Multispecific antibodies targeting HPTP-beta (ve-PTP) and VEGF

Abstract

To provide multispecific antibodies targeting HPTP-β (VE-PTP) and VEGF.SOLUTION: The disclosure provides a composition comprising a multispecific compound, including a compound targeting a phosphatase and a receptor tyrosine kinase agonist. Also provided is a method for treating conditions associated with angiogenesis comprising administering a multispecific compound targeting a phosphatase and a receptor tyrosine kinase agonist. In some embodiments, the disclosure provides a compound comprising: (a) a first domain that modulates a phosphatase where the phosphatase modulates Tie2; and (b) a second domain that specifically binds to a receptor tyrosine kinase agonist.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 735,331, filed Sep. 24, 2018, and U.S. Provisional Patent Application No. 62 / 832,461, filed Apr. 11, 2019, each of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Individual compounds having the ability to modulate distinct targets can be combined to yield multispecific compounds. Such multispecific compounds can have advantages over the parent compounds administered individually. These advantages can include, for example, a simpler dosing regimen, a longer half-life within a subject, or the ability to bind to neighboring targets. Incorporation by reference

[0003] Each patent, publication, and non-patent literature cited in this application is hereby incorporated by reference in its entirety as if each were individually incorporated by reference.

Summary of the Invention

Means for Solving the Problems

[0004] In some embodiments, the disclosure provides a compound comprising (a) a first domain that modulates a phosphatase, wherein the phosphatase modulates Tie2; and (b) a second domain that specifically binds to a receptor tyrosine kinase agonist.

[0005] In some embodiments, the disclosure provides a method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein.

Brief Description of the Drawings

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[0033] The present disclosure provides compositions and methods for modulating phosphatases, and kinases, such as receptor tyrosine kinases. The compositions and methods are provided for modulating Tie2, for example, to promote phosphorylation, signaling and / or activation of Tie2. In some embodiments, the present disclosure provides compositions and methods for targeting phosphatases that modulate Tie2 signaling. In some embodiments, the phosphatase that modulates Tie2 signaling is human protein tyrosine phosphatase-beta (HPTP-β).

[0034] The compositions and methods are provided for modulating receptor tyrosine kinases, for example, to reduce phosphorylation, signaling and / or activation of receptor tyrosine kinases. In some embodiments, the present disclosure provides compositions and methods for targeting receptor tyrosine kinase agonists, such as vascular endothelial growth factor (VEGF). In some embodiments, the present disclosure provides compositions and methods for targeting receptor tyrosine kinases, such as VEGF receptors.

[0035] In some embodiments, the present disclosure provides compositions and methods for targeting human protein tyrosine phosphatase-beta (HPTP-β) or vascular endothelial protein tyrosine phosphatase (VE-PTP or VEPTP), and vascular endothelial growth factor (VEGF). In some embodiments, the present disclosure provides multispecific compounds, agents, antibodies, fragments or derivatives thereof that target HPTP-β (VE-PTP) and VEGF.

[0036] The agents disclosed herein can be used, for example, for the treatment of disorders characterized by, for example, vascular instability, angiogenesis, neovascularization, vascular leakage and / or edema. The agents disclosed herein can be used, for example, for the treatment of vascular disorders, ocular disorders, cancer, kidney disorders and complications of diabetes. HPTP-β / VE-PTP, Tie2 and Vascular Stability

[0037] HPTP-β is a member of the receptor-like family of protein tyrosine phosphatases (PTPases). HPTP-β is a transmembrane protein mainly found in vascular endothelial cells that shows structural and functional similarities to cell adhesion molecules. Orthologs of HPTP-β are found in various species including, for example, zebrafish, chicken, dog, mouse, marmoset and monkey. The orthologs are generally referred to as vascular endothelial protein tyrosine phosphatase (VE-PTP). HPTP-β (VE-PTP) can affect vascular stability by its effect on Tie2-mediated signaling.

[0038] Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2) is a membrane receptor tyrosine kinase mainly expressed in vascular endothelial cells. Upstream factors can control Tie2 phosphorylation and affect downstream signaling and vascular stabilization. Non-limiting examples of such factors include angiopoietin 1 (Ang1 / Angpt1), angiopoietin 2 (Ang2 / Angpt2) and HPTP-β (VE-PTP).

[0039] Ang1 is an agonist of Tie2. The binding of Ang1 to Tie2 promotes receptor phosphorylation and downstream signaling, inducing vascular stabilization by highly organized angiogenesis, tightening of endothelial cell-cell junctions, enhancement of endothelial survival, reduction of endothelial inflammation, and improvement of endothelial function.

[0040] Ang2 acts as a context-dependent antagonist or agonist of Tie2. During angiogenesis, Ang2 acts as a negative regulator of Ang1-Tie2 signaling.

[0041] HPTP-β (VE-PTP) is a phosphatase that can modulate Tie2 signaling. HPTP-β (VE-PTP) can dephosphorylate the Tie2 receptor. Under physiological conditions, HPTP-β (VE-PTP) controls the duration of Tie2 phosphorylation. Thus, inhibition of HPTP-β (VE-PTP) can result in increased Tie2 phosphorylation, increased Tie2-mediated signaling, and enhanced vascular stability. An inhibitor of HPTP-β (VE-PTP) is a Tie2 activator. For example, a compound, inhibitor, antibody, antibody fragment, variant, or derivative thereof that binds to HPTP-β (VE-PTP) can promote Tie2 phosphorylation, thereby activating signaling downstream of Tie2 and promoting vascular stability.

[0042] By the processes described above, HPTP-β (VE-PTP) activity can contribute to disorders characterized by, for example, vascular instability, angiogenesis, neovascularization, vascular leakage, and / or edema. For example, HPTP-β (VE-PTP) activity can contribute to vascular disorders, ocular disorders, cancer, kidney disorders, diabetic complications, and other disorders. Inhibition of HPTP-β (VE-PTP) activity can reduce such disorders. VEGF and Vascular Stability

[0043] Vascular endothelial growth factor (VEGF) is mainly found in endothelial cells and is involved in pathological neovascularization in several diseases. VEGF is a member of the cystine knot growth factor superfamily, the PDGF family, and the VEGF family. VEGF can act as an angiogenesis promoter. The VEGF family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PGF). There are nine VEGF-A isoforms: VEGF 121 , VEGF 145 , VEGF 148 , VEGF 162 , VEGF 165 , VEGF 165b , VEGF 183 , VEGF189 and VEGF 206 。

[0044] VEGF is a hypoxia-regulated gene, and VEGF levels increase in a hypoxic or ischemic state. VEGF is an agonist of the VEGF receptor (VEGFR). VEGFR is a receptor tyrosine kinase, and binding of VEGF to VEGFR can result in phosphorylation of the receptor and subsequent downstream signaling molecules. VEGFR-mediated signaling can lead to abnormal angiogenesis, neovascularization, and increased vascular permeability, contributing to pathological vascular instability. Therefore, inhibition of VEGF can result in reduced VEGFR-mediated signaling and enhanced vascular stability. For example, an inhibitor, antibody, antibody fragment, variant, or derivative thereof that binds to VEGF can reduce ligation of VEGFR, thereby reducing VEGFR-mediated signaling and promoting vascular stability. Non-limiting examples of agents that bind to VEGF include aflibercept (Eylea®), a recombinant protein comprising the VEGF-binding portions of human VEGF receptors 1 and 2 fused to the Fc protein of human IgG1; ranibizumab (Lucentis®), a humanized monoclonal antibody fragment (Fab); bevacizumab (Avastin®), a humanized monoclonal antibody; conbercept, a recombinant fusion protein comprising extracellular domains derived from VEGF receptors 1 and 2 fused to the Fc portion of human IgG1; abicipar, a designed ankyrin repeat protein (DARPin); MP0112, a DARPin; MP0250, a DARPin; CT-322, an adnectin; and PRS-050, an anti-kallikrein.

[0045] By the process described above, VEGF can contribute to disorders characterized, for example, by vascular instability, angiogenesis, neovascularization, vascular leakage and / or edema. For example, VEGF can contribute to vascular disorders, ocular disorders, cancer, kidney disorders, complications of diabetes, and other disorders. For example, ischemia in the eye can result in increased VEGF production, leading to vascular leakage and pathologic neovascularization in the retina. Inhibition of VEGFR-mediated signaling can reduce such disorders. Receptor Tyrosine Kinase (RTK) and Receptor Tyrosine Kinase Agonist

[0046] Receptor Tyrosine Kinase (RTK) is a cell surface receptor involved in the control of cell growth, differentiation and survival. Binding of an agonist to RTK can cause adjacent RTKs, which are related to each other, to dimerize. Dimerization can cause cross-phosphorylation - each RTK in the dimer phosphorylates a number of tyrosine residues on the other RTK. Once cross-phosphorylated, the cytoplasmic tail of the RTK can initiate a signal transduction pathway, for example, by functioning as a docking platform for various intracellular proteins. RTK signaling can result in changes in gene transcription and expression in cells.

[0047] Non-limiting examples of RTKs include AATK, AATYK, AATYK1, AATYK2, ACH, ALK, ARK, AXL, BDB, BDB1, BEK, BFGFR, BREK, Brt, CAK, CCK4, CD115, CD117, CD135, CD136, CD140a, CD140b, CD167, CD202b, CD220, CD221, CD246, CD309, CD331, CD332, CD333, CD334, CDHF12, CDHR16, CDw136, CEK, CEK2, CEK3, c-Eyk, CFD1, C-FMS, C-Kit, cprk, c-ros-1, CSF1R, CSFR, D3S3195, DDR1, DDR2, DFNB97, DKFZp761P1010, Dtk, ECT1, EDDR1, EGFR, EphA10, EphA1-8, EphB1, EphB2, EphB3, EphB4, EphB6, ErbB2, ErbB3, ErbB4, Etk-2, FGFR1, FGFR2, FGFR3, FGFR4, FLG, FLK1, FLK2, FLT, FLT1, FLT2, FLT3, FLT4, FMS, GAS9, H2, H3, H4, H5, HGFR, HSCR1, IGF1R, IGFIR, IGFR, INSR, INSRR, IRR, JKT5A, JTK11, JTK12, JTK13, JTK14, JTK2, JTK4, JTK5, JWS, KAL2, KDR, KGFR, KIAA0641, KIAA1079, KIAA1883, KIT, KPI2, K-SAM, LMR1, LMR2, LMR3, LMTK1, LMTK2, LMTK3, LTK, MCF3, MEN2A, MEN2B, Mer, MERTK, MET, MGC18216, MST1R, MTC, MTC1, MTRK1, MuSK, NEP, NOK, N-SAM, NTRK2, NTRK3, NTRK4, NTRKR1, NTRKR2, PBT, PCL, PDGFR, PDGFR1, PDGFR2, PDGFRA, PDGFR-alpha, PDGFRB, PDGFR-beta, PPP1R100, PPP1R101, PPP1R77, PTC, PTK3A, PTK7, PTK8, RCCP2, Rek, RET, RET51, RON, ROR1, ROR2, ROS, ROS1, RP38, RSE, RTK6, RYK, Ryk, RYK1, SCFR, Sky, STK, STYK1, SuRTK106, TEK, TIE1,TIE2, Tif, TK14, TK25, TKT, TRK, TrkA, TrkB, TrkC, TYK1, TYKLM3, TYRO10, Tyro12, Tyro3, Tyro7, UFO, VEGFR, VEGFR1, VEGFR2, VEGFR3, VMCM and VMCM1 are included.

[0048] Non-limiting examples of RTK agonists include VEGF, Ang1, Ang2, BDNF, EGF, FGF, HGF, IGF, insulin, MSP, NGF, NT-3 and PDGF. Antibodies and antigen-binding compounds

[0049] The basic four-chain antibody unit includes two identical heavy chain (H) polypeptide sequences and two identical light chain (L) polypeptide sequences. Each heavy chain may include one N-terminal variable (V H ) region and three or four C-terminal constant (C H 1, C H 2, C H 3 and C H ) regions. Each light chain may include one N-terminal variable (V L ) region and one C-terminal constant (C L ) region. The light chain variable region is aligned with the heavy chain variable region, and the light chain constant region is aligned with the heavy chain constant region C H1 and aligned. The pairing of the heavy chain variable region and the light chain variable region forms a single antigen-binding site together. Each light chain is linked to the heavy chain by one covalent disulfide bond. The two heavy chains are linked to each other by one or more disulfide bonds depending on the isotype of the heavy chain. Each heavy chain and light chain also includes intra-chain disulfide bridges at regular intervals. The C-terminal constant region of the heavy chain includes the Fc region of the antibody, which mediates effector functions, for example, by interaction with Fc receptors or complement proteins. Figure 1 provides a simple representative schematic of the basic four-chain antibody unit; the light chain sequence is represented by "SEQ A". The heavy chain sequence is represented by "SEQ B", -S-S- indicates a disulfide bond, and N and C indicate the N-terminal and C-terminal, respectively.

[0050] The light chain can be designated as kappa or lambda based on the amino acid sequence of the constant region. The heavy chain can be designated as alpha, delta, epsilon, gamma or mu based on the amino acid sequence of the constant region. Antibodies are classified into five immunoglobulin classes or isotypes based on the heavy chain. IgA contains an alpha heavy chain, IgD contains a delta heavy chain, IgE contains an epsilon heavy chain, IgG contains a gamma heavy chain, and IgM contains a mu heavy chain. Antibodies of the IgG, IgD and IgE classes contain monomers (two heavy chains and two light chains) of the four-chain unit described above, while the IgM and IgA classes can contain multimers of the four-chain unit. The alpha and gamma classes are further divided into subclasses based on differences in the sequence and function of the heavy chain constant region. Subclasses of IgA and IgG expressed by humans include IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.

[0051] The constant region is minimally involved in antigen binding. Rather, the constant region can mediate various effector functions. Differences in the isotype or subclass of IgG can be associated with different effector functions or therapeutic properties, for example, due to interactions with different Fc receptors and / or complement proteins. Antibodies containing an Fc region that associates with an activating Fc receptor can be involved in, for example, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), induction of signal transduction by immunoreceptor tyrosine-based activation motif (ITAM) and induction of cytokine secretion. Antibodies containing an Fc region that associates with an inhibitory Fc receptor can, for example, induce signal transduction by immunoreceptor tyrosine-based inhibitory motif (ITIM).

[0052] Different antibody subclasses include different abilities to induce immune effector functions. For example, IgG1 and IgG3 can effectively recruit complement that activates CDC, IgG2 induces minimal ADCC, and IgG4 has a lower ability to cause immune effector functions. Modifications to the constant region can also affect antibody properties such as enhancement or reduction of Fc receptor ligation, enhancement or reduction of ADCC, enhancement or reduction of ADCP, enhancement or reduction of CDC, enhancement or reduction of signal transduction by ITAM, enhancement or reduction of cytokine induction, enhancement or reduction of signal transduction by ITIM, enhancement or reduction of half-life, or enhancement or reduction of co-association of the antigen with Fc receptors. Modifications can include, for example, amino acid mutations, changes in post-translational modifications (such as glycosylation), binding of domains from different isotypes or subclasses, or combinations thereof.

[0053] The compounds or antibodies of the present disclosure can include a constant region or Fc region that is selected or modified to provide appropriate antibody properties, such as appropriate properties for treating the diseases or conditions disclosed herein. In some embodiments, IgG1 can be used, for example, to promote immune activation effector functions (such as ADCC, ADCP, CDC, ITAM signal transduction, cytokine induction, or combinations thereof for the treatment of cancer). In some embodiments, IgG4 can be used, for example, when antibody antagonism in the absence of immune effector functions is desired (such as for the treatment of ocular disorders).

[0054] Non-limiting examples of antibody modifications and their effects are provided in Table 1.

Table 1-1

Table 1-2

[0055] The variable (V) region mediates antigen binding and defines the specificity of a particular antibody for an antigen. The variable region contains a relatively invariant sequence called the framework region and hypervariable regions that vary greatly in sequence among antibodies of different binding specificities. The variable region of each antibody's heavy or light chain contains four framework regions separated by three hypervariable regions. The variable regions of the heavy and light chains are folded in such a way that the hypervariable regions are brought into proximity to create an antigen-binding site. The four framework regions mostly adopt a β-sheet conformation, while the three hypervariable regions form loops that connect the β-sheet structures and, in some cases, form parts of them.

[0056] Inside the hypervariable regions are amino acid residues that mainly determine the binding specificity of the antibody. The sequences containing these residues are known as complementarity-determining regions (CDRs). One antigen-binding site of an antibody contains six CDRs, three in the hypervariable region of the light chain and three in the hypervariable region of the heavy chain. The CDRs in the light chain are designated as L1, L2, and L3, while the CDRs in the heavy chain are designated as H1, H2, and H3. The CDRs can also be designated as LCDR1, LCDR2, LCDR3, HCDR1, HCDR2, and HCDR3, respectively. The contribution of each CDR to antigen binding varies among antibodies. The CDRs can vary in length. For example, CDRs are often 5 - 14 residues long, but there are also short CDRs of 0 residues or long CDRs of 25 residues or more.

[0057] Several methods are used to predict or assign CDR sequences. These methods can use different numbering schemes since insertions and deletions in the sequences are numbered differently, for example.

[0058] The Kabat method was developed by aligning a limited number of antibody sequences and determining the positions of the most variable residues. Based on the alignment, a numbering scheme was introduced for the residues in the variable region. This numbering scheme can be used to determine the positions marking the start and end of each CDR. One iteration of the Kabat numbering system uses the following residue positions: LCDR1 around residues 24 - 34; LCDR2 around residues 50 - 56; and LCDR3 around residues 89 - 97 to identify the CDRs in the light chain variable region. One iteration of the Kabat numbering system uses the following residue positions: HCDR1 around residues 31 - 35; HCDR2 around residues 50 - 65; and HCDR3 around residues 95 - 102 to identify the CDRs in the heavy chain variable region.

[0059] The Chothia method was developed based on the analysis of three-dimensional antibody structures. This analysis determined that the hypervariable loops fit into a restricted set of conformations based on the presence of certain residues at key positions in the CDRs and adjacent framework regions. This method uses a numbering scheme similar to the Kabat method, but with different insertions and deletions of numbers. One iteration of the Chothia numbering system uses the following residue positions: LCDR1 around residues 24 - 34; LCDR2 around residues 50 - 56; and LCDR3 around residues 89 - 97 to identify the CDRs in the light chain variable region. One iteration of the Chothia numbering system uses the following residue positions: HCDR1 around residues 26 - 34; HCDR2 around residues 52 - 56; and HCDR3 around residues 95 - 102 to identify the CDRs in the heavy chain variable region.

[0060] The IMGT method (International ImMunoGeneTics database) was developed by integrating existing definitions of framework regions and CDRs, structural data, and data from the alignment of antibody variable region sequences. This integration led to the identification of conserved residues in the framework regions that can be used as reference points for identifying CDRs. Examples of conserved residues in the variable region include cysteine at approximately residue 23 (in framework region 1), tryptophan at approximately residue 41 (in framework region 2), a hydrophobic amino acid at approximately residue 89 (in framework region 3), cysteine at approximately residue 104 (in framework region 3), and phenylalanine or tryptophan at approximately residue 118 (in framework region 4). CDRs can be identified in the sequence encoding the antibody variable region of interest by using an algorithm based on computer alignment.

[0061] The numbering of the IMGT method always assigns the same number to the conserved amino acids, but the lengths of the CDRs and framework regions are allowed to vary. Thus, the IMGT numbering of residues is not necessarily continuous. The lengths of the CDRs identified by the IMGT method can vary. For example, LCDR1 or HCDR1 can be approximately 5 to approximately 12 amino acids, LCDR2 or HCDR2 can be approximately 0 to approximately 10 amino acids, and LCDR3 or HCDR3 can be approximately 5 to approximately 91 amino acids.

[0062] The Paratome method was developed based on the multiple structural alignments of available antibody-antigen complexes. The structural positions that bind to the antigen were found to be similar among the antibodies examined, and the antibody sequences from the dataset were annotated with antigen-binding regions (ABR, similar to CDR). The ABRs in the query sequence can be identified using computer tools that first align the query sequence against antibodies with solved antibody-antigen structures and then infer the positions of the ABRs based on the alignment. Antibodies with solved structures can also have the identified ABRs using a structural alignment method rather than based on sequence.

[0063] A subset of the residues within the CDR contacts the antigen. These residues that contact the antigen can be termed specificity-determining residues (SDR). However, residues other than the SDR can contribute to the binding activity by helping to maintain the three-dimensional structure of the binding site. The number of SDRs in an antibody can vary based on the size and type of the antigen recognized, for example, SDRs between 0 and 14 can be found within the CDR. SDRs can be abundant in some residues such as tyrosine, serine, tryptophan, and asparagine.

[0064] Monoclonal antibodies can be obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in small amounts. In contrast to the preparation of polyclonal antibodies that contain different antibodies against different epitopes, each monoclonal antibody is directed against a single epitope.

[0065] As used herein, a compound can be a chimeric antibody where the heavy chain and / or light chain portions are identical or homologous to the corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, but the remainder of the chain is derived from another species or is identical or homologous to the corresponding sequence in an antibody belonging to another antibody class or subclass, or an antigen-binding fragment of such an antibody.

[0066] An antibody fragment or antigen-binding fragment may include a portion of an antibody, for example, the antigen-binding region or variable region of an intact antibody. Non-limiting examples of antibody fragments include Fab, Fab’, F(ab’)2, dimers and trimers of Fab conjugates, Fv, scFv, minibodies, diabodies, triabodies and tetra-bodies, as well as linear antibodies. Fab and Fab’ are antigen-binding fragments that may include the V L and C L domains of the heavy chain linked via a disulfide bond to the V H and C H 1 domain. F(ab’)2 may include two Fabs and Fab’ joined by a disulfide bond. Fv may include V H and V L domains held together by non-covalent interactions. ScFv (single-chain variable fragment) is a fusion protein that may include V H and V L domains. By manipulating the orientation of the V H and V L domains and the length of the linker, different forms of molecules that can be monomers, dimers (diabodies), trimers (triabodies) or tetramers (tetra-bodies) can be created. A minibody is an scFv-C H 3 fusion protein assembled into a bivalent dimer.

[0067] Non-limiting examples of epitopes include amino acids, sugars, lipids, phosphoryl groups and sulfonyl groups. An epitope may have specific three-dimensional structural characteristics and / or specific charge characteristics. An epitope may be conformational or linear.

[0068] For human administration, monoclonal antibodies generated from non-human species can be further optimized by a humanization process that reduces the potential for immunogenicity while maintaining target specificity. The humanization process involves the incorporation of human DNA into the gene sequence of the gene that produces the isolated antibody. The recombinant DNA is cloned and expressed in cells for large-scale production of the new humanized antibody.

[0069] Examples of humanized antibodies are modified chimeric antibodies. Chimeric antibodies can be generated as described above. Chimeric antibodies are further mutated outside the CDRs to replace non-human sequences in the variable regions with homologous human sequences. Another example of a humanized antibody is a CDR-grafted antibody, where non-human CDR sequences are incorporated into the human heavy and light chain variable sequences of a human antibody scaffold to replace the corresponding human CDR sequences.

[0070] Humanized antibodies can be produced in mammalian cells, bioreactors, or transgenic animals such as mice, chickens, sheep, goats, pigs, or marmosets. The transgenic animals can have a corresponding portion of the genome that produces human antibodies inserted into the animal's genome.

[0071] In addition to antibodies and antibody fragments, other antigen-binding compounds can also bind to target molecules. Non-limiting examples of antigen-binding compounds derived from non-antibodies include ankyrin proteins, ankyrin repeat proteins, designed ankyrin repeat proteins (DARPins), affibodies, avimers, adnectins, anticalins, fibronomers, Kunitz domains, notchtins, β-hairpin mimics, and their receptors and derivatives, such as the VEGF receptor, or the VEGF-binding portions of human VEGF receptors 1 and 2.

