Use of Anti-ctla-4 antibodies

Abstract

This invention provides an anti-CTLA-4 antibody, a method for manufacturing the antibody, and a method for using the antibody. This invention also provides a nucleic acid encoding the anti-CTLA-4 antibody and a host cell containing the nucleic acid. This invention further provides a polypeptide containing a mutated Fc region with altered amino acids in the parental Fc region, a method for manufacturing the polypeptide, and a method for using the polypeptide.

Description

Uses of anti-CTLA-4 antibodies The present invention relates to anti-CTLA-4 antibodies and methods of using the same. Furthermore, the present invention relates to polypeptides comprising a mutant Fc region and methods of producing the polypeptides, wherein the mutant Fc region comprises an amino acid change in the parent Fc region. In vivo, cells that have mutated due to factors such as gene mutations are monitored and eliminated by the immune surveillance system. On the other hand, a persistent overactive immune response can lead to autoimmune damage to normal tissues, which can also be harmful to the body. Therefore, the immune system possesses negative feedback mechanisms (immune checkpoints) that suppress transiently activated immune responses (see, for example, Non-Patent Document 1). Immune checkpoints are believed to play a crucial role in maintaining immune homeostasis. Meanwhile, some tumors are known to exploit immune checkpoints for immune escape. Currently, research is underway on the immunosuppressive functions of key immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). CTLA-4 is a glycoprotein belonging to the immunoglobulin superfamily, which was cloned in 1987 from a cDNA library derived from a killer T cell line in mice (see, for example, Non-Patent Document 2). CTLA-4 is known to inhibit T cell immune responses. Based on the idea that inhibiting CTLA-4 function promotes T cell activation and is associated with cancer regression, a 1996 report showed that administering anti-CTLA-4 antibodies to tumor-bearing mice resulted in tumor regression (see, for example, Non-Patent Document 3). Since 2000, evaluation of the effectiveness of anti-CTLA-4 antibodies in humans has been underway, and in 2011, the anti-human CTLA-4 monoclonal antibody (ipilimumab) was approved by the US Food and Drug Administration (FDA) as the world's first immune-activating antibody drug. In addition to ipilimumab, numerous other anti-CTLA-4 monoclonal antibodies have been developed (see, for example, Patent Documents 1, 2, 3, and 4), and efforts are underway to develop these as pharmaceuticals. Drugs that inhibit immune checkpoints, thereby relieving their immunosuppressive mechanisms and ultimately enhancing immune activity, are called immune checkpoint inhibitors. Meanwhile, it was previously known that some T cells possess immunosuppressive functions. However, these cells were identified in 1995 as CD25-positive, CD4-positive T cells and designated as regulatory T cells (e.g., see Non-Patent Document 4). In 2003, the Foxp3 gene, a master gene specifically expressed in regulatory T cells and controlling their development and function, was identified. Foxp3 acts as a transcription factor, controlling the expression of various genes involved in immune responses.Among them, Foxp3 is involved in the constant expression of CTLA-4 in regulatory T cells and is believed to play a key role in the immunosuppressive function of regulatory T cells (see, for example, Non-Patent Document 5). Because regulatory T cells infiltrate tumor tissues, they are thought to weaken or inhibit tumor immune surveillance mechanisms. In fact, regulatory T cells are known to be increased in many human malignancies (see, for example, Non-Patent Document 6), and local infiltration of regulatory T cells into tumors has been reported to be a poor prognostic factor for cancer patients. Conversely, if regulatory T cells can be eliminated or reduced from tumor tissues, it is expected to enhance anti-tumor immunity. Currently, efforts are underway to develop cancer immunotherapies targeting regulatory T cells. While administration of the anti-CTLA-4 antibody ipilimumab enhances anti-tumor immunity, it has also been reported to cause autoimmune diseases due to systemic enhancement. In a clinical trial, 60% of patients receiving ipilimumab experienced adverse events, most of which were autoimmune diseases related to the skin or digestive tract. In another clinical trial, it was also reported that about half of the patients who received ipilimumab developed the same autoimmune disease. In order to suppress this side effect, there have been cases where immunosuppressants were administered to patients who had already received ipilimumab. There is a desire to develop new agents that can suppress the side effects of immune checkpoint inhibitors while maintaining anti-tumor immune responses. When therapeutic antibodies are administered into a living body, it is hoped that the target antigen will be specifically expressed only in the lesion site. However, in many cases, the same antigen is also expressed in non-lesion sites, that is, normal tissues, which can cause undesirable side effects from a therapeutic perspective. For example, antibodies against tumor antigens can exert damaging activity against tumor cells through ADCC, etc. On the other hand, when the same antigen is also expressed in normal tissues, there is a possibility that normal cells will also be damaged. To address the above-mentioned problems, a technology has been developed that exploits the fact that specific compounds are present in large quantities in target tissues (e.g., tumor tissues) to create antigen-binding molecules whose antigen-binding activity varies depending on the concentration of the compound (e.g., see Patent Document 11). Antibodies are highly stable in the blood and have few side effects, thus attracting attention as pharmaceuticals (Non-Patent Documents 12 and 13). Currently marketed antibody pharmaceuticals are almost all human IgG1 subclass antibodies. The effector functions of IgG antibodies, namely antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), have been extensively studied. Among human IgG antibodies, IgG1 subclass antibodies have been reported to have the highest ADCC and CDC activities (Non-Patent Document 14). Furthermore, antibody-dependent cell-mediated phagocytosis (ADCP), the phagocytosis of target cells by IgG antibodies, is also an effector function of antibodies (Non-Patent Documents 15 and 16). The performance of ADCC, CDC, and ADCP by IgG antibodies requires the binding of the antibody Fc region to antibody receptors (hereinafter referred to as FcγRs) and various complement components present on the surfaces of effector cells such as killer cells, natural killer cells, and activated macrophages. In humans, the FcγR protein family includes the following isoforms: FcγRIa, FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb, and their respective allotypes have also been described (Non-Patent Document 17). Enhancing cytotoxic effector functions such as ADCC, ADCP, and CDC has attracted attention as a promising approach for enhancing the anti-tumor effects of antibodies. The importance of FcγR-mediated effector functions for the anti-tumor effects of antibodies has been reported using mouse models (Non-Patent Documents 7 and 8). Furthermore, a correlation has been observed between clinical efficacy in humans and the high-affinity polymorphic allotype (V158) and the low-affinity polymorphic allotype (F158) of FcγRIIIa (Non-Patent Document 18). Similarly, it has been shown that clinical efficacy varies depending on the FcγRIIa allotype (H131 versus R131) (Non-Patent Document 19). These reports suggest that antibodies with Fc regions optimized for binding to specific FcγRs mediate more potent effector functions, thereby exerting effective anti-tumor effects. The balance of antibody binding activity against activating receptors (FcγRIa, FcγRIIa, FcγRIIIa, and FcγRIIIb) and inhibitory receptors (FcγRIIb) is a crucial factor in optimizing an antibody's effector function. By enhancing binding activity against activating receptors and using an Fc region with reduced binding activity against inhibitory receptors, it is possible to confer optimal effector function on an antibody (Non-Patent Document 20). Important amino acid residues within the hinge and CH2 regions of antibodies, as well as the sugar chain attached to Asn at EU numbering 297, have been shown to be crucial for Fc region binding to FcγRs (Non-Patent Documents 14, 21, and 22). Focusing on this binding site, Fc region variants with various FcγR binding properties have been studied, and some have been shown to exhibit enhanced FcγR binding activity (Patent Documents 5, 6, Non-Patent Documents 9, 10). For example, Lazar et al. successfully increased binding to human FcγRIIIa (V158) by approximately 370-fold by substituting Ser at EU numbering position 239, Ala at EU numbering position 330, and Ile at EU numbering position 332 in human IgG1 with Asp, Leu, and Glu, respectively (Non-Patent Documents 9, 6). Shinkawa et al. successfully increased FcγRIIIa binding by approximately 100-fold by deleting fucose from the sugar chain attached to Asn at EU numbering position 297 (Non-Patent Document 23). These methods involve introducing the same alteration or the same sugar chain modification into the Fc region of both H chains of an antibody. Meanwhile, the Fc region of an antibody has been reported to bind to FcγRs in a 1:1 ratio, independent of homodimerization, and to asymmetrically recognize FcγRs at the lower hinge and CH2 regions (Non-Patent Document 11). Considering the asymmetrical interaction between the Fc region and FcγRs, introducing different modifications to each H chain is believed to enable more precise optimization of the interaction between IgG and FcγRs. Based on this concept, methods have been reported to optimize the interaction with FcγRs by asymmetrically modifying the Fc region by adding different modifications to each H chain of an antibody (Patent Documents 7, 8, 9, and 10). In fact, asymmetrically modifying the Fc region has yielded variants that exhibit higher ADCC activity than existing ADCC-enhancing antibodies, namely, defucosylated antibodies (Patent Documents 9 and 10). In addition to ADCC activity, ADCP activity has been reported to be an important effector function of antibodies and contributes to anti-tumor effects (Non-Patent Document 24). ADCP activity can be enhanced by inhibiting the "Don't Eat Me" signal represented by CD47 (Non-Patent Document 24) and by enhancing binding to FcγRIIa (Non-Patent Document 25). However, the extracellular domains of the activating FcγR, FcγRIIa, and the inhibitory FcγRIIb, share very high amino acid sequence homology, making it difficult to selectively enhance binding to FcγRIIa (Non-Patent Document 26). Therefore, enhancing binding to FcγRIIa would also enhance binding to the inhibitory receptor, FcγRIIb, potentially weakening effector function. In fact, variants that significantly enhance their FcγRIIa binding ability compared to native IgG1 also have enhanced FcγRIIb binding ability (Patent Documents 9 and 10). Therefore, in order to achieve high ADCC / ADCP activity, it is desirable to maximize binding to FcγRIIIa and FcγRIIa without enhancing FcγRIIb binding ability. However, such variants have not yet been reported. [Prior Art] [Patent] [Patent Document 1] WO 2000 / 037504 [Patent Document 2] WO 2001 / 014424 [Patent Document 3] WO 2012 / 120125 [Patent Document 4] WO 2016 / 196237 [Patent Document 5] WO 2000 / 042072 [Patent Document 6] WO 2006 / 019447 [Patent Document 7] WO 2012 / 058768 [Patent Document 8] WO 2012 / 125850 [Patent Document 9] WO 2013 / 002362 [Patent Document 10] WO 2014 / 104165 [Patent Document 11] WO 2013 / 180200 [Non-Patent Document] [Non-patent document 1] Pardoll, Nat Rev Cancer (2012) 12: 252-264 [Non-patent document 2] Brunet et al., Nature (1987) 328: 267-270 [Non-patent document 3] Leach et al., Science (1996) 271: 1734-1736 [Non-patent document 4] Sakaguchi et al., J Immunol (1995) 155: 1151-1164 [Non-patent document 5] Takahashi et al., J Exp Med (2000) 192: 303-310 [Non-patent document 6] Nishikawa & Sakaguchi, Int J Cancer (2010) 127: 759-767 [Non-patent document 7] Clynes et al., Proc Natl Acad Sci USA (1998) 95: 652-656 [Non-patent document 8] Clynes et al., Nat Med (2000) 6: 443-446 [Non-patent document 9] Lazar et al., Proc Natl Acad Sci USA (2006) 103: 4005-4010 [Non-patent document 10] Chu et al., Mol Immunol (2008) 45: 3926-3933 [Non-patent document 11] Radaev et al., J Biol Chem (2001) 276: 16469-16477 [Non-patent document 12] Reichert et al., Nat Biotechnol (2005) 23: 1073-1078 [Non-patent document 13] Pavlou & Belsey, Eur J Pharm Biopharm (2005) 59: 389-396 [Non-patent document 14] Clark, Chem Immunol (1997) 65: 88-110 [Non-patent literature 15] Horton et al., Cancer Res (2008) 68: 8049-8057 [Non-patent literature 16] Zalevsky et al., Blood (2009) 113: 3735-3743 [Non-patent literature 17] Jefferis & Lund, Immunol Lett (2002) 82: 57-65 [Non-patent literature 18] Carton et al., Blood (2002) 99: 754-758 [Non-patent literature 19] Tamura et al., Ann Oncol (2011) 22: 1302-1307 [Non-patent literature 20] Nimmerjahn & Ravetch, Science (2005) 310: 1510-1512 [Non-patent literature 21] Greenwood et al., Eur J Immunol (1993) 23: 1098-1104 [Non-patent literature 22] Morgan et al., Immunology (1995) 86: 319-324 [Non-patent literature 23] Shinkawa et al., J Biol Chem (2003) 278: 3466-3473 [Non-patent literature 24] Tsao et al., JCI Insight (2019) 4: e131882 [Non-patent literature 25] Richards et al., Mol Cancer Ther (2008) 7: 2517-2527 [Non-patent literature 26] Mimoto et al. al., Protein Eng Des Sel (2013) 26: 589-598. [Problems to be Solved by the Invention] The present invention provides anti-CTLA-4 antibodies and methods of using the same. The present invention also provides polypeptides comprising a mutant Fc region and methods of producing the same. [Means for Solving the Problems] More specifically, the present invention provides the following [1] to

[34] . [1] An anti-CTLA-4 antibody for use in the treatment of tumors, the anti-CTLA-4 antibody comprising: (A) a variable region having CTLA-4 binding activity that is dependent on the concentration of an adenosine-containing compound; and (B) a mutant Fc region comprising multiple amino acid changes in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and the mutant Fc region comprises amino acid changes in the following positions: (i) positions 234, 235, 236, 239, 268, 270, 298, and 330 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 270, 298, 326, 330, and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region. [2] An anti-CTLA-4 antibody for use as described in [1], wherein the tumor is a solid tumor infiltrated by regulatory T (Treg) cells. [3] An anti-CTLA-4 antibody for use in cell damage, the anti-CTLA-4 antibody comprising: (A) a variable region having CTLA-4 binding activity that is dependent on the concentration of an adenosine-containing compound; and (B) a mutant Fc region comprising multiple amino acid changes in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and the mutant Fc region comprises amino acid changes in the following positions: (i) positions 234, 235, 236, 239, 268, 270, 298, and 330 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 270, 298, 326, 330, and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region. [4] The anti-CTLA-4 antibody for use as described in [3], wherein the damaged cells are Treg cells. [5] The anti-CTLA-4 antibody for use as described in [3], wherein the cell damage is through ADCC activity, CDC activity or ADCP activity. [6] The anti-CTLA-4 antibody for use as described in [3] or [4], wherein immunity is activated through damage to Treg cells. [7] The anti-CTLA-4 antibody for use as described in [1] or [2], wherein the tumor is at least one selected from the group consisting of carcinoma, lymphoma, blastoma, sarcoma and leukemia.[8] An anti-CTLA-4 antibody for use as described in [7], wherein the tumor is selected from the group consisting of lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colorectal cancer, rectal cancer, colon cancer, breast cancer, liver cancer, gastric cancer, pancreatic cancer, kidney cancer, prostate cancer, ovarian cancer, thyroid cancer, bile duct cancer, peritoneal cancer, mesothelioma, squamous cell carcinoma, cervical cancer, endometrial cancer, bladder cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, salivary gland tumor, thymoma, skin cancer, basal cell tumor, melanoma, malignant melanoma, anal cancer, penile cancer, testicular cancer, Wilms' tumor, tumor), acute myeloid leukemia (including acute myelocytic leukemia, acute myeloblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia and acute monocytic leukemia), chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma (including Birch's lymphoma, chronic lymphocytic leukemia, mycosis fungoides, mantle cell lymphoma, follicular lymphoma, diffuse large cell lymphoma, marginal zone lymphoma, hairy cell leukemia plasmacytoma, peripheral T-cell lymphoma and adult T [9] An anti-CTLA-4 antibody for use as described in [8], wherein the tumor is at least one selected from the group consisting of lung cancer, colorectal cancer, colon cancer, breast cancer, liver cancer, pancreatic cancer, kidney cancer, bladder cancer, head and neck cancer, and melanoma.

[10] An anti-CTLA-4 antibody for use as described in any one of [1] to [9], wherein the anti-CTLA-4 antibody is an immunoconjugate.

[11] An anti-CTLA-4 antibody for use as described in any one of [1] to

[10] , used in admixture with one or more pharmaceutically acceptable carriers.

[12] An anti-CTLA-4 antibody for use as described in any one of [1] to

[11] , used in combination with at least one additional therapeutic agent.

[13] An anti-CTLA-4 antibody for use as described in

[12] , wherein the additional therapeutic agent is at least one selected from the group consisting of an immune checkpoint inhibitor, an EGFR inhibitor, a HER2 inhibitor, and a chemotherapeutic agent.

[14] An anti-CTLA-4 antibody for use as described in any one of [1] to

[10] , wherein the variable region has at least one characteristic selected from the following (a) to (i): (a) the binding activity in the presence of 100 μM adenosine-containing compound is more than 2 times higher than the binding activity in the absence of the adenosine-containing compound; (b) the KD value in the presence of 100 μM adenosine-containing compound is 5×10. -7 M or less; (c) The KD value in the absence of adenosine-containing compounds is 1×10 -6 M or more; (d) forms a ternary complex with an adenosine-containing compound and CTLA-4; (e) binds to the region from amino acid 97 to amino acid 106 of human CTLA-4 (extracellular region, SEQ ID NO: 28); (f) competes with ABAM004 (VH, SEQ ID NO: 10; and VL, SEQ ID NO: 11) for binding to CTLA-4; (g) binds to the same epitope as that bound by ABAM004 (VH, SEQ ID NO: 10; and VL, SEQ ID NO: 11); (h) exhibits cytotoxicity against CTLA-4 expressing cells; and (i) binds to CTLA-4 derived from humans and mice.

[15] An anti-CTLA-4 antibody for use as described in any one of [1] or

[14] , wherein the anti-CTLA-4 antibody is a monoclonal antibody.

[16] An anti-CTLA-4 antibody for use as described in any one of [1] to

[15] , wherein the anti-CTLA-4 antibody is a human antibody, a humanized antibody, or a chimeric antibody.

[17] An anti-CTLA-4 antibody for use as described in any one of [1] to

[16] , wherein the anti-CTLA-4 antibody comprises: (a) an amino acid sequence SX 1TMN,X 1 is H, A, R or K, i.e. HVR-H1 (SEQ ID NO: 223); (b) comprising the amino acid sequence SISX 1X 2SX 3YIYYAX 4SVX 5G, X 1 is S or T, X 2 is R or Q, X 3 is G or H, X 4 is D, E or R, X 5 is K or R, i.e., HVR-H2 (SEQ ID NO: 224); and (c) comprises the amino acid sequence YGX 1REDMLWVFDY,X 1 is K or A, i.e. HVR-H3 (SEQ ID NO: 225).

[18] An anti-CTLA-4 antibody for use as described in

[17] , wherein the anti-CTLA-4 antibody further comprises: (a) an amino acid sequence X 1GX 2STX 3VGDYX 4X 5VX 6, X 1 is T, D, Q or E, X 2 is T or P, X 3 is D or G, X 4 is N or T, X 5 is Y or W, X 6 is S or H, i.e. HVR-L1 (SEQ ID NO: 226); (b) comprising the amino acid sequence X 1TX 2X 3KPX 4, X 1 is E, F or Y, X 2 is S or I, X 3 is K or S, X 4 is S, E or K, i.e. HVR-L2 (SEQ ID NO: 227); and (c) comprises the amino acid sequence X 1TYAAPLGPX 2, X 1 is S or Q, X 2 is M or T, i.e., HVR-L3 (SEQ ID NO: 228).

[19] An anti-CTLA-4 antibody for use as described in

[17] , wherein the anti-CTLA-4 antibody further comprises: a heavy chain variable region FR1 comprising any one of the amino acid sequences of SEQ ID NOs: 229 to 232, a FR2 comprising the amino acid sequence of SEQ ID NO: 233, a FR3 comprising the amino acid sequence of SEQ ID NO: 234, and a FR4 comprising the amino acid sequence of SEQ ID NO: 235.

[20] An anti-CTLA-4 antibody for use as described in

[18] , wherein the anti-CTLA-4 antibody further comprises: a light chain variable region FR1 comprising an amino acid sequence of any one of SEQ ID NOs: 236 to 238, a FR2 comprising an amino acid sequence of any one of SEQ ID NOs: 240 to 241, a FR3 comprising an amino acid sequence of any one of SEQ ID NOs: 242 to 244, and a FR4 comprising an amino acid sequence of any one of SEQ ID NOs: 245 to 246.

[21] An anti-CTLA-4 antibody for use as described in any one of [1] to

[16] , wherein the anti-CTLA-4 antibody comprises: (a) a VH sequence having at least 95% sequence identity with any one of the amino acid sequences of SEQ ID NOs: 83-86, 98, 135-141; (b) a VL sequence having at least 95% sequence identity with any one of the amino acid sequences of SEQ ID NOs: 88-95, 97, 99, 134, 144-149; or (c) a VH sequence having any one of the amino acid sequences of SEQ ID NOs: 83-86, 98, 135-141 and a VL sequence having any one of the amino acid sequences of SEQ ID NOs: 88-95, 97, 99, 134, 144-149.

[22] An anti-CTLA-4 antibody for use as described in

[21] , wherein the anti-CTLA-4 antibody comprises: (1) a VH sequence of sequence identification number: 98 and a VL sequence of sequence identification number: 99; (2) a VH sequence of sequence identification number: 83 and a VL sequence of sequence identification number: 88; (3) a VH sequence of sequence identification number: 83 and a VL sequence of sequence identification number: 89; (4) a VH sequence of sequence identification number: 83 and a VL sequence of sequence identification number: 90; (5) a VH sequence of sequence identification number: 83 and a VL sequence of sequence identification number: 91; (6) a VH sequence of sequence identification number: 83 and a VL sequence of sequence identification number: 92; (7) a VH sequence of sequence identification number: 83 and a VL sequence of sequence identification number: 93; (8) a VH sequence of sequence identification number: 83 and a VL sequence of sequence identification number: 94; (9) VH sequence of SEQ ID NO: 83 and VL sequence of SEQ ID NO: 97; (10) VH sequence of SEQ ID NO: 83 and VL sequence of SEQ ID NO: 95;(11) The VH sequence of sequence identification number: 84 and the VL sequence of sequence identification number: 97; (12) The VH sequence of sequence identification number: 85 and the VL sequence of sequence identification number: 97; (13) The VH sequence of sequence identification number: 86 and the VL sequence of sequence identification number: 97; (14) The VH sequence of sequence identification number: 86 and the VL sequence of sequence identification number: 134; (15) The VH sequence of sequence identification number: 136 and the VL sequence of sequence identification number: 97; (16) The VH sequence of sequence identification number: 135 and the VL sequence of sequence identification number: 97; (17) The VH sequence of sequence identification number: 136 and the VL sequence of sequence identification number: 95; (18) The VH sequence of sequence identification number: 137 and the VL sequence of sequence identification number: 97; (19) The VH sequence of sequence identification number: 138 and the VL sequence of sequence identification number: 97; (20) The VH sequence of sequence identification number: 138 and the VL sequence of sequence identification number: 144; (21) The VH sequence of sequence identification number: 138 and the VL sequence of sequence identification number: 145; (22) The VH sequence of sequence identification number: 138 and the VL sequence of sequence identification number: 146; (23) The VH sequence of sequence identification number: 139 and the VL sequence of sequence identification number: 146; (24) The VH sequence of sequence identification number: 140 and the VL sequence of sequence identification number: 146; (25) The VH sequence of sequence identification number: 141 and the VL sequence of sequence identification number: 146; (26) The VH sequence of sequence identification number: 140 and the VL sequence of sequence identification number: 147; (27) the VH sequence of SEQ ID NO: 141 and the VL sequence of SEQ ID NO: 147; (28) the VH sequence of SEQ ID NO: 140 and the VL sequence of SEQ ID NO: 148; (29) the VH sequence of SEQ ID NO: 141 and the VL sequence of SEQ ID NO: 148; (30) the VH sequence of SEQ ID NO: 136 and the VL sequence of SEQ ID NO: 149; (31) a first variable region comprising the VH sequence of SEQ ID NO: 140 and the VL sequence of SEQ ID NO: 146, and a second variable region comprising the VH sequence of SEQ ID NO: 141 and the VL sequence of SEQ ID NO: 146;or (32) a first variable region comprising the VH sequence of SEQ ID NO: 140 and the VL sequence of SEQ ID NO: 147, and a second variable region comprising the VH sequence of SEQ ID NO: 141 and the VL sequence of SEQ ID NO: 147.

[23] An anti-CTLA-4 antibody for use as described in any one of [1] to

[22] , wherein the anti-CTLA-4 antibody is a full-length IgG1 antibody.

[24] An anti-CTLA-4 antibody for use as described in any one of [1] to

[23] , wherein the mutant Fc region further comprises an amino acid change at position 332 as indicated by EU numbering in the first polypeptide of the parent Fc region.

[25] An anti-CTLA-4 antibody for use as described in any one of [1] to

[24] , wherein the mutant Fc region further comprises an amino acid change at position 332 as indicated by EU numbering in the second polypeptide of the parent Fc region.

[26] The anti-CTLA-4 antibody for use as described in any one of [1] to

[25] , wherein the mutant Fc region further comprises an amino acid alteration at position 236 as indicated by EU numbering in the second polypeptide of the parent Fc region.

[27] The anti-CTLA-4 antibody for use as described in any one of [1] to

[26] , wherein the mutant Fc region further comprises an amino acid alteration at positions 250 and 307 as indicated by EU numbering in the first polypeptide of the parent Fc region.

[28] The anti-CTLA-4 antibody for use as described in any one of [1] to

[27] , wherein the mutant Fc region further comprises an amino acid alteration at positions 250 and 307 as indicated by EU numbering in the second polypeptide of the parent Fc region.

[29] An anti-CTLA-4 antibody for use as described in any one of [1] to

[28] , wherein the mutant Fc region comprises at least one amino acid change selected from the group consisting of the following amino acid changes: (i) Phe at position 234, Gln at position 235, Trp at position 236, Met at position 239, Val at position 250, Asp at position 268, Glu at position 270, Ala at position 298, Pro at position 307, Met at position 330, Glu at position 332, as indicated by EU numbering in the first polypeptide of the parent Fc region;and (ii) Ala at position 236, Val at position 250, Glu at position 270, Ala at position 298, Pro at position 307, Asp at position 326, Met at position 330, Glu at position 332, and Glu at position 334, as indicated by EU numbering in the second polypeptide of the parent Fc region.

