Anti-ctla-4 antibodies and related binding molecules and methods and uses thereof

Abstract

Provided are novel monoclonal antibodies or antibody fragments against protein cytotoxic T-lymphocyte- associated protein 4 (CTLA-4). The antibodies or antibody fragments disclosed can be used to provide potent agents for the treatment of cancers via the modulation of human immune function.

Description

ANTI-CTLA-4 ANTIBODIES AND RELATED BINDING MOLECULES AND METHODS AND USES THEREOFCross-Reference to Related Applications

[0001] This application claims priority from U.S. provisional application No. 63 / 532,336 filed August 11, 2023, entitled, “ANTI-CTLA-4 ANTIBODIES AND RELATED BINDING MOLECULES AND METHODS AND USES THEREOF”, the contents of which is incorporated by reference in its entireties.Incorporation by Reference of Sequence Listing

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 281632000240.XML, created August 8, 2024, which is 169,088 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.Field

[0003] The present disclosure provides novel monoclonal antibodies or antibody fragments against protein cytotoxic T-lymphocyte- associated protein 4 (CTLA-4). CTLA-4 is a cell surface protein predominantly expressed on T cells and plays a crucial role in regulating immune responses. The novel antibodies or antibody fragments described may provide potent moieties for modulation of human immune function with potential therapeutic applications in various diseases, including cancer.Background

[0004] Cancer therapies comprise a wide range of therapeutic approaches, including surgery, radiation, and chemotherapy. While the various approaches offer a broad selection of options for treating cancer, many therapeutics suffer from disadvantages, such as a lack of selectivity of targeting cancer cells over normal, healthy cells, and the development of resistance by the cancer to the treatment. Immunotherapy targeting checkpoint molecules has emerged as one of the most compelling approaches for treating patients with cancers, due to promising results from preclinical and clinical trials. Despite this promise, certainimmunotherapies, including CTLA-4 targeting antibodies, have shown limited efficacy in a substantial number of patients and have been associated with unwanted toxicities, including immune-related adverse events. Thus there exists a need for providing improved immunotherapies. The disclosure provided herein addresses this need.Summary

[0005] In some embodiments, provided herein is an anti-cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) antibody or antigen-binding fragment thereof, comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), and a heavy chain complementarity determining region 3 (CDR-H3) contained within any one of SEQ ID NOs: 1-27 and 112, and the VL region comprises a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2) and a light chain complementarity determining region 3 (CDR-L3) contained within any one of SEQ ID NOs: 28-48 and 118, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 49, 57, 68, 74, 89 and 98, respectively.

[0006] In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR- H3 contained within SEQ ID NO: 1, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO: 2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR- Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 3, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:4, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:5, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:6, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:7, and the VL region comprises a CDR-L1, a CDR-L2,and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO:8, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR- Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:9, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 10, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 11, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 12, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 13, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 14, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 15, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 16, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 17, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 18, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 19, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:20, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:21, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 containedwithin SEQ ID NO:22, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 28; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 29; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 30; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 31; the Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 32; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 33; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 34; the VH region comprises a CDR- Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 35; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 36; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 37; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 38; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 39; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 40; the VH region comprises a CDR- Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 41; the VH regioncomprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 42; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 43; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 44; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 45; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 46; the VH region comprises a CDR- Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 23, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 41; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 41; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 41; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 41; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 22, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 41; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 41; the VH region comprises a CDR- Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 23, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 47; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 47; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 47; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 containedwithin SEQ ID NO: 47; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 22, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 47; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 47; the VH region comprises a CDR- Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 23, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 29; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 29; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 29; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 29; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 22, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 29; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 29; the VH region comprises a CDR- Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 23, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 39; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 24, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 39; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 25, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 39; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 26, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 39; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 22, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 39; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 27, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 39; or the VH region comprises a CDR-Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 5, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 48.

[0007] In some embodiments, provided herein is an anti-CTLA-4 antibody or antigenbinding fragment thereof, comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the sequence set forth in any one of SEQ ID NOs: 49-56, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in any one of SEQ ID NOs: 57-67, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in any one of SEQ ID NOs: 68-73; and the VL region comprises a light chain complementarity determining region 1 (CDR- Ll) comprising the sequence set forth in any one of SEQ ID NOs: 74-88, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in any one of SEQ ID NOs: 89-97, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in any one of SEQ ID NOs: 98-100, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 49, 57, 68, 74, 89 and 98, respectively.

[0008] In any of the embodiments herein, the VH region can comprise a heavy chain complementarity determining region 1 (CDR-H1) comprising the sequence set forth in any one of SEQ ID NOs: 50-56, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in any one of SEQ ID NOs: 58-67, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in any one of SEQ ID NOs: 69-73.

[0009] In any of the embodiments herein, the VL region can comprise a light chain complementarity determining region 1 (CDR-L1) comprising the sequence set forth in any one of SEQ ID NOs: 75-88, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in any one of SEQ ID NOs: 90-97, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in any one of SEQ ID NOs: 99-100.

[0010] In any of the embodiments herein, the VH region can comprise a CDR-H1, a CDR- H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 58, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprisea CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 69, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 51, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 50, 59, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 61, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 51, 62, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 50, 63, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 50, 57, and 69, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 53, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 53, 57, and 70, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprisea CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 54, 57, and 71, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 55, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 56, 57, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 64, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 60, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 66, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 71, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 73, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region can comprisea CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 75, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 77, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 78, 90, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 79, 90, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 80, 91, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 78, 89, and 99, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 81, 92, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 82, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 82, 93, and 98, respectively; the VH region can comprisea CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 83, 92, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 100, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 86, 94, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 87, 95, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 96, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 88, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 97, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region can comprisea CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region can comprisea CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region can comprisea CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR- L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; or the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 88, 89, and 100, respectively.

[0011] In any of the embodiments herein, the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least ator about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6, and the VLregion can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12, and the VLregion can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and the VLregion can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or99% identity to SEQ ID NO: 19, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 20, and the VLregion can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 21, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 28; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 30; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be orcan comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 31; the VHregion can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 32; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 33; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 34; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 35; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 36; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 37; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 38; the VHregion can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 40; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 42; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45; the VHregion can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 23, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 25, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 23, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 25, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 23, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24, and the VL region can be orcan comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VHregion can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 25, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 23, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 25, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; or the VH region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and the VL region can be or can comprise an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48.

[0012] In any of the embodiments herein, the VH region and the VL region can be or can comprise: the sequence set forth in SEQ ID NO: 1 and 118, respectively; the sequence set forth in SEQ ID NO: 2 and 118, respectively; the sequence set forth in SEQ ID NO: 3 and 118, respectively; the sequence set forth in SEQ ID NO: 4 and 118, respectively; the sequence set forth in SEQ ID NO: 5 and 118, respectively; the sequence set forth in SEQ ID NO: 6 and 118, respectively; the sequence set forth in SEQ ID NO: 7 and 118, respectively; the sequence set forth in SEQ ID NO: 8 and 118, respectively; the sequence set forth in SEQ ID NO: 9 and 118, respectively; the sequence set forth in SEQ ID NO: 10 and 118, respectively; the sequence set forth in SEQ ID NO: 11 and 118, respectively; the sequence set forth in SEQ ID NO: 12 and 118, respectively; the sequence set forth in SEQ ID NO: 13 and 118, respectively; the sequence set forth in SEQ ID NO: 14 and 118, respectively; the sequence set forth in SEQ ID NO: 15 and 118, respectively; the sequence set forth in SEQ ID NO: 16 and 118, respectively; the sequence set forth in SEQ ID NO: 17 and 118, respectively; the sequence set forth in SEQ IDNO: 18 and 118, respectively; the sequence set forth in SEQ ID NO: 19 and 118, respectively; the sequence set forth in SEQ ID NO: 20 and 118, respectively; the sequence set forth in SEQ ID NO: 21 and 118, respectively; the sequence set forth in SEQ ID NO: 22 and 118, respectively; the sequence set forth in SEQ ID NO: 112 and 28, respectively; the sequence set forth in SEQ ID NO: 112 and 29, respectively; the sequence set forth in SEQ ID NO: 112 and 30, respectively; the sequence set forth in SEQ ID NO: 112 and 31, respectively; the sequence set forth in SEQ ID NO: 112 and 32, respectively; the sequence set forth in SEQ ID NO: 112 and 33, respectively; the sequence set forth in SEQ ID NO: 112 and 34, respectively; the sequence set forth in SEQ ID NO: 112 and 35, respectively; the sequence set forth in SEQ ID NO: 112 and 36, respectively; the sequence set forth in SEQ ID NO: 112 and 37, respectively; the sequence set forth in SEQ ID NO: 112 and 38, respectively; the sequence set forth in SEQ ID NO: 112 and 39, respectively; the sequence set forth in SEQ ID NO: 112 and 40, respectively; the sequence set forth in SEQ ID NO: 112 and 41, respectively; the sequence set forth in SEQ ID NO: 112 and 42, respectively; the sequence set forth in SEQ ID NO: 112 and 43, respectively; the sequence set forth in SEQ ID NO: 112 and 44, respectively; the sequence set forth in SEQ ID NO: 112 and 45, respectively; the sequence set forth in SEQ ID NO: 112 and 46, respectively; the sequence set forth in SEQ ID NO: 23 and 41, respectively; the sequence set forth in SEQ ID NO: 24 and 41, respectively; the sequence set forth in SEQ ID NO: 25 and 41, respectively; the sequence set forth in SEQ ID NO: 26 and 41, respectively; the sequence set forth in SEQ ID NO: 22 and 41, respectively; the sequence set forth in SEQ ID NO: 27 and 41, respectively; the sequence set forth in SEQ ID NO: 23 and 47, respectively; the sequence set forth in SEQ ID NO: 24 and 47, respectively; the sequence set forth in SEQ ID NO: 25 and 47, respectively; the sequence set forth in SEQ ID NO: 26 and 47, respectively; the sequence set forth in SEQ ID NO: 22 and 47, respectively; the sequence set forth in SEQ ID NO: 27 and 47, respectively; the sequence set forth in SEQ ID NO: 23 and 29, respectively; the sequence set forth in SEQ ID NO: 24 and 29, respectively; the sequence set forth in SEQ ID NO: 25 and 29, respectively; the sequence set forth in SEQ ID NO: 26 and 29, respectively; the sequence set forth in SEQ ID NO: 22 and 29, respectively; the sequence set forth in SEQ ID NO: 27 and 29, respectively; the sequence set forth in SEQ ID NO: 23 and 39, respectively; the sequence set forth in SEQ ID NO: 24 and 39, respectively; the sequence set forth in SEQ ID NO: 25 and 39, respectively; the sequence set forth in SEQ ID NO: 26 and 39, respectively;the sequence set forth in SEQ ID NO: 22 and 39, respectively; the sequence set forth in SEQ ID NO: 27 and 39, respectively; or the sequence set forth in SEQ ID NO: 5 and 48, respectively.

[0013] In some embodiments, provided herein is an anti-cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) antibody or antigen-binding fragment thereof, comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region and the VL region can be or can comprise: the sequence set forth in SEQ ID NO: 1 and 118, respectively; the sequence set forth in SEQ ID NO: 2 and 118, respectively; the sequence set forth in SEQ ID NO: 3 and 118, respectively; the sequence set forth in SEQ ID NO: 4 and 118, respectively; the sequence set forth in SEQ ID NO: 5 and 118, respectively; the sequence set forth in SEQ ID NO: 6 and 118, respectively; the sequence set forth in SEQ ID NO: 7 and 118, respectively; the sequence set forth in SEQ ID NO: 8 and 118, respectively; the sequence set forth in SEQ ID NO: 9 and 118, respectively; the sequence set forth in SEQ ID NO: 10 and 118, respectively; the sequence set forth in SEQ ID NO: 11 and 118, respectively; the sequence set forth in SEQ ID NO: 12 and 118, respectively; the sequence set forth in SEQ ID NO: 13 and 118, respectively; the sequence set forth in SEQ ID NO: 14 and 118, respectively; the sequence set forth in SEQ ID NO: 15 and 118, respectively; the sequence set forth in SEQ ID NO: 16 and 118, respectively; the sequence set forth in SEQ ID NO: 17 and 118, respectively; the sequence set forth in SEQ ID NO: 18 and 118, respectively; the sequence set forth in SEQ ID NO: 19 and 118, respectively; the sequence set forth in SEQ ID NO: 20 and 118, respectively; the sequence set forth in SEQ ID NO: 21 and 118, respectively; the sequence set forth in SEQ ID NO: 22 and 118, respectively; the sequence set forth in SEQ ID NO: 112 and 28, respectively; the sequence set forth in SEQ ID NO: 112 and 29, respectively; the sequence set forth in SEQ ID NO: 112 and 30, respectively; the sequence set forth in SEQ ID NO: 112 and 31, respectively; the sequence set forth in SEQ ID NO: 112 and 32, respectively; the sequence set forth in SEQ ID NO: 112 and 33, respectively; the sequence set forth in SEQ ID NO: 112 and 34, respectively; the sequence set forth in SEQ ID NO: 112 and 35, respectively; the sequence set forth in SEQ ID NO: 112 and 36, respectively; the sequence set forth in SEQ ID NO: 112 and 37, respectively; the sequence set forth in SEQ ID NO: 112 and 38, respectively; the sequence set forth in SEQ ID NO: 112 and 39, respectively; the sequence set forth in SEQ ID NO: 112 and 40, respectively; the sequence set forth in SEQ ID NO: 112 and 41, respectively; the sequence set forth in SEQ ID NO: 112 and 42, respectively; the sequence set forth in SEQ ID NO: 112 and 43, respectively; the sequence set forth in SEQ ID NO: 112and 44, respectively; the sequence set forth in SEQ ID NO: 112 and 45, respectively; the sequence set forth in SEQ ID NO: 112 and 46, respectively; the sequence set forth in SEQ ID NO: 23 and 41, respectively; the sequence set forth in SEQ ID NO: 24 and 41, respectively; the sequence set forth in SEQ ID NO: 25 and 41, respectively; the sequence set forth in SEQ ID NO: 26 and 41, respectively; the sequence set forth in SEQ ID NO: 22 and 41, respectively; the sequence set forth in SEQ ID NO: 27 and 41, respectively; the sequence set forth in SEQ ID NO: 23 and 47, respectively; the sequence set forth in SEQ ID NO: 24 and 47, respectively; the sequence set forth in SEQ ID NO: 25 and 47, respectively; the sequence set forth in SEQ ID NO: 26 and 47, respectively; the sequence set forth in SEQ ID NO: 22 and 47, respectively; the sequence set forth in SEQ ID NO: 27 and 47, respectively; the sequence set forth in SEQ ID NO: 23 and 29, respectively; the sequence set forth in SEQ ID NO: 24 and 29, respectively; the sequence set forth in SEQ ID NO: 25 and 29, respectively; the sequence set forth in SEQ ID NO: 26 and 29, respectively; the sequence set forth in SEQ ID NO: 22 and 29, respectively; the sequence set forth in SEQ ID NO: 27 and 29, respectively; the sequence set forth in SEQ ID NO: 23 and 39, respectively; the sequence set forth in SEQ ID NO: 24 and 39, respectively; the sequence set forth in SEQ ID NO: 25 and 39, respectively; the sequence set forth in SEQ ID NO: 26 and 39, respectively; the sequence set forth in SEQ ID NO: 22 and 39, respectively; the sequence set forth in SEQ ID NO: 27 and 39, respectively; or the sequence set forth in SEQ ID NO: 5 and 48, respectively.

[0014] In some embodiments, the VH region comprises one or more amino acid residues selected from the group consisting of: a histidine (H) at position 98, an arginine (R) at position 31, a glutamic acid (E) or a histidine (H) at position 53, a histidine (H) at position 58, and a histidine (H) at position 97, or any combination thereof, and / or the VL region comprises one or more amino acid residues selected from the group consisting of: a histidine (H) at position 27a, a histidine (H) at position 30, a histidine (H) at position 31, and a histidine (H) at position 90, or any combination thereof, where numbering of amino acid residues is by Kabat numbering. In some embodiments, the amino acid residues are mutations (amino acid substitutions) compared to a reference sequence. In any of the embodiments herein, the VH region can comprise one or more mutations selected from the group consisting of: S31R, D53H, D53E, Y58H, and W97H, and / or the VL region comprises one or more mutations selected from the group consisting of: S28H, S31H, S32H, and Q91H, wherein numbering of amino acid residuesis by Kabat numbering. In some embodiments, the reference sequence is a VH sequence set forth in SEQ ID NO: 112 and a VL sequence set forth in SEQ ID NO: 118.

[0015] In any of the some embodiments herein, In any of the embodiments herein, the VH region can comprise L102H (corresponding to histidine at position 98 by Kabat numbering).

[0016] In any of the embodiments herein, the VH region can comprise a CDR-H1, a CDR- H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively. In any of the embodiments herein, the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively. In any of the embodiments herein, the VH region can comprise a CDR- Hl, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively. In any of the embodiments herein, the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively. In any of the embodiments herein, the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively. In any of the embodiments herein, the VH region can comprise a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region can comprise a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively.

