. 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No.616146.100579afl AHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQGLQGAQMGaQPWCFFesaPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMMETENRLHFTIKDPdisANRocRYEVPLETPHVHSRAPSPLYSVEFSEEPFGVIVRRQLDGRVLLNTTVAPLFFADQFLulglQLS A TSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANLYGSHPFYLALEDGG SAHG VFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVVQQYLDVVGYPFMP PYWGL GFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSRRDFTFNKDGFR DFPAMVQ ELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNETGQPLIGKVWPGST AFPD FTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSEDGCPNNELENPPY VPGVVG GTLQAATICASSHQFLSTHYNLHNLYGLTEAIASHRALVKARGTRPFVISRSTFAG HGRY AGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLGNTSEELCVRWTQ LGAFYP FMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQAHVAGETVA RPLFL EFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGTWYDLQTVPVEAL GSLPPP PAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGLTTTESRQQPMALAV ALTK GGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVRVTSEGAGLQLQKV TVLGV ATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC (SEQ ID NO: 185))nMAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRVRRANTFLEEVRKGaNLEREC muh(VEETCSYEEAFEALESSTATDVFWAKYTACETARTPRDKLAACLEGNCAEGLGTNnYRGHVibNITRSGIECQLWRSRYPHKPEINSTTHPGADLQENFCRNPDSSTTGPWCYTTDPTVmorRRQE h T CSIPVCGQDQVTVAMTPRSEGSSVNLSPPLEQCVPDRGQQYQGRLAVTTHGLPCL AWASA QAKALSKHQDFNSAVQLVENFCRNPDGDEEGVWCYVAGKPGDFGYCDLNYCEE AVEEETG DGLDEDSDRAIEGRTATSEYQTFFNPRTFGSGEADCGLRPLFEKKSLEDKTERELL ESYI DGRIVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPPWDK NFTEN DLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIALMKLKKPVAFSD YIHP VCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERP VCKDST RIRITDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGC DRDGKY GFYTHVFRLKKWIQKVIDQFGE (SEQ ID NO: 186))eMARVRGPRLPGCLALAALFSLVHSQHVFLAHQQASSLLQRARRANKGFLEEVRKnivGNLERE o CLEEPCSREEAFEALESLSATDAFWAKYTACESARNPREKLNECLEGNCAEGVGMB(nNYRGNibVSVTRSGIECQLWRSRYPHKPEINSTTHPGADLRENFCRNPDGSITGPWCYTTSPTLmorRRE h ECSVPVCGQDRVTVEVIPRSGGSTTSQSPLLETCVPDRGREYRGRLAVTTSGSRCL T AWSS EQAKALSKDQDFNPAVPLAENFCRNPDGDEEGAWCYVADQPGDFEYCDLNYCE EPVDGDL GDRLGEDPDPDAAIEGRTSEDHFQPFFNEKTFGAGEADCGLRPLFEKKQVQDQTE KELFE SYIEGRIVEGQDAEVGLSPWQVMLFRKSPQELLCGASLISDRWVLTAAHCLLYPP WDKNF TVDDLLVRIGKHSRTRYERKVEKISMLDKIYIHPRYNWKENLDRDIALLKLKRPIE LSDY IHPVCLPDKQTAAKLLHAGFKGRVTGWGNRRETWTTSVAEVQPSVLQVVNLPLV ERPVCK ASTRIRITDNMFCAGYKPGEGKRGDACEGDSGGPFVMKSPYNNRWYQMGIVSW GEGCDRD GKYGFYTHVFRLKKWIQKVIDRLGS (SEQ ID NO: 187)Attorney. 