Anti-PD-1 antibodies and related binding molecules and methods and uses thereof

Abstract

Provided are novel monoclonal antibodies or antibody fragments against protein programmed cell death 1 (PD-1). The antibodies or antibody fragments disclosed can block the binding of the PD- L1 ligand to PD-1 and provide potent agents for the treatment of cancers via the modulation of human immune function. Also provided are novel multispecific antibodies directed against PD-1 and cytotoxic T-lymphocyte-associated protein 4 CTLA-4.

Description

ANTI-PD-1 ANTIBODIES AND RELATED BINDING MOLECULES AND METHODS AND USES THEREOFCross-Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 648,094 filed on May 15, 2024, and to U.S. Provisional Patent Application No. 63 / 757,775 filed on February 12, 2025, the contents of each of which are incorporated by reference in their entirety.Reference to Electronic 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 281632000340SeqList.xml created May 14, 2025, which is 542,096 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 programmed cell death 1 (PD-1). The antibodies or antibody fragments disclosed can block the binding of the PD-L1 ligand to PD-1 and provide potent agents for the treatment of cancers via the modulation of human immune function. The present disclosure also provides binding molecules, such as bispecific antibodies, directed against PD-1 and also cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The present disclosure further relates to pharmaceutical composition and methods and uses of such antibodies and binding molecules for treatment of disease in which specific targeting of cells that express PD-1, or PD-1 and CTLA-4, is desired.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.

[0005] Interaction of PD-1, a type I cell surface receptor, with either of its two ligands, PD-L1 or PD-L2, results in a dominant negative checkpoint signal that limits subsequent antigen receptor-driven cellular activation. The ligands for PD-1 are differentially expressed on various tissues and cell types,including antigen-presenting cells of the immune system, and are upregulated on many types of tumor cells. Upregulation of PD-L1 within the tumor microenvironment is a proposed mechanism of tumors to subvert protective anti-tumor immune responses by the host. Antibodies directed at PD-1 that block the interaction of the receptor with either of its ligands hold promise in the treatment of many cancers, and many such molecules are in the clinic for use as monotherapy or in combination with other biologies. Though antibodies against PD1 are known and commercially available, it is desirable to find novel anti-PDl antibodies suitable for cancer treatments with improved efficacy and reduced side effects. Embodiments provided herein address these needs.Summary

[0006] In some embodiments, provided herein is an anti-programmed cell death protein 1 (PD-1) 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: 1-45, 157, and 165-170, 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: 46-90, 158, and 171-172.

[0007] In some embodiments, 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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-L3contained within SEQ ID NO: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; the VH region comprises a CDR-H1, 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:28, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:29, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:30, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:31, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:32, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:33, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:34, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:36, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:38, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:39, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:41, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:43, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:44, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:45, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3contained within SEQ ID NO: 46; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, 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: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 48; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 49; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 50; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 51; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 52; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 53; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 54; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 55; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 56; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 57; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 58; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 59; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 60; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 61; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 62; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 63; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3contained within SEQ ID NO: 64; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 65; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 66; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 67; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 68; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 69; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 70; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 71; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 72; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 73; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 74; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 75; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 76; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 77; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 78; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 80; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 81; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3contained within SEQ ID NO: 82; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 83; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 84; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 85; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 86; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 87; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 88; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 90; 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: 47; the VH region comprises a CDR-H1, 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: 35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 76; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 81; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 84; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 76; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3contained within SEQ ID NO: 81; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 84; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 76; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 81; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 84; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 76; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 81; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 84; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 165, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 165, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 165, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 166, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 166, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 166, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3contained within SEQ ID NO: 172; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 167, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 167, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 167, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 168, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 168, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 168, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 169, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 169, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 169, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 170, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 170, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; or the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 170, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172.

[0008] In some embodiments, provided herein is an anti-PD-1 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: 91-101, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in any one of SEQ ID NOs: 102- 112, and 173, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in any one of SEQ ID NOs: 113-123; 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: 124-134, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in any one of SEQ ID NOs: 135-145, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in any one of SEQ ID NOs:146-156.

[0009] In some embodiments, 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: 92-101, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in any one of SEQ ID NOs: 103-112, and 173, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in any one of SEQ ID NOs: 114-123.

[0010] In some embodiments, 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: 125-134, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in any one of SEQ ID NOs: 136-145, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in any one of SEQ ID NOs: 147-156.

[0011] In any of the embodiments herein, the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 92, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 93, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 94, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 96, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 97, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 102, and 113, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 101, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3comprise the sequences set forth in SEQ ID NOS: 91, 103, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 104, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 105, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 106, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 107, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 108, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 109, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 110, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 111, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 112, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 116, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 117, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102,and 118, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 119, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 120, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 122, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 123, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 101, 103, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 97, 103, and 117, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 96, 104, and 116, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 96, 107, and 117, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 97, 105, and 117, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 97, 111, and 116, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forthin SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 93, 103, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 108, and 119, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 116, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 127, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 128, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 129, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 130, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, theCDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 133, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 134, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprisethe sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 136, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 137, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 138, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 139, and 146, respectively; the CDR-H1, theCDR-H2, and theCDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 140, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 141, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 142, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 143, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 144, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 145, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 147, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 148, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 150, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2,and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 151, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 152, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 155, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 156, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 139, and 150, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 128, 138, and 148, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 144, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 140, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 137, and 152, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 152, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 141, and 154, respectively; theCDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 133, 144, and 150, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 134, 138, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 137, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 137, and 152, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 142, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 127, 140, and 151, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 106, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 140, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 141, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 142, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106,and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 140, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 141, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 142, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 140, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 141, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 142, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 140, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 141, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 142, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprisethe sequences set forth in SEQ ID NOS: 126, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 143 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 105 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 105 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 105 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 143 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 143 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 106 and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 106 and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 145 and 153, respectively; or the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 106 and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 143 and 153, respectively.

[0012] In any of the embodiments herein, the VH region 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: 1 and SEQ ID NO: 158, respectively; the VH region 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: 2 and SEQ ID NO: 158, respectively; the VH region 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: 3 and SEQ ID NO: 158, respectively; the VH region 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: 4 and SEQ ID NO: 158, respectively; the VH region 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: 5 and SEQ ID NO: 158, respectively; the VH region 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: 6 and SEQ ID NO: 158, respectively; the VH region 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: 7 and SEQ ID NO: 158, respectively; the VH region 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: 8 and SEQ ID NO: 158, respectively; the VH region 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: 9 and SEQ ID NO: 158, respectively; the VH region 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: 10 and SEQ ID NO: 158, respectively; the VH region 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: 11 and SEQ ID NO: 158, respectively; the VH region 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: 12 and SEQ ID NO: 158, respectively; the VH region 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: 13 and SEQ ID NO: 158, respectively; the VH region 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: 14 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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: 16 and SEQ ID NO: 158, respectively; the VH region 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: 17 and SEQ ID NO: 158, respectively; the VH region and the VL region is orcomprises an amino acid sequence having at least 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 SEQ ID NO: 158, respectively; the VH region 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: 19 and SEQ ID NO: 158, respectively; the VH region 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: 20 and SEQ ID NO: 158, respectively; the VH region 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: 21 and SEQ ID NO: 158, respectively; the VH region 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: 22 and SEQ ID NO: 158, respectively; the VH region 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: 23 and SEQ ID NO: 158, respectively; the VH region 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: 24 and SEQ ID NO: 158, respectively; the VH region 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: 25 and SEQ ID NO: 158, respectively; the VH region 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: 26 and SEQ ID NO: 158, respectively; the VH region 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: 27 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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: 34 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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: 36 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 or ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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: 157 and SEQ ID NO: 46, respectively; the VH region 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: 157 and SEQ ID NO: 47, respectively; the VH region 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: 157 and SEQ ID NO: 48, respectively; the VH region 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: 157 and SEQ ID NO: 49, respectively; the VH region 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: 157 and SEQ ID NO: 50, respectively; the VH region 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: 157 and SEQ ID NO: 51, respectively; the VH region 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: 157 and SEQ ID NO: 52, respectively; the VH region 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: 157 and SEQ ID NO: 53, respectively; the VH region 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: 157 and SEQ ID NO: 54, respectively; the VH region 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: 157 and SEQ ID NO: 55, respectively; the VH region 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: 157 and SEQ ID NO: 56, respectively; the VH region 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: 157 and SEQ ID NO: 57, respectively; the VH region 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: 157 and SEQ ID NO: 58, respectively; the VH region 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: 157 and SEQ ID NO: 59, respectively; the VH region 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: 157 and SEQ ID NO: 60, respectively; the VH region 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: 157 and SEQ ID NO: 61, respectively; the VH region 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: 157 and SEQ ID NO: 62, respectively; the VH region 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: 157 and SEQ ID NO: 63, respectively; the VH region 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: 157 and SEQ ID NO: 64, respectively; the VH region 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: 157 and SEQ ID NO: 65, respectively; the VH region 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: 157 and SEQ ID NO: 66, respectively; the VH region 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: 157 or ID NO: 67, respectively; the VH region 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: 157 and SEQ ID NO: 68, respectively; the VH region 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: 157 and SEQ ID NO: 69, respectively; the VH region 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: 157 and SEQ ID NO: 70, respectively; the VH region 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: 157 and SEQ ID NO: 71, respectively; the VH region 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: 157 and SEQ ID NO: 72, respectively; the VH region 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: 157 and SEQ ID NO: 73, respectively; the VH region 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: 157 and SEQ ID NO: 74, respectively; the VH region 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: 157 and SEQ ID NO: 75, respectively; the VH region and the VL region is orcomprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 157 and SEQ ID NO: 76, respectively; the VH region 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: 157 and SEQ ID NO: 77, respectively; the VH region 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: 157 and SEQ ID NO: 78, respectively; the VH region 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: 157 and SEQ ID NO: 79, respectively; the VH region 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: 157 and SEQ ID NO: 80, respectively; the VH region 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: 157 and SEQ ID NO: 81, respectively; the VH region 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: 157 and SEQ ID NO: 82, respectively; the VH region 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: 157 and SEQ ID NO: 83, respectively; the VH region 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: 157 and SEQ ID NO: 84, respectively; the VH region 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: 157 and SEQ ID NO: 85, respectively; the VH region 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: 157 and SEQ ID NO: 86, respectively; the VH region 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: 157 and SEQ ID NO: 87, respectively; the VH region 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: 157 and SEQ ID NO: 88, respectively; the VH region 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: 157 and SEQ ID NO: 89, respectively; the VH region 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: 157 and SEQ ID NO: 90, respectively; the VH region 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: 16 and SEQ ID NO: 47, respectively; the VH region 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: 23 and SEQ ID NO: 47, respectively; the VH region 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 and SEQ ID NO: 76, respectively; the VH region 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 and SEQ ID NO: 79, respectively; the VH region 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 and SEQ ID NO: 81, respectively; the VH region 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 and SEQ ID NO: 84, respectively; the VH region 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 and SEQ ID NO: 89, respectively; the VH region 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 and SEQ ID NO: 76, respectively; the VH region 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 and SEQ ID NO: 79, respectively; the VH region 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 and SEQ ID NO: 81, respectively; the VH region 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 and SEQ ID NO: 84, respectively; the VH region 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 and SEQ ID NO: 89, respectively; the VH region 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 and SEQ ID NO: 76, respectively; the VH region 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 and SEQ ID NO: 79,respectively; the VH region 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 and SEQ ID NO: 81, respectively; the VH region 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 and SEQ ID NO: 84, respectively; the VH region 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 and SEQ ID NO: 89, respectively; the VH region 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 and SEQ ID NO: 76, respectively; the VH region 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 and SEQ ID NO: 79, respectively; the VH region 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 and SEQ ID NO: 81, respectively; the VH region 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 and SEQ ID NO: 84, respectively; the VH region 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 and SEQ ID NO: 89, respectively; the VH region 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: 165 and SEQ ID NO: 79, respectively; the VH region 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: 165 and SEQ ID NO: 171, respectively; the VH region 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: 165 and SEQ ID NO: 172, respectively; the VH region 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: 166 and SEQ ID NO: 79, respectively; the VH region 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: 166 and SEQ ID NO: 171, respectively; the VH region 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: 166 and SEQ ID NO: 172, respectively; the VH region and the VL region is or comprises 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: 167 and SEQ ID NO: 79, respectively; the VH region 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: 167 and SEQ ID NO: 171, respectively; the VH region 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: 167 and SEQ ID NO: 172, respectively; the VH region 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: 168 and SEQ ID NO: 79, respectively; the VH region 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: 168 and SEQ ID NO: 171, respectively; the VH region 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: 168 and SEQ ID NO: 172, respectively; the VH region 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: 169 and SEQ ID NO: 79, respectively; the VH region 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: 169 and SEQ ID NO: 171, respectively; the VH region 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: 169 and SEQ ID NO: 172, respectively; the VH region 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: 170 and SEQ ID NO: 79, respectively; the VH region 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: 170 and SEQ ID NO: 171, respectively; or the VH region 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: 170 and SEQ ID NO: 172, respectively.