[0072] A designed ankyrin repeat protein (DARPin) can be a protein scaffold based on ankyrin repeat proteins. A DARPin can include one or more ankyrin repeats that contain a shared sequence and / or a structural motif. Each individual ankyrin repeat can contain a shared sequence and / or a structural motif, even when compared to others and including mutations, substitutions, additions and / or deletions. A DARPin can include, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or more ankyrin repeats. A DARPin can include an N-terminal capping repeat, one or more internal ankyrin repeats, and a C-terminal capping repeat. Each ankyrin repeat can include framework residues and protein-interacting residues. The framework residues can contribute to the structure or folding form, for example, the structure of the ankyrin repeat or the interaction with an adjacent ankyrin repeat. The protein-interacting residues can contribute to the binding of a target molecule, for example, by directly interacting with the target molecule or by stabilizing residues that directly interact in a three-dimensional structure that enables binding.

[0073] In the present disclosure, a compound, an antibody, a fragment or derivative thereof, or another compound that binds to a target molecule can, for example, have a K of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, less than about 10 pM, less than about 9 pM, less than about 8 pM, less than about 7 pM, less than about 6 pM, less than about 5 pM, less than about 4 pM, less than about 3 pM, less than about 2 pM, less than about 1 pM, less than about 900 fM, less than about 800 fM, less than about 700 fM, less than about 600 fM, less than about 500 fM, less than about 400 fM, less than about 300 fM, less than about 200 fM, less than about 100 fM, less than about 90 fM, less than about 80 fM, less than about 70 fM, less than about 60 fM, less than about 50 fM, less than about 40 fM, less than about 30 fM, less than about 20 fM, or less than about 10 fM D and can bind to the target.

[0074] In some embodiments, a compound, antibody, fragment or derivative thereof, or other compound that binds to a target molecule in the present disclosure is, for example, from about 10 fM to about 500 nM, from about 30 fM to about 500 nM, from about 30 fM to about 400 nM, from about 30 fM to about 300 nM, from about 30 fM to about 200 nM, from about 30 fM to about 100 nM, from about 30 fM to about 90 nM, from about 30 fM to about 80 nM, from about 30 fM to about 70 nM, from about 30 fM to about 60 nM, from about 30 fM to about 50 nM, from about 30 fM to about 40 nM, from about 30 fM to about 30 nM, from about 30 fM to about 20 nM, from about 30 fM to about 10 nM, from about 30 fM to about 9 nM, from about 30 fM to about 8 nM, from about 30 fM to about 7 nM, from about 30 fM to about 6 nM, from about 30 fM to about 5 nM, from about 30 fM to about 4 nM, from about 30 fM to about 3 nM, from about 30 fM to about 2 nM, from about 30 fM to about 1 nM, from about 30 fM to about 900 pM, from about 30 fM to about 800 pM, from about 30 fM to about 700 pM, from about 30 fM to about 600 pM, from about 30 fM to about 500 pM, from about 30 fM to about 400 pM, from about 30 fM to about 300 pM, from about 30 fM to about 200 pM, from about 30 fM to about 100 pM, from about 30 fM to about 90 pM, from about 30 fM to about 80 pM, from about 30 fM to about 70 pM, from about 30 fM to about 60 pM, from about 30 fM to about 50 pM, from about 30 fM to about 40 pM, from about 30 fM to about 30 pM, from about 30 fM to about 20 pM, from about 30 fM to about 10 pM, from about 30 fM to about 1 pM, from about 30 fM to about 900 fM, from about 30 fM to about 800 fM, from about 30 fM to about 700 fM, from about 30 fM to about 600 fM, from about 30 fM to about 500 fM, from about 30 fM to about 400 fM, from about 30 fM to about 300 fM, from about 30 fM to about 200 fM, from about 30 fM to about 100 fM, from about 30 fM to about 500 nM, from about 30 fM to about 400 nM, from about 30 fM to about 300 nM, from about 30 fM to about 200 nM, from about 30 fM to about 100 nM, from about 30 fM to about 90 nM, from about 30 fM to about 80 nM, from about 30 fM to about 70 nM, from about 30 fM to about 60 nM, from about 30 fM to about 50 nM, from about 30 fM to about 40 nM, from about 30 fM to about 30 nM, from about 30 fM to about 20 nM, from about 30 fM to about 10 nM, from about 30 fM to about 9 nM, from about 30 fM to about 8 nM, from about 30 fM to about 7 nM, from about 30 fM to about 6 nM, from about 30 fM to about 5 nM, from about 30 fM to about 4 nM, from about 30 fM to about 3 nM, from about 30 fM to about 2 nM, from about 30 fM to about 1 nM, from about 30 fM to about 900 pM, from about 30 fM to about 800 pM,From approximately 30 fM to approximately 700 pM, from approximately 30 fM to approximately 600 pM, from approximately 30 fM to approximately 500 pM, from approximately 30 fM to approximately 400 pM, from approximately 30 fM to approximately 300 pM, from approximately 30 fM to approximately 200 pM, from approximately 30 fM to approximately 100 pM, from approximately 30 fM to approximately 90 pM, from approximately 30 fM to approximately 80 pM, from approximately 30 fM to approximately 70 pM, from approximately 30 fM to approximately 60 pM, from approximately 30 fM to approximately 50 pM, from approximately 30 fM to approximately 40 pM, from approximately 30 fM to approximately 30 pM, from approximately 30 fM to approximately 20 pM, from approximately 30 fM to approximately 10 pM, from approximately 1 pM to approximately 500 nM, from approximately 1 pM to approximately 400 nM, from approximately 1 pM to approximately 300 nM, from approximately 1 pM to approximately 200 nM, from approximately 1 pM to approximately 100 nM, from approximately 1 pM to approximately 90 nM, from approximately 1 pM to approximately 80 nM, from approximately 1 pM to approximately 70 nM, from approximately 1 pM to approximately 60 nM, from approximately 1 pM to approximately 50 nM, from approximately 1 pM to approximately 40 nM, from approximately 1 pM to approximately 30 nM, from approximately 1 pM to approximately 20 nM, from approximately 1 pM to approximately 10 nM, from approximately 1 pM to approximately 9 nM, from approximately 1 pM to approximately 8 nM, from approximately 1 pM to approximately 7 nM, from approximately 1 pM to approximately 6 nM, from approximately 1 pM to approximately 5 nM, from approximately 1 pM to approximately 4 nM, from approximately 1 pM to approximately 3 nM, from approximately 1 pM to approximately 2 nM, from approximately 1 pM to approximately 1 nM, from approximately 1 pM to approximately 900 pM, from approximately 1 pM to approximately 800 pM, from approximately 1 pM to approximately 700 pM, from approximately 1 pM to approximately 600 pM, from approximately 1 pM to approximately 500 pM, from approximately 1 pM to approximately 400 pM, from approximately 1 pM to approximately 300 pM, from approximately 1 pM to approximately 200 pM, from approximately 1 pM to approximately 100 pM, from approximately 1 pM to approximately 90 pM, from approximately 1 pM to approximately 80 pM, from approximately 1 pM to approximately 70 pM, from approximately 1 pM to approximately 60 pM, from approximately 1 pM to approximately 50 pM, from approximately 1 pM to approximately 40 pM, from approximately 1 pM to approximately 30 pM, from approximately 1 pM to approximately 20 pM, from approximately 1 pM to approximately 10 pM, from approximately 100 pM to approximately 500 nM, from approximately 100 pM to approximately 400 nM, from approximately 100 pM to approximately 300 nM, from approximately 100 pM to approximately 200 nM, from approximately 100 pM to approximately 100 nM, from approximately 100 pM to approximately 90 nM, from approximately 100 pM to approximately 80 nM, from approximately 100 pM to approximately 70 nM, from approximately 100 pM to approximately 60 nM, from approximately 100 pM to approximately 50 nM, from approximately 100 pM to approximately 40 nM, from approximately 100 pM to approximately 30 nM, from approximately 100 pM to approximately 20 nM, from approximately 100 pM to approximately 10 nM, from approximately 100 pM to approximately 9 nM, from approximately 100 pM to approximately 8 nM, from approximately 100 pM to approximately 7 nM, from approximately 100 pM to approximately 6 nM, from approximately 100 pM to approximately 5 nM, from approximately 100 pM to approximately 4 nM, from approximately 100 pM to approximately 3 nM, from approximately 100 pM to approximately 2 nM, from approximately 100 pM to approximately 1 nM, from approximately 100 pM to approximately 900 pM, from approximately 100 pM to approximately 800 pM, from approximately 100 pM to approximately 700 pM,K of about 100 pM to about 600 pM, about 100 pM to about 500 pM, about 100 pM to about 400 pM, about 100 pM to about 300 pM, or about 100 pM to about 200 pM D can bind to the target.

[0075] In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 500 fM to about 500 pM D and can bind to HPTP-β (VE-PTP). In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 1 pM to about 500 pM D and can bind to HPTP-β (VE-PTP). In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 60 pM to about 500 pM D and can bind to HPTP-β (VE-PTP). In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 100 pM to about 500 pM D and can bind to HPTP-β (VE-PTP). In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 1 pM to about 300 pM D and can bind to HPTP-β (VE-PTP). In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 1 pM to about 200 pM D and can bind to HPTP-β (VE-PTP). In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 1 pM to about 120 pM D and can bind to HPTP-β (VE-PTP). In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 1 pM to about 70 pM D and can bind to HPTP-β (VE-PTP).

[0076] In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 30 fM to about 900 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 30 fM to about 600 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 30 fM to about 200 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 30 fM to about 30 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 30 fM to about 40 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 30 fM to about 1 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 30 fM to about 200 fM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 1 pM to about 900 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 1 pM to about 600 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 1 pM to about 200 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 1 pM to about 30 pM Dand can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 1 pM to about 40 pM D and can bind to VEGF.

[0077] In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 30 fM to about 2 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 35 fM to about 200 fM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 100 fM to about 2 pM D and can bind to VEGF.

[0078] In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 20 pM to about 1 nM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 20 pM to about 800 pM D and can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 20 pM to about 350 pM D and can bind to VEGF.

[0079] In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 30 fM to about 700 pM D and can bind to VEGF.

[0080] In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 40 fM to about 520 pM DIt can bind to VEGF. In some embodiments, the compounds, antibodies, fragments or derivatives thereof, or other compounds of the present disclosure have a K of about 40 fM to about 110 pM D It can bind to VEGF.

[0081] Multivalent multispecific compounds Antigen-binding compounds can be combined to yield multivalent and / or multispecific compounds. Such multivalent and / or multispecific compounds can have advantages over the parent compounds administered individually. These advantages can include, for example, a simpler dosing regimen, a longer half-life in the subject, and the ability to bind to neighboring target antigens.

[0082] Multispecific antibodies can be generated by several methods. In one method, monospecific antibodies or derivatives thereof can be chemically coupled, for example, via chemical coupling to a conjugate of two IgG antibody units.

[0083] In another method, cloning techniques can be used to add additional antigen-binding domains to a conventional IgG antibody or derivative thereof. The additional antigen-binding domains can be, for example, a single variable domain (sVD), a single-chain variable fragment (scFv), a single-chain Fab, a peptide, an ankyrin protein, ankyrin repeat protein, designed ankyrin repeat protein (DARPin), an affibody, an abimer, an adnectin, an anticalin, a finomer, a Kunitz domain, a knottin, a β-hairpin mimetic, a tetrameric polyethylene oxide cluster peptide, a peptide derived from one or more receptors (e.g., a VEGF receptor, or the VEGF-binding portion of human VEGF receptors 1 and 2), or derivatives thereof.

[0084] Additional antigen-binding domains (e.g., sVD, scFv, single-chain Fab, peptide, ankyrin protein, ankyrin repeat protein, DARPin, affibody, avimer, adnectin, anticalin, fibronomer, Kunitz domain, knottin, β-hairpin mimetic, tetrameric polyethylene oxide cluster peptide, or a peptide derived from one or more receptors) can be added to the N-terminus or C-terminus of the light and / or heavy chains of IgG or Fab, for example via a peptide linker. In some embodiments, the scFv can be added to the C-terminus of the heavy chain of IgG to provide a tetravalent bispecific antibody. The scFv can be added to the C-terminus of the light chain of IgG to provide a tetravalent bispecific antibody. The scFv can be added to the C-terminus of the light chain and the C-terminus of the heavy chain of IgG to provide a hexavalent bispecific antibody. In some embodiments, the DARPin can be added to the C-terminus of the heavy chain of IgG to provide a tetravalent bispecific antibody. The DARPin can be added to the C-terminus of the light chain of IgG to provide a tetravalent bispecific antibody. The DARPin can be added to the C-terminus of the light chain and the C-terminus of the heavy chain of IgG to provide a hexavalent bispecific antibody. Additional examples of bispecific antibodies generated by cloning techniques include (i) DVD-Ig™ (dual variable domain immunoglobulin, tandem ligation of the second V H and V L to the N-terminus of the HC and LC, respectively), (ii) Tandemab (tandem ligation of two V H -C H 1 in a combination of common LCs), (iii) DNL (natural association of two antibodies or antibody fragments immobilized by the DDD (dimerization and docking domain) from PKA (protein kinase A) and the AD (anchoring domain) from A-kinase anchor protein (AKAP), respectively), (iv) LUZ-Y (leucine zipper tethered at the C-terminus of the HC and then proteolytically removed), (v) 2-in-1-IgG (same LC and HC capable of dual recognition), and (vi) mAb 2 (C HExamples include engineered loops in three domains.

[0085] Another class of bispecific antibodies can be characterized by structures having variable domains or scFvs as building blocks. Non-limiting examples of such bispecific antibodies include two V domains joined in tandem, diabodies (VA-VB and VA-VB), heterodimers containing two polypeptide chains encoded in the order of V-V or V-V and a 5-amino acid linker, dsDb (interchain disulfide bond between the V and V of the same antibody), DART (dual affinity retargeting, interchain disulfide bond between two V), scDb (single-chain diabody), tandAb (diabody dimer with a flexible linker in the middle), and two scFvs linked in tandem by an adjustable linker. H domains, diabodies (V L A-V H B and V H A-V L B to V H -V L or V L -V H in the order of, and a 5-amino acid linker, dsDb (interchain disulfide bond between the V and V of the same antibody), DART (dual affinity retargeting, interchain disulfide bond between two V), scDb (single-chain diabody), tandAb (diabody dimer with a flexible linker in the middle), and two scFvs linked in tandem by an adjustable linker. L and V H of the same antibody), DART (dual affinity retargeting, interchain disulfide bond between two V L ), scDb (single-chain diabody), tandAb (diabody dimer with a flexible linker in the middle), and two scFvs linked in tandem by an adjustable linker.

[0086] Another class of bispecific antibodies can contain different antigen-binding fragments while maintaining the basic IgG structure. Such antibodies can include, for example, two separate heavy chains and / or two separate light chains. Various techniques can be used to promote the pairing of desired light and heavy chain combinations rather than random chain association. Non-limiting examples of such techniques include normal light chains, orthogonal Fab interfaces (complementary mutations introduced at the LC and HC interfaces in one Fab and no changes in the other Fab), crossmabs (one Fab V or C1 domain can be switched with the V and C domains of the partner and the other Fab left intact), and the use of replacement with single-chain antigen-binding domains of Fab. Further examples include C H or C H 1 domain can be switched with the V L and C L domains of the partner and the other Fab left intact), and the use of replacement with single-chain antigen-binding domains of Fab. Further examples include C HStrategies can be mentioned that introduce mutations into the 3 domains and promote heterodimerization based on steric or electrostatic complementarity. The "knobs in holes" approach can involve creating "knobs" by replacing threonine at position 366 with bulky tryptophan residues in one heavy chain, and creating corresponding "holes" by triple mutations (T366S, L368A, and Y407V) in the partner heavy chain. Another approach can involve creating alternative human IgG and IgA fragments at C H

[0087] Non-limiting schematic diagrams of bispecific antibodies are provided in Figures 2 to 15.

[0088] Figure 2 provides a schematic diagram of a tetravalent bispecific antibody having a sequence added to the heavy chain C-terminus. The light chain sequence of the IgG isotype antibody unit is represented by "SEQ A". The heavy chain sequence of the IgG isotype antibody unit is represented by "SEQ B". The linker sequence is represented by "SEQ C". The added antigen-binding domain sequence is represented by "SEQ D". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0089] Figure 3 provides a schematic diagram of a tetravalent bispecific antibody having a sequence added to the light chain C-terminus. The light chain sequence of the IgG isotype antibody unit is represented by "SEQ A". The heavy chain sequence of the IgG isotype antibody unit is represented by "SEQ B". The linker sequence is represented by "SEQ C". The added antigen-binding domain sequence is represented by "SEQ D". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0090] ​Figure 4 provides a schematic diagram of a hexavalent bispecific antibody having sequences added to the C-termini of the heavy and light chains. The light chain sequence of the IgG isotype antibody unit is represented by "SEQ A". The heavy chain sequence of the IgG isotype antibody unit is represented by "SEQ B". The linker sequences are represented by "SEQ C" and "SEQ E". The added antigen-binding domain sequences are represented by "SEQ D". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0091] Figure 5 provides a schematic diagram of a hexavalent trispecific antibody having sequences added to the C-termini of the heavy and light chains. The light chain sequence of the IgG isotype antibody unit is represented by "SEQ A". The heavy chain sequence of the IgG isotype antibody unit is represented by "SEQ B". The linker sequences are represented by "SEQ C" and "SEQ E". The added antigen-binding domain sequences are represented by "SEQ D" and "SEQ F". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0092] Figure 6 provides a schematic diagram of a bivalent bispecific antibody having two different heavy chain sequences and two different light chain sequences. The light chain sequences are represented by "SEQ A" and "SEQ D". The heavy chain sequences are represented by "SEQ B" and "SEQ C". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0093] Figure 7 provides a schematic diagram of a trivalent trispecific antibody having two different heavy chain sequences, two different light chain sequences, and a sequence added to the C-terminus of one light chain. The light chain sequences of the IgG isotype antibody units are represented by "SEQ A" and "SEQ D". The heavy chain sequences of the IgG isotype antibody units are represented by "SEQ B" and "SEQ C". The linker sequence is represented by "SEQ E". The added antigen-binding domain sequence is represented by "SEQ F". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0094] Figure 8 provides a schematic diagram of a trivalent trispecific antibody having two different heavy chain sequences, two different light chain sequences, and a sequence added to the C-terminus of one heavy chain. The light chain sequences of the IgG isotype antibody units are represented by "SEQ A" and "SEQ D". The heavy chain sequences of the IgG isotype antibody units are represented by "SEQ B" and "SEQ C". The linker sequence is represented by "SEQ E". The added antigen-binding domain sequence is represented by "SEQ F". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0095] Figure 9 provides a schematic diagram of a tetravalent antibody having two different heavy chain sequences, two different light chain sequences, and sequences added to the C-termini of both light chains. The light chain sequences of the IgG isotype antibody units are represented by "SEQ A" and "SEQ D". The heavy chain sequences of the IgG isotype antibody units are represented by "SEQ B" and "SEQ C". The linker sequences are represented by "SEQ E" and "SEQ F". The added antigen-binding domain sequences are represented by "SEQ G" and "SEQ H". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0096] Figure 10 provides a schematic diagram of a tetravalent antibody having two different heavy chain sequences, two different light chain sequences, and sequences added to both heavy chain C-termini. The light chain sequences of the IgG isotype antibody units are represented by "SEQ A" and "SEQ D". The heavy chain sequences of the IgG isotype antibody units are represented by "SEQ B" and "SEQ C". The linker sequences are represented by "SEQ E" and "SEQ F". The added antigen-binding domain sequences are represented by "SEQ G" and "SEQ H". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0097] Figure 11 provides a schematic diagram of a tetravalent antibody having two different heavy chain sequences, two different light chain sequences, and sequences added cis to one heavy chain C-terminus and one light chain C-terminus. The light chain sequences of the IgG isotype antibody units are represented by "SEQ A" and "SEQ D". The heavy chain sequences of the IgG isotype antibody units are represented by "SEQ B" and "SEQ C". The linker sequences are represented by "SEQ E" and "SEQ F". The added antigen-binding domain sequences are represented by "SEQ G" and "SEQ H". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0098] Figure 12 provides a schematic diagram of a tetravalent antibody having two different heavy chain sequences, two different light chain sequences, and sequences added trans to one heavy chain C-terminus and one light chain C-terminus. The light chain sequences of the IgG isotype antibody units are represented by "SEQ A" and "SEQ D". The heavy chain sequences of the IgG isotype antibody units are represented by "SEQ B" and "SEQ F". The added antigen-binding domain sequences are represented by "SEQ G" and "SEQ H". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0099] Figure 13 provides a schematic diagram of a pentavalent antibody having two different heavy chain sequences, two different light chain sequences, and sequences added to both heavy chain C-termini and one light chain C-terminus. The light chain sequences of the IgG isotype antibody units are represented by "SEQ A" and "SEQ D". The heavy chain sequences of the IgG isotype antibody units are represented by "SEQ B" and "SEQ C". The linker sequences are represented by "SEQ E", "SEQ F" and "SEQ G". The added antigen-binding domain sequences are represented by "SEQ H", "SEQ I" and "SEQ J". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0100] Figure 14 provides a schematic diagram of a pentavalent antibody having two different heavy chain sequences, two different light chain sequences, and sequences added to one heavy chain C-terminus and both light chain C-termini. The light chain sequences of the IgG isotype antibody units are represented by "SEQ A" and "SEQ D". The heavy chain sequences of the IgG isotype antibody units are represented by "SEQ B" and "SEQ C". The linker sequences are represented by "SEQ E", "SEQ F" and "SEQ G". The added antigen-binding domain sequences are represented by "SEQ H", "SEQ I" and "SEQ J". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0101] Figure 15 provides a schematic diagram of a hexavalent antibody having two different heavy chain sequences, two different light chain sequences, and sequences added to the heavy and light chain C-termini. The light chain sequences of the IgG isotype antibody units are represented by "SEQ A" and "SEQ D". The heavy chain sequences of the IgG isotype antibody units are represented by "SEQ B" and "SEQ C". The linker sequences are represented by "SEQ E", "SEQ F", "SEQ G", and "SEQ H". The added antigen-binding domain sequences are represented by "SEQ I", "SEQ J", "SEQ K", and "SEQ L". N and C indicate the N-terminus and C-terminus, respectively. -S-S- indicates a disulfide bond.

[0102] For example, an antigen-binding compound specific for HPTP-β (VE-PTP) can be combined with, for example, an antigen-binding compound specific for an RTK agonist to provide a multivalent multispecific compound that can bind to both HPTP-β (VE-PTP) and the RTK agonist. For example, an antigen-binding compound specific for HPTP-β (VE-PTP) can be combined with an antigen-binding compound specific for VEGF, Ang1, Ang2, BDNF, EGF, FGF, HGF, IGF, insulin, MSP, NGF, NT-3, PDGF, or any combination thereof to provide a multivalent multispecific compound that can bind to both HPTP-β (VE-PTP) and the RTK agonist.

[0103] For example, an antigen-binding compound specific for HPTP-β (VE-PTP) can be combined with, for example, an antigen-binding compound specific for VEGF to provide a multivalent multispecific compound that can bind to both HPTP-β (VE-PTP) and VEGF. A compound that binds to both HPTP-β (VE-PTP) and VEGF can inhibit HPTP-β (VE-PTP), activate Tie2, inhibit the binding of VEGF to VEGFR, and inhibit VEGFR signaling.

[0104] Sequences derived from aflibercept, a recombinant protein containing the VEGF-binding portions of human VEGF receptors 1 and 2, can be combined with antigen-binding compounds specific for HPTP-β (VE-PTP). For example, sequences derived from aflibercept can be fused to the C-terminus of the heavy chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 2). Sequences derived from aflibercept can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 3). Sequences derived from aflibercept can be fused to the C-termini of the light and heavy chains of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent bispecific antibody (Figure 4).

[0105] Sequences derived from ranibizumab, a humanized single-chain antibody fragment (scFv) inhibitor of VEGF that binds to the receptor-binding site of VEGF, can be combined with antigen-binding compounds specific for HPTP-β (VE-PTP). For example, sequences derived from ranibizumab can be fused to the C-terminus of the heavy chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 2). Sequences derived from ranibizumab can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 3). Sequences derived from ranibizumab can be fused to the C-termini of the light and heavy chains of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent bispecific antibody (Figure 4).

