antigen-binding proteins

Abstract

The antigen-binding proteins of the present invention bind to human immunodeficiency virus (HIV) envelope proteins and are useful in the treatment and prevention of HIV infection. In particular, the antigen-binding proteins bind to two distinct epitopes on the HIV envelope surface glycoprotein 120 (gp120): the V3 loop region and the CD4 binding site.

Description

[Technical Field]

[0001] The present invention relates to antigen-binding proteins that bind to the human immunodeficiency virus (HIV) envelope and their use in treating or preventing HIV infection. The antigen-binding proteins of the present invention bind to at least two different epitopes on the HIV envelope protein, particularly the V3 loop region (V3 / glycan) and the CD4 binding site (CD4bs) of the HIV envelope surface glycoprotein 120 (gp120). [Background technology]

[0002] HIV, a virus that can over time lead to acquired immunodeficiency syndrome (AIDS), remains a serious public health challenge, having claimed 40.1 million lives to date. HIV attacks the body's immune system, targeting CD4-positive white blood cells and leaving infected individuals susceptible to opportunistic infections such as tuberculosis and fungal infections, serious bacterial infections, and some cancers. Globally, 38.4 million people were living with HIV as of the end of 2021, with 1.5 million newly infected (WHO, Key Facts HIV, July 2022).

[0003] Currently, there is no cure for HIV infection, but HIV infection can be treated with antiretroviral therapy (ART), which includes many different types of drugs (nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, entry inhibitors, and integrase inhibitors) that prevent the virus from replicating and restore the body's immune system sufficiently to render infected patients symptom-free. As of 2021, 75% of people living with HIV received some form of ART. However, ART often requires lifelong daily medication, carrying the risk of serious and debilitating side effects. Furthermore, increased use of ART has also been accompanied by the emergence of drug resistance, levels of which have steadily increased in recent years.

[0004] Broadly neutralizing antibodies (bNAbs) could potentially provide longer-term HIV suppression, but individual bNAbs have met with limited success in previous studies, in part because antibody-resistant virus was already present in patients or emerged soon after treatment began (NIH Research Matters, June 14, 2022). Combinations of bNAbs are currently being studied, both with and without ART (Nature, 606, 368-374, 2022). Summary of the Invention

[0005] Additional treatment options are needed for HIV infection, especially drugs that are long-acting and effective against a broad range of HIV strains so that patients taking the drugs are less likely to develop drug resistance.

[0006] In a first aspect of the present invention, an anti-human immunodeficiency virus (HIV) gp120 binding protein is provided that binds to at least two different epitopes on HIV surface glycoprotein 120 (gp120).

[0007] In a second aspect of the present invention, a bispecific anti-HIV gp120 binding protein is provided comprising an anti-V3 bNAb and two copies of a CD4 domain, wherein the C-terminus of one CD4 domain is linked, either directly or by a linker, to the N-terminus of one anti-V3 bNAb heavy chain, and the C-terminus of the other copy of the CD4 domain is linked, either directly or by a linker, to the N-terminus of the other anti-V3 bNAb heavy chain.

[0008] In another embodiment of the present invention, a bispecific molecule is provided that binds to human immunodeficiency virus (HIV) glycoprotein gp120 and human CD4, wherein the bispecific molecule comprises (i) a first antigen-binding domain comprising an anti-V3 bNAb; (ii) a second antigen-binding domain comprising a CD4 domain; and (iii) a third antigen-binding domain comprising a CD4 domain.

[0009] In a third aspect of the present invention there is provided an anti-HIV gp120 binding protein having two identical heavy chains and two identical light chains, comprising or consisting of a heavy chain that is at least 95% identical to SEQ ID NO: 121 and a light chain that is at least 95% identical to SEQ ID NO: 63.

[0010] In a fourth aspect of the present invention there is provided an anti-HIV gp120 binding protein consisting of two identical heavy chains of SEQ ID NO: 121 and two identical light chains of SEQ ID NO: 63.

[0011] In a fifth aspect of the present invention there is provided an anti-HIV gp120 binding protein comprising or consisting of a sequence which is at least 95% identical to any one of SEQ ID NOs: 152-157.

[0012] In a sixth aspect of the present invention there is provided an anti-HIV gp120 binding protein consisting of SEQ ID NO:155.

[0013] In further aspects of the present invention, pharmaceutical compositions comprising the anti-HIV gp120 binding proteins of the present invention, methods for preventing and treating HIV infection with the anti-HIV gp120 binding proteins of the present invention, uses of the anti-HIV gp120 binding proteins of the present invention, methods for producing the anti-HIV gp120 binding proteins of the present invention, and kits comprising the anti-HIV gp120 binding proteins of the present invention are also provided. [Brief explanation of the drawings]

[0014] [Figure 1]Figure 1 shows the schematic design of the bispecific molecule of the invention. A human CD4 domain or variant thereof is fused, either directly or via a linker, to the N-terminus of either the heavy chain (A), the light chain (B), or both chains (C) of an anti-V3 bNAb. Such a design facilitates simultaneous binding of the human CD4 domain of the bispecific molecule and the V3 glycan-binding domain of the bispecific molecule to HIV-1 gp120, preventing HIV-1 virions from binding to and fusing with the cell membrane (D). [Figure 2] Figure 2 shows the IC50 values ​​(nM) of soluble CD4 domains (SEQ ID NOS: 4-15) against a panel of HIV-1 envelopes in the PSV assay (ACTOne), along with the Tm for each soluble CD4 domain. Horizontal bars indicate the geometric mean IC50. [Figure 3] Figure 3 shows that the linker length between the CD4 domain and the N-terminus of the bNAb1 heavy chain does not significantly affect antiviral activity in the PSV assay (ACTOne) (A), but alters the PK of the resulting bispecific molecule in a humanized mouse model (Tg32-hFcRn strain) (B). The thermal stability of the CD4 domain also affects the PK of the bispecific molecule (B). [Figure 4] Figure 4 shows the IC50 values ​​(nM) of two bispecific molecules of the invention (SEQ ID NOs: 121 and 63; and SEQ ID NOs: 102 and 63) with variant human CD4 domains (D1m-K8C-G99C, SEQ ID NO: 11; and D1m, SEQ ID NO: 4, respectively) fused to the N-terminus of the heavy chain of bNAb1 via a GGGGS (1xG4S) (SEQ ID NO: 90) linker, and a control molecule, against a panel of HIV-1 envelopes in a PSV assay (ACTOne) (A) and a different panel of HIV-1 envelopes from bNAb1-resistant strains in a PSV assay (ACTOne) (B). Each dot represents one HIV envelope. The horizontal bars indicate the geometric mean IC50. [Figure 5]Figure 5 shows IC50 values ​​(nM) of the single ORF versions of the most potent bispecific formats (i.e., CD4 D1 fused to the N-terminus of the bNAb1 heavy chain), also referred to as scFv-Fc molecules (SEQ ID NOs: 152-157), in a PSV assay (ACTOne cells). Horizontal bars indicate geometric mean IC50. [Figure 6] Figure 6 shows the IC50 values ​​(nM) of two bispecific molecules of the invention (SEQ ID NO:151 and SEQ ID NO:89; and SEQ ID NO:150 and SEQ ID NO:89) with variant human CD4 domains (D1m, SEQ ID NO:4 and D1mD2, SEQ ID NO:2, respectively) fused via a 4xG4S linker (SEQ ID NO:93) to the N-terminus of the heavy chain of bNAb6 (SEQ ID NO:88 and 89), respectively, and a control molecule against a panel of HIV-1 envelopes in a PSV assay (ACTOne). Each dot represents one HIV envelope. The horizontal bars indicate the geometric mean IC50. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition "Affinity," also referred to as "binding affinity," is the strength of binding of one molecule, e.g., an antigen-binding protein, to another molecule, e.g., its target antigen, at a single interaction site, i.e., at a single binding site. The binding affinity of an antigen-binding protein to its target can be determined by equilibrium methods (e.g., enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)) or kinetics (e.g., BIACORE analysis).

[0016] "Alternative antibody formats" include alternative scaffolds in which one or more CDRs of an antigen binding protein may be placed onto a suitable non-immunoglobulin protein scaffold or framework, such as an affibody, an SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005 / 0053973, 2005 / 0089932, 2005 / 0164301), or an EGF domain.

[0017] The term "antibody" is used herein to refer to a heterotetrameric glycoprotein with a molecular weight of approximately 150,000 daltons. An intact antibody is composed of two identical heavy chains (HC) and two identical light chains (LC) linked by covalent disulfide bonds. This H2L2 structure folds to form a "Y" shape with three functional domains, including two antigen-binding fragments known as the "Fab" fragment (the "top" of the "Y") and the crystallizable fragment "Fc" (the "bottom" of the "Y"). The Fab fragment consists of an amino-terminal variable domain, variable heavy (VH) or variable light (VL), and a carboxy-terminal constant domain, CH1 (heavy) and CL (light). The Fc fragment consists of two domains formed by dimerization of the paired CH2 and CH3 regions. The Fc can trigger effector functions by binding to receptors on immune cells or by binding C1q, the first component of the classical complement pathway. The five classes of antibodies, IgM, IgA, IgG, IgE, and IgD, are defined by distinct heavy chain amino acid sequences, called μ, α, γ, ε, and δ, respectively, and each heavy chain can pair with either a K or a λ light chain. The majority of antibodies in serum belong to the IgG class, and there are four isotypes of human IgG (IgG1, IgG2, IgG3, and IgG4), whose sequences differ primarily in their hinge regions. In one embodiment, an anti-CD4bs antibody, as used herein, refers to an antibody that binds to the CD4 binding site.

[0018] "Antigen-binding antibody fragment" or "antigen-binding fragment" or "antibody fragment", as used herein, includes Fab, F(ab')2, Fv, disulfide-linked Fv, single-chain Fv (scFv), disulfide-linked scFv, diabodies, TANDABS, etc., as well as modified versions of any of the foregoing (for a review of alternative "antibody" formats, see Holliger and Hudson, Nature Biotechnology, 23(9), 1126-1136, 2005).

[0019] The terms "antigen-binding protein" and "anti-gp120-binding protein" are used interchangeably herein to refer to antibodies and fragments thereof, alternative antibody formats, and other protein constructs, such as domains, that are capable of binding to HIV gp120. The envelope glycoprotein gp120 (or gp120) is a 120-kDa glycoprotein that is part of the outer layer of HIV. The envelope glycoprotein gp120 consists of three molecules of gp120 linked together and appears as viral membrane spikes anchored to the membrane by the gp41 protein. Gp120 is essential for viral infection because it facilitates HIV entry into host cells through its interaction with cell surface receptors. Gp120 is encoded by the HIV env gene. The env gene encodes a gene product of approximately 850 amino acids. The major env product is the protein gp160, which is cleaved in the endoplasmic reticulum by the intracellular protease Furin into gp120 (approximately 480 amino acids) and gp41 (approximately 345 amino acids). The amino acid sequence of an exemplary gp160 from the HIV clone WITO is provided below (SEQ ID NO: 363; the V3 loop is in bold, and the potential N332 N-linked glycosylation site is in bold and underlined): JPEG2025541605000002.jpg60170

[0020] An exemplary gp120 amino acid sequence is provided below (SEQ ID NO: 364; V3 loop is in bold, potential N332 N-linked glycosylation site is in bold and underlined): JPEG2025541605000003.jpg33170

[0021] The terms "antigen-binding site" and "paratope" are used interchangeably herein and refer to a specific site on an antigen-binding protein that is capable of contacting and specifically binding to an antigen, e.g., a site (i.e., epitope) on HIV gp120. An antigen-binding site may be formed by a single variable domain or by paired VH / VL domains such as those found in standard antibodies. Single-chain Fv (ScFv) domains can also provide an antigen-binding site.

[0022] "Avidity," also referred to as functional affinity, is the cumulative strength of binding at multiple interaction sites, e.g., the sum of the strengths of binding of two molecules (or more) to each other at multiple sites, taking into account the valency of the interactions.

[0023] A "bispecific molecule," as used herein, is an antigen-binding protein capable of binding to two different epitopes on the same antigen, i.e., the HIV gp120 protein. In particular, one epitope comprises part or all of the V3 loop region of gp120, and the other epitope comprises part or all of the CD4-binding site of gp120.

[0024] "Broadly neutralizing antibody" or "bNAb," as used herein, refers to an antibody that neutralizes more than one HIV-1 virus species (from various clades and different strains within a clade) in a neutralization assay. A broadly neutralizing antibody may neutralize at least 2, 3, 4, 5, 6, 7, 8, 9, or more different strains of HIV-1, where the strains belong to the same or different clades.

[0025] "CD4 binding site" or "CD4-binding site" or "CD4bs" refers to the site on the HIV envelope protein gp120 that binds to CD4 (cluster of differentiation 4). CD4 is a T-cell surface protein that serves as the primary receptor site for HIV during HIV infection. The CD4 binding site on gp120 is a highly conserved, discontinuous, conformational site that includes residues on either side of the HIV V4 loop that binds to CD4 (Curr HIV / AIDS Rep, 9(1):52-63, 2021).

[0026] As used herein, a "CD4 domain" refers to a soluble recombinant form of human CD4 (cluster of differentiation 4, a transmembrane glycoprotein found on T cells) or a fragment thereof that mimics the activity of native membrane-anchored human CD4 in its binding interaction with HIV envelope proteins. The CD4 domain of the present invention can bind to the CD4-binding site of HIV gp120 and block the ability of HIV gp120 to bind membrane-anchored CD4, for example, on CD4+ T cells. The CD4 domain of the present invention can induce structural rearrangement of gp120 upon binding, including structural rearrangement of part or all of the V3 region of gp120. This structural rearrangement in gp120 results in the exposure of high-affinity binding sites for chemokine coreceptors (CXCR4 and / or CCR5). Native CD4 contains four domains exposed on the extracellular surface of cells: D1, D2, D3, and D4; a transmembrane domain; and a cytoplasmic tail domain. D1 and D3 resemble Ig variable domains, while D2 and D4 resemble Ig constant domains. The CD4 domain of the present invention includes one or more of CD4 domains D1 to D4 or their variants. Examples of CD4 domains of the present invention include wild-type D1 (SEQ ID NO: 3); "mD1.22" (SEQ ID NO: 4), a CD4 D1 variant (Chen et al., JVI 88(2):1125-39, 2014); wild-type D1D2 (SEQ ID NO: 1); "mD1.22-D2" (SEQ ID NO: 2), a D1D2 variant (Fetzer et al., Journal of Virology, 92(12), 2018); and further variants of mD1.22 (SEQ ID NOs: 5-21).

[0027] "CDR" is defined as the complementarity determining region amino acid sequence of an antigen-binding protein. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable region of an immunoglobulin. In one embodiment, CDRs are defined according to the Kabat definition. In another embodiment, CDRs are defined according to the Chothia definition. In a further embodiment, the Chothia definition is derived from Discovery Studio, which uses definitions from Chothia and Lesk, J Mol Biol., 196(4):901-17 (1987) and Morea et al., Methods, 20:267-279 (2000). In another embodiment, the Chothia definition is based on Chothia from the Abysis definition. In a further embodiment, CDRs are defined according to the IMGT definition. In another embodiment, CDRs are defined according to the Honegger definition. In another embodiment, CDRs are defined according to the contact definition. Thus, "CDRs" as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.

[0028] "Domain" refers to a folded polypeptide structure that retains its tertiary structure independently of the rest of the polypeptide. Generally, domains are responsible for distinct functional properties of the polypeptide and can often be added to, removed from, or transferred to other polypeptides without loss of function of the remainder of the protein and / or the domain.

[0029] "Effector function," as used herein, refers to one or more of antibody-mediated complement activation, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), complement-dependent cell-mediated phagocytosis (CDCP), antibody-dependent complement-mediated cytolysis (ADCML), and antibody-mediated effects, including Fc-mediated phagocytosis or antibody-dependent cellular phagocytosis (ADCP).

[0030] As used herein, "epitope" refers to a portion of an antigen (e.g., gp120) that is capable of contacting and specifically binding to a specific site (paratope) on an antigen-binding protein. Epitopes can be linear or conformational / discontinuous. Conformational / discontinuous epitopes contain amino acid residues that are separated by other sequences; i.e., conformational / discontinuous epitopes do not contain a continuous sequence in the primary amino acid sequence of the antigen, but instead rely on tertiary folding of the polypeptide. Residues within a conformational / discontinuous epitope may be from different regions of the polypeptide chain, but they are in close proximity in the three-dimensional structure of the antigen.

[0031] In the case of multimeric antigens, conformational or discontinuous epitopes may comprise residues from different polypeptide chains. The specific residues contained within an epitope can be determined through three-dimensional structures obtained by computer modeling programs or by methods known in the art, such as X-ray crystallography.

[0032] Epitope mapping can be performed using a variety of techniques known to those skilled in the art, such as those described in publications such as "Epitope Mapping Protocols" in Methods in Molecular Biology by Mike Schutkowski and Ulrich Reineke (Vol. 524, 2009) and Johan Rockberg and Johan Nilvebrant (Vol. 1785, 2018). Exemplary methods include peptide-based approaches such as pepscan, in which a series of overlapping peptides are screened for binding using techniques such as ELISA or by in vitro display of a large library of peptide or protein mutants, for example, on phage. Detailed epitope information can be determined by structural techniques, including X-ray crystallography, solution nuclear magnetic resonance (NMR) spectroscopy, and cryo-electron microscopy (cryo-EM). Mutagenesis, such as alanine scanning, is an effective approach used for epitope mapping, along with binding loss analysis. Another method is hydrogen / deuterium exchange (HDX), which combines proteolysis and liquid chromatography-mass spectrometry (LC-MS) analysis to characterize discontinuous or conformational epitopes.

[0033] "Half-life" or "t 1 / 2 " refers to the time required for the serum concentration of an antigen-binding protein to reach half of its original value. The serum half-life of a protein can be measured by pharmacokinetic studies according to the method described by Kim et al., 1994, Eur. J. of Immuno. 24:542-548. According to this method, a radiolabeled protein is injected intravenously into mice, and its plasma concentration is measured periodically as a function of time, for example, from about 3 minutes to about 72 hours after injection. Pharmacokinetic analysis and other methods for determining the half-life of a molecule are well known to those of skill in the art.

[0034] The term "HIV envelope protein" or "ENV" refers to the trimeric viral membrane-associated glycoprotein (gp) or "spike." The "HIV envelope protein" or "ENV" is found on both the viral membrane and the cellular membrane of infected host cells. The env gene encodes the gp160 polypeptide, which forms a homotrimer and is cleaved into the gp120 and gp41 polypeptides. gp120 is the surface (SU) glycoprotein responsible for binding to receptor molecules, while the transmembrane (TM) glycoprotein, gp41, mediates fusion of the viral membrane with the plasma membrane. More than half of the mass of the trimeric envelope "spike" is an N-linked glycan shield that conceals most amino acid-based epitopes on gp120. Binding of the cell surface receptor CD4 to HIV gp120 induces structural rearrangements, creating high-affinity binding sites on gp120 for chemokine coreceptors (CXCR4 and / or CCR5). After gp120 binding to CXCR4 or CCR5, further conformational changes are induced, which dissociate gp120 from gp41 and allow the fusion peptide of gp41 to insert into the cell membrane, which subsequently induces a series of structural changes leading to membrane fusion (Dimitrov et al., Biochemistry 44(37):12471-12479, 2005).

[0035] The "human immunodeficiency virus (HIV)" has been characterized into two types: HIV-1 and HIV-2. HIV-1 is more virulent and infectious than HIV-2 and accounts for the majority of HIV infections worldwide, whereas HIV-2 is restricted to a significantly smaller number of people, primarily in West Africa (Gilbert et al., Statistics in Medicine 22(4):573-593). References herein to "HIV" are intended to mean "HIV-1." HIV virions are spherical, with HIV envelope proteins, viral glycoprotein "spikes," protruding outward. A conical capsid resides within the virion, enclosing two copies of positive-sense single-stranded RNA tightly bound to nucleocapsid proteins and a ribonucleoprotein complex containing enzymes necessary for viral replication.

[0036] A "linker" is an amino acid sequence that connects one domain in a polypeptide to another domain in a polypeptide. For example, a linker within the meaning of the present invention includes an amino acid sequence that connects a CD4 domain to a bNAb heavy chain or a bNAb light chain. In one embodiment, the linker is not cleavable under intracellular conditions.

[0037] A "multispecific antigen-binding protein" or "MSABP" refers to an antigen-binding protein that comprises at least two different antigen-binding sites. Each of these antigen-binding sites is capable of binding to a different epitope, which may be present on the same antigen or on different antigens. In one embodiment, a multispecific antigen-binding protein of the invention is a bispecific molecule capable of binding to two different epitopes on the HIV envelope protein. In particular, one epitope may comprise part or all of the V3 loop region of gp120, and the other epitope may comprise part or all of the CD4-binding site of gp120.

[0038] Symmetric formats of MSABPs combine multiple binding specificities in a single polypeptide chain or single HL pair, including fragment-based formats and Fc fusion proteins in which an antibody fragment is fused to a conventional antibody molecule. Examples of symmetric formats include DVD-Ig, TVD-Ig, CODV-Ig, (scFv)4-Fc, IgG-(scFv)2, tetravalent DART-Fc, F(ab)4 CrossMab, IgG-HC-scFv, IgG-LC-scFv, mAb-dAb, etc.

[0039] As used throughout this specification, "neutralizing" means that the biological activity of HIV is reduced in vitro or in vivo in the presence of an antigen-binding protein described herein, compared to the biological activity of HIV in the absence of the antigen-binding protein. For example, the neutralizing antigen-binding proteins of the present invention can inhibit HIV entry into target cells and reduce viral load in HIV-infected patients.

[0040] The "percent identity" or "% identity" between a query amino acid sequence and a subject amino acid sequence is the "identity" expressed as a percentage calculated over the entire length of the query sequence using an appropriate algorithm (e.g., BLASTP, FASTA, Needleman-Wunsch, Smith-Waterman, LALIGN, or GenePAST / KERR) or software (e.g., DNASTAR Lasergene or GenePAST / KERR) after a pairwise global sequence alignment is performed using an appropriate algorithm (e.g., Needleman-Wunsch or GenePAST / KERR) or software (e.g., DNASTAR Lasergene, GenomeQuest, EMBOSS needle, or EMBOSS infoalign). Importantly, the query amino acid sequence may be described by the amino acid sequences disclosed herein, particularly in one or more of the claims.

[0041] The query sequence may be 100% identical to the subject sequence, or the query sequence may contain up to a certain integer number of amino acid changes when compared to the subject sequence, resulting in a percent identity of less than 100%. For example, the query sequence is at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to the subject sequence. In the case of amino acid sequences, such changes include deletion, substitution (including conservative and non-conservative substitution), or insertion of at least one amino acid residue, where the changes may occur at the amino- or carboxy-terminal position of the query sequence, or anywhere between these terminal positions, and are dispersed among the amino acid residues in the query sequence individually or in one or more contiguous groups within the query sequence.

[0042] For antibody sequences, % identity may be determined over the entire length of the query sequence, including the CDRs. Alternatively, the % identity may exclude one or more, or all, of the CDRs, for example, all CDRs are 100% identical to the subject sequence, with the variation in % identity occurring in the remainder of the query sequence, e.g., the framework sequences, such that the CDR sequences are fixed and intact.

[0043] "Protein scaffold," as used herein, includes, but is not limited to, an immunoglobulin (Ig) scaffold, such as an IgG scaffold, which may be a four-chain antibody or a two-chain antibody, or which may comprise only the Fc region of an antibody, or which may comprise one or more constant regions from an antibody, which constant regions may be of human origin.

[0044] The protein scaffold may be an Ig scaffold, such as an IgG, or an IgA scaffold. An IgG scaffold may include some or all of the domains of an intact antibody (i.e., CH1, CH2, CH3, VH, VL). The antigen-binding protein may include an IgG scaffold selected from IgG1, IgG2, IgG3, IgG4, or IgG4PE. For example, the scaffold may be IgG1. The scaffold may consist of, include, or be a portion of the Fc region of an antibody.