[0013] 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 158, respectively; the sequence set forth in SEQ ID NO: 2 and 158, respectively; the sequence set forth in SEQ ID NO: 3 and 158, respectively; the sequence set forth in SEQ ID NO: 4 and 158, respectively; the sequence set forth in SEQ ID NO: 5 and 158, respectively; the sequence set forth in SEQ ID NO: 6 and 158, respectively; the sequence set forth in SEQ ID NO: 7 and 158, respectively; the sequence set forth in SEQ ID NO: 8 and 158, respectively;the sequence set forth in SEQ ID NO: 9 and 158, respectively; the sequence set forth in SEQ ID NO: 10 and 158, respectively; the sequence set forth in SEQ ID NO: 11 and 158, respectively; the sequence set forth in SEQ ID NO: 12 and 158, respectively; the sequence set forth in SEQ ID NO: 13 and 158, respectively; the sequence set forth in SEQ ID NO: 14 and 158, respectively; the sequence set forth in SEQ ID NO: 15 and 158, respectively; the sequence set forth in SEQ ID NO: 16 and 158, respectively; the sequence set forth in SEQ ID NO: 17 and 158, respectively; the sequence set forth in SEQ ID NO: 18 and 158, respectively; the sequence set forth in SEQ ID NO: 19 and 158, respectively; the sequence set forth in SEQ ID NO: 20 and 158, respectively; the sequence set forth in SEQ ID NO: 21 and 158, respectively; the sequence set forth in SEQ ID NO: 22 and 158, respectively; the sequence set forth in SEQ ID NO: 23 and 158, respectively; the sequence set forth in SEQ ID NO: 24 and 158, respectively; the sequence set forth in SEQ ID NO: 25 and 158, respectively; the sequence set forth in SEQ ID NO: 26 and 158, respectively; the sequence set forth in SEQ ID NO: 27 and 158, respectively; the sequence set forth in SEQ ID NO: 28 and 158, respectively; the sequence set forth in SEQ ID NO: 29 and 158, respectively; the sequence set forth in SEQ ID NO: 30 and 158, respectively; the sequence set forth in SEQ ID NO: 31 and 158, respectively; the sequence set forth in SEQ ID NO: 32 and 158, respectively; the sequence set forth in SEQ ID NO: 33 and 158, respectively; the sequence set forth in SEQ ID NO: 34 and 158, respectively; the sequence set forth in SEQ ID NO: 35 and 158, respectively; the sequence set forth in SEQ ID NO: 36 and 158, respectively; the sequence set forth in SEQ ID NO: 37 and 158, respectively; the sequence set forth in SEQ ID NO: 38 and 158, respectively; the sequence set forth in SEQ ID NO: 39 and 158, respectively; the sequence set forth in SEQ ID NO: 40 and 158, respectively; the sequence set forth in SEQ ID NO: 41 and 158, respectively; the sequence set forth in SEQ ID NO: 42 and 158, respectively; the sequence set forth in SEQ ID NO: 43 and 158, respectively; the sequence set forth in SEQ ID NO: 44 and 158, respectively; the sequence set forth in SEQ ID NO: 45 and 158, respectively; the sequence set forth in SEQ ID NO: 157 and 46, respectively; the sequence set forth in SEQ ID NO: 157 and 47, respectively; the sequence set forth in SEQ ID NO: 157 and 48, respectively; the sequence set forth in SEQ ID NO: 157 and 49, respectively; the sequence set forth in SEQ ID NO: 157 and 50, respectively; the sequence set forth in SEQ ID NO: 157 and 51, respectively; the sequence set forth in SEQ ID NO: 157 and 52, respectively; the sequence set forth in SEQ ID NO: 157 and 53, respectively; the sequence set forth in SEQ ID NO: 157 and 54, respectively; the sequence set forth in SEQ ID NO: 157 and 55, respectively; the sequence set forth in SEQ ID NO: 157 and 56, respectively; the sequence set forth in SEQ ID NO: 157 and 57, respectively; the sequence set forth in SEQ ID NO: 157 and 58, respectively; the sequence set forth in SEQ ID NO: 157 and 59, respectively; the sequence set forth in SEQ ID NO: 157 and 60, respectively; the sequence set forth in SEQ ID NO: 157 and 61, respectively; the sequence set forth in SEQ ID NO: 157 and 62, respectively; the sequence set forth in SEQ ID NO: 157 and 63, respectively; the sequence set forth in SEQ ID NO: 157 and 64, respectively; the sequence set forth in SEQ ID NO: 157 and 65, respectively; the sequence set forth in SEQ ID NO:157 and 66, respectively; the sequence set forth in SEQ ID NO: 157 and 67, respectively; the sequence set forth in SEQ ID NO: 157 and 68, respectively; the sequence set forth in SEQ ID NO: 157 and 69, respectively; the sequence set forth in SEQ ID NO: 157 and 70, respectively; the sequence set forth in SEQ ID NO: 157 and 71, respectively; the sequence set forth in SEQ ID NO: 157 and 72, respectively; the sequence set forth in SEQ ID NO: 157 and 73, respectively; the sequence set forth in SEQ ID NO: 157 and 74, respectively; the sequence set forth in SEQ ID NO: 157 and 75, respectively; the sequence set forth in SEQ ID NO: 157 and 76, respectively; the sequence set forth in SEQ ID NO: 157 and 77, respectively; the sequence set forth in SEQ ID NO: 157 and 78, respectively; the sequence set forth in SEQ ID NO: 157 and 79, respectively; the sequence set forth in SEQ ID NO: 157 and 80, respectively; the sequence set forth in SEQ ID NO: 157 and 81, respectively; the sequence set forth in SEQ ID NO: 157 and 82, respectively; the sequence set forth in SEQ ID NO: 157 and 83, respectively; the sequence set forth in SEQ ID NO: 157 and 84, respectively; the sequence set forth in SEQ ID NO: 157 and 85, respectively; the sequence set forth in SEQ ID NO: 157 and 86, respectively; the sequence set forth in SEQ ID NO: 157 and 87, respectively; the sequence set forth in SEQ ID NO: 157 and 88, respectively; the sequence set forth in SEQ ID NO: 157 and 89, respectively; the sequence set forth in SEQ ID NO: 157 and 90, respectively; the sequence set forth in SEQ ID NO: 16 and 47, respectively; the sequence set forth in SEQ ID NO: 23 and 47, respectively; the sequence set forth in SEQ ID NO: 35 and 76, respectively; the sequence set forth in SEQ ID NO: 35 and 79, respectively; the sequence set forth in SEQ ID NO: 35 and 81, respectively; the sequence set forth in SEQ ID NO: 35 and 84, respectively; the sequence set forth in SEQ ID NO: 35 and 89, respectively; the sequence set forth in SEQ ID NO: 37 and 76, respectively; the sequence set forth in SEQ ID NO: 37 and 79, respectively; the sequence set forth in SEQ ID NO: 37 and 81, respectively; the sequence set forth in SEQ ID NO: 37 and 84, respectively; the sequence set forth in SEQ ID NO: 37 and 89, respectively; the sequence set forth in SEQ ID NO: 40 and 76, respectively; the sequence set forth in SEQ ID NO: 40 and 79, respectively; the sequence set forth in SEQ ID NO: 40 and 81, respectively; the sequence set forth in SEQ ID NO: 40 and 84, respectively; the sequence set forth in SEQ ID NO: 40 and 89, respectively; the sequence set forth in SEQ ID NO: 42 and 76, respectively; the sequence set forth in SEQ ID NO: 42 and 79, respectively; the sequence set forth in SEQ ID NO: 42 and 81, respectively; the sequence set forth in SEQ ID NO: 42 and 84, respectively; the sequence set forth in SEQ ID NO: 42 and 89, respectively; the sequence set forth in SEQ ID NO: 165 and 79, respectively; the sequence set forth in SEQ ID NO: 165 and 171, respectively; the sequence set forth in SEQ ID NO: 165 and 172, respectively; the sequence set forth in SEQ ID NO: 166 and 79, respectively; the sequence set forth in SEQ ID NO: 166 and 171, respectively; the sequence set forth in SEQ ID NO: 166 and 172, respectively; the sequence set forth in SEQ ID NO: 167 and 79, respectively; the sequence set forth in SEQ ID NO: 167 and 171, respectively; the sequence set forth in SEQ ID NO: 167 and 172, respectively; the sequence set forth in SEQ ID NO: 168 and 79, respectively; the sequence set forth in SEQ ID NO: 168 and 171, respectively;the sequence set forth in SEQ ID NO: 168 and 172, respectively; the sequence set forth in SEQ ID NO: 169 and 79, respectively; the sequence set forth in SEQ ID NO: 169 and 171, respectively; the sequence set forth in SEQ ID NO: 169 and 172, respectively; the sequence set forth in SEQ ID NO: 170 and 79, respectively; the sequence set forth in SEQ ID NO: 170 and 171, respectively; or the sequence set forth in SEQ ID NO: 170 and 172, respectively.

[0014] In some embodiments, disclosed herein is an anti-programmed cell death protein 1 (PD-1) 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 are or comprise: the sequence set forth in SEQ ID NO: 1 and 158, respectively; the sequence set forth in SEQ ID NO: 2 and 158, respectively; the sequence set forth in SEQ ID NO: 3 and 158, respectively; the sequence set forth in SEQ ID NO: 4 and 158, respectively; the sequence set forth in SEQ ID NO: 5 and 158, respectively; the sequence set forth in SEQ ID NO: 6 and 158, respectively; the sequence set forth in SEQ ID NO: 7 and 158, respectively; the sequence set forth in SEQ ID NO: 8 and 158, respectively; the sequence set forth in SEQ ID NO: 9 and 158, respectively; the sequence set forth in SEQ ID NO: 10 and 158, respectively; the sequence set forth in SEQ ID NO: 11 and 158, respectively; the sequence set forth in SEQ ID NO: 12 and 158, respectively; the sequence set forth in SEQ ID NO: 13 and 158, respectively; the sequence set forth in SEQ ID NO: 14 and 158, respectively; the sequence set forth in SEQ ID NO: 15 and 158, respectively; the sequence set forth in SEQ ID NO: 16 and 158, respectively; the sequence set forth in SEQ ID NO: 17 and 158, respectively; the sequence set forth in SEQ ID NO: 18 and 158, respectively; the sequence set forth in SEQ ID NO: 19 and 158, respectively; the sequence set forth in SEQ ID NO: 20 and 158, respectively; the sequence set forth in SEQ ID NO: 21 and 158, respectively; the sequence set forth in SEQ ID NO: 22 and 158, respectively; the sequence set forth in SEQ ID NO: 23 and 158, respectively; the sequence set forth in SEQ ID NO: 24 and 158, respectively; the sequence set forth in SEQ ID NO: 25 and 158, respectively; the sequence set forth in SEQ ID NO: 26 and 158, respectively; the sequence set forth in SEQ ID NO: 27 and 158, respectively; the sequence set forth in SEQ ID NO: 28 and 158, respectively; the sequence set forth in SEQ ID NO: 29 and 158, respectively; the sequence set forth in SEQ ID NO: 30 and 158, respectively; the sequence set forth in SEQ ID NO: 31 and 158, respectively; the sequence set forth in SEQ ID NO: 32 and 158, respectively; the sequence set forth in SEQ ID NO: 33 and 158, respectively; the sequence set forth in SEQ ID NO: 34 and 158, respectively; the sequence set forth in SEQ ID NO: 35 and 158, respectively; the sequence set forth in SEQ ID NO: 36 and 158, respectively; the sequence set forth in SEQ ID NO: 37 and 158, respectively; the sequence set forth in SEQ ID NO: 38 and 158, respectively; the sequence set forth in SEQ ID NO: 39 and 158, respectively; the sequence set forth in SEQ ID NO: 40 and 158, respectively; the sequence set forth in SEQ ID NO: 41 and 158, respectively; the sequence set forth in SEQ ID NO: 42 and 158, respectively; the sequence set forth in SEQ ID NO: 43 and 158, respectively; the sequence set forth in SEQ ID NO: 44 and 158, respectively; the sequence set forth in SEQ ID NO: 45 and 158, respectively;the sequence set forth in SEQ ID NO: 157 and 46, respectively; the sequence set forth in SEQ ID NO: 157 and 47, respectively; the sequence set forth in SEQ ID NO: 157 and 48, respectively; the sequence set forth in SEQ ID NO: 157 and 49, respectively; the sequence set forth in SEQ ID NO: 157 and 50, respectively; the sequence set forth in SEQ ID NO: 157 and 51, respectively; the sequence set forth in SEQ ID NO: 157 and 52, respectively; the sequence set forth in SEQ ID NO: 157 and 53, respectively; the sequence set forth in SEQ ID NO: 157 and 54, respectively; the sequence set forth in SEQ ID NO: 157 and 55, respectively; the sequence set forth in SEQ ID NO: 157 and 56, respectively; the sequence set forth in SEQ ID NO: 157 and 57, respectively; the sequence set forth in SEQ ID NO: 157 and 58, respectively; the sequence set forth in SEQ ID NO: 157 and 59, respectively; the sequence set forth in SEQ ID NO: 157 and 60, respectively; the sequence set forth in SEQ ID NO: 157 and 61, respectively; the sequence set forth in SEQ ID NO: 157 and 62, respectively; the sequence set forth in SEQ ID NO: 157 and 63, respectively; the sequence set forth in SEQ ID NO: 157 and 64, respectively; the sequence set forth in SEQ ID NO: 157 and 65, respectively; the sequence set forth in SEQ ID NO: 157 and 66, respectively; the sequence set forth in SEQ ID NO: 157 and 67, respectively; the sequence set forth in SEQ ID NO: 157 and 68, respectively; the sequence set forth in SEQ ID NO: 157 and 69, respectively; the sequence set forth in SEQ ID NO: 157 and 70, respectively; the sequence set forth in SEQ ID NO: 157 and 71, respectively; the sequence set forth in SEQ ID NO: 157 and 72, respectively; the sequence set forth in SEQ ID NO: 157 and 73, respectively; the sequence set forth in SEQ ID NO: 157 and 74, respectively; the sequence set forth in SEQ ID NO: 157 and 75, respectively; the sequence set forth in SEQ ID NO: 157 and 76, respectively; the sequence set forth in SEQ ID NO: 157 and 77, respectively; the sequence set forth in SEQ ID NO: 157 and 78, respectively; the sequence set forth in SEQ ID NO: 157 and 79, respectively; the sequence set forth in SEQ ID NO: 157 and 80, respectively; the sequence set forth in SEQ ID NO: 157 and 81, respectively; the sequence set forth in SEQ ID NO: 157 and 82, respectively; the sequence set forth in SEQ ID NO: 157 and 83, respectively; the sequence set forth in SEQ ID NO: 157 and 84, respectively; the sequence set forth in SEQ ID NO: 157 and 85, respectively; the sequence set forth in SEQ ID NO: 157 and 86, respectively; the sequence set forth in SEQ ID NO: 157 and 87, respectively; the sequence set forth in SEQ ID NO: 157 and 88, respectively; the sequence set forth in SEQ ID NO: 157 and 89, respectively; the sequence set forth in SEQ ID NO: 157 and 90, respectively; the sequence set forth in SEQ ID NO: 16 and 47, respectively; the sequence set forth in SEQ ID NO: 23 and 47, respectively; the sequence set forth in SEQ ID NO: 35 and 76, respectively; the sequence set forth in SEQ ID NO: 35 and 79, respectively; the sequence set forth in SEQ ID NO: 35 and 81, respectively; the sequence set forth in SEQ ID NO: 35 and 84, respectively; the sequence set forth in SEQ ID NO: 35 and 89, respectively; the sequence set forth in SEQ ID NO: 37 and 76, respectively; the sequence set forth in SEQ ID NO: 37 and 79, respectively; the sequence set forth in SEQ ID NO: 37 and 81, respectively; the sequence set forth in SEQ ID NO: 37 and 84, respectively; the sequence set forth in SEQ ID NO: 37 and 89, respectively; the sequence set forth in SEQ ID NO:40 and 76, respectively; the sequence set forth in SEQ ID NO: 40 and 79, respectively; the sequence set forth in SEQ ID NO: 40 and 81, respectively; the sequence set forth in SEQ ID NO: 40 and 84, respectively; the sequence set forth in SEQ ID NO: 40 and 89, respectively; the sequence set forth in SEQ ID NO: 42 and 76, respectively; the sequence set forth in SEQ ID NO: 42 and 79, respectively; the sequence set forth in SEQ ID NO: 42 and 81, respectively; the sequence set forth in SEQ ID NO: 42 and 84, respectively; the sequence set forth in SEQ ID NO: 42 and 89, respectively; the sequence set forth in SEQ ID NO: 165 and 79, respectively; the sequence set forth in SEQ ID NO: 165 and 171, respectively; the sequence set forth in SEQ ID NO: 165 and 172, respectively; the sequence set forth in SEQ ID NO: 166 and 79, respectively; the sequence set forth in SEQ ID NO: 166 and 171, respectively; the sequence set forth in SEQ ID NO: 166 and 172, respectively; the sequence set forth in SEQ ID NO: 167 and 79, respectively; the sequence set forth in SEQ ID NO: 167 and 171, respectively; the sequence set forth in SEQ ID NO: 167 and 172, respectively; the sequence set forth in SEQ ID NO: 168 and 79, respectively; the sequence set forth in SEQ ID NO: 168 and 171, respectively; the sequence set forth in SEQ ID NO: 168 and 172, respectively; the sequence set forth in SEQ ID NO: 169 and 79, respectively; the sequence set forth in SEQ ID NO: 169 and 171, respectively; the sequence set forth in SEQ ID NO: 169 and 172, respectively; the sequence set forth in SEQ ID NO: 170 and 79, respectively; the sequence set forth in SEQ ID NO: 170 and 171, respectively; or the sequence set forth in SEQ ID NO: 170 and 172, respectively.

[0015] 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.

[0016] 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.

[0017] In any of the embodiments herein, the anti-PD-1 antibody or antigen-binding fragment thereof can be recombinant.

[0018] In any of the embodiments herein, the VH region and the VL region can be human or can be from a human protein.