[0106] Sequences derived from ranibizumab, a humanized monoclonal antibody fragment (Fab) that binds to VEGF and inhibits its activity, can be combined with antigen-binding compounds specific for HPTP-β (VE-PTP). For example, sequences derived from ranibizumab can be cloned into scFv, and the ranibizumab-derived scFv can be fused to the C-terminus of the heavy chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 2). The ranibizumab-derived scFv can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 3). The ranibizumab-derived scFv can be fused to the C-termini of the light and heavy chains of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent bispecific antibody (Figure 4).

[0107] Sequences derived from bevacizumab, a humanized monoclonal antibody that binds to VEGF and inhibits its activity, can be combined with antigen-binding compounds specific for HPTP-β (VE-PTP). For example, sequences derived from bevacizumab can be cloned into scFv, and the bevacizumab-derived scFv can be fused to the C-terminus of the heavy chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 2). The bevacizumab-derived scFv can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 3). The bevacizumab-derived scFv can be fused to the C-termini of the light and heavy chains of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent bispecific antibody (Figure 4).

[0108] Sequences derived from conbercept, a recombinant protein comprising the VEGF-binding portions of VEGF receptors 1 and 2, can be combined with antigen-binding compounds specific for HPTP-β (VE-PTP). For example, a sequence derived from conbercept can be fused to the C-terminus of the heavy chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 2). A sequence derived from conbercept can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 3). A sequence derived from conbercept can be fused to the C-termini of the light and heavy chains of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent bispecific antibody (Figure 4).

[0109] Sequences derived from abicipar, a VEGF-binding DARPin, can be combined with antigen-binding compounds specific for HPTP-β (VE-PTP). For example, a sequence derived from abicipar can be fused to the C-terminus of the heavy chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 2). A sequence derived from abicipar can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 3). A sequence derived from abicipar can be fused to the C-termini of the light and heavy chains of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent bispecific antibody (Figure 4).

[0110] Antigen-binding compounds specific for HPTP-β (VE-PTP) can be combined with DARPins, or amino acid sequences derived therefrom, such as the amino acid sequence containing any one of SEQ ID NOs: 158 to 217. The amino acid sequence containing any one of SEQ ID NOs: 158 to 217 can be fused to the C-terminus of the heavy chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 2). The amino acid sequence containing any one of SEQ ID NOs: 158 to 217 can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 3). The amino acid sequence containing any one of SEQ ID NOs: 158 to 217 can be fused to the C-termini of the light and heavy chains of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent bispecific antibody (Figure 4).

[0111] A number of VEGF-specific compounds can be combined with antigen-binding compounds specific for HPTP-β (VE-PTP). For example, one binding domain (e.g., an aflibercept-derived sequence) can be fused to the C-terminus of the heavy chain of an anti-HPTP-β (VE-PTP) antibody, and another binding domain (e.g., a bevacizumab-derived sequence) can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent trispecific antibody (Figure 5).

[0112] When different heavy chains are used in the basic four-chain IgG antibody unit (e.g., using the "knob-in-hole" approach), antibodies that are divalent, trivalent, tetravalent, pentavalent or hexavalent and monospecific, bispecific, trispecific, tetraspecific, pentaspecific or hexaspecific can be generated.

[0113] In a non-limiting example, one arm of the antibody unit can contain a CDR specific for HPTP-β (VE-PTP), while the other arm of the antibody unit can contain a CDR specific for VEGF (Figure 6).

[0114] In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), and a binding domain specific for VEGF (e.g., an aflibercept-derived sequence, a brolucizumab-derived sequence, a ranibizumab-derived sequence, or a bevacizumab-derived sequence) can be fused to one light chain to provide a trivalent bispecific antibody (Figure 7).

[0115] In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), and a binding domain specific for VEGF (e.g., an aflibercept-derived sequence, a brolucizumab-derived sequence, a ranibizumab-derived sequence, or a bevacizumab-derived sequence) can be fused to one heavy chain to provide a trivalent bispecific antibody (Figure 8).

[0116] In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), and a binding domain specific for VEGF (e.g., an aflibercept-derived sequence, a brolucizumab-derived sequence, a ranibizumab-derived sequence, or a bevacizumab-derived sequence) can be fused to one light chain, and a second different binding domain specific for VEGF can be fused to the other light chain to provide a tetravalent trispecific antibody (Figure 9).

[0117] In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), and a binding domain specific for VEGF (e.g., an aflibercept-derived sequence, a brolucizumab-derived sequence, a ranibizumab-derived sequence, or a bevacizumab-derived sequence) can be fused to one heavy chain, and a second different binding domain specific for VEGF can be fused to the other heavy chain to provide a tetravalent trispecific antibody (Figure 10).

[0118] In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), and a binding domain specific for VEGF (e.g., an aflibercept-derived sequence, a brolucizumab-derived sequence, a ranibizumab-derived sequence, or a bevacizumab-derived sequence) can be fused to one heavy chain, and a second different binding domain specific for VEGF can be fused in cis to one light chain to provide a tetravalent trispecific antibody (Figure 11).

[0119] In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), and a binding domain specific for VEGF (e.g., an aflibercept-derived sequence, a brolucizumab-derived sequence, a ranibizumab-derived sequence, or a bevacizumab-derived sequence) can be fused to one heavy chain, and a second different binding domain specific for VEGF can be fused in trans to one light chain to provide a tetravalent trispecific antibody (Figure 12).

[0120] In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), and a binding domain specific for VEGF (e.g., an aflibercept-derived sequence, a brolucizumab-derived sequence, a ranibizumab-derived sequence, or a bevacizumab-derived sequence) can be fused to one heavy chain, and a second different binding domain specific for VEGF can be fused to a second heavy chain, and a third different binding domain specific for VEGF can be fused to one light chain to provide a pentavalent tetra-specific antibody (Figure 13).

[0121] In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), and a binding domain specific for VEGF (e.g., an aflibercept-derived sequence, a brolucizumab-derived sequence, a ranibizumab-derived sequence, or a bevacizumab-derived sequence) can be fused to one heavy chain, a second different binding domain specific for VEGF can be fused to one light chain, and a third different binding domain specific for VEGF can be fused to the other light chain to provide a pentavalent tetra-specific antibody (Figure 14).

[0122] In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), and a binding domain specific for VEGF (e.g., an aflibercept-derived sequence, a brolucizumab-derived sequence, a ranibizumab-derived sequence, or a bevacizumab-derived sequence) can be fused to one heavy chain, a second different binding domain specific for VEGF can be fused to the other heavy chain, a third different binding domain specific for VEGF can be fused to one light chain, and a fourth binding domain specific for VEGF can be fused to the other light chain to provide a hexavalent penta-specific antibody (Figure 15).

[0123] In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), and one binding domain (e.g., the aflibercept-derived sequence) can be fused to the C-terminus of one heavy chain, and the second binding domain (e.g., the brentuximab vedotin-derived sequence) can be fused to the C-terminus of the other heavy chain to provide a tetravalent trispecific antibody (Figure 10). In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), the aflibercept-derived sequence can be fused to the C-terminus of one light chain, and the brentuximab vedotin-derived sequence can be fused to the C-terminus of another light chain to provide a tetravalent trispecific antibody (Figure 9). In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), the aflibercept-derived sequence can be fused to the C-terminus of one heavy chain, and the brentuximab vedotin-derived sequence can be fused to the C-terminus of one light chain to provide a tetravalent trispecific antibody (Figures 11 and 12). In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), the aflibercept-derived sequence can be fused to the C-terminus of one heavy chain, the brentuximab vedotin-derived sequence can be fused to the C-terminus of another heavy chain, and the ranibizumab-derived sequence can be fused to the C-termini of both light chains to provide a hexavalent tetra-specific antibody (Figure 15). In a non-limiting example, both antigen-binding fragments of the basic antibody unit can be specific for HPTP-β (VE-PTP), the aflibercept-derived sequence can be fused to the C-terminus of one heavy chain, the brentuximab vedotin-derived sequence can be fused to the C-terminus of another heavy chain, the ranibizumab-derived sequence can be fused to the C-terminus of one light chain, and the bevacizumab-derived sequence can be fused to the C-terminus of another light chain to provide a hexavalent penta-specific antibody (Figure 15).

[0124] For example, an antigen-binding compound specific for HPTP-β (VE-PTP), in combination with other amino acid sequences, can provide a multivalent multispecific compound that, for example, enhances Tie2 activation, enhances Tie2 phosphorylation, enhances Tie2 signaling, reduces VEGFR activation, reduces VEGFR phosphorylation, reduces VEGFR signaling, or a combination thereof.

[0125] An antigen-binding compound specific for HPTP-β (VE-PTP) can be combined with a biomimetic peptide derived from type IV collagen, for example, an amino acid sequence containing SEQ ID NO: 152 or SEQ ID NO: 153. The amino acid sequence containing SEQ ID NO: 152 or SEQ ID NO: 153 can be fused to the C-terminus of the heavy chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 2). The amino acid sequence containing SEQ ID NO: 152 or SEQ ID NO: 153 can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 3). The amino acid sequence containing SEQ ID NO: 152 or SEQ ID NO: 153 can be fused to the C-termini of the light and heavy chains of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent bispecific antibody (Figure 4).

[0126] An antigen-binding compound specific for HPTP-β (VE-PTP) can be combined with an Ang1 mimetic, for example, basculoctide. The sequence derived from basculoctide can be fused to the C-terminus of the heavy chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 2). The sequence derived from basculoctide can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 3). The sequence derived from basculoctide can be fused to the C-termini of the light and heavy chains of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent bispecific antibody (Figure 4).

[0127] For example, an antigen-binding compound specific for HPTP-β (VE-PTP) can be combined with, for example, an antigen-binding compound specific for RTK to provide a multivalent bispecific compound that can bind to both HPTP-β (VE-PTP) and RTK. For example, an antigen-binding compound specific for HPTP-β (VE-PTP) can be combined with an antigen-binding compound specific for VEGFR (e.g., VEGFR2) to provide a multivalent bispecific compound that can bind to both HPTP-β (VE-PTP) and VEGFR.

[0128] A compound that binds to both HPTP-β (VE-PTP) and VEGFR can inhibit HPTP-β (VE-PTP), activate Tie2, inhibit the binding of VEGF to VEGFR, and inhibit VEGFR signaling.

[0129] Sequences derived from ramucirumab, a humanized monoclonal antibody that binds to the extracellular domain of VEGFR2 and inhibits VEGFR2 signaling, can be combined with an antigen-binding compound specific for HPTP-β (VE-PTP). For example, the sequences derived from ramucirumab can be cloned into scFv, and the ramucirumab-derived scFv can be fused to the C-terminus of the heavy chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 2). The ramucirumab-derived scFv can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a tetravalent bispecific antibody (Figure 3). The ramucirumab-derived scFv can be fused to the C-termini of the light and heavy chains of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent bispecific antibody (Figure 4).

[0130] A number of compounds that enhance Tie2 activation, enhance Tie2 phosphorylation, enhance Tie2 signaling, reduce VEGFR activation, reduce VEGFR phosphorylation, reduce VEGFR signaling, or combinations thereof can be combined with antigen-binding compounds specific for HPTP-β (VE-PTP). For example, one binding domain (e.g., a sequence derived from brolucizumab) can be fused to the C-terminus of the heavy chain of an anti-HPTP-β (VE-PTP) antibody, and another binding domain (e.g., a sequence derived from basculizumab) can be fused to the C-terminus of the light chain of an HPTP-β (VE-PTP)-specific antibody to provide a hexavalent trispecific antibody (Figure 5).

[0131] The compounds, antibodies or derivatives thereof disclosed herein can have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, or more domains. Each domain can be any target disclosed herein, e.g., a phosphatase, a phosphatase that modulates Tie2 signaling, a protein tyrosine phosphatase, a receptor-like protein tyrosine phosphatase, a Tie2 modulator, HPTP-β (VE-PTP), the extracellular domain of HPTP-β (VE-PTP), the first FN3 repeat of the extracellular domain of HPTP-β (VE-PTP), a kinase, a tyrosine kinase, a receptor tyrosine kinase, a receptor tyrosine kinase activator, a receptor tyrosine kinase agonist, a growth factor, a growth factor receptor activator, a growth factor receptor agonist, a cystine knot growth factor superfamily member, an angiogenesis promoting factor, a PDGF family member, a VEGF receptor, a VEGF receptor agonist, a VEGF family member, VEGF, VEGF-A, VEGF-B, VEGF-C, VEGF-D, PGF, VEGF 121 , VEGF 145 , VEGF 148 , VEGF 162 , VEGF 165 , VEGF 165b , VEGF183 and VEGF 189 or VEGF 206 can be modulated, bound, antagonized, inhibited or activated. Inhibitors, activators, modulators and binders

[0132] Inhibitors, modulators or binders of HPTP-β (VE-PTP) of the present disclosure can include a compound, recombinant protein, antibody, antigen-binding fragment, variant or derivative thereof, Tie2 peptidomimetic, tetrameric polyethylene oxide cluster peptide, type IV collagen biomimetic peptide, DARPin or derivative thereof, affibody, abimer, adnectin, anticalin, finomer, Kunitz domain, notchkin, β-hairpin mimetic, or a peptide derived from one or more receptors, either alone or in combination with another amino acid sequence or a plurality of other amino acid sequences. The inhibitor, modulator or binder can be subject to modifications, such as enzymatic cleavage or post-translational modification.

[0133] In some embodiments, an inhibitor, modulator, or binder of HPTP-β (VE-PTP) of the present disclosure can inhibit HPTP-β (VE-PTP) by interfering with the interaction between HPTP-β (VE-PTP) and Tie2. In some embodiments, an inhibitor, modulator, or binder of HPTP-β (VE-PTP) of the present disclosure can inhibit HPTP-β (VE-PTP) by stabilizing HPTP-β (VE-PTP) in an inactive conformation. In some embodiments, an inhibitor, modulator, or binder of HPTP-β (VE-PTP) of the present disclosure can inhibit HPTP-β (VE-PTP) by promoting its internalization (e.g., promoting the endocytosis and degradation of HPTP-β (VE-PTP)). In some embodiments, an inhibitor, modulator, or binder of HPTP-β (VE-PTP) of the present disclosure can inhibit HPTP-β (VE-PTP) by blocking the binding of a ligand that activates HPTP-β (VE-PTP). In some embodiments, an inhibitor, modulator, or binder of HPTP-β (VE-PTP) of the present disclosure can inhibit HPTP-β (VE-PTP) by modulating its oligomerization.

[0134] In some embodiments, an inhibitor, modulator, or binder of HPTP-β (VE-PTP) of the present disclosure can bind to a dominant negative isoform of HPTP-β (VE-PTP). The dominant negative isoform may correspond to a form of HPTP-β (VE-PTP) deficiency in phosphatase activity that can compete with endogenous HPTP-β (VE-PTP).

[0135] Inhibitors, modulators or binders of HPTP-β (VE-PTP) of the present disclosure can include multiple HPTP-β (VE-PTP) binding sites. In some embodiments, an inhibitor, modulator or binder of HPTP-β (VE-PTP) can bind to two HPTP-β (VE-PTP) molecules simultaneously, thereby bringing the two HPTP-β (VE-PTP) molecules into proximity. In some embodiments, an inhibitor, modulator or binder of HPTP-β (VE-PTP) can bind to three HPTP-β (VE-PTP) molecules simultaneously, thereby bringing the three HPTP-β (VE-PTP) molecules into proximity. In some embodiments, an inhibitor, modulator or binder of HPTP-β (VE-PTP) can bind to four HPTP-β (VE-PTP) molecules simultaneously, thereby bringing the four HPTP-β (VE-PTP) molecules into proximity.

[0136] Inhibitors, modulators or binders of HPTP-β (VE-PTP) of the present disclosure can conjugate covalently or non-covalently with another moiety or vehicle. The moiety or vehicle can, for example, provide binding specificity for an additional target, inhibit degradation, increase half-life, increase absorption, reduce toxicity, reduce immunogenicity, and / or increase the biological activity of the inhibitor, modulator or binder. Non-limiting examples of moieties to which the inhibitor, modulator or binder can be conjugated include the Fc domain of an immunoglobulin, a peptide, a lipid, a carbohydrate, a dendrimer, an oligosaccharide, a cholesterol group such as a steroid, and a polymer such as polyethylene glycol (PEG), polylysine or dextran.

[0137] The compounds of the present disclosure can be used to target HPTP-β (VE-PTP) and restore Tie2 activity. An inhibitor, modulator or binder of HPTP-β (VE-PTP) can thus be a Tie2 activator. In some embodiments, the compounds of the present disclosure can initiate or inhibit a signaling cascade downstream of HPTP-β (VE-PTP) or Tie2, such as Akt / PI3-K signaling, Rac1 signaling, MAPK / Ras signaling or NF-κB signaling.

[0138] Inhibition of HPTP-β (VE-PTP) can result in vascular stabilization, which can be advantageous, for example, for the treatment of disorders characterized by vascular instability, angiogenesis, neovascularization, vascular leakage and / or edema. For example, inhibition of HPTP-β (VE-PTP) can be advantageous for the treatment of vascular disorders, ocular disorders, cancer, kidney disorders, diabetic complications, and other disorders. In some embodiments, the inhibitors, modulators or binders of HPTP-β (VE-PTP) of the present disclosure can be used, for example, to treat diabetic retinopathy, non-proliferative diabetic retinopathy (NPDR), glaucoma, intraocular pressure, ocular edema, ocular hemorrhage, ocular hypertension, ocular inflammation, ocular neovascularization, ocular vascular leakage, retinal perfusion or retinopathy.

[0139] The activators, modulators or binders of Tie2 of the present disclosure can include, for example, compounds, recombinant proteins, peptides, antibodies, antigen-binding fragments, variants or derivatives thereof, angiopoietin 1 recombinant proteins, Ang1 mimetics, Tie2 agonists, HPTP-β (VE-PTP) phosphatase inhibitors, Tie2 peptidomimetics, tetrameric polyethylene oxide cluster peptides, type IV collagen biomimetic peptides, DARPins or derivatives thereof, affibodies, avimers, adnectins, anticalins, finomers, Kunitz domains, notchtins, β-hairpin mimetics, or peptides derived from one or more receptors, either alone or in combination with another amino acid sequence or multiple other amino acid sequences. The activator, modulator or binder can undergo modifications, for example, enzymatic cleavage or post-translational modification.

[0140] The activators, modulators or binders of Tie2 of the present disclosure can be conjugated covalently or non-covalently with another moiety or vehicle. The moiety or vehicle can, for example, provide binding specificity for an additional target, inhibit degradation, increase half-life, increase absorption, reduce toxicity, reduce immunogenicity, and / or increase the biological activity of the activator, modulator or binder. Non-limiting examples of moieties to which the activator, modulator or binder can be conjugated include the Fc domain of an immunoglobulin, peptides, lipids, carbohydrates, dendrimers, oligosaccharides, cholesterol groups such as steroids, and polymers such as polyethylene glycol (PEG), polylysine or dextran.

[0141] In some embodiments, the compounds of the present disclosure can initiate or inhibit signal transduction cascades downstream of Tie2, such as Akt / PI3-K signal transduction, Rac1 signal transduction, MAPK / Ras signal transduction or NF-κB signal transduction.

[0142] Activation of Tie2 can result in vascular stabilization, which can be advantageous, for example, for the treatment of disorders characterized by vascular instability, angiogenesis, neovascularization, vascular leakage and / or edema. For example, activation of Tie2 can be advantageous for the treatment of eye disorders, cancer, kidney disorders, diabetic complications, and other disorders. In some embodiments, the Tie2 activator, modulator or binder of the present disclosure can be used to treat diabetic retinopathy, non-proliferative diabetic retinopathy (NPDR), glaucoma, intraocular pressure, ocular edema, eye bleeding, ocular hypertension, eye inflammation, ocular neovascularization, ocular vascular leakage, retinal perfusion or retinopathy.

[0143] The VEGF inhibitor, modulator or binder of the present disclosure can comprise a compound, recombinant protein, peptide, antibody, antigen-binding fragment, variant or derivative thereof, DARPin or derivative thereof, affibody, abimer, adnectin, anticalin, finomer, Kunitz domain, notchtin, β-hairpin mimetic, tetrameric polyethylene oxide cluster peptide, type IV collagen biomimetic peptide, or a peptide derived from one or more receptors (e.g., a VEGF receptor, or the VEGF-binding portion of human VEGF receptors 1 and 2), either alone or in combination with another amino acid sequence or a plurality of other amino acid sequences. The inhibitor, modulator or binder can be subject to modifications, for example, enzymatic cleavage or post-translational modification.

[0144] The VEGF inhibitors, modulators or binders of the present disclosure can include multiple VEGF-binding sites. In some embodiments, the VEGF inhibitors, modulators or binders can bind to two VEGF molecules simultaneously, thereby bringing the two VEGF molecules into proximity. In some embodiments, the VEGF inhibitors, modulators or binders can bind to three VEGF molecules simultaneously, thereby bringing the three VEGF molecules into proximity. In some embodiments, the VEGF inhibitors, modulators or binders can bind to four VEGF molecules simultaneously, thereby bringing the four VEGF molecules into proximity.

[0145] The VEGF inhibitors, modulators or binders of the present disclosure can be conjugated covalently or non-covalently with another moiety or vehicle. The moiety or vehicle can, for example, provide binding specificity for an additional target, inhibit degradation, increase half-life, increase absorption, reduce toxicity, reduce immunogenicity, and / or increase the biological activity of the inhibitor, modulator or binder. Non-limiting examples of moieties to which the inhibitor, modulator or binder can be conjugated include the Fc domain of an immunoglobulin, a peptide, a lipid, a carbohydrate, a dendrimer, an oligosaccharide, cholesterol groups such as steroids, and polymers such as polyethylene glycol (PEG), polylysine or dextran.

[0146] The inhibitors, modulators or binders of VEGFR of the present disclosure can include a compound, a recombinant protein, an antibody, an antigen-binding fragment, a variant or a derivative thereof, a tetrameric polyethylene oxide cluster peptide, a type IV collagen biomimetic peptide, a DARPin or a derivative thereof, an affibody, an abimer, an adnectin, an anticalin, a finomer, a Kunitz domain, a notchine, a β-hairpin mimetic, or a peptide derived from one or more receptors, either alone or in combination with another amino acid sequence or a plurality of other amino acid sequences. The inhibitor, modulator or binder can be subject to modifications, such as enzymatic cleavage or post-translational modification.

[0147] The inhibitors, modulators or binders of VEGFR of the present disclosure can include a plurality of VEGFR-binding sites. In some embodiments, the inhibitor, modulator or binder of VEGFR can bind to two VEGFR molecules simultaneously, thereby bringing the two VEGFR molecules into proximity. In some embodiments, the inhibitor, modulator or binder of VEGFR can bind to three VEGFR molecules simultaneously, thereby bringing the three VEGFR molecules into proximity. In some embodiments, the inhibitor, modulator or binder of VEGFR can bind to four VEGFR molecules simultaneously, thereby bringing the four VEGFR molecules into proximity.

[0148] The inhibitors, modulators or binders of VEGFR of the present disclosure can be conjugated covalently or non-covalently with another moiety or vehicle. The moiety or vehicle can, for example, provide binding specificity for an additional target, inhibit degradation, increase half-life, increase absorption, reduce toxicity, reduce immunogenicity, and / or increase the biological activity of the inhibitor, modulator or binder. Non-limiting examples of moieties to which the inhibitor, modulator or binder can be conjugated include the Fc domain of an immunoglobulin, peptides, lipids, carbohydrates, dendrimers, oligosaccharides, cholesterol groups such as steroids, and polymers such as polyethylene glycol (PEG), polylysine or dextran.

[0149] In some embodiments, the inhibitors, modulators or binders of VEGFR of the present disclosure can inhibit VEGFR by stabilizing VEGFR in an inactive conformation. In some embodiments, the inhibitors, modulators or binders of VEGFR of the present disclosure can inhibit VEGFR by promoting internalization of VEGFR (e.g., promoting endocytosis and degradation of VEGFR). In some embodiments, the inhibitors, modulators or binders of VEGFR of the present disclosure can inhibit VEGFR by blocking the binding of a ligand that activates VEGFR (e.g., blocking VEGF ligation of VEGFR). In some embodiments, the inhibitors, modulators or binders of VEGFR of the present disclosure can inhibit VEGFR by modulating oligomerization of VEGFR (e.g., preventing or reducing the likelihood of dimerization or oligomerization of VEGFR).