[0045] The protein scaffold may be a non-Ig scaffold. The protein scaffold may be a derivative of a scaffold selected from the group consisting of: CTLA-4, lipocalin, protein A-derived molecules such as Z domains (Affibodies, SpA), A domains (Avimers / Maxibodies) of protein A; heat shock proteins such as GroEl and GroES; transferrin (trans-body); ankyrin repeat proteins (DARPins); peptide aptamers; C-type lectin domains (tetranectins); human gamma-crystallin and human ubiquitin (affilins); PDZ domains; scorpion toxin Kunitz-type domains of human protease inhibitors; and fibronectin / adnectins, which have been engineered to bind to antigens such as gp120.

[0046] A "single variable domain" refers to a folded polypeptide domain comprising a sequence characteristic of an antibody variable domain. Thus, "single variable domain" encompasses complete antibody variable domains, such as VH, VHH, and VL, as well as modified antibody variable domains, e.g., in which one or more loops have been replaced with sequences not characteristic of antibody variable domains, or antibody variable domains that are truncated or contain N- or C-terminal extensions, and folded fragments of variable domains that retain at least the binding activity and specificity of the full-length domain. A single variable domain, as defined herein, is capable of binding an antigen or epitope independently of different variable regions or domains. A "domain antibody" or "DAB" can be considered the same as a human "single variable domain." Single variable domains may be human single variable domains, but also encompass single variable domains from other species, such as rodent (e.g., as disclosed in WO 00 / 29004), nurse shark, and camelid VHHs. Camelid VHHs are immunoglobulin single variable domain polypeptides derived from species including camel, llama, alpaca, dromedary, and guanaco, which produce heavy chain-only antibodies that naturally lack light chains. Such VHH domains may be humanized according to standard techniques available in the art, and such domains are considered to be "single variable domains."

[0047] A "stabilizing mutation" refers to a change in an amino acid residue in a polypeptide sequence that increases the thermal stability of said polypeptide. An increase in thermal stability can be achieved, for example, by increasing the melting temperature (T) by 1 to 50°C. m ) may be reflected in an increase in CD4 domain activity. CD4 domains with stabilizing mutations include SEQ ID NOs: 5-21.

[0048] A "variant sequence" substantially retains the biological characteristics of the unmodified protein. In the case of the antibody sequences disclosed herein, the VH or VL (or HC or LC) sequence may be a variant sequence having up to 10 amino acid substitutions, additions, or deletions. For example, the variant sequence may have up to 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitution(s), addition(s), or deletion(s). The sequence variation may eliminate one or more or all of the CDRs, e.g., the CDRs are the same as the VH or VL (or HC or LC) sequence, with the variation occurring in the remainder of the VH or VL (or HC or LC) sequence, such that the CDR sequences are fixed and intact.

[0049] As used herein, the terms "V3 loop region," "V3 / glycan," or "V3" refer to the third variable region (V3) of HIV gp120. Comparison of predicted amino acid sequences from several different isolates has shown that the sequence heterogeneity of gp120 is clustered in five variable regions (designated V1, V2, V3, V4, and V5). The V3 region contains post-translational modifications such as glycosylation and is essential for viral infectivity. Although only 35 amino acids long, the V3 region exhibits considerable sequence variability. Furthermore, variability in potential N-linked glycosylation sites allows for further variability in the variable regions of gp120. Together, the V3 region and the N-linked glycosylation sites within and adjacent to it are understood to comprise the "V3 loop region," "V3 / glycan," or "V3" as used herein. For example, one site of glycosylation (e.g., oligomannose, such as Man-5 through Man-9) is centered at amino acid residue N332 of gp120. Other potential N-linked glycosylation sites within and adjacent to the V3 loop region include K295, N301, N386, and N392 of gp120. While the V3 loop is generally believed to reside in the region between cysteine ​​residues C296 and C331 of gp120, several N-linked glycosylation sites are located directly adjacent to the V3 loop. The V3 loop contains a highly conserved tetrapeptide sequence, GPGR (residues 312-315) (Ivanhoff et al., Virology, 187(2), 1992). HIV-1 intracellular entry depends on the interaction of the V3 loop region with HIV coreceptors, typically CCR5 or CXCR4. The V3 loop comprises (i) the base (residues 296-299), (ii) the stem (residues 300-303 and 321-326), and (iii) the crown (residues 304-320) (Friedrich et al., Nature Communications 12, 6705 (2021)). The consensus sequence of the V3 region of gp120 (Milich et al., J Virol., 67(9):5623-5634 (1993)) is provided below: CTRPNNNTRKSIHIGPGRAFYTTGEIIGDIRQAHC (SEQ ID NO: 361)

[0050] The consensus sequence describes the most frequent residues occurring at each position in this region across multiple subtypes, although it will be appreciated that the V3 loop region of a particular strain may exhibit sequence variability.

[0051] A "V3-bNAb" or "anti-V3 bNAb" is a bNAb that binds within the V3 loop region. A V3-bNAb may also be referred to herein as an anti-V3 antibody. A V3-bNAb may bind the N332 glycan in the V3 loop region and / or other N-linked glycosylation sites within and adjacent to the V3 loop region.

[0052] Description of the Invention The antigen-binding proteins of the present invention bind to human immunodeficiency virus (HIV) envelope proteins. In particular, the antigen-binding proteins bind to HIV envelope surface glycoprotein 120 (gp120), and therefore are also referred to herein as anti-gp120 binding proteins. The anti-gp120 binding proteins of the present invention bind to at least two different epitopes on gp120, including the V3 loop region (V3) and the CD4 binding site (CD4bs) of gp120.

[0053] Bispecific molecules of the invention that bind to the V3 loop region of gp120 and CD4bs have been shown to neutralize HIV more effectively and exhibit significantly greater antiviral activity than monospecific molecules that bind only to the V3 loop region of gp120 or CD4bs, and mixtures of these monospecific molecules. Without being bound by any particular theory, the inventors hypothesize that the bispecific molecules of the invention simultaneously bind two different epitopes in the same or adjacent HIV envelope protein trimer, resulting in stronger binding (increased avidity) to the HIV envelope protein. This may be the result of a higher local concentration of the binding sites (paratopes) of the bispecific molecules being "pre-positioned" around their target binding sites (epitopes) on the HIV envelope compared to their monospecific counterparts, which in turn leads to stronger antiviral activity.

[0054] Binding of HIV gp120 to the CD4 binding site (CD4bs) The antigen-binding proteins of the present invention comprise one or more paratopes that bind to the CD4bs of HIV gp120. Such paratope-containing binding domains can be comprised by CD4 domains, including those of anti-CD4bs antibodies and their CD4bs-binding fragments, as well as other anti-CD4bs domains. Non-Ig constructs that bind to CD4bs, such as single-chain variable fragments (scFv), are also part of the present invention. In particular, non-Ig constructs, such as scFvs, that comprise one or more CDRs, preferably three light chain CDRs or three heavy chain CDRs, or a set of six CDRs of such anti-CD4bs antibodies, are also part of the present invention.

[0055] In one embodiment of the invention, the antigen binding protein of the invention comprises an anti-CD4bs antibody or CD4bs-binding fragment thereof, wherein such antibody or fragment thereof comprises a paratope that binds to the CD4bs of HIV gp 120. In a further embodiment, the anti-CD4bs antibody is selected from the group consisting of b12, HJ16, CH103-106, VRC01-03, VRC-PG04, VRC-PG04b, VRC-CH30-34, 3BNC117, 3BNC60, NIH45-46, 12A12, 12A21, 8ANC131, 8ANC134, 1NC9, and 1B2530.

[0056] In alternative or further embodiments of the invention, the paratope that binds to the CD4bs of HIV gp120 is formed by a polypeptide domain that binds to the CD4bs of HIV gp120. In a more particular embodiment, the polypeptide domain is a CD4 domain.

[0057] CD4 domain The CD4 domain of the present invention includes SEQ ID NOs: 1-21.

[0058] In one embodiment of the present invention, the CD4 domain is a CD4 D1 domain. In one embodiment, the CD4 domain is a human CD4 domain. CD4 D1 domains include human wild-type D1 (SEQ ID NO: 3), mD1.22 (also known as D1m) (SEQ ID NO: 4), and further variants of mD1.22 (SEQ ID NOs: 5-21).

[0059] In one embodiment of the present invention, the CD4 domain is a CD4 D1D2 domain. In one embodiment, the CD4 domain is a human CD4 D1D2 domain. CD4 D1D2 domains include human wild-type D1D2 (SEQ ID NO: 1) and mD1.22-D2 (SEQ ID NO: 2).

[0060] In one aspect of the present invention, a stabilized CD4 domain is provided. In one embodiment of the present invention, a stabilized CD4 D1 domain is provided. In one embodiment, the CD4 domain is thermally stable, i.e., thermostable. In one embodiment, the CD4 domain is a thermostable CD4 D1 domain.

[0061] In one embodiment of the present invention, the CD4 domain comprises one or more stabilizing mutations. In one embodiment, the stabilizing mutations are present in the CD4 D1 domain. In one embodiment, the CD4 D1 domain comprises one or more mutations selected from the group consisting of K8C, K8I, K8V, T11C, E13C, K21C, Q25E, H27C, H27D, G38C, N52W, R58N, R58T, R58V, L61M, G65C, I70C, K72C, E87G, E91H, E91Q, and G99C. In one embodiment, the CD4 D1 domain comprises K8I. In one embodiment, the CD4 D1 domain comprises K8V. In one embodiment, the CD4 D1 domain comprises T1C and K72C. In one embodiment, the CD4 D1 domain comprises K8C and G99C.

[0062] CD4 domains of the present invention that contain novel and unique stabilizing mutations include SEQ ID NOs: 5-21.

[0063] The increase in thermal stability may be reflected in an increase in melting temperature (Tm), for example, of 1 to 50°C, particularly 1 to 30°C, particularly 1 to 25°C, particularly 1 to 21°C, and more particularly 5 to 21°C. The increase in Tm is determined by measuring the Tm of the CD4 domain(s) containing one or more stabilizing mutations and subtracting the Tm of the corresponding CD4 domain(s) without said mutation(s). For example, measuring the Tm of the stabilized CD4 D1 domain and subtracting the Tm of the wild-type CD4 D1 domain. In one embodiment, the increase in Tm is about 8°C. In one embodiment, the increase in Tm is about 9°C. In one embodiment, the increase in Tm is about 12°C. In one embodiment, the increase in Tm is about 21°C.

[0064] In one embodiment, the Tm of the CD4 domain is greater than 70°C. In one embodiment, the Tm of the CD4 domain is between 70°C and 95°C. In one embodiment, the Tm of the CD4 domain is between 75°C and 95°C. In one embodiment, the Tm of the CD4 domain is between 75°C and 91°C. In one embodiment, the Tm of the CD4 domain is about 76°C, about 77°C, about 78°C, about 79°C, about 80°C, about 81°C, about 82°C, about 83°C, about 84°C, about 85°C, about 86°C, about 87°C, about 88°C, about 89°C, or about 90°C. In one embodiment, the Tm of the CD4 domain is about 90°C. In one embodiment, the Tm of the CD4 domain is about 89°C.

[0065] Tm can be determined by routine methods known in the art or as shown in the Examples, hi one embodiment, Tm is determined using the Prometheus System (NanoTemper, Munich, Germany).

[0066] Binding to the V3 loop region of HIV gp120 The antigen binding proteins of the present invention contain one or more paratopes that bind to the V3 loop region of HIV gp120. Binding domains containing such paratopes include anti-V3 bNAbs or V3-binding fragments thereof, and non-Ig constructs that bind to V3.

[0067] Antigen binding proteins of the invention may comprise the heavy chain CDRs (CDRH1, CDRH2, and CDRH3) shown in any row of Table 1. Antigen binding proteins of the invention may comprise the light chain CDRs (CDRL1, CDRL2, and CDRL3) shown in any row of Table 1. Antigen binding proteins of the invention may comprise the six CDR sets (CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3) shown in any row of Table 1.

[0068] Antigen-binding proteins of the present invention may comprise the heavy chain CDRs (CDRH1, CDRH2, and CDRH3) of any one of PGT121-123, PGT125-131, PGT135-137, QA013.2, 10-1074, 10-1074LS, PGT121.414.LS, and 2G12. Antigen-binding proteins of the present invention may comprise the light chain CDRs (CDRL1, CDRL2, and CDRL3) of any one of PGT121-123, PGT125-131, PGT135-137, QA013.2, 10-1074, 10-1074LS, PGT121.414.LS, and 2G12. An antigen binding protein of the invention may comprise the six CDR sets (CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3) of any one of PGT121-123, PGT125-131, PGT135-137, QA013.2, 10-1074, 10-1074LS, PGT121.414.LS and 2G12.

[0069] Antigen binding proteins of the invention may comprise a VH domain shown in Table 2. Antigen binding proteins of the invention may comprise a VL domain shown in Table 2. Antigen binding proteins of the invention may comprise a pair of variable domains (VH and VL) shown in either row of Table 2.

[0070] Anti-V3 bNAb The antigen-binding proteins of the present invention may comprise an anti-V3 bNAb or a V3-binding fragment thereof. Anti-V3 antibodies include antibodies comprising a CDR set (CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3) set forth in any row of Table 1.

[0071] [Table 1]

[0072] In certain embodiments, the anti-V3 antibody or V3-binding fragment thereof comprises the CDRs of bNAb 1. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a CDRH1 of SEQ ID NO: 22, a CDRH2 of SEQ ID NO: 23, a CDRH3 of SEQ ID NO: 24, a CDRL1 of SEQ ID NO: 25, a CDRL2 of SEQ ID NO: 26, and a CDRL3 of SEQ ID NO: 27.

[0073] An anti-V3 bNAb may be an antibody comprising a pair of variable domains (VH and VL) shown in any row of Table 2.

[0074] An anti-V3 bNAb may be an antibody comprising a heavy chain (HC) with or without M428L / N434S (EU numbering) "LS" mutations, and a light chain (LC) as shown in any row of Table 2. In one embodiment, the HC comprises a LS. [#TH to add additional sequence]

[0075] [Table 2]

[0076] In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 58 and a VL domain of SEQ ID NO: 59 or 60. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 58 and a VL domain of SEQ ID NO: 59. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 65 and a VL domain of SEQ ID NO: 66. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 70 and a VL domain of SEQ ID NO: 71. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 75 and a VL domain of SEQ ID NO: 76. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 80 and a VL domain of SEQ ID NO: 81. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 85 and a VL domain of SEQ ID NO: 86. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 225 and a VL domain of SEQ ID NO: 226. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 260 and a VL domain of SEQ ID NO: 261. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 265 and a VL domain of SEQ ID NO: 266. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 270 and a VL domain of SEQ ID NO: 271. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 275 and a VL domain of SEQ ID NO: 276. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 280 and a VL domain of SEQ ID NO: 281. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 285 and a VL domain of SEQ ID NO: 286. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO:290 and a VL domain of SEQ ID NO:291.In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 295 and a VL domain of SEQ ID NO: 296. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 300 and a VL domain of SEQ ID NO: 301. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 305 and a VL domain of SEQ ID NO: 306. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 310 and a VL domain of SEQ ID NO: 311. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 320 and a VL domain of SEQ ID NO: 321. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 225 or SEQ ID NO: 330 and a VL domain of SEQ ID NO: 326. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises a VH domain of SEQ ID NO: 334 and a VL domain of SEQ ID NO: 335.

[0077] In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 61 or 62 and a LC of SEQ ID NO: 63 or 64. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 62 and a LC of SEQ ID NO: 63. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 67 or 68 and a LC of SEQ ID NO: 69. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 72 or 73 and a LC of SEQ ID NO: 74. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 77 or 78 and a LC of SEQ ID NO: 79. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 82 or 83 and a LC of SEQ ID NO: 84. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 87 or 88 and a LC of SEQ ID NO: 89. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 257 or 258 and a LC of SEQ ID NO: 259. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 262 or 263 and a LC of SEQ ID NO: 264. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 267 or 268 and a LC of SEQ ID NO: 269. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 272 or 273 and a LC of SEQ ID NO: 274. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 277 or 278 and a LC of SEQ ID NO: 279. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 282 or 283 and a LC of SEQ ID NO: 284. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 292 or 293 and a LC of SEQ ID NO: 294. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 297 or 298 and a LC of SEQ ID NO: 299. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 302 or 303 and a LC of SEQ ID NO: 304. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 307 or 308 and a LC of SEQ ID NO: 309. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 312 or 313 and a LC of SEQ ID NO: 314. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 317 or 318 and a LC of SEQ ID NO: 319. In one embodiment, the anti-V3 antibody comprises a HC of SEQ ID NO: 322 or 323 and a LC of SEQ ID NO: 324.In one embodiment, the anti-V3 antibody comprises an HC of SEQ ID NO: 327, 328, 331 or 332 and an LC of SEQ ID NO: 329. In one embodiment, the anti-V3 antibody comprises an HC of SEQ ID NO: 336 or 337 and an LC of SEQ ID NO: 329.

[0078] Anti-V3 bNAbs known in the art include PGT121-123, PGT125-131, PGT135-137, DH270.6, QA013.2, 10-1074, 10-1074LS, PGT121.414.LS and 2G12, 438-B11, 447-52D, BG18, DH270.6, ePGT121v1, ePGT121v2, ePGT121v3, EPTC112, and F425-B4e8. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises the six CDRs of any one of PGT121-123, PGT125-131, PGT135-137, DH270.6, QA013.2, 10-1074, 2G12, 438-B11, 447-52D, BG18, DH270.6, ePGT121v1, ePGT121v2, ePGT121v3, EPTC112, and F425-B4e8. In one embodiment, the anti-V3 antibody or V3-binding fragment thereof comprises the VH domain and VL domain of any one of PGT121-123, PGT125-131, PGT135-137, DH270.6, QA013.2, 10-1074, 2G12, 438-B11, 447-52D, BG18, DH270.6, ePGT121v1, ePGT121v2, ePGT121v3, EPTC112, and F425-B4e8.

[0079] The antigen-binding protein of the present invention may comprise an anti-V3 scFv of any one of the anti-V3 bNAbs described above. In one embodiment, the scFv comprises the VH and VL pair shown in Table 2. In one embodiment, the scFv comprises the VH and VL pair of any one of PGT121-123, PGT125-131, PGT135-137, QA013.2, 10-1074, 10-1074LS, PGT121.414.LS, and 2G12. In one embodiment, the C-terminus of the VH domain is linked to the N-terminus of the VL domain, either directly or via a linker. In one embodiment, the C-terminus of the VL domain is linked to the N-terminus of the VH domain, either directly or via a linker. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 58 and a VL domain of SEQ ID NO: 59. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 65 and a VL domain of SEQ ID NO: 66. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 70 and a VL domain of SEQ ID NO: 71. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 75 and a VL domain of SEQ ID NO: 76. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 80 and a VL domain of SEQ ID NO: 81. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 85 and a VL domain of SEQ ID NO: 86.

[0080] The anti-V3 scFv may be fused to an Fc domain. In one embodiment, the scFv is fused to a human Fc domain directly or via a linker (scFv-Fc).

[0081] Linker Examples of suitable linkers include amino acid sequences of 1 to 150 amino acids in length, in particular 1 to 140 amino acids, 1 to 130 amino acids, 1 to 120 amino acids, 1 to 110 amino acids, 1 to 100 amino acids, 1 to 90 amino acids, 1 to 80 amino acids, 1 to 70 amino acids, 1 to 60 amino acids, 1 to 50 amino acids, 1 to 40 amino acids, 1 to 30 amino acids, 1 to 20 amino acids, 1 to 10 amino acids, and 5 to 30 amino acids.

[0082] In one embodiment, the linker is an amino acid sequence of 5 to 30 amino acids in length. In one embodiment, the linker is an amino acid sequence set forth in any one of SEQ ID NOs: 90 to 95. In one embodiment, the linker is an amino acid sequence set forth in SEQ ID NO: 90. In one embodiment, the linker is a multimer of the amino acid sequence set forth in SEQ ID NO: 90. In one embodiment, the linker is [SEQ ID NO: 90] n wherein n is an integer from 1 to 6. In one embodiment, the linker is the amino acid sequence set forth in SEQ ID NO: 91. In one embodiment, the linker is the amino acid sequence set forth in SEQ ID NO: 92. In one embodiment, the linker is the amino acid sequence set forth in SEQ ID NO: 93. In one embodiment, the linker is the amino acid sequence set forth in SEQ ID NO: 94. In one embodiment, the linker is the amino acid sequence set forth in SEQ ID NO: 95.

[0083] Any of the above-described linkers may be incorporated into the antigen-binding proteins of the present invention. In particular, any of the above-described linkers may be used to link a domain within an antigen-binding protein to another domain within the antigen-binding protein. In particular, any of the above-described linkers may be used to link a domain within an antigen-binding protein that binds to the CD4-binding site of HIV gp120 to another domain within an antigen-binding protein that binds to the V3 loop region of HIV gp120. Furthermore, any of the above-described linkers may be used to link a CD4 domain disclosed herein to a bNAb disclosed herein. In one embodiment, the linker is the amino acid sequence set forth in any one of SEQ ID NOs: 90-95. In one embodiment, the linker is the amino acid sequence set forth in SEQ ID NO: 90.

[0084] In one embodiment, a linker is used to join the C-terminus of the CD4 domain to the N-terminus of the bNAb heavy chain variable domain. In one embodiment, a linker is used to join the C-terminus of the CD4 domain to the N-terminus of the bNAb light chain variable domain. In one embodiment, a linker is used to join the C-terminus of the CD4 domain to the N-terminus of the bNAb heavy chain variable domain, and a linker is used to join the C-terminus of the CD4 domain to the N-terminus of the bNAb light chain variable domain. In one embodiment, a linker is used to join the C-terminus of the CD4 domain to the N-terminus of the bNAb heavy chain variable domain, and the same linker is used to join the C-terminus of the CD4 domain to the N-terminus of the bNAb light chain variable domain. In one embodiment, the linker is the amino acid sequence set forth in any one of SEQ ID NOs: 90-95. In one embodiment, the linker is the amino acid sequence set forth in SEQ ID NO: 90.

[0085] In one embodiment, a linker is used to join the N-terminus of the CD4 domain to the C-terminus of the bNAb heavy chain. In one embodiment, a linker is used to join the N-terminus of the CD4 domain to the C-terminus of the bNAb heavy chain variable domain. In one embodiment, a linker is used to join the N-terminus of the CD4 domain to the C-terminus of the bNAb light chain. In one embodiment, a linker is used to join the N-terminus of the CD4 domain to the C-terminus of the bNAb light chain variable domain. In one embodiment, a linker is used to join the N-terminus of the CD4 domain to the C-terminus of the Fc domain. In one embodiment, the linker is an amino acid sequence set forth in any one of SEQ ID NOs: 90-95. In one embodiment, the linker is an amino acid sequence set forth in SEQ ID NO: 90.

[0086] In one embodiment of the present invention, the domain of an antigen binding protein that binds to the CD4-binding site of HIV gp120 is directly linked to another domain within the antigen binding protein that binds to the V3 loop region of HIV gp120, i.e., no linker is used. In one embodiment, the CD4 domain disclosed herein is directly linked to a bNAb disclosed herein.

[0087] Any of the above-described linkers may be used to link the VH and VL pairs disclosed herein to form scFvs. In one embodiment, the linker between the VH and VL domains of an scFv is selected from the group consisting of SEQ ID NOs: 90 to 95. In a specific embodiment, the linker between the VH and VL domains of an scFv is SEQ ID NO: 93.

[0088] Any of the above-mentioned linkers may be used to link the scFv disclosed herein to an Fc domain. In one embodiment, the scFv is fused to a human Fc via a linker selected from the group consisting of SEQ ID NOs: 90 to 95. In one embodiment, the scFv is fused to a human Fc via the linker of SEQ ID NO: 91.

[0089] bispecific molecules The bispecific molecules of the invention comprise one or more paratopes that bind to the CD4bs of HIV gp120 and one or more paratopes that bind to the V3 loop region of HIV gp120.

[0090] The paratope that binds to the CD4bs of HIV gp120 can be formed by the CD4 domains disclosed herein, as well as other CD4bs binding domains disclosed herein, including anti-CD4bs antibodies and CD4bs binding fragments thereof, and non-Ig constructs that bind to CD4bs.

[0091] Paratopes that bind to the V3 loop region of HIV gp120 can be formed by the anti-V3 antibodies and V3-binding fragments thereof disclosed herein, as well as non-Ig constructs that bind to V3 disclosed herein.