[0017] In any of the embodiments herein, the antibody can be a full length antibody. In some embodiments, the full length antibody comprises a constant region (Fc) from an IgAl, IgA2, IgD, IgE, IgGl, IgG2, IgG3, IgG4, or IgM. In some embodiments, the constant region is a human IgGl heavy chain constant region. In some embodiments, the human IgGl heavy chain constant region comprises one or more of mutations selected from the group consisting of G236A, S239D, M252Y, S254T, T256E, A330L, I332E, M428L, and N434S, numbered 1according to the EU numbering system. In any of the embodiments herein, the human IgGl heavy chain constant region can comprise S239D / A330L / I332E mutations, numbered according to the EU numbering system. In any of the embodiments herein, the antibody region can comprise a human IgGl heavy chain constant region comprising S239D / I332E mutations, numbered according to the EU numbering system. In any of the embodiments herein, the antibody region can comprise a human IgGl heavy chain constant region comprising G236A / S239D / A330L / I332E mutations, numbered according to the EU numbering system. In any of the embodiments herein, the antibody region can comprise a human IgGl heavy chain constant region comprising G236A / A330L / I332E mutations, numbered according to the EU numbering system. In any of the embodiments herein, the antibody region can comprise a human IgGl heavy chain constant region comprising M252Y / S254T / T256E mutations, numbered according to the EU numbering system. In any of the embodiments herein, the antibody region can comprise a human IgGl heavy chain constant region comprising M428L / N434S mutations, numbered according to the EU numbering system.

[0018] In any of the embodiments herein, the antibody can be an antigen-binding fragment. In some embodiments, the antigen-binding fragment is selected from the group consisting of a single domain antibody, a single chain antibody, an unibody, a single chain variable fragment (scFv), a Fab fragment, and a F(ab')2 fragment.

[0019] In any of the embodiments herein, the anti-CTLA-4 antibody or antigen-binding fragment thereof can be recombinant. In any of the embodiments herein, the VH region and the VL region can be human or can be from a human protein.

[0020] In any of the embodiments herein, the ratio of dissociation constant for binding at acidic pH (e.g., pH 5.0 to 6.0) to the dissociation constant for binding at physiological pH (e.g., pH 7.35 to 7.45) to human CTLA-4 protein can be greater than 2. In any of the embodiments herein, the antibody or antigen-binding fragment can exhibit a ratio of a dissociation constant for binding at acidic pH (e.g., pH 5.0 to 6.0) to dissociation constant for binding at physiological pH (e.g., pH 7.35 to 7.45) of more than 7. In any of the embodiments herein, the ratio of EC50 value of the antibody or antigen-binding fragment thereof for human CTLA-4 at physiological pH (e.g., pH 7.35 to 7.45) to EC50 value of the antibody or antigen-binding fragment thereof for human CTLA-4 at acidic pH (e.g., pH 5.0 to 6.0) can be greater than 2. In any of the embodiments herein, the antibody or antigen-binding fragment thereof can possess pH dependent binding properties to human CTLA-4 that facilitates the dissociation of antibodyfrom the antibody :CTLA-4 complex upon internalization into a cell, allowing either the antibody, CTLA-4, or both to be recycled instead of being degraded in the lysosome. In any of the embodiments herein, the antibody or antigen-binding fragment thereof can preserve high affinity for CTLA-4 at pH>7, lower affinity at pH 5.5-7, and significantly reduced affinity for CTLA-4 at pH<5.5. In any of the embodiments herein, the antibody or antigen-binding fragment thereof can induce strong deletion of Treg and local T cell activation in tumor microenvironment but minimal systemic T cell activation. In any of the embodiments herein, the antibody or antigen-binding fragment thereof can induce a favorable ratio of Treg cells to T effector cells in the tumor microenvironment. In any of the embodiments herein, the antibody or antigen-binding fragment thereof can induce a favorable ratio of immune cell subsets in the tumor or blood. In any of the embodiments herein, the antibody or antigen-binding fragment can induce a favorable ratio of CTLA-4 expression on immune cell subsets in the tumor or blood. In some embodiments, the immune cell subsets comprise myeloid cells, T cells, CD4+T cells, CD8+T cells, and / or Treg cells.

[0021] In some embodiments, provided herein is a conjugate, comprising the anti-CTLA- 4 antibody or antigen-binding fragment thereof of any of the embodiments herein and a heterologous molecule or moiety. In some embodiments, the heterologous molecule or moiety is a cytotoxic agent, a drug, enzymatically active toxin or fragment thereof, or a radioactive atom.

[0022] In some embodiments, provided herein is a bispecific antibody, comprising the anti- CTLA-4 antibody or antigen-binding fragment thereof of any of the embodiments herein.

[0023] In some embodiments, provided herein is a polynucleotide comprising a nucleic acid encoding the anti-CTLA-4 antibody or antigen-binding domain thereof of any of the embodiments herein.

[0024] In some embodiments, provided herein is a vector, comprising the polynucleotide of any of the embodiments herein. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a retroviral vector or a lentiviral vector.

[0025] In some embodiments, provided herein is a cell comprising the polynucleotide of any of the embodiments herein, or the vector of any of the embodiments herein. In some embodiments, the cell is a mammalian cell.

[0026] In some embodiments, provided herein is a method of producing an antibody comprising culturing the cell of any of the embodiments herein under a condition that producesthe antibody. In some embodiments, the method further comprises recovering the antibody produced by the cell.

[0027] In some embodiments, provided herein is an antibody or antigen-binding fragment thereof produced by the method of any of the embodiments herein.

[0028] In some embodiments, provided herein is a composition comprising the anti-CTLA- 4 antibody or antigen-binding fragment thereof of any of the embodiments herein, the conjugate of any of the embodiments herein, the bispecific antibody of any of the embodiments herein. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient.

[0029] In some embodiments, provided herein is a method of stimulating an immune response in a subject, the method comprising administering to a subject in need thereof the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of the embodiments herein, the conjugate of any of the embodiments herein, the bispecific antibody of any of the embodiments herein or the composition of any of the embodiments herein. In some embodiments, stimulating an immune response treats a disease or condition in the subject.

[0030] In some embodiments, the disease or condition is a cancer.

[0031] In some embodiments, provided herein is a method of cancer immunotherapy, the method comprising administering to a subject in need thereof a therapeutically effective amount of the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of the embodiments herein, the conjugate of any of the embodiments herein, the bispecific antibody of any of the embodiments herein or the composition of any of the embodiments herein. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of the embodiments herein, the conjugate of any of the embodiments herein, the bispecific antibody of any of the embodiments herein or the composition of any of the embodiments herein is administered to the subject in need thereof at about 0.01 pg / kg body weight to about 20 mg / kg body weight.

[0032] In some embodiments, the method further comprises administering to the subject an effective amount of at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is selected from the group consisting of: viral gene therapy, immune checkpoint inhibitors, target therapies, radiation therapies, vaccination therapies, and chemotherapies. In some embodiments, the at least one additional therapeutic agent is selected from the group consisting of: pomalyst, revlimid, lenalidomide,pomalidomide, thalidomide, a DNA-alkylating platinum-containing derivative, cisplatin, 5- fluorouracil, cyclophosphamide, an anti-CD137 antibody, an anti-PD-1 antibody, an anti-PD- L1 antibody, an anti-CD20 antibody, an anti-CD40 antibody, an anti-DR5 antibody, an antiCD Id antibody, an anti-TIM3 antibody, an anti-SLAMF7 antibody, an anti-KIR receptor antibody, an anti-OX40 antibody, an anti-HER2 antibody, an anti-ErbB-2 antibody, an anti- EGFR antibody, cetuximab, rituximab, trastuzumab, pembrolizumab, an antibody drug conjugation, radiotherapy, single dose radiation, fractionated radiation, focal radiation, whole organ radiation, IL- 12, IFNa, GM-CSF, a chimeric antigen receptor, adoptively transferred T cells, an anti-cancer vaccine, and an oncolytic virus. In some embodiments, the method comprises administering to the subject an effective amount of the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of the embodiments herein, the conjugate of any of the embodiments herein, the bispecific antibody of any of the embodiments herein or the composition of any of the embodiments herein prior to a surgery or after a surgery to remove a solid tumor in the subject.Brief Description of the Drawings

[0033] FIGs. 1A-S show results of binding tests of exemplary provided antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. 1A shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB-7, CTLA-4- AB-9, CTLA-4- AB- 10, and CTLA-4- AB- 11) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. IB shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB- 13, CTLA-4- AB- 14, CTLA-4-AB-15, and CTLA-4-AB-16) and reference antibodies for binding to human CTLA- 4 at pH 5 and at pH 7.4. FIG. 1C shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB- 17, CTLA-4-AB-18, CTLA-4-AB-19, and CTLA-4-AB-20) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. ID shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB -21, CTLA-4- AB-22, CTLA-4-AB-23, and CTLA-4- AB-24) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. IE shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB-25, CTLA-4-AB-26, CTLA-4- AB-27, and CTLA-4- AB-28) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. IF shows results of binding tests of anti-CTLA- 4 antibodies (CTLA-4- AB-29, CTLA-4- AB-30, CTLA-4-AB-31, and CTLA-4- AB-32) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. 1G showsresults of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB-34, CTLA-4- AB-35, CTLA- 4-AB-36, CTLA-4-AB-37, CTLA-4-AB-38 and CTLA-4-AB-39) for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. 1H shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB -42, CTLA-4-AB-43, CTLA-4-AB-44, and CTLA-4-AB-45) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. II shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB-8, CTLA-4- AB- 12, CTLA-4- AB-33, and CTLA-4- AB-46) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. 1J shows results of binding tests of anti-CTLA-4 antibody CTLA-4- AB- 47 and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. IK shows results of binding tests of anti-CTLA-4 antibody CTLA-4-AB-48 and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. IL shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB-49, CTLA-4- AB-50, and CTLA-4- AB- 51) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. IM shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB-52, CTLA-4- AB-53, and CTLA-4- AB-54) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. IN shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4-AB-55, CTLA-4- AB-56, and CTLA-4- AB-57) and reference antibodies for binding to human CTLA- 4 at pH 5 and at pH 7.4. FIG. IO shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB-58, CTLA-4- AB-59, and CTLA-4- AB-60) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. IP shows results of binding tests of anti-CTLA- 4 antibodies and reference antibodies (CTLA-4- AB -61, CTLA-4- AB-62, and CTLA-4- AB-63) for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. IQ shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB -64, CTLA-4-AB-65, and CTLA-4-AB-66) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. 1R shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4-AB-67, CTLA-4-AB-68, and CTLA-4- AB -69) and reference antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. IS shows results of binding tests of anti-CTLA-4 antibodies (CTLA-4- AB -70, CTLA-4- AB -71, and CTLA-4- AB -72) and reference antibodies for binding to human CTLA- 4 at pH 5 and at pH 7.4.

[0034] FIGs. 2A-2C show results of binding tests of exemplary provided antibodies for binding to human CTLA-4 at different pH’s. FIG. 2A shows results of binding tests of a reference antibody for binding to human CTLA-4 at pH 5.5, pH 6, pH 6.5, pH 7 and pH 7.4.FIG. 2B shows results of binding tests of CTLA-4-AB-62 for binding to human CTLA-4 at pH 5.5, pH 6, pH 6.5, pH 7 and pH 7.4. FIG. 2C shows results of binding tests of CTLA-4- AB-68 for binding to human CTLA-4 at pH 5.5, pH 6, pH 6.5, pH 7 and pH 7.4.

[0035] FIGs. 3A-3C show effects of anti-CTLA-4 antibodies on CTLA-4 expression in treated human-CTLA-4 expressing Cells. FIG. 3A shows hCTLA-4 expression levels in cells treated with anti-CTLA-4 antibodies. FIG. 3B shows a schematic drawing of the workflow of confocal microscopy. FIG. 3C shows results of confocal microscopy. HEK293-hCTLA-4 cells were incubated with lOpg / mL antibody

[0036] FIGs. 4A-4B show effect of anti-CTLA-4 antibodies on antibody dependent cellular cytotoxicity (ADCC). FIG. 4A shows selection of NK cells. FIG. 4B shows target cell lysis was evaluated at various concentrations of four different antibodies and EC50 values calculated from dose-response curves.

[0037] FIGs. 5A-5E show in vivo anti-tumor efficacy of anti-CTLA-4 antibodies. FIG. 5A shows a schematic drawing of the experimental procedure. FIG. 5B shows tumor volume results of the vehicle, biweekly for 3 weeks, n=8. FIG. 5C shows tumor volume results of reference 1 at 1 mg / kg, biweekly for 3 weeks, n=8. FIG. 5D shows tumor volume results of CTLA-4- AB-68.1 at 1 mg / kg, biweekly for 3 weeks, n=8. FIG. 5E shows tumor volume results of CTLA-4- AB-68.1 at 10 mg / kg, biweekly for 3 weeks, n=8.

[0038] FIGs. 6A-6E show effect of anti-CTLA-4 antibodies on immune cell subsets in the tumor and blood of hCTLA4 knock-in mice. FIG. 6A shows gating strategy for tumor samples to analyze This panel was designed to analyze absolute cell numbers of CD45+, Myeloid , T cells, CD4 T, CD8 T and Treg in tumor of CT26 model in hCTLA4 knock-in mice. FIG. 6B shows gating strategy for blood samples to analyze absolute cell numbers of CD45+, Myeloid, T cells, CD4 T, CD8 T and Treg in blood of CT26 model in hCTLA4 knock-in mice, and the expression level of hCTLA-4 on Treg cells in the blood of CT26 model in hCTLA4 knock-in mice. FIG. 6C shows results of the FCM analysis for tumor samples. One-way ANOVA was used for statistical analysis. When a significant F-statistics (a ratio of treatment variance to the error variance) was obtained, comparisons between group 1 and other groups were carried out with Games-Howell (equal variances not assumed) or Tukey (equal variances assumed) test. * p<0.05; ** p<0.01; *** p<0.001. Error bars represented Standard Error of Mean (SEM). FIG. 6D shows results of the FCM analysis for blood samples showing percentages of myeloid, T cells and T cell subpopulations in CD45+ cells. FIG. 6E shows results of the FCM analysis forblood samples showing percentages of T cell subpopulations in T cells. FIG. 6F shows results of the FCM analysis for blood samples showing cell numbers of CD45+, myeloid, T cells and T cell subpopulations per 100 pL blood. FIG. 6G shows results of the FCM analysis for blood samples showing ratios between T cell subpopulations. CD4Teff refers to CD4T cells other than Treg. FIG. 6H shows MFI of hCTLA4 of Treg cells. One-way ANOVA was used for statistical analysis. When a significant F-statistics (a ratio of treatment variance to the error variance) was obtained, comparisons between group 1 and other groups were carried out with Games-Howell (equal variances not assumed) or Tukey (equal variances assumed) test. * p<0.05; ** p<0.01; *** p<0.001. Error bars represented Standard Error of Mean (SEM).Detailed Description

[0039] The present disclosure concerns anti-CTLA-4 antibodies or antibody fragments (i.e. antigen binding fragment that is able to bind CTLA-4) suitable for therapeutic use. Relative to existing known therapies, some of these anti-CTLA-4 antibodies or antibody fragments confer specific binding properties to human CTLA-4 under different pH conditions. In some embodiments, the disclosed anti-CTLA-4 antibodies or antibody fragments also exhibit physiochemical or biological properties that lead to improved efficacy and safety to anti- CTLA-4 antibodies known in the art. In some embodiments, the provided anti-CTLA-4 antibody, including any antigen binding antibody fragments, can be used to treat cancer.

[0040] Cancer is a disease state of genomic instability caused by the accumulation of point mutations, resulting in behavioral and structural alterations to disaffected cells. Cancer presents in the form of abnormal growths defined by the proliferation of morphologically ambiguous cells that have the potential to invade both proximal and distant tissues, usually in the form of solid state tumors (Hassanpour SH, Dehghani M. Review of cancer from perspective of molecular. Journal of Cancer Research and. Practice. July 2017. doi:10.1016 / j.jcrpr.2017.07.001). Consequently, these tumors severely impact local and global systems in the body, leading to premature death and severe decrease in quality of life, and the increasing prevalence of cancer has spurred significant interest in identifying treatments to reduce or eliminate tumors (Global Burden of Disease 2019 Cancer Collaboration, Kocamik JM, Compton K, et al. Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability- Adjusted Life Years for 29 Cancer GroupsFrom 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019. JAMA Oncol. 2022;8(3):420-444.).

[0041] Historically, tumors have been treated with a plethora of therapeutic approaches, including chemotherapy, radiation, and surgery (Knezevic CE, Clarke W. Cancer chemotherapy: the case for therapeutic drug monitoring. Ther Drug Monit. 2020;42(l):6-19; Baskar R, Lee KA, Yeo R, Yeoh K-W. Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3): 193-199; Sanai N, Berger MS. Surgical oncology for gliomas: the state of the art. Nat Rev Clin Oncol. 2018; 15(2): 112- 125). While their efficacy has improved over time, these strategies have limitations with respect to lack of specificity for targeting cancer cells, development of resistance to treatment, and debilitating side-effects that significantly impact the patient’s quality of life (Gyanani V, Haley JC, Goswami R. Challenges of Current Anticancer Treatment Approaches with Focus on Liposomal Drug Delivery Systems. Pharmaceuticals (Basel). 2021; 14(9)). Hence, there is considerable interest in developing mechanisms for targeted therapy, in which cancer cells can be targeted with minimal collateral damage to healthy cells.