[0150] The compounds of the present disclosure can be used to interfere with the interaction of VEGF and VEGFR, thereby reducing VEGFR phosphorylation and downstream signaling. In some embodiments, inhibition of VEGF can reduce abnormal angiogenesis, neovascularization, or increased vascular permeability, thereby reducing pathological vascular instability. In some embodiments, inhibition of VEGF can be advantageous for the treatment of disorders characterized by vascular instability, angiogenesis, neovascularization, vascular leakage, and / or edema. For example, inhibition of VEGF can be advantageous for the treatment of vascular disorders, ocular disorders, cancer, kidney disorders, diabetic complications, and other disorders. In some embodiments, the VEGF inhibitors, modulators, or binders of the present disclosure can be used to treat diabetic retinopathy, non-proliferative diabetic retinopathy (NPDR), glaucoma, intraocular pressure, ocular edema, ocular hemorrhage, hypertension, ocular inflammation, ocular neovascularization, ocular vascular leakage, retinal perfusion, or retinopathy. In some embodiments, inhibition of VEGF can reduce cancer. Method

[0151] Promotion of Tie2 signaling and inhibition of VEGFR signaling can result in vascular stabilization, which can be advantageous for the treatment of conditions by vascular components. The compounds disclosed herein can be used, for example, to treat diseases characterized by changes in the vasculature, diseases characterized by decreased Tie2 activation, or diseases characterized by the involvement of VEGF in pathogenesis, whether progressive or non-progressive, acute or chronic.

[0152] In some embodiments, the compounds disclosed herein can be used to treat eye disorders. The compounds disclosed herein can be used, for example, to treat age-related macular degeneration (dry type), age-related macular degeneration (wet type), atopic keratitis, Best disease, blepharitis, blurred vision, choroidal neovascularization, chronic retinal detachment, chronic uveitis / vitreitis, choroiditis, conjunctivitis, overwear of contact lenses, corneal graft neovascularization, corneal graft rejection, corneal neovascularization, cystoid macular edema, diabetic macular edema, diplopia, diabetic retinopathy, diseases associated with rubeosis (angle neovascularization), all forms of proliferative vitreoretinopathy including fibrotic vascular or fibrotic tissue abnormal proliferation-induced diseases, Eales disease, ocular hypertension, epidemic keratoconjunctivitis, floaters, glaucoma, hard yellow exudates within 500 μm from the center of the fovea with adjacent retinal thickening, hyperviscosity syndrome, infectious diseases causing choroiditis, infectious diseases causing retinitis, iris neovascularization, ischemic retinopathy, loss of contrast, telangectasia of the macula , marginal keratolysis, multifocal choroiditis, myopia, neovascular glaucoma, non-proliferative diabetic retinopathy (NPDR), ocular edema, eye bleeding, ocular histoplasmosis, ocular hypertension, eye inflammation, eye ischemia, eye neovascularization, eye trauma, eye vascular leakage, optic pit, papilledema, pars planitis, phlyctenulosis, polypoidal choroidal vasculopathy, complications after laser, proliferative diabetic retinopathy, pterygium sicca keratitis, radial keratotomy, retinal angiomatous proliferation, retinal degeneration, retinal edema (including macular edema), retinal neovascularization, retinal perfusion, retinal thickening within 1 disc diameter from the center of the fovea, retinal thickening within 500 μm from the center of the fovea, retinal vein occlusion (central or branch), retinitis, retinitis pigmentosa, retinopathy, retinopathy of prematurity, scleritis, Stargarts disease, superior limbic keratoconjunctivitis, surgically induced edema, surgically induced neovascularization, tractional peripheral degeneration, trachoma, trauma, uveitis, vasculitis (e.g., central retinal vein occlusion), or other eye diseases associated with eye neovascularization, vascular leakage or retinal edema, or combinations thereof can be used to treat other eye diseases.

[0153] In some embodiments, the compounds disclosed herein can be used to treat complications of diabetes (e.g., comorbidities of diabetes). The compounds disclosed herein can be used, for example, to treat acute glomerulonephritis, acute myocardial infarction, amputation, muscular atrophy, aneurysm, angina pectoris, aortic aneurysm, aortic dissection, atherosclerosis, atherosclerotic cardiovascular disease, atrial fibrillation, autonomic neuropathy, blindness, cardiovascular complications of diabetes, cerebrovascular complications of diabetes, Charcot joint disease, chronic glomerulonephritis, chronic renal failure, claudication, clinically significant macular edema, coronary artery disease, cranial nerve palsy, cystic macular degeneration, cystoid macular edema, diabetic cardiomyopathy, diabetic arthropathy of the hand, diabetic coma, diabetic encephalopathy, diabetic foot wounds, diabetic hyperglycemia, diabetic hyperlipidemia, diabetic hyperosmolar syndrome, diabetic hypoglycemia, diabetic ketoacidosis, diabetic muscle necrosis, diabetic nephropathy, diabetic neuropathy, diabetic eye disease, diabetic peripheral vascular disease, diabetic retinopathy, extensive idiopathic skeletal hyperostosis, Dupuytren's contracture, embolism, end-stage renal disease, erectile dysfunction, Forestier's disease, gangrene, gas gangrene, gastric paresis / diarrhea, heart failure, hyperglycemic emergencies, hypertension, ischemic heart disease, ketoacidosis, lipohypertrophy, metabolic complications of diabetes, mononeuropathy, myocardial infarction, nephritis, nephrosis, nephrotic syndrome, neurogenic bladder, neuropathic arthropathy, neuropathy, orthostatic hypotension, osteoarthritis, osteoporosis, periodontal disease, peripheral vascular disease, polyneuropathy, proliferative retinopathy, renal failure, renal insufficiency, restrictive lung disease, retinal detachment, retinal edema, retinopathy, stroke, thrombosis, transient ischemic attack, ulcer, ventricular fibrillation, vitreous hemorrhage, or combinations thereof.

[0154] In some embodiments, the compounds disclosed herein can be used to treat kidney disorders. The compounds disclosed herein can be used, for example, to treat acute kidney injury, acute proliferative glomerulonephritis, adenine phosphoribosyltransferase deficiency, Alport syndrome, analgesic nephropathy, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, Balkan nephropathy, benign nephrosclerosis, Bright's disease, cardiorenal syndrome, CFHR5 nephropathy, chronic kidney disease, chronic kidney disease - mineral and bone disorder, congenital nephrotic syndrome, renal pyramid syndrome, contrast-induced nephropathy, cystic kidney disease, Dent's disease, diabetic nephropathy, diffuse proliferative nephritis, distal renal tubular acidosis, diuresis, EAST syndrome, end-stage renal disease, epithelial-mesenchymal transition, Epstein syndrome, Fanconi syndrome, Fectner syndrome, focal proliferative nephritis, focal segmental glomerulosclerosis, Frey syndrome, Galloway-Mowat syndrome, Gitelman syndrome, glomerular cystic kidney, glomerulitis, Goodpasture syndrome, high anion gap metabolic acidosis, HIV-associated nephropathy, horseshoe kidney, hydronephrosis, hypertensive kidney disease, IgA nephropathy, interstitial nephritis, juvenile nephronophthisis, kidney cancer, kidney disease, kidney stone disease, Lightwood-Albright syndrome, lupus nephritis, malaria nephropathy, medullary cystic kidney disease, sponge kidney, membranous glomerulonephritis, Mesoamerican nephropathy, milk-alkali syndrome, minimal mesangial glomerulonephritis, multicystic dysplastic kidney, nephritis, nephrocalcinosis, nephrogenic diabetes insipidus, nephromegaly, nephroptosis, nephrosis, nephrotic syndrome, nutcracker syndrome, papillary nephropathy, phosphate nephropathy, polycystic kidney disease, primary hyperoxaluria, proximal renal tubular acidosis, pyelonephritis, pyonephrosis, rapidly progressive glomerulonephritis, renal agenesis, renal angina, renal artery stenosis, renal cysts, renal ischemia, renal osteodystrophy, renal papillary necrosis, renal tubular acidosis, renal vein thrombosis, secondary hypertension, serpiginous fibro-cystic kidney syndrome, shunt nephritis, sickle cell nephropathy, thin basement membrane disease, transplant glomerulitis, tubulointerstitial nephritis and uveitis, ureteritis, uremia, uremic frost, Wunderlich syndrome, or combinations thereof.

[0155] In some embodiments, the compounds disclosed herein can be used to treat cancer. The compounds disclosed herein can be used, for example, to treat acute leukemia, astrocytoma, bile duct cancer (cholangiocarcinoma), bone cancer, breast cancer, brainstem glioma, bronchioloalveolar cell lung cancer, adrenal gland cancer, anal cancer, bladder cancer, endocrine system cancer, esophageal cancer, head and neck cancer, kidney cancer, parathyroid gland cancer, penile cancer, pleural / peritoneal cancer, salivary gland cancer, small intestine cancer, thyroid cancer, ureter cancer, urethral cancer, cervical carcinoma, endometrial carcinoma, fallopian tube carcinoma, renal pelvis carcinoma, vaginal carcinoma, vulvar carcinoma, cervical cancer, chronic leukemia, colon cancer, colorectal cancer, cutaneous melanoma, epithelioma, epithelioma, Ewing sarcoma, gastric cancer, glioblastoma, glioblastoma multiforme, glioma, hematological malignancies, hepatocellular (liver) cancer, hepatoma, Hodgkin's disease, intraocular melanoma, Kaposi sarcoma, lung cancer, lymphoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, muscle cancer, central nervous system (CNS) neoplasms, nerve cancer, non-small cell lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, pediatric malignancies, pituitary adenoma, prostate cancer, rectal cancer, renal cell carcinoma, soft tissue sarcoma, schwannoma, skin cancer, spinal cord axis tumors, squamous cell carcinoma, gastric cancer, synovial sarcoma, testicular cancer, uterine cancer, or tumors and their metastases, or combinations thereof, including resistant versions of any of the above cancers, can be used to treat.

[0156] In some embodiments, the compounds disclosed herein can be used to treat diseases characterized by changes in the vasculature, diseases characterized by decreased Tie2 activation, or diseases characterized by the involvement of VEGF in pathogenesis. The compounds disclosed herein can be used, for example, to treat rosacea, acute lung injury, acute respiratory distress syndrome (ARDS), adhesion formation due to abdominal surgery, hyperlipidemia, albuminuria, allergic edema, allergy, angina, angiofibroma, arteriosclerosis, arterial occlusion, ascites, atheroma, atherosclerotic arteriosclerosis, asthma, aseptic necrosis, bacterial ulcer, Bartonella It can be used to treat bacilliformis infection, Behçet's disease, Burger's disease (thromboangiitis obliterans), cardiac fibrosis, cardiac hypertrophy, cardiomyopathy, carotid artery occlusion, cerebral infarction, chemical burns, COPD, Crohn's disease, cytokine-induced vascular leakage, unstable blood flow, diabetes (including non-insulin-dependent diabetes), functional uterine bleeding, endometriosis, Epstein-Barr virus infection, erectile dysfunction, hirsutism, follicular cysts, foot ulcers (e.g., diabetic foot ulcers), fungal ulcers, giant cell arteritis, glomerulosclerosis, Graves' disease, Hashimoto's autoimmune thyroiditis, angioma, angioendothelioma, hemophilic arthropathy, bleeding, hepatitis C, hereditary hemorrhagic telangiectasia (HHT), herpes simplex infection, herpes zoster infection, hypertension, idiopathic thrombocytopenic purpura, impaired wound healing, inflammatory and infectious processes (e.g., hepatitis, pneumonia, glomerulonephritis), interstitial fibrosis, ischemia, kidney disease, leishmaniasis, leukomalacia, lipid degeneration, liver regeneration, lupus nephritis, Lyme disease, lymphoproliferative disorders, malaria (Plasmodium infection), Mooren's ulcer, multiple sclerosis, mycobacterial infection, myocardial infarction, nasal polyps, nephrosis, nerve inflammation, neuropathy, obesity, osteomyelitis, bone spurs, ovarian hyperstimulation, Paget's disease, pannus proliferation, peripheral arterial disease, peritoneal sclerosis, pemphigoid, polyarteritis, protozoal infection, pseudoxanthoma elasticum, psoriasis, pulmonary hypertension, pyogenic granuloma, renal fibrosis, respiratory distress, rheumatoid arthritis, rickettsial infection, keloid scar, sepsis, sickle cell anemia, Stevens-Johnson disease, stroke, synovitis, systemic lupus erythematosus, syphilis, thyroid hypertrophy, thyroiditis, toxic shock syndrome, toxoplasmosis, trauma, ulcerative colitis, vascular leakage, vascular leakage syndrome, vascular malformations (e.g., Osler-Weber syndrome), venous occlusion, viral hemorrhagic fever (e.g., dengue fever), vitamin A deficiency, warts, or Wegener's granulomatosis, or combinations thereof. Array

[0157] As used herein, the abbreviations for the L-enantiomer and D-enantiomer of amino acids are as follows: alanine (A, Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys); glutamic acid (E, Glu); glutamine (Q, Gln); glycine (G, Gly); histidine (H, His); isoleucine (I, Ile); leucine (L, Leu); lysine (K, Lys); methionine (M, Met); phenylalanine (F, Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr); tryptophan (W, Trp); tyrosine (Y, Tyr); valine (V, Val). In some embodiments, the amino acid is the L-enantiomer. In some embodiments, the amino acid is the D-enantiomer.

[0158] Table 2 shows the amino acid sequences of the humanized V H antibody regions that bind to HPTP-β (VE-PTP). SEQ ID NO: 1 is V H1 and SEQ ID NO: 2 is V H2 and SEQ ID NO: 3 is V H3 and SEQ ID NO: 4 is V H4 as follows. [Table 2]

[0159] Table 3 shows the amino acid sequences of the humanized V L antibody regions that bind to HPTP-β (VE-PTP). SEQ ID NO: 5 is V L1 and SEQ ID NO: 6 is V L2 and SEQ ID NO: 7 is V L3 and SEQ ID NO: 8 is V L4 as follows. [Table 3]

[0160] Each V HThe domain can be synthesized in-frame using a constant domain sequence, such as a human IgG1, IgG2, IgG3, IgG4, IgE, IgA1, IgA2, IgM or IgD sequence. The DNA sequence encoding the full heavy chain sequence can be codon-optimized and verified.

[0161] Exemplary amino acid sequences of the constant domain sequences are provided in Table 4. In some embodiments, the V H domain is synthesized in-frame using the human IgG1 constant domain sequence. The human IgG1 constant domain sequence can include SEQ ID NO: 220. In some embodiments, the V H domain is synthesized in-frame using the human IgG2 constant domain sequence. The human IgG2 constant domain sequence can include SEQ ID NO: 221. In some embodiments, the V H domain is synthesized in-frame using the human IgG3 constant domain sequence. The human IgG3 constant domain sequence can include SEQ ID NO: 222. In some embodiments, the V H domain is synthesized in-frame using the human IgG4 constant domain sequence. The constant domain sequence of the human IgG4 isotype can be mutated at position 228 to proline rather than serine to reduce Fab arm exchange (stabilize the S228P mutation). The amino acid sequence of the IgG4 constant domain having the S228P mutation can include SEQ ID NO: 9. In some embodiments, the V H domain is synthesized in-frame using the human IgE constant domain sequence. The human IgE constant domain sequence can include SEQ ID NO: 223. In some embodiments, the V H domain is synthesized in-frame using the human IgA1 constant domain sequence. The human IgA1 constant domain sequence can include SEQ ID NO: 224. In some embodiments, the V HThe domain is synthesized in-frame using the human IgA2 constant domain sequence. The human IgA2 constant domain sequence can include SEQ ID NO: 225. In some embodiments, the V H The domain is synthesized in-frame using the human IgM constant domain sequence. The human IgM constant domain sequence can include SEQ ID NO: 226. In some embodiments, the V H The domain is synthesized in-frame using the human IgD constant domain sequence. The human IgD constant domain sequence can include SEQ ID NO: 227.

Table 4-1

Table 4-2

Table 4-3

[0162] Each V L The domain can be synthesized in-frame using a human light chain constant domain sequence, such as a kappa (IgK) or lambda (IgL) chain. The full light chain sequence can then be codon-optimized and the DNA sequence verified. Table 5 provides examples of light chain constant domain sequences.

[0163] In some embodiments, the V L The domain is synthesized in-frame using the human IgK constant domain sequence. The human IgK constant domain sequence can include SEQ ID NO: 10. In some embodiments, the V L The domain is synthesized in-frame using the human IgL constant domain sequence. The human IgL constant domain sequence can include SEQ ID NO: 228.

Table 5

[0164] Signal peptides can result in higher protein expression and / or secretion by cells. The following signal peptides can be added to all constructs disclosed herein. Heavy chain signal peptide (SEQ ID NO: 11): MGWTLVFLFLLSVTAGVHS Light chain signal peptide (SEQ ID NO: 12): MVSSAQFLGLLLLCFQGTRC

[0165] Signal peptidase can cleave the signal peptide from the protein, for example, during the secretion process, resulting in a mature protein without the signal peptide sequence. In some embodiments, the signal peptide cleaves the compounds or antibodies of the present disclosure. In some embodiments, the mature compounds or antibodies of the present disclosure do not contain the signal peptide.

[0166] Tables 6 and 7 list the full amino acid sequences of the humanized heavy and light chains that bind to HPTP-β (VE-PTP), respectively. HC1, HC2, HC3, and HC4 are the constant domains of the human IgG4 isotype with a stabilized S228P mutation, each conjugated to V H1 、V H2 、V H3 and V H4 and having an added signal peptide. Amino acids 1-19 of SEQ ID NOs: 13, 14, 15, and 16 are the heavy chain signal peptide (SEQ ID NO: 11). HC1, HC2, HC3, and HC4 without the added signal peptide are also shown (SEQ ID NOs: 246, 247, 248, and 249). In some embodiments, the mature compounds or antibodies of the present disclosure do not contain the signal peptide.

[0167] LC1, LC2, LC3, and LC4 are V L1 、V L2 、V L3 and V L4It is the constant domain of the human IgK isotype, each conjugated to and having an added signal peptide. Amino acids 1-20 of SEQ ID NOs: 17, 18, 19 and 20 are the light chain signal peptide (SEQ ID NO: 12). LC1, LC2, LC3 and LC4 without the added signal peptide are also shown (SEQ ID NOs: 250, 251, 252 and 253). In some embodiments, the mature compounds or antibodies of the present disclosure do not contain a signal peptide.

Table 6-1

Table 6-2

Table 6-3

Table 7-1

Table 7-2

[0168] Any of the V H regions disclosed herein, with or without additional added sequences, can be combined with any of the V L regions disclosed herein to generate a compound that binds to anti-HPTP-β (VE-PTP). For example, the signal peptide and constant region sequences can be added to the V H and V L regions shown in Tables 6 and 7, respectively, and the resulting heavy and light chains can pair in any combination to form an antibody. Table 8 shows 16 possible pairings of HC1-4 and LC1-4 that bind to HPTP-β (VE-PTP). Each transfection and expression of the anti-HPTP-β (VE-PTP) antibodies in Table 8 can be tracked.

Table 8-1

Table 8-2

[0169] Antibodies or antigen-binding compounds specific for HPTP-β (VE-PTP) can form multispecific compounds in combination with antibodies or compounds that activate Tie2, inhibit VEGF, or inhibit VEGFR.

[0170] Table 9 provides the sequences of biomimetic peptides derived from type IV collagen. SEQ ID NO: 152 is AXT-107, a biomimetic peptide derived from type IV collagen that targets integrins and can inhibit VEGFR phosphorylation / activation / signal transduction and promote Tie2 phosphorylation / activation / signal transduction. SEQ ID NO: 153 provides a consensus sequence, where X is any standard amino acid or non-genetically encoded amino acid. In some embodiments, X at position 7 is M, A, or G; X at position 9 is F, A, Y, or G; X at position 0 is M, A, G, D-alanine (dA), or norleucine (Nle); X at position 11 is F, A, Y, G, or 4-chlorophenylalanine (4-CiPhe); and X at positions 12 and 18 are independently selected from 2-aminobutyric acid (Abu), G, S, A, V, T, I, L, or allylglycine (AllylGly). [Table 9]

[0171] Table 10 provides the sequences related to basclotide, a synthetic Ang1 mimetic peptide that acts as a Tie2 agonist and can activate Tie2 signal transduction. SEQ ID NO: 229 provides a synthetic 7-amino acid-long sequence that binds to the Tie2 receptor. SEQ ID NO: 230 provides an 8-amino acid length with a cysteine residue added at the N-terminus, enabling covalent tethering to a polyethylene glycol backbone and resulting in a tetrameric polyethylene oxide cluster version of the peptide. [Table 10]

[0172] Antibodies or antigen-binding compounds specific for HPTP-β (VE-PTP) can form multispecific compounds that bind to HPTP-β (VE-PTP) and VEGF or VEGFR in combination with antibodies or compounds specific for VEGF or VEGFR. Tables 11, 12, 13, 14, 15, and 17 provide examples of the sequences of compounds specific for VEGF. Table 16 provides the sequences of antibodies that bind to VEGFR.

[0173] Table 11 provides the sequences related to aflibercept, which is a recombinant protein containing the VEGF-binding portions of human VEGF receptors 1 and 2 fused to the Fc portion of human IgG1. SEQ ID NO: 21 is the full amino acid sequence of aflibercept. SEQ ID NO: 22 is a truncated sequence containing the VEGF-binding portions of human VEGF receptors 1 and 2 without the Fc portion of IgG.

Table 11

[0174] Table 12 provides the sequence of brolucizumab (SEQ ID NO: 23), a humanized single-chain antibody fragment (scFv) inhibitor of VEGF that binds to the receptor-binding site of VEGF, thereby preventing the interaction of VEGF with VEGFR1 and VEGFR2.

Table 12

[0175] Table 13 provides sequences related to ranibizumab, a humanized monoclonal antibody fragment (Fab) that binds to VEGF and inhibits its activity. SEQ ID NO: 24 is the heavy chain sequence of ranibizumab. SEQ ID NO: 25 is the light chain sequence of ranibizumab. SEQ ID NO: 26 is a truncated sequence of the heavy chain of ranibizumab that can be used in the cloning of single-chain antibody fragments (scFv). SEQ ID NO: 27 is a truncated sequence of the light chain of ranibizumab that can be used in the cloning of single-chain antibody fragments (scFv). SEQ ID NO: 28 is a single-chain antibody fragment (scFv) containing SEQ ID NO: 26, SEQ ID NO: 27, and SEQ ID NO: 33 (linker peptide, underlined). [Table 13]

[0176] Table 14 provides sequences related to bevacizumab, a humanized monoclonal antibody that binds to VEGF and inhibits its activity. SEQ ID NO: 29 is the heavy chain sequence of bevacizumab. SEQ ID NO: 30 is the light chain sequence of bevacizumab. [Table 14-1] [Table 14-2]

[0177] Table 15 provides sequences related to conbercept, a recombinant protein containing extracellular domains derived from VEGF receptors 1 and 2 fused to the Fc portion of human IgG1. SEQ ID NO: 154 is the full amino acid sequence of conbercept. SEQ ID NO: 155 is a truncated sequence containing the sequences derived from VEGF receptors 1 and 2 without the Fc portion of IgG. [Table 15-1] [Table 15-2]

[0178] SEQ ID NO: 16 provides a sequence related to ramucirumab, a humanized monoclonal antibody that binds to the extracellular domain of VEGFR2 and inhibits VEGFR2 signaling. SEQ ID NO: 156 is the heavy chain sequence of ramucirumab. SEQ ID NO: 157 is the light chain sequence of ramucirumab.