[30] An anti-CTLA-4 antibody for use as described in any one of [1] to

[29] , wherein the mutant Fc region further comprises any one of the following amino acid changes (a) to (f): (a) Lys at position 356 according to EU numbering in the first polypeptide of the parent Fc region, and Glu at position 439 according to EU numbering in the second polypeptide of the parent Fc region; (b) Glu at position 439 according to EU numbering in the first polypeptide of the parent Fc region, and Lys at position 356 according to EU numbering in the second polypeptide of the parent Fc region; (c) Trp at position 366 according to EU numbering in the first polypeptide of the parent Fc region, and Ser at position 366, Ala at position 368, and Val at position 407 according to EU numbering in the second polypeptide of the parent Fc region; (d) Ser at position 366, Ala at position 368, and Val at position 407, as indicated by EU numbering, in the first polypeptide of the parent Fc region, and Trp at position 366, as indicated by EU numbering, in the second polypeptide of the parent Fc region; (e) Cys at position 349 and Trp at position 366, as indicated by EU numbering, in the first polypeptide of the parent Fc region, and Cys at position 356, Ser at position 366, Ala at position 368, and Val at position 407, as indicated by EU numbering, in the second polypeptide of the parent Fc region; (f) Cys at position 356, Ser at position 366, Ala at position 368, and Val at position 407 according to EU numbering in the first parent Fc region polypeptide, and Cys at position 349 and Trp at position 366 according to EU numbering in the second parent Fc region polypeptide.

[31] An anti-CTLA-4 antibody for use as described in any one of [1] to

[30] , wherein the mutant Fc region further comprises any one of the following amino acid changes (a) to (d) in the first polypeptide and / or the second polypeptide of the parent Fc region: Ala at position 434 as represented by EU numbering; (b) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440 as represented by EU numbering; (c) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440 as represented by EU numbering;(d) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440 as represented by EU numbering.

[32] An anti-CTLA-4 antibody for use as described in any one of [1] to

[31] , comprising a heavy chain constant region comprising a mutant Fc region.

[33] An anti-CTLA-4 antibody for use as described in

[32] , wherein the heavy chain constant region comprises: (1) a first polypeptide of SEQ ID NO: 350 and a second polypeptide of SEQ ID NO: 351; or (2) a first polypeptide of SEQ ID NO: 343 and a second polypeptide of SEQ ID NO: 344.

[34] An anti-CTLA-4 antibody for use in the treatment of tumors, the anti-CTLA-4 antibody system comprising: (1) a first H chain polypeptide of sequence identification number: 352, a second H chain polypeptide of sequence identification number: 353, and an L chain polypeptide of sequence identification number: 161; or (2) an anti-CTLA-4 antibody for use comprising a first H chain polypeptide of sequence identification number: 335, a second H chain polypeptide of sequence identification number: 336, and an L chain polypeptide of sequence identification number: 161. In one non-limiting embodiment, the present disclosure provides the following.

[101] A polypeptide comprising a mutant Fc region comprising an amino acid change in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and the mutant Fc region comprises amino acid changes at the following positions: (i) positions 234, 235, 236, 239, 268, 270, and 298 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 270, 298, 326, and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[102] The polypeptide as described in

[101] , wherein the mutant Fc region further comprises an amino acid change at position 326 as indicated by EU numbering in the first polypeptide of the parent Fc region.

[103] A polypeptide as described in

[101] or

[102] , wherein the mutant Fc region further comprises an amino acid change at position 236 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[104] A polypeptide comprising a mutant Fc region comprising an amino acid change in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and the mutant Fc region comprises amino acid changes at the following positions: (i) positions 234, 235, 236, 239, 268, 270, 298 and 326 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 236, 270, 298, 326 and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[105] The polypeptide of any one of

[101] to

[104] , wherein the mutant Fc region further comprises an amino acid alteration at position 332 as indicated by EU numbering in the first polypeptide of the parent Fc region.

[106] The polypeptide of any one of

[101] to

[105] , wherein the mutant Fc region further comprises an amino acid alteration at position 330 as indicated by EU numbering in the first polypeptide of the parent Fc region.

[107] The polypeptide of any one of

[101] to

[106] , wherein the mutant Fc region further comprises an amino acid alteration at position 332 as indicated by EU numbering in the second polypeptide of the parent Fc region.

[108] The polypeptide of any one of

[101] to

[107] , wherein the mutant Fc region further comprises an amino acid alteration at position 330 as indicated by EU numbering in the second polypeptide of the parent Fc region.

[109] A polypeptide comprising a mutant Fc region comprising amino acid changes in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and the mutant Fc region comprises amino acid changes at the following positions: (i) positions 234, 235, 236, 239, 268, 270, 298, 330, and 332 as indicated by EU numbering in the first polypeptide of the parent Fc region; and (ii) positions 236, 270, 298, 326, 330, 332, and 334 as indicated by EU numbering in the second polypeptide of the parent Fc region.

[110] The polypeptide as described in any one of

[101] to

[109] , wherein the mutant Fc region further comprises amino acid changes at positions 250 and 307 as indicated by EU numbering in the first polypeptide of the parent Fc region.

[111] A polypeptide as described in any one of

[101] to

[110] , wherein the mutant Fc region further comprises amino acid changes at positions 250 and 307 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[112] A polypeptide comprising a mutant Fc region comprising amino acid changes in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and the mutant Fc region comprises amino acid changes at the following positions: (i) positions 234, 235, 236, 239, 250, 268, 270, 298 and 307 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 250, 270, 298, 307, 326 and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[113] A polypeptide comprising a mutant Fc region comprising amino acid changes in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and the mutant Fc region comprises amino acid changes in the following positions: (i) positions 234, 235, 236, 239, 250, 268, 270, 298, 307 and 326 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 236, 250, 270, 298, 307, 326 and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[114] A polypeptide comprising a mutant Fc region comprising amino acid changes in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and the mutant Fc region comprises amino acid changes in the following positions: (i) positions 234, 235, 236, 239, 250, 268, 270, 298, 307, 330 and 332 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 236, 250, 270, 298, 307, 326, 330, 332 and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[115] The polypeptide according to any one of

[101] to

[114] , comprising at least one amino acid change selected from the group consisting of: (i) Tyr or Phe at position 234, Gln or Tyr at position 235, Trp at position 236, Met at position 239, Val at position 250, Asp at position 268, Glu at position 270, Ala at position 298, Pro at position 307, Asp at position 326, Met at position 330, Glu at position 332, as indicated by EU numbering in the first polypeptide of the parent Fc region; and (ii) Ala at position 236, Val at position 250, Glu at position 270, Ala at position 298, Pro at position 307, Asp at position 326, Met or Lys at position 330, Asp or Glu at position 332, Glu at position 334, as indicated by EU numbering in the second polypeptide of the parent Fc region.

[116] The polypeptide as described in any one of

[101] to

[115] , wherein the mutant Fc region further comprises any one of the following amino acid changes (a) to (f): (a) Lys at position 356 according to EU numbering in the first polypeptide of the parent Fc region, and Glu at position 439 according to EU numbering in the second polypeptide of the parent Fc region; (b) Glu at position 439 according to EU numbering in the first polypeptide of the parent Fc region, and Lys at position 356 according to EU numbering in the second polypeptide of the parent Fc region; (c) Trp at position 366 according to EU numbering in the first polypeptide of the parent Fc region, and Ser at position 366, Ala at position 368, and Val at position 407 according to EU numbering in the second polypeptide of the parent Fc region; (d) Ser at position 366, Ala at position 368, and Val at position 407, as indicated by EU numbering, in the first polypeptide of the parent Fc region, and Trp at position 366, as indicated by EU numbering, in the second polypeptide of the parent Fc region; (e) Cys at position 349 and Trp at position 366, as indicated by EU numbering, in the first polypeptide of the parent Fc region, and Cys at position 356, Ser at position 366, Ala at position 368, and Val at position 407, as indicated by EU numbering, in the second polypeptide of the parent Fc region; (f) Cys at position 356, Ser at position 366, Ala at position 368, and Val at position 407 according to EU numbering in the first parent Fc region polypeptide, and Cys at position 349 and Trp at position 366 according to EU numbering in the second parent Fc region polypeptide.

[117] The polypeptide as described in any one of

[101] to

[116] , wherein the mutant Fc region further comprises an amino acid change in any of the following (a) to (d) in the first polypeptide and / or the second polypeptide of the parent Fc region: (a) Ala at position 434 as represented by EU numbering; (b) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440 as represented by EU numbering; (c) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440 as represented by EU numbering; (d) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440 as represented by EU numbering.

[118] The polypeptide according to any one of

[101] to

[117] , wherein the mutant Fc region has enhanced binding activity to at least one Fcγ receptor selected from the group consisting of FcγRIa, FcγRIIa, FcγRIIb, and FcγRIIIa compared to the parent Fc region.

[119] The polypeptide according to

[118] , wherein the mutant Fc region has enhanced binding activity to FcγRIIa and FcγRIIIa compared to the parent Fc region.

[120] The polypeptide according to any one of

[101] to

[119] , wherein the mutant Fc region has enhanced selectivity between active Fcγ receptors and inhibitory Fcγ receptors compared to the parent Fc region. [120-2] The polypeptide according to any one of

[101] to

[119] , wherein the binding activity for an activating Fcγ receptor is selectively enhanced over the binding activity for an inhibitory Fcγ receptor in the mutant Fc region compared to the parent Fc region. [120-3] The polypeptide according to any one of

[101] to

[119] , wherein the ratio of the binding activity for an activating Fcγ receptor to the binding activity for an inhibitory Fcγ receptor (A / I ratio) is greater in the mutant Fc region compared to the parent Fc region.[120-4] The polypeptide as described in [120-3], wherein the aforementioned ratio (A / I ratio) in the polypeptide comprising the mutant Fc region is greater than 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 20 times, 30 times or more. More than, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 200 times, 300 times, 400 times, 500 times, 600 times, 700 times, 800 times, 900 times, 1000 times, 2000 times, 3000 times, 4000 times, 5000 times, 6000 times, 7000 times, 8000 times, 9000 times, or 10000 times. [120-5] The polypeptide according to [120-3], wherein the value of the aforementioned ratio (A / I ratio) in the polypeptide comprising a mutant Fc region is 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, 600 or more, 700 or more, 800 or more, 900 or more, 1000 or more, 2000 or more, 3000 or more, 4000 or more, 5000 or more, 6000 or more, 7000 or more, 8000 or more, 9000 or more, 10000 or more, 11000 or more, 12000 or more, 13000 or more, 14000 or more, or 15000 or more.

[121] The polypeptide as described in any one of

[120] to [120-5], wherein the active Fcγ receptor is at least one Fcγ receptor selected from the group consisting of FcγRIa, FcγRIIa, and FcγRIIIa, and the inhibitory Fcγ receptor is FcγRIIb.

[122] The polypeptide as described in any one of

[101] to

[121] , wherein the polypeptide comprising a mutant Fc region is an antibody.

[123] A method of producing a polypeptide comprising a mutant Fc region, comprising the step of introducing amino acid changes in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and introducing amino acid changes at the following positions: (i) positions 234, 235, 236, 239, 268, 270 and 298 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 270, 298, 326 and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[124] A method of producing a polypeptide comprising a mutant Fc region, comprising the step of introducing amino acid changes in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and introducing amino acid changes at the following positions: (i) positions 234, 235, 236, 239, 268, 270, 298 and 326 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 236, 270, 298, 326 and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[125] A method of producing a polypeptide comprising a mutant Fc region, comprising the step of introducing amino acid changes in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and introducing amino acid changes at the following positions: (i) positions 234, 235, 236, 239, 268, 270, 298, 330 and 332 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 236, 270, 298, 326, 330, 332 and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[126] An isolated nucleic acid encoding a polypeptide as described in any one of

[101] to

[122] .

[127] A host cell comprising the nucleic acid as described in

[126] .

[128] A method of producing a polypeptide, comprising culturing the host cell as described in

[127] in a manner to produce the polypeptide.

[129] The polypeptide as described in any one of

[101] to

[122] for use in treating tumors.

[130] The polypeptide as described in any one of

[101] to

[122] for use in damaging cells.

[131] The polypeptide as described in

[130] , wherein the damage to the cells is caused by ADCC activity, CDC activity or ADCP activity.

[132] A pharmaceutical composition comprising the polypeptide as described in any one of

[101] to

[122] and a pharmaceutically acceptable carrier.

[133] The pharmaceutical composition as described in

[132] , which is a pharmaceutical composition for treating tumors.

[134] The pharmaceutical composition as described in

[132] , which is a pharmaceutical composition for cytotoxicity.

[135] The pharmaceutical composition as described in

[134] , wherein the cell damage is caused by ADCC activity, CDC activity or ADCP activity.

[136] A method for treating tumors, comprising administering the polypeptide as described in any one of

[101] to

[122] or the pharmaceutical composition as described in

[132] .

[137] A method for damaging cells, comprising the polypeptide as described in any one of

[101] to

[122] or the pharmaceutical composition as described in

[132] .

[138] The method as described in

[137] , wherein the cell damage is caused by ADCC activity, CDC activity or ADCP activity.

[139] Use of a polypeptide as described in any one of

[101] to

[122] in the manufacture of a tumor therapeutic agent.

[140] Use of a polypeptide as described in any one of

[101] to

[122] in the manufacture of a cytotoxic agent.

[141] The use as described in

[140] , wherein the cell damage is caused by ADCC activity, CDC activity or ADCP activity.

[142] A method for altering the function of a polypeptide comprising an Fc region, comprising the steps of introducing amino acid changes in a parent Fc region, the parent Fc region being composed of two polypeptide chains, and introducing amino acid changes at the following positions: (i) positions 234, 235, 236, 239, 268, 270 and 298 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 270, 298, 326 and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[143] A method for altering the function of a polypeptide comprising an Fc region, comprising the step of introducing amino acid changes in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and introducing amino acid changes at the following positions: (i) positions 234, 235, 236, 239, 268, 270, 298 and 326 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 236, 270, 298, 326 and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[144] A method for altering the function of a polypeptide comprising an Fc region, comprising the step of introducing an amino acid change in a parent Fc region, wherein the parent Fc region is composed of two polypeptide chains, and introducing an amino acid change at the following positions: (i) positions 234, 235, 236, 239, 268, 270, 298, 330, and 332 as indicated by EU numbering in a first polypeptide of the parent Fc region; and (ii) positions 236, 270, 298, 326, 330, 332, and 334 as indicated by EU numbering in a second polypeptide of the parent Fc region.

[145] The method as described in any one of

[142] to

[144] , wherein the alteration in function is an enhancement of binding activity to FcγRIIa and FcγRIIIa.

[146] The method of any one of

[142] to

[144] , wherein the functional change is an increase in selectivity between active Fcγ receptors and inhibitory Fcγ receptors.

[147] The method of any one of

[142] to

[144] , wherein the functional change is an increase in selectivity for binding activity to active Fcγ receptors relative to binding activity to inhibitory Fcγ receptors.

[148] The method of any one of

[142] to

[144] , wherein the functional change is an increase in the ratio (A / I ratio) of binding activity to active Fcγ receptors relative to binding activity to inhibitory Fcγ receptors.

[149] The method of

[148] , wherein the ratio (A / I ratio) is increased by 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 20 times, 30 times, 40 ...

[150] The method of any one of

[142] to

[149] , wherein the activating Fcγ receptor is at least one Fcγ receptor selected from the group consisting of FcγRIa, FcγRIIa, and FcγRIIIa, and the inhibitory Fcγ receptor is FcγRIIb.