[0042] The immune system is responsible for defending the body against foreign substances, both internal and external , such as pathogens and abnormal cells (Daeron M. The immune system as a system of relations. Front Immunol. 2022; 13:984678). Composed of innate and adaptive immunity, the immune system has impressive flexibility when identifying disease-causing agents. Innate immune cells provide preconfigured responses to broad situations and stimuli (Kaur BP, Secord E. Innate Immunity. Immunol Allergy Clin North Am. 2021;41(4):535-541), and adaptive immune cells provide more tailored responses to each stimulus through learning how to distinguish between previously encountered and new stimuli (Geckin B, Konstantin Fdhse F, Dominguez-Andres J, Netea MG. Trained immunity: implications for vaccination. Curr Opin Immunol. 2022;77: 102190). Because of its capacity to be “trained” to eliminate entities deemed harmful, the adaptive immune system has potential to be utilized for targeted cancer therapy, and the emergence of therapies such as CAR-T serves as compelling evidence of this strategy (Baulu E, Gardet C, Chuvin N, Depil S. TCR- engineered T cell therapy in solid tumors: State of the art and perspectives. Sci Adv. 2023;9(7):eadf3700).

[0043] Central to the immune response are T cells, a type of white blood cell, which act as key orchestrators of immune reactions (Kumar BV, Connors TJ, Farber DL. Human T CellDevelopment, Localization, and Function throughout Life. Immunity. 2018;48(2):202-213). Starting as a hematopoietic stem cell, T cells mature into a variety of differentiated forms that can directly kill threats, recruit other immune cells to assist in the containment and eradication of threats, or mitigate excessive and indiscriminate immune activity that targets otherwise healthy and harmless cells (Shah K, Al-Haidari A, Sun J, Kazi JU. T cell receptor (TCR) signaling in health and disease. Signal Transduct Target Ther. 2021;6(l):412). A unique feature of T cells is their ability to discriminate between healthy and abnormal surface markers, with abnormal marker detection eliciting activation of T cells (Feinerman O, Germain RN, Altan-Bonnet G. Quantitative challenges in understanding ligand discrimination by alphabeta T cells. Mol Immunol. 2008;45(3):619-631).

[0044] T cell activation is tightly regulated to prevent excessive immune responses that could lead to tissue damage and autoimmune disorders. CTLA-4, a protein predominantly expressed on the surface of activated T cells, serves as an important checkpoint molecule for downregulating immune responses.

[0045] CTLA-4 acts by binding to its ligands, CD80 (B7-1) and CD86 (B7-2), on antigen- presenting cells (APCs) (Berg M, Zavazava N. Regulation of CD28 expression on CD8+ T cells by CTLA-4. J Leukoc Biol. 2008;83(4):853-863), thereby attenuating T cell activation and proliferation. The engagement of CTLA-4 with its ligands delivers inhibitory signals to T cells, leading to suppression of immune reactions (Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol. 2001;l(3):220-228). Dysregulation of the CTLA-4 pathway has been implicated in several pathological conditions, including autoimmune diseases as well as cancer, where tumor cells can exploit the immune system’s regulatory mechanisms to evade destruction (Hossen MM, Ma Y, Yin Z, et al. Current understanding of CTLA-4: from mechanism to autoimmune diseases. Front Immunol. 2023; 14: 1198365).

[0046] Mechanistically, CTLA-4 competes with CD28 to bind at CD80 / 86, with CTLA-4 having preferential binding with CD80 / 86 relative to CD28 (Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459-465). However, under conditions favoring CD28 binding to CD80 / 86, a cascade of signaling events leads to the activation and proliferation of naive T-cells in conjunction with stimulation of T cell receptor (TCR) signaling by major histocompability complex II (MHC-II) on APCs, resulting in biological events at the immunological synapse,downstream phosphorylation and post-translational modifications, transcriptional changes, and cytoskeletal remodeling (Frauwirth KA, Riley JL, Harris MH, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16(6):769-777). Upon TCR stimulation, CTLA-4 circulates to the cell surface, but is then internalized by unphosphorylated cytoplasmic domains and either recycled to the plasma membrane or subjected to lysosomal degradation (Qureshi OS, Kaur S, Hou TZ, et al. Constitutive clathrin-mediated endocytosis of CTLA-4 persists during T cell activation. J Biol Chem. 2012;287( 12):9429-9440). Taken together, these findings support a balance between achieving sufficient effector T cell activation to achieve optimal cancer immunotherapeutic effect (CITE) while maintaining sufficient regulatory T cell (Treg) function to mitigate excessive effector T cell activity, which leads to a side effect known as an immune-related adverse event (irAE) (Du X, Liu M, Su J, et al. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res. 2018;28(4):433-447; Ramos- Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020;6(l):38).

[0047] Cancer immunotherapies utilizing surface proteins like CTLA-4 are known as immune checkpoint inhibitors (ICIs), and they serve to induce an antitumor immune response by blocking immune checkpoints that downregulate intratumoral T-cell responses (Ramos- Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers. 2020;6(l ):38). Proof-of-concept experiments supporting anti- CTLA-4 therapy were initially described by James Allison’s research group, which discovered that blockade of CTLA-4 on effector and Treg compartments led to tumor size reduction (Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206(8):1717-1725). In recent years, studies have highlighted the role that soluble CTLA-4 (sCTLA4) plays in cancer progression (Ward EJ, Dahal LN, Wijesekera SK, et al. The soluble isoform of CTLA-4 as a regulator of T-cell responses. Eur J Immunol. 2013;43(5): 1274-1285), particularly sCTLA4’s link to improved growth / survival of cells grown in the presence of primary blood mononuclear cells, suggesting an immunomodulatory effect of CTLA-4 (Kennedy PT, Saulters EL, Duckworth AD, et al. Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity. Mol Ther. 2024;32(2):457-468).

[0048] Based on promising preclinical tumor model studies, the clinical potential of antibodies against CTLA-4 has been explored in different human malignancies. Although anti- CTLA-4 (Ipilimumab, marketed as Yervoy) and Tremelimumab (marketed as Imjudo) have demonstrated efficacy in treating solid tumors such as melanoma, treatment and targeting of CTLA-4 is associated with autoimmune like toxicities (Sharma P, Goswami S, Raychaudhuri D, et al. Immune checkpoint therapy-current perspectives and future directions. Cell. 2023; 186(8): 1652- 1669). Characteristic side effects from inhibition of CTLA-4 are generally called immune-related adverse events (irAEs) and the most common irAEs are skin rash, hepatitis, colitis and endocrinopathies, particularly hypopituitarism (Liu Y, Zheng P. Preserving the CTLA-4 Checkpoint for Safer and More Effective Cancer Immunotherapy. Trends Pharmacol Sci. 2020;41(l):4-12).

[0049] A key challenge in developing therapeutic antibodies against CTLA-4 is to uncouple their desirable effects from their unwanted autoimmune side effects. Without wishing to be bound by any theory, CTLA-4 is recycled between the plasma membrane and endosomes by binding to lipopolysaccharide-responsive and beige-like anchor protein (LRBA). Antibodies that bind CTLA-4 disrupt the recycling process. Consequently, CTLA-4 is systemically directed to lysosomal degradation, and autoimmunity-related adverse effects are developed due to the unstoppable action of cytotoxic T cells. Increasingly, it is recognized that complete loss of CTLA-4 recycling leads to increased irAEs, as the immune system engages in off-target actions that disaffect otherwise healthy cells. Furthermore, current anti-CTLA antibodies fail to sufficiently engage with signaling pathways that enhance effector T cell function, leading to decreased immune response to cancer cells. Strategies to improve CITE while reducing irAEs point to designing therapies that improve both CTLA-4 recycling and antibody affinity for receptors that enhance effector T cell activation. Therefore, there is a desire to improve the therapeutic potential of anti-CTLA-4 antibodies by increasing efficacy while reducing the associated irAEs.

[0050] Recently, engineered next-generation anti-CTLA-4 antibodies have been reported with improved therapeutic characteristics (Zhang Y, Du X, Liu M, et al. Hijacking antibody- induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Res. 2019;29(8):609-627). Antibodies are central components of the immune system that help prevent and control pathogen spread while providing long-term protection from reinfection. They are composed of two identical fragment antigen binding (Fab) domains thatare coupled through a hinge to a fragment crystallizable (Fc) region. The Fabs provide specificity and mediate target antigen binding, while the Fc region interacts with Fcgamma Receptors (FcgR), a class of receptors that deliver either inhibitory or activatory signals to modulate immune cell responses to regulate immune cell activity (Liu R, Oldham RJ, Teal E, Beers SA, Cragg MS. Fc-Engineering for Modulated Effector Functions-Improving Antibodies for Cancer Treatment. Antibodies (Basel). 2020;9(4)). Engagement of these receptors drives antibody effector functions including antibody-dependent cellular cytotoxicity (ADCC), a critical feature underlying the efficacy of anti-CTLA-4 in solid tumors that involves the release of cytotoxic granules by natural killer cells, granulocytes, and myeloid cells to kill target cells (Galvez-Cancino F, Simpson AP, Costoya C, et al. Fey receptors and immunomodulatory antibodies in cancer. Nat Rev Cancer. 2024;24(l):51-71). An example of these beneficial Fc enhancements is afucosylation, a process in which oligosaccharides of the Fc region are removed of focuses - a sugar molecule found in the Fc region of antibodies - that enhances antibody Fc-FcgR interactions, improving T-cell signaling and function (Shinkawa T, Nakamura K, Yamane N, et al. The absence of fucose but not the presence of galactose or bisecting N- acetylgluco s amine of human IgGl complextype oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem. 2003;278(5):3466-3473). Supporting this finding, a recent study showed that modification of anti-CTLA-4 antibody Fc regions led to improved CITE, resulting in improved T cell-mediated targeting of tumor cells independent of Treg depletion (Waight JD, Chand D, Dietrich S, et al. Selective FcyR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens. Cancer Cell.2018;33(6): 1033-1047. e5). Together, these findings support improved FcgR engagement as a potent mechanism of action for improving CITE.

[0051] Given the importance of maintaining global Treg function to reduce irAEs, additional studies have identified means to retain Treg function while inhibiting intratumoral Treg-mediated suppression by pH-dependent disassociation of CTLA-4, allowing for successful recycling of CTLA-4 that consequently reduces irAE occurrence (Zhang Y, Du X, Liu M, et al. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Res. 2019;29(8):609-627; Altman A, Kong K-F. pH- sensitive anti-CTLA4 antibodies: yes to efficacy, no to toxicity. Cell Res. 2019;29(8):601- 602). These molecules provide crucial insights that update and broaden our understanding ofthe signaling dynamics of immune checkpoints. They demonstrate that CTLA-4 trafficking plays an essential role in supporting the inhibitory signaling required to maintain tolerance, and that it may be possible to exploit the specificity of its intracellular routes to reshape the whole signaling network.

[0052] The present disclosure concerns novel anti-CTLA-4 antibodies or antibody fragments suitable for therapeutic use. Some of these antibodies have been engineered using innovative techniques to confer specific binding properties to human CTLA-4 under different pH conditions. In some embodiments, the pH sensitivity of the disclosed antibodies may enable them to selectively engage with CTLA-4 in acidic or neutral pH environments, such as within a tumor microenvironment or endosome of a cell. In some embodiments, the pH sensitivity of the disclosed antibodies may also enable them to dissociate from the target under acidic pH in endosomes, allow physiological CTLA-4 recycling, and reduce adverse effects. By leveraging pH differences between the environments where an antibody may interact with CTLA-4, the disclosed antibodies may provide options for more targeted therapy with reduced irAEs. The disclosed anti-CTLA-4 antibodies or antibody fragments may exhibit distinct physiochemical or biological properties that lead to significant improvements in efficacy and safety relative to anti-CTLA-4 antibodies known in the art.

[0053] In some embodiments, provided anti-CTLA-4 antibodies or antibody fragments thereof possess pH dependent binding properties to human CTLA-4 that facilitates the dissociation of antibody from the antibody:CTLA-4 complex upon internalization into a cell, allowing either the antibody, CTLA-4, or both to be recycled instead of being degraded in the lysosome.

[0054] In some embodiments, the antibody or antigen-binding fragment thereof preserves high affinity for CTLA-4 in neutral pH environments (such as at pH>7), lower affinity in acidic environments (such as at pH 5.5-7 found in early endosomes), and significantly reduced affinity for CTLA-4 at more acidic environments (such as at pH<5.5 found in late endosomes and lysosomes).

[0055] In some embodiments, provided anti-CTLA-4 antibodies or antibody fragments thereof have a lower binding affinity (i.e. greater dissociation constant) to CTLA-4 at an acidic pH as present in endosomes of a cell in comparison with the binding affinity of CTLA-4 present in normal tissue. In some embodiments, the dissociation constant (KD) for binding at acidic pH (e.g., pH 5.0 to 6.0) is higher than the dissociation constant for binding at physiological pH(e.g., e.g. pH 7.35 to 7.45). In some such embodiments, these anti-CTLA-4 antibodies or antibody fragments have reduced side-effects, in comparison with monoclonal anti-CTLA-4 antibodies known in the art. This may permit use of higher dosages of these anti-CTLA-4 antibodies or antibody fragments, thus providing a more effective therapeutic option without a corresponding significant increase in side effects.

[0056] In some embodiments, the provided antibodies can be used to block inhibitory activity of CTLA-4 by CTLA-4-expressing cells including regulatory T cells (Tregs), and in some cases may also mediate depletion of such cells by an ADCC mechanism. In some embodiments, depletion of Tregs in the tumor contributes to anti-tumor efficacy of the provided antibodies. In some embodiments, provided antibodies reduce CTLA-4 mediated signaling in effector T cells and exhibit activity to deplete Tregs in the tumor microenvironment that might otherwise suppress an anti-tumor immune response.

[0057] In some embodiments, the antibody or antigen-binding fragment thereof or a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof induces strong deletion of Treg and local T cell activation in tumor microenvironment but minimal systemic T cell activation. In some embodiments, the antibody or antigen-binding fragment thereof or a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof induces a favorable ratio of Treg cells to T effector cells in the tumor microenvironment.

[0058] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0059] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.I. ANTI-CTLA-4 ANTIBODIES AND ANTIGEN-BINDING FRAGMENTS AND BINDING MOLECULES THEREOF

[0060] Provided herein are anti-CTLA-4 antibodies, including full-length antibodies or antigen-binding fragments, that contain a heavy chain variable region (VH) sequence and a lightchain variable region (VL) sequence as described, or a sufficient antigen-binding portion thereof. In some such embodiments, the VH is the region of the anti-CTLA-4 antibody that comprises the three heavy chain complementarity determining regions (CDRs) and the VL chain is the region of the anti-CTLA-4 antibody that comprises the three light chain CDRs. Among provided anti-CTLA-4 antibodies, including full-length antibodies or antigen-binding fragments, are antibodies that contains a VH region sequence that contains a CDR-H1, a CDR- H2 and a CDR-H3 as described and contains a VL region sequence that contains a CDR-L1, a CDR-L2 and a CDR-L3 as described. In some embodiments, the antibodies include antibodies that specifically bind to CTLA-4, e.g., human CTLA-4. Among the provided anti-CTLA-4 antibodies are human antibodies, or antibodies that are modified from or variant of human antibodies. The antibodies include isolated antibodies. Also provided are CTLA-4-binding molecules containing such antibodies, such as single-chain proteins, fusion proteins, conjugates and / or recombinant receptors such as chimeric antigen receptors. In some embodiments, provided herein is an CTLA-4-targeted antibody-drug conjugate (ADC) comprising an anti-CTLA-4 antibody or antigen binding fragment thereof described herein. In some embodiments, provided herein is a bispecific immune cell engager that is a fusion protein comprising the anti-CTLA-4 antibody or antigen binding fragment thereof described herein. In some embodiments, the bispecific immune cell engager is a bispecific T cell engager. In some aspects, the CTLA-4-binding molecules include isolated molecules.

[0061] Also provided are polynucleotides containing nucleic acids sequences encoding all or a portion of such antibodies, including an antigen-binding fragment, or binding molecule. The provided polynucleotides can be incorporated into constructs, such as deoxyribonucleic acid (DNA) or RNA constructs, such as those that can be introduced into cells for expression of the encoded anti-CTLA-4 antibodies or binding molecules.

[0062] The term “antibody” herein is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments, including fragment antigen binding (Fab) fragments, F(ab’)2 fragments, Fab’ fragments, Fv fragments, recombinant IgG (rlgG) fragments, heavy chain variable (VH) regions capable of specifically binding the antigen, single chain antibody fragments, including single chain variable fragments (scFv), and single domain antibodies e.g., sdAb, sdFv, nanobody, VHH) fragments. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies,fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific or trispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv. Unless otherwise stated, the term “antibody” should be understood to encompass functional antibody fragments thereof also referred to herein as “antigen-binding fragments.” The term also encompasses intact or full-length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD.

[0063] The terms “complementarity determining region,” and “CDR,” synonymous with “hypervariable region” or “HVR,” are known to refer to non-contiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and / or binding affinity. In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3). “Framework regions” and “FR” are known to refer to the non-CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4).

