HUMAN ANTI-VSIG4 ANTIBODIES AND THEIR USES

Abstract

Antibodies and antigen-binding fragments thereof that bind to VSIG4 are provided. Various in vitro and in vivo methods and antibody-related compositions are described. The methods include the prevention and / or therapeutic treatment of cancer using an antibody or an antigen-binding fragment.

Description

HUMAN ANTI-VSIG4 ANTIBODIES AND THEIR USES CROSS-REFERENCE WITH RELATED APPLICATIONS This application is a PCT application claiming priority and benefit from U.S. Provisional Patent Application No. e62 / 738,255, filed September 28, 2018, and U.S. Provisional Patent Application No. s62 / 776,523, filed December 7, 2018. The disclosures of the prior applications are incorporated herein by reference in their entirety. FIELD OF INVENTION This disclosure relates to antibodies and antigen-binding fragments that bind to V-Set and the immunoglobulin domain containing 4 (VSIG4). BACKGROUND Cancer remains one of the leading causes of death worldwide. Recent statistics report that 13% of the global population dies from cancer. According to estimates from the International Agency for Research on Cancer (IARC), in 2012 there were 14.1 million new cancer cases and 8.2 million cancer deaths worldwide. By 2030, the global burden is expected to increase to 21.7 million new cancer cases and 13 million cancer deaths due to population growth and aging, as well as exposure to risk factors such as smoking, unhealthy diets, and physical inactivity. Furthermore, the pain and medical expenses associated with cancer treatment reduce the quality of life for both cancer patients and their families. Clearly, cancer is a disease for which better treatment methods urgently need to be found. Macrophages are multifunctional antigen-presenting cells that play a central role in our immune system and are relevant to cancer biology. In the context of cancer, tumor-associated macrophages (TAMs) infiltrate the tissues of malignant tumors and are known to be relevant to cancer biology and the influence of tumor progression. TAMs can be described as belonging to two categories: M1 and M2. M1 macrophages are observed to have a pro-inflammatory and cytotoxic (antitumor) function, while M2 macrophages are anti-inflammatory (protumor) and promote wound healing. According to these functions, TAMs, IVIA / t / ZUZ I / U4O0O0, especially macrophages with the M2 phenotype, are strongly associated with a worse clinical prognosis in many types of malignant tumors. The infiltrating TAMs themselves or the TAM polarization pathway are considered novel therapeutic targets for malignant tumor therapy. BRIEF DESCRIPTION OF THE INVENTION This disclosure relates, at least in part, to antibodies and fragments thereof that bind to VSIG4 (V-Set and immunoglobulin domain containing 4; also referred to as CRIg or Z39lg), and methods of using such antibodies and antigen-binding fragments to treat cancer, induce cytokine and / or chemokine secretion in macrophages, and convert M2 macrophages into M1 macrophages. In one aspect, the present invention relates to an isolated humanized antibody or antigen-binding fragment comprising: (a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 18, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 19; and (b) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 20, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 22 or SEQ ID NO: 23. In some embodiments, the antibody or antigen-binding fragment described herein may include any of: (a) a heavy-chain variable domain comprising an amino acid sequence at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14, or SEQ ID NO: 16; (b) a light-chain variable domain comprising an amino acid sequence at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 10, or SEQ ID NO: 12;or (c) a heavy-chain variable domain comprising an amino acid sequence at least 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14 or SEQ ID NO: 16, and a light-chain variable domain comprising an amino acid sequence at least 80%, the; Ma / E / ZUZI / U4OOOD %, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 8, SEO ID NO: 10 or SEO ID NO: 12. In some embodiments, the antibody or antigen-binding fragment described herein may include any of, a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14 or SEQ ID NO: 16, a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 10 or SEQ ID NO: 12 or a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14 or SEQ ID NO: 16, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 10 or SEQ ID NO: 12. In some embodiments, the antibody or antigen-binding fragment described herein may include a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the antibody or antigen-binding fragment described herein may include a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 4. In some embodiments, the antibody or antigen-binding fragment described herein may include a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the antibody or antigen-binding fragment may include a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 10.In some embodiments, the antibody or antigen-binding fragment may include a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody or antigen-binding fragment described herein may include a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody or antigen-binding fragment described herein may include a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody or antigen-binding fragment described herein has a binding affinity (Kd) for a human V-set immunoglobulin domain-containing 4 (VSIG4) molecule of 1 x 10⁷ to 1 x 10⁹. In some embodiments, the antibody or antigen-binding fragment described herein has a binding affinity (Kd) for a VSIG4 molecule of approximately 7.156 x 10⁸ to approximately 7.636 x 10⁹. In some embodiments, the antibody or antigen-binding fragment described herein has a binding affinity (Kd) for a VSIG4 molecule of approximately 7.156 x 10⁸, approximately 7.636 x 10⁹, approximately 7.952 x 10⁹, approximately 8.226 x 10⁻⁹, or approximately 8.688 x 10⁹. In another aspect, the present invention relates to a nucleic acid molecule that encodes any of the antigen- or antibody-binding fragments described herein. In another aspect, the present invention relates to a recombinant vector comprising any of the nucleic acid molecules described herein. In some embodiments, the recombinant vector described herein contains the nucleic acid molecule described herein operatively linked to a promoter. In some embodiments, the recombinant vector comprises two separate vectors, each comprising the nucleic acid sequence corresponding to the heavy and light chains of the antibody or antigen-binding fragment provided herein. In another aspect, the present invention provides a host cell comprising the nucleic acid molecule or recombinant vector described herein. In some embodiments, the host cell is a mammalian cell, a yeast cell, or a bacterial cell. In some embodiments, the host cell is a cell selected from the group consisting of E. coli, P. pastoris, Sf9, COS, HEK293, Exp1293, CHO-S, CHO-DG44, CHO-K1, and a mammalian lymphocyte. In some embodiments, the host cell is the Exp1293 cell. In another aspect, the present invention relates to a composition IVIA / I / U4O0O0 pharmaceutical that includes: any of the antigen- or antibody-binding fragments described herein, any of the nucleic acid molecules described herein, any of the recombinant vectors described herein, or any of the host cells described herein; and a pharmaceutically acceptable vehicle. By way of further example, in another aspect, the present invention relates to a method for treating a subject in need, the method comprising the steps of: (a) administering to the subject a composition comprising or administering any of the antigen-binding fragments or antibodies described herein, any of the nucleic acid molecules described herein, any of the recombinant vectors described herein, or any of the host cells described herein, thereby treating a disease or condition. In some embodiments, the subject has, or is at risk of developing, cancer.In some embodiments, the cancer is selected from bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gallbladder cancer, gastrointestinal cancer, head and neck cancer, hematologic cancer, laryngeal cancer, liver cancer, lung cancer, lymphoma, melanoma, mesothelioma, ovarian cancer, primary peritoneal cancer, salivary gland cancer, sarcoma, stomach cancer, thyroid cancer, pancreatic cancer, renal cell carcinoma, glioblastoma, and prostate cancer. In some embodiments, the subject has been or will be administered one or more additional cancer therapies selected from ionizing radiation, a chemotherapeutic agent, an antibody agent, and a cell-based therapy, such that the subject receives treatment with both. For example, in some embodiments, the one or more additional cancer therapies may include an immune checkpoint inhibitor, IL-12, GM-CSF, an anti-CD4 agent, cisplatin, fluorouracil, doxorubicin, irinotecan, paclitaxel, an indolamine 2,3-dioxygenase-1 inhibitor (IDOI), or cyclophosphamide. In another aspect, the present invention also relates to a method for increasing the secretion of cytokines or chemokines in M2 macrophages, including the method of contacting M2 macrophages with any of the antibodies or IVIA / I / U4O0O0 antigen-binding fragments described in this document. In another aspect, the present invention relates to a method for inducing the proliferation of CD8+ T lymphocytes, including the method of: (a) contacting an M2 macrophage with any of the antigen-binding fragments or antibodies described herein; and (b) co-incubating the M2 macrophage with CD8+ T lymphocytes. In another aspect, the present invention also relates to a method for converting an M2 macrophage into an M1 macrophage, including the method of contacting the M2 macrophage with any of the antibodies or antigen-binding fragments described herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention pertains. Although methods and materials similar to or equivalent to those described herein may be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, this specification, including the definitions, shall prevail. Furthermore, the materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. Other features and advantages of the invention will become evident from the following detailed description and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 is a schematic diagram illustrating the mechanism of how the administration of anti-VSIG4 antibody to macrophages results in the conversion of M2 macrophages to M1 macrophages, resulting in the proliferation of CD8+ T lymphocytes and subsequent cancer suppression. FIGURE 2A shows the alignment of VSIG4 sequences with various human B7 family proteins. FIGURE 2B is a phylogenetic tree showing the evolutionary relationship between VSIG4 and various proteins of the human B7 family. Figures 3A and 3B show the correlation of VSIG4 mRNA expression with several genes in tumor tissue. IVIA / I / U4O0O0 FIGURE 4A is an HPLC graph showing the protein profile of antibody EU103.2. FIGURE 4B is a surface plasmon resonance data showing the binding of antibody EU103.2 to VSIG4. FIGURE 5 shows light microscope images of M1 and M2 macrophages (top left and top right, respectively), and FACS analysis data showing VSIG4 expression in M1 and M2 macrophages. FIGURE 6 is a set of graphs showing the induction of proinflammatory cytokines and chemokines in M1 and M2 macrophages by EU103.2. FIGURE 7 is a set of FACS data showing reduced CD163 expression in M2 macrophages treated with EU103.2. FIGURE 8 is a set of FACS data (first six columns) and the quantification of these data (last column) showing the induction of CD8+ T lymphocyte proliferation when CD8+ T lymphocytes were co-cultured with EU103.2-treated M2 macrophages. FIGURE 9 is a FACS dataset showing VSIG4 expression in macrophages isolated from abdominal fluid of patients with ovarian cancer. FIGURE 10 is a FACS dataset showing the induction of CD8+ T lymphocyte proliferation when co-cultured with EU103.2-treated macrophages isolated from ovarian cancer patients. FIGURE 11 is a graph showing the induction of CD8+ T lymphocyte proliferation when co-cultured with anti-EU103.2 treated macrophages isolated from ovarian cancer patients. FIGURE 12 is a set of microscopic images of M1 and M2 macrophages showing morphological differences after the conversion of M2 macrophages into M1 macrophages by the EU103.2 antibody. FIGURE 13 is a FACS dataset showing that the blocking interaction between CD8+ cells and VSIG4 enhances CD8+ T lymphocyte proliferation. FIGURES 14A and 14B are sets of graphs showing enhanced CD8+ cell proliferation blocking suppression by THP-1 cells. FIGURES 15A-15C are sets of graphs showing the antitumor activities of the anti-VSIG4 antibody in three different mouse tumor models. IVIA / I / U4O0O0 FIGURE 16 is a set of graphs showing the antitumor activities of the anti-VSIG4 antibody in a mouse model with VSIG4 inactivation. FIGURE 17A is a FACS dataset showing the activation state of T lymphocytes and MDSCs in TDLN in the absence of VSIG4 signaling. FIGURE 17B is a set of graphs showing the activation state of T lymphocytes and MDSCs in TDLN in the absence of VSIG4 signaling. FIGURE 17C is a set of graphs showing the activation state of T lymphocytes and MDSCs in TDLN in the absence of VSIG4 signaling. FIGURE 17D is a set of graphs showing the activation state of T lymphocytes and MDSCs in TDLN in the absence of VSIG4 signaling. FIGURE 18A is a graph showing the suppression of tumor growth in the absence of VSIG4 signaling. FIGURE 18B is a set of histological slides showing suppression of tumor growth in the absence of VSIG4 signaling. FIGURE 19 is a graph showing the antitumor activities of the anti-VSIG4 antibody in a humanized mouse model. FIGURE 20 is a schematic diagram illustrating the mechanism of how administration of antibody EU 103.2 to macrophages results in the conversion of M2 macrophages to M1 macrophages, resulting in the proliferation of CD8+ T lymphocytes. FIGURES 21A and 21B are schematic diagrams showing the expression vectors used to clone and express humanized anti-VSIG4 antibodies. FIGURE 22 is an HPLC graph showing the protein profile of antibody A1 (EU103_T01.01). FIGURE 23 is an HPLC graph showing the