[151] The method as described in any one of

[142] to

[144] , wherein the change in the aforementioned function is the enhancement of ADCC activity, CDC activity or ADCP activity. [For carrying out the invention] The methods and processes described or cited in this specification are generally well understood, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FM Ausubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames and GR Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Manual Notebook (JE Cellis, ed., 1998) Academic Press; Animal Cell Culture (RI Freshney), ed., 1987); Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JB Griffiths, and DG Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JM Miller and MP Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (JE Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and JD Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VT DeVita et al., eds., JB Lippincott Company, 1993), and other widely used prior art techniques are generally used by those skilled in the art to which the present invention pertains. I. Definitions Unless otherwise defined, technical and scientific terms used in this specification have the same meanings as those generally understood by those skilled in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology, 2nd ed., J. Wiley & Sons (New York, NY 1994), and March, Advanced Organic Chemistry Reactions, Mechanisms and Structure, 4th ed., John Wiley & Sons (New York, NY 1992), provide general guidance to many of the terms used in this application. All references cited in this specification, including patent applications and publications, are hereby incorporated by reference in their entirety. For the purposes of this specification, where the following definitions apply and are consistent with the circumstances, terms used in the singular shall include the plural, and vice versa. It should be understood that the terms used in this specification are intended solely for the purpose of describing specific aspects and are not intended to be limiting. To the extent any of the following definitions conflict with any content incorporated by reference into this specification, the following definitions shall prevail. In this specification, the term "and / or" refers to the items listed before and after "and / or" or any combination thereof. For example, "A, B, and / or C" includes not only the items "A", "B", and "C", but also any combination selected from "A and B", "A and C", "B and C", and "A, B, and C". In the context of this specification, a "human acceptor human framework" is a framework comprising the amino acid sequence of a light chain variable region (VL) framework or a heavy chain variable region (VH) framework derived from a human immunoglobulin framework or a human consensus framework as defined below. A human acceptor framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or may also comprise amino acid sequence changes. In some aspects, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some aspects, the sequence of the VL human acceptor framework is identical to the VL human immunoglobulin framework sequence or the human consensus framework sequence. Antibody-dependent cell-mediated cytotoxicity (ADCC) is a form of cytotoxicity in which secreted immunoglobulins bind to Fc receptors (FcRs) present on specific cytotoxic cells (e.g., NK cells, neutrophils, and macrophages). These cytotoxic effector cells can then specifically bind to target cells bearing antigen and subsequently kill them through cytotoxicity. NK cells, the primary cells mediating ADCC, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess ADCC activity of a target molecule, an in vitro ADCC assay, such as those described in U.S. Patent Nos. 5,500,362, 5,821,337, or 6,737,056 (Presta), can be performed. Effector cells that can be used in such assays include PBMCs and NK cells. Alternatively, or in addition, ADCC activity of a target molecule can be assessed in vivo in an animal model, such as that disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998). Examples of "cytotoxicity" include the antibody-dependent cell-mediated cytotoxicity (ADCC) activity described above, complement-dependent cytotoxicity (CDC) activity described below, and T cell-induced cytotoxicity. CDC activity refers to cytotoxicity caused by the complement system. ADCC activity, on the other hand, refers to the activity in which an antigen present on the cell surface of a target cell binds to an antibody, the antibody further binds to an effector cell, and the effector cell then damages the target cell. Whether an antibody of interest has ADCC or CDC activity can be measured using conventional methods (e.g., Current Protocols in Immunology, Chapter 7. Immunologic studies in humans, edited by Coligan et al. (1993)). "Neutralizing activity" refers to the ability to inhibit a biological activity by binding to a molecule involved in a biological activity. In some aspects, the biological activity is caused by the binding of a ligand to a receptor. In specific aspects, the antibody binds to the ligand or receptor, thereby inhibiting the binding of the ligand to the receptor. Antibodies with this neutralizing activity are called neutralizing antibodies. The neutralizing activity of a test substance can be measured by comparing the biological activity in the presence of a ligand with that in the absence of the test substance. The term "antibody-dependent cellular phagocytosis" or "ADCP" refers to the process in which the whole or part of an antibody-coated cell is taken up into phagocytic immune cells (e.g., macrophages, neutrophils, and dendritic cells) that bind to the Fc region of an immunoglobulin. The terms "binding activity" and "binding capacity" are used interchangeably throughout this specification and refer to the total strength of non-covalent binding interactions between one or more binding sites (e.g., variable regions or Fc regions) of a molecule (e.g., an antibody or other polypeptide) and its binding partner (e.g., an antigen or Fcγ receptor). Here, "binding activity" is not strictly limited to a 1:1 interaction between members of a binding pair (e.g., antibody and antigen, or Fc region and Fcγ receptor). For example, when the members of a binding pair exhibit a 1:1 monovalent interaction, binding activity refers to the intrinsic binding affinity. When the members of a binding pair can bind monovalently or multivalently, binding activity is the sum of these binding forces. The binding activity of molecule X for its partner Y can generally be expressed as a dissociation constant (KD) or as "analyte binding per unit amount of ligand." Binding activity can be measured by conventional methods known in the art, including those described in this specification. Specific examples and exemplary aspects for measuring binding activity will be described below. An "affinity matured" antibody refers to an antibody that has one or more alterations in one or more hypervariable regions (HVRs) that improve the antibody's affinity for the antigen, compared to a parent antibody without the alterations. The term "anti-CTLA-4 antibody" or "antibody that binds to CTLA-4" refers to an antibody that binds to CTLA-4 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent when targeting CTLA-4. In one aspect, the binding of the anti-CTLA-4 antibody to CTLA-4 is less than about 10% when the binding of the anti-CTLA-4 antibody to an unrelated non-CTLA-4 protein is measured (e.g., by radioimmunoassay (RIA)). In specific aspects, the antibody that binds to CTLA-4 has a binding affinity of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, for example 10 -8 M~10 -13 M, for example 10 -9 M~10 -13 In certain aspects, the anti-CTLA-4 antibody binds to a CTLA-4 epitope that is conserved between CTLA-4 from different species. In this specification, the term "antibody" is used in the broadest sense and is not limited thereto as long as it exhibits the desired antigen-binding activity. The term "antibody" includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, and encompasses various antibody structures. "Antibody fragment" refers to a molecule other than an intact antibody that includes a portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments, although not limited thereto, include Fv, Fab, Fab', Fab'-SH, F(ab'), 2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. A reference antibody and an "antibody that binds to the same epitope" refer to an antibody that, in a competition assay, blocks its own binding to the antigen by, for example, 50% or more, and / or a reference antibody that blocks its own binding to the antigen by, for example, 50% or more, in a competition assay. Examples of competition assays are provided herein. "Autoimmune disease" refers to a non-malignant disease or disorder that arises from and targets an individual's own tissues. As used herein, the term "autoimmune disease" specifically excludes malignant or cancerous diseases or conditions, and specifically excludes B-cell lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), hairy cell leukemia, and chronic myeloid leukemia.Examples of autoimmune diseases or disorders include, but are not limited to, the following: inflammatory reactions such as inflammatory skin diseases including psoriasis and dermatitis (e.g., atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis); respiratory distress syndrome (including adult respiratory distress syndrome (ARDS)); dermatitis; meningitis; encephalitis; uveitis; colitis; glomerulonephritis; allergic conditions such as eczema and asthma, and other conditions accompanied by T cell infiltration and chronic inflammatory reactions; atherosclerosis; leukocyte adhesion retardation; rheumatoid arthritis; systemic lupus erythematosus (SLE) SLE (including, but not limited to, lupus nephritis and lupus erythematosus); diabetes mellitus (e.g., type 1 diabetes or insulin-dependent diabetes mellitus); multiple sclerosis; Raynaud's syndrome; autoimmune thyroiditis; Hashimoto's thyroiditis; allergic encephalospondylitis; Sjogren's syndrome; juvenile-onset diabetes mellitus; and acute and delayed hypersensitivity-related immune reactions mediated by cytokines and T lymphocytes as seen in classic tuberculosis, sarcoidosis, polymyositis, granulomatosis, and vasculitis; pernicious anemia (Addison's disease); diseases associated with extravasation of leukocytes; central nervous system diseases. Inflammatory disorders of the central nervous system (CNS); multiple organ damage syndrome; hemolytic anemia (including but not limited to cryoglobulinemia or Coombs-positive hemolytic anemia); myasthenia gravis; antigen-antibody complex-mediated disease; antiglomerular basement membrane disease; antiphospholipid syndrome; allergic neuritis; Graves' disease; Lambert-Eaton myasthenic syndrome; bullous pemphigoid; pemphigus; autoimmune polyglandular endocrine disorders; Reiter's disease; stiff-man syndrome; Behcet's disease; giant cell arteritis; immune complex nephritis; IgA nephropathy; IgM polyneuropathy; immune thrombocytopenic purpura (ITP) or autoimmune thrombocytopenia. The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth / proliferation. Examples of cancer include breast cancer and liver cancer. The term "complement-dependent cytotoxicity," or "CDC," refers to a mechanism in which the Fc effector domain of an antibody bound to its target activates a series of enzymatic reactions, resulting in pores in the target cell's membrane and inducing cell death. Typically, the antigen-antibody complex formed on the target cell binds to and activates the complement component C1q, which then activates the complement cascade, leading to target cell death. Complement activation can also result in the deposition of complement components on the surface of target cells, where they bind to complement receptors (such as CR3) on white blood cells, promoting ADCC. "Chemotherapeutic agents" refer to chemical compounds useful for the treatment of cancer. Examples of chemotherapeutic agents include the following: alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN (registered trademark)); alkyl sulfonates such as butacaine sulfate, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and hydroxymethylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (particularly bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL (registered trademark)); beta-Lapachone; Lappaol; colchicine; betulinic acid; camptothecins (including synthetic analogs of topotecan (HYCAMTIN (registered trademark)), CPT-11 (irinotecan (CAMPTOSAR (registered trademark))), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); podophyllotoxin; podophyllic acid acid); teniposide; cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin;Nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard mustard); nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin γ1I and calicheamicin Ω1I (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33: 183-186 (1994)); CDP323, an oral α-4 integrin inhibitor; dynemicins including dynemycin A; esperamicin;As well as neocarzinostatin chromophores and related chromophores, enediyne antibiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins mycinis), dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including ADRIAMYCIN (registered trademark)), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HCl liposome injection (DOXIL (registered trademark)), liposomal doxorubicin TCL D-99 (MYOCET (registered trademark)), pegylated liposomal doxorubicin (CAELYX (registered trademark) and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C and other mitomycins, mycophenolic acid (MYCOPHOS Antibiotics such as dapoxetine, ...Folic acid analogues such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; calusterone, dromostanolone propionate, and dapoxetine. androgens such as levopropionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate acetate); epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone;Mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2'-trichlorotriethylamine; tricothecenes (particularly T-2 toxin, verracurin A, roridin A, and roridin B). A) and anguidine); urethan; vindesine (ELDISINE (registered trademark), FILDESIN (registered trademark)); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); thiotepa; taxoids, such as paclitaxel (TAXOL (registered trademark)); albumin-modified paclitaxel nanoparticles (ABRAXANET™) and doxetaxel (TAXOTERE (registered trademark)); chloranbucil; 6-thioguanine (6- thioguanine); mercaptopurine; methotrexate; platinum agents such as cisplatin, oxaliplatin (e.g., ELOXATIN (registered trademark)), and carboplatin;Vinca rosea drugs, including vinblastine (VELBAN(registered trademark)), vincristine (ONCOVIN(registered trademark)), vindesine (ELDISINE(registered trademark), FILDESIN(registered trademark)), and vinorelbine (NAVELBINE(registered trademark)), which prevent tubulin polymerization and microtubule formation; etoposide (VP-16); effulgamide; mitoxantrone; leucovorin; novantrone; edatrexate; daunomycin; aminopterin; ibandronate; and the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, including bexarotene (TARGRETIN(registered trademark)); bisphosphonates such as clodronate (e.g., BONEFOS(registered trademark) or OSTAC(registered trademark)), etidronate (DIDROCAL(registered trademark)), NE-58095, zoledronic acid / zoledronate (ZOMETA(registered trademark)), alendronate (FOSAMAX(registered trademark)), pamidronate (AREDIA(registered trademark)), tiludronate (SKELID(registered trademark)), or risedronate (ACTONEL(registered trademark)); troxacitabine (a 1,3-Dioxolane nucleoside cytosine analogs); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways involved in abnormal cell proliferation, such as PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines such as the THERATOPE(registered trademark) vaccine and gene therapy vaccines (e.g., ALLOVECTIN(registered trademark) vaccine, LEUVECTIN(registered trademark) vaccine, and VAXID(registered trademark) vaccine); topoisomerase 1 inhibitors (e.g., LURTOTECAN(registered trademark)); rmRH (e.g., ABARELIX(registered trademark));BAY439006 (Sorafenib; Bayer); SU-11248 (Sunitinib, SUTENT (registered trademark), Pfizer); perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteasome inhibitors (e.g., PS341); Bortezomib (VELCADE (registered trademark)); CCI-779; tipifarnib (R11577); Sorafenib, ABT510; Oblimersen sodium Bcl-2 inhibitors such as sirolimus (GENASENSE (registered trademark)); pixantrone; EGFR inhibitors (see below for definition); tyrosine kinase inhibitors (see below for definition); serine-threonine kinase inhibitors such as rapamycin (sirolimus, RAPAMUNE (registered trademark)); farnesyl transferase inhibitors such as lonafarnib (SCH 6636, SARASAR (trademark)); and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing; and combinations of two or more of the foregoing, such as CHOP, a combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, a treatment regimen consisting of oxaliplatin (ELOXANTIN (trademark)) in combination with 5-FU and leucovorin. The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chains is derived from a specific source or species, while the remainder of the heavy and / or light chains is derived from a different source or species. The "class" of an antibody refers to the constant region or type of constant region present in its heavy chain. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM. Furthermore, some of these are further divided into subclasses (isotypes). For example, there are IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions corresponding to these different immunoglobulin classes are called α, δ, ε, γ, and μ, respectively. In this specification, the term "cytotoxic agent" refers to a substance that inhibits or interferes with the function of cells and / or causes cell death or destruction. Cytotoxic agents are not limited to these but include radioactive isotopes (e.g., 211At 131 I. 125 I. 90 Y. 186 Re、 188 Re、 153 Sm, 212 Bi, 32 P. 212 radioisotopes of Pb and Lu); chemotherapeutic agents or chemotherapeutic drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); proliferation inhibitors; enzymes such as nucleases and fragments thereof; antibiotics; toxins such as low molecular weight toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin (including fragments and / or variants thereof); and the various chemotherapeutic agents disclosed above. "Effecter cells" refer to white blood cells that express one or more FcRs and exert effector functions. In certain aspects, such cells express at least FcγRIII and exert ADCC effector functions. Examples of ADCC-mediating white blood cells include peripheral blood mononuclear cells (PBMCs), natural killer (NK) cells, monocytes, cytotoxic T cells, and neutrophils. Effector cells can be obtained from natural sources, such as isolated from blood. In certain aspects, effector cells can be human effector cells. "Effector function" refers to biological activities arising from the Fc region of an antibody that vary depending on the antibody's isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cell-mediated phagocytosis (ADCP); downstream regulation of cell surface receptors (e.g., B cell receptor); and B cell activation. The term "epitope" includes any determinant capable of being bound by an antibody. An epitope is a region of an antigen that is bound by an antibody that is its target, and includes specific amino acids that come into direct contact with the antibody. Epitope determinants can include chemically active surface groups of molecules such as amino acids, sugar side chains, phospho- or sulfonyl groups, and can have specific three-dimensional structural properties and / or specific charge characteristics. Generally speaking, an antibody specific for a particular target antigen will preferentially recognize an epitope on its target antigen within a complex mixture of proteins and / or macromolecules. "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. In some aspects, the FcR is a naturally occurring human FcR. In some aspects, the FcR is one that binds to IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants of these receptors and forms resulting from alternative splicing. FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which primarily possess similar amino acid sequences that differ in their cytoplasmic domains. The activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (see, for example, Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are summarized in, for example, Ravetch and Kinet, Annu. Rev. Immunol 9:457-492 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med 126:330-341 (1995). The term "FcR" in this specification encompasses other FcRs that may be identified in the future. The term "Fc receptor" or "FcR" also includes the neonatal receptor FcRn, which is responsible for regulating the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117: 587 (1976) and Kim et al., J. Immunol. 24: 249 (1994)) and the homeostasis of immunoglobulins. Methods for measuring binding to FcRn are conventional (e.g., see Ghetie and Ward., Immunol. Today 18 (12): 592-598 (1997), Ghetie et al., Nature Biotechnology, 15 (7): 637-640 (1997), Hinton et al., J. Biol. Chem. 279 (8): 6213-6216 (2004), WO2004 / 92219 (Hinton et al.)). In vivo binding to human FcRn and the serum half-life of human FcRn high-affinity binding polypeptides can be measured, for example, in transgenic mice expressing human FcRn or transfected human cell lines, or in primates administered polypeptides containing mutant Fc regions. WO 2000 / 42072 (Presta) describes antibody variants with improved or reduced FcR binding. See, for example, Shields et al. J. Biol. Chem. 9(2): 6591-6604 (2001). Throughout this specification, the term "Fc region" can be used to define the C-terminal region of an immunoglobulin heavy chain, comprising at least a portion of the constant region. This term encompasses native-sequence Fc regions and variant Fc regions. In one aspect, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) or glycine-lysine (Gly446-Lys447) residues of the Fc region may or may not be present. Throughout this specification, unless otherwise specified, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system (also known as the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. The term "antibody containing an Fc region" refers to an antibody that includes an Fc region. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) or the C-terminal glycine-lysine of the Fc region (residues 446-447) can be removed, for example, during antibody purification or by recombinant manipulation of the nucleic acid encoding the antibody. Therefore, compositions comprising antibodies containing Fc regions derived from the present invention can include antibodies with G446-K447, antibodies with G446 but not K447, antibodies with G446-K447 completely removed, or a mixture of all three types of antibodies. The term "variable region" or "variable region" refers to the domain of an antibody's heavy or light chain involved in antigen binding. The variable regions of the heavy and light chains of native antibodies (VH and VL, respectively) typically have similar structures, including four framework regions (FRs) and three hypervariable regions (HVRs) conserved within each domain (see, for example, Kindt et al. Kuby Immunology, 6th ed., WH Freeman and Co., page 91 (2007)). A single VH or VL region is sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen can be isolated by screening a complementary library of VL or VH regions, respectively, using VH or VL regions from antibodies that bind to that antigen. See, for example, Portolano et al., J. Immunol. 150: 880-887 (1993); Clarkson et al., Nature 352: 624-628 (1991). "Framework" or "FR" refers to variable region residues outside of the hypervariable region (HVR) residues. The variable region FR is typically composed of four regions: FR1, FR2, FR3, and FR4. Accordingly, the sequences of the HVRs and FRs typically appear in the following order within a VH (or VL) pair: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4. The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a structure substantially similar to that of a native antibody, or an antibody having heavy chains comprising an Fc region as defined herein. A "functional Fc region" possesses the "effector functions" of a native-sequence Fc region. Examples of "effector functions" include C1q binding, CDC, Fc receptor binding, ADCC, phagocytosis, and downstream regulation of cell surface receptors (e.g., B cell receptor, BCR). These effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable region) and can be assessed using various measurement methods disclosed in the definitions herein. A "human antibody" is an antibody that possesses an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by a human or human cell, or from a human antibody repertoire, or an antibody derived from a non-human source using other human antibody coding sequences. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. A "human consensus framework" is a framework that displays the most commonly occurring amino acid residues in a selected group of human immunoglobulin VL or VH framework sequences. Typically, the human immunoglobulin VL or VH sequence is selected from a subgroup of variable region sequences. Typically, the subgroup of sequences is a subgroup described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3. In one aspect, for VL, the subgroup is subgroup κI as described by Kabat et al., supra. In one aspect, for VH, the subgroup is subgroup III as described by Kabat et al., supra. A "humanized" antibody refers to a chimeric antibody that comprises amino acid residues from non-human HVRs and amino acid residues from human FRs. In one aspect, a humanized antibody comprises substantially the entirety of at least one, and typically two, variable regions, in which all or substantially all of the HVRs (e.g., CDRs) correspond to HVRs of a non-human antibody, and all or substantially all of the FRs correspond to FRs of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody (e.g., a non-human antibody) refers to an antibody that has been humanized. The term "hypervariable region" or "HVR," as used herein, refers to regions of an antibody variable region that are hypervariable in sequence ("complementarity determining regions" or "CDRs") and / or structurally constrained loops (forming "hypervariable loops") and / or contain antigen-contacting residues ("antigen contacts"). Typically, an antibody comprises six HVRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). Exemplary HVRs herein include the following: (a) hypervariable loops arising from amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs arising from amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigenic contacts made at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) combinations of (a), (b), and / or (c) comprising HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3). Unless otherwise indicated, HVR residues and other residues in the variable region (eg, FR residues) are numbered in this specification according to the description of Kabat et al., supra. An immunoconjugate is an antibody conjugated to one or more molecules of different species (the molecules of different species are not limited to this but include cytotoxic agents). An "isolated" antibody is one that has been separated from components of its original environment. In some aspects, the antibody is purified to a purity greater than 95% or 99% as measured by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or column chromatography (e.g., ion exchange or reversed-phase HPLC). For an overview of methods for evaluating antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007). An "isolated" nucleic acid is one that has been separated from a component of its native environment. An isolated nucleic acid includes a nucleic acid molecule contained in a cell that normally contains the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its native chromosomal location. "Isolated nucleic acid encoding an antibody" refers to one or more nucleic acid molecules encoding the heavy and light chains (or fragments thereof) of an antibody, including: nucleic acid molecules carried by one or more vectors, and nucleic acid molecules present at one or more locations in a host cell. In this specification, the terms "first polypeptide" and "second polypeptide" refer to polypeptides that constitute the Fc region of an antibody. "First polypeptide" and "second polypeptide" mean that their sequences differ from each other, preferably at least in the C H2 region. Furthermore, the C H3 region sequences may also differ. Examples of such polypeptides include polypeptides that constitute the Fc region of native IgG, or polypeptides that have been modified from polypeptides that constitute the Fc region of native IgG. Native IgG refers to polypeptides containing the same amino acid sequence as naturally occurring IgG and belonging to the class of antibodies encoded by the immunoglobulin gamma gene. For example, native human IgG refers to native human IgG1, native human IgG2, native human IgG3, and native human IgG4. Natural IgG also includes naturally occurring variants. In the present invention, the term "polypeptide" generally refers to peptides and proteins with a length of approximately 10 amino acids or more. While typically derived from biological sources, this term is not particularly limited and may include, for example, polypeptides composed of artificially designed sequences. Furthermore, the term "polypeptide" may be a natural polypeptide, a synthetic polypeptide, or a recombinant polypeptide. Furthermore, in the present invention, a protein molecule refers to a molecule comprising such a polypeptide. Preferred examples of the polypeptides of the present invention include antibodies. More preferred examples include natural IgG or antibodies modified from natural IgG. Examples of natural IgG include natural human IgG. Natural IgG refers to a polypeptide that contains the same amino acid sequence as naturally occurring IgG and belongs to the class of antibodies substantially encoded by the immunoglobulin gamma gene. For example, natural human IgG refers to natural human IgG1, natural human IgG2, natural human IgG3, natural human IgG4, and the like. Natural IgG also includes naturally occurring variants thereof. The term "polypeptide comprising an Fc region" is not particularly limited as long as it refers to a polypeptide containing an Fc region, but includes, for example, an antibody comprising an Fc region. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) or the C-terminal glycine-lysine residues of the Fc region (residues 446-447) can be removed, for example, during purification of the polypeptide (e.g., antibody) or by recombinant manipulation of the nucleic acid encoding the polypeptide. Therefore, compositions comprising polypeptides comprising an Fc region according to the present invention can include: an Fc region-containing polypeptide with G446-K447; an Fc region-containing polypeptide with G446 but without K447; an Fc region-containing polypeptide from which G446-K447 has been completely removed; or a mixture of these three types of polypeptides. An "isolated" polypeptide is one that has been separated from components of its original environment. In some aspects, the polypeptide is purified to a purity greater than 95% or 99% as measured by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or column chromatography (e.g., ion exchange or reversed-phase HPLC). For an overview of methods for assessing polypeptide purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007). "Isolated nucleic acid encoding a polypeptide" refers to one or more nucleic acid molecules encoding the polypeptide (e.g., the Fc region of an antibody or the heavy and light chains of an antibody or fragments thereof), including nucleic acid molecules carried by one or more vectors, and nucleic acid molecules present at one or more locations in a host cell. The term "vector" used in this specification refers to a nucleic acid molecule that can have another nucleic acid linked to it added. This term includes vectors that are self-replicating nucleic acid structures and vectors that can be incorporated into the gene library of a host cell into which they have been introduced. A vector can direct the expression of an operably linked nucleic acid. Such a vector is also referred to as an "expression vector" in this specification. Vectors can be introduced into host cells using methods such as viruses or electroporation, but vector introduction is not limited to in vitro introduction; vectors can also be introduced directly into living cells. The terms "host cell," "host cell line," and "host cell culture" are used interchangeably to refer to cells (including progeny of such cells) into which foreign nucleic acid has been introduced. Host cells include "transformations" and "transformed cells," encompassing the primary transformed cell and any subsequent generations of progeny derived from such cells. Progeny may not be identical in nucleic acid content to the parent cell and may contain mutations. This specification also encompasses variant progeny that possess the same function or biological activity as that of the original transformed cell, which can be used in screening or selection. The term "monoclonal antibody" as used in this specification refers to an antibody that can be obtained from a substantially homogeneous antibody cluster. That is, the individual antibodies that make up the cluster are identical and / or bind to the same epitope after excluding possible mutant antibodies (for example, mutant antibodies containing naturally occurring mutations, or mutant antibodies that occur during the production of monoclonal antibody preparations. Such variants usually exist in small amounts). Compared to a polyclonal antibody preparation that typically contains different antibodies targeting different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on the antigen. Therefore, the modifier "monoclonal" indicates the characteristic of an antibody that can be obtained from a substantially homogeneous antibody cluster and should not be interpreted as requiring the antibody to be produced by a specific method. For example, although not limited thereto, the monoclonal antibodies used in accordance with the present invention can be produced by various methods including the fusion tumor method, the recombinant DNA method, the phage display method, and methods of transfecting animals with genes containing all or part of the human immunoglobulin locus. These methods and other exemplary methods for producing monoclonal antibodies are described in this specification. A "naked antibody" is an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or a radiolabel. Naked antibodies can also be present in pharmaceutical formulations. "Native antibodies" refer to immunoglobulin molecules with various structures that occur naturally. For example, a native IgG antibody is a heterogeneous tetrameric glycoprotein of approximately 150,000 daltons composed of two identical light chains and two identical heavy chains bound by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also known as the variable heavy region or heavy chain variable region, followed by three constant regions (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also known as the variable light region or light chain variable region, followed by a constant light region (CL). Based on the amino acid sequence of its constant region, an antibody's light chain can be classified into one of two types: kappa (κ) and lambda (λ). A "native-sequence Fc region" comprises an amino acid sequence identical to an Fc region found in nature. Native-sequence human Fc regions include: native-sequence human IgG1 Fc region (non-A and A allotypes), native-sequence human IgG2 Fc region, native-sequence human IgG3 Fc region, and native-sequence human IgG4 Fc region, as well as naturally occurring variants thereof. A "mutant Fc region" comprises at least one amino acid modification (alteration), preferably comprising an amino acid sequence that differs from a native-sequence Fc region by one or more amino acid substitutions. Preferably, the mutant Fc region has at least one amino acid substitution in the native-sequence Fc region or the parent Fc region, for example, about 1 to about 30 amino acid substitutions, preferably about 1 to about 20 amino acid substitutions, more preferably about 1 to about 10 amino acid substitutions, and most preferably about 1 to about 5 amino acid substitutions, compared to the native-sequence Fc region or the parent Fc region. The mutant Fc region herein preferably has at least about 80% homology to the native-sequence Fc region or the parent Fc region, more preferably at least about 85% homology, more preferably at least about 90% homology, and most preferably at least about 95% homology. "Percent (%) amino acid sequence identity" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences to maximize percent sequence identity, introducing gaps if necessary, and ignoring any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining percent amino acid sequence identity can be achieved using various methods within the skill of the art, such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR) software, or publicly available computer software such as GENETYX (registered trademark) (GENETYX, Inc.). Appropriate parameters for achieving sequence alignment can be determined by one of ordinary skill in the art, including any algorithm necessary to achieve maximal alignment across the entire length of the compared sequences. The ALIGN-2 sequence comparison computer program is the work of Genentech. The source code, along with instructions for use, has been submitted to the U.S. Copyright Office, Wasington, DC, 20559, and is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, and can be compiled from the source code. The ALIGN-2 program was compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set according to the ALIGN-2 program and do not change. When using ALIGN-2 for amino acid sequence comparison, the % amino acid sequence identity of a sequence having or containing a predetermined amino acid sequence A to, with, or relative to a predetermined amino acid sequence B (or, alternatively, a predetermined amino acid sequence A having a certain % amino acid sequence identity to, with, or relative to a predetermined amino acid sequence B) is calculated as follows: 100 times the fraction X / Y. Here, X is the number of amino acid residues scored as identical, i.e., identical, in the alignment of A and B using the sequence alignment program ALIGN-2, and Y is the total number of amino acid residues in B. If the length of amino acid sequence A is different from the length of amino acid sequence B, it can be understood that the % amino acid sequence identity of A to B is different from the % amino acid sequence identity of B to A. Unless otherwise indicated, all % amino acid sequence identity values ​​used in this specification can be obtained using the ALIGN-2 computer program described in the previous paragraph. The terms "pharmaceutical preparation" and "pharmaceutical composition" are used interchangeably to refer to a preparation that is in a form in which the biological activity of the active ingredient contained therein can be exerted and does not contain additional elements that are toxic to an unacceptable degree to the subject to which it is administered. A "subject" or "subject" is a mammal. Mammals are not limited thereto but include domesticated animals (e.g., cattle, sheep, cats, dogs, horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, the subject or individual is a human. A "pharmaceutically acceptable carrier" refers to a component other than the active ingredient in a pharmaceutical preparation or pharmaceutical composition that is non-toxic to the subject. Pharmaceutically acceptable carriers are not limited thereto but include buffers, excipients, stabilizers, or preservatives. An "effective amount" of a dose (eg, a pharmaceutical preparation) is an amount effective, and for a period of time necessary, to achieve the desired therapeutic or prophylactic result. The term "accompanying documents" is generally included in the commercial packaging of therapeutic devices and is used to refer to the instructions for use that contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications and / or warnings regarding the use of the therapeutic device. Throughout this specification, the term "CTLA-4," unless otherwise indicated, refers to any naturally occurring CTLA-4 derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). This term also encompasses CTLA-4 that has not undergone "full-length" processing, as well as any form of CTLA-4 produced as a result of processing within cells. This term also encompasses naturally occurring CTLA-4 variants, such as splice variants and allelic variants. The amino acid sequence of human CTLA-4 is SEQ ID NO: 214, the amino acid sequence of mouse CTLA-4 is SEQ ID NO: 247, the amino acid sequence of monkey CTLA-4 is SEQ ID NO: 248, and the amino acid sequence of the extracellular region of human CTLA-4 is SEQ ID NO: 28. Throughout this specification, CTLA-4 is sometimes referred to as CTLA4. The term "regulatory T (Treg) cells" refers to a subset of T cells that regulate the immune system, maintain tolerance to self-antigens, and suppress autoimmune diseases. These cells generally inhibit or negatively regulate the induction and proliferation of effector T cells. The most commonly understood Treg cells are those that express CD4, CD25, and Foxp3 (CD4 + CD25 + Treg cells). These Tregs are distinct from helper T cells. Several different methods are used to identify and monitor Treg cells. + CD25 + Treg cells constitute mature CD4 + About 5-10% of T cell subsets and about 1-2% of Treg can be measured in whole blood. Sometimes, the expression of Foxp is also measured (CD4 + CD25 + Foxp3 + As another marker, the absence or low expression of CD127 is sometimes used in combination with the presence of CD4 and CD25. Furthermore, Treg cells also express high levels of CTLA-4 and GITR. Tregs can also be identified using the methods described in the Examples below. As used herein, the terms "substantially similar," "substantially equivalent," or "substantially identical" mean that the similarity between two values ​​(e.g., between an antibody of the present invention and a reference / comparator antibody) is sufficiently high that the difference between the two values ​​is considered by one of ordinary skill in the art to be of little or no biological and / or statistical significance from the perspective of the biological characteristic measured by the value (e.g., KD value). As used herein, "treatment" (and its grammatical derivatives, such as "treating," "the act of treating," etc.) refers to a clinical intervention intended to alter the natural course of the individual being treated, and can also be performed during a clinical morbidity for prevention. The desired effects of treatment are not limited thereto but include prevention of the onset or recurrence of the disease, alleviation of symptoms, reduction of the effects of any direct or indirect pathology caused by the disease, prevention of metastasis, reduction of the progression of the disease, recovery or alleviation of the disease state, and a remission or improved prognosis. In some aspects, the antibodies of the present invention are used to delay the onset of the disease or slow the progression of the disease. In some aspects, the polypeptides of the present invention comprising a mutant Fc region can be used to delay the onset of the disease or slow the progression of the disease. The term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive in this specification. The term "tumor tissue" refers to tissue containing at least one tumor cell. Tumor tissue is typically composed of the cluster of tumor cells (parenchyma), which constitutes the bulk of the tumor, and the connective tissue and blood vessels (stroma) that support the tumor. These two components are sometimes clearly distinct, while others are intermingled. Tumor tissue may also be infiltrated by immune cells. Meanwhile, "non-tumor tissue" refers to tissue within a living body other than tumor tissue. Healthy, normal tissue, not in a diseased state, is a typical example of non-tumor tissue. II. Compositions and Methods In one aspect, the present invention is based on the use of anti-CTLA-4 antibodies and the like. In a specific aspect, antibodies that bind to CTLA-4 are provided. The antibodies of the present invention can be used, for example, for the diagnosis or treatment of cancer. A. Exemplary Anti-CTLA-4 Antibodies In one aspect, the present invention provides an antibody that binds to CTLA-4 and is isolated. In a specific aspect, the anti-CTLA-4 antibody of the present invention has a CTLA-4 binding activity that depends on the concentration of an adenosine-containing compound. In some aspects, the binding activity to CTLA-4 is higher in the presence of an adenosine-containing compound than in the absence of an adenosine-containing compound. Alternatively, in another aspect, the binding activity to CTLA-4 is higher in the presence of a high concentration of an adenosine-containing compound than in the presence of a low concentration of an adenosine-containing compound. In yet another aspect, the difference in binding activity to CTLA-4 is, for example, more than 2 times, more than 3 times, more than 5 times, more than 10 times, more than 20 times, more than 30 times, more than 50 times, more than 100 times, more than 200 times, more than 300 times, more than 500 times, more than 1×10 3 times or more, 2×10 3 times or more, 3×10 3 times or more, 5×10 3 times or more, 1×10 4 times or more, 2×10 4 times or more, 3×10 4 times or more, 5×10 4 times or 1×10 5 times or more. In some aspects, the binding activity of the anti-CTLA-4 antibody can be represented by a KD (Dissociation constant) value. In another aspect, the KD value of the anti-CTLA-4 antibody is smaller in the presence of an adenosine-containing compound than in the absence of the adenosine-containing compound. Alternatively, in another aspect, the KD value of the anti-CTLA-4 antibody is smaller in the presence of a high concentration of an adenosine-containing compound than in the presence of a low concentration of an adenosine-containing compound. In yet another aspect, the difference in the KD value of the anti-CTLA-4 antibody is, for example, 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 20-fold or more, 30-fold or more, 50-fold or more, 100-fold or more, 200-fold or more, 300-fold or more, 500-fold or more, 1×10 3 times or more, 2×10 3 times or more, 3×10 3 times or more, 5×10 3 times or more, 1×10 4 times or more, 2×10 4 times or more, 3×10 4 times or more, 5×10 4 times or 1×10 5 The KD value of the anti-CTLA-4 antibody in the presence of adenosine-containing compounds or in the presence of high concentrations of adenosine-containing compounds can be, for example, 9×10 -7 M or less, 8×10 -7 M or less, 7×10 -7 M or less, 6×10 -7 M or less, 5×10 -7 M or less, 4×10 -7 M or less, 3×10 -7 M or less, 2×10 -7 M or less, 1×10 -7 M or less, 9×10 -8 M or less, 8×10 -8 M or less, 7×10 -8 M or less, 6×10 -8 M or less, 5×10 -8 M or less, 4×10 -8 M or less, 3×10 -8 M or less, 2×10 -8 M or less, 1×10 -8 M or less, 9×10 -9 M or less, 8×10 -9 M or less, 7×10 -9 M or less, 6×10 -9 M or less, 5×10 -9 M or less, 4×10 -9 M or less, 3×10 -9 M or less, 2×10 -9 M or less, 1×10 -9 M or less, 9×10 -10 M or less, 8×10 -10 M or less, 7×10 -10 M or less, 6×10 -10 M or less, 5×10 -10 M or less, 4×10 -10 M or less, 3×10 -10 M or less, 2×10 -10 M or less or 1×10 -10M or less. The KD value of the anti-CTLA-4 antibody in the absence of adenosine-containing compounds or in the presence of low concentrations of adenosine-containing compounds can be, for example, 1×10 -8 M or above, 2×10 -8 M or above, 3×10 -8 M or above, 4×10 -8 M or above, 5×10 -8 M or above, 6×10 -8 M and above, 7×10 -8 M or above, 8×10 -8 M and above, 9×10 -8 M or above, 1×10 -7 M or above, 2×10 -7 M or above, 3×10 -7 M or above, 4×10 -7 M or above, 5×10 -7 M or above, 6×10 -7 M and above, 7×10 -7 M or above, 8×10 -7 M and above, 9×10 -7 M or above, 1×10 -6 M or above, 2×10 -6 M or above, 3×10 -6 M or above, 4×10 -6 M or above, 5×10 -6 M or above, 6×10 -6 M and above, 7×10 -6 M or above, 8×10 -6 M or above or 9×10 -6 M or above. In another aspect, the kd (Dissociation rate constant) value can be used instead of the KD value to represent the binding activity of the anti-CTLA-4 antibody. In another aspect, the binding activity of an anti-CTLA-4 antibody can also be expressed as the amount of CTLA-4 bound per unit amount of antibody. For example, in surface plasmon resonance analysis, the amount of antibody bound to the sensor chip and the amount of antigen bound to the antibody are each measured in response units (RU). The amount of antigen bound can be divided by the amount of antibody bound, and the resulting value is defined as the amount of antigen bound per unit amount of antibody. Specific methods for measuring and calculating the binding amount are described in the Examples below. In some aspects, the amount of CTLA-4 bound is greater in the presence of an adenosine-containing compound than in the absence of the adenosine-containing compound. Alternatively, in another aspect, the amount of CTLA-4 bound is greater in the presence of a high concentration of an adenosine-containing compound than in the presence of a low concentration of the adenosine-containing compound. In another aspect, the difference in the amount of CTLA-4 bound is, for example, 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 20-fold or more, 30-fold or more, 50-fold or more, 100-fold or more, 200-fold or more, 300-fold or more, 500-fold or more, 1×10 3 times or more, 2×10 3 times or more, 3×10 3 times or more, 5×10 3 times or more, 1×10 4 times or more, 2×10 4 times or more, 3×10 4 times or more, 5×10 4 times or 1×10 5The value of the CTLA-4 binding amount in the presence of an adenosine-containing compound or in the presence of a high concentration of an adenosine-containing compound can be, for example, 0.01 or more, 0.02 or more, 0.03 or more, 0.04 or more, 0.05 or more, 0.06 or more, 0.07 or more, 0.08 or more, 0.09 or more, 0.1 or more, 0.2 or more, 0.3 or more, 0.4 or more, 0.5 or more, 0.6 or more, 0.7 or more, 0.8 or more, 0.9 or more, or 1 or more. The value of the CTLA-4 binding amount in the presence of an adenosine-containing compound or in the presence of a low concentration of an adenosine-containing compound may be, for example, 0.5 or less, 0.4 or less, 0.3 or less, 0.2 or less, 0.1 or less, 0.09 or less, 0.08 or less, 0.07 or less, 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, 0.009 or less, 0.008 or less, 0.007 or less, 0.006 or less, 0.005 or less, 0.004 or less, 0.003 or less, 0.002 or less, or 0.001 or less. In some aspects, KD values, kd values, binding amount values, etc. expressed herein are measured or calculated by surface plasmon resonance analysis at 25° C. or 37° C. (for example, see Reference Example 3 of this specification). The concentration of the adenosine-containing compound can be any concentration as long as a difference in the binding activity of the anti-CTLA-4 antibody is detected. In specific aspects, examples of a high concentration include 1 nM or higher, 3 nM or higher, 10 nM or higher, 30 nM or higher, 100 nM or higher, 300 nM or higher, 1 μM or higher, 3 μM or higher, 10 μM or higher, 30 μM or higher, 100 μM or higher, 300 μM or higher, 1 mM or higher, 3 mM or higher, 10 mM or higher, 30 mM or higher, 100 mM or higher, 300 mM or higher, or 1 M or higher. Alternatively, the high concentration may be an amount sufficient for each anti-CTLA-4 antibody to exhibit maximal binding activity. In one aspect, 1 μM, 10 μM, 100 μM, 1 mM, or a sufficient amount of each anti-CTLA-4 antibody to exhibit maximal binding activity can be selected as the high concentration herein. In a specific aspect, examples of the low concentration include 1 mM or less, 300 μM or less, 100 μM or less, 30 μM or less, 10 μM or less, 3 μM or less, 1 μM or less, 300 nM or less, 100 nM or less, 30 nM or less, 10 nM or less, 3 nM or less, 1 nM or less, 300 pM or less, 100 pM or less, 30 pM or less, 10 pM or less, 3 pM or less, 1 pM or less, and the like. Alternatively, the concentration at which each anti-CTLA-4 antibody shows minimal binding activity can be set as the low concentration here. The situation where the substantial concentration is zero (no adenosine-containing compound is present) can also be selected as an aspect of the low concentration. In one aspect, 1 mM, 100 μM, 10 μM, 1 μM, the concentration at which each anti-CTLA-4 antibody shows minimal binding activity, or the absence of an adenosine compound can be selected as the low concentration here. In another aspect, as the ratio of the high concentration to the low concentration, for example, 3 times or more, 10 times or more, 30 times or more, 100 times or more, 300 times or more, 1×10 3 times or more, 3×10 3 times or more, 1×10 4 times or more, 3×10 4 times or more, 1×10 5 times or more, 3×10 5 times or more, 1×10 6 times or more, 3×10 6 times or more, 1×10 7 times or more, 3×10 7 times or more, 1×10 8 times or more, 3×10 8 times or more, 1×10 9 times or more, 3×10 9 times or more, 1×10 10 times or more, 3×10 10 times or more, 1×10 11 times or more, 3×10 11 times or more, 1×10 12 times or more. In another aspect, the anti-CTLA-4 antibodies of the present invention also have binding activity against adenosine-containing compounds. The above-described method can be used to calculate the amount of adenosine-containing compound bound per unit amount of antibody, and this amount can be used as the binding activity of the anti-CTLA-4 antibody against adenosine-containing compounds. Specific methods for measuring and calculating the amount of binding are described in the Examples below. The value of the bound amount of the adenosine-containing compound per unit amount of the anti-CTLA-4 antibody of the present invention can be, for example, 0.0001 or more, 0.0002 or more, 0.0003 or more, 0.0004 or more, 0.0005 or more, 0.0006 or more, 0.0007 or more, 0.0008 or more, 0.0009 or more, 0.001 or more, 0.002 or more, 0.003 or more, 0.004 or more, 0.005 or more, 0.006 or more, 0.007 or more, 0.008 or more, 0.009 or more, or 0.01 or more. In another aspect, the anti-CTLA-4 antibody of the present invention forms a ternary complex with an adenosine-containing compound and CTLA-4. In one aspect, the anti-CTLA-4 antibody binds to the adenosine-containing compound via its heavy chain CDR1, CDR2, and CDR3. In one aspect, the anti-CTLA-4 antibody possesses a binding motif for the adenosine-containing compound. The binding motif for the adenosine-containing compound can be composed of, for example, at least one amino acid located at positions 33, 52, 52a, 53, 56, 58, 95, 96, 100a, 100b, or 100c according to Kabat numbering. In yet another aspect, the anti-CTLA-4 antibody binds to an adenosine-containing compound through at least one amino acid selected from the group consisting of positions 33, 52, 52a, 53, 56, 58, 95, 96, 100a, 100b, and 100c as indicated by Kabat numbering. In a specific aspect, the anti-CTLA-4 antibody has at least one amino acid selected from the group consisting of Thr at position 33, Ser at position 52, Ser at position 52a, Arg at position 53, Tyr at position 56, Tyr at position 58, Tyr at position 95, Gly at position 96, Met at position 100a, Leu at position 100b, and Trp at position 100c as indicated by Kabat numbering. The complex formed by the anti-CTLA-4 antibody and the adenosine-containing compound can further bind to CTLA-4. Furthermore, adenosine-containing compounds may be present at the interface where anti-CTLA-4 antibodies interact with CTLA-4 and may bind to both. The formation of a ternary complex between the anti-CTLA-4 antibody, the adenosine-containing compound, and CTLA-4 can be confirmed, for example, by methods such as crystal structure analysis described below (see Examples). In another aspect, the anti-CTLA-4 antibody of the present invention binds to at least one amino acid selected from the group consisting of amino acid 3 (Met), amino acid 33 (Glu), amino acid 35 (Arg), amino acid 53 (Thr), amino acid 97 (Glu), amino acid 99 (Met), amino acid 100 (Tyr), amino acid 101 (Pro), amino acid 102 (Pro), amino acid 103 (Pro), amino acid 104 (Tyr), amino acid 105 (Tyr), and amino acid 106 (Leu) of human CTLA-4 (extracellular region, SEQ ID NO: 28). These amino acids can constitute the epitope of the anti-CTLA-4 antibody of the present invention. In another aspect, the anti-CTLA-4 antibodies of the present invention bind to the region from amino acid 97 (Glu) to amino acid 106 (Leu) of human CTLA-4 (extracellular region, SEQ ID NO: 28). In another aspect, the anti-CTLA-4 antibodies of the present invention bind to the region from amino acid 99 (Met) to amino acid 106 (Leu) of human CTLA-4 (extracellular region, SEQ ID NO: 28). In another aspect, the anti-CTLA-4 antibodies of the invention compete with ABAM004 (VH, SEQ ID NO: 10; VL, SEQ ID NO: 11; HVR-H1, SEQ ID NO: 100; HVR-H2, SEQ ID NO: 101; HVR-H3, SEQ ID NO: 102; HVR-L1, SEQ ID NO: 113; HVR-L2, SEQ ID NO: 114; HVR-L3, SEQ ID NO: 115) for binding to CTLA-4. In another aspect, the anti-CTLA-4 antibodies of the invention bind to the same epitope as ABAM004. When the anti-CTLA-4 antibody is present in excess, the binding of ABAM004 to CTLA-4 can be reduced by, for example, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more. Exemplary competition assays are provided herein. In another aspect, the anti-CTLA-4 antibodies of the present invention exhibit cytotoxicity against CTLA-4-expressing cells. When CTLA-4 is expressed on the surface of target cells and bound to the anti-CTLA-4 antibody there, the cells are damaged. This cell damage can be caused by effector cells bound to the antibody, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), or by complement bound to the antibody, such as complement-dependent cytotoxicity (CDC). Alternatively, it can be caused by a cytotoxic agent (e.g., a radioisotope, chemotherapeutic agent, etc.) bound to the antibody, as in immunoconjugates. Cytotoxicity herein includes inducing cell death, inhibiting cell proliferation, and impairing cell function. When an anti-CTLA-4 antibody is present in a sufficient amount, it can cause damage to, for example, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more of the CTLA-4 expressing cells. Such cytotoxicity can be measured by comparing it to a measurement in the absence of the antibody or in the presence of a negative control antibody. This specification provides exemplary cytotoxicity assays. In another aspect, the anti-CTLA-4 antibodies of the present invention exhibit neutralizing activity against CTLA-4. CTLA-4 is known to function by interacting with its ligands, CD80 (B7-1) or CD86 (B7-2). In specific aspects, the anti-CTLA-4 antibodies inhibit the interaction of CTLA-4 with CD80 (B7-1) or CD86 (B7-2). When present in a sufficient amount, the anti-CTLA-4 antibodies can inhibit the interaction of CTLA-4 with CD80 (B7-1) or CD86 (B7-2), for example, by greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or greater than 95%. The measurement of such inhibitory activity is performed by comparison with the measurement in the absence of the antibody or in the presence of a negative control antibody. This specification provides a specific method for measuring neutralizing activity. In another aspect, the anti-CTLA-4 antibodies of the present invention bind to CTLA-4 from multiple animal species. Exemplary animal species include mammals, such as humans, monkeys, mice, rats, hamsters, guinea pigs, rabbits, pigs, cows, goats, horses, sheep, camels, dogs, and cats. In a specific aspect, the anti-CTLA-4 antibodies bind to CTLA-4 from humans and non-humans (e.g., monkeys, mice, and rats). The amino acid sequence of human CTLA-4 is represented by SEQ ID NO: 214, the amino acid sequence of monkey CTLA-4 is represented by SEQ ID NO: 247, and the amino acid sequence of mouse CTLA-4 is represented by SEQ ID NO: 248. The amino acid sequence of CTLA-4 from other animal species can also be appropriately determined by methods known to those skilled in the art. In a specific aspect, examples of the adenosine-containing compound of the present invention include adenosine (ADO), adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), cyclic adenosine monophosphate (cAMP), deoxyadenosine (dADO), deoxyadenosine triphosphate (dATP), deoxyadenosine diphosphate (dADP), deoxyadenosine monophosphate (dAMP), and γ-thioadenosine triphosphate (ATPγS). In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 223, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 224, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 225. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 223, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 224, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 225. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 226, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 227, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 226, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 227, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In another aspect, an antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 223, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 224, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 225; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 226, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 227, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 223, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 224, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 225, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 226, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 227, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 228. In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 100, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 101, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 100, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 101, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 113, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 114, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 113, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 114, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In another aspect, the antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 100, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 101, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 113, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 114, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 100, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 101, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 113, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 114, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 100, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 100, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 116, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 116, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In another aspect, the antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 100, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 116, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 100, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 116, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 105, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 106, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 105, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 106, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 105, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 106, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 105, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 106, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 108, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 108, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 121, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 153. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 121, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 153. In another aspect, the antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 108, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 121, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 153. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 108, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 121, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 153. In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 112, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 112, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 128, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 128, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 112, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 128, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 112, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 128, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 111, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 152. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 111, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 152. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 128, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 128, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 111, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 152; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 128, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 111, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 152, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 128, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 112, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 112, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 112, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 112, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 111, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 152. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 111, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 152. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 111, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 152; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 111, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 152, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the present invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 109, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In one aspect, the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 109, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. In another aspect, the present invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In one aspect, the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the antibody of the invention comprises: (a) a VH region comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 109, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102; and (b) a VL region comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In another aspect, the present invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 107, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 109, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. In certain aspects, any one or more amino acids of the anti-CTLA-4 antibodies described above are substituted at the following HVR positions: - HVR-H1 (SEQ ID NO: 223): Position 2 - HVR-H2 (SEQ ID NO: 224): Positions 4, 5, 7, 13, and 16 - HVR-H3 (SEQ ID NO: 225): Position 3 - HVR-L1 (SEQ ID NO: 226): Positions 1, 3, 6, 11, 12, and 14 - HVR-L2 (SEQ ID NO: 227): Positions 1, 3, 4, and 7 - HVR-L3 (SEQ ID NO: 228): Positions 1 and 10 In certain aspects, the substitutions provided herein are conservative substitutions. In certain aspects, any one or more of the following substitutions may be used in any combination: In -HVR-H1 (SEQ ID NO: 100): H2A, R, or K In -HVR-H2 (SEQ ID NO: 101): S4T, R5Q, G7H, D13E or R, K16R In -HVR-H3 (SEQ ID NO: 102): K3A In -HVR-L1 (SEQ ID NO: 113): T1D, Q, or E, T3P, D6G, N11T, Y12W, S14H In -HVR-L2 (SEQ ID NO: 114): E1F or Y, S3I, K4S, S7E, or K In -HVR-L3 (SEQ ID NO: 115): S1Q, M10T All possible combinations of the above substitutions are associated with HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 and are contained in the consensus sequences of SEQ ID NOs: 223, 224, 225, 226, 227, and 228, respectively. In any of the above aspects, the anti-CTLA-4 antibody is humanized. In one aspect, the anti-CTLA-4 antibody comprises the HVRs of any of the above aspects and further comprises a human acceptor framework (e.g., a human immunoglobulin framework or a human consensus framework). In another aspect, the anti-CTLA-4 antibody comprises the HVRs of any of the above aspects and further comprises a VH or VL comprising a FR sequence. In yet another aspect, the anti-CTLA-4 antibody comprises the following heavy chain and / or light chain variable region FR sequences: with respect to the heavy chain variable region, FR1 comprises the amino acid sequence of any one of SEQ ID NOs: 229-232, FR2 comprises the amino acid sequence of SEQ ID NO: 233, FR3 comprises the amino acid sequence of SEQ ID NO: 234, and FR4 comprises the amino acid sequence of SEQ ID NO: 235. Regarding the light chain variable region, FR1 comprises any one of the amino acid sequences of SEQ ID NOs: 236-238, FR2 comprises any one of the amino acid sequences of SEQ ID NOs: 240-241, FR3 comprises any one of the amino acid sequences of SEQ ID NOs: 242-244, and FR4 comprises any one of the amino acid sequences of SEQ ID NOs: 245-246. In another aspect, an anti-CTLA-4 antibody comprises a heavy chain variable region (VH) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 10. In specific aspects, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity comprises substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CTLA-4 antibody comprising such a sequence retains CTLA-4 binding ability. In specific aspects, a total of 1 to 10, 11, 12, 13, 14, or 15 amino acids are substituted, inserted, and / or deleted from SEQ ID NO: 10. In specific aspects, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-CTLA-4 antibody comprises the VH sequence of SEQ ID NO: 10 and also comprises a post-translational modification of said sequence. In one specific aspect, the VH comprises one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 100, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 101, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 102. Post-translational modifications include, but are not limited to, modification of the heavy or light chain N-terminus with glutamine or pyroglutamylation of glutamine to pyroglutamine. In another aspect, an anti-CTLA-4 antibody is provided that comprises a light chain variable region (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 11. In specific aspects, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity comprises substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but the anti-CTLA-4 antibody comprising such sequence retains the ability to bind to CTLA-4. In specific aspects, a total of 1 to 10, 11, 12, 13, 14, or 15 amino acids are substituted, inserted, and / or deleted from SEQ ID NO: 11. In specific aspects, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-CTLA-4 antibody comprises the VL sequence of SEQ ID NO: 11, and also comprises post-translational modifications of said sequence. In one specific aspect, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 113, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 114, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 115. Post-translational modifications include, but are not limited to, modification of the heavy or light chain N-terminus with glutamine or pyroglutamylation of glutamine to pyroglutamine. In another aspect, an anti-CTLA-4 antibody is provided that comprises a light chain variable region (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 149. In specific aspects, the VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity comprises substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but the anti-CTLA-4 antibody comprising such sequence retains the ability to bind to CTLA-4. In specific aspects, a total of 1 to 10, 11, 12, 13, 14, or 15 amino acids are substituted, inserted, and / or deleted from SEQ ID NO: 149. In specific aspects, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., within the FRs). Optionally, the anti-CTLA-4 antibody comprises the VL sequence of SEQ ID NO: 149, including post-translational modifications of said sequence. In one specific aspect, the VL comprises one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 117, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133. Post-translational modifications include, but are not limited to, modification of the heavy or light chain N-terminus with glutamine or pyroglutamylation of glutamine to pyroglutamine. In another aspect, an anti-CTLA-4 antibody is provided, comprising a VH sequence of any of the above aspects and a VL sequence of any of the above aspects. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 10 and SEQ ID NO: 11, respectively, and also includes post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 98 and SEQ ID NO: 99, respectively, and also includes post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 83 and SEQ ID NO: 88, respectively, and also includes post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 83 and SEQ ID NO: 89, respectively, and also includes post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 83 and SEQ ID NO: 90, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 83 and SEQ ID NO: 91, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 83 and SEQ ID NO: 92, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 83 and SEQ ID NO: 93, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 83 and SEQ ID NO: 94, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 83 and SEQ ID NO: 97, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 83 and SEQ ID NO: 95, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 84 and SEQ ID NO: 97, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 85 and SEQ ID NO: 97, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 86 and SEQ ID NO: 97, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 86 and SEQ ID NO: 134, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 136 and SEQ ID NO: 97, respectively, and also includes post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 135 and SEQ ID NO: 97, respectively, and also includes post-translational modifications of such sequences.In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 136 and SEQ ID NO: 95, respectively, including post-translational modifications thereof. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 137 and SEQ ID NO: 97, respectively, including post-translational modifications thereof. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 138 and SEQ ID NO: 97, respectively. , including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 138 and SEQ ID NO: 144, respectively, and also includes post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 138 and SEQ ID NO: 145, respectively, and also includes post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 138 and SEQ ID NO: 146, respectively, and also includes post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 139 and SEQ ID NO: 146, respectively, and also includes post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 140 and SEQ ID NO: 146, respectively, and also includes post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 141 and SEQ ID NO: 146, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 140 and SEQ ID NO: 147, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 141 and SEQ ID NO: 147, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 140 and SEQ ID NO: 148, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 141 and SEQ ID NO: 148, respectively, including post-translational modifications of such sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 136 and SEQ ID NO: 149, respectively, and post-translational modifications thereof. In another aspect, a heterogeneous anti-CTLA-4 antibody is provided, comprising at least two different variable regions selected from the variable regions comprising the aforementioned VH and VL sequences. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 140 and SEQ ID NO: 146, respectively, and the VH and VL sequences of SEQ ID NO: 141 and SEQ ID NO: 146, respectively, and post-translational modifications thereof. In one aspect, the antibody comprises the VH and VL sequences of SEQ ID NO: 140 and SEQ ID NO: 147, respectively, and the VH and VL sequences of SEQ ID NO: 141 and SEQ ID NO: 147, respectively, and post-translational modifications thereof. Post-translational modifications include, but are not limited to, modification of the N-terminus of the heavy or light chain by glutamine or by pyroglutamylation of glutamine to pyroglutamate. If the N-terminal amino acid of the heavy or light chain of the anti-CTLA-4 antibodies provided herein is glutamine, the amino acid can be substituted with glutamine. If the N-terminal amino acid of the heavy or light chain of the anti-CTLA-4 antibodies provided herein is glutamine, the amino acid can be substituted with glutamine. In another aspect, the present invention provides antibodies that bind to the same epitope as the anti-CTLA-4 antibodies provided herein. For example, in a specific aspect, antibodies are provided that bind to the same epitope as the antibodies described in Tables 17, 22, 27, and 32. In a specific aspect, an antibody is provided that binds to an epitope within a fragment of CTLA-4 comprising at least one amino acid selected from the group consisting of amino acid 3 (Met), amino acid 33 (Glu), amino acid 35 (Arg), amino acid 53 (Thr), amino acid 97 (Glu), amino acid 99 (Met), amino acid 100 (Tyr), amino acid 101 (Pro), amino acid 102 (Pro), amino acid 103 (Pro), amino acid 104 (Tyr), amino acid 105 (Tyr), and amino acid 106 (Leu) of SEQ ID NO: 28. In a specific aspect, an antibody is provided that binds to an epitope within a fragment of CTLA-4 consisting of amino acids 97 (Glu) to 106 (Leu) of SEQ ID NO: 28. In a specific aspect, an antibody is provided that binds to an epitope within a fragment of CTLA-4 consisting of amino acids 99 (Met) to 106 (Leu) of SEQ ID NO: 28. In another aspect of the present invention, the anti-CTLA-4 antibody derived from any of the above aspects comprises a chimeric, humanized, or human monoclonal antibody. In one aspect, the anti-CTLA-4 antibody is, for example, Fv, Fab, Fab', scFv, bifunctional antibody, or F(ab') In another aspect, the antibody is, for example, a complete IgG1 antibody, a complete IgG4 antibody, or a full-length antibody of other antibody species or isotypes as defined herein. In another aspect, the anti-CTLA-4 antibody of the present invention comprises an Fc region. In yet another aspect, the anti-CTLA-4 antibody of the present invention comprises a constant region. The constant region may be a heavy chain constant region (including the Fc region), a light chain constant region, or both. In some aspects, the Fc region is a native sequence Fc region. Exemplary heavy chain constant regions derived from native antibodies include those of human IgG1 (SEQ ID NO: 249), human IgG2 (SEQ ID NO: 250), human IgG3 (SEQ ID NO: 251), and human IgG4 (SEQ ID NO: 252). Other exemplary heavy chain constant regions include those of SEQ ID NO: 82, SEQ ID NO: 158, and SEQ ID NO: 334. Exemplary light chain constant regions derived from natural antibodies include those of human κ chain (SEQ ID NO: 33, SEQ ID NO: 63, SEQ ID NO: 159) and human λ chain (SEQ ID NO: 53, SEQ ID NO: 87). In another aspect, the Fc region is a mutant Fc region created by adding amino acid changes to a native-sequence Fc region. In a specific aspect, the mutant Fc region has enhanced binding activity for at least one Fcγ receptor selected from the group consisting of FcγRIa, FcγRIIa, FcγRIIb, and FcγRIIIa compared to the native-sequence Fc region. In yet another aspect, the mutant Fc region has enhanced binding activity for FcγRIIa and FcγRIIIa compared to the native-sequence Fc region. Examples of heavy chain constant regions comprising such mutant Fc regions include the heavy chain constant regions listed in Tables 39 to 43, and the heavy chain constant regions listed in SEQ ID NOs: 31, 32, 41-46, 65, 66, 81, 207, 239, 253-271, 276, 277, 278, 308, 309, 311-333, 343-348, 350, and 351. Native sequence Fc regions are typically composed of homodimers consisting of two identical polypeptide chains. In certain aspects, mutant Fc regions may be homodimers consisting of polypeptide chains with identical sequences or heterodimers consisting of polypeptide chains with different sequences. Similarly, the heavy chain constant regions comprising the Fc region may be homodimers consisting of polypeptide chains with identical sequences or heterodimers consisting of polypeptide chains with different sequences. Examples of heterologous heavy chain constant regions include a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 31 and a polypeptide chain of SEQ ID NO: 32, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 43 and a polypeptide chain of SEQ ID NO: 44, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 45 and a polypeptide chain of SEQ ID NO: 46, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 254 and a polypeptide chain of SEQ ID NO: 256, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 257 and a polypeptide chain of SEQ ID NO: 258, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 259 and a polypeptide chain of SEQ ID NO: 260. the heavy chain constant region of the polypeptide chain of sequence identification number: 260, the heavy chain constant region comprising the polypeptide chain of sequence identification number: 261 and the heavy chain constant region of the polypeptide chain of sequence identification number: 263, the heavy chain constant region comprising the polypeptide chain of sequence identification number: 262 and the heavy chain constant region of the polypeptide chain of sequence identification number: 264, the heavy chain constant region comprising the polypeptide chain of sequence identification number: 265 and the heavy chain constant region of the polypeptide chain of sequence identification number: 267, the heavy chain constant region comprising the polypeptide chain of sequence identification number: 266 and the heavy chain constant region of the polypeptide chain of sequence identification number: 268, the heavy chain constant region comprising the polypeptide chain of sequence identification number: 269 and the heavy chain constant region of the polypeptide chain of sequence identification number: 270, the heavy chain constant region comprising the polypeptide chain of sequence identification number: 2 The heavy chain constant region of the polypeptide chain of sequence identification number 71 and the polypeptide chain of sequence identification number 81, the heavy chain constant region of the polypeptide chain of sequence identification number 65 and the polypeptide chain of sequence identification number 66, the heavy chain constant region of the polypeptide chain of sequence identification number 239 and the polypeptide chain of sequence identification number 207, the heavy chain constant region of the polypeptide chain of sequence identification number 259 and the polypeptide chain of sequence identification number 276, the heavy chain constant region of the polypeptide chain of sequence identification number 65 and the polypeptide chain of sequence identification number 278, the heavy chain constant region of the polypeptide chain of sequence identification number 308 and the polypeptide chain of sequence identification number 309, the heavy chain constant region of the polypeptide chain of sequence identification number 308 and the polypeptide chain of sequence identification number 309, the heavy chain constant region of the polypeptide chain of Sequence ID No.: 311 and the heavy chain constant region of the polypeptide chain of Sequence ID No.: 312, the heavy chain constant region of the polypeptide chain of Sequence ID No.: 313 and the heavy chain constant region of the polypeptide chain of Sequence ID No.: 314, the heavy chain constant region of the polypeptide chain of Sequence ID No.: 315 and the heavy chain constant region of the polypeptide chain of Sequence ID No.: 316, the heavy chain constant region of the polypeptide chain of Sequence ID No.: 317 and the heavy chain constant region of the polypeptide chain of Sequence ID No.: 318, the heavy chain constant region of the polypeptide chain of Sequence ID No.: 319 and the heavy chain constant region of the polypeptide chain of Sequence ID No.: 320, the heavy chain constant region of the polypeptide chain of Sequence ID No.: 321 and the heavy chain constant region of the polypeptide chain of Sequence ID No.: 322,A polypeptide chain comprising a sequence identification number: 323 and a heavy chain constant region of a polypeptide chain comprising a sequence identification number: 324, a polypeptide chain comprising a sequence identification number: 325 and a heavy chain constant region of a polypeptide chain comprising a sequence identification number: 326, a polypeptide chain comprising a sequence identification number: 327 and a heavy chain constant region of a polypeptide chain comprising a sequence identification number: 328, a polypeptide chain comprising a sequence identification number: 330 and a heavy chain constant region of a polypeptide chain comprising a sequence identification number: 331, a polypeptide chain comprising a sequence identification number: 332 and a heavy chain constant region of a polypeptide chain comprising a sequence identification number: 333 The heavy chain constant region of the polypeptide chain of sequence identification number: 333, the heavy chain constant region comprising the polypeptide chain of sequence identification number: 343 and the polypeptide chain of sequence identification number: 344, the heavy chain constant region comprising the polypeptide chain of sequence identification number: 345 and the polypeptide chain of sequence identification number: 347, the heavy chain constant region comprising the polypeptide chain of sequence identification number: 346 and the polypeptide chain of sequence identification number: 348, the heavy chain constant region comprising the polypeptide chain of sequence identification number: 350 and the polypeptide chain of sequence identification number: 351, etc. In yet another aspect, the anti-CTLA-4 antibody according to any of the above aspects may be alone or in combination and may incorporate any of the features described in items 1 to 7 below. 1. Antibody Binding Activity In certain aspects, the binding activity of the antibodies provided herein is ≦10 μM, ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM or ≦0.001 nM (e.g., 10 -8 M or less, for example 10 -8 M~10 -13 M, for example 10 -9 M~10 -13 M) dissociation constant (KD). In one aspect, the binding activity of the antibody is measured by a radiolabeled antigen binding assay (RIA). In one aspect, the RIA is performed using a Fab version of the target antibody and its antigen. For example, the binding affinity of the Fab for the antigen in solution is determined by measuring the binding affinity of the Fab for the antigen in the presence of a series of increasing amounts of unlabeled antigen using a minimal concentration of ( 125I) Label the antigen to equilibrate the Fab, and then capture the bound antigen with a disk coated with an anti-Fab antibody for measurement (e.g., see Chen et al., J. Mol. Biol. 293:865-881 (1999)). To establish measurement conditions, MICROTITER (registered trademark) multiwell disks (Thermo Scientific) were coated overnight with 5 μg / ml of a capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and then blocked with 2% (w / v) bovine serum albumin in PBS for 2 to 5 hours at room temperature (approximately 23°C). In a non-adsorbent disk (Nunc #269620), 100 pM or 26 pM of [ 125 A [I]-antigen (e.g., similar to the evaluation of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res. 57:4593-4599 (1997)) is mixed with serial dilutions of the target Fab. The target Fab is then incubated overnight, although this incubation can be continued for longer periods (e.g., approximately 65 hours) to ensure equilibrium. The mixture is then transferred to a capture plate for incubation at room temperature (e.g., 1 hour). The solution is then removed, and the plate is washed eight times with 0.1% polysorbate 20 (TWEEN-20 (registered trademark)) in PBS. After drying the plate, 150 μl / well of scintillant (MICROSCINT-20 (trademark), Packard) is added and counted for 10 minutes in a TOPCOUNT (trademark) gamma counter (Packard). For use in competitive binding assays, a concentration of each Fab is selected that results in less than 20% of maximal binding. In one aspect, antibody binding activity can be measured using a ligand capture method that utilizes surface plasmon resonance analysis as the measurement principle, such as with the BIACORE (trademark registered) T200 or BIACORE (trademark registered) 4000 (GE Healthcare, Uppsala, Sweden). The instrument can be operated using BIACORE (trademark registered) control software. In one aspect, ligand capture molecules, such as anti-tag antibodies, anti-IgG antibodies, or protein A, are immobilized on a carboxymethyldextrin-coated sensor chip (GE Healthcare, Uppsala, Sweden) using an amine coupling kit (GE Healthcare, Uppsala, Sweden) according to the supplier's instructions. The ligand capture molecules are diluted in 10 mM sodium acetate solution at an appropriate pH and injected at an appropriate flow rate and injection time. Binding activity is measured using a buffer containing 0.05% polysorbate 20 (also known as Tween (trademark registration)-20) as the measurement buffer, at a flow rate of 10-30 μL / min, and preferably at 25°C or 37°C. When measuring by capturing the antibody as a ligand with a ligand-capturing molecule, after injecting the antibody to capture the target amount, sequential dilutions of the antigen or Fc receptor prepared in the measurement buffer (analyte) are injected. When measuring by capturing the antigen or Fc receptor as a ligand with a ligand-capturing molecule, after injecting the antibody to capture the target amount, sequential dilutions of the antibody prepared in the measurement buffer (analyte) are injected. In one aspect, measurement results are analyzed using BIACORE (registered trademark) Evaluation Software. Kinetic parameters are calculated by simultaneously fitting the binding and dissociation sensorgrams using a 1:1 binding model. This allows for the calculation of the association rate (k or ka), dissociation rate (k or k), and equilibrium dissociation constant (KD). For weak binding activity, particularly when dissociation is rapid and calculation of kinetic parameters is difficult, the steady-state model can be used to calculate the equilibrium dissociation constant (KD). As another parameter of binding activity, the amount of analyte bound (RU) at a specific concentration can be divided by the amount of ligand captured (RU) to calculate the "analyte bound per unit amount of ligand." 2. Antibody Fragments In certain aspects, the antibodies provided herein are antibody fragments. Antibody fragments are not limited thereto but include Fab, Fab', Fab'-SH, F(ab') 2. Fv and scFv fragments, as well as other fragments described below. For a general overview of specific antibody fragments, see Hudson et al. Nat. Med. 9: 129-134 (2003). For a general overview of scFv fragments, see, for example, Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994), WO93 / 16185, and U.S. Patents 5,571,894 and 5,587,458. For Fab and F(ab') fragments containing salvage receptor binding epitope residues and having an increased in vivo half-life, see The discussion of the 2nd segment is based on U.S. Patent No. 5,869,046. Bifunctional antibodies can be bivalent or bispecific antibody fragments with two antigen-binding sites. For example, see EP 404,097, WO 1993 / 01161, Hudson et al., Nat. Med. 9:129-134 (2003), and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003). Single-domain antibodies are antibody fragments comprising all or a portion of an antibody's heavy chain variable region, or all or a portion of its light chain variable region. In certain aspects, the single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA, e.g., see U.S. Patent No. 6,248,516 B1). Antibody fragments are not limited thereto and can be produced by various methods, including proteolytic digestion of intact antibodies described herein, and production by recombinant host cells (eg, E. coli or phage). 3. Chimeric and Humanized Antibodies In certain aspects, the antibodies provided herein are chimeric antibodies. Specific chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a non-human primate such as mouse, rat, hamster, rabbit, or monkey) and a human constant region. In another example, a chimeric antibody is a "class switch" antibody, resulting from a change in species or subclass from a parent antibody. Chimeric antibodies also include antigen-binding fragments thereof. In certain aspects, chimeric antibodies are humanized antibodies. Typically, non-human antibodies are humanized to maintain the specificity and affinity of the parent non-human antibody while reducing immunogenicity in humans. Generally, humanized antibodies comprise one or more variable regions in which the HVRs (e.g., CDRs (or portions thereof)) are derived from non-human antibodies and the FRs (or portions thereof) are derived from human antibody sequences. Humanized antibodies optionally comprise at least a portion of a human constant region. In some aspects, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues were derived), for example, to restore or improve the specificity or affinity of the antibody. Humanized antibodies and methods for their production are generally described in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, for example, in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Natl. Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing resurfacing); Dall'Acqua et al., Methods 36:43-60 (2005) (describing FR shuffling); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the "Guide selection" method for FR shuffling). Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best-fit" method (see Sims et al. J. Immunol. 151: 2296 (1993)); framework regions derived from the consensus sequence of human antibodies from a specific subgroup of light or heavy chain variable regions (see Carter et al. Proc. Natl. Acad. Sci. USA, 89: 4285 (1992) and Presta et al. J. Immunol., 151: 2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, for example, Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008)); and framework regions derived from FR library screening (see Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)). 4. Human Antibodies In certain aspects, the antibodies provided herein are human antibodies. Human antibodies can be produced by various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-374 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008). Human antibodies can be produced by administering an immunogen to a transgenic animal that has been altered to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge (loading). Such animals typically contain all or part of the human immunoglobulin locus, either replacing the endogenous immunoglobulin locus or randomly incorporated into the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin locus is typically rendered inert. For an overview of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). For example, reference is made to U.S. Patents 6,075,181 and 6,150,584 describing the XENOMOUSE (trademark) technology; U.S. Patent 5,770,429 describing the HUMAB (registered trademark); U.S. Patent Application Publication No. 7,041,870 describing the KM MOUSE (registered trademark) technology; and U.S. Patent Application Publication No. 2007 / 0061900 describing the VELOCIMOUSE (registered trademark) technology. Human variable regions from intact antibodies produced by these animals can also be further modified, for example, by combining them with different human constant regions. Human antibodies can also be produced using hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines used to produce human monoclonal antibodies have been described (e.g., see Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp.51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147:86 (1991)). Human antibodies generated using human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described in U.S. Patent No. 7,189,826 (describing the production of a monoclonal human IgM antibody from a fusion tumor cell line) and Ni, Xiandai Mianyixue, 26 (4): 265-268 (2006) (describing a human-human fusion tumor). Human fusion tumor technology (trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20 (3): 927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27 (3): 185-191 (2005). Human antibodies can also be generated by isolating variable region sequences from Fv clones selected from human-derived phage display libraries. These variable region sequences can be combined with the desired human constant regions. The following describes methods for selecting human antibodies from antibody libraries. 5. Library-derived Antibodies The antibodies of the present invention can be isolated by screening combinatorial libraries for antibodies with one or more desired activities. For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies with desired binding properties. This method is summarized in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001) and is described, for example, in McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J. Mol. Biol. 340(5):1073-1093(2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472(2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132(2004). In a specific phage display method, repertoires of VH and VL genes (cell repertoires) are separately cloned by polymerase chain reaction (PCR) and randomly recombined in a phage library. This phage library is screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). Phage typically display antibody fragments as either single-chain Fv (scFv) fragments or Fab fragments. Repertoires derived from immunized sources can provide high-affinity antibodies to the immunized source without the need for hybridoma construction. Alternatively, as described by Griffiths et al., EMBO J, 12:725-734 (1993), a naive repertoire (e.g., from humans) can be cloned to provide a single source of antibodies against a wide range of non-self and self antigens without immunization. Finally, as described by Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992), naive repertoires can be synthesized by cloning V-gene segments from stem cells prior to reprogramming using PCR primers containing random sequences encoding hypervariable CDR3 regions that have been reprogrammed in vitro. Patent documents describing human antibody phage libraries include, for example, U.S. Patent No. 5,750,373 and U.S. Patent Application Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360. Antibodies or antibody fragments isolated from human antibody libraries are referred to as human antibodies or human antibody fragments in this specification. 6. Multispecific Antibodies In certain aspects, the antibodies provided herein are multispecific antibodies (e.g., bispecific antibodies). Multispecific antibodies are monoclonal antibodies with binding specificities for at least two different sites. In certain aspects, one binding specificity is for CTLA-4, and the other is for any other antigen. In certain aspects, bispecific antibodies can bind to two different epitopes of CTLA-4. Bispecific antibodies can be used to localize cytotoxic agents to cells expressing CTLA-4. Bispecific antibodies can be prepared as full-length antibodies or antibody fragments. Methods for producing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello, Nature 305: 537 (1983), WO93 / 08829 and Traunecker et al., EMBO J. 10: 3655 (1991)) and knob-in-hole technology (see, for example, U.S. Patent No. 5,731,168). Multispecific antibodies can be prepared by: manipulating electrostatic steering effects to create Fc heterodimers (WO2009 / 089004A1); cross-linking two or more antibodies or fragments (see U.S. Patent No. 4,676,980 and Brennan et al., Science, 229:81 (1985)); using leucine zippers to create antibodies with two specificities (see Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); using "diabody" technology to create bispecific antibody fragments (see Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-chain Fv (scFv) dimers (see Gruber et al., J. Immunol., 152:5368 (1994)); and trispecific antibodies are prepared as described, for example, in Tutt et al. J. Immunol. 147:60 (1991). Altered antibodies with three or more functional antigen-binding sites, including "octopus antibodies," are also encompassed by the present specification (see, for example, US Patent Application Publication No. 2006 / 0025576 A1). In this specification, antibodies or fragments also include "dual-acting Fab" or "DAF," which contain one antigen-binding site that binds to CTLA-4 and another different antigen (see, for example, US Patent Application Publication No. 2008 / 0069820). 