[0064] The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme); Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48 (“Chothia” numbering scheme); MacCallum et al., J. Mol. Biol, 1996; 262:732-745.” (“Contact” numbering scheme); Lefranc MP et al., Dev Comp Immunol, 2003; 27(l):55-77 (“IMGT” numbering scheme); Honegger A and Pliickthun A, J Mol Biol, 2001; 309(3):657-70, (“Aho” numbering scheme); Martin et al., PNAS, 1989; 86(23):9268-9272, (“AbM” numbering scheme); and Ye et al., Nucleic Acids Res. 2013; 41(Web Server issue):W34-40, (“IgBLAST numbering scheme). Details regarding various numbering schemes are also described in, for example, Jarasch et al., Proteins, 2017; 85( 1):65- 71; Martin et al., Bioinformatics tools for antibody engineering. In: Diibel, S. (editor) Handbook of Therapeutic Antibodies, Vol. 1. Wiley-VCH, Weinheim, Germany; Martin, A.C.R. (2010). Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Kontermann, R., Diibel, S. (eds) Antibody Engineering. Springer Protocols Handbooks. Springer, Berlin, Heidelberg; and Martin, ACR, Antibody Information: How to identify the CDRs by looking at a sequence [online] bioinf.org.uk / abs / info.html, all of which areincorporated by reference in their entireties. Various prediction algorithm tools are available and known for numbering antibody residues and CDRs (e.g., AbYsis, Abnum, AbYmod, AbRSA, IgBLAST, IMGT, or ANARCI).

[0065] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, in some cases with insertions. Insertions in the sequence relative to the standard numbering scheme are indicated using insertion letter codes. For example, residues that are inserted between residues L30 and L31 are indicated as L31A, L31B, etc. Deletions in the sequence relative to the standard scheme are accommodated by skipping numbers. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering. For instance, the Chothia numbering scheme is nearly identical to the Kabat numbering scheme, except that insertions are placed at structural positions and topologically equivalents residues do get assigned the same numbers. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme. The AbM scheme is a compromise between Kabat and Chothia definitions based on that used by Oxford Molecular’s AbM antibody modeling software. The IgBLAST scheme is based on matching to germline V, D and J genes, and can be determined using National Center for Biotechnology Information (NCBI)’s IgBLAST tool.

[0066] In some embodiments, Kabat numbering can be determined by known sequence rules as described in, for example, Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. In some embodiments, the Kabat numbering scheme in some aspects can include any of the following rules to designate CDRs: CDR-L1 starts at approximately residue 24 of the light chain, always has a preceding C residue, and always has a following W residue; the end of CDR-L1 is defined by a stretch of 3 residues, where the W residue can be followed by Y, L, or F, followed by Q or L; CDR-1 has a length of 10 to 17 residues; CDR-L2 always starts 16 residues after the end of CDR-L1; the two residues before CDR-L2 are I and Y but can also be V and Y, I and K, or I and F; CDR-L2 is always 7 residues long; CDR-L3 always starts 33 residues after the end of CDR-L2, always has a preceding C residue, and is strictly followed by a F-G-X-G sequence motif, where X is any amino acid; CDR-L3 has a length of7 to 11 residues; CDR-H1 starts at approximately position 26 of the heavy chain; the first amino acid in CDR-H1 is always 9 residues after a conserved C residue; CDR-H1 is followed by an invariant W residue followed by typically V, but also can be I or A; CDR-H1 has a length of 5 to 7 residues; CDR-H2 always starts at 15 residues after the end of CDR-H1; the first residue in CDR-H2 is usually preceded by the sequence motif L-E-W-I-G but a number of variations exist; the end of CDR-H2 is defined by a motif of 3 residues - the first residue of the motif of 3 residues can be either K or R, the second residue of the motif of 3 residues can be L, I, V, F, T, or A, the third residue of the motif of 3 residues can be T, S, I, or A; CDR-H2 has a length of 16 to 19 residues; CDR-H3 always starts 33 residues after the end of CDR-H2 and is always 3 residues after a C residue - the first residue of CDR-H3 is preceded by the conserved C residue followed by two residues, which are usually A-R; the residues following CDR-H3 is strictly followed by a W-G-X-G sequence motif, where the X is any amino acid; CDR-H3 typically has a length of 3 to 25 residues; CDR-H3 can be much longer than 25 residues.

[0067] In some cases, according to the Chothia numbering scheme, exact boundary positions of certain CDRs can differ based on different definitions for the CDRs (See e.g., Martin, ACR, Antibody Information: How to identify the CDRs by looking at a sequence [online] bioinf.org.uk / abs / info.html). For example, in some instances, the boundary positions for CDR-F1 according to Chothia numbering can be F26— F32 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Fesk A.M. J Mol Biol, 1987; 196(4):901-17). In some instances, the boundary positions for CDR-F1 can be E25--E32 (Al-Fazikani et al., J Mol Biol, 1997; 273(4):927-48). In some instances, the boundary positions for CDR-F2 can be F50— F52 and for CDR-F3 can be F91— F96 (Chothia et al., Science, 1986; 233(4765):755-8; Chothia C. and Fesk A.M. J Mol Biol, 1987; 196(4):901-17; and Al-Fazikani et al., J Mol Biol, 1997; 273(4):927-48). In some instances, the boundary positions for CDR-H1 according to Chothia numbering can be H26— H32 (Chothia et al., Science, 1986; 233(4765):755-8; Chothia C. and Fesk A.M. J Mol Biol, 1987; 196(4):901-17; and Al-Fazikani et al., J Mol Biol, 1997; 273(4):927-48). In some instances, the boundary positions for CDR-H2 can be H53— H55 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Fesk A.M. J Mol Biol, 1987, 196(4):901-17); H52a-H55 (Tramontano et al., J Mol Biol, 1990, 215(1): 175-82), or H52— H56 (Al-Fazikani et al., J Mol Biol., 1997; 273(4):927-48). In some instances, the boundary positions for CDR-H3 can be H96— H101 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Fesk A.M. J Mol Biol., 1987; 196(4):901-17). In someinstances, the boundary positions for CDR-H3 can be H92— H104 (Morea et al., Biophys Chem, 1997; 68(1-3): 9-16 and Morea et al., J Mol Biol., 1998; 275(2): 269-94).

[0068] Table 1, below, exemplifies exemplary numbering and lists exemplary position boundaries of CDR-L1, CDR-L2, CDR-L3 and CDR-H1, CDR-H2, CDR-H3 as identified by Kabat, Chothia, AbM, and Contact schemes, respectively. For CDR-H1, residue numbering is listed using both the Kabat and Chothia numbering schemes. FRs are located between CDRs, for example, with FR-L1 located before CDR-L1, FR-L2 located between CDR-L1 and CDR- L2, FR-L3 located between CDR-L2 and CDR-L3 and so forth. It is noted that because the shown Kabat numbering scheme places insertions at H35A and H35B, the end of the Chothia CDR-H1 loop when numbered using the shown Kabat numbering convention varies betweenH32 and H34, depending on the length of the loop.1 - Kabat etal. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD2 - Al-Lazikani et al., J Mol Biol., 1997; 273(4):927-48).

[0069] Thus, unless otherwise specified, a “CDR” or “complementary determining region,” or individual specified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) complementary determining region as defined by any of the aforementioned schemes, or other known schemes. For example, where it is stated that a particular CDR (e.g., a CDR-H3) contains the amino acid sequence of a corresponding CDR in a given VH or VL region amino acid sequence, it is understood that such a CDR has a sequence of the corresponding CDR (e.g., CDR-H3) within the variable region, as defined by any of the aforementioned schemes, or other known schemes. In some embodiments, where it is stated that an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2, and a CDR-H3 as contained within a given VH region amino acid sequence and a CDR-L1, a CDR- L2, and a CDR-L3 as contained within a given VL region amino acid sequence, the CDRs canbe defined by any of the aforementioned schemes, such as Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known scheme. In some embodiments, specific CDR sequences are specified. Exemplary CDR sequences of provided antibodies are described using various numbering schemes, although it is understood that a provided antibody can include CDRs as described according to any of the other aforementioned numbering schemes or other known numbering schemes.

[0070] Likewise, unless otherwise specified, a FR or individual specified FR(s) (e.g., FR- Hl, FR-H2, FR-H3, FR-H4, FR-L1, FR-L2, FR-L3, and / or FR-L4), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) framework region as defined by any of the known schemes. In some instances, the scheme for identification of a particular CDR, FR, or FRs or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes. In other cases, the particular amino acid sequence of a CDR or FR is given. In some embodiments, where it is stated that an antibody or antigen-binding fragment thereof comprises a FR-H1, a FR-H2, a FR-H3, and a FR-H4 as contained within a given VH region amino acid sequence and a FR-L1, a FR-L2, a FR-L3, and a FR-L4 as contained within a given VL region amino acid sequence, the FRs can be defined by any of the aforementioned schemes, such as Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known scheme.

[0071] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable regions of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0072] Among the provided antibodies are antibody fragments. An “antibody fragment” or “antigen-binding fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Typically, an antigen binding fragment includes all CDRs of a variable heavy chain (VH) andvariable light chain (VL) sequence from antibodies that bind CTLA-4 set forth herein. Examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; heavy chain variable (VH) regions, single-chain antibody molecules such as scFvs and single-domain antibodies comprising only the VH region; and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produce two identical antigen-binding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. The Fab fragment is composed of an entire E chain along with the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CHI). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab’)2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and is still capable of crosslinking antigen. Fab’ fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CHI domain including one or more cysteines from the antibody hinge region. Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab’)2 antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known. In some embodiments, the antibody is or comprises an antibody fragment comprising a variable heavy chain (VH) and a variable light chain (VL) region. In particular embodiments, the antibodies are single-chain antibody fragments comprising a heavy chain variable (VH) region and / or a light chain variable (VL) region, such as scFvs.

[0073] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells. In some embodiments, the antibodies are recombinantly -produced fragments, such as fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g. , peptide linkers, and / or that are may not be produced by enzyme digestion of a naturally-occurring intact antibody. In some aspects, the antibody fragments are scFvs.

[0074] The term “F(ab)” refers to two of the protein fragments resulting from proteolytic cleavage of immunoglobulin G (IgG) molecules by the enzyme papain. Each F(ab) comprisesa covalent heterodimer of the VH chain and VL chain and includes an intact antigen-binding site.

[0075] The term “F(ab)2” refers to a protein fragment of IgG generated by proteolytic cleavage by the enzyme pepsin. Each F(ab’)2 fragment comprises two F(ab) fragments, thus comprising both antigen-binding sites.

[0076] An “Fv fragment” for use according to certain embodiments of the present invention can be produced by preferential proteolytic cleavage of an IgM, and on rare occasions of an IgG or IgA immunoglobulin molecule. Fv fragments are, however, more commonly derived using recombinant techniques known in the art. The Fv fragment includes a non-covalent VH"VL heterodimer including an antigen-binding site which retains much of the antigen recognition and binding capabilities of the native antibody molecule, but lacking the CHI and CL domains contained within a Fab. Inbar et al. (1972) Proc. Nat. Acad. Sci. USA 69:2659- 2662; Hochman et al. (1976) Biochem 75:2706-2710; and Ehrlich et al. (1980) Biochem 79:4091-4096.

[0077] In certain embodiments, single chain Fv (scFv) antibodies are contemplated and may be prepared using standard molecular biology techniques following the teachings of the present application with regard to selecting antibodies having the desired specificity.

[0078] In still further embodiments, chimeric antibodies may be made. For example, a chimeric antibody may comprise CDRs and framework regions from different antibodies. These antibodies may be produced through recombinant molecular biological techniques or may be physically conjugated together.

[0079] A scFv polypeptide is a covalently linked VH"VL heterodimer which is expressed from a gene fusion including VH- and Vi.-cncoding genes linked by a peptide-encoding linker. Huston et al. (1988) Proc. Nat. Acad. Sci. USA S5(16):5879-5883. A number of methods have been described to discern chemical structures for converting the naturally aggregated — but chemically separated — light and heavy polypeptide chains from an antibody V region into an scFv molecule which will fold into a three dimensional structure substantially similar to the structure of an antigen-binding site. See, e.g., U.S. Pat. Nos. 5,091,513 and 5,132,405, to Huston et al. and U.S. Pat. No. 4,946,778, to Eadner et al.

[0080] In certain embodiments, the antibodies described herein may be provided in the form of a UniBody®. A UniBody® is an IgG4 antibody with the hinge region removed (see GenMab Utrecht, The Netherlands; see also, e.g., US20090226421). This antibody technologycreates a stable, smaller antibody format with an anticipated longer therapeutic window than current small antibody formats. IgG4 antibodies are considered inert and thus do not interact with the immune system. Fully human IgG4 antibodies may be modified by eliminating the hinge region of the antibody to obtain half-molecule fragments having distinct stability properties relative to the corresponding intact IgG4 (GenMab, Utrecht). Halving the IgG4 molecule leaves only one area on the UniBody® that can bind to cognate antigens (e.g., disease targets) and the UniBody® therefore binds univalently to only one site on target cells. For certain cancer cell surface antigens, this univalent binding may not stimulate the cancer cells to grow as may be seen using bivalent antibodies having the same antigen specificity, and hence UniBody® technology may afford treatment options for some types of cancer that may be refractory to treatment with conventional antibodies. The small size of the UniBody® can be a great benefit when treating some forms of cancer, allowing for better distribution of the molecule over larger solid tumors and potentially increasing efficacy.

[0081] In certain embodiments, the antibodies of the present disclosure may be chimeric antibodies. In this regard, a chimeric antibody is comprised of an antigen-binding fragment of an anti-CTLA-4 antibody operably linked or otherwise fused to a heterologous Fc portion of a different antibody. In certain embodiments, the heterologous Fc domain is of human origin. In further embodiments, the heterologous Fc domain may be from a different Ig class from the parent antibody, including IgA (including subclasses IgAl and IgA2), IgD, IgE, IgG (including subclasses IgGl, IgG2, IgG3, and IgG4), and IgM. In further embodiments, the heterologous Fc domain may be comprised of CH2 and CH3 domains from one or more of the different Ig classes.

[0082] In certain embodiments, the antibodies of the present disclosure may be “non- naturally occurring” antibodies. Non-naturally occurring antibodies can refer to antibodies that comprise one or more amino acid modifications, such that the resultant antibody is substantially non-naturally occurring (e.g., does not exists in nature). These amino acid modifications can include point mutations, wherein a naturally occurring amino acid is substituted for another naturally occurring amino acid. In some embodiments, the amino acid modifications can include point mutations wherein a non-naturally occurring amino acid is substituted for a naturally occurring amino acid. Non-naturally occurring antibodies can also refer to antibodies that are conjugated to a heterologous protein or compound, such as a detectable marker.

[0083] Among the provided antibodies are human antibodies. A “human antibody” is an antibody with an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences, including human antibody libraries. The term excludes humanized forms of non-human antibodies comprising non-human antigen-binding regions, such as those in which all or substantially all CDRs are non-human. The term includes antigenbinding fragments of human antibodies.

[0084] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic animals, the endogenous immunoglobulin loci have generally been inactivated. Human antibodies also may be derived from human antibody libraries, including phage display and cell-free libraries, containing antibody-encoding sequences derived from a human repertoire.

[0085] Among the provided antibodies are monoclonal antibodies, including monoclonal antibody fragments. The term “monoclonal antibody” as used herein refers to an antibody obtained from or within a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical, except for possible variants containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different epitopes, each monoclonal antibody of a monoclonal antibody preparation is directed against a single epitope on an antigen. The term is not to be construed as requiring production of the antibody by any particular method. A monoclonal antibody may be made by a variety of techniques, including but not limited to generation from a hybridoma, recombinant DNA methods, phage-display and other antibody display methods.

[0086] In some aspects, the antibody or the antigen-binding fragments of the antibody is isolated.

[0087] The present disclosure contemplates variants of the antibodies disclosed herein. In certain embodiments, such variant antibodies or antigen-binding fragments, or CDRs thereof,bind to CTLA-4 at least about 50%, at least about 70%, at least about 80%, at least about 85%, at least about 90% and in certain embodiments, at least about 95% as well as an antibody sequence specifically set forth herein. In further embodiments, such variant antibodies or antigen-binding fragments, or CDRs thereof, bind to CTLA-4 with greater affinity than the antibodies set forth herein, for example, that bind quantitatively at least about 105%, 106%, 107%, 108%, 109%, or 110% as well as an antibody sequence specifically set forth herein.

[0088] In particular embodiments, a subject antibody may have: a) a heavy chain variable region having an amino acid sequence that is at least 80% identical, at least 85% identical, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% or 100% identical, to a heavy chain variable region of an anti-CTLA-4 antibody described herein; and b) a light chain variable region having an amino acid sequence that is at least 80% identical, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or 99% or 100% identical, to a light chain variable region of an anti-CTLA-4 antibody described herein.A. Exemplary Antibodies

[0089] In some embodiments, the anti-CTLA-4 antibody contains a VH region and a VL region containing a combination of six CDRs as described below. In some embodiments, the anti-CTLA-4 antibody contains a VH region and a VL region as described below. In any such embodiments, a VH region sequence can be any of the VH region sequence described herein. In any such embodiments, a VL region sequence can be any of the VL region sequence described herein. In any such embodiments, any of the VH region sequence and any of the VL region sequence described herein can be used in combination. In some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or an scFv. In some embodiments, the antibody or antigen-binding fragment further comprises at least a portion of an immunoglobulin constant region or a variant thereof. In some such embodiments, the antibody is a full-length antibody that also contains a constant region. In some embodiments, an anti- CTLA-4 antibody comprises at least one heavy chain comprising a VH region and at least a portion of a heavy chain constant region, and at least one light chain comprising a VL region and at least a portion of a light chain constant region. In some embodiments, an anti-CTLA-4 antibody comprises two heavy chains, wherein each heavy chain comprises a VH region and at least a portion of a heavy chain constant region, and two light chains, wherein each light chain comprises a VL region and at least a portion of a light chain constant region. In some embodiments, an anti-CTLA-4 antibody comprises two heavy chains, wherein each heavychain comprises a VH region and a heavy chain constant region, and two light chains, wherein each light chain comprises a VL region and a light chain constant region.