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No.616146.100579afARPCIPKSFGYSSVVCVCNATYCDSFDPPTFPALGTFSRYESTRSGRRMELSMGPIQlaANHesarTGTGLLLTLQPEQKFQKVKGFGGAMTDAAALNILALSPPAQNLLLKSYFSEEGIGYecNIIRulVPMASCDFSIRTYTYADTPDDFQLHNFSLPEEDTKLKIPLIHRALQLAQRPVSLLASgalePWT V SPTWLKTNGAVNGKGSLKGQPGDIYHQTWARYFVKFLDAYAEHKLQFWAVTAE NEPSAGL LSGYPFQCLGFTPEHQRDFIARDLGPTLANSTHHNVRLLMLDDQRLLLPHWAKVV LTDPE AAKYVHGIAVHWYLDFLAPAKATLGETHRLFPNTMLFASEACVGSKFWEQSVRL GSWDRG MQYSHSIITNLLYHVVGWTDWNLALNPEGGPNWVRNFVDSPIIVDITKDTFYKQP MFYHL GHFSKFIPEGSQRVGLVASQKNDLDAVALMHPDGSAVVVVLNRSSKDVPLTIKDP AVGFL ETISPGYSIHTYLWRRQ (SEQ ID NO: 188)esTYKKNDEVEFVRTGYGKDMIKVLHIQRDGKYHSIKEVATTVQLTLSSKKDYLHGaciDNSDVItolPTDTIKNTVNVLAKFKGIKSIETFAVTICEHFLSSFKHVIRAQVYVEEVPWKRFEKNgeGVK P HVHAFIYTPTGTHFCEVEQIRNGPPVIHSGIKDLKVLKTTQSGFEGFIKDQFTTLPEV KD RCFATQVYCKWRYHQGRDVDFEATWDTVRSIVLQKFAGPYDKGEYSPSVQKTL YDIQVLT LGQVPEIEDMEISLPNIHYLNIDMSKMGLINKEEVLLPLDNPYGKITGTVKRKLSSR L (SEQ ID NO: 189)ai ) ADKLPNIVILATGGTIAGSAATGTQTTGYKAGALGVDTLINAVPEVKKLANVKGEnimQFSNMwerhtEASENMTGDVVLKLSQRVNELLARDDVDGVVITHGTDTVEESAYFLHLTV(n KSDKPeasVVFVAAsayrMRPATAISADGPMNLLEAVRVAGDKQSRGRGVMVVLNDRIGSARYITKTNASTL nhicgDTFKANaraEEGYLGVIIGNRIYYQNRIDKLHTTRSVFDVRGLTSLPKVDILYGYQDDPEYLYDApsaAIQH GVKGIVYAGMGAGSVSVRGIAGMRKAMEKGVVVIRSTRTGNGIVPPDEELPGLV SDSLNP AHARILLMLALTRTSDPKVIQEYFHTY (SEQ ID NO: 190)afEFARPCIPKS FGYSSVVCVC NATYCDSFDP PTFPALGTFS RYESTRSGRRlaMELSMGPIQA NHTGTGLLLT LQPEQKFQKV KGFGGAMTDA AALNILALSPesarPAQNLLLKSY FSEEGIGYNI IRVPMASCDF SIRTYTYADT PDDFQLHNFSecLPEEDTKLKI PLIHRALQLA QRPVSLLASP WTSPTWLKTN GAVNGKGSLKulGQPGDIYHQT WARYFVKFLD AYAEHKLQFW AVTAENEPSA GLLSGYPFQCgilaLGFTPEHQRD FIARDLGPTL ANSTHHNVRL LMLDDQRLLL PHWAKVVLTD T PEAAKYVHGI AVHWYLDFLA PAKATLGETH RLFPNTMLFA SEACVGSKFW EQSVRLGSWD RGMQYSHSII TNLLYHVVGW TDWNLALNPE GGPNWVRNFV DSPIIVDITK DTFYKQPMFY HLGHFSKFIP EGSQRVGLVA SQKNDLDAVA LMHPDGSAVV VVLNRSSKDV PLTIKDPAVG FLETISPGYS IHTYLWHRQD LLVDTM (SEQ ID NO: 191)fo niAPSFDCGKPQVEPKKCPGR (SEQ ID NO: 192) VVGGCVAHPHSWPWQVSLRTRmrmsFGMHFCGGTLISPEWVLTAAHCof aldpLEKSPRPSSYKVILGAHetnQEVNLEPHVQEaaIEVSRLFLEPTRcm KDIALLKLSSPAVITDKVIPACLPn uurh SPNYVVADRTECFttITGWGETQGTFGAGLLKEAQLPnanVIENKVCNRYEFLNGRVQSTELibCAGHLAGGTDSCQGDSmoGGPLVCFEKDKYILQGVTSWGLcerGCARPNKPGVYVRVSRFVTWIE GVMRNN (SEQ ID NO: 1192)Attorney. 