[0092] In one embodiment, the bispecific molecule comprises a paratope formed by an anti-CD4bs antibody or CD4bs-binding fragment thereof that binds to the CD4bs of HIV gp120 and a paratope formed by an anti-V3 antibody or V3-binding fragment thereof that binds to the V3 loop region of HIV gp120.

[0093] In one embodiment, the bispecific molecule comprises an anti-CD4bs antibody, or a CD4bs binding fragment thereof, and an anti-V3 antibody, or a V3 binding fragment thereof.

[0094] In one embodiment, the bispecific molecule comprises a CD4 domain and a paratope that binds to the V3 loop region of HIV gp120 formed by an anti-V3 antibody or V3-binding fragment thereof.

[0095] In one embodiment, the bispecific molecule comprises a CD4 domain and an anti-V3 antibody or V3-binding fragment thereof.

[0096] In one embodiment, the bispecific molecule comprises a CD4 domain of any one of SEQ ID NOs: 1 to 21 and an anti-V3 antibody or V3-binding fragment thereof.

[0097] In one embodiment, the bispecific molecule comprises the CD4 domain of SEQ ID NO: 11 and an anti-V3 antibody or V3-binding fragment thereof.

[0098] In one embodiment, the bispecific molecule comprises a CD4 domain and an anti-V3 antibody selected from the group consisting of PGT121-123, PGT125-131, PGT135-137, QA013.2, 10-1074, 10-1074LS, PGT121.414.LS and 2G12, or a V3-binding fragment thereof.

[0099] In one embodiment, the bispecific molecule comprises a CD4 domain of any one of SEQ ID NOs: 1-21 and an anti-V3 antibody selected from the group consisting of PGT121-123, PGT125-131, PGT135-137, QA013.2, 10-1074, 10-1074LS, PGT121.414.LS and 2G12, or a V3-binding fragment thereof.

[0100] In one embodiment, the bispecific molecule comprises the CD4 domain of SEQ ID NO: 11 and an anti-V3 antibody selected from the group consisting of PGT121-123, PGT125-131, PGT135-137, QA013.2, 10-1074, 10-1074LS, PGT121.414.LS and 2G12, or a V3-binding fragment thereof.

[0101] In one embodiment, the bispecific molecule comprises an anti-V3 antibody, or a V3-binding fragment thereof, comprising a CD4 domain and a set of CDRs shown in any row of Table 1 (CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3).

[0102] In one embodiment, the bispecific molecule comprises an anti-V3 antibody, or a V3-binding fragment thereof, comprising the CD4 domain of any one of SEQ ID NOs: 1-21 and the CDR set shown in any row of Table 1 (CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3).

[0103] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising the CD4 domain of SEQ ID NO: 11 and the CDR set shown in any row of Table 1 (CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3), or a V3-binding fragment thereof.

[0104] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and a CDRH1 of SEQ ID NO: 22, a CDRH2 of SEQ ID NO: 23, a CDRH3 of SEQ ID NO: 24, a CDRL1 of SEQ ID NO: 25, a CDRL2 of SEQ ID NO: 26 and a CDRL3 of SEQ ID NO: 27, or a V3-binding fragment thereof.

[0105] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain and a pair of variable domains (VH and VL) shown in any row of Table 2, or a V3-binding fragment thereof.

[0106] In one embodiment, the bispecific molecule comprises an anti-V3 antibody, or a V3-binding fragment thereof, comprising the CD4 domain of any one of SEQ ID NOs: 1-21 and a pair of variable domains (VH and VL) shown in any row of Table 2.

[0107] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising the CD4 domain of SEQ ID NO: 11 and a pair of variable domains (VH and VL) shown in any row of Table 2, or a V3-binding fragment thereof.

[0108] In one embodiment, the bispecific molecule comprises an anti-V3 antibody or V3-binding fragment thereof comprising a CD4 domain and a VH domain of SEQ ID NO: 58 and a VL domain of SEQ ID NO: 59 or 60.

[0109] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and a VH domain of SEQ ID NO: 58 and a VL domain of SEQ ID NO: 59 or 60.

[0110] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and a VH domain of SEQ ID NO: 58 and a VL domain of SEQ ID NO: 59 or 60.

[0111] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and a VH domain of SEQ ID NO: 65 and a VL domain of SEQ ID NO:66.

[0112] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and a VH domain of SEQ ID NO: 65 and a VL domain of SEQ ID NO:66.

[0113] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and a VH domain of SEQ ID NO: 70 and a VL domain of SEQ ID NO: 71.

[0114] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and a VH domain of SEQ ID NO: 70 and a VL domain of SEQ ID NO: 71.

[0115] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and a VH domain of SEQ ID NO: 75 and a VL domain of SEQ ID NO:76.

[0116] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and a VH domain of SEQ ID NO: 75 and a VL domain of SEQ ID NO:76.

[0117] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and a VH domain of SEQ ID NO: 80 and a VL domain of SEQ ID NO:81.

[0118] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO:11 and a VH domain of SEQ ID NO:80 and a VL domain of SEQ ID NO:81.

[0119] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and a VH domain of SEQ ID NO: 85 and a VL domain of SEQ ID NO:86.

[0120] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO:11 and a VH domain of SEQ ID NO:85 and a VL domain of SEQ ID NO:86.

[0121] The anti-V3 antibody described above may be an antibody comprising a heavy chain (HC) with or without M428L / N434S (EU numbering) "LS" mutations. In one embodiment, the HC comprises a LS.

[0122] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and an HC of SEQ ID NO: 61 or 62 and an LC of SEQ ID NO: 63 or 64.

[0123] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and an HC of SEQ ID NO: 61 or 62 and an LC of SEQ ID NO: 63 or 64.

[0124] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and an HC of SEQ ID NO: 62 and an LC of SEQ ID NO:63.

[0125] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO:11 and an HC of SEQ ID NO:62 and an LC of SEQ ID NO:63.

[0126] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and an HC of SEQ ID NO: 67 or 68 and an LC of SEQ ID NO: 69.

[0127] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and an HC of SEQ ID NO: 67 or 68 and an LC of SEQ ID NO: 69.

[0128] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and an HC of SEQ ID NO: 72 or 73 and an LC of SEQ ID NO: 74.

[0129] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and an HC of SEQ ID NO: 72 or 73 and an LC of SEQ ID NO: 74.

[0130] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and an HC of SEQ ID NO: 77 or 78 and an LC of SEQ ID NO: 79.

[0131] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and an HC of SEQ ID NO: 77 or 78 and an LC of SEQ ID NO:79.

[0132] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and an HC of SEQ ID NO: 82 or 83 and an LC of SEQ ID NO:84.

[0133] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and an HC of SEQ ID NO: 82 or 83 and an LC of SEQ ID NO:84.

[0134] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of any one of SEQ ID NOs: 1-21 and an HC of SEQ ID NO: 87 or 88 and an LC of SEQ ID NO:89.

[0135] In one embodiment, the bispecific molecule comprises an anti-V3 antibody comprising a CD4 domain of SEQ ID NO: 11 and an HC of SEQ ID NO: 87 or 88 and an LC of SEQ ID NO:89.

[0136] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb disclosed herein and two copies of a CD4 domain disclosed herein, wherein the C-terminus of one CD4 domain is linked, either directly or by a linker, to the N-terminus of one anti-V3 bNAb heavy chain, and the C-terminus of the other copy of the CD4 domain is linked, either directly or by a linker, to the N-terminus of the other anti-V3 bNAb heavy chain.

[0137] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb disclosed herein and two copies of a CD4 domain disclosed herein, wherein the C-terminus of one CD4 domain is linked, either directly or by a linker, to the N-terminus of one anti-V3 bNAb light chain, and the C-terminus of the other copy of the CD4 domain is linked, either directly or by a linker, to the N-terminus of the other anti-V3 bNAb light chain.

[0138] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb disclosed herein and four copies of a CD4 domain disclosed herein, wherein the C-terminus of the first CD4 domain is attached, either directly or by a linker, to the N-terminus of one of the anti-V3 bNAb heavy chains; the C-terminus of the second CD4 domain is attached, either directly or by a linker, to the N-terminus of the other anti-V3 bNAb heavy chain; the third CD4 domain is attached, either directly or by a linker, to the N-terminus of one of the anti-V3 bNAb light chains; and the fourth CD4 domain is attached, either directly or by a linker, to the N-terminus of the other anti-V3 bNAb light chain.

[0139] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb disclosed herein and two copies of a CD4 domain disclosed herein, wherein the N-terminus of the first CD4 domain is attached, either directly or by a linker, to the C-terminus of one of the anti-V3 bNAb heavy chains, and the N-terminus of the other copy of the CD4 domain is attached, either directly or by a linker, to the C-terminus of the other anti-V3 bNAb heavy chain.

[0140] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb disclosed herein and two copies of the CD4 domain of SEQ ID NO: 11, wherein the C-terminus of one CD4 domain is attached to the N-terminus of one of the anti-V3 bNAb heavy chains by a linker of SEQ ID NO: 90, and the C-terminus of the other copy of the CD4 domain is attached to the N-terminus of the other anti-V3 bNAb heavy chain by a linker of SEQ ID NO: 90.

[0141] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb disclosed herein and two copies of the CD4 domain of SEQ ID NO: 11, wherein the C-terminus of one CD4 domain is attached to the N-terminus of one of the anti-V3 bNAb light chains by a linker of SEQ ID NO: 90, and the C-terminus of the other copy of the CD4 domain is attached to the N-terminus of the other anti-V3 bNAb light chain by a linker of SEQ ID NO: 90.

[0142] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb disclosed herein and four copies of the CD4 domain of SEQ ID NO: 11, wherein the C-terminus of the first CD4 domain is attached to the N-terminus of one of the anti-V3 bNAb heavy chains by a linker of SEQ ID NO: 90, the C-terminus of the second CD4 domain is attached to the N-terminus of the other anti-V3 bNAb heavy chain by a linker of SEQ ID NO: 90, the third CD4 domain is attached to the N-terminus of one of the anti-V3 bNAb light chains by a linker of SEQ ID NO: 90, and the fourth CD4 domain is attached to the N-terminus of the other anti-V3 bNAb light chain by a linker of SEQ ID NO: 90.

[0143] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb disclosed herein and two copies of the CD4 domain of SEQ ID NO: 11, wherein the N-terminus of the first CD4 domain is attached to the C-terminus of one of the anti-V3 bNAb heavy chains by a linker of SEQ ID NO: 90, and the N-terminus of the other copy of the CD4 domain is attached to the C-terminus of the other anti-V3 bNAb heavy chain by a linker of SEQ ID NO: 90.

[0144] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb comprising a VH of SEQ ID NO: 58 and a VL of SEQ ID NO: 59, and two copies of a CD4 domain of SEQ ID NO: 11, wherein the C-terminus of one CD4 domain is attached to the N-terminus of one of the anti-V3 bNAb heavy chains by a linker of SEQ ID NO: 90, and the C-terminus of the other copy of the CD4 domain is attached to the N-terminus of the other anti-V3 bNAb heavy chain by a linker of SEQ ID NO: 90.

[0145] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb comprising a VH of SEQ ID NO: 58 and a VL of SEQ ID NO: 59, and two copies of a CD4 domain of SEQ ID NO: 11, wherein the C-terminus of one CD4 domain is attached to the N-terminus of one of the anti-V3 bNAb light chains by a linker of SEQ ID NO: 90, and the C-terminus of the other copy of the CD4 domain is attached to the N-terminus of the other anti-V3 bNAb light chain by a linker of SEQ ID NO: 90.

[0146] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb comprising a VH of SEQ ID NO: 58 and a VL of SEQ ID NO: 59, and four copies of a CD4 domain of SEQ ID NO: 11, wherein the C-terminus of the first CD4 domain is attached to the N-terminus of one of the anti-V3 bNAb heavy chains by a linker of SEQ ID NO: 90, the C-terminus of the second CD4 domain is attached to the N-terminus of the other anti-V3 bNAb heavy chain by a linker of SEQ ID NO: 90, the third CD4 domain is attached to the N-terminus of one of the anti-V3 bNAb light chains by a linker of SEQ ID NO: 90, and the fourth CD4 domain is attached to the N-terminus of the other anti-V3 bNAb light chain by a linker of SEQ ID NO: 90.

[0147] In one embodiment, the bispecific molecule comprises an anti-V3 bNAb comprising a VH of SEQ ID NO: 58 and a VL of SEQ ID NO: 59, and two copies of a CD4 domain of SEQ ID NO: 11, wherein the N-terminus of the first CD4 domain is attached to the C-terminus of one of the anti-V3 bNAb heavy chains by a linker of SEQ ID NO: 90, and the N-terminus of the other copy of the CD4 domain is attached to the C-terminus of the other anti-V3 bNAb heavy chain by a linker of SEQ ID NO: 90.

[0148] In one embodiment, the bispecific molecule comprises an HC of any one of SEQ ID NOs: 96-107, 116, 117 or 119-135; and an LC of SEQ ID NO: 63.

[0149] In one embodiment, the bispecific molecule comprises an HC of SEQ ID NO: 62; and an LC of any one of SEQ ID NOs: 108-115 and 118.

[0150] In one embodiment, the bispecific molecule comprises an HC of SEQ ID NO: 68; and an LC of SEQ ID NO: 142 or 143.

[0151] In one embodiment, the bispecific molecule comprises an HC of any one of SEQ ID NOs: 136-141; and an LC of SEQ ID NO: 69.

[0152] In one embodiment, the bispecific molecule comprises an HC of SEQ ID NO: 144 or 145; and an LC of SEQ ID NO: 74.

[0153] In one embodiment, the bispecific molecule comprises a HC of SEQ ID NO: 146 or 147; and a LC of SEQ ID NO: 79.

[0154] In one embodiment, the bispecific molecule comprises a HC of SEQ ID NO: 148 or 149; and a LC of SEQ ID NO: 84.

[0155] In one embodiment, the bispecific molecule comprises an HC of SEQ ID NO: 150 or 151; and an LC of SEQ ID NO:89.

[0156] In one embodiment, the bispecific molecule consists of two heavy chains and two light chains, wherein the heavy chains are at least 95% identical to SEQ ID NO: 121 and the light chains are at least 95% identical to SEQ ID NO: 63.

[0157] In one embodiment, the bispecific molecule consists of two heavy chains and two light chains, wherein the heavy chains are at least 96% identical to SEQ ID NO: 121 and the light chains are at least 96% identical to SEQ ID NO: 63.

[0158] In one embodiment, the bispecific molecule consists of two heavy chains and two light chains, wherein the heavy chains are at least 97% identical to SEQ ID NO: 121 and the light chains are at least 97% identical to SEQ ID NO: 63.

[0159] In one embodiment, the bispecific molecule consists of two heavy chains and two light chains, wherein the heavy chains are at least 98% identical to SEQ ID NO: 121 and the light chains are at least 98% identical to SEQ ID NO: 63.

[0160] In one embodiment, the bispecific molecule consists of two heavy chains and two light chains, wherein the heavy chains are at least 99% identical to SEQ ID NO: 121 and the light chains are at least 99% identical to SEQ ID NO: 63.

[0161] In one embodiment, the bispecific molecule consists of two heavy chains of SEQ ID NO: 121 and two light chains of SEQ ID NO: 63.

[0162] The antigen-binding protein of the present invention may comprise an anti-V3 scFv of any one of the anti-V3 bNAbs described above. In one embodiment, the scFv comprises a VH and VL pair as shown in Table 2. In one embodiment, the scFv comprises a VH and VL pair of any one of PGT121-123, PGT125-131, PGT135-137, QA013.2, 10-1074, 10-1074LS, PGT121.414.LS, and 2G12. In one embodiment, the C-terminus of the VH domain is linked to the N-terminus of the VL domain, either directly or via a linker. In one embodiment, the C-terminus of the VL domain is linked to the N-terminus of the VH domain, either directly or via a linker. In one embodiment, the linker between the VH and VL domains of the scFv is selected from the group consisting of SEQ ID NOs: 90-95. In one embodiment, the linker between the VH and VL domains of the scFv is SEQ ID NO: 93.

[0163] In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 58 and a VL domain of SEQ ID NO: 59. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 65 and a VL domain of SEQ ID NO: 66. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 70 and a VL domain of SEQ ID NO: 71. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 75 and a VL domain of SEQ ID NO: 76. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 80 and a VL domain of SEQ ID NO: 81. In one embodiment, the scFv comprises a VH domain of SEQ ID NO: 85 and a VL domain of SEQ ID NO: 86. In one embodiment, a linker of SEQ ID NO: 93 joins the VH and VL domains of the scFv. In one embodiment, the linker of SEQ ID NO: 93 joins the C-terminus of the VH domain to the N-terminus of the VL domain to form the scFv. In one embodiment, the linker of SEQ ID NO: 93 joins the C-terminus of the VL domain to the N-terminus of the VH domain to form the scFv.

[0164] The anti-V3 scFv may be fused to an Fc domain. In one embodiment, the scFv is fused to a human Fc domain directly or via a linker (scFv-Fc). In one embodiment, the C-terminus of the scFv is fused to the N-terminus of the human Fc domain via a linker selected from the group consisting of SEQ ID NOs: 90 to 95. In one embodiment, the N-terminus of the scFv is fused to the C-terminus of the human Fc domain via a linker selected from the group consisting of SEQ ID NOs: 90 to 95. In one embodiment, the scFv is fused to the human Fc domain via the linker of SEQ ID NO: 91. In one embodiment, the Fc domain comprises a half-life extending mutation. In one embodiment, the half-life extending mutation is LS.

[0165] The scFv-Fc may be fused to the CD4 domain directly or via a linker. In one embodiment, the scFv-Fc is fused to the CD4 domain via a linker selected from the group consisting of SEQ ID NOs: 90 to 95.

[0166] In one embodiment, the antigen binding protein comprises or consists of: (1) an scFv comprising a VH and VL pair set forth in any row of Table 2, wherein the VH and VL domains are joined via a linker selected from the group consisting of SEQ ID NOs: 90-95 to form the scFv; (2) a CD4 domain selected from the group consisting of SEQ ID NOs: 1-21; and (3) an Fc domain comprising an LS half-life extending mutation, wherein (1), (2), and (3) are linked together in any order, either directly or via a linker, wherein the linker is each selected from the group consisting of SEQ ID NOs: 90-95.

[0167] In one embodiment, the antigen binding protein comprises or consists of: (1) an scFv comprising a VH and VL pair shown in any row of Table 2, wherein the VH and VL domains are joined via a linker of SEQ ID NO: 93 to form the scFv; (2) a CD4 domain selected from the group consisting of SEQ ID NOs: 1-21; and (3) an Fc domain comprising an LS half-life extending mutation, wherein (1), (2), and (3) are joined together in any order via a linker between each domain, wherein the linker is SEQ ID NO: 90.

[0168] In one embodiment, a bispecific molecule of the invention comprises a sequence that is at least 95%, 96%, 97%, 98%, 99% or 100% identical to any one of SEQ ID NOs: 152-157. In one embodiment, an antigen-binding protein of the invention consists of a sequence that is at least 95%, 96%, 97%, 98%, 99% or 100% identical to any one of SEQ ID NOs: 152-157. In one embodiment, an antigen-binding protein of the invention comprises or consists of SEQ ID NO: 152. In one embodiment, an antigen-binding protein of the invention comprises or consists of SEQ ID NO: 153. In one embodiment, an antigen-binding protein of the invention comprises or consists of SEQ ID NO: 154. In one embodiment, an antigen-binding protein of the invention comprises or consists of SEQ ID NO: 155. In one embodiment, an antigen-binding protein of the invention comprises or consists of SEQ ID NO: 156. In one embodiment, an antigen-binding protein of the invention comprises or consists of SEQ ID NO: 157.

[0169] Production method Antigen binding proteins may be prepared by any of a number of conventional techniques, for example, they may be purified from cells that naturally express them (e.g., antibodies may be purified from hybridomas that produce them) or they may be produced in recombinant expression systems.

[0170] A number of different expression systems and purification regimes can be used to produce the antigen binding proteins of the present invention. Generally, host cells are transformed with a recombinant expression vector encoding the desired antigen binding protein. Depending on the expression system, the expression vector may be maintained by the host as a separate genetic element or may be integrated into the host chromosome. A wide variety of host cells may be used, including prokaryotes (including gram-negative or gram-positive bacteria, e.g., Escherichia coli, Bacilli sp., Pseudomonas sp., Corynebacterium sp.), eukaryotes including yeast (e.g., Saccharomyces cerevisiae, Pichia pastoris), fungi (e.g., Aspergillus), or higher eukaryotes, including insect cells and cell lines of mammalian origin (e.g., CHO, NS0, PER.C6, HEK293, HeLa).

[0171] The host cell may be an isolated host cell. The host cell is not normally part of a multicellular organism (e.g., a plant or animal). The host cell may be a non-human host cell.

[0172] Suitable cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian host cells are known in the art.

[0173] Cells can be cultured under conditions that promote the expression of the antigen-binding protein using a variety of equipment, such as shake flasks, spinner flasks, and bioreactors. The polypeptide(s) are recovered by conventional protein purification procedures. Protein purification procedures typically consist of a series of unit operations, consisting of various filtration and chromatography processes developed to selectively concentrate and isolate the antigen-binding protein. The purified antigen-binding protein can be formulated in a pharmaceutically acceptable composition.

[0174] Fc modification Fc engineering methods can be applied to modify the functional or pharmacokinetic properties of antigen-binding proteins, particularly antibodies. Effector function can be altered by creating mutations in the Fc region that increase or decrease binding to C1q or Fcγ receptors, thereby modifying CDC or ADCC activity, respectively. Modifications to the glycosylation pattern of antibodies can also be made to change effector function.

[0175] Interactions between the Fc region of an antigen-binding protein or antibody and various Fc receptors (FcRs), including FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), FcRn, C1q, and type II Fc receptors, are thought to mediate the effector functions of the antigen-binding protein or antibody. Important biological effects can be the result of effector functionality. Typically, the ability to mediate effector functions requires the antigen-binding protein or antibody to bind to an antigen, and not all antigen-binding proteins or antibodies mediate all effector functions.

[0176] Effector function can be assessed in a number of ways, including, for example, assessing ADCC effector function of antibodies coated onto target cells mediated by natural killer (NK) cells via FcγRIII or monocytes / macrophages via FcγRI, or assessing CDC effector function of antibodies coated onto target cells mediated by the complement cascade via C1q. For example, antigen-binding proteins of the present invention can be assessed for ADCC effector function in a natural killer cell assay. Examples of such assays can be found in Shields et al., 2001, The Journal of Biological Chemistry, 276:6591-6604; Chappel et al., 1993, The Journal of Biological Chemistry, 268:25124-25131; Lazar et al., 2006, PNAS, 103:4005-4010.

[0177] Examples of assays for determining CDC function include those described in J Imm Meth, 1995, 184:29-38.

[0178] The effect of mutations on effector function (e.g., FcRn binding, FcγRs and C1q binding, CDC, ADCML, ADCC, ADCP) can be assessed, for example, as described in Grevys et al., J Immunol. 2015 Jun 1;194(11):5497-5508, or Tam et al., Antibodies 2017, 6(3); Monnet et al., 2014 mAbs, 6:2, 422-436.

[0179] Throughout this specification, amino acid residues in the Fc region of an antibody sequence or full-length antigen binding protein sequence are numbered according to the EU index numbering convention.

[0180] The long half-life of IgG antibodies has been reported to depend on their binding to FcRn. Therefore, substitutions that increase the binding affinity of IgG to FcRn at pH 6.0 while maintaining the pH dependence of the interaction with the target by manipulating the constant region have been widely studied (Ghetie et al., Nature Biotech. 15:637-640, 1997; Hinton et al., JBC 279:6213-6216, 2004; Dall'Acqua et al., 10 J Immunol 117:1129-1138, 2006). The in vivo half-life of the antigen-binding proteins of the present invention can be altered by modifying the heavy chain constant domain or the FcRn-binding domain therein.

[0181] In adult mammals, FcRn plays an important role in maintaining serum antibody levels by acting as a protective receptor that binds antibodies of the IgG isotype and protects them from degradation. IgG molecules are endocytosed by endothelial cells and, upon binding to FcRn, are recycled back into the circulation. In contrast, IgG molecules enter cells, do not bind to FcRn, and are targeted to the lysosomal pathway, where they are degraded.