[0019] In any of the embodiments herein, the antibody or antigen-binding fragment thereof can bind to human PD-1 protein with an equilibrium dissociation constant (KD) of from about 7 x 1010M to about 2 x 108M at pH 7.35 to 7.45, optionally at pH 7.40. In some embodiments, the antibody or antigen-binding fragment thereof binds to human PD-1 protein with a KD of lower than 1 x 109M, optionally from about 7 x 1010M to about 1 x 109M.

[0020] In any of the embodiments herein, the antibody or antigen-binding fragment thereof can bind to human PD-1 protein with an equilibrium dissociation constant (KD) of from about 3 x 1010M to about 4 x 108M at pH 5.0 to 6.8, optionally at pH 6.0 or pH 5.0. In some embodiments, the antibody or antigen-binding fragment thereof binds to human PD-1 protein with a KD of lower than 1 x 109M, optionally from about 3 x 1010to about 1 x 109M.

[0021] In any of the embodiments herein, the antibody or antigen-binding fragment thereof can bind to human PD-1 protein with a lower KD at pH 5.0 to 6.8, optionally pH 6.0 or pH 5.0, than pH 7.35 to 7.45, optionally pH 7.4. In any of the embodiments herein, the antibody or antigen-binding fragment thereof can bind to human PD-1 protein with a lower KD at pH 7.35 to 7.45, optionally pH 7.4, than at pH 5.0 to 6.8, optionally pH 6.0 or pH 5.0. In any of the embodiments herein, the antibody or antigenbinding fragment thereof can bind to human PD-1 protein with a KD at pH 7.35 to 7.45, optionally pH 7.4, and at pH 5.6 to 6.8, optionally pH 6.0 or pH 5.0, that is substantially the same.

[0022] In any of the embodiments herein, the antibody or antigen-binding fragment thereof can bind to human PD-1 protein with an association rate constant (Kon) of 4 x 1051 / Ms to about 2 x 1061 / Ms at pH 7.35 to 7.45, optionally at pH 7.40. In any of the embodiments herein, the antibody or antigen-binding fragment thereof can bind to human PD-1 protein with an dissociation rate constant (Koff) of 4 x 1041 / s to about 9 x 1031 / s at pH 7.35 to 7.45, optionally at pH 7.40.

[0023] In any of the embodiments herein, the antibody or antigen-binding fragment thereof can bind to human PD-1 protein with an association rate constant (Kon) of 4 x 1051 / Ms to about 5 x 1061 / Ms at pH 5.0 to 6.8, optionally at pH 6.0 pH 6.0 or pH 5.0. In any of the embodiments herein, the antibody or antigen-binding fragment thereof can bind to human PD-1 protein with an dissociation rate constant (Koff) of 4 x 1041 / s to about 2 x 1021 / s at pH 5.0 to 6.8, optionally at pH 6.0 or pH 5.0.

[0024] In some embodiments, disclosed herein is a conjugate, comprising the anti-PD-1 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.

[0025] In some embodiments, disclosed herein is a bispecific antibody, comprising the anti-PD-1 antibody or antigen-binding fragment thereof of any of any of the embodiments herein.

[0026] In some embodiments, disclosed herein is a PD-1 directed chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain comprising the anti-PD-1 antibody or antigenbinding fragment thereof of any of the embodiments herein, a transmembrane region and an intracellular signaling region.

[0027] In some embodiments, disclosed herein is a polynucleotide comprising a nucleic acid encoding the anti-PD-1 antibody or antigen-binding domain thereof of any of the embodiments herein.

[0028] In some embodiments, disclosed herein is a polynucleotide comprising a nucleic acid encoding the anti-PD-1 chimeric antigen receptor of some embodiments.

[0029] In some embodiments, disclosed 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.

[0030] In some embodiments, disclosed herein is a engineered cell comprising the anti-PD-1 antibody or antigen-binding fragment thereof of any of the embodiments herein, the bispecific antibody of some embodiments, or the conjugate of any of the embodiments herein.

[0031] In some embodiments, disclosed herein is an engineered cell comprising the PD-1 directed chimeric antigen receptor of some embodiments. In any of the embodiments herein, the cell can be a lymphocyte. In some embodiments, the cell is a natural killer (NK) cell or a T cell. In any of the embodiments herein, the cell can be a T cell and the T cell can be a CD4+ T cell or a CD8+ T cell.

[0032] In some embodiments, disclosed 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.

[0033] In some embodiments, disclosed herein is a method of producing an antibody comprising culturing the cell of any of the embodiments herein under a condition that produces the antibody. In some embodiments, the method further comprises recovering the antibody produced by the cell.

[0034] In some embodiments, disclosed herein is an antibody or antigen-binding fragment thereof produced by the method of any of the embodiments herein.

[0035] In some embodiments, disclosed herein is a composition comprising the cell of any of the embodiments herein.

[0036] In some embodiments, disclosed herein is a composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof of any of the embodiments herein, the conjugate of any of the embodiments herein, the bispecific antibody of some embodiments, or the PD-1 directed chimeric antigen receptor of some embodiments. In any of the embodiments herein, the composition can further comprise a pharmaceutically acceptable excipient.

[0037] In some embodiments, disclosed herein is a method of treatment, comprising administering the cell of any of the embodiments herein or the composition of any of the embodiments herein to a subject having a disease or disorder associated with PD-1.

[0038] In some embodiments, disclosed herein is a method of increasing the activity of an immune cell, comprising contacting an immune cell with the anti-PD-1 antibody or antigen-binding fragment thereof of any of the embodiments herein, the conjugate of any of the embodiments herein, or the bispecific antibody of some embodiments.

[0039] In some embodiments, disclosed herein is a method of increasing the activity of an immune cell, comprising administering to a subject in need thereof a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof of any of the embodiments herein, the conjugate of any of the embodiments herein, the bispecific antibody of some embodiments.

[0040] In any of the embodiments herein, the method can be used for an ex vivo treatment in a subject.

[0041] In any of the embodiments herein, the treatment can be the treatment of cancer, the treatment of an infection or infectious disease or as a vaccine adjuvant.

[0042] Provided herein is a binding molecule comprising a PD-1 binding domain that binds PD- 1, and a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) binding domain that binds CTLA-4, wherein: (a) the PD-1 binding domain comprises a heavy chain and a light chain comprising the heavy chain variable (VH) region and the light chain variable (VL ) region, respectively, of the anti- PD-1 antibody or antigen-binding fragment thereof of any of claims 1- 26, and (b) the CTLA-4 binding domain comprises a heavy chain comprising a heavy chain variable (CTLA-4 VH) region and a light chain comprising a light chain variable (CTLA-4 VL ) region, wherein: (i) the CTLA-4 VH region comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the sequence set forth in any one of SEQ ID NOs: 278-285, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in any one of SEQ ID NOs: 286-296, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in any one of SEQ ID NOs: 297-302; and the CTLA-4 VL region comprises a light chain complementarity determining region 1 (CDR-L1) comprising the sequence set forth in any one of SEQ ID NOs: 303-317, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in any one of SEQ ID NOs: 318-326, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in any one of SEQ ID NOs: 327- 329, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 278, 286, 297,303, 318, and 327, respectively; or (ii) the CTLA-4 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: 230-256, and 341, and the CTLA-4 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:257, 277, and 347, wherein the CDR- Hl, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 278, 286, 297,303, 318, and 327, respectively.

[0043] In any of the embodiments herein, the CTLA-4 VH region comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 278-285, a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 286-296, and a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 297-302; and the CTLA-4 VL region comprises a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 303-317, a CDR-L2 comprising the sequence set forth in any one of SEQ ID NOs: 318-326, and a CDR-L3 comprising the sequence set forth in any one of SEQ ID NOs: 327-329, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2 and CDR-L3 are not set forth in SEQ ID NOS: 278, 286, 297,303, 318, and 327, respectively.

[0044] In any of the embodiments herein, the CTLA-4 VH region comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO: 230, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 231, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 232, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:233, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:234, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO:235, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:236, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:237, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:238, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:239, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO:240, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:241, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:242, and theCTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:243, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:244, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO:245, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:246, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:247, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:248, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:249, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO:250, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:251, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 257; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 259; the CTLA-4 Vnregion comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 260; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 261; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 262; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 containedwithin SEQ ID NO: 263; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 264; the CTLA-4 Vnregion comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 265; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 266; the CTLA-4 Vn region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 267; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 269; the CTLA-4 Vnregion comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 271; the CTLA-4 Vn region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 272; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 273; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 274; the CTLA-4 Vnregion comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 275; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 252, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 Vn region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 253, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 254, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 255, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270;the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 251, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 256, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 252, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 253, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 254, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO: 255, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 251, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 256, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 252, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 253, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 Vnregion comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO: 254, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 255, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 251, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 256, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 252, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 Vnregion comprises a CDR-H1, a CDR- H2, and a CDR-H3 contained within SEQ ID NO: 253, and the CTLA-4 VL region comprises a CDR- Ll, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 254, and the CTLA-4 VL regioncomprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 255, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 251, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 256, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; or the CTLA-4 Vnregion comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 234, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 277.

[0045] In any of the embodiments herein, the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 287, and 297, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 298, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 280, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 279, 288, and 297, respectively, and the -LI, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 290, and 297, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 280, 291, 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 279, 292, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 279, 286, and 298, respectively, and the CDR-L1, the CDR-L2, and the CDR- L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 282, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth inSEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 282, 286, and 299, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 283, 286, and 300, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 284, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 285, 286, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR- L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 293, 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 289, and 297, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 295, and 297, respectively, and the CDR-L1, a CDR-L2, and a CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 300, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 302, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 301, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 304, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 306, 318, 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 307, 319, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 307, 319, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 310, 320, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 307, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR- L3 comprise the sequences set forth in SEQ ID NOS: 310, 321, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 311, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 311, 322, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 312, 321, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR- L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 329, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 315, 323, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 316, 324, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, andthe CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 325, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR- L3 comprise the sequences set forth in SEQ ID NOS: 317, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 326, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 296, and 297, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 302, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR- L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 301, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 302, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR- L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 301, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ IDNOS: 278, 294, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 302, respectively, and the CDR-L1, the CDR-L2, and the CDR- L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 296, and 297, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 302, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 301, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR- L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; or the CDR- Hl, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 317, 318, 329, respectively.

[0046] In any of the embodiments herein, the CTLA-4 VH region and the CTLA-4 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: 230 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 231 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 232 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 233 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 234 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 235 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 236 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 237 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 238 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 239 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 240 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 241 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 242 and SEQ ID NO: 347,respectively; the CTLA-4 VH region and the CTLA-4 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: 243 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 244 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 245 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 246 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 247 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 248 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 249 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 250 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 251 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 257, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 259, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 260, respectively; the CTLA-4VH region and the CTLA-4 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: 341 and SEQ ID NO: 261, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 262, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 263, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 264, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 265, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 266, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 267, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 26, respectively; the CTLA-4 VH region and the CTLA- 4 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: 341 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 271, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 272, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 273, respectively; the CTLA-4 VH region and the CTLA-4 VL region is orcomprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 341 and SEQ ID NO: 274, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 275, respectively; the CTLA-4 VH region and the CTLA-4 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: 252 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 253 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 255 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 251 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 256 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 252 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 253 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 255 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 251 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 256 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 252 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 253 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 255 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 251 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 256 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 252 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 253 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 255 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 251 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 256 and SEQ ID NO: 268, respectively; or theCTLA-4 VH region and the CTLA-4 VL region is or comprises an amino acid sequence having at leastat or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 234 and SEQ ID NO: 277, respectively.

[0047] In any of the embodiments herein, the CTLA-4 VH region and the CTLA-4 VL region are or comprise: the sequence set forth in SEQ ID NO: 230 and 347, respectively; the sequence set forth in SEQ ID NO: 231 and 347, respectively; the sequence set forth in SEQ ID NO: 232 and 347, respectively; the sequence set forth in SEQ ID NO: 233 and 347, respectively; the sequence set forth in SEQ ID NO: 234 and 347, respectively; the sequence set forth in SEQ ID NO: 235 and 347, respectively; the sequence set forth in SEQ ID NO: 236 and 347, respectively; the sequence set forth in SEQ ID NO: 237 and 347, respectively; the sequence set forth in SEQ ID NO: 238 and 347, respectively; the sequence set forth in SEQ ID NO: 239 and 347, respectively; the sequence set forth in SEQ ID NO: 240 and 347, respectively; the sequence set forth in SEQ ID NO: 241 and 347, respectively; the sequence set forth in SEQ ID NO: 242 and 347, respectively; the sequence set forth in SEQ ID NO: 243 and 347, respectively; the sequence set forth in SEQ ID NO: 244 and 347, respectively; the sequence set forth in SEQ ID NO: 245 and 347, respectively; the sequence set forth in SEQ ID NO: 246 and 347, respectively; the sequence set forth in SEQ ID NO: 247 and 347, respectively; the sequence set forth in SEQ ID NO: 248 and 347, respectively; the sequence set forth in SEQ ID NO: 249 and 347, respectively; the sequence set forth in SEQ ID NO: 250 and 347, respectively; the sequence set forth in SEQ ID NO: 251 and 347, respectively; the sequence set forth in SEQ ID NO: 341 and 257, respectively; the sequence set forth in SEQ ID NO: 341 and 258, respectively; the sequence set forth in SEQ ID NO: 341 and 259, respectively; the sequence set forth in SEQ ID NO: 341 and 260, respectively; the sequence set forth in SEQ ID NO: 341 and 261, respectively; the sequence set forth in SEQ ID NO: 341 and 262, respectively; the sequence set forth in SEQ ID NO: 341 and 263, respectively; the sequence set forth in SEQ ID NO: 341 and 264, respectively; the sequence set forth in SEQ ID NO: 341 and 265, respectively; the sequence set forth in SEQ ID NO: 341 and 266, respectively; the sequence set forth in SEQ ID NO: 341 and 267, respectively; the sequence set forth in SEQ ID NO: 341and 268, respectively; the sequence set forth in SEQ ID NO: 341 and 269, respectively; the sequence set forth in SEQ ID NO: 341and 270, respectively; the sequence set forth in SEQ ID NO: 341and 271, respectively; the sequence set forth in SEQ ID NO: 341and 272, respectively; the sequence set forth in SEQ ID NO: 341and 273, respectively; the sequence set forth in SEQ ID NO: 341and 274, respectively; the sequence set forth in SEQ ID NO: 341and 275, respectively; the sequence set forth in SEQ ID NO: 252 and 270, respectively; the sequence set forth in SEQ ID NO: 253 and 270, respectively; the sequence set forth in SEQ ID NO: 254 and 270, respectively; the sequence set forth in SEQ ID NO: 255 and 270, respectively; the sequence set forth in SEQ ID NO: 251 and 270, respectively; the sequence set forth in SEQ ID NO: 256 and 270, respectively; the sequence set forth in SEQ ID NO: 252 and 276, respectively; the sequence set forth in SEQ ID NO: 253 and 276, respectively; the sequence set forthin SEQ ID NO: 254 and 276, respectively; the sequence set forth in SEQ ID NO: 255 and 276, respectively; the sequence set forth in SEQ ID NO: 251 and 276, respectively; the sequence set forth in SEQ ID NO: 256 and 276, respectively; the sequence set forth in SEQ ID NO: 252 and 258, respectively; the sequence set forth in SEQ ID NO: 253 and 258, respectively; the sequence set forth in SEQ ID NO: 254 and 258, respectively; the sequence set forth in SEQ ID NO: 255 and 258, respectively; the sequence set forth in SEQ ID NO: 251 and 258, respectively; the sequence set forth in SEQ ID NO: 256 and 258, respectively; the sequence set forth in SEQ ID NO: 252 and 268, respectively; the sequence set forth in SEQ ID NO: 253 and 268, respectively; the sequence set forth in SEQ ID NO: 254 and 268, respectively; the sequence set forth in SEQ ID NO: 255 and 268, respectively; the sequence set forth in SEQ ID NO: 251 and 268, respectively; the sequence set forth in SEQ ID NO: 256 and 268, respectively; the sequence set forth in SEQ ID NO: 234 and 277, respectively.