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No.616146.100579,2esMRPSIHRTAIAAVLATAFVAGTALAQKRDNVLFQAATDEQPAVIKTLEKLVNIETgeaGTGDAsdaidpEGIAAAGNFLEAELKNLGFTVTRSKSAGLVVGDNIVGKIKGRGGKNLLLMSHirMDtapcTVYLKeuG plG ILAKAPFRVEGDKAYGPGIADDKGGNAVILHTLKLLKEYGVRDYGTITVLFNTDEyxEKGSF obrGSRDLIQEEAKLADYVLSFEPTSAGDEKLSLGTSGIAYVQVNITGKASHAGAAPELactGVNAnaLVEASDLVLRTMNIDDKAKNLRFNWTIAKAGNVSNIIPASATLNADVRYARNEDFniDAAMK b m TLEERAQQKKLPEADVKVIVTRGRPAFNAGEGGKKLVDKAVAYYKEAGGTLGVoceEERTGGG R TDAAYAALSGKPVIESLGLPGFGYHSDKAEYVDISAIPRRLYMARRLIMDLGAGK (SEQ ID NO: 193)A MSETSRTAFGGRRAVPPNNSNAAEDDLPTVELQGVVPRGVNLQEFLNVTSVHLFKIIIERWDT XrNKVDHHTDKYENNKLIVRRGQSFYVQIDFSRPYDPRRDLFRVEYVIGRYPQENKGotTYIPVcaFPIVSELQSGKWGAKIVMREDRSVRLSIQSSPKCIVGKFRMYVAVWTPYGVLRTSRnoNPETDitaTYILFNPWCEDDAVYLDNEKEREEYVLNDIGVIFYGEVNDIKTRSWSYGQFEDGILlugDTCLaoYVMDRAQMDLSGRGNPIKVSRVGSAMVNAKDDEGVLVGSWDNIYAYGVPPSA C WTGSVDIL LEYRSSENPVRYGQCWVFAGVFNTFLRCLGIPARIVTNYFSAHDNDANLQMDIFL EEDGN VNSKLTKDSVWNYHCWNEAWMTRPDLPVGFGGWQAVDSTPQENSDGMYRCGP ASVQAIKH GHVCFQFDAPFVFAEVNSDLIYITAKKDGTHVVENVDATHIGKLIVTKQIGGDGM MDITD TYKFQEGQEEERLALETALMYGAKKPLNTEGVMKSRSNVDMDFEVENAVLGKD FKLSITF RNNSHNRYTITAYLSANITFYTGVPKAEFKKETFDVTLEPLSFKKEAVLIQAGEYM GQLL EQASLHFFVTARINETRDVLAKQKSTVLTIPEIIIKVRGTQVVGSDMTVTVEFTNPL KET LRNVWVHLDGPGVTRPMKKMFREIRPNSTVQWEEVCRPWVSGHRKLIASMSSDS LRHVYG ELDVQIQRRPSM (SEQ ID NO: 194)afAPQPPNILLLLMDDMGWGDLGVYGEPSRETPLCSPSRAALLTGRLPIRNGFYTTNAlaeHARNsaLLKKAGYVSKIVGKWHLGHRPQFHPLKHGFNIPVYRDWEMVGRYYEEFPINLKTflusGEANLTolFLYWAVDATHAPVYASKPFLGTSQRGRYGDVADNTFVFFTSDNGAALISAPEQG E GSNGPF PGHVTAGQVSHQLGSIMDLFTTSLALAGLTLMDRPIFYYRGDTLMAATLGQHKA HFWTWT VTTHNLEDHTKLPLIFHLGRDPGERFPLSFEALVPAQPQLNVCNWAVMNWAPPGC EKLGK PNLDRMAAEGLLFPNFYSANAYTPQEIVGGIPDSEQLLPEDEWFGSPNCHFGPYDN KARP QIYLQEALDFIKRQARHHPFAVREIDDSIGKILELLQDLHLCGKQTTFEGGMREPAL AWW PPSDRAIDGLNLLPTLLQGRNSWENFRQGIDFCPGQNVSGASAEYQEALSRITSVV QQHQ CLTPPESIPKKCLWSH (SEQ ID NO: 195)Attorney. 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No.616146.100579afl LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAAARILKGQLesHHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSato AATERSfsRCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNE A MPPEAL SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLD LVDTWK SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEM VVVAI QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTL TVVTA DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVS MVDYA HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACI GANLGHC APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKD IDDDD DDDDDD (SEQ ID NO: 197)A SGGKLTAVDPETNMNVSEIISYWGFPSEEYLVETEDGYILCLNRIPHGRKNHSDKGFL PKPVAVFLQHGLLADSSNWVTNLANSSLGFILADAGFDVWMGNSRGNTWSRKHKTLSVSES QDEFWAAPIFSYDEMAKYDLPASINFILNKTGQEQVYYVGHSQGTTIGFIAFSQIPELAKRIKMFFL ALGEB