[0182] FcRn is thought to be involved in both antibody clearance and transcytosis across tissues (see Junghans RP (1997) Immunol. Res 16, pp. 29-57 and Ghetie et al. (2000) Annu. Rev. Immunol. 18, pp. 739-766). Human IgG1 residues determined to directly interact with human FcRn include Ile253, Ser254, Lys288, Thr307, Gln311, Asn434, and His435. Mutations at any of these positions may allow for increased serum half-life and / or altered effector properties of the antigen-binding proteins of the invention.

[0183] The antigen-binding proteins of the present invention may have amino acid modifications that increase the affinity of the constant domain or fragment thereof for FcRn. Increasing the half-life (i.e., serum half-life) of therapeutic and diagnostic IgG antibodies and other bioactive molecules has many advantages, including reducing the amount and / or frequency of administration of these molecules. In one embodiment, the antigen-binding proteins of the present invention comprise all or a portion of an IgG constant domain (FcRn-binding portion) with one or more of the following amino acid modifications:

[0184] For example, with reference to IgG1, M252Y / S254T / T256E (commonly referred to as the "YTE" mutation) and M428L / N434S (commonly referred to as the "LS" mutation) increase FcRn binding at pH 6.0 (Wang et al. 2018). In one embodiment, the antigen-binding proteins of the invention comprise an Fc domain with LS mutations. In one embodiment, the antigen-binding proteins of the invention include bNAbs in which LS mutations are present in both heavy chain Fc domains.

[0185] Half-life and FcRn binding can also be extended (for IgG1) by introducing H433K and N434F mutations (commonly referred to as "HN" or "NHance" mutations) (WO2006 / 130834).

[0186] Furthermore, various publications describe how to obtain physiologically active molecules with altered half-lives by introducing FcRn-binding polypeptides into the molecules (WO97 / 43316, US5869046, US5747035, WO96 / 32478 and WO91 / 14438) or by fusing the molecules with antibodies that have preserved FcRn-binding affinity but significantly reduced affinity for other Fc receptors (WO99 / 43713) or with FcRn-binding domains of antibodies (WO00 / 09560, US4703039).

[0187] Post-translational modifications Those skilled in the art will understand that post-translational modifications may occur during the production of antigen-binding proteins, such as the bispecific molecules of the present invention, in host cells. For example, this may include cleavage of certain leader sequences, addition of various sugar moieties in various glycosylation patterns, non-enzymatic glycosylation, deamidation, oxidation, scrambling of disulfide bonds and other cysteine ​​variants such as free sulfhydryls, racemic disulfides, thioether and trisulfide bonds, isomerization, C-terminal lysine clipping, and cyclization of N-terminal glutamine. The present invention encompasses the use of antigen-binding proteins that are subject to or have undergone one or more post-translational modifications. Thus, the antigen-binding proteins of the present invention include "antigen-binding proteins," as defined above, that have undergone post-translational modifications as described herein.

[0188] Glycation is a post-translational non-enzymatic chemical reaction between reducing sugars, such as glucose, and free amine groups in proteins, usually observed at the epsilon amine of lysine side chains or at the N-terminus of proteins. Glycation can occur during production and storage only in the presence of reducing sugars.

[0189] Deamidation can occur during production and storage and is primarily an enzymatic reaction that converts asparagine (N) to isoaspartic acid (isoaspartate) and aspartic acid (aspartate) (D) in an approximately 3:1 ratio. Therefore, this deamidation reaction is associated with the isomerization of aspartate (D) to isoaspartate. Both the deamidation of asparagine and the isomerization of aspartate involve the intermediate succinimide. Deamidation can also occur in a similar manner at glutamine residues, albeit to a much lesser extent. Deamidation can occur in the CDRs, Fab (non-CDR regions), or Fc regions.

[0190] Oxidation can occur during production and storage (i.e., in the presence of oxidizing conditions), resulting in covalent modification of proteins induced directly by reactive oxygen species or indirectly by reaction with secondary by-products of oxidative stress. Oxidation occurs primarily at methionine residues, but can also occur at tryptophan residues and free cysteine ​​residues. Oxidation can occur in the CDRs, in the Fab (non-CDR) region, or in the Fc region.

[0191] Disulfide bond scrambling can occur during production and basic storage conditions. Under certain circumstances, disulfide bonds can be broken or formed incorrectly, resulting in unpaired cysteine ​​residues (-SH). These free (unpaired) sulfhydryls (-SH) can facilitate shuffling.

[0192] Thioether formation and disulfide bond racemization can occur under basic conditions during production or storage by beta-elimination of the disulfide bridge back to a cysteine ​​residue via a dehydroalanine and persulfide intermediate. Subsequent cross-linking of dehydroalanine and cysteine ​​leads to the formation of a thioether bond, or the free cysteine ​​residue can reform the disulfide bond with a mixture of D- and L-cysteines.

[0193] The trisulfide results from the insertion of a sulfur atom into a disulfide bond (Cys-SSS-Cys) and is formed due to the presence of hydrogen sulfide in the producer cell culture medium.

[0194] N-terminal glutamine (Q) and glutamate (glutamic acid) (E) in the heavy and / or light chains likely undergo cyclization to form pyroglutamate (pGlu). While most pGlu formation occurs in the production bioreactor, it can also form non-enzymatically depending on the pH and temperature of processing and storage conditions. Cyclization of N-terminal Q or E is commonly observed in native human antibodies.

[0195] C-terminal lysine clipping is an enzymatic reaction catalyzed by carboxypeptidase and is commonly observed in recombinant and natural human antibodies. A variation of this process involves the removal of lysines from one or both heavy chains due to cellular enzymes from recombinant host cells. Administration to a human subject / patient is likely to result in the removal of any remaining C-terminal lysines.

[0196] Pharmaceutical Composition The antigen binding proteins described herein can be incorporated into pharmaceutical compositions for use in the treatment or prevention of HIV infection. In one embodiment, the pharmaceutical composition comprises the antigen binding protein in combination with one or more pharmaceutically acceptable carriers and / or excipients.

[0197] Such compositions will include pharmaceutically acceptable carriers as known and required by accepted pharmaceutical practice.

[0198] The pharmaceutical composition can be administered by injection or continuous infusion (for example, but not limited to, intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intraocular, and intraportal administration). In one embodiment, the composition is suitable for intravenous administration. In one embodiment, the composition is suitable for subcutaneous administration.

[0199] Pharmaceutical compositions may be suitable for topical administration (including but not limited to epidermal, inhaled, intranasal or intraocular administration) or enteral administration (including but not limited to oral, vaginal or rectal administration).

[0200] The pharmaceutical composition may be included in a kit containing the antigen-binding protein together with other pharmaceutical agents, such as dolutegravir or cabotegravir, and / or together with instructions for use. For convenience, the kit may include predetermined amounts of reagents along with instructions for use. The kit may also include a device used to administer the pharmaceutical composition.

[0201] The terms "individual," "subject," and "patient" are used interchangeably herein. In one embodiment, the subject is a human.

[0202] The antigen-binding proteins described herein can be used in methods for treating or preventing HIV infection and AIDs. The antigen-binding proteins described herein can be used in the manufacture of a medicament for treating or preventing HIV infection and AIDs. The described antigen-binding proteins can be used in an amount effective for therapeutic, prophylactic, or preventative treatment. A therapeutically effective amount of the antigen-binding proteins described herein is an amount effective to ameliorate or reduce one or more symptoms of HIV infection. A prophylactically effective amount of the antigen-binding proteins described herein is an amount effective to prevent one or more symptoms of HIV infection.

[0203] combination The antigen-binding proteins of the present invention can be used alone or in combination with other therapeutic agents or prodrugs thereof. Thus, combination therapy according to the present invention involves administration of the antigen-binding protein and at least one other agent that may be useful in the treatment or prevention of HIV infection and / or AIDS. The antigen-binding protein of the present invention and the other therapeutic agent may be formulated and administered together in a single pharmaceutical composition, or may be formulated and administered separately. When formulated and administered separately, administration may be simultaneous or sequential in any order.

[0204] The antigen binding proteins described herein can be combined with, for example, one or more of antiretroviral agents, anti-infective agents, immunomodulatory agents, and other HIV entry inhibitors.

[0205] Antiretroviral agents include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase translocation inhibitors (NRTTIs), protease inhibitors (PIs), entry inhibitors (EIs), integrase strand transfer inhibitors (INSTIs), maturation inhibitors (MIs), and capsid inhibitors (CIs).

[0206] NRTIs may include, but are not limited to, abacavir, adefovir, adefovir dipivoxil, alovudine, amdoxovir, apricitabine, calanolide A, censavudine, didanosine, elvucitabine, emtricitabine, fozivudine, lamivudine, rasibir, stambidine, stavudine, tenofovir disoproxil fumarate, tenofovir alafenamide, todoxil, zalcitabine, and zidovudine.

[0207] NNRTIs may include, but are not limited to, HBY 097 (Hoechst / Bayer), capravirine, delaviridine, doravirine, efavirenz, etravirine, Immunocal, lersivirine, loviride, nevirapine, oltipraz, and rilpivirine.

[0208] NRTTIs include, but are not limited to, islatravir.

[0209] PIs may include, but are not limited to, amprenavir, atazanavir, brecanavir, cobicistat, darunavir, fosamprenavir, indinavir, lasinavir, lopinavir, parinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.

[0210] EIs are discussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol. 9, pp. 243-246, October 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5, May 2000, pp. 183-194; and Meanwell et al., Current Opinion in Drug Discovery & Development (2003), 6(4), pp. 451-461. In particular, the antigen-binding proteins of the present invention may be utilized in combination with adhesion inhibitors, fusion inhibitors, and chemokine receptor agonists directed against either the CCR5 or CXCR4 co-receptors. HIV attachment inhibitors are also described in U.S. Pat. Nos. 7,354,924 and 7,745,625. EIs may include, but are not limited to, cenicriviroc, enfuvirtide, fostemsavir, ibalizumab, leronlimab, maraviroc, vicriviroc, and VIR-576.

[0211] INSTIs may include, but are not limited to, bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir.In one embodiment, the INSTI is dolutegravir or cabotegravir.In one embodiment, the INSTI is cabotegravir.

[0212] Maturation inhibitors may include, but are not limited to, Bevirimat, BMS-955176, GSK3640254, GSK3739937, PA-344, and PA-457. It is understood that GSK3640254 is a compound described in Dicker I, Jeffrey JL, Protack T, et al., Antimicrob Agents Chemother. 2022;66(1). GSK3739937, also known as VH3739937, is a compound in clinical trial NCT0493684.

[0213] Capsid inhibitors can include, but are not limited to, GSK4004280, GSK4011499, and lencapavir.

[0214] Anti-infective agents include, but are not limited to, primaquine along with clindamycin, daunorubicin, fluconazole, intraconazole, nystatin troche, ornidyl eflornithine, megestrol acetate, pentamidine isethionate, piritrexim, trimethoprim, trimetrexate, recombinant human erythropoietin, recombinant human growth hormone, spiramycin, testosterone, and total enteral nutrition.

[0215] Immunomodulatory agents include, but are not limited to, acemannan, alpha-2-interferon, AS-101, bropirimine, CL246,738, FP-21399, gamma interferon, granulocyte-macrophage colony-stimulating factor, HIV core particle immunostimulant, interleukin-2, immunoglobulin, IMREG-1, IMREG-2, imuthiol diethyldithiocarbamate, methionine enkephalin, MTP-PE muramyl tripeptide, remune, recombinant soluble human CD4, rCD4-IgG hybrid, SK&F 106528, thymopentin, and tumor necrosis factor (TNF).

[0216] The antigen-binding proteins of the present invention can also be used in combination with agents that induce HIV expression, such as latency reversing agents, including, but not limited to, histone deacetylase inhibitors (e.g., vorinostat, panobinostat, romidepsin), histone crotonyltransferase inhibitors (sodium corotonate), protein kinase C agonists (e.g., bryostatin, ingenol B), disulfiram, TLR7 agonists (e.g., GS-9620), and bromodomain inhibitors (e.g., JQ1, iBET151).

[0217] The antigen binding proteins of the present invention can also be used in combination with other agents that induce HIV expression, such as agents for clearance therapy. Some examples of agents for clearance therapy or immunological combinations for clearance include, but are not limited to, the following: bNAbs, CD4-Ig, eCD4-Ig, and dual affinity retargeting (DART) proteins.

[0218] Antigen binding proteins of the present invention include 1NC9, 1B2530, 2F5, 2G12, 3NBC60, 3BNC117, 4E10, 8ANC131, 8ANC134, 10-1074, 10-1074LS, 10E8, 12A12, 12A21, b12, CAP206-CH12, CH01-04, CH103-106, elipovimab (formerly GS-9 722), HJ16, M66.6, N6LS (also known as VRC-HIVMAB091-00-AB and the compound in clinical trial NCT03538626), NIH45-46, PG9, PG16, PGT121-123, PGT125-131, PGT135-137, PGT141-145, PGT121.414.LS, PGT151 2G12, QA013.2, VRC01-03, VRC-PG04, VRC-PG04b, VRC-CH30-34.

[0219] Other drugs that may be combined with the antigen binding proteins of the present invention include BIT225, GSK4000422 / VH4000422, and S-648414 (compound in clinical trial NCT04147715).

[0220] The scope of combinations of the compounds of the present invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful in the treatment and / or prevention of HIV infection and / or AIDS.

[0221] The present invention is defined by the following clauses:

[0222] 1. An anti-human immunodeficiency virus (HIV) gp120 binding protein that binds to at least two different epitopes on the HIV surface glycoprotein 120 (gp120).

[0223] 2. The anti-HIV gp120 binding protein of clause 1, wherein one of the at least two epitopes comprises one or more amino acid residues in the CD4-binding site of HIV gp120.

[0224] 3. The anti-HIV gp120 binding protein of clause 1 or clause 2, wherein one of the at least two epitopes comprises one or more amino acid residues in the V3 loop region (V3) of HIV gp120.

[0225] 4. The anti-HIV gp120 binding protein of clause 3, wherein one of the at least two epitopes comprises a cluster of mannose glycans centered at N332 of HIV gp120.

[0226] 5. An anti-HIV gp120 binding protein of any one of the preceding clauses, which binds to the CD4-binding site of HIV gp120 and the V3 loop region of HIV gp120.

[0227] 6. An anti-HIV gp120 binding protein of any one of the preceding clauses, comprising a CD4 domain.

[0228] 7. The anti-HIV gp120 binding protein of clause 6, wherein the CD4 domain is a CD4 D1 domain or a CD4 D1D2 domain.

[0229] 8. The anti-HIV gp120 binding protein of clause 6 or clause 7, wherein the CD4 domain comprises one or more stabilising mutations.

[0230] 9. The anti-HIV gp120 binding protein of clause 8, wherein the CD4 domain has a Tm of 70°C to 95°C.

[0231] 10. The anti-HIV gp120 binding protein of any one of clauses 6 to 9, wherein the CD4 D1 domain comprises one or more mutations selected from the group consisting of K8C, K8I, K8V, T11C, E13C, K21C, Q25E, H27C, H27D, G38C, N52W, R58N, R58T, R58V, L61M, G65C, I70C, K72C, E87G, E91H, E91Q, and G99C.

[0232] 11. The anti-HIV gp120 binding protein of clause 9, wherein the CD4 domain has a Tm of about 90°C.

[0233] 12. The anti-HIV gp120 binding protein of clause 10 or clause 11, wherein the CD4 domain comprises K8C and G99C.

[0234] 13. The anti-HIV gp120 binding protein of clause 6, comprising any one of SEQ ID NOs: 1-21.

[0235] 14. The anti-HIV gp120 binding protein of any one of clauses 6 to 13, comprising SEQ ID NO: 11.

[0236] 15. An anti-HIV gp120 binding protein of any one of clauses 3 to 14, comprising six CDR sets (CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3) set forth in any row of Table 1.

[0237] 16. The anti-HIV gp120 binding protein of clause 15, comprising a CDRH1 of SEQ ID NO:22, a CDRH2 of SEQ ID NO:23, a CDRH3 of SEQ ID NO:24, a CDRL1 of SEQ ID NO:25, a CDRL2 of SEQ ID NO:26 and a CDRL3 of SEQ ID NO:27.

[0238] 17. The anti-HIV gp120 binding protein of any one of the preceding clauses, comprising an immunoglobulin (Ig) scaffold.

[0239] 18. The anti-HIV gp120 binding protein of clause 15, clause 16 or clause 17, comprising a heavy chain variable (VH) domain and a light chain variable (VL) domain pair set forth in any row of Table 2.

[0240] 19. The anti-HIV gp120 binding protein of clause 18, comprising a VH domain of SEQ ID NO:58 and a VL domain of SEQ ID NO:59 or SEQ ID NO:60.

[0241] 20. The anti-HIV gp120 binding protein of any one of clauses 17 to 19, comprising an Fc domain.

[0242] 21. The anti-HIV gp120 binding protein of clause 20, wherein the Fc domain comprises said mutation that increases the half-life of the anti-HIV gp120 binding protein compared to the same anti-HIV gp120 binding protein without the mutation.

[0243] 22. The Fc domain contains the following set of mutations (EU numbering): M428L and N434S(LS); L309D, Q311H and N434S(DHS); M252Y, S254T and T256E(YTE); and H433K and N434F(HN) 22. The anti-HIV gp120 binding protein of clause 21, comprising any one of:

[0244] 23. The anti-HIV gp120 binding protein of clause 22, wherein the Fc domain comprises an LS.

[0245] 24. The anti-HIV gp120 binding protein of any one of the preceding clauses, including broadly neutralizing antibodies (bNAbs).

[0246] 25. The anti-HIV gp120 binding protein of clause 24, wherein the bNAb is an anti-V3 bNAb.

[0247] 26. The anti-HIV gp120 binding protein of clause 25, wherein the anti-V3 bNAb comprises a heavy chain (HC) and light chain (LC) pair set forth in any row of Table 2.

[0248] 27. The anti-HIV gp120 binding protein of clause 26, wherein the HC comprises SEQ ID NO: 61 or SEQ ID NO: 62, and the LC comprises SEQ ID NO: 63 or SEQ ID NO: 64.

[0249] 28. The anti-HIV gp120 binding protein according to clause 27, wherein HC comprises SEQ ID NO: 62 and LC comprises SEQ ID NO: 63.

[0250] 29. The anti-HIV gp120 binding protein of any one of clauses 17 to 19, comprising an anti-V3 bNAb scFv.

[0251] 30. The anti-HIV gp120 binding protein of clause 29, wherein the scFv comprises a VH domain of SEQ ID NO:58 and a VL domain of SEQ ID NO:59.

[0252] 31. The anti-HIV gp120 binding protein of clause 29 or clause 30, wherein the C-terminus of the VH domain is fused, either directly or via a linker, to the N-terminus of the VL domain.

[0253] 32. The anti-HIV gp120 binding protein of clause 29 or clause 30, wherein the C-terminus of the VL domain is fused, either directly or via a linker, to the N-terminus of the VH domain.

[0254] 33. The anti-HIV gp120 binding protein of clause 31 or clause 32, wherein the linker between the VH and VL domains of the scFv is selected from the group consisting of SEQ ID NOs: 90-95.

[0255] 34. The anti-HIV gp120 binding protein of clause 33, wherein the linker between the VH and VL domains of the scFv is SEQ ID NO: 93.

[0256] 35. The anti-HIV gp120 binding protein of any one of clauses 29 to 34, wherein the scFv is fused to a human Fc domain either directly or via a linker (scFv-Fc).

[0257] 36. The anti-HIV gp120 binding protein of clause 35, wherein the scFv is fused to a human Fc via a linker selected from the group consisting of SEQ ID NOs: 90-95.

[0258] 37. The anti-HIV gp120 binding protein of clause 35, wherein the scFv is fused to a human Fc via a linker of SEQ ID NO:91.

[0259] 38. The anti-HIV gp120 binding protein of any one of clauses 35 to 37, wherein the Fc domain is as defined in any one of claims 21 to 23.

[0260] 39. The anti-HIV gp120 binding protein of any one of clauses 35-38, comprising any one of SEQ ID NOs: 152-157.

[0261] 40. A bispecific anti-HIV gp120 binding protein comprising an anti-V3 bNAb and two copies of a CD4 domain, wherein the C-terminus of one CD4 domain is linked, either directly or by a linker, to the N-terminus of one anti-V3 bNAb heavy chain, and the C-terminus of the other copy of the CD4 domain is linked, either directly or by a linker, to the N-terminus of the other anti-V3 bNAb heavy chain.

[0262] 41. The bispecific protein of clause 40, wherein each CD4 domain is attached to each of the heavy chains via a linker.

[0263] 42. The bispecific protein according to clause 41, wherein the linker is selected from the group consisting of SEQ ID NOs: 90-95.

[0264] 43. The bispecific protein according to clause 42, wherein the linker is SEQ ID NO: 90.

[0265] 44. The bispecific protein according to any one of clauses 40-43, wherein the CD4 domain is selected from the group consisting of SEQ ID NOs: 1-21.

[0266] 45. The bispecific protein according to clause 44, wherein the CD4 domain is SEQ ID NO: 11.

[0267] 46. ​​Anti-V3 bNAbs are listed in Table 2, including bNAb1, bNAb1 * 46. ​​The bispecific protein of any one of clauses 40 to 45, wherein the bispecific protein is selected from the group consisting of bNAb1, bNAb2, bNAb3, bNAb4, bNAb5 and bNAb6.

[0268] 47. The bispecific protein of claim 46, wherein the anti-V3 bNAb is bNAb1.

[0269] 48. The bispecific protein of any one of claims 40 to 47, wherein the anti-V3 bNAb Fc comprises an LS.

[0270] 49. An anti-HIV gp120 binding protein having two identical heavy chains and two identical light chains, a heavy chain at least 95% identical to SEQ ID NO: 121; and A light chain at least 95% identical to SEQ ID NO: 63 An anti-HIV gp120 binding protein comprising or consisting of:

[0271] 50. An anti-HIV gp120 binding protein consisting of two heavy chains of SEQ ID NO: 121 and two light chains of SEQ ID NO: 63.

[0272] 51. An anti-HIV gp120 binding protein comprising or consisting of a sequence that is at least 95% identical to any one of SEQ ID NOs: 152-157.

[0273] 52. An anti-HIV gp120 binding protein consisting of SEQ ID NO: 155.

[0274] 53. A pharmaceutical composition comprising an anti-HIV gp120 binding protein according to any one of the preceding clauses and a pharmaceutically acceptable excipient.

[0275] 54. A method of treating or preventing HIV infection in a human, comprising administering to the human an anti-HIV gp120 binding protein according to any one of clauses 1 to 52, or a pharmaceutical composition according to clause 53, thereby reducing the viral load in the human.

[0276] 55. An anti-HIV gp120 binding protein according to any one of clauses 1 to 52, or a pharmaceutical composition according to clause 53, for use in the treatment or prevention of HIV infection in humans.

[0277] 56. Use of an anti-HIV gp120 binding protein according to any one of clauses 1 to 52, or a pharmaceutical composition according to clause 53, in the manufacture of a medicament for treating or preventing HIV infection in a human.

[0278] 57. A kit comprising, in separate containers, an anti-HIV gp120 binding protein according to any one of clauses 1 to 52 and an antiviral drug that inhibits HIV cell entry, replication, or transcription in humans.

[0279] 58. The kit according to clause 57, wherein the antiviral agent is selected from the group consisting of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, integrase strand transfer inhibitors (INSTIs), maturation inhibitors (MIs), capsid inhibitors (CIs) and nucleoside reverse transcriptase translocation inhibitors (NRTTIs).

[0280] 59. The kit according to clause 58, wherein the antiviral drug is an INSTI.

[0281] 60. The kit according to clause 59, wherein the INSTI is dolutegravir or cabotegravir.

[0282] 61. A nucleic acid sequence encoding an anti-HIV gp120 binding protein according to any one of clauses 1 to 52.

[0283] 62. An expression vector comprising the nucleic acid sequence of clause 61.

[0284] 63. A host cell comprising the nucleic acid sequence of clause 61 or the expression vector of clause 62.