protein profile of antibody A2 (EU103_T01.02). FIGURE 24 is an HPLC graph showing the protein profile of antibody A1.3 (EU103_T01.01S). FIGURE 25 is an HPLC graph showing the protein profile of antibody A2.3 (EU103_T01.02S). FIGURE 26A is a set of FACS data showing reduced CD163 expression in M2 macrophages treated with A1 or A2 antibodies. IVIA / t / ZUZ I / U4O0O0 FIGURE 26B is a graph showing the reduced expression of CD163 in M2 macrophages treated with A1 or A2 antibodies. FIGURE 27 is a set of graphs showing the reduction of M2-type cytokines and chemokines in M2 cells treated with A1 or A2 antibodies. FIGURE 28 is a set of FACS data showing reduced CD163 expression and increased CD86 expression in M2 macrophages treated with A1 or A2 antibodies. FIGURE 29 is a set of graphs showing the increased expression of M1-type cytokines / chemokines in M2 macrophages treated with A1 or A2 antibodies. FIGURE 30 is a graph showing data from a chemotaxis assay that measures the chemotactic capacity of macrophages after the conversion of M2 macrophages to M1 by A2 antibodies. Figures 31A-31C show the antitumor effect of A1 and A2 antibodies in a humanized mouse model. FIGURES 32A-32C show the conversion of macrophages with A2 antibodies in vivo. FIGURES 33A and 33B show the conversion of macrophages with A2 antibodies in vivo analyzing the effect of M2 to M1 macrophage conversion on tumor growth. Figures 34A-34E show the antitumor effect of A2 antibodies in a humanized mouse model. Figures 35A-35D show the antitumor effect of A2 and A2.3 antibodies in a humanized mouse model. FIGURES 36A and 36B are a co-culture assay data set showing that co-cultures of antibodies A1, A1.3, A2 and A2.3 and M2 macrophages showed increased proliferation of CD8+ T lymphocytes. FIGURE 37 is a graph showing data from a co-culture assay showing A2 and A2.3 antibody co-cultures with M2 macrophages that showed increased CD8+ T lymphocyte proliferation. FIGURES 38A and 38B are sets of graphs showing the use of HeLa-hVSIG4 cells expressing hVSIG4 to observe the proliferation of CD8+ T lymphocytes by A2 or A2.3 antibodies. FIGURE 39 is a graph showing the use of a human kinase IVIA / t / ZUZ I / U4O0O0 phosphorus array to observe the A2 antibody macrophage conversion signal pathway. FIGURE 40 shows the sequence alignment of heavy and light chains of humanized EU103.3, A1, A2, A1.3 and A2.3 antibodies. FIGURE 41 shows the generation and characterization of mice with VSIG4 inactivation (K / O). FIGURE 42 shows gene array analysis data that demonstrate a change in gene expression after the conversion of M2 macrophages to M1 macrophages by A2 antibodies. DETAILED DESCRIPTION The present invention is based, at least in part, on the discovery that inhibition of the interaction of VSIG4 with CD8+ T lymphocytes using certain anti-VSIG4 antibodies results in the proliferation of CD8+ T lymphocytes, which can lead to cancer suppression. As used herein, the term "approximately," when used herein in reference to a value, refers to a value that is similar, in context, to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the degree of relevant variation encompassed by "approximately" in that context. For example, in some embodiments, the term "approximately" may encompass a range of values ​​that are within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referenced value. As used herein, the term administration typically refers to the delivery of a composition to a subject or system to achieve the release of an agent that is in or included in the composition. Those skilled in the art will be familiar with a variety of routes that may, under appropriate circumstances, be used for administration to a subject, e.g., a human being. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, e.g., one or more of the following: topical to the dermis, intradermal, interdermal, transdermal, etc.), enteric, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intrapenetumoral, intrathecal, intravenous, IVIA / I / U4O0O0 intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreous, etc. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve the application of a fixed number of doses. In some embodiments, administration may involve intermittent dosing (e.g., a plurality of doses separated in time) and / or periodic dosing (e.g., individual doses separated by a common time period). In some embodiments, administration may involve continuous dosing (e.g., infusion) for at least a selected time period. As used herein, the term affinity typically refers to a measure of the tension with a particular ligand that binds to its partner. Affinities can be measured in various ways. In some embodiments, affinity is measured by a quantitative assay. In some of these embodiments, the concentration of the binding member can be set higher than the ligand concentration to mimic physiological conditions. Alternatively or additionally, in some embodiments, the concentration of the binding member and / or the ligand concentration can be varied. In some of these embodiments, the affinity can be compared to a reference under comparable conditions (e.g., concentrations). As used herein, the term affinity maturation refers to a process in which an antibody is developed from a reference antibody (also referred to herein as a template or original antibody), typically by mutating one or more amino acid residues, to have greater activity against a target antigen than the corresponding form of the reference antibody has against the same target antigen. The developed antibody is thus optimized compared to the reference or template antibody. As used herein, the term affinity-matured antibody typically refers to an antibody that has increased activity against a target antigen relative to a reference antibody. In some embodiments, the affinity-matured antibody exhibits increased binding to the target antigen compared to the reference or original antibody.Typically, the affinity-matured antibody binds to the same epitope as the reference antibody. IVIA / I / U4O0O0 As used herein, the term antibody refers to a polypeptide that includes sufficient canonical immunoglobulin sequence elements to confer specific binding to a particular target antigen. As known in the art, intact antibodies, as produced in nature, are tetrameric agents of approximately 150 kDa composed of two identical heavy-chain polypeptides (approximately 50 kDa each) and two identical light-chain polypeptides (approximately 25 kDa each) that associate with each other in what is commonly known as a Y-shaped structure. Each heavy chain is composed of at least four domains (each approximately 110 amino acids long): an amino-terminal variable domain (VH) (located at the tips of the Y structure), followed by three constant domains: CH1, CH2, and the carboxy-terminal CH3 (located at the base of the Y stem).A short region, known as the switch, connects the variable and constant regions of the heavy chain. The hinge connects the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in this hinge region connect the two heavy-chain polypeptides to each other in an intact antibody. Each light chain is composed of two domains: an amino-terminal variable domain (VL), followed by a carboxy-terminal constant domain (CL), separated from each other by another switch. Tetramers of intact antibodies are composed of two heavy-chain-light-chain dimers in which the heavy and light chains are linked by a single disulfide bond; two other disulfide bonds connect the heavy-chain hinge regions to each other, so that the dimers connect to each other and form the tetramer. Naturally produced antibodies are also glycosylated, usually in the CH2 domain.Each domain in a natural antibody has a structure characterized by an immunoglobulin fold formed from two beta sheets (e.g., 3-, 4-, or 5-chain sheets) packed against each other in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops known as complementarity-determining regions (CDR1, CDR2, and CDR3) and four somewhat invariant framework regions (FR1, FR2, FR3, and FR4). When natural antibodies fold, the FR regions form the beta sheets that provide the structural framework for the domains, and the CDR loop regions of the heavy and light chains bind in three-dimensional space to create a single hypervariable antigen-binding site located at the tip of the Y-shaped structure. This is the Fe region of the antibodies. The naturally occurring IVIA / t / ZUZ I / U4O0O0 binds to elements of the complement system and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. As known in the art, the affinity and / or other binding attributes of the Fe regions for Fe receptors can be modulated by glycosylation or other modification. In some embodiments, antibodies produced and / or used according to the present invention include glycosylated Fe domains, including Fe domains with such glycosylation modified or genetically engineered.For the purposes of the present invention, in certain embodiments, any polypeptide or polypeptide complex that includes sufficient immunoglobulin domain sequences such as those found in natural antibodies may be designated and / or used as an antibody, whether such polypeptide is naturally occurring (e.g., generated by an organism reacting to an antigen) or produced by recombinant engineering, chemical synthesis, or other artificial means or methods. In some embodiments, an antibody is polyclonal; in some embodiments, an antibody is monoclonal. In some embodiments, an antibody has constant region sequences that are characteristic of mouse, rabbit, primate, or human antibodies. In some embodiments, the antibody sequence elements are humanized, primatized, chimeric, etc., as known in the art.Furthermore, the term antibody, as used herein, may refer in appropriate embodiments (unless otherwise stated or clear from the context) to any of the constructs or formats developed or known in the art to utilize structural and functional features of antibodies in an alternative presentation.For example, in embodiments, an antibody used according to the present invention is in a format selected from, but not limited to, intact IgA, IgG, IgE, or IgM antibodies; bispecific or multispecific antibodies (e.g., Zybodies®, etc.); antibody fragments such as Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, and isolated CDRs or assemblies thereof; single-stranded Fvs; polypeptide-Fc fusions; single-domain antibodies (e.g., shark single-domain antibodies such as IgNAR or fragments thereof); cameloid antibodies; masked antibodies (e.g., Probodies®); small modular immunopharmaceuticals (SMIPs™); single-stranded or tandem diabodies (TandAb®); humabodies, VHHs; Anticalins®; Nanobodies® minibodies; B¡TE®s; repeat proteins. IVIA / t / ZUZ I / U4O0O0 ankyrin or DARPINs®; Avimers®; DART; TCR-like antibodies; Adnectins®; Affilins®; Trans-bodies®; Affibodies®; TrimerX®; microproteins; Fynomers®, Centyrins®; and KALBITOR®s. In some embodiments, an antibody may lack a covalent modification (e.g., glycan attachment) that it would have if it occurred naturally. In some embodiments, an antibody may contain a covalent modification (e.g., glycan attachment, a payload [e.g., a detectable fragment, a therapeutic moiety, a catalytic moiety, etc.], or another dangling group [e.g., polyethylene glycol, etc.]. As used herein, an antibody fragment refers to a portion of an antibody or antibody agent as described herein, and typically refers to a portion that includes an antigen-binding portion or a variable region thereof. An antibody fragment may be produced by any means. For example, in some embodiments, an antibody fragment may be produced enzymatically or chemically by fragmenting an intact antibody or antibody agent. Alternatively, in some embodiments, an antibody fragment may be produced recombinantly (i.e., by expressing a genetically engineered nucleic acid sequence). In some embodiments, an antibody fragment may be produced entirely or partially synthetically.In some embodiments, an antibody fragment (particularly an antigen-binding antibody fragment) may have a length of at least approximately 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 amino acids or more, in some embodiments at least approximately 200 amino acids. As used herein, the term bonding typically refers to a non-covalent association between two or more entities. Direct bonding involves physical contact between entities or fragments; indirect bonding involves physical interaction through physical contact with one or more intervening entities. Bonding between two or more entities can typically be assessed in any of a variety of contexts, including when the interacting entities or fragments are studied in isolation or in the context of more complex systems (e.g., while covalently or otherwise associated with a vehicle entity and / or in a biological system or cell). As used in this document, the terms cancer, malignancy, The terms neoplasia, tumor, and carcinoma typically refer to cells that exhibit relatively abnormal, uncontrolled, and / or autonomous growth, such that they present an aberrant growth phenotype characterized by a significant loss of control over cell proliferation. In some embodiments, a tumor may be or comprise precancerous (e.g., benign), malignant, premetastatic, metastatic, and / or nonmetastatic cells. This disclosure specifically identifies certain cancers for which its teachings may be particularly relevant. In some embodiments, a relevant cancer may be characterized as a solid tumor. In some embodiments, a relevant cancer may be characterized as a hematologic tumor.In general, examples of different types of cancers known to the technique include, for example, hematopoietic cancers, including leukemias, lymphomas (Hodgkin and non-Hodgkin), myelomas and myeloproliferative disorders; sarcomas, melanomas, adenomas, solid tissue carcinomas, squamous cell carcinomas of the mouth, throat, larynx and lung, liver cancer, genitourinary cancers such as prostate, cervical, bladder, uterine and endometrial cancer and renal cell carcinomas, bone cancer, pancreatic cancer, skin cancer, cutaneous or infraocular melanoma, endocrine system cancer, thyroid gland cancer, parathyroid gland cancer, head and neck cancers, breast cancer, gastrointestinal cancers and cancers of the nervous system, benign lesions such as papillomas and the like. As used