PVASVAFCTSPMAKLGRLPDHLIKDLFGDKEFLPQSAFLKWLGTHVCTHVILKELCE S GNLC FLLCGFNERNLNMSRVDVYTTHSPAGTSVQNMLHWSQAVKFQKFQAFDWGSSA KNYFHYN QSYPPTYNVKDMLVPTAVWSGGHDWLADVYDVNILLTQITNLVFHESIPEWEHL DFIWGL DAPWRLYNKIINLMRKYQ (SEQ ID NO: 198)A SYSPEPDQRRTLPPGWVSLGRADPEEELSLTFALRQQNVERLSELVQAVSDPSSPQFL YGKYALTLENVADLVRPSPLTLHTVQKWLLAAGAQKCHSVITQDFLTCWLSIRQAELLLPES GAEFHAN HYVGGPTETHVVRSPHPYQLPQALAPHVDFVGGLHRFPPTSSLRQRPEPQVTGTVO GLHLGPIL VTPSVIRKRYNLTSQDVGSGTSNNSQACAQFLEQYFHDSDLAQFMRLFGGNFAHQR ASVARE C VVGQQGRGRAGIEASLDVQYLMSAGANISTWVYSSPGRHEGQEPFLQWLMLLSN ESALPH VHTVSYGDDEDSLSSAYIQRVNTELMKAAARGLTLLFASGDSGAGCWSVSGRHQ FRPTFP ASSPYVTTVGGTSFQEPFLITNEIVDYISGGGFSNVFPRPSYQEEAVTKFLSSSPHLP PS SYFNASGRAYPDVAALSDGYWVVSNRVPIPWVSGTSASTPVFGGILSLINEHRILS GRPP LGFLNPRLYQQHGAGLFDVTRGCHESCLDEEVEGQGFCSGPGWDPVTGWGTPNF PALLKT LLNP (SEQ ID NO: 199)zpMKTLSQAQSK TSSQQFSFTG NSSANVIIGN QKLTINDVAR VARNGTLVSLqpTNNTDILQGI QASCDYINNA VESGEPIYGV TSGFGGMANV AISREQASEL-esQTNLVWFLKT GAGNKLPLAD VRAAMLLRAN SHMRGASGIR LELIKRMEIFailLNAGVTPYVY EFGSIGASGD LVPLSYITGS LIGLDPSFKV DFNGKEMDAPavTALRQLNLSP LTLLPKEGLA MMNGTSVMTG IAANCVYDTQ ILTAIAMGVHgep ALDIQALNGT NQSFHPFIHN SKPHPGQLWA ADQMISLLAN SQLVRDELDG KHDYRDHELI QDRYSLRCLP QYLGPIVDGI SQIAKQIEIE INSVTDNPLI DVDNQASYHG GNFLGQYVGM GMDHLRYYIG LLAKHLDVQI ALLASPEFSN GLPPSLLGNR ERKVNMGLKG LQICGNSIMP LLTFYGNSIA DRFPTHAEQF NQNINSQGYT SATLARRSVD IFQNYVAIAL MFGVQAVDLR TYKKTGHYDA RASLSPATER LYSAVRHVVG QKPTSDRPYI WNDNEQGLDE HIARISADIA AGGVIVQAVQ DILPSLH (SEQ ID NO: 201)Attorney. Docket. No.616146.100579afLDNGLARTPTMGWLHWERFMCNLDCQEEPDSCISEKLFMEMAELMVSEGWKDAlaeGYEYLCIsaDDCWMAPQRDSEGRLQADPQRFPHGIRQLANYVHSKGLKLGIYADVGNKTCAGFdisPGSFGYaglYDIDAQTFADWGVDLLKFDGCYCDSLENLADGYKHMSLALNRTGRSIVYSCEWPaLYMWPF QKPNYTEIRQYCNHWRNFADIDDSWKSIKSILDWTSFNQERIVDVAGPGGWNDPD MLVIG NFGLSWNQQVTQMALWAIMAAPLFMSNDLRHISPQAKALLQDKDVIAINQDPLG KQGYQL RQGDNFEVWERPLSGLAWAVAMINRQEIGGPRSYTIAVASLGKGVACNPACFITQ LLPVK RKLGFYEWTSRLRSHINPTGTVLLQLENTMQMSLKDLL (SEQ ID NO: 202)edHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: 203)itanex Eba ;raMEIVMTQSPS TLSASVGDRV IITCQASEII HSWLAWYQQK PGKAPKLLIYmA-luLASTLASGVP SRFSGSGSGA EFTLTISSLQ PDDFATYYCQ NVYLASTNGAuzFciacG NFGQGTKLTV LGGGGGSGGG GSGGGGSGGG GSEVQLVESG GGLVQPGGSL EulV M RLSCTASGFS LTDYYYMTWV RQAPGKGLEW VGFIDPDDDP YYATWAKGRForTISRDNSKNT LYLQMNSLRA EDTAVYYCAG GDHNSGWGLD IWGQGTLVTV SS B (SEQ ID NO: 204)ba ddeEVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA n mrISRTGGSTYY PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAGu arzibiucelVRAEDGRVRT LPSEYTFWGQ GTQVTVSSAA AEVQLVESGG GLVQPalliqcGGSLR A