[0285] 64. Two expression vectors: a first expression vector comprising a nucleic acid sequence encoding the heavy chain of SEQ ID NO: 121; and A second expression vector comprising a nucleic acid sequence encoding the light chain of SEQ ID NO: 63. A host cell comprising:

[0286] 65. A method for producing an anti-HIV gp120 binding protein, comprising culturing a host cell according to clause 63 or 64 under conditions suitable for expression of said nucleic acid sequence or vector, whereby an anti-HIV gp120 binding protein is produced.

[0287] Soluble CD4 domain with a Tm above 66.70°C.

[0288] 67. A soluble CD4 domain comprising one or more stabilizing mutations selected from the group consisting of K8C, K8I, K8V, T11C, E13C, K21C, Q25E, H27C, H27D, G38C, N52W, R58N, R58T, R58V, L61M, G65C, I70C, K72C, E87G, E91H, E91Q, and G99C.

[0289] 68. The soluble CD4 domain of clause 66 or clause 67, having a Tm between 70°C and 95°C.

[0290] 69. The soluble CD4 domain of clause 68, having a Tm of about 90°C.

[0291] 70. The soluble CD4 domain of any one of clauses 66 to 69, comprising K8C and G99C.

[0292] 71. The soluble CD4 domain of any one of clauses 66 to 68, including K8I.

[0293] 72. The soluble CD4 domain of any one of clauses 66 to 68, including K8V.

[0294] 73. The soluble CD4 domain of any one of clauses 66 to 68, comprising T11C and K72C.

[0295] 74. The soluble CD4 domain of any one of clauses 66-68, comprising any one of SEQ ID NOs: 5-21.

[0296] 75. The soluble CD4 domain of clause 74, comprising SEQ ID NO: 11.

[0297] 76. The soluble CD4 domain of any one of clauses 66 to 75, wherein the CD4 domain is fused to a human Fc domain, either directly or via a linker.

[0298] 77. The soluble CD4 domain of clause 76, wherein the Fc domain comprises an LS.

[0299] 78. The soluble CD4 domain of clause 76 or clause 77, wherein the linker is selected from the group consisting of SEQ ID NOs: 90-95. [Example]

[0300] [Example 1] Production of antigen-binding proteins Plasmids encoding the antigen-binding proteins of the present invention were expressed in EXPI293 or FREESTYLE 293-F cells using the manufacturer's standard protocol (ThermoFisher Scientific, Waltham, MA). The expressed medium was collected by centrifugation (4000 rpm, 10 minutes), and the antigen-binding proteins were purified by filtration through a 0.22 μm filter (Millipore Sigma, Burlington, MA) and fast protein liquid chromatography (FPLC) (AKTA™ Pure, Cytiva, Marlborough, MA). The medium was then passed through a Mabselect SuRe column (Cytiva, Marlborough, MA) to capture the antigen-binding proteins. The column was subsequently washed with phosphate-buffered saline (PBS) before elution.

[0301] The antigen-binding protein was then exchanged into the final buffer by dialysis, a desalting column, and a preparative size-exclusion column (SEC). The purity of the antigen-binding protein was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and by size-exclusion column high-performance liquid chromatography (SEC-HPLC).

[0302] The antigen-binding protein concentrations were determined by measuring the absorbance at a wavelength of 280 nm (A280) with a NanoDrop instrument (ThermoFisher Scientific, Waltham, MA), and their molecular weights were measured by using liquid chromatography-mass spectrometry (LC-MS) to confirm their identities.

[0303] Endotoxin levels in the final purified product were measured with the ENDOSAFE system (Charles River Labs, Wilmington, MA) to ensure they were sufficiently low (typically less than 1 EU (endotoxin unit) / mg protein) for downstream antiviral studies.

[0304] [Example 2] Antiviral activity The antiviral activity of the antigen-binding proteins was measured in a pseudotyped virus (PSV) assay. Pseudotyped HIV-1 viruses (PSVs) contain deletions in the genome that render them unable to produce infectious virions, and can be used to measure the activity of cell entry inhibitors (i.e., molecules that prevent HIV-1 virions from binding to the target cell membrane and / or prevent HIV-1 entry into target cells), including the antigen-binding proteins of the present invention.

[0305] PSVs were produced in HEK-293T cells (ATCC, Manassas, VA) by cotransfecting an expression plasmid encoding the HIV-1 gp160 envelope gene and an HIV-1 backbone plasmid using TRANSIT-2020 transfection reagent (Mirus Bio, Madison, WI). To evaluate the efficacy of the antigen-binding proteins of the present invention against a wide range of HIV-1 strains, a panel of HIV-1 PSVs expressing various gp160 envelope trimers was generated.

[0306] i.ACTOne cells The genome of the PSV used in this assay contains a luciferase gene that is expressed once the virus enters the cell, and therefore the luminescent signal (after adding the luciferase substrate) can be used to determine the level of viral infection.

[0307] The 50% tissue culture infectious dose (TCID) of a single thawed aliquot of each batch of PSV was determined in ACTOne cells. The ACTOne cell line used in this assay was derived in-house from a genetically engineered 293T cell clone expressing CD4, CXCR4, and CCR5. Cells were maintained in growth medium composed of Dulbecco's Modified Eagle's Medium (DMEM, Life Technologies) at 37°C in a humidified 5% CO2-95% air environment. Cell monolayers were disrupted by treatment with trypsin-EDTA (0.05%).

[0308] To perform the antiviral assay, ACTOne cells were detached by treating the cell culture flask with trypsin (trypsinization) and 2.5 × 10 5 The cells were resuspended in growth medium containing 2% DMSO to a density of 100 μl of cells / ml. 100 μl of these cells were added to 10 μl of preloaded antigen-binding protein in a 96-well plate. Subsequently, 90 μl of PSV was added to each well. The assay plate was incubated at 37°C in a humidified incubator with a 5% CO2 level. After 72 hours of incubation, the plate was developed by adding 50 μl of BRIGHTGLO luciferase reagent (Promega, Madison, WI) to each well and transferring the plate to an ENVISION multilabel plate reader (PerkinElmer, Waltham, MA) to measure luminescence and determine the level of virus that had infected the cells. The higher the luminescence signal, the higher the level of infection.

[0309] The raw data was analyzed in the IDBS system using an in-house template to calculate half-maximal inhibitory concentration (IC50) values ​​reflecting the activity of the antigen binding proteins of the invention in inhibiting viral entry (the lower the number, the more active the molecule).

[0310] ii.TZM.bl cells Alternatively, PSV assays were performed using a luciferase-based assay in the TZM.bl cell line, derived from a HeLa cell clone engineered to express CD4, CCR5, and CXCR4 and contain integrated reporter genes for firefly luciferase and E. coli β-galactosidase under the control of the HIV-1 long terminal repeat (Wei et al., Antimicrobial agents and chemotherapy 46:1896-905 (2002)), allowing for sensitive and accurate measurement of infection.

[0311] Detailed materials and methodology have been described elsewhere (Mentefiori, Curr. Protoc. Immunol., 2005, Chapter 12; Seaman et al., Journal of Virology, February 2010, 84(3), pp. 1439-1452). Briefly, the assay measures the reduction of luciferase reporter gene expression in TZM.bl cells after one round of virus infection.

[0312] Five-fold serial dilutions of the antigen-binding proteins of the invention from 50 μg / ml to 3.2 ng / ml were performed in duplicate in 10% DMEM growth medium (100 μl / well). Virus in an amount of 200 TCID50 (50% tissue culture infectious dose) was added to each well in a volume of 50 μl, and the plates were incubated at 37°C for 1 hour.

[0313] TZM.bl cells were then added (1 × 10 in a 100 μl volume) in 10% D-MEM growth medium containing DEAE-dextran (Sigma, St. Louis, MO) at a final concentration of 11 μg / ml. 4 Assay controls included TZM.bl cells alone (cell control) and TZM.bl cells with virus (virus control).

[0314] After 48 hours of incubation at 37°C, 150 μl of assay medium was removed from each well and 100 μl of BRIGHTGLO luciferase reagent (Promega, Madison, WI) was added. After 2 minutes of cell lysis, 150 μl of cell lysate was transferred to a 96-well black solid plate and luminescence was measured using a Victor 3 luminometer (Perkin Elmer).

[0315] The 50% and 80% inhibitory concentration (IC50 and IC80) values ​​were calculated as the serum dilution that caused a 50% and 80% reduction, respectively, in relative luminescence units (RLU) compared to the levels in virus control wells after subtraction of cell control RLU. All data were analyzed using neutralizing antibody analysis software provided by the CAVD Vaccine Immunology Statistical Center with a five-parameter curve fit.

[0316] [Example 3] Stability of soluble CD4 domains All tested soluble human CD4 domains contain a "base" set of mutations in human CD4 domain 1 (D1) spanning the wild-type sequence (SEQ ID NO: 3) that alone allows folding of human CD4 D1. Soluble CD4 D1 with this set of mutations is known as mD1.22 (Chen et al., J Virol. 2014 Jan;88(2):1125-39), and the mutations therein consist of L5Y, S23N, A55V, I76P, L96V, and F98V (SEQ ID NO: 4, also referred to herein as D1m).

[0317] To achieve better developability and pharmacokinetics, additional mutations were introduced into mD1.22 (SEQ ID NO: 4) to enhance its thermal stability. These stabilizing mutations were designed based on several methods: 1) computational simulation using free energy perturbation (FEP+, Schrodinger, New York, NY, USA); 2) computational simulation using disulfide bond scanning in the Molecular Operating Environment program (MOE, Chemical Computing Group, Montreal, Canada); and 3) using phage display under thermally challenging conditions to pan a library of human CD4 D1 mutated at each residue against 19 other amino acids (site-saturation mutagenesis, TWIST BioScience, San Francisco, CA, USA) (i.e., incubating the phage at room temperature, 70°C, and 80°C, and then selecting CD4 domain variants that could still bind to recombinant HIV-1 gp120 (CN54 strain, Acro Biosystems, Beijing, China).

[0318] The best-behaving variants (SEQ ID NOs: 5-21) were fused to a 6xHis tag at their C-terminus and expressed and purified from mammalian cells using the method described in Example 1, except that instead of a Mabselect SuRe column, purification was via Ni-NTA resin (Cytiva, Marlborough, MA) using the standard protocol from the supplier.

[0319] These purified CD4 D1 variants (with a C-terminal 6xHis tag) were then evaluated to determine their melting temperatures (Tm, using Prometheus System, NanoTemper, Munich, Germany), indicative of thermal stability, and their antiviral activity against HIV-1 pseudotyped viruses (see Example 2 above for methods using ACTOne cells).

[0320] As shown in Table 3 below and Figure 2, several CD4 D1 variants (SEQ ID NOS: 5-15) exhibited dramatically improved thermostability over the "baseline" or "control" CD4 D1 (D1m, SEQ ID NOS: 4) while maintaining similar antiviral activity.

[0321] [Table 3]

[0322] [Example 4] Antigen-binding protein format and linker length The fusion position of the CD4 domain in the anti-V3 bNAb (e.g., whether the CD4 domain is fused to the light chain or the heavy chain or both, whether the CD4 domain is fused to the N-terminus or C-terminus of these chains, or whether the CD4 domain is fused in the middle of the heavy chain (between the CH1 and CH2 domains)) has an effect on the antiviral potency of the resulting bispecific, as shown in Table 4.1 and Table 5 below.

[0323] We observed that the most potent bispecific molecule resulted from fusing CD4 D1 to the N-terminus of the heavy chain of bNAb1 (molecule 1 in Table 4.1, which neutralized six envelopes with an IC50 of less than 160 pM and one envelope with an IC50 of approximately 3 nM in the PSV assay). In this bispecific format, the linker length between the CD4 domain and the N-terminus of the bNAb1 heavy chain does not significantly affect antiviral activity (Figure 3A), but dramatically alters the pharmacokinetics (PK) of the resulting bispecific molecule (Figure 3B).

[0324] As shown in Figure 3B, in a humanized mouse model (Tg32 strain in which the human fetal Fc receptor (hFcRn) replaced the corresponding mouse gene (mFcRn), The Jackson Laboratory, Bar Harbor, Maine, USA), the shorter linker bispecific (D1m_1xG4S_bNAb1, SEQ ID NOs: 102 and 63) exhibited better PK (longer half-life and lower clearance rate) than the longer linker bispecific (D1m_4xG4S_bNAb1, SEQ ID NOs: 105 and 63).

[0325] [Table 4-1]

[0326] [Table 4-2]

[0327] [Table 5-1] [Table 5-2]

[0328] Thermostabilization of CD4 D1 (see Example 3 above) further enhanced the PK of the bispecific molecules (D1m-K8C-G99C_1×G4S_bNAb1, SEQ ID NOs: 121 and 63; D1m-T11C-K72C_1×G4S_bNAb1, SEQ ID NOs: 122 and 63; D1m-K8I_1×G4S_bNAb1, SEQ ID NOs: 119 and 63; and D1m-K8V_1×G4S_bNAb1, SEQ ID NOs: 120 and 63), as shown in Table 6 below.

[0329] [Table 6]

[0330] Therefore, the best molecules for further development will contain a shorter linker between the CD4 domain and the bNAb (1xG4S) and contain thermally stable CD4 domain(s).

[0331] [Example 5] Antiviral activity of bNAb1-derived bispecific molecules As shown in Figure 4A, bispecific molecules (D1m_1×G4S_bNAb1 bispecific with SEQ ID NOs: 102 and 63; and D1m-K8C-G99C_1×G4S_bNAb1 bispecific with SEQ ID NOs: 121 and 63) with a human CD4 domain (CD4 D1m, SEQ ID NO: 4, and its K8C and G99C variants, SEQ ID NO: 11, respectively) fused via a GGGGS linker (SEQ ID NO: 90) to the N-terminus of each heavy chain of bNAb1 (SEQ ID NOs: 62 and 63) showed dramatically and consistently higher activity (completely neutralizing all envelopes tested with a geometric mean IC50 of approximately 0.1 nM) than the two individual components (human CD4 domain and bNAb1) alone and their mixture (which did not neutralize all envelopes tested, a much higher geometric mean IC50 than the bispecific molecule). This clearly demonstrates that the fusion strategy provides potent antiviral synergy.

[0332] Interestingly, soluble CD4 has been thought to have a negative synergistic effect with bNAb1, based on the finding that mixing soluble CD4 with bNAb1 can weaken its antiviral activity (Ivan et al., Plos Biol. 17(1), January 2019). The present inventors found that fusing soluble CD4 with bNAb1 instead of mixing it dramatically enhanced its antiviral activity.

[0333] Figure 4B shows the antiviral activity of the bispecific molecules (SEQ ID NOs: 102 and 63; and SEQ ID NOs: 121 and 63) and control molecules against a panel of PSV strains insensitive to bNAb1. It can be seen that the bispecific molecules (completely neutralized all envelopes tested with a geometric mean IC50 of approximately 0.2 nM) were much more potent than the individual components alone or their mixtures (which did not neutralize all envelopes tested, with a geometric mean IC50 of over 10 nM), demonstrating strong antiviral synergy. Such synergy was most evident against strains insensitive to both CD4 and bNAb1, where the bispecific molecules alone showed good activity and complete inhibition of viral entry, while neither the soluble CD4 domain, bNAb1, nor their mixtures showed significant activity.

[0334] As shown in Table 4.1 above, all bispecific molecules tested were able to inhibit viral entry, but the most consistently potent bispecific molecule was when a CD4 domain was fused to the N-terminus of each heavy chain of bNAb1, which correlates well with the structure-based design (Figure 1D).

[0335] Furthermore, as shown in Table 4.2 above, when tested in a PSV assay against HIV-1 envelopes insensitive to several entry inhibitors (10E8, N6, temzavir, ibalizumab, and maraviroc), the bispecific molecules (SEQ ID NOs: 121 and 63) completely neutralized all of these envelopes with IC50s of less than 400 pM.

[0336] Furthermore, the most potent bispecific format (i.e., CD4 D1 fused to the N-terminus of the bNAb1 heavy chain) was converted to a single open reading frame (ORF) version by replacing the Fab arm with an scFv fragment of bNAb1. As shown in Figure 5, such single ORF molecules (SEQ ID NOS: 152-157), also referred to as scFv-Fc molecules, showed comparable potency to the leading bispecific format in a PSV assay (ACTOne cells).

[0337] Given that these single ORF molecules are each encoded by a single, <2 kb gene and contain an Fc domain for increased half-life, they can be easily delivered by gene therapy vehicles such as adeno-associated viruses (AAVs), allowing them to be secreted into the circulation at therapeutic concentrations. Such a strategy would result in an "ultra-long" acting therapy against HIV-1.

[0338] [Example 6] Antiviral activity of bNAb6-derived bispecific molecules Figure 6 and Table 7 below show the antiviral activity of bispecific molecules derived from bNAb6 and control molecules.

[0339] A plot of IC50 values ​​from the PSV assay (ACTOne) (Figure 6) clearly shows that when CD4 domain 1 (D1m, SEQ ID NO: 4) or domains 1 and 2 (D1mD2, SEQ ID NO: 2) are fused to the N-terminus of the bNAb6 (SEQ ID NOs: 88 and 89) heavy chain, the resulting molecules are much more active than a simple mixture of soluble CD4 domain and bNAb6 antibodies, indicating strong synergy.

[0340] Table 7 shows the antiviral activity of bispecific molecules (D1m_4xG4S_bNAb6, SEQ ID NO: 151 and SEQ ID NO: 89; D1mD2_4xG4S_bNAb6, SEQ ID NO: 150 and SEQ ID NO: 89; and D1m-K8C-G99C_1xG4S_bNAb6 (SEQ ID NO: 362+89)) and control molecules against HIV-1 strains resistant to bNAb6 antibodies. As can be seen, the bNAb6-derived bispecific molecules are much more potent than the mixture against double-resistant or insensitive strains.

[0341] [Table 7-1] [Table 7-2]

[0342] [Example 7] Antiviral activity of additional anti-V3 bNAb-derived bispecific molecules Additional bispecific molecules containing a CD4 domain fused to other anti-V3 bNAbs (bNAb2, bNAb3, bNAb4) were tested, and similar synergistic antiviral activity was observed against one or more envelopes, as shown in Table 5 above and Tables 8-23 below.

[0343] Therefore, the strategy of fusing a soluble CD4 domain to anti-V3 loop bNAbs may be generally applicable to enhance the potency and spectrum of these bNAbs.

[0344] conclusion In free HIV-1 virus, the V3 loop of gp120 exists in its natural "closed" state. The V3 loop is known to adopt various conformations (from various structures in the Protein Databank), demonstrating its flexibility. During HIV-1 infection, binding of gp120 to CD4 on the cell surface induces a conformational change in the V3 loop, opening it to bind co-receptors such as CXCR4 or CCR5.

[0345] Anti-V3 bNAbs primarily recognize the glycan pattern on the V3 loop of gp120, along with the backbone atoms of several amino acid residues in the V3 loop (Krumm et al., Retrovirology 13(8), 2016). Such "plasticity" of the V3 loop may facilitate the binding of anti-V3 loop bNAbs to this loop when it is "opened" by CD4 binding.

[0346] We hypothesize that if soluble CD4 and anti-V3 bNAb are simply mixed together, synergistic activity will not be observed because the conformational change in the V3 loop induced by soluble CD4 may be too transient for the anti-V3 bNAb to capture. However, in the context of a bispecific molecule, when CD4 binds to the CD4-binding site (CD4bs) on gp120, the anti-V3 bNAb reaches a high local concentration where it can immediately capture exposed V3 loop glycans, which in turn stabilizes the binding of soluble CD4 to gp120, forming a positive feedback loop.

[0347] [Table 8]

[0348] [Table 9]

[0349] [Table 10]

[0350] [Table 11]

[0351] [Table 12]

[0352] [Table 13]

[0353] [Table 14]

[0354] [Table 15]

[0355] [Table 16]

[0356] [Table 17]

[0357] [Table 18]

[0358] [Table 19]

[0359] [Table 20]

[0360] [Table 21]

[0361] [Table 22]

[0362] [Table 23]

[0363] [Example 8] Broad-spectrum antiviral activity of bNAb1-derived bispecific molecules (SEQ ID NO: 121 and SEQ ID NO: 63) A selected bispecific molecule derived from bNAb1, having two heavy chains (SEQ ID NO: 121) and two light chains (SEQ ID NO: 63), was independently tested in a PSV assay (TMZ.bl - see Example 3 above) against an external panel of pseudotyped HIV-1 viruses containing 119 HIV-1 envelopes and one control envelope to further evaluate its breadth and potency. As shown in Table 24, the bispecific molecule completely and potently inhibited all 119 HIV-1 envelopes in this assay.

[0364] [Table 24-1] [Table 24-2] [Table 24-3]

[0365] [Example 9] Activity of bNAb1-Derived Bispecific Molecules against Laboratory and Clinical Isolates of HIV-1 in Replicating Virus Assays method Clinical and laboratory isolates All clinical and laboratory isolates were originally obtained from the NIH AIDS Reagent Program (now the NIH HIV Reagent Program, https: / / www.hivreagentprogram.org / ). 4-3 The proviral clone (obtained from the NIH) was used to 4-3A replicating reporter virus, NLRepRluc, was generated by replacing a portion of the nef gene from the proviral clone with the Renilla luciferase gene. Virus was produced by transfection of HEK293T cells using Lipofectamine Plus (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions. Replication-competent virus was harvested 3 days after transfection of HEK293T cells with the modified pNLRepRluc proviral clone and titrated in MT-2 cells using luciferase activity as a biomarker.

[0366] Clinical isolates were first propagated in human PBMC cells. T-tropic laboratory virus strain IIIB, NL 4-3 The HXB2, LAI, MN, and RF viruses were propagated in MT-2 cells, while the M-tropic laboratory strains BaL and JR-FL were propagated in PM1 cells. The titers of virus stocks were determined in PBMCs using a viral infectivity assay with a p24 antigen endpoint (p24 ELISA kit; PerkinElmer Life Sciences). All viruses were resistant to 50% tissue culture infectious doses (TCID 50 ) were further titrated in MT2 or CCR5-B6 cells prior to the experiment by using luciferase enzyme activity as the endpoint for determination.

[0367] cell MT-2 cells were obtained from the American Type Culture Collection (ATCC) and propagated in RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum (FBS), 100 units / ml penicillin G, 100 μg / ml streptomycin, 10 mM HEPES buffer pH 7.55, and 2 mM L-glutamine. HEK293T cells were obtained from the ATCC and propagated in DMEM medium supplemented with 10% heat-inactivated FBS. ACTOne cells were originally derived from HEK293T cells and express CD4, CCR5, and CXCR4. ACTOne cells are grown in DMEM medium supplemented with 10% heat-inactivated FBS, 100 U / ml penicillin G, 100 μg / ml streptomycin, 5 μg / ml blasticidin, 200 μg / ml G418, and 1.5 μg / ml puromycin. CCR5-B6 cells were generated in-house at ViiV Branford, CT, USA. To generate CCR5-B6 cells, human CCR5 lentiviral particles were used to infect MT4-B6 cells (obtained from Bristol-Myers Squibb) harboring an integrated copy of the LTR-firefly luciferase reporter (backbone: plenti-P2A-Puro, RC223291L3V, Origene), and stable cells were selected using G418 (0.6 mg / ml) and puromycin (2 μg / ml). CCR5-B6 cells express firefly luciferase from the HIV-1 LTR promoter after infection with HIV. CCR5-B6 cells are grown in RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum (FBS), 10 mM HEPES buffer pH 7.55, 2 mM L-glutamine, 100 units / ml penicillin G, and 100 μg / ml streptomycin, 2 μg / ml puromycin, and 0.6 mg / ml G418.

[0368] Replication virus assay Assay using NLRepRluc virus NLRepRluc was used to infect MT-2 cells at a multiplicity of 0.01 for 1 hour, after which the protein was added to a 96-well plate. Antibodies were serially diluted 4-fold, and 11 concentrations were plated in triplicate. After 4 days of incubation, cells were processed and quantified for virus growth by the amount of luciferase expressed. Luciferase was quantified using ENDUREN substrate from Promega (Madison, WI) according to the manufacturer's instructions. Luciferase activity was immediately measured in an ENVISION multilabel plate reader (PerkinElmer, Waltham, MA). EC 50 Values ​​were calculated by comparing the amount of luciferase produced in the presence of antigen-binding protein compared to wells where no antigen-binding protein was added (DMSO control). A 5-parameter sigmoidal equation was used to fit the resulting signal versus concentration curve to determine 50% maximal inhibition (EC 50 The concentration of each antigen-binding protein that resulted in a .gamma. ) was determined. Results from three independent experiments were averaged and plotted, with error bars representing one standard deviation.