7. Antibody Variants In certain aspects, amino acid sequence variants of the antibodies provided herein are also contemplated. For example, it is also desirable to improve the binding affinity and / or other biological properties of the antibody. Antibody amino acid sequence variants can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from the antibody amino acid sequence and / or insertions into the antibody amino acid sequence and / or substitutions of residues in the antibody amino acid sequence. Any combination of deletions, insertions, and substitutions can be performed to complete the final construct, provided that the final construct possesses the desired characteristics (e.g., antigen binding). a) Substitution, Insertion, and Deletion Variants In certain aspects, antibody variants are provided that have one or more amino acid substitutions. Target sites for introduction of substitution mutations include HVRs and FRs. Conservative substitutions are disclosed under the heading "Preferred Substitutions" in Table 1. More substantial alterations are provided under the heading "Example Substitutions" in Table 1 and are described in detail below, along with reference to the types of amino acid side chains. Amino acid substitutions can also be introduced into the target antibody, and the products can be screened for desired activities, such as maintained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. [Table 1] Amino acids can be grouped according to the common side chain properties: (1) Hydrophobic: norleucine, methionine (Met), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile); (2) Neutral hydrophilic: cysteine ​​(Cys), serine (Ser), threonine (Thr), aspartic acid (Asn), glutamine (Gln); (3) Acidic: aspartic acid (Asp), glutamic acid (Glu); (4) Basic: histidine (His), lysine (Lys), arginine (Arg); (5) Residues that affect chain orientation: glycine (Gly), proline (Pro); (6) Aromatic: tryptophan (Trp), tyrosine (Tyr), phenylalanine (Phe). A non-conservative substitution involves exchanging a member of one class for a member of another class. One type of substitutional variant involves substitution of one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Typically, the resulting variants selected for further study should have modifications (e.g., improvements) in specific biological properties compared to the parent antibody (e.g., increased affinity, reduced immunogenicity), and / or substantially retain the specific biological properties of the parent antibody. An exemplary substitutional variant is an affinity-matured antibody, which can be suitably prepared using, for example, phage display-based affinity maturation techniques (e.g., those described herein). Briefly, one or more HVR residues are mutated, the mutant antibodies are then displayed on phage, and screened for a specific biological activity (e.g., binding affinity). Alterations (e.g., substitutions) can be made in the HVRs, for example, to improve antibody affinity. Such alterations can be made in HVR "hotspots," residues encoded by codons that are frequently mutated during somatic maturation (e.g., see Chowdhury, Methods Mol. Biol. 207:179-196 (2008)) and / or residues that contact the antigen. The resulting mutant VH or VL can be tested for binding affinity. Affinity maturation by construction and reselection from secondary libraries is described, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some aspects of affinity maturation, diversity can be introduced into the variable genes selected for maturation using any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then generated. This library is then screened to identify randomized antibody variants with the desired affinity. Other methods for introducing diversity include HVR-directed randomization of a few HVR residues (e.g., 4-6 residues at a time). HVR residues involved in antigen binding can be specifically identified using, for example, alanine scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are often targeted. In certain aspects, substitutions, insertions, or deletions can be made within one or more HVRs, as long as such alterations do not substantially reduce the ability of the antibody to bind to the antigen. For example, conservative alterations that do not substantially reduce binding affinity (e.g., conservative substitutions as provided herein) can be made within the HVRs. Such alterations can, for example, be made outside of the antigen-contacting residues of the HVRs. In certain aspects of the mutant VH and VL sequences described above, each HVR is unchanged or contains only one, two, or three amino acid substitutions. A method for identifying residues or regions of an antibody that can be targeted for mutagenesis is called "alanine scanning mutagenesis," as described in Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues such as arginine, aspartic acid, histidine, lysine, and glutamine) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the antibody-antigen interaction is affected. Following these initial substitutions, further substitutions can be introduced at amino acid positions that demonstrate functional sensitivity. Alternatively, or additionally, crystal structures of the antigen-antibody complex can be analyzed to identify contact points between the antibody and antigen. These contact residues and adjacent residues can be targeted as substitution candidates or excluded from the substitution pool. Variants can then be screened to determine whether they possess the desired properties. Insertions of amino acid sequences, like insertions of single or multiple amino acid residues within the sequence, encompass fusions ranging from one to more than 100 residues at the amino and / or carboxyl termini. Examples of terminal insertions include antibodies with a methionine residue at the N-terminus. Insertional variants other than antibody molecules include antibodies with polypeptides that increase the plasma half-life of enzymes (e.g., ADEPT) or antibodies fused to the N- or C-terminus. b) Glycosylation Variants: In certain aspects, the antibodies provided herein are modified to increase or decrease the degree of glycosylation of the antibody. Addition or deletion of glycosylation sites to an antibody can be conveniently achieved by altering the amino acid sequence to create or remove one or more glycosylation sites. When an antibody contains an Fc region, the carbohydrates attached thereto can be modified. Natural antibodies produced by mammalian cells typically contain branched bi-branched oligosaccharides, which are usually attached to Asn297 of the CH2 region of the Fc region via an N-linkage. For example, see Wright et al. TIBTECH 15:26-32 (1997). Oligosaccharides include, for example, various carbohydrates such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid. Furthermore, fucose is attached to GlcNAc in the "backbone" of the bi-branched oligosaccharide structure. In some aspects, modifications of the oligosaccharides in the antibodies of the present invention can also be performed to create antibody variants with specifically improved properties. In one aspect, antibody variants are provided that lack carbohydrate structures that are fucose added (directly or indirectly) to the Fc region. For example, the amount of fucose in such antibodies may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose can be measured, for example, by MALDI-TOF mass spectrometry as described in WO2008 / 077546, by calculating the average amount of fucose within the sugar chains at Asn297 relative to the sum of all sugar structures (e.g., complex, hybrid, and high-mannose structures) added to Asn297. Asn297 represents an aspartic acid residue located near position 297 of the Fc region (EU numbering of Fc region residues). However, due to slight sequence diversity among various antibodies, Asn297 can also be located ±3 amino acids upstream or downstream of position 297, that is, between positions 294 and 300. Such fucosylated variants can have improved ADCC activity. For example, see U.S. Patent Application Publication Nos. 2003 / 0157108 (Presta, L.) and 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd.). Examples of publications on “defucosylated” or “fucose-deficient” antibody variants include US2003 / 0157108, WO2000 / 61739, WO2001 / 29246, US2003 / 0115614, US2002 / 0164328, US2004 / 0093621, US2004 / 0132140, US2004 / 0110704, US2004 / 0110282, US2004 / 0109865, WO2003 / 085119, WO2003 / 084570, WO2005 / 035586, WO2005 / 035778, WO2005 / 053742, WO2002 / 031140, Okazaki et al. J. Mol. Biol. 336: 1239-1249 (2004), Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004).Examples of cell lines that can produce defucosylated antibodies include Lec13 CHO cells that lack protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249: 533-545 (1986); U.S. Patent Application Publication No. US2003 / 0157108 A1, Presta, L; and WO2004 / 056312 A1, Adams et al., especially Example 11) and knockout cell lines, such as CHO cells knocked out of the alpha-1,6-fucosyltransferase gene FUT8 (see, for example, Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94 (4): 680-688 (2006); and WO2003 / 085107). For example, antibody variants are provided that have bisected oligosaccharides, wherein two branched oligosaccharides attached to the Fc region of the antibody are bisected by GlcNAc. Such antibody variants can have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described in, for example, WO2003 / 011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and US2005 / 0123546 (Umana et al.). Also provided are antibody variants in which the oligosaccharide attached to the Fc region contains at least one galactose residue. Such antibody variants can have improved CDC function. Such antibody variants are described, for example, in WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S.). c) Fc Region Variants: In certain aspects, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein to generate an Fc region variant. An Fc region variant may comprise a human Fc region sequence (e.g., the Fc region of human IgG1, IgG2, IgG3, or IgG4) comprising an amino acid modification (e.g., substitution) at one or more amino acid positions. In certain aspects, antibody variants that possess some, but not all, effector functions are also contemplated by the present invention. These effector functions make the antibody a promising candidate for use in situations where in vivo half-life is important but specific effector functions (such as complement and ADCC) are not required or are detrimental. To confirm reduction or absence of CDC and / or ADCC activity, in vitro and / or in vivo cytotoxicity measurements can be performed. For example, Fc receptor (FcR) binding measurements can be performed to confirm that the antibody lacks FcγR binding (thus, a high probability of lacking ADCC activity) while maintaining FcRn binding ability. While NK cells, the primary cells that mediate ADCC, express only FcγRIII, monocytes, on the other hand, express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for evaluating ADCC activity of target molecules are described in U.S. Pat. No. 5,500,362 (e.g., see Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); and U.S. Pat. No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive cytotoxicity assays can be used (e.g., see the ACT1 (trademark) non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA); and the CytoTox 96 (registered trademark) non-radioactive cytotoxicity assays (Promega, Madison, WI). Useful effector cells for these assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells.Alternatively, or in addition, the ADCC activity of the target molecule can be assessed in vivo using an animal model such as that described in Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). Furthermore, to confirm that the antibody lacks CDC activity due to its inability to bind to C1q, C1q binding can be measured. For example, see the C1q and C3c binding ELISAs described in WO2006 / 029879 and WO2005 / 100402. Furthermore, CDC measurement can be performed to evaluate complement activation (e.g., see Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). Furthermore, FcRn binding and in vivo clearance / half-life can also be determined using methods known in the art (e.g., see Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)). Antibodies with reduced effector function include those with one or more substitutions at Fc region residues 238, 265, 269, 270, 297, 327, and 329 ( U.S. Patent No. 6,737,056 ). Such Fc variants include the so-called "DANA" Fc variant with alanine substitutions at residues 265 and 297 ( U.S. Patent No. 7,332,581 ), and Fc variants with two or more substitutions at amino acid positions 265, 269, 270, 297, and 327. Specific antibody variants with increased or decreased binding to FcRs have been described (see US Pat. No. 6,737,056; WO 2004 / 056312 and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001)). In specific aspects, the antibody variant comprises an Fc region concomitant with one or more amino acid substitutions that improve ADCC, eg, substitutions at positions 298, 333, and / or 334 of the Fc region (EU numbering of residues). In some aspects, alterations are made in the Fc region that result in altered (i.e., either increased or decreased) C1q binding and / or complement-dependent cytotoxicity (CDC), as described, for example, in U.S. Pat. No. 6,194,551, WO99 / 51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000). Antibodies with increased half-life and increased binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976); Kim et al., J. Immunol. 24:249 (1994)), are described in U.S. Patent Application Publication No. 2005 / 0014934 A1 (Hinton et al.). These antibodies comprise an Fc region with one or more substitutions that increase the Fc region's binding to FcRn. Such Fc variants include those accompanied by substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434 (e.g., substitution of Fc region residue 434 ( U.S. Patent No. 7,371,826 )). For other examples of Fc region variants, see Duncan & Winter, Nature 322: 738-740 (1988); US Patent No. 5,648,260; US Patent No. 5,624,821; and WO94 / 29351. d) Cysteine-Altered Antibody Variants: In certain aspects, it is desirable to generate cysteine-altered antibodies (e.g., "thioMAbs") in which one or more residues of an antibody are substituted with cysteine ​​residues. In certain aspects, the residues to be substituted are present at accessible sites on the antibody. Substituting these residues with cysteine ​​creates a reactive thiol group at an accessible site on the antibody. This reactive thiol group can be used to conjugate the antibody to other moieties (e.g., drug moieties or linker-drug moieties) and to generate immunoconjugates as described in further detail herein. In certain aspects, one or more of the following residues can be substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine-altered antibodies can also be generated, for example, as described in U.S. Patent No. 7,521,541. e) Antibody Derivatives In certain aspects, the antibodies provided herein may be further modified to include additional non-proteinaceous moieties known in the art and readily available. Suitable moieties for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, polydextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), polydextrose or poly(n-vinyl pyrrolidone), polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde is advantageous in manufacturing due to its stability in water. The polymer can be of any molecular weight and may be branched or unbranched. The number of polymers added to an antibody can vary widely. If more than one polymer is added, they can be the same or different molecules. Generally speaking, the number and / or type of polymers used in derivatization is not limited to these, but can be determined based on considerations such as the specific properties or functions of the antibody to be improved and whether the antibody derivative is to be used therapeutically under specific conditions. In another embodiment, a conjugate of an antibody and a non-protein moiety that can be selectively heated by exposure to radiation is provided. In one embodiment, the non-protein moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation can be of any wavelength, but is not limited thereto, including wavelengths that heat the non-protein moiety to a temperature that is not harmful to normal cells but causes cell death in the vicinity of the antibody-non-protein moiety. The anti-CTLA-4 antibodies of the present specification can be combined with various existing technologies. As a non-limiting embodiment of such a combination of technologies, a cell expressing a chimeric antigen receptor (CAR) using an anti-CTLA-4 antibody is produced. Here, examples of cells include, for example, T cells, γδT cells, NK cells, NKT cells, cytokine-induced killer (CIK) cells, and macrophages (Int J Mol Sci. (2019) 20 (11), 2839, Nat Rev Drug Discov. (2020) 19 (5), 308). As a non-limiting method for producing T cells (CAR-T) expressing such a CAR, a method of introducing a CAR into effector cells such as T cells by genetic modification technology can be cited, wherein the CAR comprises an antigen-binding region (e.g., scFv) of an anti-CTLA-4 antibody, a transmembrane region of a TCR, and a signaling region of a costimulatory molecule such as CD28 for enhancing T cell activation. As a non-limiting example of a technology that can be combined with the anti-CTLA-4 antibody of the present specification, the preparation of a T cell redirecting antibody using an anti-CTLA-4 antibody is exemplified (Nature (1985) 314 (6012), 628-31, Int J Cancer (1988) 41 (4), 609-15, Proc Natl Acad Sci USA (1986) 83 (5), 1453-7). As a non-limiting embodiment of such a T cell redirecting antibody, a bispecific antibody can be cited, wherein the bispecific antibody comprises: a binding region for any of the constituent subunits of the T cell receptor (TCR) complex on T cells, particularly a binding region for the CD3ε chain of CD3; and an antigen-binding region of an anti-CTLA-4 antibody. B. Recombinant Methods and Compositions For example, as described in U.S. Patent No. 4,816,567, antibodies can be produced using recombinant methods or compositions. In one aspect, an isolated nucleic acid encoding an anti-CTLA-4 antibody described in this specification is provided. Such nucleic acid can also encode an amino acid sequence comprising VL and / or an amino acid sequence comprising VH of the antibody (e.g., the light chain and / or heavy chain of the antibody). In another aspect, one or more vectors (e.g., expression vectors) comprising such nucleic acid are provided. In another aspect, a host cell comprising such nucleic acid is provided. In one of these aspects, the host cell comprises (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising VL of the antibody and an amino acid sequence comprising VH of the antibody; or (2) a first vector and a second vector, wherein the first vector comprises a nucleic acid encoding an amino acid sequence comprising VL of the antibody and the second vector comprises a nucleic acid encoding an amino acid sequence comprising VH of the antibody (e.g., transformed). In one aspect, the host cell is eukaryotic (e.g., Chinese hamster ovary (CHO) cells) or a cell of the lymphoid system (e.g., Y0, NS0, Sp2 / 0 cells). In one aspect, a method for producing an anti-CTLA-4 antibody is provided, comprising: culturing a host cell as described above containing a nucleic acid encoding the antibody under conditions suitable for expression of the anti-CTLA-4 antibody; and optionally, recovering the antibody from the host cell (or host cell culture medium). For recombinant production of anti-CTLA-4 antibodies, nucleic acid encoding the antibody (e.g., those described above) is isolated and inserted into one or more vectors for further cloning and / or expression in host cells. Such nucleic acid can be readily isolated and sequenced using conventional protocols (e.g., by using oligonucleotide probes that specifically bind to the genes encoding the heavy and light chains of the antibody). Host cells suitable for cloning or expressing antibody-encoding vectors include the prokaryotic and eukaryotic cells described herein. For example, antibodies can be produced in bacteria, particularly when glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patents 5,648,237, 5,789,199, and 5,840,523 (also see Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, for expression of antibody fragments in Escherichia coli). After expression, antibodies can be isolated from the bacterial cell paste into a soluble fraction and further purified. In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast are also suitable hosts for the colonization or expression of antibody-encoding vectors. These include fungi and yeast strains whose glycosylation pathways have been "humanized," resulting in the production of antibodies with partially or completely human glycosylation patterns. See Gerngross, Nat. Biotech. 22: 1409-1414 (2004) and Li et al., Nat. Biotech. 24: 210-215 (2006). Host cells derived from multicellular organisms (invertebrates and vertebrates) are also suitable for expressing glycosylated antibodies. Examples of invertebrate cells include plant and insect cells. A number of baculovirus strains have been identified that can be used for conjugation with insect cells, particularly transformation of fall armyworm (Spodoptera frugiperda) cells. Plant cell cultures can also be used as hosts. For example, see U.S. Patents 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (which describe the PLANTIBODIES (trademark) technology for genetically modifying plants to produce antibodies). Vertebrate cells can also be used as hosts. For example, adapted mammalian cell lines that proliferate in a planktonic state are useful. Other examples of useful mammalian host cell lines include monkey kidney CV1 (COS-7) transformed by SV40; human fetal kidney (293 or 293 cells as described, for example, in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney (BHK) cells; mouse Sertoli cells (TM4 cells as described, for example, in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney (CV1) cells; African green monkey kidney (VERO-76) cells; human uterine cervical carcinoma (HELA); dog kidney (MDCK) cells; Buffalo rat liver (BRL 3A) cells; human lung (W138) cells; human liver (Hep G2) cells; mouse mammary carcinoma (MMT 060562); TRI cells (e.g., Mather et al., Annals NY Acad. Sci. 383:44-68 (1982)); MRC5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0, and Sp2 / 0. For an overview of specific mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003). Polyclonal antibodies are preferably raised in animals by multiple subcutaneous (sc) or intraperitoneal (ip) injections of the relevant antigen and an adjuvant. For example, keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin or soybean trypsin inhibitor, bifunctional substances or derivatizing agents such as maleimide benzylsulfonic acid succinimide ester (through conjugation at cysteine ​​residues), N-hydroxysuccinimide (through conjugation at lysine residues), glutaraldehyde, succinic anhydride, SOCl 2 or R 1 N=C=NR (where R and R 1are different alkyl groups), it is useful to conjugate the relevant antigen to a protein that is immunogenic in the species being immunized. Animals (typically non-human mammals), such as rabbits or mice, are immunized with the antigen, immunogenic conjugate, or derivative by combining 100 μg or 5 μg of the protein or conjugate with three volumes of Freund's complete adjuvant (for rabbits or mice, respectively). This solution is then injected intradermally at multiple sites. One month later, the animal is boosted with 1 / 5 to 1 / 10 the initial dose of the peptide or conjugate in Freund's complete adjuvant via subcutaneous injection at multiple sites. Seven to 14 days later, blood is collected from the animal and the serum analyzed for antibody titers. The animal is boosted until the titer reaches a plateau. Preferably, the animal is boosted with the conjugate, which is the same antigen but conjugated to a different protein and / or via a different cross-linking reagent. The conjugate can also be prepared as a protein fusion in recombinant cell culture. Furthermore, the use of a coagulant such as alum is also suitable to enhance the immune response. A monoclonal antibody refers to an antibody obtained from a substantially homogeneous collection of antibodies. That is, the individual antibodies comprising the collection are identical except for potential naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation). Thus, the modifier "monoclonal" indicates the characteristic of an antibody that is not a mixture of other antibodies. For example, monoclonal antibodies can be produced using the hybridoma method first described in Kohler et al., Nature 256(5517):495-497 (1975). In the hybridoma method, mice or other suitable host animals, such as hamsters, are immunized as described above in this specification to produce antibodies that specifically bind to the protein used for immunization or to induce lymphocytes capable of producing antibodies. Alternatively, lymphocytes can be immunized in vitro. Immunizing agents typically contain an antigenic protein or a fusion variant thereof. Generally, peripheral blood lymphocytes (PBLs) are used when human cells are desired, while spleen cells or lymph node cells are used when non-human mammalian cells are desired. Lymphocytes are then fused with an immortalized cell line using an appropriate fusing agent such as polyethylene glycol to form hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press (1986), pp. 59-103). Immortalized cell lines are typically transformed mammalian cells, particularly myeloma cells of rodent, bovine, or human origin. Rat or mouse myeloma cell lines are commonly used. The resulting fused tumor cells are seeded and grown in an appropriate culture medium, preferably containing one or more substances that inhibit the growth or survival of the unfused parental myeloma cells. For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT), the culture medium for the fused tumor typically contains hypoxanthine, aminopterin, and thymidine (HAT medium), substances that inhibit the growth of HGPRT-deficient cells. The preferred immortalized myeloma cell lines are cells that fuse efficiently, assist the selected antibody-producing cells in stably producing antibodies at high levels, and are sensitive to culture media such as HAT medium. Among these, preferred are mouse myeloma lines, for example, those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center in San Diego, California, USA, and SP-2 cells (and their derivatives, such as X63-Ag8-653) available from the American Type Culture Collection in Manassas, Virginia, USA. Human myeloma cell lines and mouse-human heteromyeloma cell lines have also been described for the production of human monoclonal antibodies (Kozbor et al., J Immunol. 133 (6): 3001-3005 (1984), Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, pp. 51-63 (1987)). The culture medium in which the fused tumor cells proliferate is analyzed to determine whether monoclonal antibodies against the antigen are produced. Preferably, the binding specificity of the monoclonal antibodies produced by the fused tumor cells is determined by immunoprecipitation or an in vitro binding assay such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques and assays are well known in the art. For example, binding affinity can be determined by Scatchard analysis as described in Munson, Anal Biochem. 107(1):220-239 (1980). After identifying fused tumor cells that produce antibodies with the desired specificity, affinity, and / or activity, the clones can be subcloned using limiting dilution methods and then propagated using standard methods (Goding, supra). Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640. Furthermore, the fused tumor cells can be propagated in vivo as tumors in mammals. Monoclonal antibodies secreted by subclones are suitably isolated from culture medium, ascites, or serum by conventional immunoglobulin purification methods such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. Antibodies can be produced by immunizing an appropriate host animal with an antigen. In one aspect, the antigen is a polypeptide comprising full-length CTLA-4. In another aspect, the antigen is a polypeptide comprising soluble CTLA-4. In one aspect, the antigen is a polypeptide comprising a region corresponding to amino acids 97 (Glu) to 106 (Leu) of human CTLA-4 (extracellular region, SEQ ID NO: 28). In another aspect, the antigen is a polypeptide comprising a region corresponding to amino acids 99 (Met) to 106 (Leu) of human CTLA-4 (extracellular region, SEQ ID NO: 28). The present invention also encompasses antibodies produced by immunizing an animal with an antigen. The antibodies may incorporate any of the features described above for the exemplary anti-CTLA-4 antibodies, either individually or in combination. C. Measurement Methods (Analysis) The anti-CTLA-4 antibodies provided herein can be identified, screened, or their physical / chemical properties and / or biological activities can be clarified using various measurement methods known in the art. 1. Binding and Other Measurement Methods In one aspect, the antibodies of the present invention are tested for their antigen binding activity by conventional methods such as ELISA, Western blotting, and surface plasmon resonance analysis. In another aspect, competition assays can be used to identify antibodies that compete with the anti-CTLA-4 antibodies described herein (e.g., those described in Tables 17, 22, 27, and 32) for binding to CTLA-4. In certain aspects, the presence of an excess of such a competing antibody prevents (e.g., reduces) binding of a reference antibody to CTLA-4 by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more. In some examples, binding is inhibited by at least 80%, 85%, 90%, 95%, or more. In certain aspects, such a competing antibody binds to the same epitope (e.g., a linear or three-dimensional epitope) as the epitope bound by an anti-CTLA-4 antibody described herein (e.g., those described in Tables 17, 22, 27, and 32). Detailed examples of methods for mapping epitopes bound by antibodies are provided by Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, NJ). In an exemplary competition assay, immobilized CTLA-4 is incubated in a solution containing a first labeled antibody that binds to CTLA-4 and a second unlabeled antibody to be tested for its ability to compete with the first antibody for CTLA-4 binding. The second antibody can be present in the fusion tumor supernatant. As a control, immobilized CTLA-4 is incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions permissive for binding of the first antibody to CTLA-4, excess unbound antibody is removed, and the amount of label bound to the immobilized CTLA-4 is measured. If the amount of label bound to immobilized CTLA-4 is substantially reduced in the test sample compared to the control sample, this indicates that the second antibody is competing with the first antibody for CTLA-4 binding. See Harlow and Lane (1988) Antibodies: A Laboratory Manual ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). 2. Activity Measurement Methods In one aspect, methods for measuring the biological activity of anti-CTLA-4 antibodies for identifying biologically active antibodies are provided. Examples of biological activities include cell proliferation inhibition, cytotoxicity (e.g., ADCC / CDC activity, ADCP activity), immunopotentiating activity, and CTLA-4 inhibition. Antibodies exhibiting such biological activities in vivo and / or in vitro are also provided. In certain aspects, the antibodies of the invention are tested for such biological activity. In certain aspects, the antibodies of the present invention are tested for their ability to inhibit cell growth or proliferation in vitro. Methods for measuring inhibition of cell growth or proliferation are well known in the art. A specific cell proliferation assay, exemplified by the "cell killing" assay described herein, measures cell viability. One such assay is the CellTiter-Glo (trademark) Luminescent Cell Viability Assay sold by Promega (Madison, WI). This assay determines the number of viable cells in culture based on the presence of ATP, an indicator of metabolically active cells. See Crouch et al (1993) J. Immunol. Meth. 160:81-88; U.S. Patent No. 6,602,677. The assay can be performed in a 96- or 384-well format compatible with automated high-throughput screening (HTS). See Cree et al (1995) Anticancer Drugs 6:398-404. The analysis process involves adding a single reagent (CellTiter-Glo (registered trademark) reagent) directly to cultured cells. This lyses the cells and generates a luminescent signal through the luciferase reaction. The luminescent signal is proportional to the amount of ATP present, which is directly proportional to the number of viable cells in the culture. Data can be recorded using a luminometer or CCD camera. Luminescence values ​​are expressed as relative light units (RLU). Another method for measuring cell proliferation is the colorimetric "MTT" assay, which utilizes mitochondrial reductase to measure the oxidation of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to triphenylmethyl ester. Like the CellTiter-Glo assay, this assay reveals the number of metabolically active cells present in a cell culture. For example, see Mosmann (1983) J. Immunol. Meth. 65:55-63 and Zhang et al. (2005) Cancer Res. 65:3877-3882. Cells used in any of the above-mentioned in vitro assays include cells or cell lines that naturally express CTLA-4 or have been manipulated to express CTLA-4. Such cells also include cell lines that express CTLA-4 and cell lines that do not normally express CTLA-4 but have been transfected with a nucleic acid encoding CTLA-4. In one aspect, anti-CTLA-4 antibodies are tested for their ability to inhibit cell growth or proliferation in vivo. In a specific aspect, anti-CTLA-4 antibodies are tested for their ability to inhibit tumor growth in vivo. In vivo model systems such as xenografts can be used for such testing. In an exemplary xenograft system, human tumor cells are introduced into appropriately immunocompromised non-human animals, such as athymic "nude" mice. Antibodies of the present invention are administered to these animals, and the ability of the antibodies to inhibit or reduce tumor growth is measured. In specific aspects of the aforementioned xenograft systems, the human tumor cells are derived from human patients. Such xenograft models are commercially available from Oncotest GmbH (Frieberg, Germany). In specific aspects, human tumor cells are introduced into appropriately immunocompromised non-human animals by subcutaneous injection or by transplantation into an appropriate site, such as the mammary fat pad. Any of the above-described assays can also be understood to be performed using the immunoconjugates of the present invention in place of or in addition to the anti-CTLA-4 antibody. A representative assay for measuring ADCC activity of therapeutic antibodies is based on 51 The Cr release analyzer comprises the following steps: the target cells are [ 51 Cr]Na 2CrO 4. Labeling; opsonizing target cells expressing an antigen on their cell surface with an antibody; combining the opsonized, radiolabeled target cells with effector cells at an appropriate ratio in a microtiter plate in the presence or absence of the test antibody; incubating the cell mixture for preferably 16-18 hours at 37°C; recovering the supernatant; and analyzing the supernatant sample for radioactivity. The cytotoxicity of the test antibody is then determined, for example, using the following formula: Specific cytotoxicity (%) = (radioactivity in the presence of antibody - radioactivity in the absence of antibody) / (maximum radioactivity - radioactivity in the absence of antibody) × 100. Graphs can be generated by varying the target cell:effector cell ratio or the antibody concentration. To assess complement activation, a complement-dependent cytotoxicity (CDC) assay can be performed, for example, as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996). Briefly, the polypeptide variants and human complement are diluted to various concentrations in buffer. Cells expressing the antigen to which the polypeptide variants bind are diluted to ∼1 × 10 6 The mixture of peptide variants, diluted human complement and antigen-presenting cells was added to a flat-bottomed 96-well tissue culture plate and incubated at 37°C with 5% CO Incubate for 2 hours to promote complement-mediated cell lysis. Next, add 50 μl of Alamar Blue (Accumed International) to each well and incubate overnight at 37°C. Measure absorbance using a 96-well fluorimeter with excitation at 530 nm and luminescence at 590 nm. Results are expressed as relative fluorescence units (RFUs). Sample concentrations can be calculated from a standard curve, and the activity of the peptide variant of interest is reported as a percentage compared to the non-variant peptide. An exemplary assay for ADCP activity may include the following: coating target bioparticles, such as Escherichia coli-labeled FITC (Molecular Probes) or Staphylococcus aureus-FITC, with a test antibody to form opsonized particles; adding the opsonized particles to THP-1 effector cells (a monocytic cell line available from ATCC) at a ratio of 1:1, 10:1, 30:1, 60:1, 75:1, or 100:1 to allow FcγR-mediated phagocytosis; preferably, incubating the cells with the E. coli-FITC / antibody at 37°C for 1.5 hours; following the incubation, adding trypan blue to the cells (preferably at room temperature for 2-3 minutes) to eliminate fluorescence from external bacteria that have not been internalized and are attached to the cell surface; transferring the cells to FACS buffer (e.g., 0.1% BSA, 0.1% sodium azide in PBS) and analyzing the fluorescence of the THP-1 cells using FACS (e.g., BD FACS Calibur). To analyze the extent of ADCP, it is preferred to set a gate on THP-1 cells and measure the median fluorescence intensity. In a preferred embodiment, ADCP analysis is performed using E. coli-FITC in culture (control), E. coli-FITC and THP-1 cells (used to measure FcγR-independent ADCP activity), and E. coli-FITC, THP-1 cells, and a test antibody (used to measure FcγR-dependent ADCP activity). Antibody-induced cytotoxicity is usually accompanied by antibody binding to the cell surface. Whether the antigen is expressed on the surface of the target cell can be appropriately confirmed by methods known to those skilled in the art, such as FACS. Immune activation can be detected by using cellular immune response or humoral immune response as indicators. Specifically, it includes an increase in the expression of cytokines (e.g., IL-6, G-CSF, IL-12, TNFα and IFNγ, etc.) or their receptors, the promotion