LSCAASGRTF SYNPMGWFRQ APGKGRELVA AISRTGGSTY YPDSVEGRFTpaWISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR TLPSEYTFWG Cnov QGTQVTVSS (SEQ ID NO: 205)edHAEGTFTSDVSSYLEGQAAKEEFIAWLVRGRG (SEQ ID NO: 206)itulgariLedHGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK (SEQ ID NO:ita207)nesixiLedHGEGTFTSDVSSYLEGQAAKEFIAWLVKGRHGEGTFTSDVSSYLEGQAAKEFIAWituLVKGRlgiDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVblADESAE A NCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPR LVRPEV DVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADK AACLLP KLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKL VTDLTK VHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVEND EMPA DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYE TTLEKC CAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKV PQVST PTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVT KCCTES LVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHK PKAT KEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL (SEQ ID NO: 208)Attorney. Docket. No.616146.100579edHGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSAESKYGPPituCPPCPAlgPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNalu AKTKP D REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTL PPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRLT VDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 209)edHGDGSFSDEMNTILDNLAARDFINWLIQTKITD (SEQ ID NO: 210)itulgudeTedKCTATCATCATQRLANFLVHSSNNFGPILLPPNAVGSNTY (SEQ ID NO: 211)itnilmarPliHSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 212)datpiv AniCYIQNCPLG (SEQ ID NO: 213)cotebraCedH-RGD-SV-EEEEEE-H-TFPQRL-EMHWKLQDI-VQWLQL-GK (SEQ ID NO: 214)itarapireTedH-RGD-SV-EEEEEE-H-TFPQRL-EMHWKLQDI-VQWLQL-GK (SEQ ID NO: 215)itarapolab AedHCCEWCGPGCWCCWNC (SEQ ID NO: 216)itanacelPedHSCNSC-FVGLGCGRLRRASLGCKDMGARA-YILAL-OH (SEQ ID NO: 217)itiriseN niI I DRVYIHPF (SEQ ID NO: 218)snetoign AtnKLLLLKLLLLKLLLLKLLLLK (SEQ ID NO: 219)atcanicu LAttorney. Docket. No.616146.100579edCKNFTCWKVCT-NH2 (SEQ ID NO: 220)itoerisaPedRCDAHFRCT (SEQ ID NO: 221)itonalemteSnitetneorm PecalpeR) YNSGKLEEFV QGNLERECME EKCSFEEARE VFENTERTTE FWKQYVDGDQXIF CESNPCLNGG SCKDDINSYE CWCPFGFEGK NCELDVTCNI KNGRCEQFCK -cNSADNKVVCS CTEGYRLAEN QKSCEPAVPF PCGRVSVSQT SKLTRAETVFF(aPDVDYVNSTE AETILDNITQ STQSFNDFTR VVGGEDAKPG QFPWQVVLNGflaKVDAFCGGSI VNEKWIVTAA HCVETGVKIT VVAGEHNIEE TEHTEQKRNVgoIRIIPHHNYN AAINKYNHDI ALLELDEPLV LNSYVTPICI ADKEYTNIFLcaKFGSGYVSGW GRVFHKGRSA LVLQYLRVPL VDRATCLRST KFTIYNNMFCnonAGFHEGGRDS CQGDSGGPHV TEVEGTSFLT GIISWGEECA