[0369] Replication virus assays using laboratory strains and clinical isolates Duplicate laboratory strains and clinical isolates were prepared as described above. MT2 or CCR5-B6 cells were resuspended in the appropriate medium and distributed into 96-well assay plates (26,000 cells / well in 100 μL; Corning, Tewksbury, MA) containing serial dilutions of inhibitors in DMSO (5- or 3-fold dilutions, columns 1–10). Blank controls were wells containing DMSO (columns 11 and 12). Undiluted stock virus was added to the first well, and 100 μl of virus culture medium was loaded into wells already containing compound and cells (total of 200 μl / well). Duplicate whole virus of the laboratory strain or clinical isolate was added to 50% tissue culture infectious dose (TCID ) of the 50% TCID , resulting in a final DMSO concentration of 1%. 50The 50% effective concentration (EC) was determined by diluting the 50% effective concentration (EC) in RPMI-1640 culture medium. The plates were incubated at 37°C and 5% CO for approximately 4 days. Renilla luciferase activity was then measured (Enduren reagent, Promega Corp., Madison, WI) using an EnVision Multilabel plate reader (Perkin Elmer, Inc., Waltham, MA). 50 ) = 1 / [1 + (ED 50 The median effect was calculated by using the exponential form of the median effect equation (ΔP < 0.05 / drug concentration).

[0370] result Table 25.1 shows that bNAb1-derived bispecific molecules are consistently approximately 10-fold more active than mixtures of some of the components (bNAb1 and CD4 domains), and further demonstrates that clear antiviral synergy results from the fusion of these component binding domains.

[0371] [Table 25-1]

[0372] A bNAb1-derived bispecific molecule (D1m-K8C-G99C_1×G4S_bNAb1, SEQ ID NO: 121+63) was tested against a panel of 13 clinical and 8 laboratory HIV-1 isolates in a replicating virus assay using MT-2 and CCR5-B6 cells. As shown in Table 25.2, the molecule neutralized all strains with an EC50 of less than 1 nM (geometric mean EC50 was 0.11 nM for clinical isolates and 0.26 nM for laboratory strains), further demonstrating its strong potency and breadth of activity.

[0373] [Table 25-2]

[0374] [Example 10] In vitro resistance barrier To assess the resistance barrier of the bispecific molecule, we examined the relative rate at which the HIV NL4-3 virus was able to evade inhibition by a panel of antibodies versus a DMSO control.

[0375] MT2 cells (2.0 × 10 cells / mL) in RPMI 1640 + 50 mg / ml penicillin and streptomycin + 10 mM HEPES buffer pH 7.55 + 2 mM L-glutamine + 0.2% DMSO) 5 The cells were pre-infected with 1000kJ / well (1000kJ / cells) at an MOI (multiplicity of infection) of 0.005 for 2.5 hours, followed by pelleting to remove unbound virus particles. One mL of infected cells was added to each well of a 24-well plate. Antibody dilutions at 20, 30, or 40 times the IC50 value were then added in duplicate to achieve a 2 mL assay volume (1 mL of 2x stock).

[0376] Every 3–4 days, images of the wells were taken, and 1 mL of each well was removed and replaced with fresh preparation for each condition. This process continued until viral breakthrough (observation of >80% cytopathic effect (CPE)) or elimination of infected cells (via exposure-induced elimination) was confirmed. Once either condition was achieved, samples were collected as pellets and supernatants (via centrifugation) and stored at -80°C until genotyping was performed to confirm the presence of resistance mutations. The number of days from infection to breakthrough was used to estimate the resistance barrier for a given molecule. The longer it took for the virus to develop CPE, indicating resistance, the higher the resistance barrier.

[0377] Table 26 shows that in this experimental setting, the bNAb1-derived bispecific molecules (SEQ ID NO: 105 and SEQ ID NO: 63) exhibited a much higher resistance barrier than either the soluble CD4 domain or bNAb1 alone at all concentrations, further demonstrating the synergy between the soluble CD4 domain and bNAb1 when fused together.

[0378] [Table 26]

[0379] [Example 11] Anti-HIV-2 activity of bNAb1-derived bispecific molecules (SEQ ID NO: 121 and SEQ ID NO: 63) in pseudotyped and replicating virus assays HIV-2 differs from HIV-1 in that it arose from transmission of simian immunodeficiency virus (SIV) from sooty mangabeys (SIVsmm) to humans (Gao et al., J Virol. 1994;68(11):7433-7447), whereas HIV-1 arose from transmission from chimpanzees and western gorillas (HIV-1 groups M and O, respectively). HIV-2 is also capable of causing AIDS, but is much less pathogenic and widespread than HIV-1 (de Silva et al., Trends Microbiol. 2008;16(12):588-595; Da Silva et al., AIDS. 2008;22(10):1195-1202). Also, CD4 was used for infection (Sattentau et al., AIDS. 1988;2(2):101-105), but HIV-2 shares only 40% identity with HIV-1 in the gp160 amino acid sequence and is therefore less sensitive or insensitive to HIV-1 envelope-directed bnAbs (Kong et al., JVI 2012;86(2):947-960). The bNAb1-derived bispecific molecule (SEQ ID NO: 121 and SEQ ID NO: 63) showed strong potency and antiviral synergy against two HIV-2 Env pseudotypes tested in PSV assays and the laboratory NIHZ strain examined in replicating virus assays (Table 27), demonstrating its exceptional breadth of anti-HIV activity and excellent synergy.

[0380] [Table 27]

[0381] Sequence Listing

[0382] [Table 28-1]