herein, the term CDR refers to a complementarity-determining region within an antibody variable region. There are three CDRs in each of the heavy chain and light chain variable regions, designated CDR1, CDR2, and CDR3, respectively. A set of CDRs, or CDR group, refers to a group of three or six CDRs occurring in a single antigen-binding variable region or in the CDRs of related heavy and light chain antigen-binding variable regions. Certain systems have been established in the art for defining CDR boundaries (e.g., Kabat, Chothia, etc.); those skilled in the art appreciate the differences between these systems and are able to understand the CDR boundaries to the extent necessary to understand and implement the claimed invention. As used herein, the term chemotherapeutic agent has its technically understood meaning to refer to one or IVIA / t / ZUZ I / U4O0O0 plus pro-apoptotic, cytostatic, and / or cytotoxic agents, for example, specifically including agents used and / or recommended for use in the treatment of one or more diseases, disorders, or conditions associated with undesirable cell proliferation. In many embodiments, chemotherapeutic agents are useful in the treatment of cancer.In some embodiments, a chemotherapeutic agent may be or comprise one or more alkylating agents, one or more anthracyclines, one or more cytoskeletal disruptors (e.g., microtubule-targeting agents such as taxanes, maytansine and analogues thereof), one or more epotylones, one or more histone deacetylase (HDAC) inhibitors, one or more topoisomerase inhibitors (e.g., topoisomerase I and / or topoisomerase II inhibitors), one or more kinase inhibitors, one or more nucleotide analogues or nucleotide precursor analogues, one or more peptide antibiotics, one or more platinum-based agents, one or more retinoids, one or more vinca alkaloids, and / or one or more analogues of one or more of the following (i.e., sharing relevant antiproliferative activity).In some particular embodiments, a chemotherapeutic agent may be or comprise one or more of actinomycin, all-trans retinoic acid, auristatin, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, curcumin, cytarabine, daunorubicin, docetaxel, doxyfluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, maytansine and / or analogues thereof (e.g., DM1), mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, a maytansine, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, Topotecan, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof. In some embodiments, a chemotherapeutic agent may be used in the context of an antibody-drug conjugate.In some embodiments, a chemotherapeutic agent is one contained in an antibody-drug conjugate selected from the group consisting of: hLL1-doxorubicin, hRS7-SN-38, hMN-14SN-38, hLL2-SN-38, hA20-SN-38, hLL2-SN-38, hA20-SN-38, hLL1-SN-38, hRS7-Pro-2-P-Dox, hMN-14-Pro-2-P-Dox, hLL2-Pro-2-P-Dox, hA20-Pro-2-P-Dox, hPAM4-Pro-2-P-Dox, hLL1-Pro-2-P-Dox, P4 / D10-dox, ogemortubicin, ogemortubicin brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamycin, glembatumomab vedotin, SAR3419, SAR566658, BIIBO15, BT062, SGN-75, SGN-CD19A, AMG-172, AMG-595, SGN-ME-9345, SGN-ME ASG-22ME, ASG-16M8F, MDX-1203, MLNIVIA / I / U4O0O0. 0264, anti-PSMA ADC, RG-7450, RG-7458, RG-7593, RG-7596, RG-7598, RG-7599, RG-7600, RG-7636, ABT-414, IMGN-853, IMGN-529, B lorvotuzumab mertansine. As used herein, the term combination therapy refers to situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents). In some embodiments, the two or more therapeutic regimens may be administered concurrently. In some embodiments, the two or more therapeutic regimens may be administered sequentially (e.g., a first regimen administered before any dose of a second regimen). In some embodiments, the two or more therapeutic regimens are administered in overlapping dosing schedules. In some embodiments, the administration of combination therapy may involve administering one or more therapeutic agents or modalities to a subject who is also receiving the other agent(s) or modality. As used herein, the term frame or frame region refers to the sequences of a variable region excluding the CDRs. Because a CDR sequence can be determined by different systems, a frame sequence is similarly subject to correspondingly different interpretations. The six CDRs divide the frame regions of the heavy and light chains into four subregions (FR1, FR2, FR3, and FR4) in each chain, with CDR1 located between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4. Without specifying particular subregions as FR1, FR2, FR3, or FR4, a frame region, as referred to by others, represents the combined FRs within the variable region of a single naturally occurring immunoglobulin chain.As used herein, an FR represents one of four subregions; FR1, for instance, represents the first frame region closest to the amino-terminal end of the variable region and 5' with respect to CDR1, and FR represents two or more of the subregions that constitute a frame region. As used herein, the term humanized is commonly used to refer to antibodies (or antibody components) whose amino acid sequence includes sequences from the Vh and Vl regions of a reference antibody generated in a non-human species (e.g., a mouse), but also includes modifications to those sequences relative to the reference antibody intended to make them more human-like, i.e., more IVIA / I / U4O0O0 is similar to human germline variable sequences. In some embodiments, a humanized antibody (or antibody component) is one that binds immunospecifically to an antigen of interest and has a frame region (FR) that has substantially the same amino acid sequence as a human antibody, and a complementarity-determining region (CDR) that has substantially the same amino acid sequence as a non-human antibody. A humanized antibody comprises substantially all of at least one, and usually two, variable domains (Fab, Fab', F(ab')2, FabC, Fv) in which all or essentially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor immunoglobulin) and all or essentially all of the conserved frame regions are those of a human immunoglobulin consensus sequence.In some embodiments, a humanized antibody also optionally comprises at least a portion of an immunoglobulin constant region (Fe), typically that of a human immunoglobulin constant region. In some embodiments, a humanized antibody contains both the light chain and at least the variable domain of a heavy chain. The antibody may also include a Ch1, hinge, Ch2, Ch3, and, optionally, a Ch4 region of a heavy chain constant region. As used herein, the term in vitro refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multicellular organism. As used herein, the term in vivo refers to events that occur within a multicellular organism, such as a human or a non-human animal. In the context of cell-based systems, the term may be used to refer to events that occur in a living cell (as opposed to, for example, in vitro systems). As used herein, the term "isolated" refers to a substance and / or entity (1) that has been separated from at least some of the components with which it was associated when it was initially produced (either in nature and / or in an experimental setting), and / or (2) that has been designed, produced, prepared, and / or manufactured by human hands. Isolated substances and / or entities may be separated from at least approximately 10%, approximately 20%, approximately 30%, approximately 40%, approximately 50%, IVIA / t / ZUZ I / U4O0O0 approximately 60%, approximately 70%, approximately 80%, approximately 90%, approximately 93%, approximately 96%, approximately 91%, approximately 94%, approximately 97%, approximately 92%, approximately 95%, approximately 98%, approximately 99%, or more of approximately 99% of the other components with which they were initially associated. In some embodiments, the isolated agents are approximately 80%, approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or more of approximately 99% pure. As used herein, a substance is pure if it is substantially free of other components.In some embodiments, as those skilled in the art will understand, a substance may still be considered isolated or even pure, after having been combined with certain other components such as, for example, one or more carriers or excipients (for example, buffer, solvent, water, etc.); in such embodiments, the percentage of isolation or purity of the substance is calculated without including such carriers or excipients.To give just one example, in some embodiments, a biological polymer such as a polypeptide or polynucleotide found in nature is considered an isolated polypeptide when: a) by virtue of its origin or source, it is not associated with some or all of the accompanying components in its natural state; b) it is substantially free of other polypeptides or nucleic acids of the same species as the one that produces it in nature; or c) it is expressed or otherwise associated with components of a cell or other expression system that is not of the species that produces it in nature. Therefore, for example, in some embodiments, a polypeptide that is chemically synthesized or synthesized in a cellular system different from the one that produces it in nature is considered an isolated polypeptide.Alternatively or additionally, in some embodiments, a polypeptide that has been subjected to one or more purification techniques may be considered an isolated polypeptide to the extent that it has been separated from other components a) with which it is associated in nature; and / or b) with which it was associated when it was initially produced. As used herein, the term Kd refers to the dissociation constant of a binding agent (e.g., an antibody or binding component thereof) from a complex with its member (e.g., the epitope to which the antibody or binding component thereof binds). As used herein, the term macrophage refers to a cell of the monocyte / macrophage lineage found in the spleen or differentiated into a tissue macrophage. These cells include follicular dendritic cells (FDCs), dendritic cells, Langerhans cells, and other tissue macrophages. Macrophages are phagocytes and antigen-presenting cells that differentiate from monocytes in the circulating peripheral blood. They play an important role in both innate and adaptive immunity by activating T lymphocytes. Macrophages that activate Th1 T lymphocytes provide an inflammatory response and are called M1 macrophages. M1 macrophages, also known as cytolytic macrophages, inhibit cell proliferation, cause tissue damage, and are aggressive against bacteria. Macrophages that activate Th2 T lymphocytes provide an anti-inflammatory response and are called M2 macrophages.M2 macrophages, also known as repair macrophages, promote cell proliferation and tissue repair and are anti-inflammatory. As used herein, the term tumor-associated macrophages (TAMs) generally refers to macrophages that exist in the microenvironment of a cancer, e.g., a tumor. As used herein, the term "operationally linked" refers to a juxtaposition in which the described components are in a relationship that enables them to function as intended. A control element operationally linked to a functional element is associated in such a way that the expression and / or activity of the functional element is achieved under conditions compatible with the control element. In some embodiments, operationally linked control elements are contiguous (e.g., covalently linked) with the encoding elements of interest; in other embodiments, the control elements act in transit or otherwise from the functional element of interest. As used herein, the term pharmaceutical composition refers to a composition in which an active agent is formulated together with one or more pharmaceutically acceptable vehicles. In some embodiments, the composition is suitable for administration to a human or animal subject. In some embodiments, the active agent is present in a unit-dose quantity. IVIA / I / U4O0O0 appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. As used herein, the term polypeptide generally has its recognized meaning in the art of a polymer of at least three amino acids. Those skilled in the art will appreciate that the term polypeptide is intended to be general enough to encompass not only polypeptides having a complete sequence mentioned herein, but also polypeptides representing functional fragments (i.e., fragments that retain at least some activity) of such complete polypeptides. Furthermore, those skilled in the art understand that protein sequences generally tolerate some substitution without destroying activity.Therefore, any polypeptide that retains activity and shares at least approximately 30–40% overall sequence identity, often greater than approximately 50%, 60%, 70%, or 80%, and that generally includes at least one region of much greater identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99% in one or more highly conserved regions, generally spanning at least 3–4 and often up to 20 or more amino acids, with another polypeptide of the same class, is encompassed within the relevant term "polypeptide" as used herein. Polypeptides may contain L-amino acids, D-amino acids, or both, and may contain any of a variety of modifications or amino acid analogues known in the art. Useful modifications include, for example, terminal acetylation, amidation, methylation, etc.In some embodiments, proteins may comprise naturally occurring amino acids, non-natural amino acids, synthetic amino acids, and combinations thereof. The term peptide is generally used to refer to a polypeptide that is less than approximately 100 amino acids, less than approximately 50 amino acids, less than 20 amino acids, or less than 10 amino acids in length. In some embodiments, proteins are antibodies, antibody fragments, biologically active portions thereof, and / or characteristic portions thereof. As used herein, the term prevent or prevention, when used in relation to the occurrence of a disease, disorder, and / or condition, refers to reducing the risk of developing the disease, disorder, and / or condition. IVIA / t / ZUZ I / U4O0O0 The prevention and / or delay in the onset and / or severity of one or more characteristics or symptoms of the disease, disorder, or condition. In some embodiments, prevention is assessed on a population basis, such that an