MKGKYGIYTKertVSRYVNWIKE KTKLTDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISRfE TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR DELTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GK (SEQ ID NO: 223) (DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK) (SEQ ID NO: 224)Attorney. Docket. No.616146.100579XIYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPFCLNGGniSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGYmu RLAENblA QKSCEPAVPFPCGRVSVSQTSKLTRAETVFPDVDYVNSTEAETILDNITQSTQSFND FTR VVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVA GEHNIEE TEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNI FL KFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLRSTKFTIYNNMFCAGFH EGGRDS CQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT PVSQT SKLTRAETVFPDVDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKL VNEVT EFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNEC FLQHKD DNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYK AAFTE CCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLS QRFPKAE FAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKP LLEKS HCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDY SVVLLL RLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYK FQNAL LVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLC VLHEKT PVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIK KQT ALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQ AALGL (SEQ ID NO: 225)mYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNProfCLNGGosiSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGY8 RLAEN41alQKSCEPAVPFPCGRVSVSQTSKLTRAEAVFPDVDYVNSTEAETILDNITQSTQSFNADFTRXIVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVA F GEHNIEE TEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNI FL KFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLRSTKFTIYNNMFCAGFH EGGRDS CQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT (SEQ ID NO: 226)mrYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPofCLNGGosiSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGY8 RLAEN41alQKSCEPAVPFPCGRVSVSQTSKLTRAEAVFPDVDYVNSTEAETILDNITQSTQSFNADFTRXIVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVA F GEHNIEE TEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNI FL KFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLRSTKFTIYNNMFCAGFH EGGRDS CQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT (SEQ ID NO: 227)Attorney. Docket. No.616146.100579mrYNSGKLEEFVQGNLERECMEEKCSFEEAREVFENTERTTEFWKQYVDGDQCESNPofCLNGGosiSCKDDINSYECWCPFGFEGKNCELDVTCNIKNGRCEQFCKNSADNKVVCSCTEGY84RLAEN1rQKSCEPAVPFPCGRVSVSQTSKLTRAEAVFPDVDYVNSTEAETILDNITQSTQSFN hTDFTRXIVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVTAAHCVETGVKITVVA F GEHNIEE TEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVTPICIADKEYTNI FL KFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLRSTKFTIYNNMFCAGFH EGGRDS CQGDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT (SEQ ID NO: 228)7 QVQLLQSGAAVTKPGASVRVSCEASGYNIRDYFIHWWRQAPGQGLQWVGWINPDIQMTQSPSSLSASVGDTVTITC11KTGQPNNPRQFQGRVSLTRHASWDFDTFSFYMDLKALRSDDTAVYFCARQRSDY QANGYLNWYQQRRGKAPKLLICN WDFDVWGSGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV YDGSKLERGVPSRFSGRRWGQE B 3 SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD YNLTINNLQPEDIATYFCQVYEF KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH VVPGTRLDLKRTVAAPSVFIFPP EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC SDEQLKSGTASVVCLLNNFYPR KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA EAKVQWKVDNALQSGNSQESV VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL TEQDSKDSTYSLSSTLTLSKADY HNHYTQKSLSLSPGK (SEQ ID NO: 229) EKHKVYACEVTHQGLSSPVTKS FNRGEC (SEQ ID NO: 1229)12QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWIRRSPGKGLEWIGYVHKSG SDISVAPGETARISCGEKSLGSR1 DTNYSPSLKSRVNLSLDTSKNQVSLSLVAATAADSGKYYCARTLHGRRIYGIVAF AVQWYQHRAGQAPSLIIYNNQDTG NEWFTYFYMDVWGNGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY RPSGIPERFSGSPDSPFGTTATLTI P FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK TSVEAGDEADYYCHIWDSRVPT PSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV KWVFGGGTTLTVLGQPKAAPSV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN TLFPPSSEELQANKATLVCLISDF GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK YPGAVTVAWKADSSPVKAGVE GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC TTTPSKQSNNKYAASSYLSLTPE SVMHEALHNHYTQKSLSLSPGK* (SEQ ID NO: 230) QWKSHRSYSCQVTHEGSTVEKT VAPTECS* (SEQ ID NO: 1230)2 MWPPGSASQPPPSPAAATGLHPAARPVSLQCRLSMCPARSLLLVATLVLLDHLSL1-LARNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKIDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKM YQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDF YKTKIKLCILLHAFRIRAVTIDRVMSYLNAS* (SEQ ID NO: 231)e t s The past, present, and future of enzyme-based therapies - PMC (nih.gov)mnyeeizmpn Eeacral eh peT RAttorney. Docket. No.616146.100579 Table 2. Immunomodulatory Small Molecules for Alginate and Device Modification. Small Molecule StructureZ4A10 Z1A3 Z2A19 Z1A14 Z1A17 Z1A34 Z1A43 Z4A43Attorney. Docket. No.616146.100579 B2A17 Z1A16