Table 16

[0179] Table 17 provides DARPins and DARPin-derived amino acid sequences that bind to VEGF and inhibit VEGFR signaling. SEQ ID NOs: 158 - 168 contain designed ankyrin repeats with binding specificity for VEGF. SEQ ID NO: 169 contains a designed ankyrin repeat with binding specificity for VEGF and a designed ankyrin repeat with binding specificity for serum albumin. SEQ ID NO: 170 contains a designed ankyrin repeat with binding specificity for VEGF, a designed ankyrin repeat with binding specificity for hepatocyte growth factor, and a designed ankyrin repeat with binding specificity for serum albumin. SEQ ID NOs: 171 - 177 contain designed ankyrin repeats with binding specificity for VEGF. SEQ ID NO: 173 provides the sequence of abicipar, which contains a designed ankyrin repeat with binding specificity for VEGF. SEQ ID NOs: 178 - 190 provide individual designed ankyrin repeat sequence motifs with binding specificity for VEGF, where X represents any amino acid. SEQ ID NOs: 191 - 217 contain designed ankyrin repeats with binding specificity for VEGF.

Table 17-1

Table 17-2

Table 17-3

Table 17-4

Table 17-5

Table 17-6

[0180] Antibodies or antigen-binding compounds specific for VEGF can be combined with antibodies or antigen-binding compounds specific for HPTP-β (VE-PTP) to form multispecific compounds such as bispecific compounds that bind to VEGF and HPTP-β (VE-PTP). Any compound according to the present disclosure that is specific for VEGF can be combined with any compound according to the present disclosure that is specific for HPTP-β (VE-PTP). Any of the compounds according to the present disclosure that are specific for VEGF or HPTP-β (VE-PTP) can be modified if necessary for the generation of multispecific compounds. Non-limiting examples of modifications necessary for the generation of multispecific compounds include addition of amino acid residues, removal of amino acid residues, replacement of amino acid residues, and use of linkers. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues can be added to the N-terminus and / or C-terminus of the sequences disclosed herein, and the resulting sequences can be used in the generation of multispecific constructs. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more residues can be removed from the N-terminus and / or C-terminus of the sequences disclosed herein, and the remaining sequences can be used in the generation of multispecific constructs. For example, N-terminal and / or C-terminal residues can be removed from SEQ ID NO: 173 (e.g., to give SEQ ID NO: 244), and the truncated sequence can be used in a multispecific construct. In some embodiments, the sequences in any of SEQ ID NOs: 13-20 or 246-253 can be modified. For example, one or more C-terminal residues can be removed (e.g., the C-terminal lysine can be removed from any of SEQ ID NOs: 13-16 or 246-249, and the remaining residues (residues 1-467) can be used in a multispecific construct).

[0181] The compounds described herein can include a linker between different domains of the compound. The linker can be a chemical bond, e.g., a covalent or non-covalent bond. The linkers described herein can include flexible linkers or rigid linkers.

[0182] The linkers of the present disclosure can include chemical linkers. For example, two amino acid sequences of the present disclosure can be linked together by a chemical linker. Each chemical linker of the present disclosure can be alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene or heteroarylene, any of which can be optionally substituted. In some embodiments, the chemical linkers of the present disclosure can be esters, ethers, amides, thioethers or polyethylene glycol (PEG). In some embodiments, the linker can reverse the order of the amino acid sequences in the compound, e.g., such that the amino acid sequences linked by the linker are head-to-head rather than head-to-tail. Non-limiting examples of such linkers include diesters of dicarboxylic acids such as oxalyl diester, malonyl diester, succinyl diester, glutaryl diester, adipyl diester, pimeloyl diester, fumaroyl diester, maleoyl diester, phthalyl diester, isophthalyl diester and terephthalyl diester. Non-limiting examples of such linkers include diamides of dicarboxylic acids such as oxalyl diamide, malonyl diamide, succinyl diamide, glutaryl diamide, adipyl diamide, pimeloyl diamide, fumaroyl diamide, maleoyl diamide, phthalyl diamide, isophthalyl diamide and terephthalyl diamide. Non-limiting examples of such linkers include diamides of diamino linkers such as ethylenediamine, 1,2-di(methylamino)ethane, 1,3-diaminopropane, 1,3-di(methylamino)propane, 1,4-di(methylamino)butane, 1,5-di(methylamino)pentane, 1,6-di(methylamino)hexane and pipyrizine.

[0183] Non-limiting examples of optional substituents include hydroxyl group, sulfhydryl group, halogen, amino group, nitro group, nitroso group, cyano group, azide group, sulfoxide group, sulfone group, sulfonamide group, carboxyl group, carboxyaldehyde group, imine group, alkyl group, haloalkyl group, alkenyl group, haloalkenyl group, alkynyl group, haloalkynyl group, alkoxy group, aryl group, aryloxy group, aralkyl group, arylalkoxy group, heterocyclyl group, acyl group, acyloxy group, carbamate group, amide group, ureido group, epoxy group and ester group.

[0184] The linker can be a peptide. The linker can include a linker sequence, for example, a linker peptide sequence. The linker sequence can be, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 51, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70 amino acid residues in length.

[0185] A flexible linker can have a sequence containing stretches of glycine and serine residues. The small-sized glycine and serine residues provide flexibility and allow mobility of the linked functional domains. Incorporation of serine or threonine can maintain the stability of the linker in aqueous solution by forming hydrogen bonds with water molecules, thereby reducing unwanted interactions between the linker and the protein moiety.

[0186] A flexible linker can also contain additional amino acids such as threonine and alanine to maintain flexibility, and polar amino acids such as lysine and glutamine to improve solubility.

[0187] The flexible linker can include repeats of SEQ ID NO: 42 (GGGS), for example, SEQ ID NOs: 42 to 55. The flexible linker can include repeats of SEQ ID NO: 31 (GGGGS), for example, SEQ ID NOs: 31 to 41. Some other types of flexible linkers including SEQ ID NO: 59 (KESGSVSSEQLAQFRSLD) and SEQ ID NO: 60 (EGKSSGSGSESKST) can also be used. The linker of SEQ ID NO: 61 (GSAGSAAGSGEF) can also be used, where large hydrophobic residues are minimized to maintain good solubility in aqueous solution. The length of the flexible linker can be adjusted to allow proper folding or to achieve optimal biological activity of the fusion protein.

[0188] The rigid linker can have, for example, an alpha helix structure. The alpha helical rigid linker can act as a spacer between protein domains. The rigid linker can include repeats of SEQ ID NO: 62 (EAAAK), for example, SEQ ID NOs: 62 to 66. The rigid linker can include repeats of SEQ ID NO: 67 (EAAAR), for example, SEQ ID NOs: 67 to 72. The rigid linker can have a proline-rich sequence (XP)n, where X represents alanine, lysine, glutamine or any amino acid. The presence of proline in the non-helical linker can increase rigidity and allow effective separation of protein domains.

[0189] The linker can include any of the sequences disclosed in Table 18, which can be used to link any part of the compounds disclosed herein to any part of another compound disclosed herein.

Table 18-1

Table 18-2

Table 18-3

[0190] The VEGF-binding and VEGFR-binding compounds described in Tables 11, 12, 13, 14, 15, 16 and 17 can be combined with the HPTP-β (VE-PTP)-binding compounds described in Tables 2, 3, 6, 7 and 8.

[0191] Any of the 16 antibodies described in Table 8 can be combined with aflibercept or an aflibercept-related sequence to yield a bispecific antibody. Non-limiting schematic examples are presented in Figures 2, 3 and 4. For example, SEQ ID NO: 22 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 of antibody HC2:LC1 to yield a tetravalent bispecific antibody with SEQ ID NO: 22 added to the heavy chain of HC2:LC1 (Figure 2). SEQ ID NO: 22 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to yield a tetravalent bispecific antibody with SEQ ID NO: 22 added to the light chain of HC2:LC1 (Figure 3). SEQ ID NO: 22 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 and SEQ ID NO: 22 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to yield a hexavalent bispecific antibody with SEQ ID NO: 22 added to the heavy and light chains of HC2:LC1 (Figure 4).

[0192] Any of the 16 antibodies described in Table 8 can, in combination with ranibizumab or a ranibizumab-related sequence, give rise to a bispecific antibody. Non-limiting schematic examples are presented in FIGS. 2, 3, and 4. For example, SEQ ID NO: 23 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 of antibody HC2:LC1 to yield a tetravalent bispecific antibody with SEQ ID NO: 23 added to the heavy chain of HC2:LC1 (FIG. 2). SEQ ID NO: 23 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to yield a tetravalent bispecific antibody with SEQ ID NO: 23 added to the light chain of HC2:LC1 (FIG. 3). SEQ ID NO: 23 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247, and SEQ ID NO: 23 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to yield a hexavalent bispecific antibody with SEQ ID NO: 23 added to both the heavy and light chains of HC2:LC1 (FIG. 4).

[0193] Any of the 16 antibodies described in Table 8 can, in combination with bevacizumab or a bevacizumab-related sequence, give rise to a bispecific antibody. Non-limiting schematic examples are presented in FIGS. 2, 3, and 4. For example, SEQ ID NO: 28 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 of antibody HC2:LC1 to yield a tetravalent bispecific antibody with SEQ ID NO: 28 added to the heavy chain of HC2:LC1 (FIG. 2). SEQ ID NO: 28 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to yield a tetravalent bispecific antibody with SEQ ID NO: 28 added to the light chain of HC2:LC1 (FIG. 3). SEQ ID NO: 28 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247, and SEQ ID NO: 28 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to yield a hexavalent bispecific antibody with SEQ ID NO: 28 added to both the heavy and light chains of HC2:LC1 (FIG. 4).

[0194] Any of the 16 antibodies described in Table 8 can, in combination with bevacizumab or a bevacizumab-related sequence, give rise to a bispecific antibody. Non-limiting schematic examples are presented in FIGS. 2, 3, and 4. For example, the antigen-binding scFv of bevacizumab could be generated as demonstrated for ranibizumab in Table 13. The bevacizumab-derived antigen-binding scFv can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 of antibody HC2:LC1 to give rise to a tetravalent bispecific antibody with the bevacizumab-derived antigen-binding scFv added to the heavy chain of HC2:LC1 (FIG. 2). The bevacizumab-derived antigen-binding scFv can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to give rise to a tetravalent bispecific antibody with the bevacizumab-derived antigen-binding scFv added to the light chain of HC2:LC1 (FIG. 3). The bevacizumab-derived antigen-binding scFv can be added onto SEQ ID NO: 14 or SEQ ID NO: 247, and the bevacizumab-derived antigen-binding scFv can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to give rise to a hexavalent bispecific antibody with the bevacizumab-derived antigen-binding scFv added to the heavy and light chains of HC2:LC1 (FIG. 4).

[0195] Any one of the 16 antibodies described in Table 8 can, in combination with abicipar or an abicipar-related sequence, give rise to a bispecific antibody. Non-limiting schematic examples are presented in FIGS. 2, 3, and 4. For example, SEQ ID NO: 173 or SEQ ID NO: 244 can be added onto SEQ ID NO: 14, SEQ ID NO: 247, residues 1 to 467 of SEQ ID NO: 14, or residues 1 to 467 of SEQ ID NO: 247 of antibody HC2:LC1 to give rise to a tetravalent bispecific antibody in which SEQ ID NO: 173 or SEQ ID NO: 244 is added to the heavy chain of HC2:LC1 (FIG. 2). SEQ ID NO: 173 or SEQ ID NO: 244 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to give rise to a tetravalent bispecific antibody in which SEQ ID NO: 173 or SEQ ID NO: 244 is added to the light chain of HC2:LC1 (FIG. 3). SEQ ID NO: 173 or SEQ ID NO: 244 can be added onto SEQ ID NO: 14, SEQ ID NO: 247, residues 1 to 467 of SEQ ID NO: 14, or residues 1 to 467 of SEQ ID NO: 247, and SEQ ID NO: 173 or SEQ ID NO: 244 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to give rise to a hexavalent bispecific antibody in which SEQ ID NO: 173 or SEQ ID NO: 244 is added to the heavy and light chains of HC2:LC1 (FIG. 4).

[0196] Any one of the 16 antibodies described in Table 8 can, in combination with conbercept or a conbercept-related sequence, give rise to a bispecific antibody. Non-limiting schematic examples are presented in FIGS. 2, 3, and 4. For example, SEQ ID NO: 155 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 of antibody HC2:LC1 to give rise to a tetravalent bispecific antibody in which SEQ ID NO: 155 is added to the heavy chain of HC2:LC1 (FIG. 2). SEQ ID NO: 155 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to give rise to a tetravalent bispecific antibody in which SEQ ID NO: 155 is added to the light chain of HC2:LC1 (FIG. 3). SEQ ID NO: 155 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247, and SEQ ID NO: 155 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to give rise to a hexavalent bispecific antibody in which SEQ ID NO: 155 is added to the heavy and light chains of HC2:LC1 (FIG. 4).

[0197] Any of the 16 antibodies described in Table 8 can give rise to bispecific antibodies in combination with ramucirumab or ramucirumab-related sequences. Non-limiting schematic examples are presented in Figures 2, 3, and 4. For example, the antigen-binding scFv of ramucirumab could be generated as demonstrated for ranibizumab in Table 13. The ramucirumab-derived antigen-binding scFv could be added onto SEQ ID NO: 14 or SEQ ID NO: 247 of antibody HC2:LC1 to give rise to a tetravalent bispecific antibody with the ramucirumab-derived antigen-binding scFv added to the heavy chain of HC2:LC1 (Figure 2). The ramucirumab-derived antigen-binding scFv could be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to give rise to a tetravalent bispecific antibody with the ramucirumab-derived antigen-binding scFv added to the light chain of HC2:LC1 (Figure 3). The ramucirumab-derived antigen-binding scFv could be added onto SEQ ID NO: 14 or SEQ ID NO: 247, and the ramucirumab-derived antigen-binding scFv could be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to give rise to a hexavalent bispecific antibody with the ramucirumab-derived antigen-binding scFv added to both the heavy and light chains of HC2:LC1 (Figure 4).

[0198] Any of the 16 antibodies described in Table 8 can give rise to a multispecific antibody in combination with a DARPin, a DARPin repeat, or a sequence derived therefrom. Non-limiting schematic examples are presented in FIGS. 2, 3, and 4. For example, an amino acid sequence containing any of SEQ ID NOs: 158-217 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 of antibody HC2:LC1 to give rise to a tetravalent bispecific antibody with an amino acid sequence containing any of SEQ ID NOs: 158-217 added to the heavy chain of HC2:LC1 (FIG. 2). An amino acid sequence containing any of SEQ ID NOs: 158-217 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to give rise to a tetravalent bispecific antibody with an amino acid sequence containing any of SEQ ID NOs: 158-217 added to the light chain of HC2:LC1 (FIG. 3). An amino acid sequence containing any of SEQ ID NOs: 158-217 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 and onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to give rise to a hexavalent bispecific antibody with an amino acid sequence containing any of SEQ ID NOs: 158-217 added to the heavy and light chains of HC2:LC1 (FIG. 4).

[0199] The Tie2 activating compounds described in Tables 9 and 10 can be combined with the HPTP-β (VE-PTP) binding compounds described in Tables 2, 3, 6, 7, and 8.

[0200] Any of the 16 antibodies described in Table 8 can generate a multispecific antibody in combination with a biomimetic peptide sequence derived from type IV collagen. Non-limiting schematic examples are presented in FIGS. 2, 3, and 4. For example, an amino acid sequence containing SEQ ID NO: 152 or SEQ ID NO: 153 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 of antibody HC2:LC1 to generate a tetravalent bispecific antibody with an amino acid sequence containing SEQ ID NO: 152 or SEQ ID NO: 153 added to the heavy chain of HC2:LC1 (FIG. 2). The amino acid sequence containing SEQ ID NO: 152 or SEQ ID NO: 153 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to generate a tetravalent bispecific antibody with an amino acid sequence containing SEQ ID NO: 152 or SEQ ID NO: 153 added to the light chain of HC2:LC1 (FIG. 3). The amino acid sequence containing SEQ ID NO: 152 or SEQ ID NO: 153 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 and SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to generate a hexavalent bispecific antibody with an amino acid sequence containing SEQ ID NO: 152 or SEQ ID NO: 153 added to the heavy and light chains of HC2:LC1 (FIG. 4).

[0201] Any of the 16 antibodies described in Table 8 can generate a multispecific antibody in combination with an Ang2 mimetic or a sequence derived therefrom. Non-limiting schematic examples are presented in FIGS. 2, 3, and 4. For example, an amino acid sequence containing any of SEQ ID NOs: 229-230 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 of antibody HC2:LC1 to generate a tetravalent bispecific antibody with an amino acid sequence containing any of SEQ ID NOs: 229-230 added to the heavy chain of HC2:LC1 (FIG. 2). The amino acid sequence containing any of SEQ ID NOs: 229-230 can be added onto SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to generate a tetravalent bispecific antibody with an amino acid sequence containing any of SEQ ID NOs: 229-230 added to the light chain of HC2:LC1 (FIG. 3). The amino acid sequence containing any of SEQ ID NOs: 229-230 can be added onto SEQ ID NO: 14 or SEQ ID NO: 247 and SEQ ID NO: 17 or SEQ ID NO: 250 of antibody HC2:LC1 to generate a hexavalent bispecific antibody with an amino acid sequence containing any of SEQ ID NOs: 229-230 added to the heavy and light chains of HC2:LC1 (FIG. 4).

[0202] The Tie2 activating compounds described in Tables 9 and 10 can, in combination with the VEGF-binding and VEGFR-binding compounds described in Tables 11, 12, 13, 14, 15, 16 and 17, give rise to multispecific compounds.

[0203] Any of the compounds in the present disclosure, for example, the multispecific fusion constructs described above, can be modified as necessary to promote the folding or biological activity of the desired protein. CDR

[0204] The sequences in the present disclosure can include complementarity determining regions (CDRs). The CDRs can be identified by the Kabat method, the Chothia method, the IMGT method or the Paratome method. The CDRs of the sequences herein can be, for example, 0 to 91 residues in length, 0 to 25 residues in length, 5 to 14 residues in length, about 0 residues in length, about 1 residue in length, about 2 residues in length, about 3 residues in length, about 4 residues in length, about 5 residues in length, about 6 residues in length, about 7 residues in length, about 8 residues in length, about 9 residues in length, about 10 residues in length, about 11 residues in length, about 12 residues in length, about 13 residues in length, about 14 residues in length, about 15 residues in length, about 16 residues in length, about 17 residues in length, about 18 residues in length, about 19 residues in length, about 20 residues in length, about 21 residues in length, about 22 residues in length, about 23 residues in length, about 24 residues in length or about 25 residues in length.

[0205] The compounds of the present disclosure having binding specificity for HPTP-β (VE-PTP) or the ability to modulate HPTP-β (VE-PTP) can include, for example, any of the CDRs in Tables 19, 20, 21, 22, 23 or 24.

[0206] Table 19 provides non-limiting examples of HCDR1 sequences specific for HPTP-β (VE-PTP).

Table 19

[0207] Table 20 provides non-limiting examples of HCDR2 sequences specific for HPTP-β (VE-PTP). [Table 20]

[0208] Table 21 provides non-limiting examples of HCDR3 sequences specific for HPTP-β (VE-PTP). [Table 21]

[0209] Table 22 provides non-limiting examples of LCDR1 sequences specific for HPTP-β (VE-PTP). [Table 22-1] [Table 22-2]

[0210] Table 23 provides non-limiting examples of LCDR2 sequences specific for HPTP-β (VE-PTP). [Table 23]

[0211] Table 24 provides non-limiting examples of LCDR3 sequences specific for HPTP-β (VE-PTP). [Table 24]

[0212] Compounds of the present disclosure having binding specificity for VEGF or the ability to modulate VEGF can include any of the CDRs in Table 25, Table 26, Table 27, Table 28, Table 29 or Table 30.

[0213] Table 25 provides non-limiting examples of HCDR1 sequences specific for VEGF. [Table 25]

[0214] Table 26 provides non-limiting examples of HCDR2 sequences specific for VEGF. [Table 26]

[0215] Table 27 provides non-limiting examples of HCDR3 sequences specific for VEGF. [Table 27]

[0216] Table 28 provides non-limiting examples of LCDR1 sequences specific for VEGF. [Table 28]

[0217] Table 29 provides non-limiting examples of LCDR2 sequences specific for VEGF. [Table 29-1] [Table 29-2]

[0218] Table 30 provides non-limiting examples of LCDR3 sequences specific for VEGF. [Table 30]

[0219] Table 31 provides the aflibercept-derived sequences corresponding to the D2 domain of human VEGF receptor 1 (SEQ ID NO: 147) and the D3 domain of human VEGF receptor 2 (SEQ ID NO: 148). [Table 31]

[0220] Table 32 provides Abisipal-derived sequences. SEQ ID NOs: 233 to 236 correspond to ankyrin repeats within Abisipal. SEQ ID NOs: 237 to 242 provide consensus sequences for VEGF-binding ankyrin repeats. In SEQ ID NO: 237, X1 is K, T, or Y; X2 is N or M; X3 is T or F; X4 is S or A; X5 is H or R; X6 is A, Y, H, or N; X7 is A or T. In SEQ ID NO: 238, X1 is K, M, N, R, or V; X2 is Y, H, M, or V; X3 is F, L, M, or V; X4 is R, H, V, A, K, or N; X5 is F, D, H, T, Y, M, or K; X6 is A, H, N, or Y. In SEQ ID NO: 239, X1 is L, S, or T; X2 is G, S, or C; X3 is S or A; X4 is Q, S, M, or N; X5 is L, M, or Q; X6 is A, H, N, Y, or D. In SEQ ID NO: 240, X1 is K, S, I, N, T, or V; X2 is K, N, W, A, H, M, Q, or S; X3 is F, Q, L, H, or V; X4 is F or T; X5 is Q or H; X6 is Y or S; X7 is N, H, Y, or M; X8 is A, H, N, or Y. In SEQ ID NO: 241, X1 is A, N, R, V, Y, E, H, I, K, L, Q, S, or T; X2 is S, A, N, R, D, F, L, P, T, or Y; X3 is T, V, S, A, L, or F; X4 is W, F, or H; X5 is P, I, A, L, S, T, V, or Y; X6 is W, F, I, L, T, or V; X7 is L or P; X8 is A, H, N, or Y. In SEQ ID NO: 242, X1 is H, Q, A, K, R, D, I, L, M, N, V, or Y; X2 is Y, F, or H; X3 is Q, F, or T; X4 is W, M, G, H, N, or T; X5 is T, A, M, L, or V; X6 is I, L, V, D, or T; X7 is A, H, N, or Y. SEQ ID NO: 244 provides a truncated sequence derived from an Abisipal containing a designed ankyrin repeat with binding specificity for VEGF.

Table 32

[0221] The sequences of the compounds in this specification may have at least about 70% identity, at least about 71% identity, at least about 72% identity, at least about 73% identity, at least about 74% identity, at least about 75% identity, at least about 76% identity, at least about 77% identity, at least about 78% identity, at least about 79% identity, at least about 80% identity, at least about 81% identity, at least about 82% identity, at least about 83% identity, at least about 84% identity, at least about 85% identity, at least about 86% identity, at least about 87% identity, at least about 88% identity, at least about 89% identity, at least about 90% identity, at least about 91% identity, at least about 92% identity, at least about 93% identity, at least about 94% identity, at least about 95% identity, at least about 96% identity, at least about 97% identity, at least about 98% identity, at least about 99% identity, at least about 99.1% identity, at least about 99.2% identity, at least about 99.3% identity, at least about 99.4% identity, at least about 99.5% identity, at least about 99.6% identity, at least about 99.7% identity, at least about 99.8% identity, or at least about 99.9% identity with the amino acid sequences provided in this specification.

[0222] Homology between two or more sequences can be determined using a variety of methods and software programs such as NCBI BLAST, Clustal W, MAFFT, Clustal Omega, AlignMe, Praline or another suitable method or algorithm. Pharmaceutical composition

[0223] The pharmaceutical compositions of the present disclosure can be a combination of any pharmaceutical compound described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and / or excipients. The pharmaceutical compositions facilitate the administration of the compounds to an organism.

[0224] The pharmaceutical preparations for administration can contain an aqueous solution of the active compound in water-soluble form. Suspensions of the active compound can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension such as sodium carboxymethylcellulose, sorbitol or dextran. The suspension can also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of highly concentrated solutions. The active ingredient can be in powder form for constitution with a suitable vehicle, for example sterile pyrogen-free water, before use.

[0225] In the methods of treatment or uses provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal such as a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and associated health of the subject, the potency of the compound used and other factors.