[0090] Anti-CTLA-4 antibodies, including antigen-binding fragments thereof, include any combination of the heavy chain and light chain complementarity-determining regions (CDRs) discussed herein. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment thereof comprises any one of the CDR-H1 as described herein, any one of the CDR- H2 as described herein, any one of the CDR-H3 as described herein, any one of the CDR-L1 as described herein, any one of the CDR-L2 as described herein and any one of the CDR-L3 as described herein. In some of any such embodiments, any one or more of the CDR-H1, the CDR-H2 and the CDR-H3 sequences described herein, and any one or more of the CDR-L1, the CDR-L2 and the CDR-L3 sequences described herein can be used in combination.

[0091] In some embodiments, a provided anti-CTLA-4 antibody or an antigen-binding fragment thereof has a CDR-H1, a CDR-H2 and a CDR-H3 present in a VH region amino acid sequence set forth in any one of SEQ ID NOs: 1-27 and 112, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in any one of SEQ ID NOs: 1-27 and 112. In some embodiments, a provided anti-CTLA-4 antibody or an antigen-binding fragment thereof has a CDR-L1, a CDR-L2 and a CDR-L3 present in a VL region amino acid sequence set forth in any one of SEQ ID NOs: 28-48 and 118, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in any one of SEQ ID NOs: 28-48 and 118. In some embodiments, the provided anti- CTLA-4 antibody contains a combination of any of such six CDRs (a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2 and a CDR-L3) described above). In some embodiments, a provided anti-CTLA-4 antibody or an antigen-binding fragment thereof has a CDR-H1, a CDR- H2 and a CDR-H3 present in a VH region amino acid sequence set forth in any one of SEQ ID NOs: 1-27 and 112, and a CDR-L1, a CDR-L2 and a CDR-L3 present in a VL region amino acid sequence set forth in any one of SEQ ID NOs: 28-48 and 118, wherein the CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 49, 57, 68, 74, 89 and 98, respectively. In some embodiments, the combination of six CDRs (a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2 and a CDR-L3) is according to Kabat numbering. In some embodiments, the combination of six CDRs (a CDR-H1, a CDR-H2, aCDR-H3, a CDR-L1, a CDR-L2 and a CDR-L3) is according to Chothia numbering. In some embodiments, the combination of six CDRs (a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2 and a CDR-L3) is according to AbM numbering, In some embodiments, the combination of six CDRs (a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2 and a CDR-L3) is according to IMGT numbering. In some embodiments, the combination of six CDRs (a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2 and a CDR-L3) is according to IgBLAST numbering.

[0092] Exemplary heavy and light chain CDR sequences of the anti-CTLA-4 antibodies and antigen-binding fragments thereof are provided in Tables 2A and 2B.Table 2A: Heavy chain CDR sequencesTable 2B: Light chain CDR sequences

[0093] In some of any of the provided embodiments, the VH region contains a CDR-H1 set forth in any one of SEQ ID NOs: 49-56, a CDR-H2 set forth in any one of SEQ ID NOs: 57- 67, and a CDR-H3 set forth in any one of SEQ ID NOs: 68-73; and the VL region contains a CDR-L1 set forth in any one of SEQ ID NOs: 74-88, a CDR-L2 set forth in any one of SEQ ID NOs: 89-97, and a CDR-L3 set forth in any one of SEQ ID NOs: 98-100. In some embodiments, the anti-CTLA-4 antibody or antigen-binding fragment does not contain the combination of CDRs set forth in SEQ ID NO: 49, SEQ ID NO: 57, SEQ ID NO: 68, SEQ ID NO: 74, SEQ ID NO: 89, and SEQ ID NO: 98. In some embodiments, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 49, 57, 68, 74, 89 and 98, respectively. In some embodiments, the VH region comprises a CDR-H1 comprising the sequence set forth in in any one of SEQ ID NOs: 49-56, a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 57-67, and a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 68-73, and the VL region comprises a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 75-88, a CDR-L2 comprising the sequence set forth in any one of SEQ ID NOs: 90-97; and a CDR-L3 comprising the sequence set forth in any one of SEQ ID NOs: 99 and 100. In some embodiments, the VH region comprises a CDR- H1 comprising the sequence set forth in any one of SEQ ID NOs: 50-56, a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 58-67, and a CDR-H3 comprising thesequence set forth in any one of SEQ ID NOs: 69-73, and the VL region comprises a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 74-88, a CDR-L2 comprising the sequence set forth in any one of SEQ ID NOs: 89-97; and a CDR-L3 comprising the sequence set forth in any one of SEQ ID NOs: 98-100. Also among the antibodies are those having sequences at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identical to any such CDR sequence, e.g., any of the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3. In some embodiments, among the antibodies are those in which a CDR contained therein has no more than 2 amino acid difference compared to any such above CDR sequence, e.g., any of the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3. In some embodiments, among the antibodies are those in which a CDR contained therein has no more than 1 amino acid difference compared to any such above CDR sequence, e.g., any of the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3.

[0094] In some of any of the provided embodiments, the VH region contains a CDR-H1 set forth in any one of SEQ ID NOs: 50-56, a CDR-H2 set forth in any one of SEQ ID NOs: 58- 67, and a CDR-H3 set forth in any one of SEQ ID NOs: 69-73; and the VL region contains a CDR-L1 set forth in any one of SEQ ID NOs: 75-88, a CDR-L2 set forth in any one of SEQ ID NOs: 90-97, and a CDR-L3 set forth in any one of SEQ ID NOs: 99-100.

[0095] In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 1. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR- Hl, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 2. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR- H3 present in SEQ ID NO: 3. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 4. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 5. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 6. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 7. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 8. In someembodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR- Hl, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 9. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR- H3 present in SEQ ID NO: 10. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 11. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 12. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR- Hl, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 13. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR- H3 present in SEQ ID NO: 14. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 15. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 16. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR- Hl, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 17. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR- H3 present in SEQ ID NO: 18. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR- Hl, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR- H3 present in SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 23. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 24. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR- Hl, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 25. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR- H3 present in SEQ ID NO: 26. In some embodiments, the antibody or antigen-bindingfragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 27. In some embodiments, the antibody or antigen-binding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 112. In some embodiments, the CDR sequence is according to Kabat numbering. In some embodiments, the CDR sequence is according to Chothia numbering. In some embodiments, the CDR sequence is according to AbM numbering. In some embodiments, the CDR sequence is according to IMGT numbering. In some embodiments, the CDR sequence is according to IgBLAST numbering.

[0096] In some embodiments, the antibody or antigen -binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR- Ll, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 29. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR- L3 present in SEQ ID NO: 30. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 31. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 32. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 33. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 34. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR- Ll, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 36. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR- L3 present in SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 38. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 39. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 40. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQID NO: 41. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 42. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR- Ll, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 43. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR- L3 present in SEQ ID NO: 44. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 46. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 46. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 47. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQID NO: 48. In some embodiments, the antibody or antigen-binding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 118. In some embodiments, the CDR sequence is according to Kabat numbering. In some embodiments, the CDR sequence is according to Chothia numbering. In some embodiments, the CDR sequence is according to AbM numbering. In some embodiments, the CDR sequence is according to IMGT numbering. In some embodiments, the CDR sequence is according to IgBLAST numbering.

[0097] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 58, and 68, respectively; SEQ ID NOS: 49, 57, and 69, respectively; SEQ ID NOS: 51, 57, and 68, respectively; SEQ ID NOS: 50, 59, and 68, respectively; SEQ ID NOS: 52, 60, and 68, respectively; SEQ ID NOS: 52, 61, and 68, respectively; SEQ IDNOS: 51, 62, and 68, respectively; SEQ ID NOS: 50, 63, and 68, respectively; SEQ ID NOS:50, 57, and 69, respectively; SEQ ID NOS: 53, 57, and 68, respectively; SEQ ID NOS: 53, 57, and 70, respectively; SEQ ID NOS: 54, 57, and 71, respectively; SEQ ID NOS: 55, 57, and 68, respectively; SEQ ID NOS: 56, 57, and 72, respectively; SEQ ID NOS: 49, 64, and 68, respectively; SEQ ID NOS: 49, 60, and 68, respectively; SEQ ID NOS: 49, 65, and 68, respectively; SEQ ID NOS: 49, 66, and 68, respectively; SEQ ID NOS: 49, 57, and 71, respectively; SEQ ID NOS: 49, 57, and 73, respectively; SEQ ID NOS: 49, 57, and 72, respectively; SEQ ID NOS: 49, 57, and 68, respectively; SEQ ID NOS: 49, 67, and 68,respectively; SEQ ID NOS: 49, 65, and 73, respectively; SEQ ID NOS: 52, 60, and 72, respectively; SEQ ID NOS: 52, 67, and 68, respectively; SEQ ID NOS: 49, 57, and 72, respectively; or SEQ ID NOS: 49, 65, and 72, respectively.

[0098] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 75, 89, and 98, respectively; SEQ ID NOS: 76, 89, and 98, respectively; SEQ ID NOS: 77, 89, and 98, respectively; SEQ ID NOS: 78, 90, and 98, respectively; SEQ ID NOS: 79, 90, and 98, respectively; SEQ ID NOS: 80, 91, and 98, respectively; SEQ ID NOS: 78, 89, and 99, respectively; SEQ ID NOS: 81, 92, and 98, respectively; SEQ ID NOS: 82, 89, and 98, respectively; SEQ ID NOS: 82, 93, and 98, respectively; SEQ ID NOS: 83, 92, and 98, respectively; SEQ ID NOS: 84, 89, and 99, respectively; SEQ ID NOS: 84, 89, and 100, respectively; SEQ ID NOS: 85, 89, and 98, respectively; SEQ ID NOS: 86, 94, and 98, respectively; SEQ ID NOS: 87, 95, and 98, respectively; SEQ ID NOS: 85, 96, and 98, respectively; SEQ ID NOS: 88, 89, and 98, respectively; SEQ ID NOS: 74, 97, and 98, respectively; SEQ ID NOS: 74, 89, and 98, respectively; SEQ ID NOS: 84, 89, and 98, respectively; or SEQ ID NOS: 88, 89, and 100, respectively.

[0099] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 58, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0100] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 69, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0101] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 51, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0102] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 50, 59, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0103] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0104] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 61, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0105] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 51, 62, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0106] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 50, 63, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0107] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 50, 57, and 69, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0108] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence setforth in SEQ ID NOS: 53, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0109] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 53, 57, and 70, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0110] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 54, 57, and 71, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0111] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 55, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0112] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 56, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0113] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 64, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0114] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 60, and 68, respectively, and the VL region comprises a CDR-L1, aCDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0115] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0116] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 66, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0117] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 71, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0118] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 73, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0119] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively.

[0120] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 75, 89, and 98, respectively.

[0121] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively.

[0122] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 77, 89, and 98, respectively.

[0123] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 78, 90, and 98, respectively.

[0124] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 79, 90, and 98, respectively.

[0125] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 80, 91, and 98, respectively.

[0126] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 78, 89, and 99, respectively.

[0127] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence setforth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 81, 92, and 98, respectively.

[0128] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 82, 89, and 98, respectively.

[0129] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 82, 93, and 98, respectively.

[0130] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 83, 92, and 98, respectively.

[0131] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively.

[0132] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 100, respectively.

[0133] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, aCDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively.

[0134] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 86, 94, and 98, respectively.

[0135] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 87, 95, and 98, respectively.

[0136] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 96, and 98, respectively.

[0137] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 88, 89, and 98, respectively.

[0138] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 97, and 98, respectively.

[0139] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively.

[0140] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively.

[0141] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively.

[0142] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively.

[0143] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively.

[0144] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively.

[0145] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively.

[0146] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence setforth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively.

[0147] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively.

[0148] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively.

[0149] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively.

[0150] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively.

[0151] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively.

[0152] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region comprises a CDR-L1, aCDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively.

[0153] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively.

[0154] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively.

[0155] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively.

[0156] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively.

[0157] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively.

[0158] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively.

[0159] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively.

[0160] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively.

[0161] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively.

[0162] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively.

[0163] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 88, 89, and 100, respectively.

[0164] In some embodiments, the provided antibody is a human antibody or antigenbinding fragment thereof that contains a framework region that contains human germline gene segment sequences. For example, in some embodiments, the human antibody contains a VH region in which the framework region, e.g.FRl, FR2, FR3 and FR4, has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a framework region encoded by a human germline antibody segment, such as a V segment and / or J segment. In some embodiments, the human antibody contains a VL region in which the framework region e.g.FRl, FR2, FR3 andFR4, has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a framework region encoded by a human germline antibody segment, such as a V segment and / or J segment. For example, in some such embodiments, the framework region sequence contained within the VH region and / or VL region differs by no more than 10 amino acids, such as no more than 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid, compared to the framework region sequence encoded by a human germline antibody segment.

[0165] In some embodiments of the antibody or antigen-binding fragment thereof provided herein, the VH region comprises any of the CDR-H1, CDR-H2 and CDR-H3 as described and comprises a framework region 1 (FR1), a FR2, a FR3 and / or a FR4 having at least at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the VH region amino acid sequence set forth in any one of SEQ ID NOs: 1-27 and 112. In some embodiments of the antibody or antigen-binding fragment thereof provided herein, the VH region comprises any of the CDR-H1, CDR-H2 and CDR-H3 as described and comprises a framework region 1 (FR1), a FR2, a FR3 and / or a FR4 contained within the VH region amino acid sequence set forth in any one of SEQ ID NOs: 1-27 and 112.

[0166] In some embodiments of the antibody or antigen-binding fragment thereof provided herein, the VH region comprises any of the CDR-L1, CDR-L2 and CDR-L3 as described and comprises a framework region 1 (FR1), a FR2, a FR3 and / or a FR4 having at least at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the VL region amino acid sequence set forth in any one of SEQ ID NOs: 28-48 and 118. In some embodiments of the antibody or antigen-binding fragment thereof provided herein, the VL region comprises any of the CDR-H1, CDR-H2 and CDR-H3 as described and comprises a framework region 1 (FR1), a FR2, a FR3 and / or a FR4 contained within the VH region amino acid sequence set forth in any one of SEQ ID NOs: 28-48 and 118.

[0167] In some embodiments, any of the provided anti-CTLA-4 antibodies or antigen binding fragments has a VH region having the amino acid sequence set forth in any one of SEQ ID NOs: 1-27 and 112, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in any one of SEQ ID NOs: 1-27 and 112, and has a VL region having the amino acid sequence set forth in any one of SEQ ID NOs: 28-48 and118, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in any one of SEQ ID NOs: 28-48 and 118.

[0168] In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 1, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 2, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 3, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 3. In some embodiment, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 4, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 5, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 5. In some embodiment, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 6, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 7, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 7. In some embodiment, the antibody or antigen-binding fragment has a VH region having the amino acidsequence set forth in SEQ ID NO: 8, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 8. In some embodiment, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 9, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 10, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 11, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 12, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 13, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 14, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 15, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acidsequence set forth in SEQ ID NO: 16, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 17, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 17. In some embodiment, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 18, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 19, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 20, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 21, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the antibody or antigen-binding fragment has has a VH region having the amino acid sequence set forth in SEQ ID NO: 22, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 23, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acidsequence set forth in SEQ ID NO: 24, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 24. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 25, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 26, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 26. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 27, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the antibody or antigen-binding fragment has a VH region having the amino acid sequence set forth in SEQ ID NO: 112, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the antibody or antigen-binding fragment does not have a VH region having the amino acid sequence set forth in SEQ ID NO: 112.

[0169] In some embodiments, the antibody or antigen -binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 28, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 29, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 30, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 31, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 31. In some embodiments, a VL region having the amino acid sequence set forth in SEQ ID NO: 32, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 33, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 33. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 34, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 35, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 36, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 37, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 37. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 38, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL regionamino acid sequence set forth in SEQ ID NO: 38. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 39, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 40, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 41, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 42, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 42. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 43, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 44, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 44. In some embodiment, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 45, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 45. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 46, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL regionamino acid sequence set forth in SEQ ID NO: 46. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 47, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 48, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 48. In some embodiments, the antibody or antigen-binding fragment has a VL region having the amino acid sequence set forth in SEQ ID NO: 118, or an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 118. In some embodiments, the antibody or antigen-binding fragment does not have a VL region having the amino acid sequence set forth in SEQ ID NO: 118.

[0170] In some embodiments, the antibody or antigen-binding fragment has a VH region having an amino acid sequence that is less than 100% identical to SEQ ID NO: 112 and has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the antibody or antigen-binding fragment has a VL region having an amino acid sequence that is less than 100% identical to SEQ ID NO: 118 and has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in SEQ ID NO: 118. In some embodiments, the VH region does not have the amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the VL region does not have the amino acid sequence set forth in SEQ ID NO: 118. In some embodiments, the VH region and the VL region of the antibody are not set forth SEQ ID NO: 112 and 118, respectively. In some embodiments, the antibody or antigen-binding fragment has a VH region having an amino acid sequence that is less than 100% identical to SEQ ID NO: 112 and has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region amino acid sequence set forth in SEQ ID NO: 112, and a VL region having an amino acid sequence set forth in SEQ ID NO: 118. In some embodiments, the antibody or antigen-bindingfragment has a VH region having an amino acid sequence set forth in SEQ ID NO: 112, and a VL region having an amino acid sequence that is less than 100% identical to SEQ ID NO: 118 and has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in set forth in SEQ ID NO: 118.