[0048] Provided herein is a binding molecule comprising a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) binding domain that binds CTLA-4, and a PD-1 binding domain that binds PD-1, wherein: (a) the PD-1 binding domain comprises a heavy chain and a light chain comprising the heavy chain variable (VH) region (PD-1 VH ) and the light chain variable (VL) region (PD-1 VL), respectively, of the anti-PD-1 antibody or antigen-binding fragment thereof of some of any embodiments, and (b) the CTLA-4 binding domain comprises a heavy chain variable (CTLA-4 VH) region and a light chain variable (CTLA-4 VL ) region, wherein: the CTLA-4 VH region comprises the sequence set forth in:QVQLVESGGGVVQPGRSLRLSCAASGFTFSX 1 YTMHWVRQAPGKGLEW VTFIS YX2GNNKX 3YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGX4X5GPFDYWGQGTLVTVSS, wherein XI is S or R; X2 is E or H; X3 is H or Y; X4 is W or H; and X5 is L or H (SEQ ID NO: 407); and the CTLA-4 VL region comprises the sequence set forth in: EIVLTQSPGTLSLSPGERATLSCRASQX1VGHX2YLAWYQQKPGQAPRLLIYGAFSRATGIPD RFSGSGSGTDFTLTISRLEPEDFAVYYCQX3YGSSPWTFGQGTKVEIK, wherein XI is H or S; X2 is H or S; and X3 is Q or H (SEQ ID NO: 408).

[0049] In any of the embodiments herein, the CTLA-4 VH region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 278 or SEQ ID NO: 281, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 289 or SEQ ID NO: 296, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 297 or SEQ ID NO: 301; and the CTLA-4 VL region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 305 or SEQ ID NO: 313; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 318, and a CDR-L3 comprising the sequence set forth in SEQ ID NO: 327 or SEQ ID NO: 328.

[0050] In any of the embodiments herein, the CTLA-4 VH region comprises: (a) a serine (S) at position 31, a glutamic acid (E) at position 54, a histidine (H) at position 59, a tryptophan (W) atposition 101, and a leucine (L) at position 102, wherein the numbering is relative to SEQ ID NO: 407, or (b) a arginine (R) at position 31, a glutamic acid (E) at position 54, a tyrosine (Y) at position 59, a tryptophan (W) at position 101, and a histidine (H) at position 102, wherein the numbering is relative to SEQ ID NO: 407.

[0051] In any of the embodiments herein, the CTLA-4 VL region comprises: (a) a histidine (H) at position 28, a serine (S) at position 32, and a glutamine (Q) at position 91, wherein the numbering is relative to SEQ ID NO: 408, or (b) a serine (S) at position 28, a serine (S) at position 32, and a histidine (H) at position 91, wherein the numbering is relative to SEQ ID NO: 408.

[0052] In any of the embodiments herein, the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 252 and SEQ ID NO: 268, respectively.

[0053] In any of the embodiments herein, the CTLA-4 VH region and the CTLA-4 VL region are or comprise: the sequence set forth in SEQ ID NO: 254 and 258, respectively; the sequence set forth in SEQ ID NO: 254 and 268, respectively; the sequence set forth in SEQ ID NO: 252 and 268, respectively.

[0054] In any of the embodiments herein, the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 268, respectively.

[0055] In any of the embodiments herein, the PD-1 VH region and the PD-1 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: 168 and SEQ ID NO: 172, respectively.

[0056] In any of the embodiments herein, the PD-1 VH region is or comprises an amino acid sequence set forth in SEQ ID NO: 168, and the PD-1 VL region is or comprises an amino acid sequence set forth in SEQ ID NO: 172.

[0057] In any of the embodiments herein, the CTLA-4 binding domain and the PD-1 binding domain are Fab fragments each comprising a VH region and a VL region, wherein one of the Fabfragments is a crossover Fab such that the VH region and the VL region of such Fab are replaced by each other.

[0058] In any of the embodiments herein, the CTLA-4 binding domain is a crossover CTLA-4 Fab and the PD-1 binding domain is a Fab, wherein: the crossover CTLA-4 Fab comprises: (a) a heavy chain (HC1) comprising the CTLA-4 VL region and a heavy chain constant region 1 (CHI), designated CTLA-4 VL-CH1 ; and (b) a light chain (LC1) comprising the CTLA-4 VH region and a light chain constant region (CL), designated CTLA-4 VH-CL; and the PD-1 binding domain comprises (a) a heavy chain 2 (HC2) comprising the PD-1 VH region and a heavy chain constant region 1 (CHI), designated PD-1 VH-CH1 ; and (b) a light chain 2 (LC2) comprising the PD-1 VL region and a light chain constant region (CL), designated PD-1 VL-CL.

[0059] In any of the embodiments herein, the CHI of the CTLA-4 VL-CH1 comprises the amino acid sequence set forth in SEQ ID NO: 363 and the CL of the CTLA-4 VH-CL comprises the amino acid sequence set forth in SEQ ID NO: 367.

[0060] In any of the embodiments herein, the CHI of the PD-1 VH-CH1 comprises the amino acid sequence set forth in SEQ ID NO: 371 and the CL of the PD-1 VL-CL comprises the amino acid sequence set forth in SEQ ID NO: 175.

[0061] In any of the embodiments herein, the CTLA-4 binding domain is a CTLA-4 Fab and the PD-1 binding domain is a crossover Fab, wherein: the CTLA-4 Fab comprises: (a) a heavy chain (HC1) comprising the CTLA-4 VH region and a heavy chain constant region 1 (CHI), designated CTLA-4 VH-CH1 ; and (b) a light chain (LC1) comprising the CTLA-4 VL region and a light chain constant region (CL), designated CTLA-4 VL-CL; and the PD-1 binding domain comprises (a) a heavy chain 2 (HC2) comprising the PD-1 VL region and a heavy chain constant region 1 (CHI), designated PD-1 VL-CH1 ; and (b) a light chain 2 (LC2) comprising the PD-1 VH region and a light chain constant region (CL), designated PD-1 VH-CL.

[0062] In any of the embodiments herein, the CHI of the PD-1 VL-CH1 comprises the amino acid sequence set forth in SEQ ID NO: 363 and the CL of the PD-1 VH-CL comprises the amino acid sequence set forth in SEQ ID NO: 367.

[0063] In any of the embodiments herein, the CHI of the CTLA-4 VH-CH1 comprises the amino acid sequence set forth in SEQ ID NO: 371 and the CL of the CTLA-4 VL-CL comprises the amino acid sequence set forth in SEQ ID NO: 175.

[0064] In any of the embodiments herein, the CTLA-4 VH comprises the sequence of amino acids set forth in SEQ ID NO: 254 and the CTLA-4 VL comprises the sequence of amino acids set forth in SEQ ID NO: 268; and the PD-1 VH comprises the sequence of amino acids set forth in SEQ ID NO: 168 and the PD-1 VL comprise the sequence of amino acids set forth in SEQ ID NO: 172.

[0065] In any of the embodiments herein, the provided binding molecule further comprises an Fc region comprising a first and second polypeptide each comprising a hinge-CH2-CH3, wherein one of the first polypeptide and second polypeptide is linked to the CHI of the CTLA-4 Fab and the other of the first polypeptide and second polypeptide is linked to the CHI of the PD-1 Fab. In any of the embodiments herein, the Fc region is a heterodimeric Fc region. In any of the embodiments herein, each of the first and second polypeptide of the heterodimeric Fc comprises one or more amino acid substitutions in a wild-type Fc polypeptide region to effect heterodimer formation between the first polypeptide and the second polypeptide.

[0066] In any of the embodiments herein, the wild-type Fc region is an IgGl Fc region. In any of the embodiments herein, the wild-type Fc region comprises the sequence set forth in SEQ ID NO:407 or SEQ ID NO: 408. In any of the embodiments herein, the one more amino acid substitutions are a knob-into-hole modification, a charge mutation to reduce or prevent self-association due to charge repulsion, or disulfide bonding pairing mutation. In any of the embodiments herein, the one or more amino acid substitutions are: (i) amino acid substitution T366W in the first polypeptide of the heterodimeric Fc and amino acid substitutions T366S, L368A and Y407V in the second polypeptide of the heterodimeric Fc; (ii) amino acid substitution E356K, E357K and D399K in the first polypeptide of the heterodimeric Fc and amino acid substitutions K439E, K370E and K409D in the second polypeptide of the heterodimeric Fc; or (iii) amino acid substitution S354C on the first polypeptide of the heterodimeric Fc and amino acid substitution Y349C on the second polypeptide of the heterodimeric Fc. In any of the embodiments herein, the one or more substitutions are a knob-into- hole modification. In any of the embodiments herein, the one or more amino acid substitutions of the first Fc polypeptide comprises Thr366Trp and the one or more amino acid substitutions of the second Fc polypeptide of the heterodimeric Fc comprises the Thr366Ser, Leu368Ala and Tyr407Val. In any of the embodiments herein, the first and / or second Fc polypeptide further comprises the amino acid substitution. H435R. In any of the embodiments herein, the heterodimeric Fc region comprises one or more amino acid substitutions to reduce binding affinity to an Fc receptor and / or to reduce effector function, optionally as compared to a wild-type IgGl Fc domain. In any of the embodiments herein, the one or more amino acid substitutions are selected from L234A, L234V, L235A, L235E, G237A, D265S, S267K, R292C, N297G, V302C, and P329G by EU numbering. In any of the embodiments herein, the one or more amino acid substitution comprises L234A and L235A. In any of the embodiments herein, the one or more amino acid substitution comprises L234A, L235A, and D265S. In any of the embodiments herein, the one or more amino acid substitution comprises L234A, L235A, and P329G. In any of the embodiments herein, one or both polypeptides of the heterodimeric Fc lacks Lys447.

[0067] In any of the embodiments herein, one of the first polypeptide and the second polypeptide of the heterodimeric Fc region 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% sequence identity SEQ ID NO: 364; and the other of the first polypeptide and second polypeptide of the heterodimeric Fc region 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% sequence identity SEQ ID NO: 373.

[0068] In any of the embodiments herein, one of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 364; and the other of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 373. In any of the embodiments herein, the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 364 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO:373. In any of the embodiments herein, the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 373 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO:364. In any of the embodiments herein, (a) a heavy chain 1 (HC1) polypeptide comprising a VL sequence set forth in SEQ ID NO:268, a CHI sequence set forth in SEQ ID NO:363, and a hinge-CH2-CH3 sequence set forth in SEQ ID NO: 364; (b) a light chain 1 (LC1) polypeptide comprising a VH sequence set forth in SEQ ID NO:254 and a CL sequence set forth in SEQ ID NO: 367; (c) a HC2 polypeptide comprising a Vn sequence set forth in SEQ ID NO:168,a CHI sequence set forth in SEQ ID NO:371, and a hinge-CH2-CH3 sequence set forth in SEQ ID NO:373; and (d) a LC2 polypeptide comprising a VL sequence set forth in SEQ ID NO: 172 and a CL sequence set forth in SEQ ID NO: 175. In any of the embodiments herein, the binding molecule provided comprises a) a HC1 polypeptide that 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: 378; (b) a HC2 polypeptide that 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: 387; (c) a LC1 polypeptide that 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: 381; and (d) a LC2 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: 389.

[0069] In any of the embodiments herein, the provided binding molecule comprises (a) a HC1 polypeptide that is or comprises the amino acid sequence set forth in SEQ ID NO: 378; (b) a HC2 polypeptide that is or comprises the amino acid sequence set forth in SEQ ID NO: 387; (c) a LC1 polypeptide that is or comprises the amino acid sequence set forth in SEQ ID NO: 381; and (d) a LC2 polypeptide that is or comprises the amino acid sequence set forth in SEQ ID NO: 389. In any of the embodiments herein, the provided binding molecule comprises (a) a heavy chain 1 (HC1) polypeptidecomprising a VL sequence set forth in SEQ ID NO: 172, a CHI sequence set forth in SEQ ID NO:363, and a hinge-CH2-CH3 sequence set forth in SEQ ID NO: 364; (b) a LC1 polypeptide comprising a VH sequence set forth in SEQ ID NO: 168, and a CL sequence set forth in SEQ ID NO:367; and (c) a HC2 polypeptide comprising a VH sequence set forth in SEQ ID NO:254, a CHI sequence set forth in SEQ ID NO:371, and a hinge-CH2-CH3 sequence set forth in SEQ ID NO: 373; and (d) a LC2 polypeptide comprising a VL sequence set forth in SEQ ID NO:268, and a CL sequence set forth in SEQ ID NO: 175.

[0070] In any of the embodiments herein, the provided binding molecule comprises (a) a HC1 polypeptide that 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: 360; (b) a HC2 polypeptide that 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: 370; (c) a LC1 polypeptide that 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: 366 and (d) a LC2 that 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: 375.

[0071] In any of the embodiments herein, the provided binding molecule comprises (a) a HC1 polypeptide that is or comprises an amino acid sequence set forth in SEQ ID NO: 360; (b) a HC2 polypeptide that is or comprises an amino acid sequence set forth in SEQ ID NO: 370; (c) a LC1 polypeptide that is or comprises an amino acid sequence set forth in SEQ ID NO: 366 and (d) a LC2 polypeptide that is or comprises an amino acid sequence set forth in SEQ ID NO: 375.

[0072] In any of the embodiments herein, the heavy chain and / or the light chain further comprising a signal peptide.

[0073] Provided herein is a polynucleotide or polynucleotides comprising a nucleic acid sequence encoding any of the provided binding molecules or portion thereof, including a heavy or light chain thereof. In some embodiments, the binding molecule is a bispecific antibody directed against PD-1 and CTLA-4. Provided herein is a polynucleotide comprising a nucleic acid comprising a nucleic acid sequence encoding any of the provided the bispecific antibodies or portion thereof. Provided herein is a vector comprising any of the provided polynucleotides. In some embodiments, the vector is useful for expressing a provided binding molecule, such as a bispecific antibody.

[0074] In any of the embodiments herein, the vector is a viral vector. In any of the embodiments herein, the viral vector is a retroviral vector or a lentiviral vector.

[0075] Provided herein is a cell comprising any of the provided polynucleotides or vectors. In any of the embodiments herein, the cell is a mammalian cell.

[0076] Provided herein is a method of producing a binding molecule, such as a bispecific antibody, comprising culturing any of the provided cells under a condition that produces the binding molecule, wherein optionally the binding molecule is an antibody. In any of the embodiments herein, any of the provided methods further comprising recovering the binding molecule, such as a bispecific antibody, produced by the cell.

[0077] Provided herein is a binding molecule, such as a bispecific antibody, produced by any of the provided methods. Provided herein is a composition comprising any of the binding molecules, such as bispecific antibodies, provided herein. In any of the embodiments herein, the composition further comprises a pharmaceutically acceptable excipient.

[0078] Provided herein is a method for treating a subject with a disease or condition, the method comprising administering a therapeutically effective amount of any of the provided binding molecules, such as bispecific antibodies, or compositions. In any of the embodiments herein, the disease or condition is a cancer.