agent is considered to prevent a particular disease, disorder, or condition if a statistically significant decrease in the development, frequency, and / or severity of one or more symptoms of the disease, disorder, or condition is observed in a population susceptible to the disease, disorder, or condition. As used herein, the term recombinant is intended to refer to polypeptides that are designed, engineered, prepared, expressed, created, manufactured and / or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell; polypeptides isolated from a recombinant combinatorial human polypeptide library; polypeptides isolated from an animal (e.g., a mouse, rabbit, sheep, fish, etc.).) that is transgenic or has otherwise been engineered to express a gene or genes, or gene components that encode and / or directly express the polypeptide or one or more components, portions, elements, or domains thereof; and / or polypeptides prepared, expressed, created, or isolated by any other means involving splicing or ligating selected nucleic acid sequence elements together, chemically synthesizing selected sequence elements, and / or otherwise generating a nucleic acid that encodes and / or directs the expression of the polypeptide or one or more components, portions, elements, or domains thereof. In some embodiments, one or more of these selected sequence elements are found in nature. In some embodiments, one or more of these selected sequence elements are engineered by computer simulation.In some embodiments, one or more of these selected sequence elements are the result of mutagenesis (e.g., in vivo or in vitro) of a known sequence element, e.g., from a natural or synthetic source such as, e.g., in the germline of a source organism of interest (e.g., a human, a mouse, etc.). As used herein, the term specific binding refers to the ability to discriminate between potential binding members in the environment where binding will occur. A binding agent that interacts with a particular target when other potential targets are present is said to bind. IVIA / t / ZUZ I / U4O0O0 specifically to the target with which it interacts. In some embodiments, specific binding is assessed by detecting or determining the degree of association between the binding agent and its member; in some embodiments, specific binding is assessed by detecting or determining the degree of dissociation of a binding agent-member complex; in some embodiments, specific binding is assessed by detecting or determining the ability of the binding agent to compete in an alternative interaction between its member and another entity. In some embodiments, specific binding is assessed by performing such detections or determinations over a range of concentrations. As used herein, the term subject refers to an organism, typically a mammal (e.g., a human being, in some embodiments including prenatal human forms). In some embodiments, a subject suffers from a relevant disease, disorder, or condition. In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a subject exhibits one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, a subject does not exhibit any symptoms or characteristics of a disease, disorder, or condition. In some embodiments, a subject is someone with one or more characteristic traits of susceptibility to or risk for a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual who has been given a diagnosis and / or administered therapy. As used herein, the term "therapeutic agent" generally refers to any agent that produces a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered a therapeutic agent if it demonstrates a statistically significant effect in an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, an appropriate population may be defined by various criteria, such as a particular age group, gender, genetic background, pre-existing clinical conditions, etc. In some embodiments, a therapeutic agent is a substance that can be used to relieve, alleviate, mitigate, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or features of a disease, disorder, and / or condition.In some realizations, a therapeutic agent is an agent that has been or must be approved by a government agency before it can be used. IVIA / I / U4O0O0 cannot be marketed for administration to humans. In some embodiments, a therapeutic agent is an agent for which a medical prescription is required for administration to humans. As used herein, the term "therapeutically effective amount" means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, and / or condition according to a therapeutic dosing regimen, to treat the disease, disorder, and / or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence and / or severity of, stabilizes one or more features of, and / or delays the onset of, one or more symptoms of the disease, disorder, and / or condition. Those skilled in the art will appreciate that the term "therapeutically effective amount" does not, in fact, require that satisfactory treatment be achieved in a particular individual.Rather, a therapeutically effective amount may be that amount which provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. For example, in some embodiments, the term "therapeutically effective amount" refers to an amount which, when administered to an individual in need in the context of the therapy of the invention, will block, stabilize, attenuate, or reverse a cancer-supporting process occurring in that individual, or enhance or augment a cancer-suppressing process in that individual. In the context of cancer treatment, a therapeutically effective amount is an amount which, when administered to a person diagnosed with cancer, will prevent, stabilize, inhibit, or reduce the further development of cancer in that individual.A particularly preferred therapeutically effective amount of a composition described herein reverses (in a therapeutic treatment) the development of a malignant neoplasm such as pancreatic carcinoma or helps to achieve or prolong remission of a malignant neoplasm. A therapeutically effective amount administered to an individual to treat cancer in that individual may be the same as, or different from, a therapeutically effective amount administered to promote remission or inhibit metastasis. As with most cancer therapies, the therapeutic methods described herein should not be interpreted as, restricted to, or limited to a cure for cancer; rather, the treatment methods are directed to the use of the described compositions to treat cancer, i.e., to... IVIA / t / ZUZ I / U4OOOD effect a desirable or beneficial change in the health of an individual with cancer. Such benefits are recognized by healthcare providers trained in the field of oncology and include, but are not limited to, stabilization of the patient's condition, a decrease in tumor size (tumor regression), improvement in vital functions (e.g., improved function of cancerous tissues or organs), a decrease or inhibition of further metastasis, a decrease in opportunistic infections, increased survivability, decreased pain, improved motor function, improved cognitive function, improved sense of energy (vitality, decreased discomfort), improved sense of well-being, restoration of normal appetite, restoration of healthy weight gain, and combinations thereof.In addition, the regression of a particular tumor in an individual (e.g., as a result of the treatments described herein) can also be assessed by taking samples of cancer cells from the site of a tumor, such as a pancreatic adenocarcinoma (e.g., during the course of treatment) and testing the cancer cells to determine the level of metabolic and signaling markers to monitor the status of the cancer cells to verify at the molecular level the regression of the cancer cells to a less malignant phenotype.For example, tumor regression induced by the methods of the present invention would be indicated by a decrease in any of the pro-angiogenic markers discussed above, an increase in the anti-angiogenic markers described herein, or the normalization (i.e., the return to a state found in normal individuals without cancer) of the metabolic pathways, intercellular signaling pathways, or intracellular signaling pathways that exhibit abnormal activity in individuals diagnosed with cancer. Those skilled in the art will appreciate that, in some embodiments, a therapeutically effective amount can be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective amount can be formulated and / or administered in multiple doses, for example, as part of a dosing regimen. As used herein in the context of molecules, e.g. nucleic acids, proteins, or small molecules, the term variant refers to a molecule that shows significant structural identity with a reference molecule but differs structurally from the reference molecule, e.g., in the presence or absence or at the level of one or more chemical residues in MA / l / U^OOJD comparison with the reference entity. In some embodiments, a variant also differs functionally from its reference molecule. In general, whether a particular molecule is properly considered a variant of a reference molecule is based on its degree of structural identity with the reference molecule. As those skilled in the field will appreciate, any biological or chemical reference molecule has certain characteristic structural elements. A variant, by definition, is a distinct molecule that shares one or more of such characteristic structural elements but differs in at least one aspect from the reference molecule.To give a few examples, a polypeptide may have a characteristic sequence element composed of a plurality of amino acids that have designated positions relative to each other in linear or three-dimensional space and / or that contribute to a particular structural motif and / or biological function; a nucleic acid may have a characteristic sequence element composed of a plurality of nucleotide residues that have designated positions relative to one another in linear or three-dimensional space. In some embodiments, a variant of a polypeptide or nucleic acid may differ from a reference polypeptide or nucleic acid as a result of one or more differences in the amino acid or nucleotide sequence.In some embodiments, a polypeptide or nucleic acid variant exhibits general sequence identity with a reference polypeptide or nucleic acid that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 99%. In some embodiments, a polypeptide or nucleic acid variant does not share at least one characteristic sequence element with a reference polypeptide or nucleic acid. In some embodiments, a reference polypeptide or nucleic acid has one or more biological activities. In some embodiments, a polypeptide or nucleic acid variant shares one or more of the biological activities of the reference polypeptide or nucleic acid. As used herein, the term vector refers to a nucleic acid molecule capable of carrying another nucleic acid to which it has been attached. One type of vector is a plasmid, which refers to a circular, double-stranded DNA loop into which additional DNA segments can be attached. Another type of vector is a viral vector, in which additional DNA segments can be attached to the viral genome. Certain vectors are suitable for autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors that have a IVIA / t / ZUZ I / U4O0O0 bacterial origin of replication and mammalian episomal vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell after their introduction into the host cell and are thus replicated along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as expression vectors. Conventional techniques for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection) can be used. Enzymatic reactions and purification techniques can be performed according to the manufacturer's specifications or as is customary in the art or as described herein.The techniques and procedures described above can generally be carried out in accordance with well-known conventional methods in the field and as described in various general and more specific references cited and discussed throughout this descriptive report. See, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual (2nd ed., Coid Spring Harbor Laboratory Press, Coid Spring Harbor, NY (1989)), which is incorporated herein as a reference for any purpose. Macrophages in cancer Macrophages are phagocytes and antigen-presenting cells that differentiate from monocytes in circulating peripheral blood. These cells are known to play an important role in both innate and adaptive immunity by activating T lymphocytes. Macrophages that activate Th1 T lymphocytes provide an inflammatory response and are called M1 macrophages. M1 macrophages, also known as cytolytic macrophages, inhibit cell proliferation, cause tissue damage, and are aggressive against bacteria. Macrophages that activate Th2 T lymphocytes provide an anti-inflammatory response and are called M2 macrophages. M2 macrophages, also known as repair macrophages, promote cell proliferation and tissue repair and are anti-inflammatory. While macrophages are formed through the differentiation of monocytes, monocytes mature into M1 (CD68+ and CD80+) or M2 (CD68+ and CD163+) macrophages depending on the cytokines and growth factors that drive their differentiation. Lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) activate monocytes to differentiate into M1 macrophages that secrete high levels of IVIA / I / U4O0O0 interleukin-1 (IL-1) and interleukin-12 (IL-12) and low levels of interleukin-10 (IL-10). Alternatively, interleukin-4 (IL-4), IL-10, the interleukin-1 receptor antagonist (IL-1ra) and transforming growth factor beta (TGF-β) activate monocytes to differentiate into M2 macrophages that secrete high levels of IL-10, TGF-β and insulin-like growth factor 1 (IGF-1) and low levels of IL-12. The role of immunity in oncogenesis has become increasingly appreciated. Since macrophages are known to play important roles in both innate and adaptive immunity, they have been recognized as key components of tumors and their microenvironment. Tumor-associated macrophages (TAMs) generally refer to macrophages present in the microenvironment of a cancer. The role of TAMs in tumor growth, invasion, and metastasis has been extensively investigated, and TAMs are known to exhibit a broad spectrum of phenotypes, ranging from the M1-like phenotype in early-stage