Table 28-2

Table 28-3

Table 28-4

Table 28-5

Table 28-6

Table 28-7

Table 28-8

Table 28-9

Table 28-10

Table 28-11

[0383] Sequence number 1<00​​​​​KKVVLGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKIEDSDTYICEVEDQKEEVQLVVFGLTANSDTHLLQGQSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLELQDSGTWTCTVLQNQKKVEFKIDIVVLAF Sequence number 3 KKVVLGKKGDTVELTCTASQKKSIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRADSRRSLWDQGNFPLIIKNLKIEDSDTYICEVEDQKEEVQLLVFG Sequence number 4 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 5 KKVVYGKVGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 6 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKQEVQLVVVG Sequence number 7 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKHEVQLVVVG Sequence number 8 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVGDQKEEVQLVVVG Sequence number 9 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLWDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 10 KKVVYGKIGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 11 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVC Sequence number 12 KKVVYGKKGDCVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIICNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 13 KKVVYGKKGDTVCLTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLCIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 14 KKVVYGKKGDTVELTCTASQKKNIQFCWKNSNQIKILCNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 15 KKVVYGKKGDTVELTCTASQCKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQCNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 16 KKVVYGKKGDTVELTCTASQKKNIEFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 17 KKVVYGKKGDTVELTCTASQKKNIQFDWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 18 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSVRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 19 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSNRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 20 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSTRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 21 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSMWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVG Sequence number 22 ACNSFWG Sequence number 23 SLSHCASYWNRGWTYHNPSLKS Sequence number 24 FGGEVLRYTDWPKPAWVDL Sequence number 25 TGTSNNFVS Sequence number 26 DVNKRPS Sequence number 27 GSLVGNWDVI Sequence number 28 DSYWS Sequence number 29 YVHKSGDTNYSPSLKS Sequence number 30 TLHGRRIYGIVAFNEWFTYFYMDV Sequence number 31 GEKSLGSRAVQ Sequence number 32 NNQDRPS Sequence number 33 HIWDSRVPTKWV Sequence number 34 SDHSWT Sequence number 35 DIHYNGATTYNPSLRS Sequence number 36 NAIRIYGVVALGEWFHYGMDV Sequence number 37 SGAPLTSRFTY Sequence number 38 RSSQRSS Sequence number 39 QSSDTSDSYKM Sequence number 40 NYYWT Sequence number 41 YISDRESATYNPSLNS Sequence number 42 ARRGQRIYGVVSFGEFFYYYSMDV Sequence number 43 GRQALGSRAVQ Sequence number 44 NNQDRPS Sequence number 45 HMWDSRSGFSWS Sequence number 46 GGEWGDKDYHWG Sequence number 47 SIHWRGTTHYKESLRR Sequence number 48 HRHHDVFMLVPIAGWFDV Sequence number 49 RASQNINKNLA Sequence number 50 ETYSKIA Sequence number 51 QQYEEWPRT Sequence number 52 DFYIH Sequence number 53 WMNPQTGRTNTARNFQG Sequence number 54 GGWISLYYDSSYYPNFDH Sequence number 55 TGTKYDVGSHDLVS Sequence number 56 EVNKRPS Sequence number 57 CSFGGSATVV Sequence number 58 QPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSS Sequence number 59 QSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVL Sequence number 60 QSALTQPPSASGSPGQSITISCTGTSNNYVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVL Sequence number 61 QPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 62 QPQLQESGPTLVEASETLSLTCAVSGDSTACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 63 QSALTQPPSAGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYCGSLVGNWDVIFGGGTKLTVLGQPAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 64 QSALTQPPSAGSPGQSITISCTGTSNNYVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 65 QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWIRRSPGKGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTSKNQVSLSLVAATAADSGKYYCARTLHGRRIYGIVAFNEWFTYFYMDVWGNGTQVTVSS Sequence number 66 SDISVAPGETARISCGEKSLGSRAVQWYQHRAGQAPSLIIYNNQDRPSGIPERFSGSPDSPFGTTATLTITSVEAGDEADYYCHIWDSRVPTKWVFGGGTTLTVL Sequence number 67 QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWIRRSPGKGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTSKNQVSLSLVAATAADSGKYYCARTLHGRRIYGIVAFNEWFTYFYMDVWGNGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 68 QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWIRRSPGKGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTSKNQVSLSLVAATAADSGKYYCARTLHGRRIYGIVAFNEWFTYFYMDVWGNGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 69 SDISVAPGETARISCGEKSLGSRAVQWYQHRAGQAPSLIIYNNQDRPSGIPERFSGSPDSPFGTTATLTITSVEAGDEADYYCHIWDSRVPTKWVFGGGTTLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS Sequence number 70 QVQLRESGPGLVKPSETLSLSCTVSNDSRPSDHSWTWVRQSPGKALEWIGDIHYNGATTYNPSLRSRVRIELDQSIPRFSLKMTSMTAADTGMYYCARNAIRIYGVVALGEWFHYGMDVWGQGTAVTVSS Sequence number 71 SSELTQPPSVSVSPGQTARITCSGAPLTSRFTYWYRQKPGQAPVLIISRSSQRSSGWSGRFSASWSGTTVTLTIRGVQADDEADYYCQSSDTSDSYKMFGGGTKLTVL Sequence number 72 QVQLRESGPGLVKPSETLSLSCTVSNDSRPSDHSWTWVRQSPGKALEWIGDIHYNGATTYNPSLRSRVRIELDQSIPRFSLKMTSMTAADTGMYYCARNAIRIYGVVALGEWFHYGMDVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 73 QVQLRESGPGLVKPSETLSLSCTVSNDSRPSDHSWTWVRQSPGKALEWIGDIHYNGATTYNPSLRSRVRIELDQSIPRFSLKMTSMTAADTGMYYCARNAIRIYGVVALGEWFHYGMDVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 74 SSELTQPPSVSVSPGQTARITCSGAPLTSRFTYWYRQKPGQAPVLIISRSSQRSSGWSGRFSASWSGTTVTLTIRGVQADDEADYYCQSSDTSDSYKMFGGGTKLTVLGQPAAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTEC Sequence number 75 QVQLQESGPGLVKPSETLSVTCSVSGDSMNNYYWTWIRQSPGKGLEWIGYISDRESATYNPSLNSRVVISRDTSKNQLSLKLNSVTPADTAVYYCATARRGQRIYGVVSFGEFFYYYSMDVWGKGTTVTVSS Sequence number 76 SYVRPLSVALGETARISCGRQALGSRAVQWYQHRPGQAPILLIYNNQDRPSGIPERFSGTPDINFGTRATLTISGVEAGDEADYYCHMWDSRSGFSWSFGGATRLTVL Sequence number 77 QVQLQESGPGLVKPSETLSVTCSVSGDSMNNYYWTWIRQSPGKGLEWIGYISDRESATYNPSLNSRVVISRDTSKNQLSLKLNSVTPADTAVYYCATARRGQRIYGVVSFGEFFYYYSMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 78 QVQLQESGPGLVKPSETLSVTCSVSGDSMNNYYWTWIRQSPGKGLEWIGYISDRESATYNPSLNSRVVISRDTSKNQLSLKLNSVTPADTAVYYCATARRGQRIYGVVSFGEFFYYYSMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 79 SYVRPLSVALGETARISCGRQALGSRAVQWYQHRPGQAPILLIYNNQDRPSGIPERFSGTPDINFGTRATLTISGVEAGDEADYYCHMWDSRSGFSWSFGGATRLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 80 QLQMQESGPGLVKPSETLSLSCTVSGDSIRGGEWGDKDYHWGWVRHSAGKGLEWIGSIHWRGTTHYKESLRRRVSMSIDTSRNWFSLRLASVTAADTAVYFCARHRHHDVFMLVPIAGWFDVWGPGVQVTVSS Sequence number 81 EIVMTQSPDTLSVSPGETVTLSCRASQNINKNLAWYQYKPGQSPRLVIFETYSKIAAFPARFVASGSGTEFTLTINNMQSEDVAVYYCQQYEEWPRTFGQGTKVDIK Sequence number 82 QLQMQESGPGLVKPSETLSLSCTVSGDSIRGGEWGDKDYHWGWVRHSAGKGLEWIGSIHWRGTTHYKESLRRRVSMSIDTSRNWFSLRLASVTAADTAVYFCARHRHHDVFMLVPIAGWFDVWGPGVQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 83 QLQMQESGPGLVKPSETLSLSCTVSGDSIRGGEWGDKDYHWGWVRHSAGKGLEWIGSIHWRGTTHYKESLRRRVSMSIDTSRNWFSLRLASVTAADTAVYFCARHRHHDVFMLVPIAGWFDVWGPGVQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 84 EIVMTQSPDTLSVSPGETVTLSCRASQNINKNLAWYQYKPGQSPRLVIFETYSKIAAFPARFVASGSGTEFTLTINNMQSEDVAVYYCQQYEEWPRTFGQGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence number 85 QVQLVQSGAQMKNPGASVKVSCAPSGYTFTDFYIHWLRQAPGQGLQWMGWMNPQTGRTNTARNFQGRVTMTRDTSIGTAYMELRSLTSDDTAIYYCTTGGWISLYYDSSYYPNFDHWGQGTLLTVSS Sequence number 86 QSALTQPASVSGSPGQSITISCTGTKYDVGSHDLVSWYQQYPGKVPKYMIYEVNKRPSGVSNRFSGSKSGNTASLTISGLRAEDEADYYCCSFGGSATVVCGGGTKVTVL Sequence number 87 QVQLVQSGAQMKNPGASVKVSCAPSGYTFTDFYIHWLRQAPGQGLQWMGWMNPQTGRTNTARNFQGRVTMTRDTSIGTAYMELRSLTSDDTAIYYCTTGGWISLYYDSYYPNFDHWGQGTLLTVSSASTKGPSVFPLAPSSKSTGGAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 88 QVQLVQSGAQMKNPGASVKVSCAPSGYTFTDFYIHWLRQAPGQGLQWMGWMNPQTGRTNTARNFQGRVTMTRDTSIGTAYMELRSLTSDDTAIYYCTTGGWISLYYDSYYPNFDHWGQGTLLTVSSASTKGPSVFPLAPSSKSTGGAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 89 QSALTQPASVSGSPGQSITISCTGTKYDVGSHDLVSWYQQYPGKVPKYMIYEVNKRPSGVSNRFSGSKGNTASLTISGLRAEDEADYYCCSFGGSATVVCGGGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAVETTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 90 GGGGS Sequence number 91 GGGGSGGGGGS Sequence number 92 GGGGSGGGGGSGGGGGS Sequence number 93 GGGGSGGGGGSGGGGGSGGGGGS Sequence number 94 GGGGSGGGGGSGGGGGSGGGGGSGGGGGS Sequence number 95 GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS Sequence number 96 KKVVLGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKIEDSDTYICEVEDQKEEVQLVVFGLTANSDTHLLQGQSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLELQDSGTWTCTVLQNQKKVEFKIDIVVLAFQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 97 KKVVLGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKIEDSDTYICEVEDQKEEVQLVVFGLTANSDTHLLQGQSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLELQDSGTWTCTVLQNQKKVEFKIDIVVLAFGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 98 KKVVLGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKIEDSDTYICEVEDQKEEVQLVVFGLTANSDTHLLQGQSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLELQDSGTWTCTVLQNQKKVEFKIDIVVLAFGGGGSGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 99 KKVVLGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKIEDSDTYICEVEDQKEEVQLVVFGLTANSDTHLLQGQSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLELQDSGTWTCTVLQNQKKVEFKIDIVVLAFGGGGSGGGGSGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 100 KKVVLGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKIEDSDTYICEVEDQKEEVQLVVFGLTANSDTHLLQGQSLTLTLESPPGSSSPVQCRSPRGKNIQGGKTLSVSQLELQDSGTWTCTVLQNQK KVEFKIDIVVLAFGGGGSGGGGSGGGGSGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 101 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQP PGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 102 KKVVYGKKDGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 103 KKVVYGKKDGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNS FWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 104 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTA ACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 105 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGGSGGGSQPQLQESGPTLVEASETLSLTCAVSGD STAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 106 KKVVYGKKDGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGSGGGGSGGGSQPQLQESGPTLVEASETLSLTCA VSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 107 KKVVYGKKDGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGSGGGGSGGGGSGGGSQPQLQESGPTLVEASETLS LTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 108 KKVVYGKKDGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVP DRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 109 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 110 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 111 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 112 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGGSGGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 113 KKVVYGKKDGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGGSGGGGSGGGGSQSALTQPPSAGSSPGQSITISCTGTSNNFVSWYQQHAGKAPKL VIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 114 KKVVYGKKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGGSGGGGGSGGGGGSGGGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 115 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPS GVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 116 QPQLQESGPTLVEASETLSLTCAVSGDSTACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCGGGGSSKKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFL TKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 117 QPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGGGGGSKKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVC Sequence number 118 QSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSGGGGSKKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVC Sequence number 119 KKVVYGKIGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 120 KKVVYGKVGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 121 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 122 KKVVYGKKGDCVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIICNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 123 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKQEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 124 KKVVYGKKDGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKHEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 125 KKVVYGKKGDTVELTCTASQKKNIEFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 126 KKVVYGKKDGDTVELTCTASQKKNIQFDWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 127 KKVVYGKKDGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSVRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 128 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSNRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 129 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRWDSTRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 130 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQILGNQGSFLTKGPSKLNDRVDSRRSMWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 131 KKVVYGKKGDTVCLTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLCIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 132 KKVVYGKKDGDTVELTCTASQKKNIQFCWKNSNQIKILCNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 133 KKVVYGKKDGDTVELTCTASQCKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQCNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 134 KKVVYGKKDGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVGDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 135 KKVVYGKKDGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLWDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGW VRQPPGKGLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTGSVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPNSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 136 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWI RRSPGKGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTSKNQVSLSLVAATAADSKGYYCARTLHGRRIYGIVAFNEWFTYPYMDVWGNGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVREPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 137 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSGGGSQMQLQESGPGLVKPSETLSLTCSVSGASISDSY WSWIRRSPGKGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTSKNQVSLSLVAATAADSKGKYYCARTLHGRRIYGIVAFNEWFTYPYMDVWGNGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVREPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 138 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSGGGGSGGGSQMQLQESGPGLVKPSETLSLTCSVSGASIS DSYWSWIRRSPGKGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTSKNQVSLSLVAATAADSKGKYYCARTLHGRRIYGIVAFNEWFTYPYMDVWGNGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 139 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSGGGGSGGGSGGGGSQMQLQESGPGLVKPSETLSLTCSVSG ASISDSYWSWIRRSPGKGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTSKNQVSLSLVAATAASGKYYCARTLHGRRIYGIVAFNEWFTYPYMDVWGNGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 140 QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWIRRSPGKGLEWIGYVHKSGDTNYSPSKSRVNLSLDTSKNQVSLSLVAATAADSGKYYCARTLHGRRIYGIVAFNEWFTYFYMDVWNGTGVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCGGGGSKKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLT KGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSDKTHTCPPPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 141 QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWIRRSPGKGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTSKNQVSLSLVAATAADSGKYYCARTLHGRRIYGIVAFNEWFTYFYMDVWGNGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGGGGGSKKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVC Sequence number 142 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSSDISVAPGETARISCGEKSLGSRAVQWYQHRAGQAPSLIIYNNQDRPSGIPERFSGSPDSPFGTTATLTITSVEAGDEADYYCHIWDSRVPTKWVFGGGTTLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS Sequence number 143 SDISVAPGETARISCGEKSLGSRAVQWYQHRAGQAPSLIIYNNQDRPSGIPERFSGSPDSPFGTTATLTITSVEAGDEADYYCHIWDSRVPTKWVFGGGTTLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECSGGGGSKKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVC Sequence number 144 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQVQLRESGPGLVKPSETLSLSCTVSNDSRPSDHSWTWVRQSPGKALEWIGDIHYNGATTYNPSLRSRVRIELDQSIPRFSLKMTSMTAADTGMYYCARNAIRIYGVVALGEWFHYGMDVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 145 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSGGGGSGGGGSGGGGSQVQLRESGPGLVKPSETLSLSCTVSNDSRPSDHSWTWVRQSPGKALEWIGDIHYNGATTYNPSLRSRVRIELDQSIPRFSLKMTSMTAADTGMYYCARNAIRIYGVVALGEWFHYGMDVWGQGTAVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 146 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQVQLQESGPGLVKPSETLSVTCSVSGDSMNNYYWTWIRQSPGKGLEWIGYISDRESATYNPSLNSRVVISRDTSKNQLSLKLNSVTPADTAVYYCATARRGQRIYGVVSFGEFFYYYSMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 147 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSGGGSGGGGSGGGSQVQLQESGPGLVKPSETLSVTCSVSG DSMNNYYWTWIRQSPGKGLEWIGYISDRESATYNPSLNSRVVISRDTSKNQLSLKLNSVTPADTAVYYCATARRGQRIYGVVSFGEFFYYYSMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 148 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQLQMQESGPGLVKPSETLSLSCTVSGDSIRGGEWGDKDYHWGWVRHSAGKGLEWIGSIHWRGTTHYKESLRRRVSMSIDTSRNWFSLRLASVTAADTAVYFCARHRHHDVFMLVPIAGWFDVWGPGVQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 149 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSGGGGSGGGGSGGGGSQLQMQESGPGLVKPSETLSLSCTVSGDSIRGGEWGDKDYHWGWVRHSAGKGLEWIGSIHWRGTTHYKESLRRRVSMSIDTSRNWFSLRLASVTAADTAVYFCARHRHHDVFMLVPIAGWFDVWGPGVQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 150 KKVVLGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIIKLKIEDSDTYICEVEDQKEEVQLVVFGLTANSDTHLLQGQSLTLTLESPPGSSSPVQCRSPRGKNIQGGKTLSVSQLELQDSGTWTCTVLQN QKKVEFKIDIVVLAFGGGGSGGGGSGGGGSGGGGSQVQLVQSGAQMKNPGASVKVSCAPSGYTFTDFYIHWLRQAPGQGLQWMGWMNPQTGRTNTARNFQGRVTMTRDTSIGTAYMELRSLTSDDTAIYYCTTGWISLYYDSSYYPNFDHWGQGTLLTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 151 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGGSGGGGSQVQLVQSGAQMKNPGASVKVSCAPS GYTFTDFYIHWLRQAPGQGLQWMGWMNPQTGRTNTARNFQGRVTMTRDTSIGTAYMELRSLTSDDTAIYYCTTGGWISLYYDSSYYPNFDHWGQGTLLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 152 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGGSGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKCLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGCGTKLTVLGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 153 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKCLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGCGTKLTVLGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 154 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKCLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGCGTKLTVLGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 155 KKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKCLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGCGTKLTVLGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 156 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSKKVVYGKKGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTAACNSFWGWVRQPPGKCLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSQSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGCGTKLTVL Sequence number 157 QSALTQPPSAGSPGQSITISCTGTSNNFVSWYQQHAGKAPKLVIYDVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCGSLVGNWDVIFGCGTKLTVLGGGGSGGGGSGGGGSGGGSQPQLQESGPTLVEASETLSLTCAVSGDSTA ACNSFWGWVRQPPGKCLEWVGSLSHCASYWNRGWTYHNPSLKSRLTLLALDTPKNLVFLKLNSVTAADTATYYCARFGGEVLRYTDWPKPAWVDLWGRGTLVTVSSGGGGSGGGGSGGGGSGGGGSKKVVYGKKDGDTVELTCTASQKKNIQFHWKN SNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVGGGGGSGGGGSGGGSSDKTHTCPPCPAPELLGGPSVFLFPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLPGK Sequence number 158 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 159 DNYWS Sequence number 160 YVHDSGDTNYNPSLKS Sequence number 161 TKHGRRIYGVVAFKEWFTYFYMDV Sequence number 162 GEESLGSRSVI Sequence number 163 NNNDRPS Sequence number 164 HIWDSRRPTNWV Sequence number 165 DAYWS Sequence number 166 YVHHSGDTNYNPSLKR Sequence number 167 ALHGKRIYGIVALGELFTYFYMDV Sequence number 168 GKESIGSRAVQ Sequence number 169 NNQDRPA Sequence number 170 HIYDARGGTNWV Sequence number 171 ACTIVITY Sequence number 172 SLSHCQSFWGSGWTFHNPSLKS Sequence number 173 FDGEVLVYNHWPKPAWVDL Sequence number 174 NGTATNFVS Sequence number 175 GVDKRPP Sequence number 176 GSLVGNWDVI Sequence number 177 RECREATION Sequence number 178 GLSHCAGYYNTGWTYHNPSLKS Sequence number 179 FDGEVLVYHDWPKPAWVDL Sequence number 180 TGTSNRFVS Sequence number 181 GVNKRPS Sequence number 182 SSLVGNWDVI Sequence number 183 RCNYFWG Sequence number 184 SLSHCRSYYNTDWTYHNPSLKS Sequence number 185 FGGEVLVYRDWPKPAWVDL Sequence number 186 TGTSNNFVS Sequence number 187 EVNKRPS Sequence number 188 SSLVGNWDVI Sequence number189 TGHYYWG Sequence number 190 HIHYTTAVLHNPSLKS Sequence number 191 SGGDILYYYEWQKPHWFSP Sequence number 192 NGTSSDIGGWNFVS Sequence number 193 EVNKRPS Sequence number 194 SSLFGRWDVV Sequence number 185 HAPPY Sequence number 196: HIHYNTAVLHNPALKS Sequence number 197 SGGDILYYIEWQKPHWFYP Sequence number 198 SGTGSDIGSWNFVS Sequence number 199 EVNRRRS Sequence number 200 SSLSGRWDIV Sequence number 201 TWENTY YEARS Sequence number 202 SIHWRGRTTHYKTSFRS Sequence number 203 HKYHDIFRVVPVAGWFDP Sequence number 204 RASQNVKNNLA Sequence number 205 DASSRAG Sequence number 206 QQYEEWPRT Sequence number 207 GGEWGDSDYHWG Sequence number 208 SIHWRGTTHYNAPFRG Sequence number 209 HKYHDIVMVVPIAGWFDP Sequence number 210 RASQSVKNNLA Sequence number 211 DTSSRAS Sequence number 212 QQYEEWPRT Sequence number 213 DVWLN Sequence number 214 RIKSRTDGGTTDYAASVKG Sequence number 215 DGFIMIRGVSEDYYYYYMDV Sequence number 216 SGSSSNIGNNYVL Sequence number 217 GNNKRPS Sequence number 218 ATWDSGLSADWV Sequence number 219 SYVMH Sequence number 220 AISSDGETTYHANSVKG Sequence number 221 DRYYETSGSNAFDV Sequence number 222 QASQDISNYLN Sequence number 223 TASNLET Sequence number 224 QQYDNLGDLS Sequence number 225 NFAIH Sequence number226 GRVPVVGIYKYGKKFHD Sequence number 227 WRGCGMCPYDTSSYYNDASDV Sequence number 228 RASQNISSSWIA Sequence number 229 AASRAA Sequence number 230 QYYGGSFFT Sequence number 231 AHTMN Sequence number 232 SISTSSTYRDYADAVKG Sequence number 233 KGSDRLSDNDPFD Sequence number 234 RASQSIETWLA Sequence number 235 KASTLKT Sequence number 236 QHYAGYSAT Sequence number 237 SSYWS Sequence number 238 YTHHSGDTNYAPSLKS Sequence number 239 TLHGRRIYGVVAFNEFTYFYVEV Sequence number 240 GGSIGSRAVQ Sequence number 241 NNQDRPP Sequence number 242 HIWDSRRPTNWV Sequence number 243 SSYWS Sequence number 244 YTHHSGDTNYAPSLKS Sequence number 245 TLHGRRIYGVVAFNEYYTYFYWPT Sequence number 246 GGESIGSRAVQ Sequence number 247 NNQDRPP Sequence number 248 HIWDSRRPTNWE Sequence number 249 SSYWS Sequence number 250 YTHHSGDTNYAPSLKS Sequence number 251 TLHGRRIYGVVAFNEYYTYFYWPT Sequence number 252 TGTSSDIGASDYVS Sequence number 253 DVTKRPS Sequence number 254 SSDAGRHTLL Sequence number 255 QVHLQESGPGLVKPSETLSLTCNVSGTLVRDNYWSWIRQPLGKQPEWIGYVHDSGDTNYNPSLKSRVHLSLDKSKNLVSLRLTGVTAADSAIYYCATTKHGRRIYGVVAFKEWFTYFYMDVWGKGTSVTVSS Sequence number 256 TFVSVAPGQTARITCGEESLGSRSVIWYQQRPGQAPSLIIYNNNDRPSGIPDRFSGSPGSTFGTTATLTITSVEAGDEADYYCHIWDSRRPTNWVFGEGTTLIVL Sequence number 257 QVHLQESGPGLVKPSETLSLTCNVSGTLVRDNYWSWIRQPLGKQPEWIGYVHDSGDTNYNPSLKSRVHLSLDKSKNLVSLRLTGVTAADSAIYYCATTKHGRRIYGVVAFKEWFTYFYMDVWGKGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 258 QVHLQESGPGLVKPSETLSLTCNVSGTLVRDNYWSWIRQPLGKQPEWIGYVHDSGDTNYNPSLKSRVHLSLDKSKNLVSLRLTGVTAADSAIYYCATTKHGRRIYGVVAFKEWFTYFYMDVWGKGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 259 TFVSVAPGQTARITCGEESLGSRSVIWYQQRPGQAPSLIIYNNNDRPSGIPDRFSGSPGSTFGTTATLTITSVEAGDEADYYCHIWDSRRPTNWVFGEGTTLIVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 260 QLHLQESGPGLVKPPETLSLTCSVSGASINDAYWSWIRQSPGKRPEWVGYVHHSGDTNYNPSLKRRVTFSLDTAKNEVSLKLVDLTAADSATYFCARALHGKRIYGIVALGELFTYFYMDVWGKGTAVTVSS Sequence number 261 SSMSVSPGETAKISCGKESIGSRAVQWYQQKPGQPPSLIIYNNQDRPAGVPERFSASPDFRPGTTATLTITNVDAEDEADYYCHIYDARGGTNWVFDRGTTLTVL Sequence number 262 QLHLQESGPGLVKPPETLSLTCSVSGASINDAYWSWIRQSPGKRPEWVGYVHHSGDTNYNPSLKRVRVTFSLDTAKNEVSLKLVDLTAADSATYFCARALHGKRIYGIVALGELFTYFYMDVWGKGTAVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 263 QLHLQESGPGLVKPPETLSLTCSVSGASINDAYWSWIRQSPGKRPEWVGYVHHSGDTNYNPSLKRVRVTFSLDTAKNEVSLKLVDLTAADSATYFCARALHGKRIYGIVALGELFTYFYMDVWGKGTAVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 264 SSMSVSPGETAKISCGKESIGSRAVQWYQQKPGQPPSLIIYNNQDRPAGVPERFSASPDFRPGTTATLTITNVDAEDEADYYCHIYDARGGTNWVFDRGTTLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 265 QSQLQESGPRLVEASETLSLTCNVSGESTGACTYFWGWVRQAPGKGLEWIGSLSHCQSFWGSGWTFHNPSLKSRLTISLDTPKNQVFLKLTSLTAADTATYYCARFDGEVLVYNHWPKPAWVDLWGRGIPVTVTVSS Sequence number 266 QSALTQPPSASGSPGQSITISCNGTATNFVSWYQQFPDKAPKLIIFGVDKRPPGVPDRFSGSRSGTTASLTVSRLQTDDEAVYYCGSLVGNWDVIFGGGTTLTVL Sequence number 267 QSQLQESGPRLVEASETLSLTCNVSGESTGACTYFWGWVRQAPGKGLEWIGSLSHCQSFWGSGWTFHNPSLKSRLTISLDTPKNQVFLKLTSLTAADTATYYCARFDGEVLVYNHWPKPAWVDLWGRGIPVTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 268 QSQLQESGPRLVEASETLSLTCNVSGESTGACTYFWGWVRQAPGKGLEWIGSLSHCQSFWGSGWTFHNPSLKSRLTISLDTPKNQVFLKLTSLTAADTATYYCARFDGEVLVYNHWPKPAWVDLWGRGIPVTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number269 QSALTQPPSASGSPGQSITISCNGTATNFVSWYQQFPDKAPKLIIFGVDKRPPGVPDRFSGSRSGTTASLTVSRLQTDDEAVYYCGSLVGNWDVIFGGGTTLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 270 QPQLQESGPGLVEASETLSLTCTVSGDSTAACDYFWGWVRQPPGKGLEWIGGLSHCAGYYNTGWTYHNPSLKSRLTISLDTPKNQVFLKLNSVTAADTAIYYCARFDGEVLVYHDWPKPAWVDLWGRGTLVTVTVSS Sequence number 271 QSALTQPPSASGSPGQSISISCTGTSNRFVSWYQQHPGKAPKLVIYGVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCSSLVGNWDVIFGGGTKLTVL Sequence number 272 QPQLQESGPGLVEASETLSLTCTVSGDSTAACDYFWGWVRQPPGKGLEWIGGLSHCAGYYNTGWTYHNPSLKSRLTISLDTPKNQVFLKLNSVTAADTAIYYCARFDGEVLVYHDWPKPAWVDLWGRGTLVTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 273 QPQLQESGPGLVEASETLSLTCTVSGDSTAACDYFWGWVRQPPGKGLEWIGGLSHCAGYYNTGWTYHNPSLKSRLTISLDTPKNQVFLKLNSVTAADTAIYYCARFDGEVLVYHDWPKPAWVDLWGRGTLVTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number274 QSALTQPPSASGSPGQSISISCTGTSNRFVSWYQQHPGKAPKLVIYGVNKRPSGVPDRFSGSKSGNTASLTVSGLQTDDEAVYYCSSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 275 QPQLQESGPGLVEASETLSLTCTVSGDSTGRCNYFWGWVRQPPGKGLEWIGSLSHCRSYYNTDWTYHNPSLKSRLTISLDTPKNQVFLRLTSVTAADTATYYCARFGGEVLVYRDWPKPAWVDLWGRGTLVTVSS Sequence number 276 QSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQYPGKAPKLVIYEVNKRPSGVPDRFSGSKSGSTASLTVSGLQADDEGVYYCSSLVGNWDVIFGGGTKLTVL Sequence number 277 QPQLQESGPGLVEASETLSLTCTVSGDSTGRCNYFWGWVRQPPGKGLEWIGSLSHCRSYYNTDWTYHNPSLKSRLTISLDTPKNQVFLRLTSVTAADTATYYCARFGGEVLVYRDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 278 QPQLQESGPGLVEASETLSLTCTVSGDSTGRCNYFWGWVRQPPGKGLEWIGSLSHCRSYYNTDWTYHNPSLKSRLTISLDTPKNQVFLRLTSVTAADTATYYCARFGGEVLVYRDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 279 QSALTQPPSASGSPGQSITISCTGTSNNFVSWYQQYPGKAPKLVIYEVNKRPSGVPDRFSGSKSGSTASLTVSGLQADDEGVYYCSSLVGNWDVIFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 280 QVQLQESGPGLVKPAETLSLTCSVSGESINTGHYYWGWVRQVPGKGLEWIGHIHYTTAVLHNPSLKSRLTIKIYTLRNQITLRLSNVTAADTAVYHCVRSGGDILYYYEWQKPHWFSPWGPGIHVTVSS Sequence number 281 QSALTQPPSASGSLGQSVTISCNGTSSDIGGWNFVSWYQQFPGRAPRLIIFEVNKRPSGVPGRFSGSKSGNSASLTVSGLQSDDEGQYFCSSLFGRWDVVFGGGTKLTVL Sequence number 282 QVQLQESGPGLVKPAETLSLTCSVSGESINTGHYYWGWVRQVPGKGLEWIGHIHYTTAVLHNPSLKSRLTIKIYTLRNQITLRLSNVTAADTAVYHCVRSGGDILYYYEWQKPHWFSPWGPGIHVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 283 QVQLQESGPGLVKPAETLSLTCSVSGESINTGHYYWGWVRQVPGKGLEWIGHIHYTTAVLHNPSLKSRLTIKIYTLRNQITLRLSNVTAADTAVYHCVRSGGDILYYYEWQKPHWFSPWGPGIHVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 284 QSALTQPPSASGSLGQSVTISCNGTSSDIGGWNFVSWYQQFPGRAPRLIIFEVNKRPSGVPGRFSGSKSGNSASLTVSGLQSDDEGQYFCSSLFGRWDVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 285 QVQLQESGPGLVKPSETLSLTCTVSGDSINTGHHYWGWVRQVPGKGPEWIAHIHYNTAVLHNPALKSRVTISIFTLKNLITLSLSNVTAADTAVYFCVRSGGDILYYIEWQKPHWFYPWGPGILVTVSS Sequence number 286 QSALTQPPSASGSLGQSLTISCSGTGSDIGSWNFVSWYQQFPGRAPNLIIFEVNRRRSGVPDRFSGSKSGNTASLTVSGLRSEDEAEYFCSSLSGRWDIVFGGGTKVTVL Sequence number 287 QVQLQESGPGLVKPSETLSLTCTVSGDSINTGHHYWGWVRQVPGKGPEWIAHIHYNTAVLHNPALKSRVTISIFTLKNLITLSLSNVTAADTAVYFCVRSGGDILYYIEWQKPHWFYPWGPILVTSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 288 QVQLQESGPGLVKPSETLSLTCTVSGDSINTGHHYWGWVRQVPGKGPEWIAHIHYNTAVLHNPALKSRVTISIFTLKNLITLSLSNVTAADTAVYFCVRSGGDILYYIEWQKPHWFYPWGPILVTSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 289 QSALTQPPSASGSLGQSLTISCSGTGSDIGSWNFVSWYQQFPGRAPNLIIFEVNRRRSGVPDRFSGSKSGNTASLTVSGLRSEDEAEYFCSSLSGRWDIVFGGGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 290 QLQLQESGPGLVKPSETLSLTCTVSGGSMRGTDWGENDFHYGWIRQSSAKGLEWIGSIHWRGRTTHYKTSFRSRATLSIDTSNNRFSLTFSFVTAADTAVYYCARHKYHDIFRVVPVAGWFDPWGQGLLVTVSS Sequence number 291 EIVMTQSPPTLSVSPGETATLSCRASQNVKNNLAWYQLKPGQAPRLLIFDASSRAGGIPDRFSGSGYGTDFTLTVNSVQSEDFGDYFCQQYEEWPRTFGQGTKVDIK Sequence number 292 QLQLQESGPGLVKPSETLSLTCTVSGGSMRGTDWGENDFHYGWIRQSSAKGLEWIGSIHWRGRTTHYKTSFRSRATLSIDTSNNRFSLTFSFVTAADTAVYYCARHKYHDIFRVVPVAGWFDPWGQGLLVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 293 QLQLQESGPGLVKPSETLSLTCTVSGGSMRGTDWGENDFHYGWIRQSSAKGLEWIGSIHWRGRTTHYKTSFRSRATLSIDTSNNRFSLTFSFVTAADTAVYYCARHKYHDIFRVVPVAGWFDPWGQGLLVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 294 EIVMTQSPPTLSVSPGETATLSCRASQNVKNNLAWYQLKPGQAPRLLIFDASSRAGGIPDRFSGSGYGTDFTLTVNSVQSEDFGDYFCQQYEEWPRTFGQGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence number 295 EVHLEESGPGLVRPSETLSLTCTASGGSIRGGEWGDSDYHWGWVRHSPEKGLEWIGSIHWRGTTHYNAPFRGRGRLSIDLSRNQFSLRLTSVTAEDTAVYYCVKHKYHDIVMVVPIAGWFDPWGQGLQVTVSS Sequence number 296 EIMMTQSPAILSVSPGDRATLSCRASQSVKNNLAWYQKRPGQAPRLLIFDTSSRASGIPARFSGGGSGTEFTLTVNSMQSEDFATYYCQQYEEWPRTFGQGTKVEIK Sequence number 297 EVHLEESGPGLVRPSETLSLTCTASGGSIRGGEWGDSDYHWGWVRHSPEKGLEWIGSIHWRGTTHYNAPFRGRGRSIDLSRNQFSLRLTSVTAEDTAVYYCVKHKYHDIVMVVPIAGWFDPWGQGLQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 298 EVHLEESGPGLVRPSETLSLTCTASGGSIRGGEWGDSDYHWGWVRHSPEKGLEWIGSIHWRGTTHYNAPFRGRGRSIDLSRNQFSLRLTSVTAEDTAVYYCVKHKYHDIVMVVPIAGWFDPWGQGLQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 299 EIMMTQSPAILSVSPGDRATLSCRASQSVKNNLAWYQKRPGQAPRLLIFDTSSRASGIPARFSGGGSGTEFTLTVNSMQSEDFATYYCQQYEEWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence number 300 EVQLVESGGGLVKPGGSLRLTCVASGFTFSDVWLNWVRQAPGKGLEWVGRIKSRTDGGTTDYAASVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYSCTTDGFIMIRGVSEDYYYYYMDVWGKGTTVTVSS Sequence number 301 QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVLWYQQFPGTAPKLLIYGNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYFCATWDSGLSADWVFGGGTKLTVL Sequence number 302 EVQLVESGGGLVKPGGSLRLTCVASGFTFSDVWLNWVRQAPGKGLEWVGRIKSRTDGGTTDYAASDVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYSCTTTDGFIMIRGVSEDYYYYYMDVWGKGTTTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 303 EVQLVESGGGLVKPGGSLRLTCVASGFTFSDVWLNWVRQAPGKGLEWVGRIKSRTDGGTTDYAASDVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYSCTTTDGFIMIRGVSEDYYYYYMDVWGKGTTTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 304 QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVLWYQQFPGTAPKLLIYGNNKRPSGIPDRFSGSKSGTSATLGITGLQTGDEADYFCATWDSGLSADWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 305 QVQLVQSGGGLVQPGGSLRLSCAAFGFNFSSYVMHWVRQAPGQGLEYLSAISSDGETTYHANSVKGRFTSSRDNSKNTLFLQMGSLRTEDVAVYYCARDRYYETSGSNAFDVWGQGTMVVVSS Sequence number 306 NSVLTQSPSSLSASVGDRVTITCQASQDISNYLNWYQHKPGKAPKLLIYTASNLETGVPSRFSGGGSGTHFSFTITSLQPEDAATYFCQQYDNLGDLSFGGGTKVEIK Sequence number 307 QVQLVQSGGGLVQPGGSLRLSCAAFGFNFSSYVMHWVRQAPGQGLEYLSAISSDGETTYHANSVKGRFTSSRDNSKNTLFLQMGSLRTEDVAVYYCARDRYYETSGSNAFDVWGQGTMMVVVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 308 QVQLVQSGGGLVQPGGSLRLSCAAFGFNFSSYVMHWVRQAPGQGLEYLSAISSDGETTYHANSVKGRFTSSRDNSKNTLFLQMGSLRTEDVAVYYCARDRYYETSGSNAFDVWGQGTMMVVVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 309 NSVLTQSPSSLSASVGDRVTITCQASQDISNYLNWYQHKPGKAPKLLIYTASNLETGVPSRFSGGGSGTHFSFTITSLQPEDAATYFCQQYDNLGDLSFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence number 310 QVQLVQSGAEVRKPGSSVTISCKPVGGTFTNFAIHWVRQAPGQGLEWVGGRVPVGIYKYGKKFHDRLRLYEDDPMKTVFLELRSLTSDDTGVYYCTRWRGCGMCPYDTSSYNDASDVWGPGTKVIVSA Sequence number 311 EIVLTQSPVTLSLSSGETGTLSCRASQNISSSWIAWYQQRRGQVPRLLISAASARAAGIPDRFTGRGSGTDFTLTITRLEPEDFGVYSCQYYGGSFFTFGPGTQVDVK Sequence number 312 QVQLVQSGAEVRKPGSSVTISCKPVGGTFTNFAIHWVRQAPGQGLEWVGGRVPVVGIYKYGKKFHDLRLYEDDPMKTVFLELRSLTSDTGVYYCTRWRGCGMCPYDTSSYYNDASDVWGPGTKVIVSAASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 313 QVQLVQSGAEVRKPGSSVTISCKPVGGTFTNFAIHWVRQAPGQGLEWVGGRVPVVGIYKYGKKFHDLRLYEDDPMKTVFLELRSLTSDTGVYYCTRWRGCGMCPYDTSSYYNDASDVWGPGTKVIVSAASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 314 EIVLTQSPVTLSLSSGETGTLSCRASQNISSSWIAWYQQRRGQVPRLLISAASARAAGIPDRFTGRGSGTDFTLTITRLEPEDFGVYSCQYYGGSFFTFGPGTQVDVKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence number 315 EVQLVESGGGLVKAGGSLILSCGVSNFRISAHTMNWVRRVPGGGLEWVASISTSSTYRDYADAVKGRFTVSRDDLEDFVYLQMHKMRVEDTAIYYCARKGSDRLSDNDPFDAWGPGTVVTVSP Sequence number 316 DVVMTQSPSTLSASVGDTITITCRASQSIETWLAWYQQKPGKAPKLLIYKASTLKTGVPSRFSGSGSGTEFTLTISGLQFDDFATYHCQHYAGYSATFGQGTRVEIK Sequence number 317 EVQLVESGGGLVKAGGSLILSCGVSNFRISAHTMNWVRRVPGGGLEWVASISTSSTYRDYADAVKGRFTVSRDDLEDFVYLQMHKMRVEDTAIYYCARKGSDRLSDNDPFDAWGPGTVVTVSPASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 318 EVQLVESGGGLVKAGGSLILSCGVSNFRISAHTMNWVRRVPGGGLEWVASISTSSTYRDYADAVKGRFTVSRDDLEDFVYLQMHKMRVEDTAIYYCARKGSDRLSDNDPFDAWGPGTVVTVSPASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 319 DVVMTQSPSTLSASVGDTITITCRASQSIETWLAWYQQKPGKAPKLLIYKASTLKTGVPSRFSGSGSGTEFTLTISGLQFDDFATYHCQHYAGYSATFGQGTRVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence number 320 QMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWLRETPGKGLEWIGYTHHSGDTNYAPSLKSRVHLGLHPSKNQVSLSLTSVTAADTAVYYCARTLHGRRIYGVVAFNEFFTYFYWEVWGKGTQVTVSS Sequence number 321 SDISVAPGETVRISCGGESIGSRAVQWYQHRAGQAPKLIIYNNQDRPPGIPERFSGSPDIDFGTTATLTITNVEAGDEATYYCHIWDSRRPTNWVFGGGTTLTVL Sequence number 322 QMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWLRETPGKGLEWIGYTHHSGDTNYAPSLKSRVHLGLHPSKNQVSLSLTSVTAADTAVYYCARTLHGRRIYGVVAFNEFTYFYVEVWGKGTQVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 323 QMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWLRETPGKGLEWIGYTHHSGDTNYAPSLKSRVHLGLHPSKNQVSLSLTSVTAADTAVYYCARTLHGRRIYGVVAFNEFTYFYVEVWGKGTQVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 324 SDISVAPGETVRISCGGESIGSRAVQWYQHRAGQAPKLIIYNNQDRPPGIPERFSGSPDIDFGTTATLTITNVEAGDEATYYCHIWDSRRPTNWVFGGGTTLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 325 QMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWLRETPGKGLEWIGYTHHSGDTNYAPSLKSRVHLGLHPSKNQVSLSLTSVTAADTAVYYCARTLHGRRIYGVVAFNEYYTYFYWPTWGKGTQVTVSS Sequence number 326 SDISVAPGETVRITCGGESIGSRAVQWYQHRPGQAPRLIIYNNQDRPPGIPERFSGSPDIDFGTTATLTISNVEAGDEATYYCHIWDSRRPTNWELGPGTTLTVL Sequence number 327 QMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWLRETPGKGLEWIGYTHHSGDTNYAPSLKSRVHLGLHPSKNQVSLSLTSVTAADTAVYYCARTLHGRRIYGVVAFNEYYTYFYWPTWGKGTQVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 328 QMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWLRETPGKGLEWIGYTHHSGDTNYAPSLKSRVHLGLHPSKNQVSLSLTSVTAADTAVYYCARTLHGRRIYGVVAFNEYYTYFYWPTWGKGTQVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 329 SDISVAPGETVRITCGGESIGSRAVQWYQHRPGQAPRLIIYNNQDRPPGIPERFSGSPDIDFGTTATLTISNVEAGDEATYYCHIWDSRRPTNWELGPGTTLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 330 QMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWLRETPGKGLEWIGYTHHSGDTNYAPSLKSRVTIGLDPSKNQVSLSLTSVTAADTAVYYCARTLHGRRIYGVVAFNEYYTYFYWPTWGKGTQVTVSS Sequence number 331 QMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWLRETPGKGLEWIGYTHHSGDTNYAPSLKSRVTIGLDPSKNQVSLSLTSVTAADTAVYYCARTLHGRRIYGVVAFNEYYTYFYWPTWGKGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 332 QMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWLRETPGKGLEWIGYTHHSGDTNYAPSLKSRVTIGLDPSKNQVSLTSVTAADTAVYYCARTLHGRRIYGVVAFNEYYTYFYWPTWGKGTQVTVSSASTKGPSVFPLAPSSKSTGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 333 QMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWLRETPGKGLEWIGYTHHSGDTNYAPSLKSRVTIGLDPSKNQVSLSLTSVTAADTAVYCARTLHGRRIYGVVAFNEYYTYFYWPTWGKGTQVTVSS Sequence number 334 QSVLTQPPSASGSPGQSVTISCTGTSDIGASDYVSWYQQYPGEAPKVIIYDVTKRPSGVPDRFSGSKSGTTASLTVSGLQAEDEADYCSSDAGRHTLLFGGGTKVTVL Sequence number 335 QVQLLESGPGLVRPSETLTLTCSVFNSRVSGYYYSWIRQPPGRGLEWIASTHFSLRPSRNPSLLRVTTSIDTERYQVFLNMRSVTAADTAVYFCARGDASGWRADYFPHWGQGTLVVVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence number 336 QVQLLESGPGLVRPSETLTLTCSVFNSRVSGYYYSWIRQPPGRGLEWIASTHFSLRPSRNPSLLSRVTTSIDTERYQVFLNMRSVTAADTAVYFCARGDASGWRADYFPHWGQGTLVVVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPCPAPELLGGPSVFLFPPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 337 QSVLTQPPSASGSPGQSVTISCTGTSSDIGASDYVSWYQQYPGEAPKVIIYDVTKRPSGVPDRFSGSKSGTTASLTVSGLQAEDEADYYCSSDAGRHTLLFGGGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 338 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQVHLQESGPGLVKPSETLSLTCNVSGTLVRDNYWSWIRQPLGKQPEWIGYVHDSGDTNYNPSLKSRVHLSLDKSKNLVSLRLTGVTAADSAIYYCATTKHGRRIYGVVAFKEWFTYFYMDVWGKGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 339 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSQLHLQESGPGLVKPPETLSLTCSVSGASINDAYWSWI RQSPGKRPEWVGYVHHSGDTNYNPSLKRRVTFSLDTAKNEVSLKLVDLTAADSATYFCARALHGKRIYGIVALGELFTYFYMDVWGKGTATVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 340 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQSQLQESGPRLVEASETLSLTCNVSGESTGACTYFWGWVRQAPGKGLEWIGSLSHCQSFWGSGWTFHNPSLKSRLTISLDTPKNQVFLKLTSLTAADTATYYCARFDGEVLVYNHWPKPAWVDLWGRGIPVTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 341 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSQPQLQESGPGLVEASETLSLTCTVSGDSTAACDYFWGW VRQPPGKGLEWIGGLSHCAGYYNTGWTYHNPSLKSRLTISLDTPKNQVFLKLNSVTAADTAIYYCARFDGEVLVYHDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 342 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSQPQLQESGPGLVEASETLSLTCTVSGDSTGRCNYFWGW VRQPPGKGLEWIGSLSHCRSYYNTDWTYHNPSLKSRLTISLDTPKNQVFLRLTSVTAADTATYYCARFGGEVLVYRDWPKPAWVDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 343 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQVQLQESGPGLVKPAETLSLTCSVSGESINTGHYYWGWVRQVPGKGLEWIGHIHYTTAVLHNPSLKSRLTIKIYTLRNQITLRLSNVTAADTAVYHCVRSGGDILYYYEWQKPHWFSPWGPGIHVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 344 QVQLQESGPGLVKPAETLSLTCSVSGESINTGHYYWGWVRQVPGKGLEWIGHIHYTTAVLHNPSLKSRLTIKIYTLRNQITLRLSNVTAADTAVYHCVRSGGDILYYYEWQKPHWFSPWGPGIHVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGKGGGGSKKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVC Sequence number 345 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQSALTQPPSASGSLGQSVTISCNGTSSDIGGWNFVSWYQQFPGRAPRLIIFEVNKRPSGVPGRFSGSKSGNSASLTVSGLQSDDEGQYFCSSLFGRWDVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 346 QSALTQPPSASGSLGQSVTISCNGTSSDIGGWNFVSWYQQFPGRAPRLIIFEVNKRPSGVPGRFSGSKSGNSASLTVSGLQSDDEGQYFCSSLFGRWDVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSGGGGSKKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVC Sequence number 347 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQVQLQESGPGLVKPSETLSLTCTVSGDSINTGHHYWGWVRQVPGKGPEWIAHIHYNTAVLHNPALKSRVTISIFTLKNLITLSLSNVTAADTAVYFCVRSGGDILYYIEWQKPHWFYPWGPGILVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 348 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSQLQLQESGPGLVKPSETLSLTCTVSGGSMRGTTDWGEND FHYGWIRQSSAKGLEWIGSIHWRGRTTHYKTSFRSRATLSIDTSNNRFSLTFSFVTAADTAVYYCARHKYHDIFRVVPVAGWFDPWGQGLLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 349 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSEVHLEESGPGLVRPSETLSLTCTASGGSIRGGEWGDSDYHWGWVRHSPEKGLEWIGSIHWRGTTHYNAPFRGRGRLSIDLSRNQFSLRLTSVTAEDTAVYYCVKHKYHDIVMVVPIAGWFDPWGQGLQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 350 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGSEVQLVESGGGLVKPGGSLRTCVASGFTFSDVWLNWVRQAPGKGLEWVGRIKSRDTGGTTDYAAASVKGRFTISRDDSKNTLYLQMNSLKTEDTAVYSCTTDGFIMIRGVSEDYYYYYMDVWGKGTTTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 351 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSQVQLVQSGGGLVQPGGSLRLSCAAFGFNFSSYVMH WVRQAPGQGLEYLSAISSDGETTYHANSVKGRFTSSRDNSKNTLFLQMGSLRTEDVAVYYCARDRYYETSGSNAFDVWGQGTMVVVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 352 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSQVQLVQSGAEVRKPGSSVTISCKPVGGTFTNFAIHWV RQAPGQGLEWVGGRPVVGIYKYGKKFHDRLRLYEDDPMKTVFLELRSLTSDDTGVYYCTRWRGCGMCPYDTSSYNDSDVWGPGTKVIVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 353 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSEVQLVESGGGLVKAGGSLILSCVSNFRISAHTMN WVRRVPGGGLEWWASISTSSTRYDYADAVKGRFTVSRDDLEDFVYLQMHKMRVEDTAIYYCARKGSDRLSDNDPFDAWGPGTVVTVSPASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 354 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSQMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWL RETPGKGLEWIGYTHHSGDTNYAPSLKSRVHLGLHPSKNQVSLSLTSVTAADTAVYCARTLHGRRIYGVAFNEFFTYWEVWGKGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 355 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSQMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWL RETPGKGLEWIGYTHHSGDTNYAPSLKSRVHLGLHPSKNQVSLSLTSVTAADTAVYCARTLHGRRIYGVVAFNEYYTYFYWPTWGKGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 356 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSQMQLQESGPGLVKPGETLSLTCSVSGASISSSYWSWL RETPGKGLEWIGYTHHSGDTNYAPSLKSRVTIGLDPSKNQVSLSLTSVTAADTAVYCARTLHGRRIYGVAFNEYYTYFYWPTWGKGTQVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 357 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQVQLLESGPGLVRPSETLTLTCSVFNSRVSGYYYSWIRQPPGRGLEWIASTHFSLRPSRNPSLLSRVTTSIDTERYQVFLNMRSVTAADTAVYFCARGDASGWRADYFPHWGQGTLVVVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 358 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVCGGGGSQSVLTQPPSASGSPGQSVTISCTGTSSDIGASDYVSWYQQYPGEAPKVIIYDVTKRPSGVPDRFSGSKSGTTASLTVSGLQAEDEADYYCSSDAGRHTLLFGGGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS Sequence number 359 QVQLLESGPGLVRPSETLTLTCSVFNSRVSGYYYSWIRQPPGRGLEWIASTHFSLRPSRNPSLLSRVTTSIDTERYQVFLNMRSVTAADTAVYFCARGDASGWRADYFPHWGQGTLVVVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGKGGGGSKKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVC Sequence number 360 QSVLTQPPSASGSPGQSVTISCTGTSSDIGASDYVSWYQQYPGEAPKVIIYDVTKRPSGVPDRFSGSKSGTTASLTVSGLQAEDEADYYCSSDAGRHTLLFGGGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSGGGGSKKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNFPLIIKNLKPEDSDTYICEVEDQKEEVQLVVVC Sequence number 361 CTRPNNNTRKSIHIGPGRAFYTTGEIIGDIRQAHC Sequence number 362 KKVVYGKCGDTVELTCTASQKKNIQFHWKNSNQIKILGNQGSFLTKGPSKLNDRVDSRRSLWDQGNPLIINKLPEDSDTYICEVEDQKEEVQLVVVCGGGGSQVQLVQSGAQMKNPGASVKVSCAPSGYTFTDFYIHW LRQAPGQGLQWMGWMNPQTGRTNTARNFQGRVTMTRDTSIGTAYMELRSTSDDTAIYYCTTGGWISLYYDSSYYPNFDHWGQGTLLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK Sequence number 363 MKVMGTKKNYQHLWRWGIMLLGMLMMSSAAEQLWVTVYYGVPVWREANTTLFCASDAKAYDTEVHNVWATHACVPTDPNPQEVVMGNVTEDFNMWKNNMVEQMHEDIISLWDQSLKPCVKLTPLCVTLHCTNVTISSTNGSTANVTMREEMKNCSFNTTTVIRDKIQKEYALFYKLDIVPIEGKNTNTSYRLINCNTSVITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGKGPCRNVSTVQCTHGIKPVVSTQLLLNGSLAEEDIIIRSENFTNNGKNIIVQLKEPVKINCTRPGNNTRRSINIGPGRAFYATGAIIGDIRKAHCNISTEQWNNTLTQIVDKLREQFGNKTIIFNQSSGGDPEVVMHTFNCGGEFFYCNSTQLFNSTWFNNGTSTWNSTADNITLPCRIKQVINMWQEVGKAMYAPPIRGQIDCSSNITGLILTRDGGSNSSQNETFRPGGGNMKDNWRSELYKYKVVKIEPLGIAPTRAKRRVVQREKRAVTLGAVFLGFLGAAGSTMGAASLTLTVQARLLLSGIVQQQSNLLRAIEAQQHMLQLTVWGIKQLQARVLAIERYLKDQQLLGIWGCSGKLICTTTVPWNTSWSNKSYDYIWNNMTWMQWEREIDNYTGFIYTLIEESQNQQEKNELELLELDKWASLWNWFNITNWLWYIKLFIMIIGGLVGLRIVCAVLSIVNRVRQGYSPLSFQTRLPNPRGPDRPEETEGEGGERDRDRSARLVNGFLAIIWDDLRSLCLFSYHRLRDLLLIVARVVEILGRRGWEILKYWWNLLKYWSQELKNSAVSLLNVTAIAVAEGTDRVIEIVQRAVRAILHIPTRIRQGFERALL Sequence number 364 AEQLWVIVYYGVPVWREANTTLFCASDAKAYDTEVHNVWATHACVPTDPNPQEVVMGNVTEDFNMWKNNMVEQMHEDIISLWDQSLKPCVKLTPLCVTLHCTNVTISSTNGSTANVTMREEMKNCSFNTTTVIRDKIQKEYALFYKLDIVPIEGKNTNTSYRLINCNTSVITQACPKVSFEPIPIHYCAPAGFAILKCNNKTFNGKGPCRNVSTVQCTHGIKPVVSTQLLLNGSLAEEDIIIRSENFTNNGKNIIVQLKEPVKINCTRPGNNTRRSINIGPGRAFYATGAIIGDIRKAHCNISTEQWNNTLTQIVDKLREQFGNKTIIFNQSSGGDPEVVMHTFNCGGEFFYCNSTQLFNSTWFNNGTSTWNSTADNITLPCRIKQVINMWQEVGKAMYAPPIRGQIDCSSNITGLILTRDGGSNSSQNETFRPGGGNMKDNWRSELYKYKVVKIEPLGIAPTRAKRRVVQREKR Sequence number 365 SDISVAPGETVRITCGGESIGSRAVQWYQHRPGQAPRLIIYNNQDRPPGIPERFSGSPDIDFGTTATLTISNVEAGDEATYYCHIWDSRRPTNWELGPGTTLTVL Sequence number 366 SDISVAPGETVRITCGGESIGSRAVQWYQHRPGQAPRLIIYNNQDRPPGIPERFSGSPDIDFGTTATLTISNVEAGDEATYYCHIWDSRRPTNWELGPGTTLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS

Claims

1. (i) an anti-V3 bNAb comprising two heavy chains and two light chains; and (ii) a bispecific anti-HIV gp120 binding protein comprising at least one CD4 domain, wherein the CD4 domain is linked, either directly or via a linker, to the N-terminus or C-terminus of one of the heavy or light chains of the anti-V3 bNAb.

2. 2. The bispecific protein of claim 1, wherein the CD4 domain is attached to the N-terminus or C-terminus of the heavy chain of one or both anti-V3 bNAbs via a linker.

3. 2. The bispecific protein of claim 1 , wherein the CD4 domain is attached to the N-terminus or C-terminus of the light chain of one or both anti-V3 bNAbs via a linker.

4. 2. The bispecific protein of claim 1, further comprising at least four CD4 domains.

5. 5. The bispecific protein of claim 4, wherein the C-terminus of the first and second CD4 domains is linked by a linker to the N-terminus of each of the anti-V3 heavy chains, and the C-terminus of the third and fourth CD4 domains is linked by a linker to the N-terminus of each of the anti-V3 light chains.

6. 6. The bispecific protein of claim 1, wherein the linker is selected from the group consisting of SEQ ID NOs: 90-95.

7. The bispecific protein of claim 6, wherein the linker is SEQ ID NO:

90.

8. 6. The bispecific protein of claim 1, wherein the CD4 domain is selected from the group consisting of SEQ ID NOs: 1 to 21.

9. 9. The bispecific protein of claim 8, wherein the CD4 domain is SEQ ID NO:

11.

10. The anti-V3 bNAbs are bNAb1, bNAb1, and bNAb1 as listed in Table 2. ＊ 10. The bispecific protein of claim 1, wherein the bispecific protein is selected from the group consisting of bNAb1, bNAb2, bNAb3, bNAb4, bNAb5 and bNAb6.

11. The bispecific protein of claim 10 , wherein the anti-V3 bNAb is bNAb1.

12. The bispecific protein of any one of claims 1 to 11, wherein the Fc of the anti-V3 bNAb comprises an LS.

13. An anti-HIV gp120 binding protein having two identical heavy chains and two identical light chains, a heavy chain at least 95% identical to SEQ ID NO: 121; and A light chain at least 95% identical to SEQ ID NO: 63 An anti-HIV gp120 binding protein comprising or consisting of:

14. An anti-HIV gp120 binding protein consisting of two heavy chains of SEQ ID NO: 121 and two light chains of SEQ ID NO:

63.

15. A pharmaceutical composition comprising an anti-HIV gp120 binding protein according to any one of the preceding claims and a pharmaceutically acceptable excipient.

16. 19. A method of treating or preventing HIV infection in a human, comprising administering to said human an anti-HIV gp120 binding protein of any one of claims 1 to 14, or a pharmaceutical composition of claim 15, thereby reducing the viral load in said human.

17. An anti-HIV gp120 binding protein according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15, for use in the treatment or prevention of HIV infection in humans.

18. Use of an anti-HIV gp120 binding protein according to any one of claims 1 to 14, or a pharmaceutical composition according to claim 15, in the manufacture of a medicament for treating or preventing HIV infection in humans.

19. A kit comprising, in separate containers, the anti-HIV gp120 binding protein according to any one of claims 1 to 14 and an antiviral drug that inhibits HIV cell entry, replication, or transcription in humans.

20. 20. The kit of claim 19, wherein the antiviral agent is selected from the group consisting of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, integrase strand transfer inhibitors (INSTIs), maturation inhibitors (MIs), capsid inhibitors (CIs), and nucleoside reverse transcriptase translocation inhibitors (NRTTIs).

21. 21. The kit of claim 20, wherein the antiviral agent is INSTI.

22. 22. The kit of claim 21, wherein the INSTI is dolutegravir or cabotegravir.

23. A nucleic acid sequence encoding the anti-HIV gp120 binding protein of any one of claims 1 to 14.

24. 24. An expression vector comprising the nucleic acid sequence of claim 23.

25. 25. A host cell comprising the nucleic acid sequence of claim 23 or the expression vector of claim 24.

26. Two expression vectors: a first expression vector comprising a nucleic acid sequence encoding the heavy chain of SEQ ID NO: 121; and A second expression vector comprising a nucleic acid sequence encoding the light chain of SEQ ID NO:

63. A host cell comprising:

27. A method for producing an anti-HIV gp120 binding protein, comprising culturing a host cell described in claim 25 or 26 under conditions suitable for expression of the nucleic acid sequence or vector, thereby producing an anti-HIV gp120 binding protein.

28. A soluble CD4 domain with a Tm above 70°C.

29. A soluble CD4 domain comprising one or more stabilizing mutations selected from the group consisting of K8C, K8I, K8V, T11C, E13C, K21C, Q25E, H27C, H27D, G38C, N52W, R58N, R58T, R58V, L61M, G65C, I70C, K72C, E87G, E91H, E91Q, and G99C.

30. 30. The soluble CD4 domain of claim 28 or 29, having a Tm of 70°C to 95°C.

31. 29. The soluble CD4 domain of claim 28, having a Tm of about 90°C.

32. A soluble CD4 domain according to any one of claims 28 to 31, comprising K8C and G99C.

33. A soluble CD4 domain according to any one of claims 28 to 31, comprising K8I.

34. A soluble CD4 domain according to any one of claims 28 to 31, comprising K8V.

35. A soluble CD4 domain according to any one of claims 28 to 34, comprising T11C and K72C.

36. A soluble CD4 domain according to any one of claims 28 to 35, comprising any one of SEQ ID NOs: 5 to 21.

37. 37. The soluble CD4 domain of claim 36, comprising SEQ ID NO:

11.

38. The soluble CD4 domain of any one of claims 28 to 37, wherein the CD4 domain is fused to a human Fc domain directly or via a linker.

39. 39. The soluble CD4 domain of claim 38, wherein the Fc domain comprises an LS.

40. The soluble CD4 domain of claim 38 or claim 39, wherein the linker is selected from the group consisting of SEQ ID NOs: 90 to 95.

41. (i) an anti-V3 bNAb or an antigen-binding Fab' or F(ab')2 fragment thereof; and (ii) a bispecific anti-HIV gp120 binding protein comprising at least one CD4 domain, wherein the C-terminus of the CD4 domain is linked, either directly or via a linker, to the N-terminus of the heavy chain variable region or the light chain variable region of the anti-V3.

42. 42. The bispecific protein of claim 41 , wherein the anti-V3 bNAB is an antigen-binding Fab′ fragment and the CD4 domain is attached to the heavy chain variable region of the Fab′ fragment of the anti-V3 bNAb via a linker.

43. 42. The bispecific protein of claim 41 , wherein the anti-V3 bNAB is an antigen-binding Fab′ fragment and the CD4 domain is attached to the light chain variable region of the Fab′ fragment of the anti-V3 bNAb via a linker.

44. 42. The bispecific protein of claim 41 , further comprising at least two CD4 domains, wherein the anti-V3 bNAB is an antigen-binding Fab′ fragment, and wherein a first CD4 domain is attached to the heavy chain variable region of the Fab′ fragment of the anti-V3 bNAb via a linker, and a second CD4 domain is attached to the light chain variable region of the Fab′ fragment of the anti-V3 bNAb via a linker.

45. 42. The bispecific protein of claim 41 , further comprising at least two CD4 domains, wherein said anti-V3 bNAB is an antigen-binding F(ab′)2 fragment, and wherein each of said CD4 domains is linked via a linker to each of the heavy chain variable regions of the F(ab′)2 fragment of said anti-V3 bNAb.

46. 42. The bispecific protein of claim 41 , further comprising at least two CD4 domains, wherein said anti-V3 bNAB is an antigen-binding F(ab′)2 fragment, and wherein each of said CD4 domains is linked via a linker to each of the light chain variable regions of the F(ab′)2 fragment of said anti-V3 bNAb.

47. 42. The bispecific protein of claim 41 , further comprising at least four CD4 domains, wherein said anti-V3 bNAB is an antigen-binding F(ab′)2 fragment, and each of said CD4 domains is linked via a linker to each of the heavy chain variable regions and each of the light chain variable regions of the F(ab′)2 fragment of said anti-V3 bNAb.

48. 49. The bispecific protein of any one of claims 41 to 48, wherein the C-terminus of the CD4 domain is linked via a linker to the N-terminus of the heavy or light chain variable region of the Fab or F(ab')2 fragment of the anti-V3 bNAB, respectively.

49. 29. The bispecific protein of any one of claims 41 to 28, wherein the linker is selected from the group consisting of SEQ ID NOs: 90 to 95.

50. 50. The bispecific protein of claim 49, wherein the linker is SEQ ID NO:

90.

51. 51. The bispecific protein of any one of claims 41 to 50, wherein the CD4 domain is selected from the group consisting of SEQ ID NOs: 1 to 21.

52. 52. The bispecific protein of claim 51 , wherein the CD4 domain is SEQ ID NO:

11.

53. The anti-V3 bNAb or antigen-binding fragment thereof is selected from the group consisting of bNAb1, ... ＊ 49. The bispecific protein of any one of claims 41 to 48, wherein the bispecific protein is selected from the group consisting of bNAb1, bNAb2, bNAb3, bNAb4, bNAb5 and bNAb6.

54. 54. The bispecific protein of claim 53, wherein the anti-V3 bNAb is bNAb1.

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