[0079] Provided herein is a method of cancer immunotherapy, the method comprising administering to a subject in need thereof a therapeutically effective amount of any of the provided binding molecules, such as bispecific antibodies, or compositions. In any of the embodiments herein, the cancer is a solid tumor. In any of the embodiments herein, the cancer is a melanoma, breast carcinoma, HCC, Renal cell carcinoma, Colorectal carcinoma, non-small-cell lung carcinoma, Cervical cancer or Mesothelioma. In any of the embodiments herein, administering the binding molecules, such as bispecific antibody, to the subject results in higher Teff-to-suppressor cells (myeloid-derived suppressor cell and Treg) ratios. In any of the embodiments herein, administering the binding molecule, such as bispecific antibody, to the subject results in increased pro-inflammatory cytokines, optionally interferon-gamma (IFN-y) and / or tumor necrosis factor-alpha (TNF-a).

[0080] In any of the embodiments herein, the method comprises administering to the subject an effective amount of any of the provided binding molecules, such as bispecific antibodies, or the compositions prior to a surgery or after a surgery to remove a solid tumor in the subject.Brief Description of the Drawings

[0081] FIG.l depicts the EC50 values for exemplary provided antibodies for binding to human PD-1 at normal pH about 7.4.

[0082] FIG.2 depicts the IC50 values for exemplary provided antibodies for inhibition of PD-1 binding to human PD-L1 in a standard reporter assay.

[0083] FIG. 3 shows a schematic drawing of a standard reporter assay to test for inhibition of PD- 1 binding to human PD-L1.

[0084] FIGs. 4A-4F show the thermal melt curves measured by Differential Scanning Fluorimetry (DSF). FIG. 4A shows the thermal melt curve of PDl-abl l3. FIG. 4B shows the thermal melt curve of PDl-abl 16. FIG. 4C shows the thermal melt curve of PDl-abl 19. FIG. 4D shows the thermal melt curve of PDl-abl 22. FIG. 4E shows the thermal melt curve of PDl-abl 25. FIG. 4F shows the thermal melt curve of PDl-abl29.

[0085] FIGs. 5A-5S show results of binding tests of exemplary provided antibodies for binding to human CTLA-4 at pH 5 and at pH 7.4. FIG. 5A 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. 5B 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. 5C 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. 5D 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. 5E 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. 5F 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. 5G shows results 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. 5H 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. 51 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. 5J 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. 5K 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. 5L 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. 5M 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. 5N 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. 50 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. 5P 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. 5Q 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. 5R 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. 5S 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.

[0086] FIGs. 6A-6C show results of binding tests of exemplary provided antibodies for binding to human CTLA-4 at different pH’s. FIG. 6A 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. 6B 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. 6C 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.

[0087] FIGs. 7A-7C show effects of anti-CTLA-4 antibodies on CTLA-4 expression in treated human-CTLA-4 expressing Cells. FIG. 7A shows hCTLA-4 expression levels in cells treated with anti- CTLA-4 antibodies. FIG. 7B shows a schematic drawing of the workflow of confocal microscopy. FIG. 7C shows results of confocal microscopy. HEK293-hCTLA-4 cells were incubated with lOpg / mL antibody

[0088] FIGs. 8A-8B show effect of anti-CTLA-4 antibodies on antibody dependent cellular cytotoxicity (ADCC). FIG. 8A shows selection of NK cells. FIG. 8B shows target cell lysis was evaluated at various concentrations of four different antibodies and EC50 values calculated from doseresponse curves.

[0089] FIGs. 9A-9E show in vivo anti-tumor efficacy of anti-CTLA-4 antibodies. FIG. 9A shows a schematic drawing of the experimental procedure. FIG.9B shows tumor volume results of the vehicle, biweekly for 3 weeks, n=8. FIG. 9C shows tumor volume results of reference 1 at 1 mg / kg, biweekly for 3 weeks, n=8. FIG. 9D shows tumor volume results of CTLA-4- AB-68.1 at 1 mg / kg, biweekly for 3 weeks, n=8. FIG. 9E shows tumor volume results of CTLA-4- AB -68.1 at 10 mg / kg, biweekly for 3 weeks, n=8.

[0090] FIGs. 10A-10H show effect of anti-CTLA-4 antibodies on immune cell subsets in the tumor and blood of hCTLA4 knock-in mice. FIG. 10A 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. 10B shows gating strategyfor 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. 10C 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. 10D shows results of the FCM analysis for blood samples showing percentages of myeloid, T cells and T cell subpopulations in CD45+ cells. FIG. 10E shows results of the FCM analysis for blood samples showing percentages of T cell subpopulations in T cells. FIG. 10F 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. 10G shows results of the FCM analysis for blood samples showing ratios between T cell subpopulations. CD4Teff refers to CD4T cells other than Treg. FIG. 10H shows mean fluorescence intensity (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).

[0091] FIG.ll depicts an exemplary format (“Crossmab”) of a PD-l / CTLA-4 bispecifc antibody binding molecule. The binding molecule includes a variable heavy (VH) chain and a variable light (VL) chain of an anti- PD-1 antibody, and a variable heavy (VH) chain and a variable light (VL) chain of an anti-CTLA-4 antibody, each configured as Fabs such that for one the VH and a VL region are interchanged in one binding arm (“crossmab” format). As depicted, the Fc region of the bispecific antibody is formed with a heterodimeric Fc containing knob-into-hole heterodimeric connections to form two different heavy chains. In one configuration is an antibody designated PC_abl in which the Targetl is CTLA4 and the CTLA4 Fab is a crossmab format and the Target2 is PD-1 with a conventional PD-1 Fab. In another configuration is an antibody designated PC_ab2 in which the Targetl is PD-1 and the PD-1 Fab is a crossmab format, and the Target2 is CTLA-4 with a conventional CTLA-4 Fab.

[0092] FIGs 12A-12B show reducing and non-reducing SDS-PAGE gels showing the heavy and light chains of the bispecific antibodies.

[0093] FIGs. 13A-13B show SEC-HPLC results for CTLA-4 / PD-l-abl and CTLA-4 / PD-l-ab2.

[0094] FIGs. 14A-14C are binding results of the engineered bispecific PD-l / CTLA-4 antibodies from an Enzyme-Linked Immuno-Sorbent Assay at different pH 5.0 and 7.4.Detailed Description

[0095] The present disclosure concerns anti-PD-1 antibodies or antibody fragments suitable for therapeutic use. The present disclosure additionally concerns binding molecules, such as multispecific antibodies (e.g., bispecific antibodies), that contain a PD1 binding domain (e.g., antibody fragment, such as a Fab) that binds PD-1 and a CTLA-4 binding domain (e.g., antibody fragment, such as a Fab) for therapeutic use.

[0096] PD1 (Programmed cell death 1; also known as CD279 (cluster of differentiation 279)), is a cell surface receptor protein expressed primarily on T-cells, but also on other immune cells.The PD-1 pathway is a regulator in the induction and maintenance of immunological tolerance. The protein functions as an "immune checkpoint" inhibitor, i.e. it acts to modulate the activity of cells in the immune system so as to regulate and limit autoimmune diseases. PD-1 has two ligands, PD-L1 and PD-L2, which interact with the cell surface receptor. On binding, PD-1 induces an intracellular signal, which negatively regulates T-cell responses. On the surface of activated T cells, PD-1 expression is upregulated after the recognition of peripheral antigens by T cells; subsequently, the elevated binding of PD-1 to PD-L1 and PD-L2 becomes a key step for downstream inhibitory signaling. PD-1 is also associated with increased Treg-cell proliferation and enhanced immunosuppressive function. In some embodiments, provided anti-PD-1 antibodies or antibody fragments act as PD-1 inhibitors to activate the immune system to attack tumors, including in methods for treating cancer.

[0097] Relative to existing known therapies, some of these anti-PD-1 antibodies or antibody fragments may exhibit improved binding kinetics to PD-1 in a tumor environment versus PD-1 present in normal tissue. The disclosed anti-PD-1 antibodies or antibody fragments may also exhibit physiochemical or biological properties that lead to improved efficacy and safety to anti-PD-1 antibodies known in the art.

[0098] In some embodiments, provided anti-PD-1 antibodies or antibody fragments have a higher binding affinity to PD-1 in a tumor in comparison with PD-1 present in normal tissue. In some such embodiments, these anti-PD-1 antibodies or antibody fragments have at least comparable efficacy as well as a longer half-life, but reduced side-effects, in comparison with monoclonal anti-PD-1 antibodies known in the art. This may permit use of higher dosages of these anti-PD-1 antibodies or antibody fragments, thus providing a more effective therapeutic option without a corresponding significant increase in side effects.

[0099] In provided embodiments, a binding molecule, such as a bispecific antibody, that is directed against PD-1 and also CTLA-4 can simultaneously block the PD-1 and also block CTLA-4 to thus reduce immune responses to the tumor site. Likewise, among the provided binding molecules containing a PD-1 binding domain and a CTLA-4 binding domain are binding molecules that comprisea CTLA-4 binding domain that confers specific binding properties to human CTLA-4 under different pH conditions. In some embodiments, the disclosed binding molecules also exhibit physiochemical or biological properties that lead to improved efficacy and safety as compared to CTLA-4 binding domains known in the art.

[0100] An altered pH microenvironment is the most common microenvironment found in disease states such as tumor microenvironments, and it is the most uniform within the disease microenvironment compared to other properties such as hypoxia (see e.g. Fogh Andersen et al. (1995) Clin. Chem., 41:1522-1525; Bhujwalla et al. (2002) NMR Biomed., 15:114-119; Helmlinger et al. (1997) Nature Med., 3:177; Gerweck and Seetharaman (1996), Cancer Res. 56(6): 1194-1198). For example, in many tumors the ‘Warburg effect’ creates a microenvironment with a pH ranging from 5.6 to 6.8.

[0101] The immune system is responsible for defending the body against foreign substances, such as pathogens and abnormal cells. Central to the immune response are T cells, a type of white blood cell, which act as key orchestrators of immune reactions. 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.

[0102] CTLA-4 acts by binding to its ligands, CD80 (B7-1) and CD86 (B7-2), on antigen- presenting cells (APCs), 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. 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.

[0103] Based on promising preclinical tumor model studies, the clinical potential of antibodies against CTLA-4 has been explored in different human malignancies. Although a specific anti-CTLA-4 antibody (Ipilimumab, marketed as Yervoy) has demonstrated efficacy in treating melanoma, treatment and targeting of CTLA-4 is associated with autoimmune like toxicities. Characteristic side effects from inhibition of CTLA-4 are generally called immune-related adverse events (ir AEs) and the most common irAEs are skin rash, hepatitis, colitis and endocrinopathies, particularly hypopituitarism. 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. Therefore, there is a desire to improve the therapeutic potential of CTLA-4 binding domains by increasing efficacy while reducing the associated irAEs.

[0104] In some embodiments, the provided binding molecules comprise a CTLA-4 binding domain that 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.

[0105] In some embodiments, the provided binding molecules preserve 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).

[0106] In some embodiments, provided binding molecules comprise a CTLA-4 binding domain that has 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 binding molecules 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 binding molecules, thus providing a more effective therapeutic option without a corresponding significant increase in side effects.

[0107] In some embodiments, the provided binding molecules comprise a CTLA-4 binding domain that 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, the provided binding molecules comprise a CTLA- 4 binding domain that reduces 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.

[0108] In some embodiments, the binding molecule or a pharmaceutical composition comprising the binding molecule induces strong deletion of Treg and local T cell activation in tumor microenvironment but minimal systemic T cell activation. In some embodiments, the binding molecule or a pharmaceutical composition comprising the binding molecule induces a favorable ratio of Treg cells to T effector cells in the tumor microenvironment.

[0109] 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.

[0110] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.I. ANTI-PD-1 ANTIBODIES AND ANTIGEN-BINDING FRAGMENTS AND BINDING MOLECULES THEREOF

[0111] Provided herein are anti-PD-1 antibodies, including full-length antibodies or antigenbinding fragments, that contain a heavy chain variable region (VH) sequence and a light chain 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-PD-1 antibody that comprises the three heavy chain complementarity determining regions (CDRs) and the VL chain is the region of the anti-PD-1 antibody that comprises the three light chain CDRs. Among provided anti-PD-1 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 PD-1, e.g., human PD-1. Among the provided anti-PD-1 antibodies are human antibodies, or antibodies that are modified from or variant of human antibodies. The antibodies include isolated antibodies. Also provided are PD-1 -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 PD-1 -targeted antibodydrug conjugate (ADC) comprising an anti-PD-1 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-PD-1 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 PD-1 -binding molecules include isolated molecules.

[0112] 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-PD-1 antibodies or binding molecules.

[0113] 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 “antigenbinding 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.

[0114] 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).

[0115] 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 are incorporated 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).

[0116] 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.

[0117] 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 of 7 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 Cresidue 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.

[0118] 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-L1 according to Chothia numbering can be L26— L32 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Lesk A.M. J Mol Biol, 1987; 196(4):901-17). In some instances, the boundary positions for CDR-L1 can be L25— L32 (Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48). In some instances, the boundary positions for CDR-L2 can be L50— L52 and for CDR-L3 can be L91— L96 (Chothia et al., Science, 1986; 233(4765):755-8; Chothia C. and Lesk A.M. J Mol Biol, 1987; 196(4):901-17; and Al-Lazikani 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 Lesk A.M. J Mol Biol, 1987; 196(4):901-17; and Al-Lazikani 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 Lesk A.M. J Mol Biol, 1987, 196(4):901-17); H52a-H55 (Tramontane et al., J Mol Biol, 1990, 215(1): 175-82), or H52— H56 (Al-Lazikani 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 Lesk A.M. J Mol Biol., 1987; 196(4):901-17). In some instances, 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).

[0119] 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 between H32 and H34, depending on the length of the loop.1 - Kabat et al. (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).

[0120] 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 can be 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.

[0121] Likewise, unless otherwise specified, a FR or individual specified FR(s) (e.g., FR-H1, FR- H2, FR-H3, FR-H4, FR-E1, FR-E2, FR-E3, and / or FR-E4), 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, IgBEAST, 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-E1, a FR-E2, a FR-E3, and a FR-E4 as contained within a given VL region amino acid sequence, the FRs can be defined by any of theaforementioned schemes, such as Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known scheme.

[0122] 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).

[0123] 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) and variable light chain (VL) sequence from antibodies that bind PD-1 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 L 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 cross-linking 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.

[0124] 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 someembodiments, 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.

[0125] 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) comprises a covalent heterodimer of the VH chain and VL chain and includes an intact antigen-binding site.

[0126] 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.

[0127] 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 / 5'.2106-21 \ 0 and Ehrlich et al. (1980) Biochem 79:4091-4096.

[0128] 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.

[0129] 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.

[0130] A scFv polypeptide is a covalently linked VH::VL heterodimer which is expressed from a gene fusion including VH- and V| -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 Ladner et al.

[0131] 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 technology creates a stable, smallerantibody 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 halfmolecule 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.

[0132] 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- PD-1 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.

[0133] 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 exist 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.

[0134] 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 antibodyencoding 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 antigen-binding fragments of human antibodies.

[0135] 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.

[0136] 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.

[0137] In some aspects, the antibody or the antigen-binding fragments of the antibody is isolated.

[0138] 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 PD-1 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 PD-1 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.

[0139] 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-PD-1 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-PD-1 antibody described herein.A. Exemplary Antibodies

[0140] In some embodiments, the anti-PD-1 antibody contains a VH region and a VL region containing a combination of six CDRs as described below. In some embodiments, the anti-PD-1 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- PD-1 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-PD-1 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-PD-1 antibody comprises two heavy chains, wherein each heavy chain 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.

[0141] Anti-PDl 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-PD-1 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 here. 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.