selected tumors to the M2-like phenotype in most advanced tumors.As evidence of their role in promoting tumorigenesis, M2 macrophages exhibit the characteristic phenotype of elevated expression of IL-10, IL-4, MMPs, and VEGF, but decreased expression of proinflammatory cytokines and cytotoxic INO and ROI, which are implicated in tumoricidal activities. In addition to their intrinsic function in promoting tumorigenesis, TAMs also contribute to the suppression of antitumor immunity by altering T-cell responses and the balance in the tumor microenvironment. In addition to promoting cell proliferation, which plays an anti-inflammatory role, M2 macrophages can induce vascularization in a tumor area in cancer. Therefore, in such scenarios, it would be useful to inhibit M2 polarization of macrophages and induce M1 polarization, which is known to attack tumor cells. VSIG4 VSIG4 (V-set immunoglobulin-containing domain 4) is a B7 family-related membrane protein belonging to the complement receptor immunoglobulin superfamily (CRIg) that is known to negatively regulate CD8+ T lymphocyte proliferation and IL-2 production by binding to C3b and C3β. VSIG4 expression is restricted to tissue macrophages, including peritoneal macrophages and Kupffer cells residing in the liver. Figures 2A and 2B show the relationship of VSIG4 (homology and phylogeny relationships, IVIA / I / U4O0O0 respectively) with another B7 protein family (VSIG4 is referred to as EU103 in Figures 2A and 2B). Figure 2A shows the alignment of the amino acid sequence of VSIG4 with several other B7 family proteins. Figures 2B show the evolutionary relationship between VSIG4 and other B family proteins. Anti-VSIG4 antibody to treat cancer Tumor-associated macrophages (TAMs) are key cells that create an immunosuppressive tumor microenvironment (TME), providing multiple targets for immunotherapies. Macrophages are also known to be highly plastic and can repolarize and acquire an anti-tumorigenic phenotype similar to M1. Tumor-associated macrophages (TAMs) are typically known for their pro-tumor functions, such as promoting cancer cell motility, metastasis formation, and angiogenesis. TAM formation depends on microenvironmental factors present during tumor development. TAMs are abundant in many cancers, especially in the tumor microenvironment, and often exhibit an M2-like immunosuppressive phenotype that promotes tumor growth and therapy resistance. TAMs also produce immunosuppressive cytokines such as IL-10, TGF-β, and PGE2, very small amounts of nitric oxide (NO) or retinoblastoma (ROI), and low levels of inflammatory cytokines such as IL-12, IL-1β, TNF-α, and IL-6. The conversion of macrophages into TAMs results in a reduced capacity to present tumor-associated antigens and stimulate the antitumor functions of T lymphocytes and natural killer (NK) cells. Furthermore, TAMs cannot lyse tumor cells.Therefore, TAM targeting is a novel therapeutic strategy for suppressing or treating cancer, for example, by administering agents to alter TAM recruitment and distribution, depleting existing TAMs, or inducing the re-education (or conversion) of TAMs from an M2 to an M1 phenotype. This disclosure is based on the discovery that VSIG4-expressing M2 macrophages can be treated with humanized anti-VSIG4 antibodies to convert (or repolarize) the M2 macrophages into tumor-suppressing M1 macrophages, thereby inducing CD8+ T lymphocyte proliferation and the production of proinflammatory cytokines that lead to tumor suppression. Furthermore, the use of anti-VSIG4 antibodies can effectively suppress cancer by targeting both (1) the conversion of M2 macrophages into M1 macrophages and (2) the induction of CD8+ T lymphocyte proliferation and the production of proinflammatory cytokines. IVIA / t / ZUZ I / U4O0O0, thus influencing the tumor microenvironment itself. This approach of using an anti-VSIG4 antibody to suppress cancer is superior to other therapies that only induce T-cell proliferation or only block tumor-supporting macrophage activities. See Figure 1 (which schematically shows the effects of anti-VSIG4 antibodies on macrophage function, their effects on T-cell proliferation, and the subsequent cancer suppression). Humanization of mouse antibody Although the mouse immune system can rapidly produce monoclonal antibodies for biological studies, in a clinical setting, the use of these murine antibodies can result in a human anti-mouse antibody (HAMA) response. While chimeric antibodies can reduce anti-IgG responses in humans, murine variable domains may still contain provocative T-cell epitope content, necessitating humanization of their framework regions. Classical antibody humanization typically begins by transferring the six murine complementarity-determining regions (CDRs) into a human antibody framework (Jones et al., Nature 321, 522-525 (1986)). These CDR-grafted antibodies generally do not retain their original affinity for antigen binding, and in fact, affinity is often severely impaired. In addition to the CDRs, certain non-human framework remnants must also be incorporated into the variable domains to maintain proper CDR conformation (Chothia et al., Nature 342:877 (1989)). The incorporation of murine remnants into key positions in human frameworks to restore function is generally termed backmutations. Backmutations can support the structural conformation of the grafted CDRs and restore antigen binding and affinity.Many of the frame positions likely to affect affinity have been identified; therefore, structural modeling to select new fragments in a stepwise manner can generally lead to variants with restored antigen binding. Alternatively, phage antibody libraries targeting these fragments can also be used to enhance and accelerate the affinity maturation process (Wu et al., J. Mol. Biol. 294:151-162 (1999) and Wu, H. Methods in Mol. Biol. 207:197-212 (2003)). Antibody affinity maturation Affinity maturation is a process by which B lymphocytes IVIA / I / U4OOOD cells activated by Tfh lymphocytes produce antibodies with increasing affinity for a specific antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce antibodies with successively higher affinities. A secondary response can generate antibodies with an affinity several times greater than that of a primary response. Affinity maturation is an important strategy in antibody optimization to generate safe and effective second-generation therapeutic agents. Traditionally, therapeutic antibodies are obtained by immunizing transgenic mice or animals expressing human immunoglobulin genes with the desired antigen. Antigen-stimulated immune cells from these animals are transformed into hybridomas and subsequently screened to identify monoclonal antibodies with low nanomolar affinities for their target antigen.In vivo, natural affinity maturation by the immune system occurs through somatic hypermutation and clonal selection, whereas in vitro, laboratory affinity maturation can be achieved through mutation and selection. Furthermore, other methods for affinity maturation besides those using B lymphocytes activated by TFH lymphocytes are known and fall within the scope of this disclosure. EXAMPLES The invention is described in more detail in the following examples, which do not limit the scope of the invention described in the claims. PROCEDURES AND MATERIALS The following methods and materials were used for the experiments described in the Examples. Isolation of CD14+ monocytes from human PBMCs The differentiation of macrophages into M1 or M2 macrophages was performed by isolating PBMCs from subjects and incubating the macrophages in 50 ng / ml hGM-CSF for 6 days to convert them into M1 macrophages or by incubating the macrophages in 100 ng / ml M-CSF for 6 days to convert them into M2 macrophages (Figure 5). The conversion of macrophages into M1 or M2 macrophages was confirmed by phenotype verification (Figures 6 and 7). The subsequent conversion of M1 or M2 macrophages into M1 macrophages was performed by incubating the macrophages in LPS (100 ng / ml) + IFNy (100 ng / ml) or 500 ng / ml of anti-VSIG4 antibody (EU103.2) for 24 hours (Figure 12). IVIA / I / U4O0O0 The conversion of IVI1 or M2 macrophages into M2 macrophages was performed by incubating the macrophages in 20 ng / ml of IL-4 for 24 h (Figure 12). Humanized anti-VSIG4 antibody - EU103.2 antibody The EU103.2 antibody is a humanized anti-VSIG4 antibody generated from the mu6H8 mouse anti-VSIG4 antibody. Figures 4A and 4B show the biochemical characterization of the EU103.2 antibody using size exclusion HPLC (Figure 4A) and surface plasmon resonance experiments, which demonstrate the binding of VSIG4 to the EU103.2 antibody (Figure 4B). Table 1 below presents a summary of the purification data for the EU103.2 antibody. IVIA / I / U4O0O0 TABLE 1: SUMMARY OF SIZE EXCLUSION HPLC DATA FOR ANTIBODY EU103.2 Total concentration per 30 ml (x5) of transfection Expi293F EU103.2 1.2 mg / ml x 7 ml 0.37 mg / ml x 2 ml 9.14 mg Humanization of mouse anti-VSIG4 antibody - EU103.3 antibody The humanized anti-VSIG4 antibody hu6H8 (or EU103.3) was produced as described below. humanization of VH of mu6H8 The scaffold for the humanized VH variant was produced using mouse 6H8 antibody and Blast (https: / / blast.ncbi.nlm.nih.gov / Blast.cgi?PAGE=Proteins) (germline gene: VH2-5 / D3-3 / JH6c). Kabat numbering was used to classify the CDRs, and the humanized VH was engineered using the scaffold and classified as mu6H8 VH CDRs, VH2, VH27, VH30, VH93, and VH94 back mutations. (hu6H8.3 VH) mu6H8 VL humanization The scaffold for the humanized VL variant was produced using mouse 6H8 antibody and Blast (https: / / blast.ncbi.nlm.nih.gov / Blast.cgi?PAGE=Proteins) (germline gene: A17 / JK2). Kabat numbering was used to classify the CDRs, and the humanized VL was engineered using the scaffold and classified as mu6H8, VH2, VH4, VH36, and VH46 CDRs. (hu6H8.3 VL) Cloning and expression of IgG antibodies - EU103.3 Antibody The heavy chain variable region sequence was modified by FES mutations (L234F, L235E, P331S) to construct the pOptivec heavy chain expression plasmid (Invitrogen) without Fe effector functions, as shown in Figure 21A. The light chain variable region sequence was constructed using pcDNA3.3 (Invitrogen) and synthesized using IDT, as shown in Figure 21B. The gene encoding the heavy chain (HC) was flanked by EcoR1 and the restriction enzyme Nhe1 to construct the pOptivec plasmid vector (FES), and the gene encoding the light chain (LC) was flanked by EcoR1 and the restriction enzyme BsIW1 to construct the pcDNA3.3 plasmid vector. Cloning was performed with the mutation sites subcloned into the hu6H8.3 backbone.The resulting insertion genes and linearized vectors were each cloned using the In-Fusion® HD cloning kit (Clontech) and the sequencing primer was identified using the IRES reverse CMV direct primer from EMCV. Mice with VSIG4 inactivation VSIG inactivated (K / O) mice were generated by homologous recombination, replacing exon 1 with the neomycin resistance gene. A targeting vector was generated for use in homologous recombination in embryonic stem cells. E1 and E2 denote exons 1 and 2 of the CRIg gene (Figure 41A). Homologous recombination of the CRIg allele in the heterozygous female offspring of ES cell clone 1 and 2 (C1, C2) chimeric mice bred with TS mice was confirmed by Southern blot analysis (Figure 41B). Peripheral blood leukocyte counts were compared between male and female TS and K / O mice. Total blood cell counts were determined using a hematocritometer. Leukocytes were incubated with fluorochrome-conjugated antibodies specific for various cell surface markers, and the number of different leukocyte subsets was determined by flow cytometry.The data represent the mean + SD of 5-7 mice (Figure 41C). Antibodies A1, A2, A1.3 and A2.3 Antibodies A1 and A2 are generated by affinity maturation of antibody EU103.3 (see Table 2 below), wherein the variable regions of the light chain at positions 76, 90 and / or 92 (kabat number) are mutated, as shown below in Table 2. IVIA / I / U4O0O0 Antibodies A1.3 and A2.3 are generated from antibodies A1 and A2, respectively, to further improve affinity for VSIG4. Figure 40 shows the alignment of amino acid sequences for the heavy chains and the light chains of EU 103.3, A1, A2, A1.3, and A2.3, along with the consensus amino acid sequences for the heavy and light chains. Amino acid residues that differ between the different antibodies are shown in rectangular boxes. IVIA / t / ZUZ I / U4O0O0 TABLE 2: HUMANIZED ANTIT-VSIG4 ANTIBODY CLONES SCREENED IN AFFINITY MATURATION EXPERIMENTS Name of Ab Library HC LC Mutation sites (HC) (Kabat numbering) Mutation sites (LC) (Kabat numbering) T01.01 (A1) L3A TS T01L1 - H90Q, R92G T01.02 (A2) L3A TS T01L2, R29G, H T01.03 L3B TS T01L3 - L76F, H90Q, R92F T01.04 L3B TS T01L4 - L76F, H90Q, R92L T01.05 H3B T01H1 TS N99H - T01.06 H3B T01H2, H10 Q3 N99H, H90Q. T01H3 TS K98E, N99K - T01.08 L2 TS T01L5 - S52E, M106I T01.09 L2 TS T01L6 - L54R, M106I T01.10 L2 TS T01L7 - S52E, L54R, M106I Ab Name Library HC LC Mutation Sites (HC) (Kabat Numbering) Mutation Sites (LC) (Kabat Numbering) T01.11 H1 T01H4 TS S32Y - T01.12 H1 T01H5 TS S32F - T01.13 H2A T01H6 TS D50E, F52Y, W53S, D54G, D55E - T01.14 H2A T01H7 TS D50E, W53S - T01.15 L1C TS T01L8 - L76F T01.16 L1C TS T01L9 - M33V, L76F T01.17 L1A TS T01L10 - K27E, L76F T01.18 L1B TS T01L11 - T27E,L76F T01.19 L1B TS T01L12 - T27K, L76F T01.20 H1 T01H8 TS S32W - Production of antibodies with high binding affinity The humanized antibody gene was inserted into a plasmid and expressed as IgG using the Exp1293 expression system (Invitrogen) and then purified using AktaPure (GE Healthcare), AktaPrime Purifier (GE Healthcare), and MabselectSURE column (GE Healthcare, Cat. No. 11-0034-95). The purified antibodies were passed through a desalination column (GE Healthcare, Cat. No. 17-140801) with PBS buffer change, and the antibody concentration was measured using Multiskan GO (Thermo). TABLE 3: PRODUCTION YIELDS OF ANTIBODIES WITH HIGH BINDING AFFINITY Ab Name Culture Volume (mi) Ab Con. (mg / ml) Yield (mg) T01.01 (A1) 30 0.68 1.020 T01.02 (A2) 30 0.22 0.330 T01.03 30 0.87 0.104 T01.04 30 0.99 0.119 T01.05 30 0.26 0.390 T01.06 30 1.2 0.144 T01.07 30 0.33 0.495 T01.08 30 1.46 0.292 T01.09 30 1.73 0.346 T01.10 30 2.07 0.414 T01.11 30 0.27 0.054 T01.12 30 1.26 0.252 T01.13 30 0.72 0.144 T01.14 30 0.89 0.178 T01.15 30 0.21 0.042 T01.16 30 1.05 0.21 T01.17 30 0.76 0.15 T01.18 30 0.33 0.07 T01.19 30 0.44 0.09 T01.20 30 0.99 0.198 QrQQbO / 1 7P7 / 3 / YIL Differentiation of PBMC-derived macrophages M1 and M2 macrophages were obtained from PBMC using the following protocol. 