[0171] In some embodiments, the antibody or antigen-binding fragment provided herein, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 1, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 3, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 4, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 6, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises anamino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 7, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VHregion is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 8, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 9, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 11, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 13, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 14, and the VL region is or comprises an amino acidsequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 15, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VHregion is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 16, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 18, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 19, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 20, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 21, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequencehaving at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 28; the VHregion is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 30; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 31; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 32; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 33; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence havingat least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 34; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 35; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VLregion is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 36; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 37; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 38; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 40; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region is or comprises an amino acid sequence having at least at orabout 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 42; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 44; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 45; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 112, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 46; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 23, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 25, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 41; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 23, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 25, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 47; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 23, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 25, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 29; the VHregion is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 23, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 24, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 25, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 26, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; or the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48.

[0172] In some embodiments, the VH region of the antibody or antigen-binding fragment thereof comprises the amino acid sequence of any one of SEQ ID NOs: 1-27 and 112, and the VL region of the antibody or antigen-binding fragment comprises the amino acid sequence of any one of SEQ ID NOs: 28-48 and 118.

[0173] In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 1 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 2 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 3 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 4 and 118, respectively. In some embodiments of the antibody or antigenbinding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 5 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 6 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 7 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 8 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 9 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 10 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 11 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 12 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 13 and 118, respectively. In some embodiments of theantibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 14 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 15 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 16 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 17 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 18 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 19 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 20 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 21 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 22 and 118, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 28, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 29, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 30, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 31, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 32, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 33, respectively. In some embodiments of the antibody orantigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 34, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 35, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 36, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 37, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 38, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 39, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 40, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 41, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 42, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 43, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 44, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 45, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 112 and 46, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 23 and 41, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 24 and 41, respectively. In some embodiments of the antibody or antigen-bindingfragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 25 and 41, respectively. In some embodiments of the antibody or antigenbinding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 26 and 41, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 22 and 41, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 27 and 41, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 23 and 47, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 24 and 47, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 25 and 47, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 26 and 47, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 22 and 47, respectively. In some embodiments of the antibody or antigenbinding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 27 and 47, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 23 and 29, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 24 and 29, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 25 and 29, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 26 and 29, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 22 and 29, respectively. In some embodiments of the antibody or antigen-binding fragmentprovided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 27 and 29, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 23 and 39, respectively. In some embodiments of the antibody or antigenbinding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 24 and 39, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 25 and 39, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 26 and 39, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 22 and 39, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 27 and 39, respectively. In some embodiments of the antibody or antigen-binding fragment provided herein, the VH region and the VL region are or comprise the sequence set forth in SEQ ID NO: 5 and 48, respectively.

[0174] Table El provides the SEQ ID NOS: of exemplary provided antibody or antigenbinding fragment thereof. In some embodiments, the CTLA-4-binding antibody or fragment thereof comprises a VH region that comprises the CDR-H1, the CDR-H2 and the CDR-H3 sequence and a VL region that comprises the CDR-L1, the CDR-L2 and the CDR-L3 sequence set forth in the SEQ ID NOS: listed in each row of Table El below (by Kabat numbering scheme). In some embodiments, the CTLA-4-binding antibody or fragment thereof comprises a VH region sequence and a VL region sequence set forth in the SEQ ID NOS: listed in each row of Table El below, or an antibody comprising a VH region and a VL region amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VH region sequence and the VL region sequence set forth in the SEQ ID NOS: listed in each row of Table El below. In some embodiments, the CTLA-4-binding antibody or fragment thereof comprises a VH region sequence and a VL region sequence set forth in the SEQ ID NOS: listed in each row of Table El below.

[0175] In some embodiments, the provided antibody or antigen-binding fragment thereof comprises a VH region and a VL region, wherein the VH region of the antibody or antigen-binding fragment thereof can contain a combination of any of the CDR-H1, the CDR-H2 and the CDR-H3 amino acid sequences set forth in Table El, and the VL region of the antibody or antigen-binding fragment thereof can contain a combination of any of the CDR-L1, the CDR- L2 and the CDR-L3 amino acid sequences set forth in Table El. In some embodiments, the provided antibody or antigen-binding fragment thereof comprises a VH region and / or a VL region set forth in Table El, in any combination, orientation or containing a different linker. In some aspects, the antibody or antigen-binding fragment thereof comprises a VH region described in Table El. In some aspects, the antibody or antigen-binding fragment thereof comprises a VL region described in Table El.

[0176] In some embodiments, provided antibodies include those that include amino acid residues (such as due to mutation compared to a reference sequence) that alter pH binding such that the antibodies exhibit better binding at neutral pH (e.g., pH 7.4) compared to acidic pH (e.g., pH 5.0). Results herein surprisingly found enrichment of a number of antibodies, including antibody fragments, with such activity that contain one or more of the following amino acids in the VH region: arginine (R) at position 31, glutamic acid (E) or histidine (H) at position 54, histidine (H) at position 59, histidine (H) at position 101, or histidine (H) at position 102 (corresponding to arginine (R) at position 31, glutamic acid (E) or histidine (H) at position 53, histidine (H) at position 58, histidine (H) at position 97, or histidine (H) at position 98, respectively, based on Kabat numbering), or any combination thereof; and / or in the VL region: histidine (H) at position 28, histidine (H) at position 31, histidine (H) at position 32, or a histidine (H) at position 91 (corresponding to histidine (H) at position 27a, histidine (H) at position 30, histidine (H) at position 31, or histidine (H) at position 90, respectively, based on Kabat numbering), or any combination thereof. In some embodiments, provided antibodies, including antibody fragments, herein contain one or more amino acid mutation in the VH region that is S31H, D54H, D54E, Y59H, W101H, or L102H, which correspond to S31R, D53H, D53E, Y58H, W97H, or L98H based on Kabat numbering, respectively, or any combination thereof, compared to the VH region set forth in SEQ ID NO: 112; and / or one or more amino acid mutation in the VL region that is S28H, S31H, S32H, or Q91H, which correspond to S27aH, S30H, S31H, or Q90H based on Kabat numbering, respectively, or any combination thereof, compared to the VL region set forth in SEQ ID NO: 118.

[0177] In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises one or more mutations selected from the group consisting of:S31R, D54H, D54E, Y59H, W101H, and L102H (S31R, D53H, D53E, Y58H, W97H, and L98H, respectively, based on Kabat numbering) in the VH region, such as compared to a reference anti-CTLA-4 antibody VH, e.g. set forth in SEQ ID NO: 112.

[0178] In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprise a histidine (H) at position 98 based on Kabat numbering (e.g., L102H mutation compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering) (e.g., S31R mutation compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a glutamic acid (E) at position 53 based on Kabat numbering) (e.g., D54E mutation compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 53 based on Kabat numbering (e.g., D54H mutation compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 58 based on Kabat numbering (e.g., Y59H mutation compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 97 based on Kabat numbering (e.g., W101H mutation compared to SEQ ID NO: 112) in the VH region.

[0179] In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering and a arginine (R) at position 31 based on Kabat numbering (e.g., L102H and S31R mutation compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti- CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering and a glutamic acid (E) at position 53 based on Kabat numbering (e.g., L102H and D54E mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering and a histidine (H) at position 53 based on Kabat numbering (e.g., L102H and D54H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering and a histidine (H) at position 58 based on Kabat numbering (e.g., L102H and Y59Hmutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H and W 101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering) and a glutamic acid (E) at position 53 based on Kabat numbering (e.g., S31R and D54E mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering and a histidine (H) at position 53 based on Kabat numbering (e.g., S31R and D54H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering and a histidine (H) at position 58 based on Kabat numbering (e.g., S31R and Y59H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering and a histidine (H) at position 97 based on Kabat numbering (e.g., S31R and W 101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a glutamic acid (E) at position 53 based on Kabat numbering and a histidine (H) at position 58 based on Kabat numbering (e.g., D54E and Y59H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a glutamic acid (E) at position 53 based on Kabat numbering and a histidine (H) at position 97 based on Kabat numbering (e.g., D54E and W 101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 53 based on Kabat numbering and a histidine (H) at position 58 based on Kabat numbering (e.g., D54H and Y59H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 53 based on Kabat numbering and a histidine (H) at position 97 based on Kabat numbering (e.g., D54H and W 101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H)at position 58 based on Kabat numbering and a histidine (H) at position 97 based on Kabat numbering (e.g., Y59H and W 101H mutations compared to SEQ ID NO: 112) in the VH region.

[0180] In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering and a glutamic acid (E) at position 53 based on Kabat numbering (e.g., L102H, S31R, and D54E mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigenbinding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering and a histidine (H) at position 53 based on Kabat numbering (e.g., L102H, S31R, and D54H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering and a histidine (H) at position 58 based on Kabat numbering (e.g., L102H, S31R, and Y59H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, S31R, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, a glutamic acid (E) at position 53 based on Kabat numbering and a histidine (H) at position 58 based on Kabat numbering (e.g., L102H, D54E, and Y59H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti- CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, a glutamic acid (E) at position 53 based on Kabat numbering and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, D54E, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, a a histidine (H) at position 53 based on Kabat numbering and a histidine (H) at position 58 based on Kabat numbering (e.g., L102H, D54H, and Y59H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine(H) at position 98 based on Kabat numbering, a histidine (H) at position 53 based on Kabat numbering and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, D54H, and W 101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, a histidine (H) at position 58 based on Kabat numbering and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, Y59H, and W 101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering), a glutamic acid (E) at position based on Kabat numbering, and a histidine (H) at position 58 based on Kabat numbering (e.g., S31R, D54E, and Y59H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering), a glutamic acid (E) at position 53 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., S31R, D54E, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering), a histidine (H) at position 53 based on Kabat numbering, and a histidine (H) at position 58 based on Kabat numbering (e.g., S31R, D54H, and Y59H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering), a histidine (H) at position 53 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., S31R, D54H, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering), a histidine (H) at position 58 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., S31R, Y59H, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a glutamic acid (E) at position 53 based on Kabat numbering, a histidine (H) at position 58 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., D54E, Y59H, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-bindingfragment thereof comprises a histidine (H) at position 53 based on Kabat numbering, a histidine (H) at position 58 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., D54H, Y59H, and W101H mutations compared to SEQ ID NO: 112) in the VH region.

[0181] In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering, a glutamic acid (E) at position 53 based on Kabat numbering, and a histidine (H) at position 58 based on Kabat numbering (e.g., L102H, S31R, D54E, and Y59H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering, a glutamic acid (E) at position 53 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, S31R, D54E, and W 101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering, a histidine (H) at position 53 based on Kabat numbering, and a histidine (H) at position 58 based on Kabat numbering (e.g., L102H, S31R, D54H, and Y59H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti- CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering, a histidine (H) at position 53 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, S31R, D54H, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering, a histidine (H) at position 58 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, S31R, Y59H, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, a glutamic acid (E) at position 53 based on Kabat numbering, a histidine (H) at position 58 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, D54E,Y59H, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, a histidine (H) at position 53, a histidine (H) at position 58 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, D54H, Y59H, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises an arginine (R) at position 31 based on Kabat numbering, a glutamic acid (E) at position 53 based on Kabat numbering, a histidine (H) at position 58 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., S31R, D54E, Y59H, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering, a glutamic acid (E) at position 53 based on Kabat numbering, a histidine (H) at position 58 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, S31R, D54E, Y59H, and W101H mutations compared to SEQ ID NO: 112) in the VH region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 98 based on Kabat numbering, an arginine (R) at position 31 based on Kabat numbering, a histidine (H) at position 53 based on Kabat numbering, a histidine (H) at position 58 based on Kabat numbering, and a histidine (H) at position 97 based on Kabat numbering (e.g., L102H, S31R, D54H, Y59H, and W101H mutations compared to SEQ ID NO: 112) in the VH region.

[0182] In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises one or more mutations selected from the group consisting of: S28H, S31H, S32H, and Q91H (S27aH, S30H, S31H, and Q90H, respectively, based on Kabat numbering) in the VL region, such as compared to a reference anti-CTLA-4 antibody VL, e.g. set forth in SEQ ID NO: 118. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 27a based on Kabat numbering (e.g., S28H mutation compared to SEQ ID NO: 118) in the VL region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 30 based on Kabat numbering (e.g., S31H mutation compared to SEQ ID NO: 118) in the VL region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 31 based on Kabat numbering (e.g., S32H mutation compared to SEQ ID NO: 118) in the VL region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 90 based on Kabat numbering (e.g., Q91H mutation compared to SEQ ID NO: 118) in the VL region.

[0183] In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 27a based on Kabat numbering and a histidine (H) at position 30 based on Kabat numbering (e.g., S28H and S31H mutations compared to SEQ ID NO: 118) in the VL region. In some embodiments, the provided anti- CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position27a based on Kabat numbering and a histidine (H) at position 31 based on Kabat numbering (e.g., S28H and S32H mutations compared to SEQ ID NO: 118) in the VL region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 27a based on Kabat numbering and a histidine (H) at position 90 based on Kabat numbering (e.g., S28H and Q91H mutations compared to SEQ ID NO: 118) in the VL region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 30 based on Kabat numbering and a histidine (H) at position 31 based on Kabat numbering (e.g., S31H and S32H mutations compared to SEQ ID NO: 118) in the VL region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 30 based on Kabat numbering and a histidine (H) at position 90 based on Kabat numbering (e.g., S31H and Q91H mutations compared to SEQ ID NO: 118) in the VL region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 31 based on Kabat numbering and a histidine (H) at position 90 based on Kabat numbering (e.g., S32H and Q91H mutations compared to SEQ ID NO: 118) in the VL region.

[0184] In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 27a based on Kabat numbering, a histidine (H) at position 30 based on Kabat numbering, and a histidine (H) at position 31 based on Kabat numbering) (e.g., S28H, S31H, S32H mutations compared to SEQ ID NO: 118 (S27aH, S30H, S31H mutations compared to SEQ ID NO: 118, based on Kabat numbering)) in the VL region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-bindingfragment thereof comprises a histidine (H) at position 28 (position 27a based on Kabat numbering), a histidine (H) at position 30 based on Kabat numbering, and a histidine (H) at position 90 based on Kabat numbering (e.g., S28H, S31H, Q91H mutations compared to SEQ ID NO: 118) in the VL region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 27a based on Kabat numbering, a histidine (H) at position 31 based on Kabat numbering, and a histidine (H) at position 90 based on Kabat numbering (e.g., S28H, S32H, Q91H mutations compared to SEQ ID NO: 118) in the VL region. In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 30 based on Kabat numbering, a histidine (H) at position 31 based on Kabat numbering, and a histidine (H) at position 90 based on Kabat numbering (e.g., S31H, S32H, Q91H mutations compared to SEQ ID NO: 118) in the VL region.

[0185] In some embodiments, the provided anti-CTLA-4 antibody or antigen-binding fragment thereof comprises a histidine (H) at position 27a based on Kabat numbering, a histidine (H) at position 30 based on Kabat numbering, a histidine (H) at position 31 based on Kabat numbering, and a histidine (H) at position 91 (position 90 based on Kabat numbering) (e.g., S28H, S31H, S32H, Q91H mutations compared to SEQ ID NO: 118) in the VL region.

[0186] In some embodiments, the VH region comprises an arginine (R) at position 31, glutamic acid (E) or histidine (H) at position 53, histidine (H) at position 58, histidine (H) at position 97, or histidine (H) at position 98, respectively, based on Kabat numbering, or any combination thereof (e.g., S31R, D54H, D54E, Y59H, W101H, or L102H mutations, or any combination thereof, compared to SEQ ID NO:112), and the VL region comprises a histidine (H) at position 27a, histidine (H) at position 30, histidine (H) at position 31, or histidine (H) at position 90, respectively, based on Kabat numbering), or any combination thereof (e.g., S28H, S31H, S32H, or Q91H mutations, or any combination thereof, compared to SEQ ID NO: 118).