[0142] In some embodiments, a provided anti-PD-1 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: 1-45, 157, and 165-170, 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: 1-45, 157, and 165- 170. In some embodiments, a provided anti-PD-1 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 oneof SEQ ID NOs: 46-90, 158, and 171-172, 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: 46-90, 158, and 171-172. In some embodiments, the provided anti-PD-1 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-PD-1 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: 1-45, 157, 165-170, 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: 46-90, 158, and 171-172. 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, a CDR-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.

[0143] Exemplary heavy and light chain CDR sequences of the anti-PD-1 antibodies and antigenbinding fragments thereof are provided in Tables 2A and 2B.

[0144] In some of any of the provided embodiments, the VH region contains a CDR-H1 set forth in any one of SEQ ID NOs: 91-101, a CDR-H2 set forth in any one of SEQ ID NOs: 102-112, and 173, and a CDR-H3 set forth in any one of SEQ ID NOs: 113-123; and the VL region contains a CDR-L1 set forth in any one of SEQ ID NOs: 124-134, a CDR-L2 set forth in any one of SEQ ID NOs: 135-145, and a CDR-L3 set forth in any one of SEQ ID NOs: 146-156. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment does not contain the combination of CDRs set forth in SEQ ID NO: 91, SEQ ID NO: 102, SEQ ID NO: 113, SEQ ID NO: 124, SEQ ID NO: 135 and SEQ ID NO: 146. In some embodiments, the VH region comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 92-101, a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 103-112, and 173, and a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 114-123, and the VL region comprises a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 124-134, a CDR-L2 comprising the sequence set forth in any one of SEQ ID NOs: 135-145; and a CDR-L3 comprising the sequence set forth in any one of SEQ ID NOs: 146-156. In some embodiments, the VH region comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 91-101, a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 102-112, and 173, and a CDR- H3 comprising the sequence set forth in any one of SEQ ID NOs: 113-123, and the VL region comprises a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 125-134, a CDR-L2 comprising the sequence set forth in any one of SEQ ID NOs: 136-145; and a CDR-L3 comprising the sequence set forth in any one of SEQ ID NOs: 147-156. 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.

[0145] In some of any of the provided embodiments, the VH region contains a CDR-H1 set forth in any one of SEQ ID NOs: 92-101, a CDR-H2 set forth in any one of SEQ ID NOs: 103-112, and 173, and a CDR-H3 set forth in any one of SEQ ID NOs: 114-123.; and the VL region contains a CDR-L1 set forth in any one of SEQ ID NOs: 125-134, a CDR-L2 set forth in any one of SEQ ID NOs: 136-145, and a CDR-L3 set forth in any one of SEQ ID NOs: 147-156.

[0146] 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-H1, 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 antigenbinding 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 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: 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 antigenbinding 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-H1, 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 antigenbinding fragment has a VH region that contains a CDR-H1, 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 aVH 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-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO:21. In some embodiments, the antibody or antigenbinding 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-H1, 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 antigenbinding fragment 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:28. 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:29. 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:30. 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:31. In some embodiments, the antibody or antigenbinding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO:32. 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:33. 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:34. 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:35. 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:36. In some embodiments, the antibody or antigenbinding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO:37. 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:38. 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:39. 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:40. 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:41. In some embodiments, the antibody or antigenbinding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQID NO:42. 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:43. 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:44. 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:45. 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: 157. In some embodiments, the antibody or antigenbinding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 165. 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:166. 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: 167. 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:168. 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: 169. In some embodiments, the antibody or antigenbinding fragment has a VH region that contains a CDR-H1, a CDR-H2 and a CDR-H3 present in SEQ ID NO: 170. 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.

[0147] 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 SEQ ID 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:49. In some embodiments, the antibody or antigenbinding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO:50. 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:51. 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:52. 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:53. 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:54. In some embodiments, the antibody or antigenbinding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQID NO:55. 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:56. n some embodiments of 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:57. 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:58. 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:59. In some embodiments, the antibody or antigenbinding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO:60. 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:61. 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:62. 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:63. 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:64. In some embodiments, the antibody or antigenbinding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO: 65. 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:66. 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: 67. 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:68. 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:69. In some embodiments, the antibody or antigenbinding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO:70. 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:71. 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:72. 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:73. 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:74. In some embodiments, the antibody or antigenbinding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO:75. 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:76. 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: 77. In some embodiments, the antibody or antigen-binding fragment has aVL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO:78. 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:79. In some embodiments, the antibody or antigenbinding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO:80. 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:81. 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: 82. 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:83. 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: 84. In some embodiments, the antibody or antigenbinding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO:85. 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:86. 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: 87. 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:88. 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: 89. In some embodiments, the antibody or antigenbinding fragment has a VL region that contains a CDR-L1, a CDR-L2 and a CDR-L3 present in SEQ ID NO:90. 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: 158. 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: 171. 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: 172. 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.

[0148] In some embodiments of the anti-PD-1 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: 92, 102, and 113, respectively; SEQ ID NOS: 93, 102, and 113, respectively; SEQ ID NOS: 94, 102, and 113, respectively; SEQ ID NOS: 95, 102, and 113, respectively; SEQ ID NOS: 96, 102, and 113, respectively; SEQ ID NOS: 97, 102, and 113, respectively; SEQ ID NOS: 98, 102, and 113, respectively; SEQ ID NOS: 99, 102, and 113, respectively; SEQ ID NOS: 100, 102, and 113, respectively; SEQ ID NOS: 101, 102, and 113, respectively; SEQ ID NOS: 91, 103, and 113,respectively; SEQ ID NOS: 91, 104, and 113, respectively; SEQ ID NOS: 91, 105, and 113, respectively; SEQ ID NOS: 91, 106, and 113, respectively; SEQ ID NOS: 91, 107, and 113, respectively; SEQ ID NOS: 91, 108, and 113, respectively; SEQ ID NOS: 91, 109, and 113, respectively; SEQ ID NOS: 91, 110, and 113, respectively; SEQ ID NOS: 91, 111, and 113, respectively; SEQ ID NOS: 91, 112, and 113, respectively; SEQ ID NOS: 91, 102, and 114, respectively; SEQ ID NOS: 91, 102, and 115, respectively; SEQ ID NOS: 91, 102, and 116, respectively; SEQ ID NOS: 91, 102, and 117, respectively; SEQ ID NOS: 91, 102, and 118, respectively; SEQ ID NOS: 91, 102, and 119, respectively; SEQ ID NOS: 91, 102, and 120, respectively; SEQ ID NOS: 91, 102, and 121, respectively; SEQ ID NOS: 91, 102, and 122, respectively; SEQ ID NOS: 91, 102, and 123, respectively; SEQ ID NOS: 101, 103, and 114, respectively; SEQ ID NOS: 97, 103, and 117, respectively; SEQ ID NOS: 99, 105, and 115, respectively; SEQ ID NOS: 96, 104, and 116, respectively; SEQ ID NOS: 98, 106, and 114, respectively; SEQ ID NOS: 96, 107, and 117, respectively; SEQ ID NOS: 97, 105, and 117, respectively; SEQ ID NOS: 99, 111, and 115, respectively; SEQ ID NOS: 97, 111, and 116, respectively; SEQ ID NOS: 100, 105, and 121, respectively; SEQ ID NOS: 93, 103, and 115, respectively; SEQ ID NOS: 100, 108, and 119, respectively; SEQ ID NOS: 99, 111, and 116, respectively; SEQ ID NOS: 91, 102, and 113, respectively; SEQ ID NOS: 91, 106, and 113, respectively; SEQ ID NOS: 100, 173, and 121, respectively; SEQ ID NOS: 95, 105, and 121, respectively; SEQ ID NOS: 95, 173, and 121, respectively; SEQ ID NOS: 95, 106, and 114, respectively; or SEQ ID NOS: 91, 102, and 114, respectively.

[0149] In some embodiments of the anti-PD-1 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:124, 135, and 146, respectively; SEQ ID NOS: 125, 135, and 146, respectively; SEQ ID NOS: 126,135, and 146, respectively; SEQ ID NOS: 127, 135, and 146, respectively; SEQ ID NOS: 128, 135, and146, respectively; SEQ ID NOS: 129, 135, and 146, respectively; SEQ ID NOS: 130, 135, and 146, respectively; SEQ ID NOS: 131, 135, and 146, respectively; SEQ ID NOS: 132, 135, and 146, respectively; SEQ ID NOS: 133, 135, and 146, respectively; SEQ ID NOS: 134, 135, and 146, respectively; SEQ ID NOS: 124, 136, and 146, respectively; SEQ ID NOS: 124, 137, and 146, respectively; SEQ ID NOS: 124, 138, and 146, respectively; SEQ ID NOS: 124, 139, and 146, respectively; SEQ ID NOS: 124, 140, and 146, respectively; SEQ ID NOS: 124, 141, and 146, respectively; SEQ ID NOS: 124, 142, and 146, respectively; SEQ ID NOS: 124, 143, and 146, respectively; SEQ ID NOS: 124, 144, and 146, respectively; SEQ ID NOS: 124, 145, and 146, respectively; SEQ ID NOS: 124, 135, and 147, respectively; SEQ ID NOS: 124, 135, and 148, respectively; SEQ ID NOS: 124, 135, and 149, respectively; SEQ ID NOS: 124, 135, and 150, respectively; SEQ ID NOS: 124, 135, and 151, respectively; SEQ ID NOS: 124, 135, and 152, respectively; SEQ ID NOS: 124, 135, and 153, respectively; SEQ ID NOS: 124, 135, and 154,respectively; SEQ ID NOS: 124, 135, and 155, respectively; SEQ ID NOS: 124, 135, and 156, respectively; SEQ ID NOS: 131, 142, and 149, respectively; SEQ ID NOS: 131, 139, and 150, respectively; SEQ ID NOS: 128, 138, and 148, respectively; SEQ ID NOS: 126, 145, and 153, respectively; SEQ ID NOS: 126, 144, and 154, respectively; SEQ ID NOS: 125, 140, and 153, respectively; SEQ ID NOS: 132, 137, and 152, respectively; SEQ ID NOS: 131, 142, and 152, respectively; SEQ ID NOS: 132, 141, and 154, respectively; SEQ ID NOS: 133, 144, and 150, respectively; SEQ ID NOS: 134, 138, and 149, respectively; SEQ ID NOS: 126, 137, and 149, respectively; SEQ ID NOS: 126, 137, and 152, respectively; SEQ ID NOS: 132, 142, and 154, respectively; SEQ ID NOS: 127, 140, and 151, respectively; SEQ ID NOS: 132, 145, and 153, respectively; SEQ ID NOS: or 126, 143, and 153, respectively.

[0150] In some embodiments of the anti-PD-1 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: 92, 102, and 113, 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: 124, 135, and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 93, 102, and 113, 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: 124, 135, and 146, respectively. In some embodiments of the anti- PD-1 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: 94, 102, and 113, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 95, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135, and 146, respectively. In some embodiments of the anti-PD-1 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: 96, 102, and 113, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 97, 102, and 113, 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: 124, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 98, 102, and 113, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ IDNOS: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 99, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 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: 100, 102, and 113, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 101, 102, and 113, 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: 124, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 91, 103, and 113, 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: 125, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 104, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 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: 91, 105, and 113, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 106, and 113, 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: 125, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 91, 107, and 113, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 108, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 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 IDNOS: 91, 109, and 113, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 110, and 113, 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: 124, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 91, 111, and 113, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 112, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135, 146, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 114, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 115, 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: 124, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 116, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 117, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 118, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 119, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 120, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 121, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 122, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 123, 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: 124, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 101, 103, and 114, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 97, 103, and 117, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135, and 146, respectively. In some embodiments of the anti-PD-1 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: 99, 105, and 115, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 96, 104, and 116, 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: 124, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 98, 106, and 114, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 96, 107, and 117, respectively, and the VL region comprises a CDR-LI, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 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: 97, 105, and 117, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 99, 111, and 115, 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: 124, 135, and 146, respectively. In some embodiments of the anti- PD-1 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: 97, 111, and 116, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 100, 105, and 121, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 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: 93, 103, and 115, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 100, 108, and 119, 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: 124, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 99, 111, and 116, 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: 124, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 125, 135 and 146, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 126, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR-Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 127, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 113, 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: 128, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 129, 135 and 146, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 130, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 131, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 113, 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: 132, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 133, 135 and 146, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 134, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 124, 136 and 146, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 113, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ IDNOS: 124, 137 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 138 and 146, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 124, 139 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 124, 140 and 146, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 113, 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: 124, 141 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 142 and 146, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 124, 143 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 124, 144 and 146, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 113, 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: 124, 145 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135 and 147, respectively. In some embodiments of the anti-PD-1 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 IDNOS: 91, 102, and 113, 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: 124, 135 and 148, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 124, 135 and 149, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 113, 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: 124, 135 and 150, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135 and 151, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 124, 135 and 152, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 124, 135 and 153, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 113, 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: 124, 135 and 154, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 124, 135 and 155, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 124, 135 and 156, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 131, 142 and 149, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 131, 139 and 150, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 128, 138, and 148, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 126, 145 and 153, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 126, 144 and 154, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 113, 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: 125, 140 and 153, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 132, 137 and 152, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 131, 142 and 152, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 132, 141 and 154, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 113, 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: 133, 144 and 150, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR-LI, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 134, 138 and 149, respectively. In some embodiments of the anti-PD-1 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: 91, 102, and 113, 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: 126, 137 and 149, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, 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: 126, 137 and 152, respectively. In some embodiments of the anti- PD-1 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: 91, 102, and 113, 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: 132, 142 and 154, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 127, 140 and 151, respectively. In some embodiments of the anti-PD-1 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: 91, 106, and 113, 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: 126, 135 and 146, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 91, 102, and 114, 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: 126, 135 and 146, respectively. In some embodiments of the anti- PD-1 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: 99, 105, and 115, 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: 131, 142 and 149, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 126, 145 and 153, respectively. In some embodiments of the anti-PD-1 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: 99, 105, and 115, 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: 125, 140, and 153, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR-Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 99, 105, and 115, 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: 132, 141 and 154, respectively. In some embodiments of the anti- PD-1 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: 99, 105, and 115, 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: 132, 142 and 154, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 131, 142 and 149, respectively. In some embodiments of the anti-PD-1 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: 98, 106, and 114, 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: 126, 145 and 153, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 98, 106, and 114, 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: 125, 140 and 153, respectively. In some embodiments of the anti- PD-1 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: 98, 106, and 114, 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: 132, 141 and 154, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 132, 142 and 154, respectively. In some embodiments of the anti-PD-1 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: 99, 111, and 115, 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: 131, 142 and 149, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 99, 111, and 115, 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: 126, 145 and 153, respectively. In some embodiments of the anti- PD-1 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: 99, 111, and 115, respectively, and the VL region comprises a CDR-L1, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ IDNOS: 125, 140 and 153, respectively. In some embodiments of the anti-PD-1 antibody or antigenbinding fragment, the VH region comprises a CDR-H1, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the VL region comprises a CDR- Ll, a CDR-L2 and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 132, 141 and 154, respectively. In some embodiments of the anti-PD-1 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: 99, 111, and 115, 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: 132, 142 and 154, respectively. In some embodiments of the anti-PD-1 antibody or antigen-binding fragment, the VH region comprises a CDR- Hl, a CDR-H2 and a CDR-H3 comprising the sequence set forth in SEQ ID NOS: 100, 105 and 121, 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: 131, 142 a...

Claims

1. CLAIMS1. An anti-programmed cell death protein 1 (PD-1) 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: 1-45, 157, and 165-170, 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: 46-90, 158, and 171-172.