1. Blood mixture with PBS (1:1), 20 ml over 10 ml of Ficoll-Paque™ Plus (GE Healthcare, N.ede Cat 17-1440-02) 2. Centrifuge at 400xg for 35 min (2 accelerations, 0 brakes) 3. Isolation and washing of PBMC with RPMI-1640 medium (WelGene, N.ede Cat LB011 -01) at 2000 rpm for 5 min x 2 times 4. Count 5. MAC buffer (2% FBS (Millipore, Cat. No. TMS-013-BKR) in PBS (WelGene, Cat. No. LB004-02), 1 - 2 ml of suspension 6. Add microbeads-CD14 (20ul / 107cells) (Miltenyi Biotec, Cat. No. 130-050-201) 7. Incubation for 30 min on ice 8. Wash with MAC buffer at 2000 rpm for 5 min x 2 times 9. Count 10. Load the cells into the MAC column (Miltenyi Biotec, N.sde Cat. 130-042401) 11. Positive selection and counting 12. Suspension in culture medium (RPMI-1640 + 10% FBS + Penicillin / Streptomycin (Gibco, Cat. No. 15140-122) + Glutamax (Gibco, Cat. No. 35050-061) + 20 - 40 ng / ml rhM-CSF (Biolegend, Cat. No. 574806) 13. Seed the CD14+ cells in a 100 mm culture plate (1 x106 cells / 10 ml / plate) (Thermo Scientific, Cat. No. 150466) 14. Every 3 days thereafter, change the culture medium to fresh. 15. After 7-10 days, check M0 macrophage differentiation using FAC 16. Differentiation of M0 to M1 or M2 macrophages by 20ng / ml of LPS (SigmaAldrich, Cat. No. L4391) + 20 ng / ml of rhlFNy (Biolegend, Cat. No. 570204) (M1) and 20 ng / ml of rhlL4 (Biolegend, Cat. No. 574002) + 20 ng / ml of rhlL13 (Biolegend, Cat. No. 571102) (M2) in culture medium (RPMI1640 + 10% FBS + Penicillin / Streptomycin + Glutamax) for 2 days 17. After differentiation of M1 or M2, check the cell phenotype using FAC 18. For the conversion of M2 macrophages to M1, add 20 ug / ml of antibodies or 20 ng / ml of LPS + 20 ng / ml of rhlFNy (positive control) to fresh culture medium (RPMI-1640 + 10% FBS + Penicillin / Streptomycin + Glutamax) for 2 days 19. After M2 to M1 conversion, verification of cell phenotype by FAC and verification of cytokines / chemokines in cultured surface by LEGENDplex™ (Biolegend, n.ede Cat. 740502) FAC Analysis The following antibodies were used for FAC analysis: • hCD14-BV650 (BD Bioscience, cat. no. 563419) • hCD14-BV421 (BD Bioscience, Bde cat. no. 565283) • hlFNy-PE / Cy7 (BD Bioscience, η.3rd cat. 55784-BDV-4) • hCD14-BV421 Bioscience, η.ede cat. 563109) • hCD8-V450 (BD Bioscience, no.3de cat. 560347) • hCD68-PE (Biolegend, no.3de cat. 333808) • hCD93-PE (Biolegend, no.3de cat. 33608) HLA-DR-BV421 (Biolegend, cat. 307636) • hCD45-PE (Biolegend, cat. 304008) • hCD64-APC (Biolegend, cat. 305014) • hCD163-APC / Cy7 (Biolegend, cat. 305014). 333622) • hCD86-PerCP / Cy5.5 (Biolegend, cat. 305420) • hCD86-BV421 (BD Bioscience, cat. 562432) EXAMPLE 1: VSIG4 EXPRESSION IN MACROPHAGE VSIG4 is expressed in M2 macrophages. Figures 3A and 3B show correlative data for VSIG4 expression (measured by mRNA) with that of several genes associated with type 2 (M2) macrophages and tumor-associated macrophages. As shown in Figure 3A, VSIG4 expression is negatively correlated with the expression of CXCL11, CXCL13, ZNMB, IFNAR1, and IFNAR2, but positively correlated with the expression of CCL19, IRF5, and IL1A. Figure 3B shows that VSIG4 expression is positively correlated with the expression of CD163, CSF1R, MSR1, TGFBR2, STAT6, IL1R1, IL1ORA, MS4A4A, CCL2, CCL14, CCL17, and MS4A6A. Figure 5 shows VSIG4 expression in M2 macrophages. The two panels in the top row of Figure 5 show light microscope images illustrating the morphology of M1 and M2 macrophages. The second and third rows show flow cytometry data for lymphocytes stained for CD14 and VSIG4, demonstrating that M2 cells (stained positive for CD14) also express VSIG4. EXAMPLE 2: HUMAN ANTI-VSIG4 ANTIBODY INDUCES CYTOKINE AND CHEMOKINE SECRETION IN M2 MACROPHAGES M1 and M2 macrophages were treated with the antibody EU 103.2, and the secretion of proinflammatory cytokines and chemokines was measured. As shown in Figure 6, treatment of M2 macrophages with EU 103.2 resulted in the induction of the cytokines and chemokines IL12, IFNγ, IL10, and IL23. EXAMPLE 3: HUMANIZED ANTI-VSIG4 ANTIBODY CONVERTS M2 MACROPHAGES INTO M1 MACROPHAGES To further test the effects of EU103.2 on macrophages, M2 macrophages were treated with the EU103.2 antibody and stained for the M2 macrophage marker CD163. As shown in Figure 7, treatment with EU103.2 reduced the expression of the M2 macrophage marker CD163 in M2 macrophages, suggesting that blocking VSIG4 using EU103.2 resulted in the conversion of M2 macrophages into a different cell type. Next, the effects of the EU103.2 antibody on the macrophage-T lymphocyte interaction were tested by co-incubating M2 macrophages with CD8+ T lymphocytes with or without treatment with EU103.2 antibodies. As shown in Figure 8, M2 macrophages treated with EU103.2, when co-incubated with CD8+ T lymphocytes, resulted in the proliferation of CD8+ T lymphocytes, indicating that M2 macrophages become M1 macrophages when treated with the EU103.2 antibody, since M1 macrophages induce the proliferation of CD8+ T lymphocytes while M2 macrophages suppress the proliferation of CD8+ T lymphocytes. Next, to further investigate the effects of the EU103.2 antibody on human macrophages in the context of cancer biology, abdominal fluid samples were collected from ovarian cancer patients and analyzed first to determine VSIG4 expression. As shown in Figure 9, macrophages obtained from the abdominal fluid of ovarian cancer patients included M2 macrophages that co-expressed VSIG4 and CD14, and as shown in Figures 10 and 11, they induced CD8+ T lymphocyte proliferation. IVIA / t / ZUZ I / U4O0O0 Furthermore, microscope images confirm that treatment with EU103.2 antibodies converted M2 macrophages into M1 macrophages, as shown in Figure 12. The role of VSIG4 signaling in the proliferation of CD8+ T lymphocytes by macrophages was further confirmed by co-culturing VSIG4-expressing HeLa cells with PBMCs, with or without anti-VSIG4 antibody to block VSIG4, as shown in Figure 13. This experiment demonstrated that blocking the interaction between VSIG4 and CD8+ T lymphocytes leads to increased proliferation of CD8+ T lymphocytes. To further examine the role of VSIG4 in CD8+ T lymphocytes, THP-1 monocytic cells were co-incubated in various proportions with T lymphocytes, either in the presence of an anti-VSIG4 antibody or a control IgG antibody, to demonstrate that the anti-VSIG4 antibody was able to increase CD8+ T lymphocytes by 4 divisions, compared to the control IgG. EXAMPLE 4: ANTITUMOR EFFECTS OF BLOCKING VSIG4 SIGNALING USING ANTI-VSIG4 ANTIBODY OR VSIG4 INACTIVATED MOUSE MODEL To determine the antitumor effects of the anti-VSIG4 antibody, three mouse tumor models were used: the MC38 mouse model of colon adenocarcinoma, the B16F10 mouse model of melanoma, and the 3LL mouse model of lung carcinoma. VSIG4-deficient mice were used in these models and compared to wild-type mice, as shown in Figures 15A, 15B, and 15C, respectively. Tumor growth was suppressed, particularly in the MC38 and 3LL mouse tumor models, in VSIG4-inactivated mice compared to wild-type mice (see Figures 15A and 15C, respectively), confirming that tumor growth is suppressed in the absence of VSIG4 signaling. Similar suppression of tumor growth was observed in the MC38 mouse tumor model in wild-type mice that were injected with anti-VSIG4 antibody, compared to mice injected with control IgG, as shown in Figure 16. The degree of suppression of tumor growth by the anti-VSIG4 antibody was at least as pronounced, if not greater, than that of mice with VSIG4 inactivation. Next, the activation state of the lymphocytes in the lymph nodes that The tumor draining process was examined in VSIG4-inactivated mice and compared to wild-type mice. As shown in Figures 17A and 17B, comparable levels of CD4+ and CD8+ lymphocytes were observed in VSIG4-inactivated mice compared to their wild-type counterparts, and comparable CD62L expression was observed in CD4+ and CD8+ lymphocytes between VSIG4-inactivated and wild-type mice. Furthermore, VSIG4-inactivated mice had increased CD8p+ T lymphocytes compared to wild-type mice, as shown in Figure 17C, but comparable levels of CD11p+ / Gr-1- lymphocytes, as shown in Figure 17D. To further evaluate the role of VSIG4 signaling in tumor growth, the CD38-positive colon adenocarcinoma mouse tumor model was used in both VSIG4-inactivated and wild-type mice. The chemotherapy agent Claforan (CTX) was injected intraperitoneally on days 18 and 23 post-tumor injection in the subject mice, as shown in the schematic diagram at the top of Figure 18A. Claforan injection resulted in a greater reduction in tumor volume in VSIG4-inactivated mice compared to wild-type mice, and this reduction in tumor size was maintained 40 days post-injection. In contrast, in wild-type mice, CTX injection resulted in a slight reduction in tumor size, followed by continued tumor growth, as shown in Figure 18A.Images of mice and micrographs of tumor sections for both VSIG4-inactivated mice and a wild-type mouse on day 24 after tumor injection are shown in Figure 18B. Tumor sections were collected from VSIG4+ / + and VSIG4LC57BL / 6 mice on day 24 and paraffin-embedded sections of the tumor tissues were stained with H&E. The effects of anti-VSIG4 tumor suppression in the humanized mouse model were evaluated by injecting 10 mg / kg of anti-VSIG4 antibody on days 19, 22, 25, 28, and 31 after injection of HT29 cancer cells into humanized mice, as shown in Figure 19. Significant suppression of tumor growth was observed in mice that received anti-VSIG4 antibody compared to those that received a control IgG injection. These experiments demonstrated, as shown schematically in the MA / l / U^OOJD Figure 20 shows that VSIG4 signaling modulates the suppression of T lymphocyte proliferation by M2 macrophages, and that blocking VSIG4 signaling results in (1) the suppression of M2 macrophage-induced T lymphocyte proliferation, leading to CD8+ T lymphocyte proliferation and tumor suppression; and (2) the conversion of M2 macrophages into M1 macrophages. EXAMPLE 5: EVALUATION OF ANTIBODIES A1, A2, A1.3 and A2.3 Antibody clones A1, A2, A1.3, and A2.3 were developed by affinity maturation of EU103.2 antibodies. The protein profile by size exclusion HPLC is shown in Figures 22, 23, 24, and 25, respectively, and is summarized below in Table 4. IVIA / t / ZUZ I / U4O0O0 TABLE 4: HPL SEC DATA (J) FOR antibodies A1, A2, A1.3 and A2.3 Ab Time Area Height Width % of Area Log(PM) PM A1 7.551 8.57E+02 29.91175 0.4484 100.000 2.135 136.605 A2 7.567 2.62E+02 8.96929 0.4567 100.000 2.128 134.380 A1.3 7.525 2.02E+03 106.8666 0.2842 100.000 2.134 136.081 A2.3 7.542 6.61 E+02 34.47963 0.2898 100,000 2,126 133,730 As shown in Figures 26A and 26B, A1 or A2 antibodies were applied to differentiated M2 macrophages for 2 days, and FAC analysis showed a decrease in CD163, a marker of M2 macrophages, and a significant increase in CD86, a marker for M1 macrophages. Treatment with LPS / IFNy for two days was used as a positive control. Treatment with A1 and A2 antibodies showed an increase in the M1 / M2 ratio. Specifically, the A2 antibody showed an increase in the ratio close to that of the positive control group. Then, as shown in Figure 27, A1 or A2 antibodies were applied to differentiated M2 macrophages for 2 days, repolarizing them to M1 macrophages, and changes in cytokine and chemokine production were measured in the culture medium using LEGENDplex™. This was to confirm the repolarization of M2 macrophages to M1 macrophages. Treatment with LPS / IFNy for two days was used as a positive control. Both groups A1 and A2 showed an increase in M1-type cytokines / chemokines (TNFα, IL6, IFNγ, IP-10, and IL12p40) compared to M2 macrophages, while the production of M2-type cytokines / chemokines (IL-10, arginase, TARO, and IL43 1RA) was reduced. Specifically, the increase in TNFα and IL6 production was comparable to that of the positive control group. Furthermore, as shown in Figure 28, A1 or A2 antibodies were applied to differentiated M2 macrophages for 2 days, and FAC analysis was performed to show a reduction in the expression of CD163, a marker for M2 macrophages, and a significant increase in the expression of CD86, a marker for M1 macrophages. Treatment with LPS / IFNy for two days was used as a positive control. To further determine the repolarization of M2 macrophages to M1 macrophages by A1 and A2 antibodies, A1 or A2 antibodies at different concentrations (5, 10, and 20 µg / ml) were applied to differentiated M2 macrophages for 2 days, and the production of cytokines and chemokines by the macrophages was evaluated, as shown in Figure 29. The change in cytokine / chemokine production in the culture medium was measured using LEGENDplex™. Treatment with LPS / IFNγ for two days was used as a positive control. Both the A1 and A2 groups showed an increase in TNFα, IL-6, and IP-10, which are associated with M1 macrophages, and this trend was particularly pronounced when the M2 macrophages were treated with the A2 antibody. Arginase production, which is associated with M2 macrophages, was reduced independently of antibody concentration. The chemotactic capacity of macrophages after the conversion of M2 macrophages to M1 macrophages by the A2 antibody was evaluated by a chemotaxis assay. Using a 24-well, 5-pm Transwell pore chamber (Corning, N.sde Cat. CLS3421-48EA), the lower chamber was treated with the chemoattractant rhCCL19 (Biolegend, N.ede Cat. 582104), which is an M1-type chemokine, at a concentration of 100 ng / ml (volume 400 μL), and the upper chamber was treated with repolarized M1 macrophages at 1.5 ~ 5x105 cells / 600 μL, where M2 or A2 was applied for 2 days (treatment with LPS / IFNy for two days was used as a positive control). After a 4-hour incubation period at 37°C and 5% CO2, 100 µL of cells from the lower chamber were transferred to a 96-well plate. Then, 10 µL of CCK-8 solution (Dojindo, N.Qde Cat. CK04) was added to each well, and after a 1-hour incubation period, the absorbance was measured (450 nm).As shown in Figure 30, the M1 macrophages of group