of proliferation of immune cells (e.g., B cells, T cells, NK cells, macrophages, monocytes, etc.), hyperactivation, hyperfunction or enhanced cytotoxicity. In particular, T cell activation can be detected by measuring the hyperexpression of activation markers such as CD25, CD69 and ICOS. For example, in patients who have been administered ipilimumab, an anti-CTLA-4 antibody, it is known that after administration, ICOS in the peripheral blood + CD4 + T cells increase, which is believed to be the effect of systemic immune activation caused by the administration of anti-CTLA-4 antibodies (Cancer Immunol. Res. (2013) 1 (4): 229-234). T cell activation requires not only stimulation by the antigen receptor (TCR) but also auxiliary stimulation via CD28. When CD28 on the T cell surface binds to B7-1 (CD80) or B7-2 (CD86) on the surface of antigen-presenting cells, the auxiliary signal is transmitted to the T cell, leading to its activation. Meanwhile, CTLA-4 is expressed on the surface of activated T cells. CTLA-4 has a stronger affinity than CD28 and, because it binds to CD80 or CD86, it preferentially interacts with them over CD28, inhibiting T cell activation. Based on this mechanism of action, the inhibitory activity against CTLA-4 can be measured as the activity of inhibiting the binding of CTLA-4 to CD80 or CD86. In one aspect, the assay for measuring the inhibitory activity against CTLA-4 includes the following steps: a step of binding the purified CTLA-4 protein to a support such as a microwell plate or magnetic beads; a step of adding a test antibody and labeled soluble CD80 or CD86; a step of washing away unbound components; and a step of quantifying the bound labeled CD80 or CD86. Whether the test antibody cross-reacts with CD28 can be confirmed by performing the same assay in which CTLA-4 is replaced with CD28. In another aspect, the inhibitory activity against CTLA-4 can also be measured using a functional assay for detecting T cell activation as described above. For example, in a system that uses cells expressing CD80 or CD86 to stimulate T cell clustering and measure T cell activation, the addition of a test antibody with CTLA-4 inhibitory activity will result in further enhanced T cell activation. D. Immunoconjugates The present invention also provides immunoconjugates comprising an anti-CTLA-4 antibody of the present disclosure conjugated to one or more cytotoxic agents (e.g., chemotherapeutic agents or drugs, proliferation inhibitors, toxins (e.g., protein toxins of bacterial, fungal, plant, or animal origin, enzymatically active toxins, or fragments thereof), or radioactive isotopes). In one embodiment, the immunoconjugate is an antibody-drug conjugate (ADC) formed by conjugating an antibody to one or more drugs including, but not limited to, the following: maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064, and European Patent No. 0,425,235 B1); for example, monomethyl auristatin ( auristatin) agent portion DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483, 5,780,588, and 7,498,298) such as mitotic inhibitors (auristatin); dolastatin; calicheamicin or its derivatives (see U.S. Patent Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., Cancer Res. 53: 3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)); anthracyclines such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem.45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vindesine; taxanes such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; crescent toxin; and CC1065. In another embodiment, although not limited thereto, the immunoconjugate comprises an antibody described herein conjugated to a toxin or fragment thereof comprising the following enzymatic activities: diphtheria A chain, a non-binding active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), lysine A chain, abrin A chain, modeccin A chain, α-sarcin, Aleurites fordii toxin, dianthin toxin, Phytolacca americana toxin (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crocin, saponaria officinalis toxin, officinalis inhibitors, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and crescent toxin. In another aspect, the immunoconjugate comprises an antibody described herein conjugated to a radioactive atom to form a radioconjugate. Various radioisotopes can be used to prepare radioconjugates. For example, 211 At 131 I. 125 I. 90 Y. 186 Re、 188 Re、 153 Sm, 212 Bi, 32 P. 212 Radioactive isotopes of Pb and Lu. When used for the purpose of detecting radioconjugates, the radioconjugate can contain radioactive atoms for scintigraphy (e.g. Tc-99m or 123 I) or spin labels for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging MRI) (for example, here also iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron). Conjugates of antibodies and cytotoxic agents can be made using a variety of bifunctional protein linkers, such as N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (e.g., dimethyl adipimidate HCl), active esters (e.g., disuccinimidyl suberate), and thiocyanate. Suberate), aldehydes (e.g., glutaraldehyde), diazide compounds (e.g., bis(p-azidobenzyl)hexanediamine), bisidiazonium derivatives (e.g., bis-(p-diazoniumbenzyl)ethylenediamine), diisocyanates (e.g., toluene 2,6-diisocyanate), and diactive fluorine compounds (e.g., 1,5-difluoro-2,4-dinitrobenzene). For example, lysine immunotoxins can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1-isocyanatophenyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radionuclides to antibodies. See WO94 / 11026. The linker can be a "cleavable linker" that facilitates release of the cytotoxic drug within cells. For example, an acid-labile linker, a peptidase-sensitive linker, a photolabile linker, a dimethyl linker, or a disulfide-containing linker can be used (Chari et al., Cancer Res. 52: 127-131 (1992); US Pat. No. 5,208,020). The immunoconjugates or ADCs of the present disclosure expressly contemplate conjugates prepared using, but not limited to, cross-linking reagents including BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfonyl) benzoate) (e.g., commercially available from Pierce Biotechnology, Inc., Rockford, IL., USA). E. Methods and Compositions for Diagnosis and Detection In certain aspects, any of the anti-CTLA-4 antibodies provided herein are also useful for detecting the presence of CTLA-4 in a biological sample. As used herein, the term "detecting" encompasses both quantitative and qualitative detection. In certain aspects, the biological sample comprises cells or tissues, e.g., serum, whole blood, plasma, biopsy samples, tissue samples, cell suspensions, saliva, sputum, oral fluid, cerebrospinal fluid, amniotic fluid, ascites, milk, colostrum, mammary secretions, lymph, urine, sweat, tears, gastric fluid, joint fluid, ascites, tears, or mucus. In one aspect, an anti-CTLA-4 antibody for use in a diagnostic or detection method is provided. In yet another aspect, a method for detecting the presence of CTLA-4 in a biological sample is provided. In a specific aspect, the method comprises: contacting an anti-CTLA-4 antibody described herein with the biological sample under conditions that allow binding of the anti-CTLA-4 antibody to CTLA-4; and detecting whether a complex is formed between the anti-CTLA-4 antibody and CTLA-4. This method can be an in vitro method or an in vivo method. In one aspect, the anti-CTLA-4 antibody is used to select subjects suitable for treatment with the anti-CTLA-4 antibody, for example, when CTLA-4 is a biomarker for selecting patients. The antibodies of the present invention can be used, for example, to examine the state of immune response or diagnose immune system dysfunction. In certain aspects, labeled anti-CTLA-4 antibodies are provided. Labels include, but are not limited to, directly detectable labels or moieties (e.g., fluorescent labels, colorimetric labels, high electron density labels, chemiluminescent labels, and radioactive labels) and moieties that are indirectly detected, such as through enzyme reactions or intermolecular interactions (e.g., enzymes or ligands). Exemplary labels, although not limited thereto, include the following: radioisotopes; 32 P. 14 C. 125 I. 3 H and 131 I. Luminophores such as rare earth chelates or fluorescein and its derivatives, rhodamine and its derivatives, dansyl chloride, umbelliferone, luciferases such as firefly luciferase and bacterial luciferase (U.S. Patent No. 4,737,456), luciferin, 2,3-dihydrophthalazinedione, horseradish peroxidase (HRP), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, monosaccharide oxidases (such as glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), uricase, and xanthine oxidase. oxidase), those linked to enzymes that oxidize pigment precursors using hydrogen peroxide (e.g., HRP, lactoperoxidase, or microperoxidase), biotin / avidin, spin labels, phage labels, stable free radicals, and the like. F. Pharmaceutical Formulations Pharmaceutical formulations of the anti-CTLA-4 antibodies described herein are prepared by mixing an antibody having a desired purity with one or more pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)) in the form of a lyophilized preparation or an aqueous solution. Pharmaceutically acceptable carriers are generally non-toxic to the recipient in the amounts and concentrations used, but are not limited thereto. Examples include, but are not limited to, buffers such as phosphates, citrates, and other organic acids; antioxidants such as ascorbic acid and methionine; preservatives (octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride); chloride); phenolic, butyl, or benzyl alcohol; alkyl parabens such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol; small molecule (less than approximately 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, aspartic acid, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, and sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers described herein further include interstitial drug dispersants such as soluble neutral-active hyaluronidase glycoproteins (sHASEGPs) (e.g., human soluble PH-20 hyaluronidase glycoproteins such as rHuPH20 (HYLENEX (registered trademark), Baxter International, Inc.)). Specific exemplary sHASEGPs and methods of use thereof (including rHuPH20) are described in U.S. Patent Application Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one embodiment, sHASEGPs are combined with one or more additional glycosaminoglycans, such as chondroitinase. Exemplary freeze-dried antibody formulations are described in US Pat. No. 6,267,958. Aqueous antibody formulations include those described in US Pat. No. 6,171,586 and WO 2006 / 044908, the latter formulation comprising a histidine-acetate buffer. The formulations described herein may contain more than one active ingredient, as necessary for the specific indication being treated. Preferably, the active ingredients have complementary activities that do not adversely affect each other. Such active ingredients are appropriately combined in amounts effective for the intended purpose. Active ingredients can be encapsulated in microcapsules prepared by droplet formation (coacervation) or interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or microemulsions. This technique is described in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Ed. (1980). A preferred example of a sustained-release preparation comprises a semipermeable matrix of a solid hydrophobic polymer containing the antibody, such as a film or a microcapsule. Preparations for in vivo administration are generally sterile. Sterility is readily achieved, for example, by filtration through sterile filtration membranes. G. Therapeutic Methods and Therapeutic Compositions The anti-CTLA-4 antibodies provided herein can be used in therapeutic methods. In one aspect, an anti-CTLA-4 antibody is provided for use as a pharmaceutical. In another aspect, an anti-CTLA-4 antibody is provided for use in the treatment of tumors. In a specific aspect, an anti-CTLA-4 antibody is provided for use in a therapeutic method. In a specific aspect, the present invention provides an anti-CTLA-4 antibody for use in a method for treating a subject having a tumor, i.e., a method comprising administering to the subject an effective amount of the anti-CTLA-4 antibody. In one such aspect, the method further comprises administering to the subject an effective amount of at least one additional therapeutic agent (e.g., as described below). In another aspect, the present invention provides an anti-CTLA-4 antibody for use in cell damage. In a specific aspect, the present invention provides an anti-CTLA-4 antibody for use in a method for damaging cells in a subject, i.e., a method comprising administering to the subject an effective amount of the anti-CTLA-4 antibody for cell damage. In yet another aspect, the present invention provides an anti-CTLA-4 antibody for use in immune activation. In a specific aspect, the present invention provides an anti-CTLA-4 antibody for use in a method for immunoactivation in a subject, comprising administering to the subject an effective amount of the anti-CTLA-4 antibody for immune activation. The "subject" in any of the above aspects is preferably a human. In certain aspects, the tumor is a solid tumor. In solid tumors, tumor cells typically proliferate into clusters, forming the bulk of the tumor tissue. Furthermore, in vivo tumor tissue often contains infiltrates of immune cells, such as lymphocytes, which also form part of the tumor tissue. In certain aspects, immune cells, particularly regulatory T (Treg) cells, infiltrate the tumor tissue. In one aspect, cell damage is caused by ADCC activity, CDC activity, or ADCP activity. In one aspect, damage is caused to cells expressing CTLA-4 on their cell surface. In another aspect, the damaged cells are Treg cells. In a specific aspect, damage is caused to Treg cells infiltrating the tumor tissue. In one aspect, damage to Treg cells results in immune activation (via relief of Treg cell immunosuppression). In another aspect, immune activation (particularly anti-tumor immunity) is activated in the tumor tissue. In certain aspects, the immune activation is activation of T cells. In another aspect, the extent of the pharmaceutical effect of the anti-CTLA-4 antibodies of the present invention varies depending on the tissue within an individual. In certain aspects, the extent of the effect varies depending on the concentration of adenosine-containing compounds within the tissue. In yet another aspect, the effect is greater in tissues with high concentrations of adenosine-containing compounds compared to tissues with low concentrations of adenosine-containing compounds. Examples of tissues with high concentrations of adenosine-containing compounds include tumor tissue. Examples of tissues with low concentrations of adenosine-containing compounds include non-tumor tissues such as normal tissue. In some aspects, greater immune activation occurs in tumor tissues compared to non-tumor tissues. This difference in response need not be observed at the full dose of the anti-CTLA-4 antibody, but rather within a specific range of doses. In another aspect, immune activation occurs at a lower dose in tumor tissues compared to non-tumor tissues. In another aspect, therapeutic effects are observed at doses below the point at which side effects are observed. In certain aspects, the so-called therapeutic effect refers to the manifestation of an anti-tumor effect (for example, tumor regression, induction of cell death or inhibition of proliferation of tumor cells, etc.), and the so-called side effect refers to the onset of autoimmune diseases (including damage to normal tissues caused by excessive immune response). In another aspect, the extent of the pharmaceutical effect achieved by an anti-CTLA-4 antibody of the present invention varies depending on whether the antibody exhibits CTLA-4 binding activity that is dependent on an adenosine-containing compound (i.e., varies with the concentration of the adenosine-containing compound). In certain aspects, the anti-CTLA-4 antibody of the present invention exhibits CTLA-4 binding activity that increases with increasing concentration of the adenosine-containing compound. In certain aspects, a control anti-CTLA-4 antibody is one that lacks concentration-dependent CTLA-4 binding activity. In specific aspects, an antibody lacking concentration-dependent CTLA-4 binding activity for an adenosine-containing compound means an antibody whose CTLA-4 binding activity in the presence and absence of the adenosine-containing compound differs by, for example, less than 2-fold, less than 1.8-fold, less than 1.5-fold, less than 1.3-fold, less than 1.2-fold, or 1.1-fold. The anti-CTLA-4 antibodies of the present invention and the control anti-CTLA-4 antibodies should have substantially equal CTLA-4 binding activities in the presence of a sufficient amount of adenosine-containing compound. In certain situations, the anti-CTLA-4 antibodies of the present invention and a control anti-CTLA-4 antibody exhibit different effects as pharmaceuticals. In certain aspects, the effects as pharmaceuticals differ in tissues with low concentrations of adenosine compounds. Examples of tissues with low concentrations of adenosine compounds include non-tumor tissues such as normal tissue. Anti-CTLA-4 antibodies can also be provided as pharmaceutical formulations containing these antibodies. In certain aspects, in tissues with low concentrations of adenosine compounds, the anti-CTLA-4 antibodies of the present invention exhibit a lower degree of immune activation than the control anti-CTLA-4 antibody. In certain aspects, in tissues with low concentrations of adenosine compounds, a higher dose of the anti-CTLA-4 antibody of the present invention is required for immune activation than the control anti-CTLA-4 antibody. In certain aspects, in tissues with low concentrations of adenosine compounds, the anti-CTLA-4 antibody of the present invention exhibits a lower degree of side effects than the control anti-CTLA-4 antibody. In certain aspects, side effects are observed with higher doses of the anti-CTLA-4 antibodies of the invention in tissues with lower concentrations of adenosine compounds, compared to a control anti-CTLA-4 antibody. This difference in response need not be observed in all tissues (e.g., in all tissues with low concentrations of adenosine compounds) but may be observed in only some tissues. In certain aspects, the side effect is an autoimmune disorder (including damage to normal tissues due to an excessive immune response). In certain aspects, the anti-CTLA-4 antibodies of the present invention and a control anti-CTLA-4 antibody have substantially equivalent pharmaceutical effects achieved through each antibody. In certain aspects, the pharmaceutical effects are substantially equivalent in tissues with high concentrations of adenosine compounds. Examples of tissues with high concentrations of adenosine compounds include tumor tissue. Anti-CTLA-4 antibodies can be provided as pharmaceutical formulations containing these antibodies. In certain aspects, the degree of immune activation achieved by the anti-CTLA-4 antibodies of the present invention and a control anti-CTLA-4 antibody in tissues with high concentrations of adenosine compounds is substantially equivalent. In certain aspects, the dosage required for immune activation in tissues with high concentrations of adenosine compounds is substantially equivalent between the anti-CTLA-4 antibodies of the present invention and a control anti-CTLA-4 antibody. In certain aspects, the degree of therapeutic effect achieved by the anti-CTLA-4 antibodies of the present invention and a control anti-CTLA-4 antibody in tissues with high concentrations of adenosine compounds is substantially equivalent. In certain aspects, in tissues containing high concentrations of adenosine compounds, the dosages of the anti-CTLA-4 antibodies of the invention and a control anti-CTLA-4 antibody are substantially equivalent when a therapeutic effect is observed. In certain aspects, the therapeutic effect is an anti-tumor effect (e.g., tumor regression, induction of cell death, or inhibition of proliferation of tumor cells). In a specific embodiment, the tumor is selected from the group consisting of carcinoma, lymphoma, blastoma, sarcoma and leukemia. In another embodiment, the tumor is selected from the group consisting of lung cancer, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colorectal cancer, rectal cancer, colon cancer, breast cancer, liver cancer, stomach cancer, pancreatic cancer, kidney cancer, prostate cancer, ovarian cancer, thyroid cancer, bile duct cancer, peritoneal cancer, mesothelioma, squamous cell carcinoma, cervical cancer, endometrial cancer, bladder cancer, esophageal cancer, head and neck cancer, nasopharyngeal cancer, salivary gland tumor, thymoma, skin cancer, basal cell tumor, melanoma, malignant melanoma, anal cancer, penile cancer, testicular cancer, Wilms' tumor, ovarian cancer ... tumor), acute myeloid leukemia (including acute myelocytic leukemia, acute myeloblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia and acute monocytic leukemia), chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma (including Birch's lymphoma, chronic lymphocytic leukemia, mycosis fungoides, mantle cell lymphoma, follicular lymphoma, diffuse large cell lymphoma, marginal zone lymphoma, hairy cell leukemia plasmacytoma, peripheral T-cell lymphoma and adult T The invention further comprises a method for treating a patient with a tumor selected from the group consisting of: hematopoietic stem cell leukemia / lymphoma, Langerhans cell histiocytosis, multiple myeloma, myelodysplastic syndrome, brain tumor (including glioma, astrocytoma, glioblastoma, meningioma, and ependymoma), neuroblastoma, retinoblastoma, osteosarcoma, Kaposi's sarcoma, Ewing's sarcoma, angiosarcoma, and hemangiopericytoma. In certain aspects, the tumor can be selected from the group consisting of lung cancer, colorectal cancer, colon cancer, breast cancer, liver cancer, pancreatic cancer, kidney cancer, bladder cancer, head and neck cancer, and melanoma. In another aspect, the present invention provides use of an anti-CTLA-4 antibody in the manufacture or preparation of a pharmaceutical. In one aspect, the pharmaceutical is for use in treating tumors. In another aspect, the pharmaceutical is for use in a method of treating tumors, comprising administering an effective amount of a pharmaceutical to a subject having a tumor. In one of these aspects, the method further comprises administering to the subject at least one additional effective amount of a therapeutic agent (e.g., as described below). In another aspect, the pharmaceutical is for use in injuring cells. In another aspect, the pharmaceutical is for use in a method of injuring cells in a subject, comprising administering to the subject an effective amount of a pharmaceutical for cell injuring. In another aspect, the pharmaceutical is for use in an immune activation method. In yet another aspect, the pharmaceutical is for use in a method of activating immunity in a subject, comprising administering to the subject an effective amount of a pharmaceutical for immune activation. In any of the above aspects, the "subject" may be a human. In yet another aspect, the present invention provides a method for treating a tumor. In one aspect, the method comprises administering an effective amount of an anti-CTLA-4 antibody to a subject having such a tumor. In one of these aspects, the method further comprises administering to the subject an effective amount of at least one additional therapeutic agent (e.g., as described below). In any of the above aspects, the "subject" may be a human. In another aspect, the present invention provides a method for damaging cells in a subject. In one aspect, the method comprises administering to the subject an effective amount of an anti-CTLA-4 antibody for cell damage. In another aspect, the present invention provides a method for immune activation in a subject. In one aspect, the method comprises administering to the subject an effective amount of an anti-CTLA-4 antibody for immune activation. In one aspect, the "subject" is a human. In yet another aspect, the present invention provides a pharmaceutical formulation (pharmaceutical composition) comprising any of the anti-CTLA-4 antibodies provided herein (e.g., for use in any of the above-described treatment methods). In one aspect, the pharmaceutical formulation (pharmaceutical composition) comprises any of the anti-CTLA-4 antibodies provided herein and a pharmaceutically acceptable carrier. In one aspect, the present invention provides a pharmaceutical formulation (pharmaceutical composition) for use in treating tumors. In one aspect, the present invention provides a pharmaceutical formulation (pharmaceutical composition) for use in damaging cells. In one aspect, the present invention provides a pharmaceutical formulation (pharmaceutical composition) for stimulating immune activation. In another aspect, the pharmaceutical formulation (pharmaceutical composition) comprises any of the anti-CTLA-4 antibodies provided herein and at least one additional therapeutic agent (e.g., as described below). In yet another aspect, the present invention provides a method for preparing a medicament or pharmaceutical preparation, comprising the step of mixing any of the anti-CTLA-4 antibodies provided herein with a pharmaceutically acceptable carrier (e.g., for use in any of the aforementioned therapeutic methods). In one aspect, the method for preparing a medicament or pharmaceutical preparation further comprises the step of adding at least one additional therapeutic agent to the medicament or pharmaceutical preparation. The antibodies of the present invention can be used alone or in combination with other therapeutic agents. For example, the antibodies of the present invention can be administered concurrently with at least one additional therapeutic agent. In certain aspects, the additional therapy is an immune checkpoint inhibitor, an EGFR inhibitor, a HER2 inhibitor, or a chemotherapeutic agent. Examples of immune checkpoint inhibitors include anti-CTLA-4 inhibitors, anti-PD-1 inhibitors, anti-PD-L1 inhibitors, anti-PD-L2 inhibitors, anti-TIM-3 inhibitors, anti-LAG-3 inhibitors, anti-TIGIT inhibitors, anti-BTLA inhibitors, and anti-VISTA inhibitors. Examples of anti-CTLA-4 inhibitors include ipilimumab and tremelimumab. Examples of anti-PD-1 inhibitors include nivolumab and pembrolizumab. Examples of anti-PD-L1 inhibitors include atezolizumab, durvalumab, and avelumab. Examples of anti-PD-L2 inhibitors include anti-PD-L2 inhibitory antibodies. Examples of anti-TIM-3 inhibitors include, for example, anti-TIM-3 inhibitory antibodies. Examples of anti-LAG-3 inhibitors include, for example, anti-LAG-3 inhibitory antibodies. Examples of anti-TIGIT inhibitors include, for example, anti-TIGIT inhibitory antibodies. Examples of anti-BTLA inhibitors include, for example, anti-BTLA inhibitory antibodies. Examples of anti-VISTA inhibitors include, for example, anti-VISTA inhibitory antibodies. Examples of EGFR inhibitors include, for example, cetuximab, panitumumab, nimotuzumab, necitumumab, and zalutumumab. Examples of HER2 inhibitors include, for example, trastuzumab, trastuzumab emtansine, and pertuzumab. Combination therapy as described above includes combined administration (of two or more therapeutic agents in the same or separate formulations) and single administration. In the case of single administration, the antibody of the present invention can be administered before, simultaneously with, and / or after the administration of the additional therapeutic agent. In one aspect, the anti-CTLA-4 antibody and the additional therapeutic agent are administered within about 1 month, or within about 1, 2, or 3 weeks, or within about 1, 2, 3, 4, 5, or 6 days of each other. The antibodies of the present invention can also be used in combination with radiation therapy. The antibodies of the present invention (and any additional therapeutic agents) can be administered by any suitable means, including parenteral administration, intrapulmonary administration, and nasal administration, or intralesional administration in the case of desired local treatment. Parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Administration can be accomplished, in part, by any preferred route of injection, such as intravenous or subcutaneous injection, depending on whether the administration is short-term or long-term. Although not limited thereto, various dosing regimens, including single administration or repeated administration at various time points, single rapid administration (bolus injection), and pulse injection, are contemplated herein. The antibodies of the present invention are formulated, administered, and cast in a manner consistent with good medical practice. From this point of view, factors to be considered include: the specific disease being treated, the specific mammal being treated, the clinical symptoms of each patient, the cause of the disease, the delivery site of the agent, the method of administration, the administration regimen, and other factors known to medical practitioners. Antibodies are optionally but not necessarily formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents will depend on the amount of antibody present in the preparation, the type of disorder or treatment, and the other factors mentioned above. These are generally used in the same dosage and route of administration as described in this specification, or in about 1 to 99% of the dosage described in this specification, or in any dosage level based on experience / clinically appropriate judgment. For disease prevention or treatment, the appropriate dosage of the antibodies of the present invention (when used alone or in combination with one or more additional therapeutic agents) depends on the type of disease being treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for prophylactic or therapeutic purposes, the patient's medical history, their clinical history and response to the antibody, and the attending physician's discretion. The antibody is preferably administered to the patient once or over a continuous course. Depending on the type and severity of the disease, an initial dose of approximately 1 μg / kg to 15 mg / kg (e.g., 0.1 mg / kg to 10 mg / kg) of the antibody can be used as a candidate for administration to the patient, whether administered as a single or multiple separate doses or by continuous infusion. A typical daily dose depends on the aforementioned factors and may range from approximately 1 μg / kg to 100 mg / kg or more. In cases of repeated administration over several days or longer, treatment is typically continued until disease symptoms are suppressed to the desired level, depending on the condition. An exemplary dosage of the antibody is in the range of about 0.05 mg / kg to about 10 mg / kg. Thus, one or more doses of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg, or 10 mg / kg (or any combination thereof) can be administered to the patient. Such doses can be administered intermittently, for example, every week or every three weeks (e.g., such that the patient receives about 2 to about 20, or, for example, about 6, doses of the antibody). Following a high initial loading dose, one or more lower doses can be administered. The progress of this therapy is easily monitored using conventional techniques and measurements. It should be understood that any of the above-described formulations or treatment methods can be practiced using the immunoconjugates of the present invention in place of or in addition to anti-CTLA-4 antibodies. The anti-CTLA-4 antibodies of the present specification can be administered by administering or incorporating nucleic acids encoding the anti-CTLA-4 antibodies into living organisms using a vector or the like, thereby directly expressing the anti-CTLA-4 antibodies in vivo. However, they can also be administered without using a vector. Examples of vectors include viral vectors and plasmid vectors, and further examples include adenovirus (Adenoviridae) vectors. Nucleic acids encoding the anti-CTLA-4 antibodies can be administered directly into living organisms, or cells into which nucleic acids encoding the anti-CTLA-4 antibodies have been introduced can be administered into living organisms. For example, anti-CTLA-4 antibodies can be administered by chemically modifying mRNA encoding the anti-CTLA-4 antibodies to improve their stability in vivo, and then directly administering the mRNA to humans to express the anti-CTLA-4 antibodies in vivo (see EP2101823B and WO2013 / 120629). Alternatively, B cells that have been transfected with nucleic acids encoding anti-CTLA-4 antibodies can be administered (Sci Immunol. (2019) 4 (35), eaax0644). Alternatively, bacteria that have been transfected with nucleic acids encoding anti-CTLA-4 antibodies can be administered (Nature Reviews Cancer (2018) 18, 727-743). As a non-limiting example of a technology that can be combined with the anti-CTLA-4 antibodies of this specification, the use of anti-CTLA-4 antibodies to produce T cells that secrete T cell redirecting antibodies is exemplified (Trends Immunol. (2019) 40 (3) 243-257). As a non-limiting example of a method for producing such a T cell, a method of introducing a nucleic acid encoding a bispecific antibody into effector cells such as T cells by genetic modification technology can be cited, wherein the bispecific antibody comprises: a binding region for any of the constituent subunits of the T cell receptor (TCR) complex on T cells, particularly a binding region for the CD3ε chain of CD3; and an antigen-binding region of an anti-CTLA-4 antibody. H. Products. In another aspect, the present invention provides a product comprising a device for treating, preventing, and / or diagnosing the aforementioned disorders. The product comprises a container and a label or instructions attached to the container. Preferred containers include bottles, vials, syringes, and IV (intravenous) solution bags. Containers can be made of a variety of materials, including glass and plastic. The container can hold the composition alone or in combination with other compositions effective for treating, preventing, and / or diagnosing a condition. Furthermore, the container can have a sterile connection port (for example, the container can be an intravenous solution bag or vial with a stopper puncturable for subcutaneous injection). At least one active ingredient in the composition is an antibody of the present invention. The label or instructions disclose the use of the composition for treating a selected condition. Furthermore, the product may comprise (a) a first container containing a composition comprising an antibody of the present invention; and (b) a second container containing a composition comprising another cytotoxic agent or other therapeutic agent. The product of this aspect of the present invention may further include instructions for use, which disclose that the composition can be used to treat a specific condition. Alternatively, or in addition, the product may further include a second (or third) container containing a pharmaceutically acceptable buffer such as sterile water