2. The anti-PD-1 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:3, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ IDNO: 15, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; the VH region comprises a CDR-H1, 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: 158; 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: 158; 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: 158; 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: 158; 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: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:28, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:29, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:30, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:31, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:32, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ IDNO:33, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:34, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:36, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:38, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:39, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:41, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:43, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:44, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:45, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 158; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, 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-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, 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: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 48; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 49; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 50; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, andthe VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 51; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 52; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 53; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 54; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 55; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 56; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 57; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 58; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 59; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 60; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1 , a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 61 ; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 62; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 63; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 64; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 65; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 66; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 67; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 68; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL regioncomprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 69; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 70; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 71; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 72; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 73; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 74; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 75; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 76; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 77; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 78; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 80; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 81; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 82; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 83; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 84; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 85; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 86; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL regioncomprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 87; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 88; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 157, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 90; 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: 47; the VH region comprises a CDR-H1, 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: 35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 76; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 81; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 84; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 35, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 76; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 81; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 84; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 37, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 76; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 40, and the VL regioncomprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 81; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 84; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 76; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 81; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 84; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 165, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 165, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 165, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 166, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 166, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 166, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 167, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 167, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 167, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 168, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 168, and the VL regioncomprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 168, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 169, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 169, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 169, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 170, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 79; the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 170, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 171; or the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 170, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 172.

3. An anti-PD-1 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: 91-101, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in any one of SEQ ID NOs: 102- 112, and 173, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in any one of SEQ ID NOs: 113-123; 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: 124-134, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in any one of SEQ ID NOs: 135-145, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in any one of SEQ ID NOs:146-156.

4. The anti-PD-1 antibody or antigen-binding fragment thereof of claim 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: 92-101, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in any one of SEQ ID NOs: 103-112, and 173, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in any one of SEQ ID NOs:l 14-123.

5. The anti-PD-1 antibody or antigen-binding fragment thereof of claim 3, 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: 125-134, a light chain complementaritydetermining region 2 (CDR-L2) comprising the sequence set forth in any one of SEQ ID NOs: 136-145, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in any one of SEQ ID NOs:147-156.

6. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-5, wherein: the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 92, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 93, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 94, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 96, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 97, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 102, and 113, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 101, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 103, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 104, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 105, and 113, respectively, and theCDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 106, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 107, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 108, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 109, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 110, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 111, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 112, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 116, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 117, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 118, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 119, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 120, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forthin SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 122, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 123, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 101, 103, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 97, 103, and 117, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 96, 104, and 116, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 96, 107, and 117, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 97, 105, and 117, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 97, 111, and 116, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 93, 103, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprisethe sequences set forth in SEQ ID NOS: 100, 108, and 119, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 116, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 127, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 128, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 129, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 130, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, theCDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 133, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 134, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 136, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 137, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2,and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 138, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 139, and 146, respectively; the CDR-H1, theCDR-H2, and theCDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 140, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 141, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 142, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 143, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 144, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 145, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 147, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 148, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 150, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 151, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 152, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 153, respectively; theCDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 155, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 124, 135, and 156, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 139, and 150, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 128, 138, and 148, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 144, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 140, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 137, and 152, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 152, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 141, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 133, 144, and 150, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 134, 138, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102,and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 137, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 137, and 152, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 142, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 127, 140, and 151, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 106, and 113, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 91, 102, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 135, and 146, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 140, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 141, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 105, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 142, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 140, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forthin SEQ ID NOS: 132, 141, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 98, 106, and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 142, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 140, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 141, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 99, 111, and 115, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 142, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 131, 142, and 149, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 125, 140, and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 141, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 105, and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 142, and 154, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 100, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 143 and 153, respectively; the CDR-H1, the CDR-H2,and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 105 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 105 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 105 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 143 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 173 and 121, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 143 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 106 and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 145 and 153, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 106 and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 132, 145 and 153, respectively; or the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 95, 106 and 114, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 126, 143 and 153, respectively.

7. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-6, wherein: the VH region 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: 1 and SEQ ID NO: 158, respectively; the VH region 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: 2 and SEQ ID NO: 158, respectively; the VH region 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: 3 and SEQ ID NO: 158, respectively; the VH region 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: 4 and SEQ ID NO: 158, respectively; the VH region 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: 5 andSEQ ID NO: 158, respectively; the VH region 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: 6 and SEQ ID NO: 158, respectively; the VH region 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: 7 and SEQ ID NO: 158, respectively; the VH region 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: 8 and SEQ ID NO: 158, respectively; the VH region 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: 9 and SEQ ID NO: 158, respectively; the VH region 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: 10 and SEQ ID NO: 158, respectively; the VH region 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: 11 and SEQ ID NO: 158, respectively; the VH region 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: 12 and SEQ ID NO: 158, respectively; the VH region 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: 13 and SEQ ID NO: 158, respectively; the VH region 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: 14 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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: 16 and SEQ ID NO: 158, respectively; the VH region 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: 17 and SEQ ID NO: 158, respectively; the VH region 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: 18 and SEQ ID NO: 158, respectively; the VH region 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: 19 and SEQ ID NO: 158, respectively; the VH region and the VL region is or comprises 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: 20 and SEQ ID NO: 158, respectively; the VH region 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: 21 and SEQ ID NO: 158, respectively; the VH region 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: 22 and SEQ ID NO: 158, respectively; the VH region 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: 23 and SEQ ID NO: 158, respectively; the VH region 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: 24 and SEQ ID NO: 158, respectively; the VH region 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: 25 and SEQ ID NO: 158, respectively; the VH region 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: 26 and SEQ ID NO: 158, respectively; the VH region 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: 27 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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: 34 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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: 36 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 or ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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 and SEQ ID NO: 158, respectively; the VH region 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: 157 and SEQ ID NO: 46, respectively; the VH region 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: 157 and SEQ ID NO: 47, respectively; the VH region 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: 157 and SEQ ID NO: 48, respectively; the VH region and the VL region is or comprises 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: 157 and SEQ ID NO: 49, respectively; the VH region 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: 157 and SEQ ID NO: 50, respectively; the VH region 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: 157 and SEQ ID NO: 51, respectively; the VH region 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: 157 and SEQ ID NO: 52, respectively; the VH region 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: 157 and SEQ ID NO: 53, respectively; the VH region 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: 157 and SEQ ID NO: 54, respectively; the VH region 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: 157 and SEQ ID NO: 55, respectively; the VH region 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: 157 and SEQ ID NO: 56, respectively; the VH region 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: 157 and SEQ ID NO: 57, respectively; the VH region 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: 157 and SEQ ID NO: 58, respectively; the VH region 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: 157 and SEQ ID NO: 59, respectively; the VH region 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: 157 and SEQ ID NO: 60, respectively; the VH region 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: 157 and SEQ ID NO: 61, respectively; the VH region 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: 157 and SEQ ID NO: 62, respectively; the VH region 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: 157 and SEQ ID NO: 63, respectively; the VH region 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: 157 and SEQ ID NO: 64, respectively; the VH region 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: 157 and SEQ ID NO: 65, respectively; the VH region 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: 157 and SEQ ID NO: 66, respectively; the VH region 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: 157 or ID NO: 67, respectively; the VH region 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: 157 and SEQ ID NO: 68, respectively; the VH region 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: 157 and SEQ ID NO: 69, respectively; the VH region 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: 157 and SEQ ID NO: 70, respectively; the VH region 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: 157 and SEQ ID NO: 71, respectively; the VH region 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: 157 and SEQ ID NO: 72, respectively; the VH region 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: 157 and SEQ ID NO: 73, respectively; the VH region 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: 157 and SEQ ID NO: 74, respectively; the VH region 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: 157 and SEQ ID NO: 75, respectively; the VH region 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: 157 and SEQ ID NO: 76, respectively; the VH region 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: 157 and SEQ ID NO: 77, respectively; the VH region and the VL region is or comprises 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: 157 and SEQ ID NO: 78, respectively; the VH region 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: 157 and SEQ ID NO: 79, respectively; the VH region 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: 157 and SEQ ID NO: 80, respectively; the VH region 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: 157 and SEQ ID NO: 81, respectively; the VH region 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: 157 and SEQ ID NO: 82, respectively; the VH region 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: 157 and SEQ ID NO: 83, respectively; the VH region 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: 157 and SEQ ID NO: 84, respectively; the VH region 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: 157 and SEQ ID NO: 85, respectively; the VH region 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: 157 and SEQ ID NO: 86, respectively; the VH region 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: 157 and SEQ ID NO: 87, respectively; the VH region 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: 157 and SEQ ID NO: 88, respectively; the VH region 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: 157 and SEQ ID NO: 89, respectively; the VH region 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: 157 and SEQ ID NO: 90, respectively; the VH region 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: 16 and SEQ ID NO: 47, respectively; the VH region 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: 23 and SEQ ID NO: 47, respectively; the VH region 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 and SEQ ID NO: 76, respectively; the VH region 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 and SEQ ID NO: 79, respectively; the VH region 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 and SEQ ID NO: 81, respectively; the VH region 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 and SEQ ID NO: 84, respectively; the VH region 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 and SEQ ID NO: 89, respectively; the VH region 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 and SEQ ID NO: 76, respectively; the VH region 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 and SEQ ID NO: 79, respectively; the VH region 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 and SEQ ID NO: 81, respectively; the VH region 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 and SEQ ID NO: 84, respectively; the VH region 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 and SEQ ID NO: 89, respectively; the VH region 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 and SEQ ID NO: 76, respectively; the VH region 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 and SEQ ID NO: 79, respectively; the VH region 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 and SEQ ID NO: 81, respectively; the VH region 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 and SEQ ID NO: 84, respectively; the VH region and the VL region is orcomprises an amino acid sequence having at least 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 and SEQ ID NO: 89, respectively; the VH region 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 and SEQ ID NO: 76, respectively; the VH region 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 and SEQ ID NO: 79, respectively; the VH region 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 and SEQ ID NO: 81, respectively; the VH region 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 and SEQ ID NO: 84, respectively; the VH region 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 and SEQ ID NO: 89, respectively; the VH region 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: 165 and SEQ ID NO: 79, respectively; the VH region 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: 165 and SEQ ID NO: 171, respectively; the VH region 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: 165 and SEQ ID NO: 172, respectively; the VH region 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: 166 and SEQ ID NO: 79, respectively; the VH region 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: 166 and SEQ ID NO: 171, respectively; the VH region 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: 166 and SEQ ID NO: 172, respectively; the VH region 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: 167 and SEQ ID NO: 79, respectively; the VH region 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: 167 and SEQ ID NO: 171, respectively; the VH region 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: 167 and SEQ ID NO: 172, respectively; the VH region 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: 168 and SEQ ID NO: 79, respectively; the VH region 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: 168 and SEQ ID NO: 171, respectively; the VH region 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: 168 and SEQ ID NO: 172, respectively; the VH region 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: 169 and SEQ ID NO: 79, respectively; the VH region 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: 169 and SEQ ID NO: 171, respectively; the VH region 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: 169 and SEQ ID NO: 172, respectively; the VH region 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: 170 and SEQ ID NO: 79, respectively; the VH region 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: 170 and SEQ ID NO: 171, respectively; or the VH region 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: 170 and SEQ ID NO: 172, respectively.

8. The anti-PD-1 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 158, respectively; the sequence set forth in SEQ ID NO: 2 and 158, respectively; the sequence set forth in SEQ ID NO: 3 and 158, respectively; the sequence set forth in SEQ ID NO: 4 and 158, respectively; the sequence set forth in SEQ ID NO: 5 and 158, respectively; the sequence set forth in SEQ ID NO: 6 and 158, respectively; the sequence set forth in SEQ ID NO: 7 and 158, respectively; the sequence set forth in SEQ ID NO: 8 and 158, respectively; the sequence set forth in SEQ ID NO: 9 and 158, respectively; the sequence set forth in SEQ ID NO: 10 and 158, respectively; the sequence set forth in SEQ ID NO: 11 and 158, respectively; the sequence set forth in SEQ ID NO: 12 and 158, respectively; the sequence set forth in SEQ ID NO: 13 and 158, respectively; the sequence set forth in SEQ ID NO: 14 and 158, respectively; the sequence set forth in SEQ ID NO: 15 and 158, respectively; the sequence set forth in SEQ ID NO: 16 and 158, respectively; the sequence set forth in SEQ ID NO: 17 and 158,respectively; the sequence set forth in SEQ ID NO: 18 and 158, respectively; the sequence set forth in SEQ ID NO: 19 and 158, respectively; the sequence set forth in SEQ ID NO: 20 and 158, respectively; the sequence set forth in SEQ ID NO: 21 and 158, respectively; the sequence set forth in SEQ ID NO: 22 and 158, respectively; the sequence set forth in SEQ ID NO: 23 and 158, respectively; the sequence set forth in SEQ ID NO: 24 and 158, respectively; the sequence set forth in SEQ ID NO: 25 and 158, respectively; the sequence set forth in SEQ ID NO: 26 and 158, respectively; the sequence set forth in SEQ ID NO: 27 and 158, respectively; the sequence set forth in SEQ ID NO: 28 and 158, respectively; the sequence set forth in SEQ ID NO: 29 and 158, respectively; the sequence set forth in SEQ ID NO: 30 and 158, respectively; the sequence set forth in SEQ ID NO: 31 and 158, respectively; the sequence set forth in SEQ ID NO: 32 and 158, respectively; the sequence set forth in SEQ ID NO: 33 and 158, respectively; the sequence set forth in SEQ ID NO: 34 and 158, respectively; the sequence set forth in SEQ ID NO: 35 and 158, respectively; the sequence set forth in SEQ ID NO: 36 and 158, respectively; the sequence set forth in SEQ ID NO: 37 and 158, respectively; the sequence set forth in SEQ ID NO: 38 and 158, respectively; the sequence set forth in SEQ ID NO: 39 and 158, respectively; the sequence set forth in SEQ ID NO: 40 and 158, respectively; the sequence set forth in SEQ ID NO: 41 and 158, respectively; the sequence set forth in SEQ ID NO: 42 and 158, respectively; the sequence set forth in SEQ ID NO: 43 and 158, respectively; the sequence set forth in SEQ ID NO: 44 and 158, respectively; the sequence set forth in SEQ ID NO: 45 and 158, respectively; the sequence set forth in SEQ ID NO: 157 and 46, respectively; the sequence set forth in SEQ ID NO: 157 and 47, respectively; the sequence set forth in SEQ ID NO: 157 and 48, respectively; the sequence set forth in SEQ ID NO: 157 and 49, respectively; the sequence set forth in SEQ ID NO: 157 and 50, respectively; the sequence set forth in SEQ ID NO: 157 and 51, respectively; the sequence set forth in SEQ ID NO: 157 and 52, respectively; the sequence set forth in SEQ ID NO: 157 and 53, respectively; the sequence set forth in SEQ ID NO: 157 and 54, respectively; the sequence set forth in SEQ ID NO: 157 and 55, respectively; the sequence set forth in SEQ ID NO: 157 and 56, respectively; the sequence set forth in SEQ ID NO: 157 and 57, respectively; the sequence set forth in SEQ ID NO: 157 and 58, respectively; the sequence set forth in SEQ ID NO: 157 and 59, respectively; the sequence set forth in SEQ ID NO: 157 and 60, respectively; the sequence set forth in SEQ ID NO: 157 and 61, respectively; the sequence set forth in SEQ ID NO: 157 and 62, respectively; the sequence set forth in SEQ ID NO: 157 and 63, respectively; the sequence set forth in SEQ ID NO: 157 and 64, respectively; the sequence set forth in SEQ ID NO: 157 and 65, respectively; the sequence set forth in SEQ ID NO: 157 and 66, respectively; the sequence set forth in SEQ ID NO: 157 and 67, respectively; the sequence set forth in SEQ ID NO: 157 and 68, respectively; the sequence set forth in SEQ ID NO: 157 and 69, respectively; the sequence set forth in SEQ ID NO: 157 and 70, respectively; the sequence set forth in SEQ ID NO: 157 and 71, respectively; the sequence set forth in SEQ ID NO: 157 and 72, respectively; the sequence set forth in SEQ ID NO: 157 and 73, respectively; the sequence set forth in SEQ ID NO: 157 and 74, respectively; the sequence set forth inSEQ ID NO: 157 and 75, respectively; the sequence set forth in SEQ ID NO: 157 and 76, respectively; the sequence set forth in SEQ ID NO: 157 and 77, respectively; the sequence set forth in SEQ ID NO: 157 and 78, respectively; the sequence set forth in SEQ ID NO: 157 and 79, respectively; the sequence set forth in SEQ ID NO: 157 and 80, respectively; the sequence set forth in SEQ ID NO: 157 and 81, respectively; the sequence set forth in SEQ ID NO: 157 and 82, respectively; the sequence set forth in SEQ ID NO: 157 and 83, respectively; the sequence set forth in SEQ ID NO: 157 and 84, respectively; the sequence set forth in SEQ ID NO: 157 and 85, respectively; the sequence set forth in SEQ ID NO: 157 and 86, respectively; the sequence set forth in SEQ ID NO: 157 and 87, respectively; the sequence set forth in SEQ ID NO: 157 and 88, respectively; the sequence set forth in SEQ ID NO: 157 and 89, respectively; the sequence set forth in SEQ ID NO: 157 and 90, respectively; the sequence set forth in SEQ ID NO: 16 and 47, respectively; the sequence set forth in SEQ ID NO: 23 and 47, respectively; the sequence set forth in SEQ ID NO: 35 and 76, respectively; the sequence set forth in SEQ ID NO: 35 and 79, respectively; the sequence set forth in SEQ ID NO: 35 and 81, respectively; the sequence set forth in SEQ ID NO: 35 and 84, respectively; the sequence set forth in SEQ ID NO: 35 and 89, respectively; the sequence set forth in SEQ ID NO: 37 and 76, respectively; the sequence set forth in SEQ ID NO: 37 and 79, respectively; the sequence set forth in SEQ ID NO: 37 and 81, respectively; the sequence set forth in SEQ ID NO: 37 and 84, respectively; the sequence set forth in SEQ ID NO: 37 and 89, respectively; the sequence set forth in SEQ ID NO: 40 and 76, respectively; the sequence set forth in SEQ ID NO: 40 and 79, respectively; the sequence set forth in SEQ ID NO: 40 and 81, respectively; the sequence set forth in SEQ ID NO: 40 and 84, respectively; the sequence set forth in SEQ ID NO: 40 and 89, respectively; the sequence set forth in SEQ ID NO: 42 and 76, respectively; the sequence set forth in SEQ ID NO: 42 and 79, respectively; the sequence set forth in SEQ ID NO: 42 and 81, respectively; the sequence set forth in SEQ ID NO: 42 and 84, respectively; the sequence set forth in SEQ ID NO: 42 and 89, respectively; the sequence set forth in SEQ ID NO: 165 and 79, respectively; the sequence set forth in SEQ ID NO: 165 and 171, respectively; the sequence set forth in SEQ ID NO: 165 and 172, respectively; the sequence set forth in SEQ ID NO: 166 and 79, respectively; the sequence set forth in SEQ ID NO: 166 and 171, respectively; the sequence set forth in SEQ ID NO: 166 and 172, respectively; the sequence set forth in SEQ ID NO: 167 and 79, respectively; the sequence set forth in SEQ ID NO: 167 and 171, respectively; the sequence set forth in SEQ ID NO: 167 and 172, respectively; the sequence set forth in SEQ ID NO: 168 and 79, respectively; the sequence set forth in SEQ ID NO: 168 and 171, respectively; the sequence set forth in SEQ ID NO: 168 and 172, respectively; the sequence set forth in SEQ ID NO: 169 and 79, respectively; the sequence set forth in SEQ ID NO: 169 and 171, respectively; the sequence set forth in SEQ ID NO: 169 and 172, respectively; the sequence set forth in SEQ ID NO: 170 and 79, respectively; the sequence set forth in SEQ ID NO: 170 and 171, respectively; or the sequence set forth in SEQ ID NO: 170 and 172, respectively.