A2 showed chemotactic capacity, confirming the conversion of M2 macrophages to M1 by the A2 antibody. A gene matrix analysis was performed to analyze the change in expression IVIA / t / ZUZ I / U4O0O0 gene expression after conversion of M2 macrophages to M1 macrophages by A2 antibodies, as shown in Figure 42. M2 macrophages were treated with A2 antibodies and the cells were collected after two days. (Macrogen, Agilent Human GE 8x60K V3) Analysis shows an increase in the expression of the M1 phenotype marker and M1-like cytokines / chemokines, similar to cells treated with LPS / IFNy as a positive control, and a reduction in the expression of the M2 phenotype marker and M2-like cytokines / chemokines. EXAMPLE 6: ANTITUMOR EFFECTS OF A1, A2, A1.3 and A2.3 ANTIBODIES The antitumor effect of A1 and A2 antibodies was evaluated using a humanized mouse model. Human CD34 cells were injected into NBSGW mice, and blood samples were collected and human CD45 cells were measured in PBMCs to observe mouse humanization over a period of 12–14 weeks. HCT-15 colon cancer cells, at 1 x 10⁷ cells / mouse, were injected into the humanized mice, and after 5 days the mice were divided into three groups, each of which received injections of hlgG (Sigma-Aldrich, N.Q. de Cat. I4506), antibody A1, or antibody A2. The antibodies were injected every three days for a total of 5 injections, as shown schematically in Figure 31 A. Tumor sizes were observed and after sacrificing the mice, blood serum was used to measure IFNy using ELISA (invitrogen, N.sde Cat. 88-7316-88) and tumor samples were used to analyze infiltrated leukocytes. As shown in Figures 31B and 31C, no antitumor effect of the A1 antibodies was observed, but the A2 antibody group samples showed a smaller tumor size and an increase in IFNy, confirming the antitumor effect of the A2 antibodies. Next, the effect of M2 macrophage conversion to M1 macrophages by antibody A2 was evaluated in the context of in vivo tumor growth. As shown schematically in Figure 32A, SW480 colon cancer cells were injected into mice (1 x 10⁷ cells / mouse), and once the tumor size reached a certain point (~1000 mm³), differentiated M2 macrophages (7 x 10⁵ cells / mouse) were injected with either hlgG or antibody A2. The antibodies were injected every 2 days for a total of 5 injections. After the first injection, blood samples were collected on days 4, 7, and 11 post-injection, and these blood samples were used to isolate serum or PBMCs for analysis of the change. IVIA / I / U4O0O0 in macrophage phenotype by FAC analysis. On day 7 after the injection of tumor cells, a change in the M1 macrophage phenotype was observed in the group with A2 antibodies, as shown in Figure 32B. Although there were no changes in CD163, an M2 macrophage marker, the expression of M1 macrophage markers CD86 and HLA-DR notably increased compared to the hlgG group, confirming the conversion of M2 macrophages to M1 by the A2 antibody, as shown in Figure 32C. Next, the effect of M2 to M1 macrophage conversion on tumor growth was analyzed. As shown schematically in Figure 33A, mice were injected with a mixture of HCT-15 colon cancer cells (8 x 10⁶ cells / mouse) and varying concentrations of M2 macrophages (2.5 x 10⁵ / 5 x 10⁵ / 1 x 10⁶ cells / mouse). After 2 days, hlgG or A2 antibody was injected every 3 days for a total of 5 injections. As shown in Figures 33 B, antibody A2 reduced or slowed tumor growth in a dose-dependent manner on day 14 after tumor injection, compared to hlgG control mice, and this effect persisted on day 25 after tumor injection. The antitumor effects of the A2 antibody were then evaluated in a humanized mouse model using a different mouse tumor model. As shown schematically in Figure 34A, human CD34 cells were injected into NBSGW mice. Blood samples were then collected, and human CD45 cells were measured in PBMCs to observe the humanization of the mice over a period of 12–14 weeks. SW480 colon cancer cells (1 × 10⁷ cells / mouse) were injected into the mice, and after 5 days, the mice were divided into two groups. Each group was injected with either hlgG or the A2 antibody (20 mg / kg). The antibodies were injected every 3 days for a total of 5 injections per group. The size of the tumor was observed and after sacrificing the mice, blood serum was used to measure IFNy using ELISA and tumor samples were used to analyze infiltrated leukocytes. No antitumor effect of the A1 antibodies was observed, but as shown in Figures 34B and 34C, the A2 antibody group samples showed a smaller tumor size and an increase in IFNy was observed, further confirming the antitumor effects of the A2 antibody. IVIA / t / ZUZ I / U4O0O0 Overall, the group receiving A2 antibody injections showed smaller tumor size and increased serum IFNγ levels. Furthermore, as shown in Figure 34D, an increase in CD8+ T lymphocytes, specifically IFNγ-secreting CD8γ T lymphocytes, was observed. As shown in Figure 34E, decreased expression of CD93 and CD163 (an M2 macrophage marker) and increased expression of CD86 (an M1 macrophage marker) were observed, while no changes in HLA-DR were noted. These data confirm that the A2 antibody mediates the cytotoxic activity of CD8+ T lymphocytes. The antitumor effect of A2 and A2.3 antibodies was then compared in a humanized mouse model. As shown schematically in Figure 35A, human CD34 cells were injected into NBSGW mice. Blood samples were then collected, and human CD45 cells were measured in PBMCs to observe the humanization of the mice over a period of 12–14 weeks. HCT-15 colon cancer cells, at 1 x 10⁷ cells / mouse, were injected into the humanized mice. Once the tumor size reached a certain size (~100 mm³), the mice were divided into three groups, each of which received injections of either hlgG, A2, or A2.3 antibodies (20 mg / kg). The antibodies were injected every three days for a total of five injections. The size of the tumor was observed and after the first injection blood samples were collected at D5 and D13 where inflammatory cytokines were observed in the blood serum.As shown in Figure 35 B, both antibodies A2 and A2.3 reduced tumor size. Subsequently, the four anti-VSIG4 antibodies, A1, A1.3, A2, and A2.3, were evaluated for their effects on CD8+ T lymphocyte proliferation. Antibodies A1, A1.3, A2, and A2.3 were added to donor-isolated macrophages to convert M2 macrophages to M1 macrophages and were co-cultured with CD8+ T lymphocytes isolated from PBMCs of the same donor for a co-culture assay. CD8+ T lymphocytes were labeled with CFSE (Life Technologies, Cat. No. V12883) and co-cultured in a 96-well plate coated with anti-CD3 (BD ​​Biocoat, Cat. No. 354725) in a 2:1 ratio with macrophages after conversion (CD8+ T: Macrophage = 2 x 10⁵ cells / well: 1 x 10⁵ cells / well). After 5 days, the collected cells were stained with hCD8-V450 and analyzed by FAC assay. CD8+ T lymphocyte proliferation was confirmed by observing the reduction in CFSE levels.While M2 macrophages negatively regulated the proliferation of CD8+ T lymphocytes, A1 antibody co-cultures. IVIA / t / ZUZ I / U4O0O0 A1.3, A2 and A2.3 resulted in the conversion of M2 macrophages into M1 macrophages and resulted in an increase in the proliferation of CD8+ T lymphocytes, as shown in Figures 36 A and 36 B. Similar experiments were performed comparing the effects of antibody A2 and A2.3 using macrophages and T lymphocytes isolated from different donors than in the previous experiment (i.e., different from the donors in Figure 36). Antibodies A2 and A2.3 were applied to macrophages to convert M2 macrophages to M1 macrophages, and CD8+ T lymphocytes were isolated from PBMCs from the same donor used for a co-culture assay. CD8+ T lymphocytes were labeled CFSE (Life Technologies, N.sde Cat. V12883) and co-cultured in a 96-well plate coated with anti-CD3 (BD ​​Biocoat, N.ade Cat. 354725) in a 1:1 or 2:1 ratio with macrophages after conversion (CD8+ T: Macrophage = 2 x 10⁵ cells / well: 2 x 10⁵ cells / well or 2 x 10⁵ cells / well: 1 x 10⁵ cells / well). After 5 days, the collected cells were stained with hCD8-V450 and analyzed by FAC assay.The proliferation of CD8+ T lymphocytes was confirmed by observing the reduction in CFSE levels. While M2 macrophages negatively regulated CD8+ T lymphocyte proliferation, the addition of A2 and A2.3 antibodies to convert M2 macrophages into M1 macrophages resulted in increased CD8+ T lymphocyte proliferation. Subsequently, HeLa cells expressing hVSIG4 (HeLa-hVSIG4 cells) were used to confirm the role of VSIG4 signaling in the induction of A2 and A2 antibody-mediated CD8+ T lymphocyte proliferation.3. CD8+ T lymphocytes were isolated from PBMCs of a healthy donor, labeled with CFSE, and applied to an anti-CD3 coated plate (2 x 10⁵ cells / well). After 1 day, HeLa or HeLa-hVSIG4 cells were added to the wells following irradiation at 30 Gy (X-rays) (1 x 10⁵ or 0.5 x 10⁵ cells / well). After 5 days, CD8+ T lymphocyte proliferation was analyzed by measuring CFSE levels using FAC assay. CD8+ T lymphocytes were also treated with anti-CD3 (Mi Iteny i Biotech, N.ade Cat. 130-093-387) at different concentrations, and after 1 day, HeLa or HeLa-hVSIG4 cells were added to the wells after irradiation with 30 Gy (X-rays) – (1 x 10⁵ cells / well). After 5 days, 100 µL of the cultured cells were transferred to a separate 96-well plate, and CCK8 was added to each well (10 µL / well). After 5 hours, absorbance was measured at 450 nm, confirming the proliferation of CD8+ T lymphocytes, as shown in the Figures. IVIA / I / U4O0O0 A and 38 B, HeLa-hVSIG4 negatively regulated CD8+ T lymphocyte proliferation, while treatment with A2 or A2.3 induces T lymphocyte proliferation. A human phosphorylation kinase array was used to examine the signaling pathway through which the A2 antibody repolarizes the macrophage. As shown in Figure 39, conversion of M2 macrophages to M1 macrophages by treatment with A2 antibodies resulted in a significant increase in the phosphorylation of JNK, MSK1 / 2, and p38a, as measured using Proteome Profiler™ antibody arrays (R&D Systems, N.sde Cal ARY003B). ANTIBODY SEQUENCE AND BINDING AFFINITY INFORMATION Sequence information and binding affinity information for the various anti-VSIG4 antibodies described herein are provided in TABLES 5-12 below. IVIA / I / U4O0J0 TABLE 5: VH AND VL SEQUENCES OF THE EU103.2 ANTIBODY Ab Name EU103.2VH Sequence (amino acid) QVQLQESGPGLVKPSQTLSLTCSFSGISLTTSGMGVGWIRQPPGK GLEWLADIFWDDNKYYNP SLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCVRVYYKNDGYFD VWGQGTLVTVSS (SEQ ID NO: 2) EU103.2VL (amino acid) EIVMTQSPATLSVSPGERATLSCRASKSVTTSGYSFMHWYQQKP GQAPRLLIYLASNLEPGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQHSRELPYTFGQGTKLEIK (SEQ ID NO: 4) TABLE 6: VH AND VL SEQUENCES OF THE EU103.3 ANTIBODY Ab Name Sequence EU103.3_VH (hu6H8.3_VH) (amino acid) QVTLKESG PTLVKPTQTLTLTCTFSGISLTTSG MG VG Wl RQPP GKALEWLADIFWDDNKYYN PSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCVRVYYKND GYFDVWGKGTTVTVS (SEQ ID NO: 6) EU103.3_VL DIVLTQSPLSLPVTLGQPASISCRASKSVTTSGYSFMHWYQQRP GQSPRLLIYLASNLEPGVP (hu6H8.3_VL) (amino acid) DRFSGSGSGTDFTLKISRVEAEDVGVYYCQHSRELPYTFGQGT KLEIK (SEQ ID NO: 8) IVIA / I / U4O0O0 TABLE 7: VH AND VL SEQUENCES OF ANTIBODY A1 Nombre de Ab Secuencia A1VH (aminoacid) QVTLKESG PTLVKPTQTLTLTCTFSGISLTTSG MG VG Wl RQPPG KAL EWLADIFWDDNKYYNPS LKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCVRVYYKNDGYFDVW GKGTTVTVSS (SEQ ID NO: 6) A1VL DIVLTQSPLSLPVTLGQPASISCRASKSVTTSGYSFMHWYQQRPGQS PRLLIYLASNLEPGVPDR (aminoacid) FSGSGSGTDFTLKISRVEAEDVGVYYCQQSGELPYTFGQGTKLEIK (SEQ ID NO: 10) TABLE 8: SECUENCIAS VH Y VL DEL ANTICUERPO A2 Nombre de Ab Secuencia A2VH (aminoacid) QVTLKESG PTLVKPTQTLTLTCTFSGISLTTSGMGVGWIRQPPGKALE WLADIFWDDNKYYNPS LKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCVRVYYKNDGYFDVW GKGTTVTVSS (SEQ ID NO: 6) Number of Ab Secuencia A2VL (aminoácido) DIVLTQSPLSLPVTLGQPASISCRASKSVTTSGYSFMHWYQQRPGQS PRLLIYLASNLEPGVPDR FSGSGSGTDFTLKIFRVEAEDVGVYYCQQSGELPYTFGQGTKLEIK (SEQ ID NO: 12) IVIA / I / U4O0O0 TABLE 9: SECUENCIAS VH Y VL DEL ANTICUERPO A1.3 Nombre de Ab Secuencia A1.3_VH (aminoacid) QVTLVESGPTLVKPGQTLTLTCTFSGISLTTSGMGVGWIRQPPGKALE WLADIFWDDNKYYNPS LKGRLTITKDTSKNQVYLTMTNMDPVDTATYYCVRVYYKNDGYFDVW GKGTTVTVSS (SEQ ID NO: 14) A1.3_VL (aminoacid) DIVLTQSPLSLPVTLGQPASISCRASKSVTTSGYSFMHWYQQRPGQSP RLLIYLASNLEPGVPDR FSGSGSGTDFTLKISRVEAEDVGVYYCQQSGELPYTFGQGTKLEIK (SEQ ID NO: 10) TABLE 10: SECUENCIAS VH Y VL DEL ANTICUERPO A2.3 A2.3_VH (amino) (aminoácido) DIVLTQSPLSLPVTLGQPASISCRASKSVTTSGYSFMHWYQQRPGQSP RLLIYLASNLEPGVPDR FSGSGSGTDFTLKIFRVEAEDVGVYYCQQSGELPYTFGQGTKLEIK (SEQ ID NO: 12) TABLE 11: SECUENCIAS CDR DE ANTIQUERPOS EU103.2, EU103.3, Α1, A2, A1.3 y A2 3_____________________________________________________________________ IVIA / I / U4O0O0 VH CDR1 VH CDR2 VH CDR3 VL CDR1 VL CDR2 VL CDR3 EU103.2 GISLTT (SEQ ID NO: 17) IFWDDNK (SEQ ID NO: 18) VRVYYKNDGYFDV (SEQ ID NO: 19) KSVTTS (SEQ ID NO: 20) LAS (SEQ ID NO: 21) QHSRELPYT (SEQ ID NO: 22) EU103.3 GISLTT (SEQ ID NO: 17) IFWDDNK (SEQ ID NO: 18) VRVYYKNDGYFDV (SEQ ID NO: 19) KSVTTS (SEQ ID NO: 20) LAS (SEQ ID NO: 21) QHSRELPYT (SEQ ID NO: 22) < GISLTT (SEQ ID NO: 22) 17) IFWDDNK (SEQ ID NO: 18) VRVYYKNDGYFDV (SEQ ID NO: 19) KSVTTS (SEO ID NO: 20) LAS (SEQ ID NO: 21) QQSGELPYT (SEQ ID NO: 23) OJ < GISLTT (SEQ ID NO: 17) IFWDDNK (SEQ ID NO: 18) VRVYYKNDGYFDV (SEQ ID NO: 19) KSVTTS (SEQ ID NO: 20) LAS (SEQ ID NO: 21) QQSGELPYT (SEQ ID NO: 23) A1.3 GISLTT (SEQ ID NO: 17) IFWDDNK (SEQ ID NO: 18) VRVYYKNDGYFDV (SEQ ID NO: 19) KSVTTS (SEO ID NO: 20) LAS (SEQ ID NO: 21) QQSGELPYT (SEQ ID NO: 23) A2.3 GISLTT (SEQ ID NO: 17) IFWDDNK (SEQ ID NO: 18) VRVYYKNDGYFDV (SEQ ID NO: 19) KSVTTS (SEQ ID NO: 20) LAS (SEQ ID NO: 21) QQSGELPYT (SEQ ID NO: 23) TABLE 12: BINDING AFFINITY (Kd) OF ANTIBODIES EU103.2, EU103.3, A1, A2, A1.3yA2.3 FOR VSIG4 Antibody Ka(1 / Ms) Kd(1 / s) KD (M) EU103.2 1.834E+5 0.01313 7.156E-8 A1 3.779E+5 0.003283 8.688E-9 A1.3 4.022E+5 0.003198 7.952E-9 A2 3.604E+5 0.002964 8.226E-9 A2.3 4.037E+5 0.003083 7.636E-9 OTHER ACHIEVEMENTS It should be understood that, although the invention has been described in conjunction with a detailed description thereof, the foregoing description is intended to illustrate, and not limit, the scope of the invention, which is defined by the scope of the appended claims. Other aspects and advantages are included within the scope of the following claims.