[0187] Exemplary antibody VH and VL regions with one or more of the above residues are set forth in Tables 3A and 3B. Provided herein are any antibody or antigen binding fragment comprising at least one of such VH or VL region set forth in Table 3A or Table 3B, paired with any respective other VH and VL described herein. Also provided are antibodies or antigen binding fragments containing a paired combination of any VH set forth in Table 3A and any VL set forth in Table 3B. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in any one of SEQ ID NOs: 5, 6, 14, 17-19, and 21-27, and a VL setforth in any one of SEQ ID NOs: 29, 30, 32, 34, 39-41, 44, and 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 5 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 5 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 5 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 5 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 5 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 5 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 5 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 5 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 5 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 6 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 6 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 6 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 6 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 6 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 6 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 6 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 6 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 6 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 14 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 14 and a VL set forth inSEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 14 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 14 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 14 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 14 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 14 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 14 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 14 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 17 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 17 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 17 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 17 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 17 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 17 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 17 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 17 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 17 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 18 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 18 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 18 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 18 and a VL set forth in SEQ IDNO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 18 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 18 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 18 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 18 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 18 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 19 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 19 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 19 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 19 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 19 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 19 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 19 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 19 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 19 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 21 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 21 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 21 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 21 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 21 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 21 and a VL set forth in SEQ IDNO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 21 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 21 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 21 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 22 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 22 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 22 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 22 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 22 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 22 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 22 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 22 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 22 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 23 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 23 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 23 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 23 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 23 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 23 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 23 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 23 and a VL set forth in SEQ IDNO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 23 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 24 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 24 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 24 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 24 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 24 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 24 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 24 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 24 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 24 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 25 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 25 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 25 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 25 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 25 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 25 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 25 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 25 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 25 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 26 and a VL set forth in SEQ IDNO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 26 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 26 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 26 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 26 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 26 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 26 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 26 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 26 and a VL set forth in SEQ ID NO: 47. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 27 and a VL set forth in SEQ ID NO: 29. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 27 and a VL set forth in SEQ ID NO: 30. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 27 and a VL set forth in SEQ ID NO: 32. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 27 and a VL set forth in SEQ ID NO: 34. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 27 and a VL set forth in SEQ ID NO: 39. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 27 and a VL set forth in SEQ ID NO: 40. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 27 and a VL set forth in SEQ ID NO: 41. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 27 and a VL set forth in SEQ ID NO: 44. In some embodiments, the antibody or antigen binding fragment comprises a VH set forth in SEQ ID NO: 27 and a VL set forth in SEQ ID NO: 47. The above examples are non-limiting and any combinations are contemplated and provided by the present disclosure.

[0188] Also provided herein are antibodies that contain a VH region sequence that exhibits a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% to any of such VH region sequences in Table 3A, in which oneof the pH residues in Table 3A is present. Also provided herein are antibodies that contain a VL region sequence that exhibits a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% to any of such VLregion sequences in Table 3B, in which one of the pH residues in Table 3B is present. Also provided herein are antibodies that contain a VH region sequence that exhibits a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% to any of such VH region sequences in Table 3A, in which one of the pH residues in Table 3A is present; and a VL region sequence that exhibits a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% to any of such VL region sequences in Table 3B, in which one of the pH residues in Table 3B is present.

[0189] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89 and 98, respectively. In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises the sequence set forth in SEQ ID NO: 25 and the VL comprises the sequence set forth in SEQ ID NO: 29.

[0190] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67 and 68, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89 and 99, respectively. In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises the sequence set forth in SEQ ID NO: 23 and the VL comprises the sequence set forth in SEQ ID NO: 39.

[0191] In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, 72, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89 and 99, respectively. In some embodiments of the anti-CTLA-4 antibody or antigen-binding fragment, the VH region comprises the sequence set forth in SEQ ID NO: 25 and the VL comprises the sequence set forth in SEQ ID NO: 39.

[0192] In certain embodiments, antibody variable domains as described are fused to immunoglobulin constant domain sequences. In certain embodiments, the fusion is with an Ig heavy chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. In some of any of the embodiments herein, the antibody further comprises a heavy chain constantdomain and / or a light chain constant domain. In some embodiments, the heavy chain and / or light constant domain is murine or human.

[0193] A “constant region” or “constant domain” is a domain in an antibody heavy or light chain that contains a sequence of amino acids that is comparatively more conserved among antibodies than the variable region domain. The constant regions of immunoglobulins show less sequence diversity than the variable regions, and are responsible for binding a number of natural proteins to elicit important biochemical events. Each light chain has a single light chain constant region (CL) domain, which is either of the kappa or lambda type. Each heavy chain contains one or more heavy chain constant region (CH) domains that can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, having heavy chains designated ex, 8, e, y and p., respectively. Full-length IgA, IgD and IgG isotypes contain CHI, CH2, CH3 and a hinge region, while IgE and IgM contain CHI, CH2, CH3 and CH4. The y and ex classes are further divided into subclasses on the basis of relatively minor differences in the CH sequence and function, e.g., humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl and IgA2. IgGl antibodies can exist in multiple polymorphic variants termed allotypes (reviewed in Jefferis and Lefranc 2009. mAbs Vol 1 Issue 4 1-7) any of which are suitable. In humans there are five different classes of antibodies including IgA (which includes subclasses IgAl and IgA2), IgD, IgE, IgG (which includes subclasses IgGl, IgG2, IgG3, and IgG4), and IgM. The distinguishing features between these antibody classes are their constant, Fc regions, although subtler differences may exist in the V region. An antibody constant region can include an Fc portion. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region usually includes the region containing the CH2 and CH3 domains and the hinge region, such as an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof.

[0194] In certain embodiments, a provided antibody contains an Ig heavy chain constant domain comprising at least part of the hinge, CH2, and CH3 regions. Certain embodiments have the first heavy-chain constant region (CHI) containing the site necessary for light chain bonding, present in at least one of the fusions. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host cell. This provides for greater flexibility in adjusting the mutual proportions of the three polypeptide fragments inembodiments when unequal ratios of the three polypeptide chains used in the construction provide the optimum yield of the desired fusion antibody. It is, however, possible to insert the coding sequences for two or all three polypeptide chains into a single expression vector when the expression of at least two polypeptide chains in equal ratios results in high yields or when the ratios have no significant effect on the yield of the desired chain combination.

[0195] In some embodiments, the antibody or antigen-binding fragment thereof, may contain at least a portion of an immunoglobulin constant region, such as one or more constant region domain. In some embodiments, the constant regions include a light chain constant region and / or a heavy chain constant region 1 (CHI). In some embodiments, the antibody includes at least a portion of a hinge region or a variant thereof. In some embodiments, the antibody includes a CH2 and / or CH3 domain, such as an Fc region. In some embodiments, the Fc region is an Fc region from an IgAl, IgA2, IgD, IgE, IgGl, IgG2, IgG3, IgG4, or IgM.

[0196] In some embodiments, the heavy chain includes a variable heavy chain as described that is joined to a human constant region. In some embodiments, the human constant region includes the CH1-CH2-CH3 constant domains. In some embodiments, the human constant region is human IgGl or is derived from human IgGl, or is or is derived from a naturally occurring variant thereof. In some embodiments, the naturally occurring variant is an IgG allotype for instance with the K97R, D239E, or L241M mutation.

[0197] In some embodiments, the heavy chain constant region is mutated or modified, i.e., is a modified constant region. In some embodiments, the heavy chain constant region is a modified human IgG heavy chain constant region.

[0198] In some cases, the mutations include one or more amino acid substitutions in the heavy chain constant region, such as the heavy chain constant region of IgGl, to increase effector activity of the heavy chain constant region. In some embodiments, increased effector activity is an enhanced antibody dependent cell cytotoxicity (ADCC), such as mediated by FcyR-expressing cells. In some embodiments, the one or more amino acid substitutions results in binding to FcyRI. FcyRIIa or FcyRIIIa that is enhanced compared to an antibody in which the heavy chain constant region does not contain the one or more amino acid substitutions. In some embodiments, the enhanced binding to the Fcyl, Fcylla and / or Fey Illa receptor results in increased ADCC. Since an activity of the provided antibodies is to mediate depletion of CTLA- 4-expressing cells, such as Tregs, via ADCC, enhanced binding to the FcyR (e.g, FcyRI. FcyRIIa or FcyRIIIa) mediates a reduction of Tregs at the tumor site. Exemplary amino acidI l lsubstitutions in the heavy chain constant region to enhance FcR binding and / or ADCC can include any as described in U.S. Patent No. US7317091 or U.S. Patent No. 10196445, or any combination of any such described amino acid substitutions.

[0199] In in some embodiments, the heavy chain constant region contains at least one amino acid substitution selected from the group consisting of P230A, E233D, L234E, L234Y, L234I, L235D, L235S, L235Y, L235I, S239D, S239E, S239N, S239Q, S239T, V240I, V240M, F243L, V264I, V264T, V264Y, V266I, E272Y, K274T, K274E, K274R, K274L, K274Y, F275W, N276L, Y278T, V302I, E318R, S324D, S324I, S324V, N325T, K326I, K326T, L328M, L328I, L328Q, L328D, L328V, L328T, A330Y, A330L, A330I, I332D, I332E, I332N, I332Q, T335D, T335R, and T335Y, wherein the numbering of the residues in the Fc region is that of the EU index as in Kabat. In some embodiments, the heavy chain constant region contains at amino acid substitutions V264I, F243E / V264I, E328M, I332E, E328M / I332E, V264VI332E, S298A / I332E, S239E / I332E, S239Q / I332E, S239E, A330Y, I332D, E328VI332E, E328Q / I332E, V264T, V240I, V266I, S239D, S239D / I332D, S239D / I332E, S239D / I332N, S239D / I332Q, S239E / I332D, S239E / I332N, S239E / I332Q, S239N / I332D, S239N / I332E, S239Q / I332D, A330Y / I332E, V264VA330Y / I332E,A330E / I332E, V264VA330E / I332E, E234E, E234Y, E234I, E235D, E235S, E235Y, E235I, S239T, V240M, V264Y, A330I, N325T, E328D / I332E, E328V / I332E, E328T / I332E, E328VI332E, S239E / V264VI332E, S239Q / V264VI332E, S239E / V264VA330Y / I332E, S239D / A330Y / I332E, S239N / A330Y / I332E, S239D / A330E / I332E, S239N / A330E / I332E, V264VS298A / I332E, S239D / S298A / I332E, S239N / S298A / I332E, S239D / V264VI332E, S239D / V264VS298A / I332E, S239D / V264VA330E / I332E, S239D / I332E / A330I, P230A, P230A / E233D / I332E, E272Y, K274T, K274E, K274R, K274E, K274Y, F275W, N276E, Y278T, V302I, E318R, S324D, S324I, S324V, K326I, K326T, T335D, T335R, T335Y, V240VV266I, S239D / A330Y / I332E / E234I, S239D / A330Y / I332E / E235D,S239D / A330Y / I332E / V240I, S239D / A330Y / I332E / V264T, S239D / A330Y / I332E / K326E, or S239D / A330Y / I332E / K326T, wherein the numbering of the residues in the Fc region is that of the EU index as in Kabat.

[0200] In some embodiments, the mutation in the IgG (e.g., IgGl) heavy chain to enhance binding to FcyR-expressing cells is selected from one or more mutations G236A, S239D, S298A, A330E, I332E, E333A and K334A, wherein the numbering of the residues in the Fc region is that of the EU index as in Kabat. In some embodiments, the mutation in the IgG heavychain to enhance binding to FcyR-expressing cells is selected from mutations S239D and I332E. In some embodiments, the mutation in the IgG heavy chain to enhance binding to FcyR- expressing cells is selected from mutations S239D, A330L and I332E. In some embodiments, the mutation in the IgG heavy chain to enhance binding to FcyR-expressing cells is selected from mutations G236A, A330L and I332E. In some embodiments, the mutation in the IgG heavy chain to enhance binding to FcyR-expressing cells is selected from mutations G236A, S239D, A330E and I332E. In some embodiments, the mutation in the IgG heavy chain to enhance binding to FcyR-expressing cells is selected from mutations S298A, E333A and K334A.

[0201] In some embodiments, the mutation in the IgG heavy chain increase the affinity of IgG for the neonatal Fc receptor, FcRn, which prolongs the in vivo half-life of antibodies and results in increased anti-tumor activity. In some embodiments, the mutations in the IgG is M428E and / or N434S.

[0202] In some cases, the mutations include one or more amino acid substitutions to reduce effector activity of the heavy chain constant region. In some embodiments, the heavy chain constant region is modified to reduce effector activity of the antibody. In some embodiments, the modified human IgG heavy chain constant region has reduced effector activity. In some embodiments, effector activity is reduced compared to a wild-type human IgG heavy chain constant region. In some of any of the described embodiments, the modified human IgG heavy chain constant region is modified compared to the constant region of wildtype human IgGl. In some embodiments, the modified human IgG heavy chain constant region has a sequence that is modified by one or more amino acid substitutions compared to SEQ ID NO: 196 (or a naturally occurring variant thereof, e.g. with K97R, D239E or E241M mutations) and that exhibits at least 85%, at least 90%, at least 95% or at least 98% sequence identity to SEQ ID NO: 196 or the natural variant thereof and contains the one or more amino acid substitutions, for example to reduce effector activity of the heavy chain constant region.

[0203] Various examples of mutations to heavy chain constant regions to alter, such as reduce, effector function are known, including any as described below. In some embodiments, reference to amino acid substitutions in a heavy chain constant region is by EU numbering by Kabat (also called Kabat numbering) unless described with reference to a specific SEQ ID NO. EU numbering is known and is according to the most recently updated IMGT Scientific Chart (IMGT®, the international ImMunoGeneTics information system®,http: / / www.imgt.org / IMGTScientificChart / Numbering / Hu_IGHGnber.html (created: 17 May 2001, last updated: 10 Jan 2013) and the EU index as reported in Kabat, E.A. et al. Sequences of Proteins of Immunological interest. 5th ed. US Department of Health and Human Services, NIH publication No. 91-3242 (1991).

[0204] In some embodiments, the heavy chain constant region is modified to alter antibody-dependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC), e.g., the amino acid modifications described in Natsume et al., 2008 Cancer Res, 68(10): 3863-72; Idusogie et al., 2001 J Immunol, 166(4): 2571-5; Moore et al., 2010 mAbs, 2(2): 181-189; Lazar et al., 2006 PNAS, 103(11): 4005-4010, Shields et al., 2001 JBC, 276(9): 6591-6604; Stavenhagen et al., 2007 Cancer Res, 67(18): 8882...

Claims

CLAIMS1. An anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody or antigenbinding fragment thereof, comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), and a heavy chain complementarity determining region 3 (CDR-H3) contained within any one of SEQ ID NOs: 1-27 and 112, and the VL region comprises a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2) and a light chain complementarity determining region 3 (CDR-L3) contained within any one of SEQ ID NOs: 28-48 and 118, wherein the CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 49, 57, 68, 74, 89 and 98, respectively.

2. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 1, wherein: the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:1, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:3, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:4, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:5, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:6, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:7, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:8, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:9, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 10, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 11, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 12, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:13, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 14, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 15, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:16, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 17, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 18, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 19, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:20, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:21, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:22, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 118; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 28; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 29; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 30; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 31; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 32; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 33; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 112, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 34;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:2, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO:;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:26, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 39; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 22, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 39; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:27, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 39; or the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 5, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 48.

3. An anti-CTLA-4 antibody or antigen-binding fragment thereof, comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the sequence set forth in any one of SEQ ID NOs: 49-56, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in any one of SEQ ID NOs: 57-67, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in any one of SEQ ID NOs: 68-73; and the VL region comprises a light chain complementarity determining region 1 (CDR-L1) comprising the sequence set forth in any one of SEQ ID NOs: 74-88, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in any one of SEQ ID NOs: 89-97, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in any one of SEQ ID NOs: 98-100, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 49, 57, 68, 74, 89 and 98, respectively.

4. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-3, wherein the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the sequence set forth in any one of SEQ ID NOs: 50-56, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in any one of SEQ ID NOs: 58-67, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in any one of SEQ ID NOs: 69-73.

5. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claims 1-4, wherein the VL region comprises a light chain complementarity determining region 1 (CDR-L1) comprising the sequence set forth in any one of SEQ ID NOs: 75-88, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in any one of SEQ ID NOs: 90-97, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in any one of SEQ ID NOs: 99-100.

6. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-5, wherein: the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 58, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 69, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 51, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 50, 59, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 61, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 51, 62, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 50, 63, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 50, 57, and 69, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 53, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 53, 57, and 70, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 54, 57, and 71, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 55, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 56, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 64, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 60, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 66, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 71, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 73, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 75, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 77, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 78, 90, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 79, 90, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 80, 91, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 78, 89, and 99, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 81, 92, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 82, 89, and 98, respectively;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 82, 93, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 83, 92, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 100, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 86, 94, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 87, 95, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 96, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 88, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 74, 97, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 73, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 57, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 65, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively; or the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 88, 89, and 100, respectively.

7. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-6, wherein: the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:5, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:6, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%,8%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%,8%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 118; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:0, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:1, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:3, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:18; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,7%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:8; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:2, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%,%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39; or the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 5, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 48.

8. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-7, wherein the VH region and the VL region are or comprise: the sequence set forth in SEQ ID NO: 1 and 118, respectively; the sequence set forth in SEQ ID NO: 2 and 118, respectively; the sequence set forth in SEQ ID NO: 3 and 118, respectively; the sequence set forth in SEQ ID NO: 4 and 118, respectively; the sequence set forth in SEQ ID NO: 5 and 118, respectively; the sequence set forth in SEQ ID NO: 6 and 118, respectively; the sequence set forth in SEQ ID NO: 7 and 118, respectively; the sequence set forth in SEQ ID NO: 8 and 118, respectively; the sequence set forth in SEQ ID NO: 9 and 118, respectively; the sequence set forth in SEQ ID NO: 10 and 118, respectively; the sequence set forth in SEQ ID NO: 11 and 118, respectively; the sequence set forth in SEQ ID NO: 12 and 118, respectively; the sequence set forth in SEQ ID NO: 13 and 118, respectively; the sequence set forth in SEQ ID NO: 14 and 118, respectively; the sequence set forth in SEQ ID NO: 15 and 118, respectively; the sequence set forth in SEQ ID NO: 16 and 118, respectively; the sequence set forth in SEQ ID NO: 17 and 118, respectively; the sequence set forth in SEQ ID NO: 18 and 118, respectively; the sequence set forth in SEQ ID NO: 19 and 118, respectively; the sequence set forth in SEQ ID NO: 20 and 118, respectively; the sequence set forth in SEQ ID NO: 21 and 118, respectively; the sequence set forth in SEQ ID NO: 22 and 118, respectively; the sequence set forth in SEQ ID NO: 112 and 28, respectively; the sequence set forth in SEQ ID NO: 112 and 29, respectively; the sequence set forth in SEQ ID NO: 112 and 30, respectively; the sequence set forth in SEQ ID NO: 112 and 31, respectively; the sequence set forth inSEQ ID NO: 112 and 32, respectively; the sequence set forth in SEQ ID NO: 112 and 33, respectively; the sequence set forth in SEQ ID NO: 112 and 34, respectively; the sequence set forth in SEQ ID NO: 112 and 35, respectively; the sequence set forth in SEQ ID NO: 112 and 36, respectively; the sequence set forth in SEQ ID NO: 112 and 37, respectively; the sequence set forth in SEQ ID NO: 112 and 38, respectively; the sequence set forth in SEQ ID NO: 112 and 39, respectively; the sequence set forth in SEQ ID NO: 112 and 40, respectively; the sequence set forth in SEQ ID NO: 112 and 41, respectively; the sequence set forth in SEQ ID NO: 112 and 42, respectively; the sequence set forth in SEQ ID NO: 112 and 43, respectively; the sequence set forth in SEQ ID NO: 112 and 44, respectively; the sequence set forth in SEQ ID NO: 112 and 45, respectively; the sequence set forth in SEQ ID NO: 112 and 46, respectively; the sequence set forth in SEQ ID NO: 23 and 41, respectively; the sequence set forth in SEQ ID NO: 24 and 41, respectively; the sequence set forth in SEQ ID NO: 25 and 41, respectively; the sequence set forth in SEQ ID NO: 26 and 41, respectively; the sequence set forth in SEQ ID NO:22 and 41, respectively; the sequence set forth in SEQ ID NO: 27 and 41, respectively; the sequence set forth in SEQ ID NO: 23 and 47, respectively; the sequence set forth in SEQ ID NO: 24 and 47, respectively; the sequence set forth in SEQ ID NO: 25 and 47, respectively; the sequence set forth in SEQ ID NO: 26 and 47, respectively; the sequence set forth in SEQ ID NO: 22 and 47, respectively; the sequence set forth in SEQ ID NO: 27 and 47, respectively; the sequence set forth in SEQ ID NO:23 and 29, respectively; the sequence set forth in SEQ ID NO: 24 and 29, respectively; the sequence set forth in SEQ ID NO: 25 and 29, respectively; the sequence set forth in SEQ ID NO: 26 and 29, respectively; the sequence set forth in SEQ ID NO: 22 and 29, respectively; the sequence set forth in SEQ ID NO: 27 and 29, respectively; the sequence set forth in SEQ ID NO: 23 and 39, respectively; the sequence set forth in SEQ ID NO: 24 and 39, respectively; the sequence set forth in SEQ ID NO: 25 and 39, respectively; the sequence set forth in SEQ ID NO: 26 and 39, respectively; the sequence set forth in SEQ ID NO: 22 and 39, respectively; the sequence set forth in SEQ ID NO: 27 and 39, respectively; or the sequence set forth in SEQ ID NO: 5 and 48, respectively.

9. An anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody or antigenbinding fragment thereof, comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region and the VL region are or comprise: the sequence set forth in SEQ ID NO: 1 and 118, respectively; the sequence set forth in SEQ ID NO: 2 and 118, respectively; the sequence set forth in SEQ ID NO: 3 and 118, respectively; the sequence set forth in SEQ ID NO: 4 and 118, respectively; the sequence set forth in SEQ ID NO: 5 and 118, respectively; the sequence set forth in SEQ ID NO: 6 and 118, respectively; the sequence set forth in SEQ ID NO: 7 and 118, respectively; the sequence set forth in SEQ ID NO: 8 and 118, respectively; the sequence set forth in SEQ ID NO: 9 and 118, respectively; the sequence set forth in SEQ ID NO: 10 and 118, respectively; the sequence setforth in SEQ ID NO: 11 and 118, respectively; the sequence set forth in SEQ ID NO: 12 and 118, respectively; the sequence set forth in SEQ ID NO: 13 and 118, respectively; the sequence set forth in SEQ ID NO: 14 and 118, respectively; the sequence set forth in SEQ ID NO: 15 and 118, respectively; the sequence set forth in SEQ ID NO: 16 and 118, respectively; the sequence set forth in SEQ ID NO: 17 and 118, respectively; the sequence set forth in SEQ ID NO: 18 and 118, respectively; the sequence set forth in SEQ ID NO: 19 and 118, respectively; the sequence set forth in SEQ ID NO: 20 and 118, respectively; the sequence set forth in SEQ ID NO: 21 and 118, respectively; the sequence set forth in SEQ ID NO: 22 and 118, respectively; the sequence set forth in SEQ ID NO: 112 and 28, respectively; the sequence set forth in SEQ ID NO: 112 and 29, respectively; the sequence set forth in SEQ ID NO: 112 and 30, respectively; the sequence set forth in SEQ ID NO: 112 and 31, respectively; the sequence set forth in SEQ ID NO: 112 and 32, respectively; the sequence set forth in SEQ ID NO: 112 and 33, respectively; the sequence set forth in SEQ ID NO: 112 and 34, respectively; the sequence set forth in SEQ ID NO: 112 and 35, respectively; the sequence set forth in SEQ ID NO: 112 and 36, respectively; the sequence set forth in SEQ ID NO: 112 and 37, respectively; the sequence set forth in SEQ ID NO: 112 and 38, respectively; the sequence set forth in SEQ ID NO: 112 and 39, respectively; the sequence set forth in SEQ ID NO: 112 and 40, respectively; the sequence set forth in SEQ ID NO: 112 and 41, respectively; the sequence set forth in SEQ ID NO: 112 and 42, respectively; the sequence set forth in SEQ ID NO: 112 and 43, respectively; the sequence set forth in SEQ ID NO: 112 and 44, respectively; the sequence set forth in SEQ ID NO: 112 and 45, respectively; the sequence set forth in SEQ ID NO: 112 and 46, respectively; the sequence set forth in SEQ ID NO: 23 and 41, respectively; the sequence set forth in SEQ ID NO: 24 and 41, respectively; the sequence set forth in SEQ ID NO: 25 and 41, respectively; the sequence set forth in SEQ ID NO: 26 and 41, respectively; the sequence set forth in SEQ ID NO: 22 and 41, respectively; the sequence set forth in SEQ ID NO: 27 and 41, respectively; the sequence set forth in SEQ ID NO: 23 and 47, respectively; the sequence set forth in SEQ ID NO: 24 and 47, respectively; the sequence set forth in SEQ ID NO: 25 and 47, respectively; the sequence set forth in SEQ ID NO: 26 and 47, respectively; the sequence set forth in SEQ ID NO: 22 and 47, respectively; the sequence set forth in SEQ ID NO: 27 and 47, respectively; the sequence set forth in SEQ ID NO: 23 and 29, respectively; the sequence set forth in SEQ ID NO: 24 and 29, respectively; the sequence set forth in SEQ ID NO: 25 and 29, respectively; the sequence set forth in SEQ ID NO:26 and 29, respectively; the sequence set forth in SEQ ID NO: 22 and 29, respectively; the sequence set forth in SEQ ID NO: 27 and 29, respectively; the sequence set forth in SEQ ID NO: 23 and 39, respectively; the sequence set forth in SEQ ID NO: 24 and 39, respectively; the sequence set forth in SEQ ID NO: 25 and 39, respectively; the sequence set forth in SEQ ID NO: 26 and 39, respectively; the sequence set forth in SEQ ID NO: 22 and 39, respectively; the sequence set forth in SEQ ID NO:27 and 39, respectively; or the sequence set forth in SEQ ID NO: 5 and 48, respectively.

10. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-9, wherein the VH region comprises one or more amino acid residues selected from the group consisting of: a histidine (H) at position 98, an arginine (R) at position 31, a glutamic acid (E) or a histidine (H) at position 53, a histidine (H) at position 58, and a histidine (H) at position 97, or any combination thereof, and / or the VL region comprises one or more amino acid residues selected from the group consisting of: a histidine (H) at position 27a, a histidine (H) at position 30, a histidine (H) at position 31 , and a histidine (H) at position 90, or any combination thereof, wherein numbering of amino acid residues is by Kabat numbering.

11. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-10 wherein the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 85, 89, and 98, respectively, optionally wherein the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 25 and the VL region comprises the sequence of amino acids set forth in SEQ ID NO: 41.

12. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-10, wherein the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 98, respectively, optionally wherein the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 23 and the VL region comprises the sequence of amino acids set forth in SEQ ID NO: 47.

13. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-10, wherein the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 76, 89, and 98, respectively, optionally wherein the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 25 and the VL region comprises the sequence of amino acids set forth in SEQ ID NO: 29.

14. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-10, wherein the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 49, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively,optionally wherein the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 23 and the VL region comprises the sequence of amino acids set forth in SEQ ID NO: 39.

15. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-10, wherein the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 60, and 72, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively, optionally wherein the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 25 and the VL region comprises the sequence of amino acids set forth in SEQ ID NO: 39.

16. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-10, wherein the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 52, 67, and 68, respectively, and the VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 84, 89, and 99, respectively, optionally wherein the VH region comprises the sequence of amino acids set forth in SEQ ID NO: 26 and the VL region comprises the sequence of amino acids set forth in SEQ ID NO: 39.

17. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-16, wherein the antibody is a full length antibody.

18. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 17, wherein the full length antibody comprises a constant region (Fc) from an IgAl, IgA2, IgD, IgE, IgGl, IgG2, IgG3, IgG4, or IgM.

19. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 18, wherein the constant region is a human IgGl heavy chain constant region.

20. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 19, wherein the human IgGl heavy chain constant region comprises one or more of mutations selected from the group consisting of G236A, S239D, M252Y, S254T, T256E, A330L, I332E, M428L, and N434S, numbered according to the EU numbering system.

21. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 19 or 20, wherein the human IgGl heavy chain constant region comprises S239D / A330L / I332E mutations, numbered according to the EU numbering system.

22. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 19 or 20, wherein the antibody comprises a human IgGl heavy chain constant region comprising S239D / I332E mutations, numbered according to the EU numbering system.

23. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 19 or 20, wherein the antibody comprises a human IgGl heavy chain constant region comprising G236A / S239D / A330L / I332E mutations, numbered according to the EU numbering system.

24. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 19 or 20, wherein the antibody comprises a human IgGl heavy chain constant region comprising G236A / A330L / I332E mutations, numbered according to the EU numbering system.

25. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 19 or 20, wherein the antibody comprises a human IgGl heavy chain constant region comprising M252Y / S254T / T256E mutations, numbered according to the EU numbering system.

26. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 19 or 20, wherein the antibody comprises a human IgGl heavy chain constant region comprising M428L / N434S mutations, numbered according to the EU numbering system.

27. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-16, wherein the antibody is an antigen-binding fragment.

28. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 27, wherein the antigen-binding fragment is selected from the group consisting of a single domain antibody, a single chain antibody, an unibody, a single chain variable fragment (scFv), a Fab fragment, and a F(ab')2 fragment.

29. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-16, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof is recombinant.

30. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-29, wherein the VH region and the VL region is human or is from a human protein.

31. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-30, wherein the ratio of dissociation constant for binding at acidic pH (e.g., pH 5.0 to 6.0) to the dissociation constant for binding at physiological pH (e.g., pH 7.35 to 7.45) to human CTLA-4 protein is greater than 2.

32. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-31, wherein the antibody or antigen-binding fragment exhibits a ratio of a dissociation constant for binding at acidic pH (e.g., pH 5.0 to 6.0) to dissociation constant for binding at physiological pH (e.g., pH 7.35 to 7.45) of more than 7.

33. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-32, wherein the ratio of EC50 value of the antibody or antigen-binding fragment thereof for human CTLA- 4 at physiological pH (e.g., pH 7.35 to 7.45) to EC50 value of the antibody or antigen-binding fragment thereof for human CTLA-4 at acidic pH (e.g., pH 5.0 to 6.0) is greater than 2.

34. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-33, wherein the antibody or antigen-binding fragment thereof possesses pH dependent binding properties to human CTLA-4 that facilitates the dissociation of antibody from the antibody: CTLA-4 complex upon internalization into a cell, allowing either the antibody, CTLA-4, or both to be recycled instead of being degraded in the lysosome.

35. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-34, wherein the antibody or antigen-binding fragment thereof preserves high affinity for CTLA-4 at pH>7, lower affinity at pH 5.5-7, and significantly reduced affinity for CTLA-4 at pH<5.5.

36. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-35, wherein the antibody or antigen-binding fragment thereof induces strong deletion of Treg and local T cell activation in tumor microenvironment but minimal systemic T cell activation.

37. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-36, wherein the antibody or antigen-binding fragment thereof induces a favorable ratio of regulatory T cells (Treg cells) to T effector cells in the tumor microenvironment.

38. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-37, wherein the antibody or antigen-binding fragment thereof induces a favorable ratio of immune cell subsets in the tumor or blood.

39. The anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-38, wherein the antibody or antigen-binding fragment induces a favorable ratio of CTLA-4 expression on immune cell subsets in the tumor or blood.

40. The anti-CTLA-4 antibody or antigen-binding fragment thereof of claim 38 or 39, wherein the immune cell subsets comprise myeloid cells, T cells, CD4+T cells, CD8+T cells, and / or Treg cells.

41. A conjugate, comprising the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-40 and a heterologous molecule or moiety.

42. The conjugate of claim 41, wherein the heterologous molecule or moiety is a cytotoxic agent, a drug, enzymatically active toxin or fragment thereof, or a radioactive atom.

43. A bispecific antibody, comprising the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-40.

44. A polynucleotide comprising a nucleic acid encoding the anti-CTLA-4 antibody or antigen-binding domain thereof of any of claims 1-40.

45. A vector, comprising the polynucleotide of claim 44.

46. The vector of claim 45, wherein the vector is a viral vector.

47. The vector of claim 46, wherein the viral vector is a retroviral vector or a lentiviral vector.

48. A cell comprising the polynucleotide of claim 41, or the vector of any of claims 45-47.

49. The cell of claim 48, wherein the cell is a mammalian cell.

50. A method of producing an antibody comprising culturing the cell of claim 48 or 49 under a condition that produces the antibody.

51. The method of claim 50, further comprising recovering the antibody produced by the cell.

52. An antibody or antigen-binding fragment thereof produced by the method of claim 50 or claim 51.

53. A composition comprising the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-40 and 52, the conjugate of claim 41 or 42, the bispecific antibody of claim 43.

54. The composition of claim 53, further comprising a pharmaceutically acceptable excipient.

55. A method of stimulating an immune response in a subject, the method comprising administering to a subject in need thereof the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-40 and 52, the conjugate of claim 41 or 42, the bispecific antibody of claim 43 or the composition of claim 53 or 54.

56. The method of claim 55, wherein stimulating an immune response treats a disease or condition in the subject.

57. The method of claim 56, wherein the disease or condition is a cancer.

58. A method of cancer immunotherapy, the method comprising administering to a subject in need thereof a therapeutically effective amount of the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-40 and 52, the conjugate of claim 41 or 42, the bispecific antibody of claim 43 or the composition of claim 53 or 54.

59. The method of claim 58, wherein the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-40 and 52, the conjugate of claim 41 or 42, the bispecific antibody of claim 43 or the composition of claim 53 or 54 is administered to the subject in need thereof at about 0.01 pg / kg body weight to about 20 mg / kg body weight.

60. The method of claim 58 or 59, further comprising administering to the subject an effective amount of at least one additional therapeutic agent.

61. The method of claim 60, wherein the at least one additional therapeutic agent is selected from the group consisting of: viral gene therapy, immune checkpoint inhibitors, target therapies, radiation therapies, vaccination therapies, and chemotherapies.

62. The method of claim 61 , wherein the at least one additional therapeutic agent is selected from the group consisting of: pomalyst, revlimid, lenalidomide, pomalidomide, thalidomide, a DNA- alkylating platinum-containing derivative, cisplatin, 5-fluorouracil, cyclophosphamide, an anti-CD137 antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, an anti-CD20 antibody, an anti-CD40 antibody, an anti-DR5 antibody, an anti-CDld antibody, an anti-TIM3 antibody, an anti-SLAMF7 antibody, an anti-KIR receptor antibody, an anti-OX40 antibody, an anti-HER2 antibody, an anti-ErbB- 2 antibody, an anti-EGFR antibody, cetuximab, rituximab, trastuzumab, pembrolizumab, an antibody drug conjugation, radiotherapy, single dose radiation, fractionated radiation, focal radiation, whole organ radiation, IL-12, IFNa, GM-CSF, a chimeric antigen receptor, adoptively transferred T cells, an anti-cancer vaccine, and an oncolytic virus.

63. The method of any of claims 58-62, wherein the method comprises administering to the subject an effective amount of the anti-CTLA-4 antibody or antigen-binding fragment thereof of any of claims 1-40 and 52, the conjugate of claim 41 or 42, the bispecific antibody of claim 43 or the composition of claim 53 or 54 prior to a surgery or after a surgery to remove a solid tumor in the subject.

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