for injection (BWFI), phosphate-buffered saline, a linker solution, and a dextrose solution. From a commercial or user perspective, the product may further include other desired equipment, such as other buffers, diluents, filters, needles, and syringes. It should be understood that any of the above products may include the immunoconjugate of the present invention in place of or in addition to the anti-CTLA-4 antibody. In one aspect, the present invention provides an isolated polypeptide comprising a mutant Fc region. In some aspects, the polypeptide is an antibody. In some aspects, the polypeptide is an Fc fusion protein. In specific aspects, the mutant Fc region comprises at least one amino acid residue alteration (e.g., substitution) compared to the corresponding sequence in an Fc region of a native sequence or reference variant sequence (sometimes collectively referred to herein as a "parent" Fc region). A native sequence Fc region is typically constructed as a homodimer composed of two identical polypeptide chains. The amino acid alterations in the mutant Fc region of the present invention can be introduced into either or both polypeptide chains of the parent Fc region. In some aspects, the present invention provides mutant Fc regions that have altered function compared to the parental Fc region. In specific aspects, the mutant Fc regions of the present invention have enhanced binding activity to Fcγ receptors compared to the parental Fc region. In specific aspects, the mutant Fc regions of the present invention have enhanced binding activity to at least one Fcγ receptor selected from the group consisting of FcγRIa, FcγRIIa, FcγRIIb, and FcγRIIIa compared to the parental Fc region. In some aspects, the mutant Fc regions of the present invention have enhanced binding activity to FcγRIIa. In some aspects, the mutant Fc regions of the present invention have enhanced binding activity to FcγRIIIa. In yet another aspect, the mutant Fc regions of the present invention have enhanced binding activity to FcγRIIa and FcγRIIIa. In another aspect, the mutant Fc regions of the present invention have enhanced ADCC activity, CDC activity, or ADCP activity compared to the parental Fc region. In some aspects, the mutant Fc region of the present invention comprises at least one amino acid alteration at at least one position selected from the group consisting of positions 234, 235, 236, 298, 330, 332, and 334, as represented by EU numbering. Alternatively, amino acid alterations described in International Publications WO2013 / 002362 or WO2014 / 104165 can also be used in the present invention. In specific aspects, the binding activity of the parental Fc region and the mutant Fc region can be expressed using KD (dissociation constant) values. In one aspect, the ratio of [KD value of the parental Fc region for FcγRIIa] / [KD value of the mutant Fc region for FcγRIIa] is, for example, 1.5 or greater, 2 or greater, 3 or greater, 4 or greater, 5 or greater, 6 or greater, 7 or greater, 8 or greater, 9 or greater, 10 or greater, 15 or greater, 20 or greater, 25 or greater, 30 or greater, 40 or greater, or 50 or greater. In another aspect, FcγRIIa can be FcγRIIa R or FcγRIIa H. Alternatively, it can be both. Therefore, the KD value of the Fc region for FcγRIIa can be the KD value of the Fc region for FcγRIIa R or the KD value of the Fc region for FcγRIIa H. Alternatively, it can be the sum or average of the two. In one aspect, the ratio of [binding activity of the parental Fc region to FcγRIIIa] / [binding activity of the mutant Fc region to FcγRIIIa] is, for example, 2 or more, 3 or more, 5 or more, 10 or more, 20 or more, 30 or more, 50 or more, 100 or more, 200 or more, 300 or more, 500 or more, 1×10 3 Above, 2×10 3 Above, 3×10 3 Above or 5×10 3 In another embodiment, FcγRIIIa may be FcγRIIIa F or FcγRIIIa V. Alternatively, it may be both. Therefore, the KD value of the Fc region for FcγRIIIa may be the KD value of the Fc region for FcγRIIIa F or the KD value of the Fc region for FcγRIIIa V. Alternatively, it may be the sum or average of the two. In one embodiment, the KD value of the mutant Fc region for FcγRIIa is, for example, 1.0×10 -6 M or less, 5.0×10 -7 M or less, 3.0×10 -7 M or less, 2.0×10 -7 M or less, 1.0×10 -7 M or less, 5.0×10 -8 M or less, 3.0×10 -8 M or less, 2.0×10 -8 M or less, 1.0×10 -8 M or less, 5.0×10 -9 M or less, 3.0×10 -9 M or less, 2.0×10 -9 M or less or 1.0×10 -9 M or less. In another aspect, FcγRIIa may be FcγRIIa R or FcγRIIa H. Alternatively, it may be both. In one aspect, the KD value of the mutant Fc region for FcγRIIIa is, for example, 1.0×10 -6 M or less, 5.0×10 -7 M or less, 3.0×10 -7 M or less, 2.0×10 -7 M or less, 1.0×10 -7 M or less, 5.0×10 -8 M or less, 3.0×10 -8 M or less, 2.0×10 -8 M or less, 1.0×10 -8 M or less, 5.0×10 -9 M or less, 3.0×10 -9 M or less, 2.0×10 -9 M, 1.0×10 -9 M or less, 5.0×10 -10 M or less, 3.0×10 -10 M or less, 2.0×10 -10 M or 1.0×10 -10 M or less. In another aspect, FcγRIIIa may be FcγRIIIa F or FcγRIIIa V. Furthermore, it may be both. In another aspect, the binding activities of the parental Fc region and the mutant Fc region can be expressed as kd (Dissociation rate constant) values ​​instead of KD values. In another aspect, the binding activity of the parental Fc region and the mutant Fc region can also be expressed as the amount of Fcγ receptor binding per unit amount of the Fc region. For example, in surface plasmon resonance analysis, the amount of Fcγ receptor binding to the Fc region immobilized on the sensor chip and the amount of Fcγ receptor binding rebound thereto are each measured as a response unit (RU). The amount of Fcγ receptor binding here is divided by the amount of Fc region binding, and the resulting value can be defined as the amount of Fcγ receptor binding per unit amount of the Fc region. The specific method for measuring and calculating the binding amount is described in the Examples below. In some aspects, the ratio of [binding amount of the mutant Fc region to FcγRIIa] / [binding amount of the parental Fc region to FcγRIIa] is, for example, 1.5 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, 40 or more, or 50 or more. In some aspects, the ratio of [binding amount of the mutant Fc region to FcγRIIIa] / [binding amount of the parental Fc region to FcγRIIIa] is, for example, 2 or more, 3 or more, 5 or more, 10 or more, 20 or more, 30 or more, 50 or more, 100 or more, 200 or more, 300 or more, 500 or more, 1×10 3 Above, 2×10 3 Above, 3×10 3 Above or 5×10 3 above. In certain aspects, KD values, kd values, binding amount values, etc. indicated herein are measured or calculated by surface plasmon resonance analysis at 25° C. or 37° C. (for example, see Reference Example 8 of this specification). In certain aspects, the mutant Fc regions of the present invention exhibit increased selectivity for activating Fcγ receptors over inhibitory Fcγ receptors compared to the parental Fc region. In other words, compared to the parental Fc region, the mutant Fc regions of the present invention exhibit significantly enhanced binding activity for activating Fcγ receptors compared to inhibitory Fcγ receptors. In certain aspects, the activating Fcγ receptor is at least one Fcγ receptor selected from the group consisting of FcγRIa, FcγRIIa R, FcγRIIa H, FcγRIIIa F, and FcγRIIIa V, and the inhibitory Fcγ receptor is FcγRIIb. In some aspects, the mutant Fc regions of the present invention exhibit increased selectivity for FcγRIIa over FcγRIIb. In some aspects, the mutant Fc regions of the present invention exhibit increased selectivity for FcγRIIIa over FcγRIIb. In yet another aspect, the mutant Fc regions of the present invention have improved selectivity between FcγRIIa and FcγRIIb and between FcγRIIIa and FcγRIIb. In some aspects, the mutant Fc region of the present invention comprises at least one amino acid alteration at at least one position selected from the group consisting of positions 236, 239, 268, 270, and 326, as represented by EU numbering. Alternatively, the amino acid alterations described in International Publications WO2013 / 002362 or WO2014 / 104165 can also be used in the present invention. In certain aspects, the binding activity of the parental Fc region and the mutant Fc region can be expressed as a KD (dissociation constant) value. Aspects for binding activity to FcγRIIa and FcγRIIIa are as described above. In one aspect, the ratio of [KD value of the parental Fc region for FcγRIIb] / [KD value of the mutant Fc region for FcγRIIb] is, for example, 10 or less, 5 or less, 3 or less, 2 or less, 1 or less, 0.5 or less, 0.3 or less, 0.2 or less, or 0.1 or less. In another aspect, the binding activity of the parental Fc region and the mutant Fc region can be expressed as a kd (dissociation rate constant) value, instead of a KD value. In another aspect, the binding activity of the parental Fc region and the mutant Fc region can also be expressed as the amount of Fcγ receptor binding per unit amount of the Fc region as described above. In some aspects, the ratio of [FcγRIIb binding by the mutant Fc region] / [FcγRIIb binding by the parent Fc region] is, for example, 10 or less, 5 or less, 3 or less, 2 or less, 1 or less, 0.5 or less, 0.3 or less, 0.2 or less, or 0.1 or less. In some aspects, the amount of FcγRIIb binding by the mutant Fc region is, for example, 0.5 or less, 0.3 or less, 0.2 or less, 0.1 or less, 0.05 or less, 0.03 or less, 0.02 or less, 0.01 or less, 0.005 or less, 0.003 or less, 0.002 or less, or 0.001 or less. In certain aspects, enhanced selectivity between activating and inhibitory Fcγ receptors refers to enhanced selectivity for binding activity to activating Fcγ receptors relative to binding activity to inhibitory Fcγ receptors. In other words, it refers to an increase in the ratio of binding activity to activating Fcγ receptors relative to binding activity to inhibitory Fcγ receptors (A / I ratio). This ratio (A / I ratio) is used as an indicator of excellent effector function, and polypeptides with a high A / I ratio can be evaluated as having excellent effector function. The Fcγ receptor binding activity of parental and mutant Fc regions can be expressed using KD values, kd values, or the amount of Fcγ receptor binding per unit amount of the Fc region. The A / I ratio can be expressed using the KD value, kd value, or binding amount as follows: [KD value for inhibitory Fcγ receptor] / [KD value for active Fcγ receptor], [kd value for inhibitory Fcγ receptor] / [kd value for active Fcγ receptor], or [bound amount for active Fcγ receptor] / [bound amount for inhibitory Fcγ receptor], respectively. In one aspect, the A / I ratio of the mutant Fc region of the present invention is increased by 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 1.6 times or more, 1.7 times or more, 1.8 times or more, 1.9 times or more, 2 times or more, 3 times or more, 4 times or more, 5 times or more, 6 times or more, 7 times or more, 8 times or more, 9 times or more, 10 times or more, 20 times or more, 30 times or more, 40 times or more, 50 ...6 times or more, 8 times or more, 9 times or more, 10 times or more, 20 times or more, 30 times or more, 40 times or more, 50 times or more, 6 times or more, 6 times or more, 8 times or more, 9 times or more, 10 times or more, 20 times or more, 30 times or more, 40 times or more, 50 times or more, 6 times or more, 6 times or more, 8 times or more, 50 times or more, 6 times or more, 7 times or more, 8 More than 100 times, more than 70 times, more than 80 times, more than 90 times, more than 100 times, more than 200 times, more than 300 times, more than 400 times, more than 500 times, more than 600 times, more than 700 times, more than 800 times, more than 900 times, more than 1000 times, more than 2000 times, more than 3000 times, more than 4000 times, more than 5000 times, more than 6000 times, more than 7000 times, more than 8000 times, more than 9000 times or more than 10000 times. In one aspect, the A / I ratio of the mutant Fc region of the present invention is 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 200 or more, 300 or more, 400 or more, 500 or more, 600 or more, 700 or more, 800 or more, 900 or more, 1000 or more, 2000 or more, 3000 or more, 4000 or more, 5000 or more, 6000 or more, 7000 or more, 8000 or more, 9000 or more, 10000 or more, 11000 or more, 12000 or more, 13000 or more, 14000 or more, or 15000 or more. In one aspect, the A / I ratio is the ratio of binding activity to FcγRIa relative to binding activity to FcγRIIb, the ratio of binding activity to FcγRIIa relative to binding activity to FcγRIIb, the ratio of binding activity to FcγRIIIa relative to binding activity to FcγRIIb, or the ratio of [the sum or average of two or three of the binding activity to FcγRIa, the binding activity to FcγRIIa, and the binding activity to FcγRIIIa] relative to binding activity to FcγRIIb. In specific aspects, FcγRIIa is FcγRIIa R, FcγRIIa H, or both, and therefore, the binding activity to FcγRIIa is the sum or average of the binding activity to FcγRIIa R, the binding activity to FcγRIIa H, or both. In a specific aspect, FcγRIIIa is FcγRIIIa F, FcγRIIIa V, or both. Therefore, the binding activity to FcγRIIIa is the sum or average of the binding activity to FcγRIIIa F, the binding activity to FcγRIIIa V, or both. In some aspects, the mutant Fc regions of the invention comprise amino acid alterations at the following positions: (i) positions 234, 235, 236, 239, 268, 270, and 298, by EU numbering, in a first polypeptide of a parent Fc region; and (ii) positions 270, 298, 326, and 334, by EU numbering, in a second polypeptide of a parent Fc region. In specific aspects, the mutant Fc regions of the invention further comprise an amino acid alteration at position 326, by EU numbering, in the first polypeptide of the parent Fc region. In specific aspects, the mutant Fc regions of the invention further comprise an amino acid alteration at position 236, by EU numbering, in the second polypeptide of the parent Fc region. In specific aspects, the mutant Fc regions of the invention further comprise an amino acid alteration at position 332, by EU numbering, in the first polypeptide of the parent Fc region. In a specific aspect, the mutant Fc region of the present invention further comprises an amino acid alteration at position 330, as indicated by EU numbering, in the first polypeptide of the parent Fc region. In a specific aspect, the mutant Fc region of the present invention further comprises an amino acid alteration at position 332, as indicated by EU numbering, in the second polypeptide of the parent Fc region. In a specific aspect, the mutant Fc region of the present invention further comprises an amino acid alteration at position 330, as indicated by EU numbering, in the second polypeptide of the parent Fc region. Alternatively, the amino acid alterations described in International Publications WO2013 / 002362 or WO2014 / 104165 can also be used in the present invention. In some aspects, the mutant Fc regions of the invention comprise amino acid alterations at the following positions: (i) positions 234, 235, 236, 239, 268, 270, 298, and 330, by EU numbering, in a first polypeptide of a parent Fc region; and (ii) positions 270, 298, 326, 330, and 334, by EU numbering, in a second polypeptide of a parent Fc region. In specific aspects, the mutant Fc regions of the invention further comprise an amino acid alteration at position 326, by EU numbering, in the first polypeptide of the parent Fc region. In specific aspects, the mutant Fc regions of the invention further comprise an amino acid alteration at position 236, by EU numbering, in the second polypeptide of the parent Fc region. In specific aspects, the mutant Fc regions of the invention further comprise an amino acid alteration at position 332, by EU numbering, in the first polypeptide of the parent Fc region. In certain aspects, the mutant Fc region of the present invention further comprises an amino acid alteration at position 332, as represented by EU numbering, in the second polypeptide of the parent Fc region. In certain aspects, or alternatively, the amino acid alterations described in International Publications WO2013 / 002362 or WO2014 / 104165 can also be used in the present invention. In certain aspects, the mutant Fc regions of the present invention have improved stability compared to the parental Fc region. In certain aspects, stability refers to thermodynamic stability. The thermodynamic stability of a polypeptide can be assessed using, for example, an indicator such as the Tm value. The Tm value can be measured using methods known to those skilled in the art, such as CD (circular dichroism), DSC (differential scanning calorimetry), and DSF (differential scanning fluorimetry). In one aspect, the Tm value of the CH2 region of the mutant Fc region of the present invention is increased by 0.1°C or greater, 0.2°C or greater, 0.3°C or greater, 0.4°C or greater, 0.5°C or greater, 1°C or greater, 2°C or greater, 3°C or greater, 4°C or greater, 5°C or greater, or 10°C or greater, compared to the parental Fc region. In some aspects, the mutant Fc regions of the present invention comprise at least one amino acid alteration at at least one position selected from the group consisting of positions 250 and 307, as represented by EU numbering, in the first and / or second polypeptides of the parent Fc region. Alternatively, the amino acid alterations described in International Publication No. WO2013 / 118858 can also be used in the present invention. In a specific aspect, the mutant Fc region of the present invention is composed of two polypeptide chains with distinct sequences. In yet another aspect, the mutant Fc region of the present invention promotes heterodimerization between a first polypeptide and a second polypeptide. When heterodimeric proteins are produced using recombinant methods, it is preferred that the distinct polypeptide chains preferentially assemble to form heterodimers rather than identical polypeptide chains assemble to form homodimers. Whether the mutant Fc region promotes heterodimerization can be determined, for example, by separating homodimers and heterodimers from the produced mutant Fc region using chromatography or other methods and determining the ratio of their respective components. In some aspects, the mutant Fc regions of the present invention comprise at least one amino acid alteration at at least one position selected from the group consisting of positions 349, 356, 366, 368, 407, and 439, as represented by EU numbering, in the first and / or second polypeptides of the parent Fc region. Alternatively, the amino acid alterations described in International Publications WO2006 / 106905 or WO1996 / 027011 can also be used in the present invention. In certain aspects, the mutant Fc regions of the present invention have enhanced FcRn binding activity at acidic pH. In some aspects, acidic pH refers to pH 4.0-6.5. In yet another aspect, the acidic pH is at least one selected from the group consisting of pH 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, and 6.5. In certain aspects, the acidic pH is pH 5.8. In some aspects, the mutant Fc region of the present invention comprises at least one amino acid alteration at at least one position selected from the group consisting of positions 428, 434, 436, 438, and 440, as represented by EU numbering, in the first and / or second polypeptide of the parent Fc region. Alternatively, the amino acid alterations described in International Publication No. WO2016 / 125495 can also be used in the present invention. In one aspect, the mutant Fc region of the invention comprises at least one amino acid alteration at at least one position selected from the group consisting of positions 234, 235, 236, 239, 250, 268, 270, 298, 307, 326, 330, 332, 334, 349, 356, 366, 368, 407, 428, 434, 436, 438, 439, and 440 by EU numbering. In one aspect, the mutant Fc region of the invention comprises amino acid alterations at positions 234, 235, 236, 239, 268, 270, 298, 326, and 334, as indicated by EU numbering. In a specific aspect, the mutant Fc region of the invention comprises amino acid alterations at positions 234, 235, 236, 239, 268, 270, and 298, as indicated by EU numbering, in a first polypeptide of a parent Fc region, and (ii) amino acid alterations at positions 270, 298, 326, and 334, as indicated by EU numbering, in a second polypeptide of a parent Fc region. In another specific aspect, the mutant Fc region of the invention comprises amino acid alterations at (i) positions 234, 235, 236, 239, 268, 270, 298, and 326 by EU numbering in a first parent Fc region polypeptide, and (ii) positions 236, 270, 298, 326, and 334 by EU numbering in a second parent Fc region polypeptide. In one aspect, the mutant Fc region of the invention comprises amino acid alterations at positions 234, 235, 236, 239, 268, 270, 298, 326, 330, and 334, as indicated by EU numbering. In a specific aspect, the mutant Fc region of the invention comprises amino acid alterations at positions 234, 235, 236, 239, 268, 270, 298, and 330, as indicated by EU numbering, in a first polypeptide of a parent Fc region, and (ii) amino acid alterations at positions 270, 298, 326, 330, and 334, as indicated by EU numbering, in a second polypeptide of a parent Fc region. In one aspect, the mutant Fc region of the invention comprises amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, 326, and 334, as indicated by EU numbering. In a specific aspect, the mutant Fc region of the invention comprises (i) amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, and 307, as indicated by EU numbering, in a first polypeptide of a parent Fc region; and (ii) amino acid alterations at positions 250, 270, 298, 307, 326, and 334, as indicated by EU numbering, in a second polypeptide of a parent Fc region. In another specific aspect, the mutant Fc region of the invention comprises (i) amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, and 326 by EU numbering in a first parent Fc region polypeptide; and (ii) amino acid alterations at positions 236, 250, 270, 298, 307, 326, and 334 by EU numbering in a second parent Fc region polypeptide. In one aspect, the mutant Fc region of the invention comprises amino acid alterations at positions 234, 235, 236, 239, 268, 270, 298, 326, 330, 332, and 334, as indicated by EU numbering. In a specific aspect, the mutant Fc region of the invention comprises (i) amino acid alterations at positions 234, 235, 236, 239, 268, 270, 298, 330, and 332, as indicated by EU numbering, in a first polypeptide of a parent Fc region; and (ii) amino acid alterations at positions 236, 270, 298, 326, 330, 332, and 334, as indicated by EU numbering, in a second polypeptide of a parent Fc region. In one aspect, the mutant Fc region of the invention comprises amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, 326, 330, 332, and 334 as indicated by EU numbering. In a specific aspect, the mutant Fc region of the invention comprises (i) amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, 330, and 332 as indicated by EU numbering in a first polypeptide of a parent Fc region; and (ii) amino acid alterations at positions 236, 250, 270, 298, 307, 326, 330, 332, and 334 as indicated by EU numbering in a second polypeptide of a parent Fc region. In another specific aspect, the mutant Fc region of the invention comprises (i) amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, and 326 by EU numbering in a first parent Fc region polypeptide; and (ii) amino acid alterations at positions 236, 250, 270, 298, 307, 326, 330, 332, and 334 by EU numbering in a second parent Fc region polypeptide. In one aspect, the mutant Fc region of the invention comprises amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, 326, 332, and 334, as indicated by EU numbering. In a specific aspect, the mutant Fc region of the invention comprises (i) amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, 326, and 332, as indicated by EU numbering, in a first polypeptide of a parent Fc region; and (ii) amino acid alterations at positions 236, 250, 270, 298, 307, 326, 332, and 334, as indicated by EU numbering, in a second polypeptide of a parent Fc region. In one aspect, the mutant Fc region of the invention comprises amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, 326, 332, and 334, as indicated by EU numbering. In a specific aspect, the mutant Fc region of the invention comprises (i) amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, and 332, as indicated by EU numbering, in a first polypeptide of a parent Fc region; and (ii) amino acid alterations at positions 250, 270, 298, 307, 326, 332, and 334, as indicated by EU numbering, in a second polypeptide of a parent Fc region. In one aspect, the mutant Fc region of the invention comprises amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, 326, 330, and 334, as indicated by EU numbering. In a specific aspect, the mutant Fc region of the invention comprises (i) amino acid alterations at positions 234, 235, 236, 239, 250, 268, 270, 298, 307, and 330, as indicated by EU numbering, in a first polypeptide of a parent Fc region; and (ii) amino acid alterations at positions 250, 270, 298, 307, 326, 330, and 334, as indicated by EU numbering, in a second polypeptide of a parent Fc region. In another embodiment, the mutant Fc region of the present invention comprises a moiety selected from (i) Tyr or Phe at position 234, Gln or Tyr at position 235, Trp at position 236, Met at position 239, Val at position 250, Asp at position 268, Glu at position 270, Ala at position 298, Pro at position 307, Asp at position 326, and Met at position 237; (i) at least one amino acid change from the group consisting of (i) Ala at position 236, Val at position 250, Glu at position 270, Ala at position 298, Pro at position 307, Asp at position 326, Met or Lys at position 330, Asp or Glu at position 332, and Glu at position 334, as indicated by EU numbering in the second polypeptide of the parent Fc region. In yet another aspect, the mutant Fc region of the present invention further comprises any one of the following amino acid alterations (a) to (f): (a) Lys at position 356 by EU numbering in the first polypeptide of the parent Fc region, and Glu at position 439 by EU numbering in the second polypeptide of the parent Fc region; (b) Glu at position 439 by EU numbering in the first polypeptide of the parent Fc region, and Lys at position 356 by EU numbering in the second polypeptide of the parent Fc region; (c) Trp at position 366 by EU numbering in the first polypeptide of the parent Fc region, and Ser at position 366, Ala at position 368, and Val at position 407 by EU numbering in the second polypeptide of the parent Fc region; (d) Ser at position 366, Ala at position 368, and Val at position 407, as indicated by EU numbering, in the first polypeptide of the parent Fc region, and Trp at position 366, as indicated by EU numbering, in the second polypeptide of the parent Fc region; (e) Cys at position 349 and Trp at position 366, as indicated by EU numbering, in the first polypeptide of the parent Fc region, and Cys at position 356, Ser at position 366, Ala at position 368, and Val at position 407, as indicated by EU numbering, in the second polypeptide of the parent Fc region; (f) Cys at position 356, Ser at position 366, Ala at position 368, and Val at position 407 according to EU numbering in the first parent Fc region polypeptide, and Cys at position 349 and Trp at position 366 according to EU numbering in the second parent Fc region polypeptide. In another aspect, the mutant Fc region of the present invention further comprises any one of the following amino acid changes (a) to (d) in the first polypeptide and / or the second polypeptide of the parent Fc region: (a) Ala at position 434 as indicated by EU numbering; (b) Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440 as indicated by EU numbering; (c) Leu at position 428, Ala at position 434, Thr at position 436, Arg at position 438, and Glu at position 440 as indicated by EU numbering; (d) Leu at position 428, Ala at position 434, Arg at position 438, and Glu at position 440 as indicated by EU numbering. In a specific aspect, the polypeptide comprising a mutant Fc region of the present invention is the heavy chain constant region of an antibody. In yet another aspect, the present invention provides a polypeptide comprising any one of the amino acid sequences of SEQ ID NOs: 280, 281, 283-305, 308, 309, 311-333. In yet another aspect, the present invention provides a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 308 and a polypeptide chain of SEQ ID NO: 309, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 311 and a polypeptide chain of SEQ ID NO: 312, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 313 and a polypeptide chain of SEQ ID NO: 314, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 315 and a polypeptide chain of SEQ ID NO: 316, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 317 and a polypeptide chain of SEQ ID NO: 318, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 319 and a polypeptide chain of SEQ ID NO: 320, a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 321 and a polypeptide chain of SEQ ID NO: 322, and a heavy chain constant region comprising a polypeptide chain of SEQ ID NO: 323 and a polypeptide chain of SEQ ID NO: 324. heavy chain constant region, a heavy chain constant region comprising the polypeptide chain of SEQ ID NO: 325 and the polypeptide chain of SEQ ID NO: 326, a heavy chain constant region comprising the polypeptide chain of SEQ ID NO: 327 and the polypeptide chain of SEQ ID NO: 328, a heavy chain constant region comprising the polypeptide chain of SEQ ID NO: 330 and the polypeptide chain of SEQ ID NO: 331, a heavy chain constant region comprising the polypeptide chain of SEQ ID NO: 332 and the polypeptide chain of SEQ ID NO: 333, a heavy chain constant region comprising the polypeptide chain of SEQ ID NO: 343 and the polypeptide chain of SEQ ID NO: 344, a heavy chain constant region comprising the polypeptide chain of SEQ ID NO: 345 and the polypeptide chain of SEQ ID NO: 347, a heavy chain constant region comprising the polypeptide chain of SEQ ID NO: 346 and the polypeptide chain of SEQ ID NO: 348, and a heavy chain constant region comprising the polypeptide chain of SEQ ID NO: 350 and the polypeptide chain of SEQ ID NO: 351. The so-called "Fcγ receptor" (referred to as Fcγ receptor, FcγR, or FcgR in this specification) refers to a receptor that can bind to the Fc region of IgG1, IgG2, IgG3, and IgG4 monoclonal antibodies, and actually means any member of the protein family encoded by the Fcγ receptor gene. In humans, this family includes: FcγRI (CD64), including isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), including isoforms FcγRIIa (including allotypes H131 (H-type) and R131 (R-type)), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16), including isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIIb-NA1 and FcγRIIIb-NA2), and further includes, but is not limited to, all human FcγRs, FcγR isoforms, or allotypes that have not yet been discovered. FcγRIIb1 and FcγRIIb2 have been reported as splice variants of human FcγRIIb. Furthermore, a splice variant called FcγRIIb3 has been reported (J Exp Med, 1989, 170:1369-1385). In addition to these splice variants, human FcγRIIb also includes all splice variants registered with NCBI, NP_001002273.1, NP_001002274.1, NP_001002275.1, NP_001177757.1, and NP_003992.3. Furthermore, human FcγRIIb includes all previously reported genetic polymorphisms (Arthritis Rheum. 48:3242-3252 (2003); Kono et al., Hum. Mol. Genet. 14:2881-2892 (2005); and Kyogoju et al., Arthritis Rheum. 46:1242-1254 (2002)) in addition to FcγRIIb, as well as all genetic polymorphisms to be reported in the future. There are two allotypes of FcγRIIa, one of which has histidine at position 131 (H-type) and the other of which has arginine at position 131 (R-type) (Warrmerdam, J. Exp. Med. 172: 19-25 (1990)). FcγRs include, but are not limited to, those derived from humans, mice, rats, rabbits, and monkeys and may be derived from any organism. Mouse FcγRs include, but are not limited to, FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), and FcγRIII-2 (CD16-2), as well as any mouse FcγR or FcγR isoform. The amino acid sequence of human FcγRI is described in SEQ ID NO: 131 (NP_000557.1), the amino acid sequence of human FcγRIIa is described in SEQ ID NO: 132 (AAH20823.1), SEQ ID NO: 142, SEQ ID NO: 143, or SEQ ID NO: 150, the amino acid sequence of human FcγRIIb is described in SEQ ID NO: 151 (AAI46679.1), SEQ ID NO: 169, or SEQ ID NO: 172, the amino acid sequence of human FcγRIIIa is described in SEQ ID NO: 174 (AAH33678.1), SEQ ID NO: 175, SEQ ID NO: 176, or SEQ ID NO: 177, and the amino acid sequence of human FcγRIIIb is described in SEQ ID NO: 178 (AAI28563.1). Unlike Fcγ receptors, which belong to the immunoglobulin superfamily, human FcRn is structurally similar to polypeptides of the major histocompatibility complex (MHC) class I, sharing 22-29% sequence identity with class I MHC molecules (Ghetie et al., Immunol. Today (1997) 18(12), 592-598). FcRn is expressed as a heterodimer consisting of a soluble β chain or light chain (β2 microglobulin) and a complexed transmembrane α chain or heavy chain. Like MHC, the α chain of FcRn consists of three extracellular domains (α1, α2, and α3), with a short cytoplasmic domain that retains the protein on the cell surface. The α1 and α2 regions interact with the FcRn-binding domain of the antibody Fc region (Raghavan et al. (Immunity (1994) 1, 303-315). The amino acid sequence of human FcRn is described in SEQ ID NO: 179 (NP_004098.1), and the amino acid sequence of β2 microglobulin is described in SEQ ID NO: 180 (NP_004039.1). As used herein, the term "parent Fc region" refers to the Fc region prior to the introduction of the amino acid modificatio...

Claims

1. Use of an anti-CTLA-4 antibody in the preparation of a pharmaceutical composition for the treatment of tumors, the anti-CTLA-4 antibody comprising: (1) a VH sequence of sequence identification number 140 and a VL sequence of sequence identification number 146; (2) a VH sequence of sequence identification number 141 and a VL sequence of sequence identification number 146; (3) a VH sequence of sequence identification number 140 and a VL sequence of sequence identification number 147; (4) a VH sequence of sequence identification number 141 and a VL sequence of sequence identification number 147; (5) A first variable region containing the VH sequence with sequence number 140 and the VL sequence with sequence number 146, and a second variable region containing the VH sequence with sequence number 141 and the VL sequence with sequence number 146; or (6) A first variable region containing the VH sequence with sequence number 140 and the VL sequence with sequence number 147, and a second variable region containing the VH sequence with sequence number 141 and the VL sequence with sequence number 147; wherein the tumor is colorectal cancer or colon cancer.

2. As in the purpose of request item 1, wherein, The pharmaceutical composition contains a pharmaceutically acceptable carrier.

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