[0226] The pharmaceutical composition can be formulated using one or more physiologically acceptable carriers that include excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation. The formulation can be modified according to the selected route of administration. The pharmaceutical composition containing the compounds described herein can be manufactured, for example, by processes such as mixing, dissolving, emulsifying, encapsulating, enclosing or compressing.

[0227] The pharmaceutical composition can contain at least one pharmaceutically acceptable carrier, diluent or excipient, and the compounds described herein in the form of the free base or a pharmaceutically acceptable salt. The pharmaceutical composition can contain solubilizing agents, stabilizers, isotonicity enhancers, buffers and preservatives.

[0228] The method for the preparation of a composition containing the compounds described herein involves formulating the compound with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid composition. Examples of solid compositions include, for example, powders, tablets, dispersible granules, capsules and cachets. Examples of liquid compositions include, for example, solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles or nanoparticles containing the compounds disclosed herein. Examples of semi-solid compositions include, for example, gels, suspensions and creams. The composition can be in the form of a liquid solution or suspension, a suitable solid form for a solution or suspension in a liquid prior to use, or an emulsion. These compositions can also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers and other pharmaceutically acceptable additives.

[0229] Non-limiting examples of dosage forms suitable for use in the present disclosure include liquids, powders, gels, nanosuspensions, nanoparticles, microgels, aqueous or oily suspensions, emulsions, and any combination thereof.

[0230] Non-limiting examples of pharmaceutically acceptable excipients suitable for use in the present disclosure include binders, disintegrants, anti-adhesion agents, antistatic agents, surfactants, antioxidants, coating agents, colorants, plasticizers, preservatives, suspending agents, emulsifying agents, antibacterial agents, spheronizing agents, and any combination thereof.

[0231] The compositions of the present disclosure can be, for example, in an immediate release form or a controlled release formulation. Immediate release formulations can be formulated to allow the compound to act rapidly. Non-limiting examples of immediate release formulations include formulations that are immediately soluble. Controlled release formulations are pharmaceutical formulations that are adapted or formulated such that the release rate and release profile of the active agent can match physiological and chronotherapeutic requirements or result in the release of the active agent at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gelling dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed therein), granules within a matrix, polymer mixtures, and agglomerates of granules.

[0232] In part, controlled release formulations are in a delayed release form. Delayed release forms can be formulated to delay the action of the compound over a long period of time. Delayed release forms can be formulated, for example, to delay the release of an effective dose of one or more compounds for about 4 hours, about 8 hours, about 12 hours, about 16 hours, or about 24 hours.

[0233] Controlled release formulations can be in a sustained release form. Sustained release forms can be formulated, for example, to sustain the action of the compound over a long period of time. Sustained release forms can be formulated to provide an effective dose of any of the compounds described herein (e.g., provide a physiologically effective blood profile) over about 4 hours, about 8 hours, about 12 hours, about 16 hours, or about 24 hours.

[0234] The disclosed compositions can optionally include a pharmaceutically acceptable preservative.

[0235] Non-limiting examples of pharmaceutically acceptable excipients include, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated herein by reference in its entirety.

[0236] The compounds described herein can advantageously be formulated into pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers. For example, see Remington ’s Pharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub. Co., Easton, PA, which is incorporated herein by reference in its entirety, for disclosure of typical carriers and conventional methods of preparing pharmaceutical compositions. Such carriers can be carriers for administration of compositions to humans and non-humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. The pharmaceutical compositions can also contain one or more additional active ingredients such as antibacterial, anti-inflammatory, and anesthetic agents.

[0237] ​Non-limiting examples of pharmaceutically acceptable carriers include physiological saline, Ringer's solution, and dextrose solution. In some embodiments, the pH of the solution can be from about 5 to about 8, and can be from about 7 to about 7.5. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the compound. The matrix can be in the form of a shaped article, such as a film, liposome, microparticle, or microcapsule.

[0238] Compositions suitable for topical administration can be used. In some embodiments, the compositions of the present disclosure can include a liquid containing the active agent in solution, suspension, or both. The liquid composition can include a gel. The liquid composition can be, for example, aqueous. The composition is an aqueous composition that can be gelled in situ. Repeatedly, the composition is an aqueous solution that can be gelled in situ. Such a composition can include a gelling agent at a concentration effective to promote gelation upon contact with the tears in or outside the eye. The aqueous composition can have an ophthalmically compatible pH and osmolality. The composition can include an ophthalmic depot formulation containing the active agent for subconjunctival administration. The microparticles containing the active agent can be encapsulated in a biocompatible pharmaceutically acceptable polymer or lipid encapsulating agent. The depot formulation can be adapted to release all or substantially all of the active substance over a long period of time. The polymer or lipid matrix, if present, can be adapted to degrade sufficiently to be transported from the site of administration after release of all or substantially all of the active agent. The depot formulation can be a liquid formulation containing a pharmaceutically acceptable polymer and the dissolved or dispersed active agent. Upon injection, the polymer forms a depot at the injection site, for example, by gelation or precipitation. The composition can include a solid article that can be inserted into a suitable location of the eye, such as between the eye and the eyelid or within the conjunctival sac, where the article releases the active agent. Suitable solid articles for implantation into the eye in such a manner can include a polymer and can be biodegradable or non-biodegradable in vivo.

[0239] In addition to the agents disclosed herein, pharmaceutical formulations can include additional carriers, as well as thickeners, diluents, buffers, preservatives, and surfactants.

[0240] The pH of the disclosed compositions can range from about 3 to about 12. The pH of the composition can be, for example, in pH units of about 3 to about 4, about 4 to about 5, about 5 to about 6, about 6 to about 7, about 7 to about 8, about 8 to about 9, about 9 to about 10, about 10 to about 11, or about 11 to about 12. The pH of the composition can be, for example, in pH units of about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12. The pH of the composition can be, for example, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 pH units. The pH of the composition can be, for example, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, or at most 12 pH units. The pharmaceutical formulations disclosed herein can have a pH of about 5.5 to about 6.5. For example, the formulations of the present disclosure can have a pH of about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5. In some embodiments, the pH is 6.2 ± 0.3, 6.2 ± 0.2, 6.2 ± 0.1, about 6.2, or 6.2.

[0241] If the pH is outside the range desired by the formulator, the pH can be adjusted by using pharmaceutically acceptable acids and bases as appropriate.

[0242] Depending on the intended mode of administration, the pharmaceutical composition can be in the form of a solid, semi-solid, or liquid dosage form, for example, in a unit dosage form appropriate for a single administration of an exact dosage amount, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels.

[0243] For solid compositions, examples of non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.

[0244] Non-limiting examples of pharmaceutical active agents suitable for combination with the compositions of the present disclosure include anti-infective agents, i.e., aminoglycosides, antiviral agents, antibacterial agents, anticholinergic / anticonvulsant agents, antidiabetic agents, antihypertensive agents, antineoplastic agents, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunological agents, immunosuppressants, and ophthalmic preparations.

[0245] In some embodiments, the pharmaceutical compositions provided herein include a therapeutically effective amount of a compound mixed with a pharmaceutically acceptable carrier and / or excipient, such as saline, phosphate buffered saline, phosphates and amino acids, polymers, polyols, sugars, buffers, preservatives, and other proteins. Exemplary agents include octylphenoxypolyethoxyethanol compounds, polyethylene glycol monostearate compounds, polyoxyethylene sorbitan fatty acid esters, sucrose, fructose, dextrose, maltose, glucose, mannitol, dextran, sorbitol, inositol, galactitol, xylitol, lactose, trehalose, bovine or human serum albumin, citrate, acetate, Ringer's solution and Hank's solution, cysteine, arginine, carnitine, alanine, glycine, lysine, valine, leucine, polyvinylpyrrolidone, polyethylene, and glycol.

[0246] In some embodiments, the pharmaceutical formulations disclosed herein can include (i) a compound or antibody disclosed herein; (ii) a buffer; (iii) a non-ionic surfactant; (iv) an isotonicity agent; and (v) a stabilizer. In some embodiments, the pharmaceutical formulations disclosed herein are stable liquid pharmaceutical formulations.

[0247] In some embodiments, the ophthalmic formulations disclosed herein can include: (i) a compound or antibody disclosed herein; (ii) a buffer; (iii) a nonionic surfactant; (iv) an isotonicity agent; and (v) a stabilizer. In some embodiments, the ophthalmic formulations disclosed herein are stable liquid pharmaceutical formulations or stable liquid ophthalmic formulations.

[0248] In some embodiments, the pharmaceutical or ophthalmic formulations disclosed herein are liquid formulations that can contain from about 5 mg / mL to about 150 mg / mL of an antibody or compound, from about 7.5 mg / mL to about 140 mg / mL of an antibody or compound, from about 10 mg / mL to about 130 mg / mL of an antibody or compound, from about 10 mg / mL to about 100 mg / mL of an antibody or compound, from about 20 mg / mL to about 80 mg / mL of an antibody or compound, or from about 30 mg / mL to about 70 mg / mL of an antibody or compound. For example, the formulations of the present disclosure can contain from about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 120 mg / mL, about 140 mg / mL or about 150 mg / mL of a compound, antibody or antigen-binding fragment thereof described herein.

[0249] In some embodiments, the pharmaceutical or ophthalmic formulations disclosed herein can include a buffer. In some embodiments, the buffer serves to maintain a stable pH and assist in stabilizing the compounds or antibodies disclosed herein. In some embodiments, the buffer or buffer system includes at least one buffer having a buffering range that completely or partially overlaps with a range of pH 5.5 to 7.4. In some embodiments, the buffer has a pKa of about 6.2 ± 0.5. In some embodiments, the buffer includes a sodium phosphate buffer. In some embodiments, the sodium phosphate is present at a concentration of about 5 mM to about 15 mM, about 6 mM to about 14 mM, about 7 mM to about 13 mM, about 8 mM to about 12 mM, about 9 mM to about 11 mM, or about 10 mM. In certain embodiments, the buffer system includes 10 mM sodium phosphate at a pH of 6.2 ± 0.3 or 6.1 ± 0.3.

[0250] In some embodiments, the pharmaceutical or ophthalmic formulations disclosed herein can include a nonionic surfactant. In some embodiments, the nonionic surfactant is a nonionic polymer containing a polyoxyethylene moiety. In some embodiments, the nonionic surfactant is any one or more of polysorbate 20, poloxamer 188, or polyethylene glycol 3350. In some embodiments, the nonionic surfactant is polysorbate 20. In some embodiments, the nonionic surfactant is polysorbate 80. In some embodiments, the pharmaceutical or ophthalmic formulations disclosed herein can contain from about 0.01% to about 1% nonionic surfactant. For example, the formulations of the present disclosure can contain about 0.0085%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about 0.20%, about 0.21%, about 0.22%, about 0.23%, about 0.24%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.15%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1.45%, about 1.5%, about 1.55%, about 1.6%, about 1.65%, about 1.7%, about 1.75%, about 1.8%, about 1.85%, about 1.9%, about 1.95% or about 2% of polysorbate 20, polysorbate 80, or poloxamer 188.

[0251] In some embodiments, the pharmaceutical or ophthalmic formulations disclosed herein can include an isotonic agent. In some embodiments, the isotonic agent is sodium chloride or potassium chloride. In some embodiments, the isotonic agent is sodium chloride. In some embodiments, sodium chloride is present at a concentration of about 5 mM to about 100 mM, about 10 mM to about 50 mM, or about 40 mM.

[0252] In some embodiments, the pharmaceutical or ophthalmic formulations disclosed herein can include a stabilizer. In some embodiments, the stabilizer is a heat stabilizer that can stabilize the antibodies or compounds disclosed herein under heat stress conditions. In some embodiments, the stabilizer maintains more than about 93% of the compound or antibody in an undenatured conformation when the solution containing the compound or antibody and the heat stabilizer is maintained at about 45°C for up to about 28 days. In some embodiments, the stabilizer prevents aggregation of the compound or antibody, and less than about 4% of the compound or antibody aggregates when the solution containing the compound or antibody and the heat stabilizer is maintained at about 45°C for up to about 28 days. In some embodiments, the stabilizer maintains more than about 96% of the compound or antibody in an undenatured conformation when the solution containing the compound or antibody and the heat stabilizer is maintained at about 37°C for up to about 28 days. In some embodiments, the stabilizer prevents aggregation of the compound or antibody, and less than about 2% of the compound or antibody aggregates when the solution containing the compound or antibody and the heat stabilizer is maintained at about 37°C for up to about 28 days.

[0253] In some embodiments, the heat stabilizer is a sugar or sugar alcohol, such as sucrose, sorbitol, glycerol, trehalose or mannitol, or any combination thereof. In some embodiments, the stabilizer is a sugar. In some embodiments, the sugar is sucrose, mannitol or trehalose. In some embodiments, the stabilizer is sucrose. In some embodiments, the pharmaceutical or ophthalmic formulation disclosed herein can comprise from about 1% to about 20% sugar or sugar alcohol, from about 2% to about 18% sugar or sugar alcohol, from about 3% to about 15% sugar or sugar alcohol, from about 4% to about 10% sugar or sugar alcohol or about 5% sugar or sugar alcohol. For example, the pharmaceutical or ophthalmic formulation of the present disclosure can comprise about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13% or about 14% sugar or sugar alcohol (such as sucrose, trehalose or mannitol). In some embodiments, the stabilizer is at a concentration of about 1% w / v to about 20% w / v. In some embodiments, the stabilizer is sucrose at a concentration of about 1% w / v to about 15% w / v or about 1% w / v to about 10% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 5% w / v or about 5% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 7.5% w / v or about 7.5% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 10% w / v or about 10% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 12.5% w / v or about 12.5% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 15% w / v or about 15% w / v. In some embodiments, the stabilizer is sucrose at a concentration of 20% w / v or about 20% w / v. Administration of Pharmaceutical Composition

[0254] The pharmaceutical compositions disclosed herein can be administered in a therapeutically effective amount by various forms and routes, for example, orally, topically, parenterally, by intravenous injection, intravenous infusion, subcutaneous injection, subcutaneous infusion, intramuscular injection, intramuscular infusion, intradermal injection, intradermal infusion, intraperitoneal injection, intraperitoneal infusion, intracerebral injection, intracerebral infusion, subarachnoid injection, subarachnoid infusion, intraocular injection, intraspinal injection, intrasternal injection, intraocular administration, endothelial administration, topical administration, nasal administration, pulmonary administration, rectal administration, intraarterial administration, intrathecal administration, inhalation, intralesional administration, intradermal administration, epidural administration, absorption through the epithelium or inner layer of the mucosa (e.g., oral mucosa, rectal and intestinal mucosa), intracapsular administration, subcapsular administration, intracardiac administration, intratracheal administration, subepidermal administration, subarachnoid administration, subcapsular administration, intraspinal administration or intrasternal administration.

[0255] The pharmaceutical compositions can be administered by topical methods, for example, via direct injection of the compound into the organ, optionally in the form of a depot formulation or sustained release formulation or implant. The pharmaceutical compositions can be provided in the form of an immediate release formulation, an extended release formulation, or an intermediate release formulation. The immediate release form can provide immediate release. The extended release formulation can provide controlled release or sustained delayed release.

[0256] In some embodiments, a pump can be used for the delivery of the pharmaceutical compositions. In some embodiments, a pen delivery device can be used, for example, for subcutaneous delivery of the compositions of the present disclosure. Such pen delivery devices can be reusable or disposable. A reusable pen delivery device can use a replaceable cartridge containing the pharmaceutical compositions disclosed herein. When all of the pharmaceutical compositions in the cartridge have been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical compositions. The pen delivery device can then be reused. A disposable pen does not have a replaceable cartridge. Rather, a disposable pen delivery device is pre-filled with the pharmaceutical compositions held in a reservoir within the device. When the pharmaceutical compositions are emptied from the reservoir, the entire device is discarded.

[0257] The pharmaceutical compositions disclosed herein can be administered to the eye via any suitable form or route, including, for example, topical, oral, systemic, intravitreal, intracameral, intracanieral, subconjunctival, sub-Tenon's capsule, retrobulbar, intraocular, intrastromal, corneal within, posterior adjacent cells, periorbital, subretinal or suprachoroidal administration. The delivery method can include invasive methods for direct delivery of the composition to eye cells. In some embodiments, a liquid pharmaceutical composition containing an antibody or a compound is delivered via subretinal injection, intravitreal injection (e.g., anterior, central or posterior vitreous injection), intravitreal implant, orbital injection, orbital administration, subcutaneous injection, intracameral injection, intracanieral injection, subconjunctival injection, subconjunctival implant, injection into the anterior chamber via the limbus of the ear side, intrastromal injection, intracorneal injection, aqueous humor injection, sub-Tenon's capsule injection or sub-Tenon's capsule implant. The composition can be administered by injecting the formulation into any part of the eye, including the anterior chamber, posterior chamber, vitreous cavity (intravitreal), appropriate retina and / or subretinal space.

[0258] The pharmaceutical compositions disclosed herein can be delivered via non-invasive methods. Examples of non-invasive modes of administering the formulation can include using a needle-free injection device and topical administration, such as eye drops to the cornea. Multiple administration routes can be used for efficient delivery of the pharmaceutical composition. In some embodiments, the composition is delivered via multiple administration routes, such as subretinal and intravitreal, to increase the efficiency of antibody delivery. In some embodiments, subretinal and / or intravitreal injections precede vitrectomy.

[0259] In some embodiments, a liquid formulation containing an antibody or compound at a concentration of 10 mg / mL to 120 mg / mL is pre-filled into a syringe and administered intravitreally in a volume of up to about 500 μL. In some embodiments, a liquid formulation containing an antibody or compound at a concentration of 10 mg / mL to 120 mg / mL is pre-filled into a syringe and administered intravitreally in a volume of up to about 100 μL. In some embodiments, a liquid formulation containing an antibody or compound at a concentration of 10 mg / mL to 120 mg / mL is pre-filled into a syringe and administered intravitreally in a volume of about 50 μL.

[0260] The pharmaceutical compositions disclosed herein can target any suitable ocular cells, including, for example, endothelial cells such as vascular endothelial cells, retinal cells such as retinal pigment epithelium (RPE), corneal cells, fibroblasts, astrocytes, glial cells, pericytes, iris epithelial cells, cells of neural origin, ciliary epithelial cells, Müller cells, muscle cells surrounding and attached to the eye such as the cells of the lateral rectus muscle, orbital fat cells, scleral and episcleral cells, cells of the fibrous zonular network, or connective tissue cells. Drug Administration

[0261] The compounds, antibodies or therapeutic agents described herein can be administered before, during or after the onset of a disease or condition, and the timing of administration of the composition containing the compound, antibody or therapeutic agent can be varied. For example, the composition can be used as a prophylactic agent and can be continuously administered to a subject having a tendency to develop a condition or disease in order to reduce the likelihood of the onset of the disease or condition. The composition can be administered to a subject already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition, or in an amount sufficient to cure, treat, ameliorate or alleviate the condition. The composition can be administered to the subject during the onset of symptoms or as soon as possible after the onset of symptoms. Administration of the compound, antibody or therapeutic agent can be initiated within the first 48 hours, within the first 24 hours, within the first 6 hours or within 3 hours of the onset of symptoms. The first administration can be via any practical route, for example, by any route described herein using any formulation described herein. The compound, antibody or therapeutic agent can be administered as soon as practicable after the onset of the disease or condition has been detected or suspected, for example, for a period necessary for the treatment of a disease such as from about 1 month to about 3 months. The length of treatment can be varied for each subject. The effective amount for this use can be varied based on the severity and course of the disease or condition, previous therapy, the health status, weight and response to the drug of the subject, and the judgment of the physician treating the subject. Improvement of clinical symptoms can be monitored, for example, by indirect ophthalmoscopy, fundus photography, fluorescein angiography, electroretinogram examination, external eye examination, slit lamp biomicroscopy, applanation tonometry, corneal thickness measurement, optical coherence tomography, or autorefraction method.

[0262] The pharmaceutical compositions described herein can be in a suitable unit dosage form for single administration of an accurate dosage. In a unit dosage form, the formulation can be divided into unit doses containing a suitable amount of one or more compounds, antibodies, or therapeutic agents. The unit dosage can be in the form of packages containing separate amounts of the formulation. Non-limiting examples are packaged injections, vials, and ampoules. The aqueous suspension compositions disclosed herein can be packaged in non-resealable containers for a single dose. Multiple-dose resealable containers can be used, for example, in combination with or without a preservative. The injectable formulations disclosed herein can be presented in unit dosage form, for example, in ampoules, or in multiple-dose containers with a preservative.

[0263] The multiple compounds, antibodies, or therapeutic agents disclosed herein can be administered in any order or simultaneously. In the case of simultaneous administration, the multiple compounds, antibodies, or therapeutic agents can be provided in a single unified form or in multiple forms, for example, as multiple separate injections or infusions. The compounds, antibodies, or therapeutic agents can be packaged together or separately in a single package or multiple packages. One or all of the compounds, antibodies, or therapeutic agents can be administered in multiple doses. If not simultaneous, the timing between multiple doses can be varied up to about one month.

[0264] Intraocular injections can be performed at any time interval to improve the efficiency of delivery and / or to minimize or avoid damage to the surrounding tissue. The time interval between two or more intraocular injections can be, for example, from about 1 minute to about 60 minutes, from about 1 minute to about 5 minutes, from about 5 minutes to about 10 minutes, from about 10 minutes to about 15 minutes, from about 15 minutes to about 20 minutes, from about 20 minutes to about 25 minutes, from about 25 minutes to about 30 minutes, from about 30 minutes to about 35 minutes, from about 35 minutes to about 40 minutes, from about 40 minutes to about 45 minutes, from about 45 minutes to about 50 minutes, from about 50 minutes to about 55 minutes, or from about 55 minutes to about 60 minutes.

[0265] Intraocular injection can be performed at any rate. The rate of intraocular injection can be, for example, about 1 μL / second to about 500 μL / second, about 1 μL / second to about 10 μL / second, about 10 μL / second to about 20 μL / second, about 20 μL / second to about 30 μL / second, about 30 μL / second to about 40 μL / second, about 40 μL / second to about 50 μL / second, about 50 μL / second to about 60 μL / second, about 60 μL / second to about 70 μL / second, about 70 μL / second to about 80 μL / second, about 80 μL / second to about 90 μL / second, about 90 μL / second to about 100 μL / second, about 100 μL / second to about 110 μL / second, about 110 μL / second to about 120 μL / second, about 120 μL / second to about 130 μL / second, about 130 μL / second to about 140 μL / second, about 140 μL / second to about 150 μL / second, about 150 μL / second to about 160 μL / second, about 160 μL / second to about 170 μL / second, about 170 μL / second to about 180 μL / second, about 180 μL / second to about 190 μL / second, about 190 μL / second to about 200 μL / second, about 200 μL / second to about 300 μL / second, about 300 μL / second to about 400 μL / second or about 400 μL / second to about 500 μL / second.

[0266] The compounds, antibodies or therapeutic agents disclosed herein can be administered at a dosage of about 0.0001 mg / kg to about 1000 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 20 mg / kg, about 0.02 mg / kg to about 7 mg / kg, about 0.03 mg / kg to about 5 mg / kg, about 0.05 mg / kg to about 3 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, about 0.2 mg / kg to about 0.6 mg / kg, about 0.3 mg / kg to about 0.7 mg / kg, about 0.4 mg / kg to about 0.8 mg / kg, about 0.1 mg / kg to about 0.9 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 10 mg / kg, about 5 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg or about 3 mg / kg to about 7 mg / kg based on the mass of the subject.

[0267] The compounds, antibodies or therapeutic agents described in this specification can be administered at any desired interval. Administration of the compounds, antibodies or therapeutic agents can have a regular or irregular dosing schedule to suit either the person administering the compounds, antibodies or therapeutic agents or the subject receiving the compounds, antibodies or therapeutic agents. For example, the compounds, antibodies or therapeutic agents can be administered twice a day, once a day, five times a week, four times a week, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, once every six weeks, once every eight weeks, once every two months, once every twelve weeks, once every three months, once every four months, once every six months, once a year, or at a lower frequency. In some embodiments, the administration is bi-weekly.

[0268] The amount administered can be the same amount at each dose, or the dosage can vary between doses. For example, a first amount can be administered in the morning and a second amount can be administered at night.