Claims

1. An isolated humanized antibody or antigen-binding fragment thereof, characterized in that it comprises: a. a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 17, a heavy chain CDF12 comprising the amino acid sequence of SEQ ID NO: 18, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 19; and b. a light chain CDR1 having the amino acid sequence of SEQ ID NO: 20, a light chain CDR2 each comprising the amino acid sequence of SEQ ID NO: 21 and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 22 or SEQ ID NO:

23.

2. The antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment comprises any of the following: a. a heavy-chain variable domain comprising an amino acid sequence that is at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14, or SEQ ID NO: 16; b. a light-chain variable domain comprising an amino acid sequence that is at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 10, or SEQ ID NO: 12; or c.a heavy chain variable domain comprising an amino acid sequence at least 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14 or SEQ ID NO: 16, and a light chain variable domain comprising an amino acid sequence at least 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 10 or SEQ ID NO:

12.

3. The antibody or antigen-binding fragment of any one of claims 1-2, wherein the antibody or antigen-binding fragment comprises any of the following: a. a heavy-chain variable domain comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14 or SEQ ID NO: 16; b. a light-chain variable domain comprising the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 10 or SEQ ID NO: 12; or c. a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 6, SEQ ID NO: 14 or SEQ ID NO: 16, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 10 or SEQ ID NO:

12.

4. The antibody or antigen-binding fragment of claim 1, wherein the antibody wherein the light chain CDR3 comprises the amino acid sequence of SEQ ID NO:

23.

5. The antibody or antigen-binding fragment of claim 2, wherein the antibody or antigen-binding fragment comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

4.

6. The antibody or antigen-binding fragment of claim 2, wherein the antibody or antigen-binding fragment comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

8.

7. The antibody or antigen-binding fragment of claim 2, wherein the antibody or antigen-binding fragment comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 6 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

10.

8. The antibody or antigen-binding fragment of claim 2, wherein the antibody or antigen-binding fragment comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 6 IVIA / t / ZUZ I / U4O0O0 55 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

12.

9. The antibody or antigen-binding fragment of claim 2, wherein the antibody or antigen-binding fragment comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 14 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

10.

10. The antibody or antigen-binding fragment of claim 2, wherein the antibody or antigen-binding fragment comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

12.

11. The antibody or antigen-binding fragment of any one of claims 1-10, wherein the antibody or antigen-binding fragment has a binding affinity (Kd) for a human V-set and immunoglobulin domain containing 4 (VSIG4) molecule of 1 x 10'7 to 1 x 10~9.

12. The antibody or antigen-binding fragment of any one of claims 1-11, wherein the antibody or antigen-binding fragment has a binding affinity (Kd) for a VSIG4 molecule of approximately 7.156 x 10'8 to approximately 7.636 x 10'9.

13. The antibody or antigen-binding fragment of any one of claims 1-11, wherein the antibody or antigen-binding fragment has a binding affinity (Kd) for a VSIG4 molecule of approximately 7.156 x 10'8, approximately 7.636 x 10'9, approximately 7.952 x 10'9, approximately 8.226 x 10'9, or approximately 8.688 x 10'9.

14. A nucleic acid molecule encoding the antibody or antigen-binding fragment according to any of claims 1-13.

15. A recombinant vector comprising the nucleic acid molecule of claim 14.

16. The recombinant vector of claim 15, wherein the nucleic acid molecule of claim 14 is operatively linked to a promoter.

17. The recombinant vector of claim 15 or 16, wherein the vector comprises two separate vectors, each comprising the nucleic acid sequence corresponding to the heavy chain and light chain of the antibody or IVIA / t / ZUZ I / U4O0O0 antigen-binding fragment.

18. A host cell comprising the nucleic acid molecule of claim 14 or the recombinant vector of any of claims 15-17.

19. The host cell of claim 18, wherein the host cell is a mammalian cell, a yeast cell, or a bacterial cell.

20. The host cell of claim 19, wherein the host cell is a cell selected from the group consisting of E. coli, P. pastoris, Sf9, COS, HEK293, Expi293, CHO-S, CHO-DG44, CHO-K1 and a mammalian lymphocyte.

21. The host cell of claim 20, wherein the host cell is cell Exp¡293.

22. A pharmaceutical composition comprising: the antibody or antigen-binding fragment of any one of claims 1-13, the nucleic acid molecule of claim 14, the recombinant vector of any one of claims 15-17, or the host cell of any one of claims 18-21; and a pharmaceutically acceptable carrier.

23. A method of treating a subject in need thereof, the method comprising the steps of: a. administering to the subject a composition comprising or releasing the antibody or antigen-binding fragment of any one of claim 113, the nucleic acid molecule of claim 14, the recombinant vector of any one of claims 15-17, or the host cell of any one of claims 18-21, thereby treating a disease or condition.

24. The method of claim 23, wherein the subject has, or is at risk of developing, cancer.

25. The method of claim 24, wherein the cancer is selected from bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, cancer of the fallopian tubes, gallbladder cancer, gastrointestinal cancer, head and neck cancer, hematologic cancer, laryngeal cancer, liver cancer, lung cancer, lymphoma, melanoma, mesothelioma, ovarian cancer, primary peritoneal cancer, salivary gland cancer, sarcoma, stomach cancer, thyroid cancer, pancreatic cancer, renal cell carcinoma, glioblastoma, and prostate cancer.

26. The method of any one of claims 23-25, wherein the subject has been or will be administered one or more additional cancer therapies selected from ionizing radiation, a chemotherapeutic agent, an antibody agent, and a cell-based therapy, such that the subject is treated with both.

27. The method of claim 26, wherein one or more additional cancer therapies comprise an immune checkpoint inhibitor, IL-12, GM-CSF, an anti-CD4 agent, cisplatin, fluorouracil, doxorubicin, irinotecan, paclitaxel, indolamine 2,3-dioxygenase-1 inhibitor (IDOI), or cyclophosphamide.

28. A method for increasing the secretion of cytokines or chemokines in M2 macrophages comprising: a. Contacting the M2 macrophages with the antibody or antigen-binding fragment of any one of claims 1-13.

29. A method for inducing the proliferation of CD8+ T lymphocytes, the method comprising: a. contacting an M2 macrophage with the antibody or antigen-binding fragment of any one of claims 1-13; and b. co-incubating the M2 macrophage with CD8+ T lymphocytes.

30. A method for converting an M2 macrophage into an M1 macrophage, the method comprising contacting the M2 macrophage with the antibody or antigen-binding fragment of any one of claims 1-13.