Claims

Attorney. Docket. No.616146.100579 CLAIMS What is claimed is:

1. A biohybrid device housing engineered cells expressing at least one peptide-based therapeutic agent, the biohybrid device comprising: a house containing engineered cells, an oxygenator disposed inside or in adjacent to the house; wherein each of the engineered cells comprises a vector; wherein the vector has at least one promoter followed by at least one peptide encoding sequence.

2. The biohybrid device according to claim 1, wherein the engineered cells are ARPE-19 cells transfected by the vector.

3. The biohybrid device according to claim 1, wherein the at least one peptide encoding sequence comprises a first peptide encoding sequence and a second peptide encoding sequence.

4. The biohybrid device according to claim 3, wherein the vector further comprises a IRES DNA sequence or a P2A sequence locates between the first peptide encoding sequence and the second peptide encoding sequence.

5. The biohybrid device according to claim 3, wherein the at least one promoter comprises a first promoter and a second promoter, wherein the first promoter is followed by the first peptide encoding sequence and the second promoter is followed by the second peptide encoding sequence.

6. The biohybrid device according to claim 1, wherein the vector further comprises a selectable marker driven by a selectable marker promoter.

7. The biohybrid device according to claim 1, wherein the vector further comprises anAttorney. Docket. No.616146.100579 expression enhancing component which enhances the expression of the at least one peptide encoding sequence.

8. The biohybrid device according to claim 3, wherein the first peptide encoding sequence encodes one of a light chain and a heavy chain of the therapeutic agent, and the second peptide encoding sequence encodes the other of the light chain and the heavy chain of the therapeutic agent.

9. The biohybrid device according to claim 1, wherein the therapeutic agent comprises one of natalizumab, ipilimumab, pembrolizumab, PGT121, 3BNC117, GLP-1 analogs, interleukin- 12, atezolizumab and any fragments thereof.

10. The biohybrid device according to claim 1, wherein the therapeutic agent comprises one of cytokines, interferon gamma, and metabolic regulators.

11. The biohybrid device according to claim 1, wherein the at least one promoter comprises one of a CAG promoter, a hPGK promoter, and a CMV promoter.

12. The biohybrid device according to claim 1, wherein the engineered cells are encapsulated in an encapsulation comprising a biocompatible material.

13. The biohybrid device according to claim 12, wherein the biocompatible material comprises hydrogel.

14. The biohybrid device according to claim 12, wherein the biocompatible material is coated with at least one immunomodulatory small molecule.

15. A method for treating a subject having a medical condition with engineered cells expressing at least one therapeutic agent, the method comprising placing a biohybrid device according to claim 1 inside a body of the subject for a period of time.Attorney. Docket. No.616146.100579 16. A method for treating a subject having a medical condition with engineered cells expressing at least one therapeutic agent, the method comprising: producing engineered cells which are configured to express at least one therapeutic agent; disposing the engineered cells into a biohybrid device; and placing the biohybrid device inside a body of the subject for a period of time.

17. The method according to claim 16, wherein the step of producing the engineered cells comprises transfecting ARPE-19 cells with vectors, wherein each of the vectors has at least one promoter followed by at least one peptide encoding sequence.

18. The method according to claim 17, wherein the at least one peptide encoding sequence comprises a first peptide encoding sequence and a second peptide encoding sequence.

19. The method according to claim 18, wherein each of the vectors further comprises a IRES DNA sequence or a P2A sequence locates between the first peptide encoding sequence and the second peptide encoding sequence.

20. The method according to claim 19, wherein the at least one promoter comprises a first promoter and a second promoter, wherein the first promoter is followed by the first peptide encoding sequence and the second promoter is followed by the second peptide encoding sequence.

21. The method according to claim 16, wherein the engineered cells comprise a first type of engineered cells and a second type of engineered cells.

22. The method according to claim 21, wherein the first type of engineered cells is configured to express a first type of therapeutic agent, and the second type of engineered cells is configured to express a second type of therapeutic agent, wherein the first type of therapeutic agent is different from the second type of the therapeutic agent.Attorney. Docket. No.616146.100579 23. The method according to claim 16, wherein the engineered cells are encapsulated in one or more capsules.

24. The method according to claim 23, wherein the step of disposing the engineered cells into the biohybrid device comprises disposing the one or more capsules containing the engineered cells into the biohybrid device.

25. The method according to claim 24, wherein the one or more capsules containing the engineered cells are cryopreserved for a period of time before being thawed and disposed into the biohybrid device.

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