[0269] The compounds, antibodies or therapeutic agents described herein can be administered in any amount that is necessary or convenient. For example, the compounds described herein can be administered to a subject, per dose, by any route of administration, in an amount of about 0.05 mg to about 300 mg, about 0.1 mg to about 300 mg, about 0.1 mg to about 200 mg, about 0.1 mg to about 100 mg, about 0.05 mg to about 1.5 mg, about 0.1 mg to about 1.5 mg, about 0.05 mg to about 1 mg, about 1 mg to about 1.5 mg, about 0.5 mg to about 6 mg, about 1 mg to about 4 mg, about 2 mg to about 10 mg, about 10 mg to about 30 mg, about 30 mg to about 50 mg, about 50 mg to about 70 mg, about 70 mg to about 100 mg, or about 0.1 mg to about 1 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.11 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.21 mg, about 0.22 mg, about 0.23 mg, about 0.24 mg, about 0.25 mg, about 0.26 mg, about 0.27 mg, about 0.28 mg, about 0.29 mg, about 0.3 mg, about 0.31 mg, about 0.32 mg, about 0.33 mg, about 0.34 mg, about 0.35 mg, about 0.36 mg, about 0.37 mg, about 0.38 mg, about 0.39 mg, about 0.4 mg, about 0.41 mg, about 0.42 mg, about 0.43 mg, about 0.44 mg, about 0.45 mg, about 0.46 mg, about 0.47 mg, about 0.48 mg, about 0.49 mg, about 0.5 mg, about 0.51 mg, about 0.52 mg, about 0.53 mg, about 0.54 mg, about 0.55 mg, about 0.56 mg, about 0.57 mg, about 0.58 mg, about 0.59 mg, about 0.6 mg, about 0.61 mg, about 0.62 mg, about 0.63 mg, about 0.64 mg, about 0.65 mg, about 0.66 mg, about 0.67 mg, about 0.68 mg, about 0.69 mg, about 0.7 mg, about 0.71 mg, about 0.72 mg, about 0.73 mg, about 0.74 mg, about 0.75 mg, about 0.76 mg, about 0.77 mg, about 0.78 mg, about 0.79 mg, about 0.8 mg, about 0.81 mg, about 0.82 mg, about 0.83 mg, about 0.84 mg, about 0.85 mg, about 0.86 mg, about 0.87 mg, about 0.88 mg, about 0.89 mg, about 0.9 mg, about 0.91 mg, about 0.92 mg, about 0.It can be administered in an amount of 93 mg, about 0.94 mg, about 0.95 mg, about 0.96 mg, about 0.97 mg, about 0.98 mg, about 0.99 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg or about 300 mg. Combination therapy

[0270] The pharmaceutical compositions provided herein can be administered in combination with other therapies, such as chemotherapy, radiation, surgery, anti-inflammatory agents or vitamins. The other agents can be administered before, after, or simultaneously with the pharmaceutical composition.

[0271] In some embodiments, the compounds or antibodies described herein can be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0272] In some embodiments, the present disclosure provides co - administration of, for example, a multispecific compound or antibody that targets HPTP - β (VE - PTP) and VEGF, and one or more additional anti - VEGF agents that can stabilize the vasculature against angiogenesis. In some embodiments, co - administration of the multispecific compound or antibody and one or more additional anti - VEGF agents can stabilize the vasculature against leakage. The anti - VEGF agent can be a compound, a recombinant protein, an antibody, an antigen - binding fragment, a variant or a derivative thereof (e.g., scFv), a protein comprising one or more designed ankyrin repeats, a designed ankyrin repeat protein (DARPin), an ankyrin protein, an ankyrin repeat protein, an affibody, an abimer, an adnectin, an anticalin, a fibronomer, a Kunitz domain, a notchtin, a β - hairpin mimetic, or a peptide derived from one or more receptors, e.g., the VEGF - binding portions of VEGF receptors or human VEGF receptors 1 and 2.

[0273] Non-limiting examples of anti-VEGF agents include VEGF receptor tyrosine kinase inhibitors such as bevacizumab (Avastin®), ranibizumab (Lucentis®), aflibercept (Eylea®), conbercept, brolucizumab, RTH258, sorafenib, sunitinib, axitinib, pazopanib, vandetanib, cabozantinib, regorafenib, and 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474), VEGF variants, soluble VEGF receptor fragments or traps, aptamers (e.g., pegaptanib) that can block VEGF or VEGFR, neutralizing anti-VEGFR antibodies or fragments thereof (e.g., ramucirumab, p1C11, 1121, 1121B), anti-KDR antibodies, anti-flt1 antibodies, low molecular weight inhibitors of VEGFR tyrosine kinase, DARPins that bind to VEGF (e.g., abicipar, MP0112, MP0250), proteins containing one or more designed ankyrin repeats that bind to VEGF, adnectins (e.g., CT-322), anticalins (e.g., PRS-050), and biomimetic peptides derived from type IV collagen (e.g., AXT-107).

[0274] Further non-limiting examples of agents that modulate VEGF include anti-inflammatory agents such as dexamethasone, fluocinolone, and triamcinolone. For example, multispecific compounds or antibodies that target HPTP-β (VE-PTP) and VEGF can be administered, in any combination, with any additional anti-VEGF agent, for example, at the start of treatment, at any point during treatment, or at any point after treatment with an additional anti-VEGF agent has ended. In addition, the dosage of the multispecific compound or antibody can be adjusted during treatment. Also, the dosage of the additional anti-VEGF agent can be adjusted during treatment. The multispecific compound or antibody can be administered, for example, monthly, once every three months, once every six months, or once a year, where the additional anti-VEGF agent is administered at any frequency during treatment. Also disclosed herein are methods for treating the diseases or conditions disclosed herein. The method comprises administering to a subject, a) a therapeutically effective amount of a multispecific compound or antibody that targets, for example, HPTP-β (VE-PTP) and VEGF, and b) a therapeutically effective amount of an additional anti-VEGF agent comprising administering, the administration of the multispecific compound or antibody and the additional anti-VEGF agent can be carried out as described herein.

[0275] In some embodiments, the present disclosure provides co - administration of, for example, a multispecific compound or antibody that targets HPTP - β (VE - PTP) and VEGF, and one or more additional anti - HPTP - β (VE - PTP) agents that can stabilize the vasculature against angiogenesis. In some embodiments, co - administration of the multispecific compound or antibody and one or more additional anti - HPTP - β (VE - PTP) agents can stabilize the vasculature against leakage. The anti - HPTP - β (VE - PTP) agent can be a compound, recombinant protein, antibody, antigen - binding fragment, variant or derivative thereof (e.g., scFv), a protein comprising one or more designed ankyrin repeats, a designed ankyrin repeat protein (DARPin), an ankyrin protein, an ankyrin repeat protein, an affibody, an abimer, an adnectin, an anticalin, a finomer, a Kunitz domain, a notchin, a β - hairpin mimetic, or a peptide derived from one or more receptors. In some embodiments, the additional anti - HPTP - β (VE - PTP) agent can activate Tie2 signaling by promoting phosphorylation of a protein, e.g., phosphorylation of the Tie2 protein. In some embodiments, the additional anti - HPTP - β (VE - PTP) agent can bind to HPTP - β (VE - PTP).

[0276] For example, multispecific compounds or antibodies that target HPTP-β (VE-PTP) and VEGF can be administered, in any combination and in combination with any additional anti-HPTP-β (VE-PTP) agent, at any time, for example, at the start of treatment, at any point during treatment, or at any point after treatment with the additional anti-HPTP-β (VE-PTP) agent has ended. The dosage of the multispecific compound or antibody can be adjusted during treatment. The dosage of the additional anti-HPTP-β (VE-PTP) agent can be adjusted during treatment. The multispecific compound or antibody can be administered, for example, monthly, once every three months, once every six months, or once a year, where the additional anti-HPTP-β (VE-PTP) agent is administered at any frequency during treatment. Also disclosed herein are methods for treating the diseases or conditions disclosed herein. The method comprises administering to a subject, a) a therapeutically effective amount of a multispecific compound or antibody that targets, for example, HPTP-β (VE-PTP) and VEGF, and b) a therapeutically effective amount of an additional anti-HPTP-β (VE-PTP) agent and the administration of the multispecific compound or antibody and the additional anti-HPTP-β (VE-PTP) agent can be carried out as described herein.

[0277] In some embodiments, the present disclosure provides co - administration of, for example, a multispecific compound or antibody that targets HPTP - β (VE - PTP) and VEGF, and one or more additional Tie2 receptor - activating compounds. The additional Tie2 receptor - activating compounds can be, for example, angiopoietin - 1 recombinant protein, Ang1 mimetic, Tie2 agonist, peptide, HPTP - β (VE - PTP) phosphatase inhibitor, Tie2 peptidomimetic, tetrameric polyethylene oxide cluster peptide, type IV collagen biomimetic peptide, compound, recombinant protein, antibody, antigen - binding fragment, variant or derivative thereof (e.g., scFv), affibody, abimer, adnectin, a protein containing one or more designed ankyrin repeats, designed ankyrin repeat protein (DARPin), ankyrin protein, ankyrin repeat protein, afibody, abimer, adnectin, anticalin, finomer, Kunitz domain, knottin, β - hairpin mimetic, or a peptide derived from one or more receptors. In some embodiments, one or more additional Tie2 receptor - activating compounds are small molecules. In some embodiments, one or more additional Tie2 receptor - activating compounds improve drainage by the ocular lymphatics, Schlemm's canal or limbal lymphatics. In some embodiments, one or more additional Tie2 receptor - activating compounds are administered as eye drops. In some embodiments, one or more additional Tie2 receptor - activating compounds are administered to treat primary open - angle glaucoma, age - related macular degeneration, cardiovascular disease or polycystic kidney disease. In some embodiments, one or more additional Tie2 receptor - activating compounds can be, for example, MAN - 01, AXT - 107 or bivatuzumab. In some embodiments, the compounds disclosed herein can be co - administered with, for example, MAN - 01, AXT - 107 or bivatuzumab.

[0278] For example, multispecific compounds or antibodies targeting HPTP-β (VE-PTP) and VEGF can be administered in any combination with any additional Tie2 receptor activating compound, for example, at the start of treatment, at any point during treatment, or at any point after treatment with an additional Tie2 receptor activating compound has ended. The dosage of the multispecific compound or antibody can be adjusted during treatment. The dosage of the additional Tie2 receptor activating compound can be adjusted during treatment. The multispecific compound or antibody can be administered, for example, monthly, once every three months, once every six months, or once a year, where the additional Tie2 receptor activating compound is administered at any frequency during treatment with the multispecific compound or antibody. Also disclosed herein are methods for treating the diseases or conditions disclosed herein. The method comprises administering to a subject, a) a therapeutically effective amount of a multispecific compound or antibody targeting, for example, HPTP-β (VE-PTP) and VEGF, and b) a therapeutically effective amount of a Tie2 activator and the administration of the multispecific compound or antibody and the additional Tie2 receptor activating compound can be carried out as described herein. The oxygen-induced ischemic retinopathy model can be considered to mimic aspects of proliferative retinopathy and proliferative diabetic retinopathy. One-week-old mice are placed in a sealed chamber and exposed to hyperoxia (75 ± 3% oxygen) for 5 days, which can result in oxygen-induced neovascularization, for example, at the junction between the vascularized and avascular retina between postnatal days 17 and 21. The mice are dosed with the compound of interest, for example, the antibody or compound of the present disclosure, to determine the effect on neovascularization and / or vascular leakage. Neovascularization and / or vascular leakage can be evaluated as described below. Mouse model Oxygen-induced ischemic retinopathy model

[0279] The Rho / VEGF mouse model Rho / VEGF mouse model

[0280] The Rho / VEGF mouse model can mimic the aspects of neovascular age-related macular degeneration. Transgenic mice with vascular endothelial growth factor (VEGF) expression driven by the rhodopsin promoter (rho / VEGF mice) can develop retinal neovascularization, retinal vascular tuft proliferation, and retinal vascular leakage. In rho / VEGF mice, VEGF expression in photoreceptors can begin between postnatal days 5 and 10, a period during which the deep capillary bed is developing. Neovascularization can originate from the deep capillary bed of the retina and grow into the subretinal space. The mice can be dosed with a compound of interest, such as an antibody or compound of the present disclosure, to determine its effect on neovascularization and / or vascular leakage. Neovascularization and / or vascular leakage can be evaluated as described below. Tet / opsin / VEGF mouse model

[0281] Mice with VEGF under the control of a reverse tetracycline transactivator (rtTA)-inducible promoter coupled to the rhodopsin promoter (Tet / opsin / VEGF mice) can be used as an induction model for neovascularization, retinal vascular leakage, and retinal detachment. In these mice, expression of the VEGF transgene in the retina can be induced by administering doxycycline. Neovascularization can be clearly discernible by 3 to 4 days after VEGF induction. Neovascularization can be more extensive and can cause folds on the outer retina, followed by total retinal detachment within about 5 days. The mice can be dosed with a compound of interest, such as an antibody or compound of the present disclosure, to determine its effect on neovascularization, vascular leakage, and / or retinal detachment. Neovascularization and / or vascular leakage can be evaluated as described below. To evaluate retinal detachment, the eyes can be frozen at the cutting temperature in an embedding solution, cut into 10-micron sections throughout the eye, and the sections stained with hematoxylin. The sections can be examined by light microscopy to determine the average length of retinal detachment per section, measured by image analysis, and the percentage of retinal detachment calculated. Tet / opsin / Ang2 mouse model

[0282] Tet / Opsin / Ang2 mice have inducible expression of Ang2 in the retina. These mice can be used to study the effects of Ang2 expression under various experimental conditions. For example, Tet / Opsin / Ang2 mice can be used to determine the effect of Ang2 expression on angiogenesis in the presence or absence of low levels of VEGF, or the effect of Ang2 expression in an oxygen-induced ischemic retinopathy model. The mice can be dosed with a compound of interest, such as an antibody or compound of the present disclosure, to determine the effect of Ang2 expression on therapeutic efficacy. Laser-induced choroidal neovascularization model

[0283] The laser-induced choroidal neovascularization model can be considered to mimic aspects of age-related macular degeneration with neovascularization. Anesthetized mice can have their pupils dilated and can be delivered burns, for example, to the retina by a krypton laser using a slit lamp system and a coverslip as a contact lens. Multiple burns can occur in one eye, for example, three burns per eye. The burns can cause rupture of Bruch's membrane. Choroidal neovascularization can be evaluated at various time points after laser treatment, for example, 1 week, 2 weeks, or 4 weeks after laser treatment. The mice can be dosed with a compound of interest, such as an antibody or compound of the present disclosure, to determine the effect on angiogenesis. The eyecups can be stained with FITC-labeled GSA, flat-mounted choroid, and the area of choroidal neovascularization at each Bruch's membrane rupture site measured by fluorescence microscopy and image analysis. Angiogenesis and / or vascular leakage can also be evaluated as described below. Evaluation of angiogenesis

[0284] Angiogenesis can be evaluated using various techniques.

[0285] Fluorescein angiography can be performed by taking consecutive fundus photographs after injection of the dye to reveal the blood vessels, enabling identification of the presence, location, and size of the neovascular complex. For example, an intraperitoneal injection of 0.3 mL of 1% sodium fluorescein can be given, consecutive fundus photographs can be taken, and the areas of choroidal neovascularization, total lesion area, and leakage area can be measured.

[0286] The eyes can be processed for evaluation by fluorescence microscopy, light microscopy, or electron microscopy. For example, mice can be perfused with fluorescently labeled dextran, or the eyes can be injected with antibodies targeting GSA or PECAM. The eyes can be processed for observation under a fluorescence microscope, and the degree of neovascularization can be quantified, for example, by quantifying the area of neovascularization per retina, by quantifying the area of neovascularization at each Bruch's membrane rupture site, or by quantifying the number of nuclei of new blood vessels extending from the retina into the vitreous.

[0287] The area of retinal neovascularization can be determined, for example, using FITC-labeled GSA lectin and a fluorescence microscope. The eyes are fixed in 10% formalin, incised intact, washed with PBS, blocked with 8% pig serum, and stained with FITC-labeled GSA lectin for an appropriate time (e.g., 40 - 50 minutes) to stain retinal neovascularization and vitreous blood vessels rather than the blood vessels of the normal retina. The retina can be mounted flat, digital images can be acquired with a fluorescence microscope, and combined into a single image of the entire retina. Software can be used to measure the area of neovascularization per retina.

[0288] The area of subretinal neovascularization can be determined, for example, using FITC-labeled GSA lectin and a fluorescence microscope. The eyes can be fixed in 10% formalin, the retinas can be dissected, blocked with 5% porcine serum, stained with FITC-conjugated GSA for 2 hours to stain vascular cells, and mounted flat with the photoreceptor side up. The area of subretinal neovascularization can be measured by fluorescence microscopy and image analysis. Evaluation of retinal vascular leakage

[0289] Retinal vascular leakage can be evaluated by measuring extravasated serum albumin using immunofluorescence techniques. For example, the eyes can be fixed in 10% formalin, the retinas can be dissected, washed, blocked, and stained using an anti-albumin antibody and a fluorescent-conjugated secondary antibody. The blood vessels can be labeled by counterstaining with GSA lectin, and the retinas can be mounted flat. The retinas can be examined by fluorescence microscopy, and the area of albumin staining can be determined by image analysis. Retinal vascular leakage is associated with, for example, diabetic macular edema and macular edema resulting from retinal vein occlusion. Miles assay for vascular leakage

[0290] The Miles assay can be used to evaluate vascular leakage in the subcutaneous blood vessels of the skin. Evans blue is a dye that binds to albumin. Under physiological conditions, the endothelium is impermeable to albumin, and thus albumin bound to Evans blue remains confined within the blood vessels. In pathological conditions that promote increased vascular permeability, endothelial cells partially lose their close contacts. The endothelium becomes permeable to small proteins such as albumin. Mice can be intravenously injected with Evans blue dye in 1% PBS and can be intradermally injected with VEGF. Thirty minutes after the intradermal injection, the tissue at the intradermal injection site can be excised and extracted in formamide to evaluate the extravasation of Evans blue dye. Vascular leakage can be quantified, for example, by measuring the dye incorporated per milligram of tissue using spectrophotometry and a standard curve. Mice can be dosed with the compound of interest, for example, the antibodies or compounds of the present disclosure, to determine the effect on vascular leakage. Cancer model

[0291] The efficacy of the compounds or antibodies of the present disclosure as a treatment for cancer can be tested in various cancer models. In some cancer models, cancer cells derived from a cell line can be transplanted into recipient animals, for example, mice. Non-limiting examples of suitable mouse strains include C57BL6, BALB / C, C3H, FVB / N, and FVB / N-Tg(MMTV-PyVT)634Mul. Non-limiting examples of suitable cancer cell lines include 4T1, E0771, and P0008. Cells of the 4T1 or E0771 cell line can be transplanted, for example, into the mammary gland as a model of breast cancer. 4T1 or E0771 cells can be transplanted, for example, into the third mammary fat pad of female nude mice.

[0292] The size of the solid tumor can be measured with calipers and the tumor volume can be calculated. The tumor is processed for histopathological evaluation or fluorescence microscopy to evaluate, for example, tumor area, tumor grade, number of metastases, metastasis area, number of cell nuclei per tumor nest, intratumoral vessel diameter, intratumoral vessel density, tumor vessel maturity, perivascular cell coverage, and proximity between perivascular cells and endothelial cells, or to grade the tumor nests as intravascular or extravascular.

[0293] The natural metastasis model can be used to study the effect of the compounds or antibodies of the present disclosure on metastasis. After tumor implantation, the primary tumor can be resected (e.g., when it reaches a size of 5 mm), and then the animals can be evaluated macroscopically or histopathologically for metastases to determine, for example, the number and size of metastases in the lungs, liver, lymph nodes, and bone.

[0294] To evaluate the effect of vascular stability on metastasis, a model in which tumor cells can be injected intravenously can be used, and then the animals can be evaluated for intravascular metastases to the extravascular space. For example, 4T-1 cells can be injected intravenously and the lungs can be processed for histopathological evaluation to quantify intravascular metastases to the extravascular space.

[0295] Metastases can be counted and measured macroscopically, for example, by immersing the lungs in Bouin's fluid and then examining it under a stereomicroscope.

[0296] To measure tumor vascular permeability in vivo, a multiphoton microscope can be used. Animals can be injected with fluorescently labeled bovine serum albumin, for example, at time points before and after treatment. At each time point, two separate regions within the tumor can be selected, and 200-micron image stacks recording BSA fluorescence can be acquired every 10 minutes for 1 hour in each region using a multiphoton laser scanning microscope. The analysis approach can include three-dimensional vascular tracing to create vascular measurement criteria, and a three-dimensional map of voxel intensity versus distance to the nearest blood vessel over time. The images can be corrected for sample movement over time by three-dimensional image registration. A normalized transvascular flux can be calculated. Exemplary CDR combinations

[0297] In some embodiments, the antibodies or compounds of the present disclosure include HCDR1. In some embodiments the antibodies or compounds of the present disclosure include HCDR2. In some embodiments, the antibodies or compounds of the present disclosure include HCDR3. In some embodiments, the antibodies or compounds of the present disclosure include LCDR1. In some embodiments, the antibodies or compounds of the present disclosure include LCDR2. In some embodiments the antibodies or compounds of the present disclosure include LCDR3.

[0298] In some embodiments, the antibodies or compounds of the present disclosure include HCDR1 and HCDR2. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1 and HCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1 and LCDR1. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1 and LCDR2. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1 and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR2 and HCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR2 and LCDR1. In some embodiments, the antibodies or compounds of the present disclosure include HCDR2 and includes LCDR2. In some embodiments, the antibody or compound of the present disclosure includes HCDR2 and LCDR3. In some embodiments, the antibody or compound of the present disclosure includes HCDR3 and LCDR1 and. In some embodiments, the antibody or compound of the present disclosure includes HCDR3 and LCDR2. In some embodiments, the antibody or compound of the present disclosure includes HCDR3 and LCDR3. In some embodiments, the antibody or compound of the present disclosure includes LCDR1 and LCDR2. In some embodiments, the antibody or compound of the present disclosure includes LCDR1 and LCDR3. In some embodiments, the antibody or compound of the present disclosure includes LCDR2 and LCDR3.

[0299] In some embodiments, the antibody or compound of the present disclosure includes HCDR1, HCDR2 and HCDR3 . In some embodiments, the antibody or compound of the present disclosure includes HCDR1, HCDR2 and LCDR1 . In some embodiments, the antibody or compound of the present disclosure includes HCDR1, HCDR2 and LCDR2 . In some embodiments, the antibody or compound of the present disclosure includes HCDR1, HCDR2 and LCDR3 . In some embodiments, the antibody or compound of the present disclosure includes HCDR1, HCDR3 and LCDR1 . In some embodiments, the antibody or compound of the present disclosure includes HCDR1, HCDR3 and LCDR2 . In some embodiments, the antibody or compound of the present disclosure includes HCDR1, HCDR3 and LCDR3 . In some embodiments, the antibody or compound of the present disclosure includes HCDR1, LCDR1 and LCDR2 . In some embodiments, the antibody or compound of the present disclosure includes HCDR1, LCDR1 and LCDR3 . In some embodiments, the antibody or compound of the present disclosure includes HCDR1, LCDR2 and LCDR3 。In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR2, HCDR3, and LCDR1 。In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR2, HCDR3, and LCDR2 。In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR2, HCDR3, and LCDR3 。In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR2, LCDR1, and LCDR2 。In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR2, LCDR1, and LCDR3 。In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR2, LCDR2, and LCDR3 。In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR3, LCDR1, and LCDR2 。In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR3, LCDR1, and LCDR3 。In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR3, LCDR2, and LCDR3 。In some embodiments, the antibodies or compounds of the present disclosure comprise LCDR1, LCDR2, and LCDR3 。

[0300] In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR1, HCDR2, HCDR3, and LCDR1. In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR1, HCDR2, HCDR3, and LCDR2. In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR1, HCDR2, HCDR3, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR1, HCDR2, LCDR1, and LCDR2. In some embodiments, the antibodies or compounds of the present disclosure comprise HCDR1, HCDR2, LCDR1, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure , including HCDR1, HCDR2, LCDR2, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1, HCDR3, LCDR1, and LCDR2. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1, HCDR3, LCDR1, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1, HCDR3, LCDR2, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1, LCDR1, LCDR2, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR2, HCDR3, LCDR1, and LCDR2. In some embodiments, the antibodies or compounds of the present disclosure include HCDR2, HCDR3, LCDR1, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR2, HCDR3, LCDR2, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR2, LCDR1, LCDR2, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR3, LCDR1, LCDR2 and including LCDR3.

[0301] In some embodiments, the antibodies or compounds of the present disclosure include HCDR1, HCDR2, HCDR3, LCDR1, and LCDR2. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1, HCDR2, HCDR3, LCDR1, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1, HCDR2, HCDR3, LCDR2, and LCDR3. In some embodiments, the antibodies or compounds of the present disclosure include HCDR1, HCDR2, LCDR1, LCDR2, and LCDR3. In some embodiments of the present disclosure, the antibodies or compounds include HCDR1, HCDR3, LCDR1, LCDR2, and LCDR3. In some embodiments the antibodies or compounds of the present disclosure include HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 including.

[0302] In some embodiments, the antibodies or compounds of the present disclosure include HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3.

[0303] In some embodiments, the antibodies or compounds of the present disclosure include any one of SEQ ID NOs: 76 to 80. In some embodiments, the antibodies or compounds of the present disclosure include any one of SEQ ID NOs: 81 to 87. In some embodiments, the antibodies or compounds of the present disclosure include any one of SEQ ID NOs: 88 to 90. In some embodiments, the antibodies or compounds of the present disclosure include any one of SEQ ID NOs: 91 to 93. In some embodiments, the antibodies or compounds of the present disclosure include any one of SEQ ID NOs: 94 to 96. In some embodiments, the antibodies or compounds of the present disclosure include any one of SEQ ID NOs: 97 to 98.

[0304] In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80 and any one of SEQ ID NOs: 81 - 87. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80 and any one of SEQ ID NOs: 88 - 90. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80 and any one of SEQ ID NOs: 91 - 93. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80 and any one of SEQ ID NOs: 94 - 96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80 and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81 - 87 and any one of SEQ ID NOs: 88 - 90. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81 - 87 and any one of SEQ ID NOs: 91 - 93. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81 - 87 and any one of SEQ ID NOs: 94 - 96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81 - 87 and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 88 - 90 and any one of SEQ ID NOs: 91 - 93. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 88 - 90 and any one of SEQ ID NOs: 94 - 96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 88 - 90 and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 91 - 93 and any one of SEQ ID NOs: 94 - 96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 91 - 93 and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 94 - 96 and any one of SEQ ID NOs: 97 - 98.

[0305] In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 76-80, any one of SEQ ID NOs: 81-87, and any one of SEQ ID NOs: 88-90. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 76-80, any one of SEQ ID NOs: 81-87, and any one of SEQ ID NOs: 91-93. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 76-80, any one of SEQ ID NOs: 81-87, and any one of SEQ ID NOs: 94-96. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 76-80, any one of SEQ ID NOs: 81-87, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 76-80, any one of SEQ ID NOs: 88-90, and any one of SEQ ID NOs: 91-93. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 76-80, any one of SEQ ID NOs: 88-90, and any one of SEQ ID NOs: 94-96. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 76-80, any one of SEQ ID NOs: 88-90, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 76-80, any one of SEQ ID NOs: 91-93, and any one of SEQ ID NOs: 94-96. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 76-80, any one of SEQ ID NOs: 91-93, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 76-80, any one of SEQ ID NOs: 94-96, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 81-87, any one of SEQ ID NOs: 88-90, and any one of SEQ ID NOs: 91-93. In some embodiments, the antibodies or compounds of the present disclosure comprise any one of SEQ ID NOs: 81-87, any one of SEQ ID NOs: 88-90, and any one of SEQ ID NOs: 94-96.In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81-87, any one of SEQ ID NOs: 88-90, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81-87, any one of SEQ ID NOs: 91-93, and any one of SEQ ID NOs: 94-96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81-87, any one of SEQ ID NOs: 91-93, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81-87, any one of SEQ ID NOs: 94-96, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 88-90, any one of SEQ ID NOs: 91-93, and any one of SEQ ID NOs: 94-96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 88-90, any one of SEQ ID NOs: 91-93, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 88-90, any one of SEQ ID NOs: 94-96, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 91-93, any one of SEQ ID NOs: 94-96, and any one of SEQ ID NOs: 97-98.

[0306] In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 88 - 90, and any one of SEQ ID NOs: 91 - 93. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 88 - 90, and any one of SEQ ID NOs: 94 - 96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 88 - 90, and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 91 - 93, and any one of SEQ ID NOs: 94 - 96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 91 - 93, and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 94 - 96, and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 88 - 90, any one of SEQ ID NOs: 91 - 93, and any one of SEQ ID NOs: 94 - 96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 88 - 90, any one of SEQ ID NOs: 91 - 93, and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 88 - 90, any one of SEQ ID NOs: 94 - 96, and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 91 - 93, any one of SEQ ID NOs: 94 - 96, and any one of SEQ ID NOs: 97 - 98.In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81-87, any one of SEQ ID NOs: 88-90, any one of SEQ ID NOs: 91-93, and any one of SEQ ID NOs: 94-96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81-87, any one of SEQ ID NOs: 88-90, any one of SEQ ID NOs: 91-93, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81-87, any one of SEQ ID NOs: 88-90, any one of SEQ ID NOs: 94-96, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81-87, any one of SEQ ID NOs: 91-93, any one of SEQ ID NOs: 94-96, and any one of SEQ ID NOs: 97-98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 88-90, any one of SEQ ID NOs: 91-93, any one of SEQ ID NOs: 94-96, and any one of SEQ ID NOs: 97-98.

[0307] In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 88 - 90, any one of SEQ ID NOs: 91 - 93, and any one of SEQ ID NOs: 94 - 96. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 88 - 90, any one of SEQ ID NOs: 91 - 93, and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 88 - 90, any one of SEQ ID NOs: 94 - 96, and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 91 - 93, any one of SEQ ID NOs: 94 - 96, and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 88 - 90, any one of SEQ ID NOs: 91 - 93, any one of SEQ ID NOs: 94 - 96, and any one of SEQ ID NOs: 97 - 98. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 88 - 90, any one of SEQ ID NOs: 91 - 93, any one of SEQ ID NOs: 94 - 96, and any one of SEQ ID NOs: 97 - 98.

[0308] In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 76 - 80, any one of SEQ ID NOs: 81 - 87, any one of SEQ ID NOs: 88 - 90, any one of SEQ ID NOs: 91 - 93, any one of SEQ ID NOs: 94 - 96, and any one of SEQ ID NOs: 97 - 98.

[0309] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 88. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82.

[0310] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76 and SEQ ID NO: 81. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76 and SEQ ID NO: 88. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76 and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76 and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81 and SEQ ID NO: 88. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81 and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81 and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 88 and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 88 and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 88 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 91 and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 91 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 94 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77 and SEQ ID NO: 82. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77 and SEQ ID NO: 88. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77 and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77 and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82 and SEQ ID NO: 88. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82 and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82 and SEQ ID NO: 94.In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 82 and SEQ ID NO: 97.

[0311] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 81, and SEQ ID NO: 88. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 81, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 81, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 81, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 88, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 88, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 88, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81, SEQ ID NO: 88, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81, SEQ ID NO: 88, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81, SEQ ID NO: 88, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 88, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97.In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 82, and SEQ ID NO: 88. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 82, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 82, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 82, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 88, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 88, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 88, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82, SEQ ID NO: 88, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82, SEQ ID NO: 88, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82, SEQ ID NO: 88, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82, SEQ ID NO: 94, and SEQ ID NO: 97.

[0312] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 88, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 88, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 88, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 88, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 76, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81, SEQ ID NO: 88, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 81, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 88, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 88, and SEQ ID NO: 94.In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 88, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 88, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 77, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82, SEQ ID NO: 88, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 82, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97.

[0313] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 88, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 76, SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 81, SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 94. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 88, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 88, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 82, SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97.

[0314] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 76, SEQ ID NO: 81, SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 77, SEQ ID NO: 82, SEQ ID NO: 88, SEQ ID NO: 91, SEQ ID NO: 94, and SEQ ID NO: 97.

[0315] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 78. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 83. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 92. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 97.

[0316] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 78 and SEQ ID NO: 83. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 78 and SEQ ID NO: 89. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 78 and SEQ ID NO: 92. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 78 and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 78 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 83 and SEQ ID NO: 89. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 83 and SEQ ID NO: 92. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 83 and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 83 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89 and SEQ ID NO: 92. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89 and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 92 and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 92 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 95 and SEQ ID NO: 97.

[0317] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, and SEQ ID NO: 89. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, and SEQ ID NO: 92. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 89, and SEQ ID NO: 92. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 89, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 89, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 92, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 92, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 89, and SEQ ID NO: 92. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 89, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 89, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 92, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 92, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 89, SEQ ID NO: 92, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 89, SEQ ID NO: 92, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 89, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 92, SEQ ID NO: 95, and SEQ ID NO: 97.

[0318] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 89, and SEQ ID NO: 92. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 89, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 89, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 92, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 92, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 89, SEQ ID NO: 92, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 89, SEQ ID NO: 92, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 89, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 92, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 89, SEQ ID NO: 92, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 89, SEQ ID NO: 92, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 89, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 92, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 89, SEQ ID NO: 92, SEQ ID NO: 95, and SEQ ID NO: 97.

[0319] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 89, SEQ ID NO: 92, and SEQ ID NO: 95. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 89, SEQ ID NO: 92, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 89, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 92, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 89, SEQ ID NO: 92, SEQ ID NO: 95, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 83, SEQ ID NO: 89, SEQ ID NO: 92, SEQ ID NO: 95, and SEQ ID NO: 97.

[0320] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 78, SEQ ID NO: 83, SEQ ID NO: 89, SEQ ID NO: 92, SEQ ID NO: 95, and SEQ ID NO: 97.

[0321] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 84. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 90. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 86.

[0322] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79 and SEQ ID NO: 84. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79 and SEQ ID NO: 90. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79 and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79 and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79 and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84 and SEQ ID NO: 90. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84 and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84 and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84 and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 90 and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 90 and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 90 and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 93 and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 93 and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 96 and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79 and SEQ ID NO: 86. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86 and SEQ ID NO: 90. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86 and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86 and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86 and SEQ ID NO: 98.

[0323] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 84, and SEQ ID NO: 90. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 84, and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 84, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 84, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 90, and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 90, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 90, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84, SEQ ID NO: 90, and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84, SEQ ID NO: 90, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84, SEQ ID NO: 90, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 90, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98.In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 86, and SEQ ID NO: 90. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 86, and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 86, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 86, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86, SEQ ID NO: 90, and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86, SEQ ID NO: 90, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86, SEQ ID NO: 90, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86, SEQ ID NO: 96, and SEQ ID NO: 98.

[0324] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 90, and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 90, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 90, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 90, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84, SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84, SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84, SEQ ID NO: 90, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 84, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 90, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 90, and SEQ ID NO: 93. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 90, and SEQ ID NO: 96.In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 90, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 86, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98.

[0325] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 90, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 90, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 84, SEQ ID NO: 90, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 93, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98.

[0326] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 84, SEQ ID NO: 90, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 79, SEQ ID NO: 86, SEQ ID NO: 90, SEQ ID NO: 93, SEQ ID NO: 96, and SEQ ID NO: 98.

[0327] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 87.

[0328] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80 and SEQ ID NO: 85. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80 and SEQ ID NO: 89. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80 and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80 and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85 and SEQ ID NO: 89. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85 and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85 and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89 and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89 and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 91 and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 91 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 96 and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80 and SEQ ID NO: 87. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 87 and SEQ ID NO: 89. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 87 and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 87 and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 87 and SEQ ID NO: 97.

[0329] In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 85, and SEQ ID NO: 89. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 85, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 85, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 85, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 89, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 89, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 89, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85, SEQ ID NO: 89, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85, SEQ ID NO: 89, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85, SEQ ID NO: 89, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 85, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 89, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97.In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, and SEQ ID NO: 89. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 87, SEQ ID NO: 89, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 87, SEQ ID NO: 89, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 87, SEQ ID NO: 89, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 87, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 87, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 87, SEQ ID NO: 96, and SEQ ID NO: 97.

[0330] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 89, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 89, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 89, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 85, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 89, and SEQ ID NO: 91. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 89, and SEQ ID NO: 96.In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 89, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure comprise SEQ ID NO: 87, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97.

[0331] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 96. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97.

[0332] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, and SEQ ID NO: 97.

[0333] In some embodiments, the antibodies or compounds of the present disclosure include any one of SEQ ID NOs: 99 - 113 It includes. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 114 to 123. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 124 to 131. In some embodiments, the antibody or compound of the present disclosure includes SEQ ID NO any one of 132 to 137. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 138 to 143. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 144 to 146.

[0334] In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 to 113 and any one of SEQ ID NOs: 114 to 123. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 to 113 and any one of SEQ ID NOs: 124 to 131 It includes. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 to 113 any one and any one of SEQ ID NOs: 132 to 137. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 to 113 and any one of SEQ ID NOs: 138 to 143 any one. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 to 113 It includes any one of them and any one of SEQ ID NOs: 144 to 146. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 114 to 123 and any one of SEQ ID NOs: 124 to 131. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 114 to 123 and any one of SEQ ID NOs: 132 to 137. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 114 to 123 and any one of SEQ ID NOs: 138 to 143. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 114 to 123 and any one of SEQ ID NOs: 144 to 146. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 124 to 131 and any one of SEQ ID NOs: 132 to 137. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 124 to 131 and any one of SEQ ID NOs: 138 to 143. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 124 to 131 and any one of SEQ ID NOs: 144 ~ 146. In some embodiments, the antibody or compound of the present disclosure includes any one of the sequences from SEQ ID NOs: 132 to 137 and any one of SEQ ID NOs: 138 to 143. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 132 to 137 and any one of SEQ ID NOs: 144 to 146. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 138 to 143 and any one of SEQ ID NOs: 144 to 146.

[0335] In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 to 113 , any one of SEQ ID NOs: 114 to 123 and any one of SEQ ID NOs: 124 to 131. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 to 113, any one of the sequences It includes any one of numbers 114 to 123 and any one of sequence numbers 132 to 137. In some embodiments, the antibody or compound of the present disclosure includes any one of sequence numbers 99 to 113, any one of sequence numbers 114 to 123 and any one of sequence numbers 138 to 143. In some embodiments the antibody or compound of the present disclosure includes any one of sequence numbers 99 to 113, sequence numbers 114 to 123 any one of and any one of sequence numbers 144 to 146. In some embodiments, the antibody or compound of the present disclosure includes any one of sequence numbers 99 to 113, any one of sequence numbers 124 to 131 any one of and any one of sequence numbers 132 to 137. In some embodiments, the antibody or compound of the present disclosure includes any one of sequence numbers 99 to 113, any one of sequence numbers 124 to 131 any one of and any one of sequence numbers 138 to 143. In some embodiments, the antibody or compound of the present disclosure includes any one of sequence numbers 99 to 113, any one of sequence numbers 124 to 131 and any one of sequence numbers 144 to 146. In some embodiments, the antibody or compound of the present disclosure includes any one of sequence numbers 99 to 113, any one of sequence numbers 132 to 137 and any one of sequence numbers 138 to 143. In some embodiments, the antibody or compound of the present disclosure includes any one of sequence numbers 99 to 113, any one of sequence numbers 132 to 137 and any one of sequence numbers 144 to 146. In some embodiments, the antibody or compound of the present disclosure includes any one of sequence numbers 99 to 113, any one of sequence numbers 138 to 143 and sequence numbers 144 to 146 comprises any one of the following. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 124 - 131, and any one of SEQ ID NOs: 132 - 137. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 124 - 131, and any one of SEQ ID NOs: 138 - 143. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 124 - 131, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 132 - 137, and any one of SEQ ID NOs: 138 - 143. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 132 - 137, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 132 - 137, and any one of SEQ ID NOs: 138 - 143. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 132 - 137, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 132 - 137, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146.

[0336] In some embodiments, the antibody or compound of the present disclosure comprises any one of SEQ ID NOs: 99 - 113 , any one of SEQ ID NOs: 114 to 123, any one of SEQ ID NOs: 124 to 131, and any one of SEQ ID NOs: 132 to 137. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 to 113, any one of SEQ ID NOs: 114 to 123, any one of SEQ ID NOs: 124 to 131, and any one of SEQ ID NOs: 138 to 143. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 to 113, any one of SEQ ID NOs: 114 to 123, any one of SEQ ID NOs: 124 to 131, and any one of SEQ ID NOs: 144 to 146. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 to 113, any one of SEQ ID NOs: 114 to 123, any one of SEQ ID NOs: 132 to 137, and SEQ ID NO NO: 138 to 143. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 to 113, any one of SEQ ID NOs: 114 to 123, any one of SEQ ID NOs: 132 to 137, and any one of SEQ ID NOs: 144 to 146. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 to 113, any one of SEQ ID NOs: 114 to 123, any one of SEQ ID NOs: 138 to 143, and any one of SEQ ID NOs: 144 to 146. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 to 113, any one of SEQ ID NOs: 124 to 131, any one of SEQ ID NOs: 132 to 137, and SEQ ID NO NO: 138 to 143. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 to 113, any one of SEQ ID NOs: 124 to 131, any one of SEQ ID NOs: 132 to 137, and any one of SEQ ID NOs: 144 to 146. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 to 113, any one of SEQ ID NOs: 124 to 131, 1. It includes any one of SEQ ID NOs: 138 - 143 and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 - 113, any one of SEQ ID NOs: 132 - 137, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 132 - 137, and any one of SEQ ID NOs: 138 - 143. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 132 - 137, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 132 - 137, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 132 - 137, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146.

[0337] In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 - 113 、any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 132 - 137, and any one of SEQ ID NOs: 138 - 143. In some embodiments, the antibody or compound of the present disclosure is any one of SEQ ID NOs: 99 - 113, any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: It includes any one of the following: any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 132 - 137, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 - 113, any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 - 113 any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 132 - 137, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 - 113, any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 132 - 137, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146. In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 132 - 137, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146.

[0338] In some embodiments, the antibody or compound of the present disclosure includes any one of SEQ ID NOs: 99 - 113 any one of SEQ ID NOs: 114 - 123, any one of SEQ ID NOs: 124 - 131, any one of SEQ ID NOs: 132 - 137, any one of SEQ ID NOs: 138 - 143, and any one of SEQ ID NOs: 144 - 146.

[0339] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 103, SEQ ID NO: 118, SEQ ID NO: 125, SEQ ID NO: 132, SEQ ID NO: 140, and SEQ ID NO: 144. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 108, SEQ ID NO: 123, SEQ ID NO: 127, SEQ ID NO: 135, SEQ ID NO: 143, and SEQ ID NO: 145. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 113, SEQ ID NO: 123, SEQ ID NO: 130, SEQ ID NO: 135, SEQ ID NO: 143, and SEQ ID NO: 145.

[0340] In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 103, SEQ ID NO: 118, SEQ ID NO: 125 , SEQ ID NO: 132, SEQ ID NO: 140, and SEQ ID NO: 144. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 103, SEQ ID NO: 118, SEQ ID NO: 125, SEQ ID NO: 132, SEQ ID NO: 140, and SEQ ID NO: 144. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80 , SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 108, SEQ ID NO: 123, SEQ ID NO: 127, SEQ ID NO: 135, SEQ ID NO: 143, and SEQ ID NO: 145. In some embodiments In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 108, SEQ ID NO: 123, SEQ ID NO: 127, SEQ ID NO: 135, SEQ ID NO: 143, and SEQ ID NO: 145. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 85, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 113, SEQ ID NO: 123, SEQ ID NO: 130, SEQ ID NO: 135, SEQ ID NO: 143, and SEQ ID NO: 145. In some embodiments, the antibodies or compounds of the present disclosure include SEQ ID NO: 80, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 113, SEQ ID NO: 123, SEQ ID NO: 130, SEQ ID NO: 135, SEQ ID NO: 143, and SEQ ID NO: 145

Example

[0341] (Example 1) Tetravalent bispecific antibody containing antibody HC2:LC1 and aflibercept-derived sequences To generate a tetravalent bispecific antibody in which the heavy chain of antibody HC2:LC1 is fused with a VEGF-binding domain derived from aflibercept, an amino acid sequence containing the following N-terminal to C-terminal amino acid sequences was generated: 1) SEQ ID NO: 14 (heavy chain of antibody HC2:LC1); 2) SEQ ID NO: 31 (linker peptide, underlined); and 3) SEQ ID NO: 22 (aflibercept-derived sequence).

[0342] The resulting polypeptide (SEQ ID NO: 149) was co-expressed with SEQ ID NO: 17 to provide a tetravalent bispecific antibody HC2-AFL:LC1 containing the sequences shown in Table 33. Amino acids 1-19 of SEQ ID NO: 149 are the heavy chain signal peptide (SEQ ID NO: 11). Amino acids 1-20 of SEQ ID NO: 17 are the light chain signal peptide (SEQ ID NO: 12). In some embodiments, mature HC2-AFL:LC1 does not contain a signal peptide. For example, mature HC2-AFL:LC1 of the present disclosure may include SEQ ID NO: 254 and SEQ ID NO: 250.

Table 33

[0343] To generate a tetravalent bispecific antibody in which the heavy chain of antibody HC2:LC1 is fused with a VEGF-binding domain derived from brolucizumab, an amino acid sequence containing the following N-terminal to C-terminal amino acid sequences was generated: 1) SEQ ID NO: 14 (heavy chain of antibody HC2:LC1); 2) SEQ ID NO: 31 (linker peptide, underlined); and 3) SEQ ID NO: 23 (sequence derived from brolucizumab).

[0344] The resulting polypeptide (SEQ ID NO: 150) was co-expressed with SEQ ID NO: 17 to provide a tetravalent bispecific antibody HC2-BRO:LC1 containing the sequence shown in Table 34. Amino acids 1-19 of SEQ ID NO: 150 are the heavy chain signal peptide (SEQ ID NO: 11). Amino acids 1-20 of SEQ ID NO: 17 are the light chain signal peptide (SEQ ID NO: 12). In some embodiments, mature HC2-BRO:LC1 does not contain a signal peptide. For example, mature HC2-BRO:LC1 of the present disclosure may contain SEQ ID NO: 255 and SEQ ID NO: 250.

Table 34-1

Table 34-2

[0345] To generate a tetravalent bispecific antibody in which the heavy chain of antibody HC2:LC1 is fused with a VEGF-binding domain derived from ranibizumab, an amino acid sequence containing the following N-terminal to C-terminal amino acid sequences was generated: 1) SEQ ID NO: 14 (heavy chain of antibody HC2:LC1); 2) SEQ ID NO: 31 (linker peptide, underlined); and 3) SEQ ID NO: 28 (ranibizumab-derived sequence).

[0346] The obtained polypeptide (SEQ ID NO: 151) was co-expressed with SEQ ID NO: 17 to provide a tetravalent bispecific antibody HC2-RAN:LC1 containing the sequences shown in Table 35. Amino acids 1 to 19 of SEQ ID NO: 151 are the heavy chain signal peptide (SEQ ID NO: 11). Amino acids 1 to 20 of SEQ ID NO: 17 are the light chain signal peptide (SEQ ID NO: 12). In some embodiments, mature HC2-RAN:LC1 does not contain a signal peptide. For example, mature HC2-RAN:LC1 of the present disclosure may contain SEQ ID NO: 256 and SEQ ID NO: 250.

Table 35-1

Table 35-2

[0347] The following multispecific antibodies of the present disclosure were generated: (i) HC2-RAN:LC1, (ii) HC2-AFL:LC1, (iii) HC2-BRO:LC1, (iv) HC2-ABI:LC1, (v) HC2:LC1-AFL, (vi) HC2:LC1-BRO, (vii) HC2:LC1-ABI, (viii) HC2-AFL:LC1-AFL, (ix) HC2-BRO:LC1-BRO, and (x) HC2-ABI:LC1-ABI. Enzyme-linked immunosorbent assay (ELISA) was p...

Claims

[Claim 1] The invention described in the specification.

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