9. An anti-programmed cell death protein 1 (PD-1) 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 are or comprise: the sequence set forth in SEQ ID NO: 1 and 158, respectively; the sequence set forth in SEQ ID NO: 2 and 158, respectively; the sequence set forth in SEQ ID NO: 3 and 158, respectively; the sequence set forth in SEQ ID NO: 4 and 158, respectively; the sequence set forth in SEQ ID NO: 5 and 158, respectively; the sequence set forth in SEQ ID NO: 6 and 158, respectively; the sequence set forth in SEQ ID NO: 7 and 158, respectively; the sequence set forth in SEQ ID NO: 8 and 158, respectively; the sequence set forth in SEQ ID NO: 9 and 158, respectively; the sequence set forth in SEQ ID NO: 10 and 158, respectively; the sequence set forth in SEQ ID NO: 11 and 158, respectively; the sequence set forth in SEQ ID NO: 12 and 158, respectively; the sequence set forth in SEQ ID NO: 13 and 158, respectively; the sequence set forth in SEQ ID NO: 14 and 158, respectively; the sequence set forth in SEQ ID NO: 15 and 158, respectively; the sequence set forth in SEQ ID NO: 16 and 158, respectively; the sequence set forth in SEQ ID NO: 17 and 158, respectively; the sequence set forth in SEQ ID NO: 18 and 158, respectively; the sequence set forth in SEQ ID NO: 19 and 158, respectively; the sequence set forth in SEQ ID NO: 20 and 158, respectively; the sequence set forth in SEQ ID NO: 21 and 158, respectively; the sequence set forth in SEQ ID NO: 22 and 158, respectively; the sequence set forth in SEQ ID NO: 23 and 158, respectively; the sequence set forth in SEQ ID NO: 24 and 158, respectively; the sequence set forth in SEQ ID NO: 25 and 158, respectively; the sequence set forth in SEQ ID NO: 26 and 158, respectively; the sequence set forth in SEQ ID NO: 27 and 158, respectively; the sequence set forth in SEQ ID NO: 28 and 158, respectively; the sequence set forth in SEQ ID NO: 29 and 158, respectively; the sequence set forth in SEQ ID NO: 30 and 158, respectively; the sequence set forth in SEQ ID NO: 31 and 158, respectively; the sequence set forth in SEQ ID NO: 32 and 158, respectively; the sequence set forth in SEQ ID NO: 33 and 158, respectively; the sequence set forth in SEQ ID NO: 34 and 158, respectively; the sequence set forth in SEQ ID NO: 35 and 158, respectively; the sequence set forth in SEQ ID NO: 36 and 158, respectively; the sequence set forth in SEQ ID NO: 37 and 158, respectively; the sequence set forth in SEQ ID NO: 38 and 158, respectively; the sequence set forth in SEQ ID NO: 39 and 158, respectively; the sequence set forth in SEQ ID NO: 40 and 158, respectively; the sequence set forth in SEQ ID NO: 41 and 158, respectively; the sequence set forth in SEQ ID NO: 42 and 158, respectively; the sequence set forth in SEQ ID NO: 43 and 158, respectively; the sequence set forth in SEQ ID NO: 44 and 158, respectively; the sequence set forth in SEQ ID NO: 45 and 158, respectively; the sequence set forth in SEQ ID NO: 157 and 46, respectively; the sequence set forth in SEQ ID NO: 157 and 47, respectively; the sequence set forth in SEQ ID NO: 157 and 48, respectively; the sequence set forth in SEQ ID NO: 157 and 49, respectively; the sequence set forth in SEQ ID NO: 157 and 50, respectively; the sequence set forth in SEQ ID NO: 157 and 51, respectively; the sequence set forth in SEQ ID NO: 157 and 52, respectively; the sequence set forth in SEQ ID NO: 157 and 53, respectively; the sequence set forth in SEQ ID NO:157 and 54, respectively; the sequence set forth in SEQ ID NO: 157 and 55, respectively; the sequence set forth in SEQ ID NO: 157 and 56, respectively; the sequence set forth in SEQ ID NO: 157 and 57, respectively; the sequence set forth in SEQ ID NO: 157 and 58, respectively; the sequence set forth in SEQ ID NO: 157 and 59, respectively; the sequence set forth in SEQ ID NO: 157 and 60, respectively; the sequence set forth in SEQ ID NO: 157 and 61, respectively; the sequence set forth in SEQ ID NO: 157 and 62, respectively; the sequence set forth in SEQ ID NO: 157 and 63, respectively; the sequence set forth in SEQ ID NO: 157 and 64, respectively; the sequence set forth in SEQ ID NO: 157 and 65, respectively; the sequence set forth in SEQ ID NO: 157 and 66, respectively; the sequence set forth in SEQ ID NO: 157 and 67, respectively; the sequence set forth in SEQ ID NO: 157 and 68, respectively; the sequence set forth in SEQ ID NO: 157 and 69, respectively; the sequence set forth in SEQ ID NO: 157 and 70, respectively; the sequence set forth in SEQ ID NO: 157 and 71, respectively; the sequence set forth in SEQ ID NO: 157 and 72, respectively; the sequence set forth in SEQ ID NO: 157 and 73, respectively; the sequence set forth in SEQ ID NO: 157 and 74, respectively; the sequence set forth in SEQ ID NO: 157 and 75, respectively; the sequence set forth in SEQ ID NO: 157 and 76, respectively; the sequence set forth in SEQ ID NO: 157 and 77, respectively; the sequence set forth in SEQ ID NO: 157 and 78, respectively; the sequence set forth in SEQ ID NO: 157 and 79, respectively; the sequence set forth in SEQ ID NO: 157 and 80, respectively; the sequence set forth in SEQ ID NO: 157 and 81, respectively; the sequence set forth in SEQ ID NO: 157 and 82, respectively; the sequence set forth in SEQ ID NO: 157 and 83, respectively; the sequence set forth in SEQ ID NO: 157 and 84, respectively; the sequence set forth in SEQ ID NO: 157 and 85, respectively; the sequence set forth in SEQ ID NO: 157 and 86, respectively; the sequence set forth in SEQ ID NO: 157 and 87, respectively; the sequence set forth in SEQ ID NO: 157 and 88, respectively; the sequence set forth in SEQ ID NO: 157 and 89, respectively; the sequence set forth in SEQ ID NO: 157 and 90, respectively; the sequence set forth in SEQ ID NO: 16 and 47, respectively; the sequence set forth in SEQ ID NO: 23 and 47, respectively; the sequence set forth in SEQ ID NO: 35 and 76, respectively; the sequence set forth in SEQ ID NO: 35 and 79, respectively; the sequence set forth in SEQ ID NO: 35 and 81, respectively; the sequence set forth in SEQ ID NO: 35 and 84, respectively; the sequence set forth in SEQ ID NO: 35 and 89, respectively; the sequence set forth in SEQ ID NO: 37 and 76, respectively; the sequence set forth in SEQ ID NO: 37 and 79, respectively; the sequence set forth in SEQ ID NO: 37 and 81, respectively; the sequence set forth in SEQ ID NO: 37 and 84, respectively; the sequence set forth in SEQ ID NO: 37 and 89, respectively; the sequence set forth in SEQ ID NO: 40 and 76, respectively; the sequence set forth in SEQ ID NO: 40 and 79, respectively; the sequence set forth in SEQ ID NO: 40 and 81, respectively; the sequence set forth in SEQ ID NO: 40 and 84, respectively; the sequence set forth in SEQ ID NO: 40 and 89, respectively; the sequence set forth in SEQ ID NO: 42 and 76, respectively; the sequence set forth in SEQ ID NO: 42 and 79, respectively; the sequence set forth in SEQ ID NO: 42 and 81, respectively; the sequence set forth in SEQ ID NO: 42 and 84, respectively; the sequence setforth in SEQ ID NO: 42 and 89, respectively; the sequence set forth in SEQ ID NO: 165 and 79, respectively; the sequence set forth in SEQ ID NO: 165 and 171, respectively; the sequence set forth in SEQ ID NO: 165 and 172, respectively; the sequence set forth in SEQ ID NO: 166 and 79, respectively; the sequence set forth in SEQ ID NO: 166 and 171, respectively; the sequence set forth in SEQ ID NO: 166 and 172, respectively; the sequence set forth in SEQ ID NO: 167 and 79, respectively; the sequence set forth in SEQ ID NO: 167 and 171, respectively; the sequence set forth in SEQ ID NO: 167 and 172, respectively; the sequence set forth in SEQ ID NO: 168 and 79, respectively; the sequence set forth in SEQ ID NO: 168 and 171, respectively; the sequence set forth in SEQ ID NO: 168 and 172, respectively; the sequence set forth in SEQ ID NO: 169 and 79, respectively; the sequence set forth in SEQ ID NO: 169 and 171, respectively; the sequence set forth in SEQ ID NO: 169 and 172, respectively; the sequence set forth in SEQ ID NO: 170 and 79, respectively; the sequence set forth in SEQ ID NO: 170 and 171, respectively; or the sequence set forth in SEQ ID NO: 170 and 172, respectively.

10. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-9, wherein the antibody is a full length antibody.

11. The anti-PD-1 antibody or antigen-binding fragment thereof of claim 10, wherein the full length antibody comprises a constant region (Fc) from an IgAl, IgA2, IgD, IgE, IgGl, IgG2, IgG3, IgG4, or IgM.

12. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-9, wherein the antibody is an antigen-binding fragment.

13. The anti-PD-1 antibody or antigen-binding fragment thereof of claim 12, 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.

14. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-13, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is recombinant.

15. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-14, wherein the VH region and the VL region is human or is from a human protein.

16. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-15, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with an equilibrium dissociation constant (KD) of from about 7 x 1010M to about 2 x 108M at pH 7.35 to 7.45, optionally at pH 7.40.

17. The anti-PD-1 antibody or antigen-binding fragment thereof of claim 16, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with a KD of lower than 1 x 109M, optionally from about 7 x 1010M to about 1 x 109M.

18. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-17, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with an equilibrium dissociation constant (KD) of from about 3 x 1010M to about 4 x 108M at pH 5.0 to 6.8, optionally at pH 6.0 or pH 5.0.

19. The anti-PD-1 antibody or antigen-binding fragment thereof of claim 18, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with a KD of lower than 1 x 109M, optionally from about 3 x 1010to about 1 x 109M.

20. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-19, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with a lower KD at pH 5.0 to 6.8, optionally pH 6.0 or pH 5.0, than pH 7.35 to 7.45, optionally pH 7.4.

21. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-19, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with a lower KD at pH 7.35 to 7.45, optionally pH 7.4, than at pH 5.0 to 6.8, optionally pH 6.0 or pH 5.0.

22. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-19, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with a KD at pH 7.35 to 7.45, optionally pH 7.4, and at pH 5.6 to 6.8, optionally pH 6.0 or pH 5.0, that is substantially the same.

23. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-22, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with an association rate constant (Kon) of 4 x 1051 / Ms to about 2 x 1061 / Ms at pH 7.35 to 7.45, optionally at pH 7.40.

24. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-23, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with an dissociation rate constant (Koff) of 4 x 1041 / s to about 9 x 1031 / s at pH 7.35 to 7.45, optionally at pH 7.40.

25. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-24, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with an association rate constant (Kon) of 4 x 1051 / Ms to about 5 x 1061 / Ms at pH 5.0 to 6.8, optionally at pH 6.0 or pH 5.0.

26. The anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-25, wherein the antibody or antigen-binding fragment thereof binds to human PD-1 protein with an dissociation rate constant (Koff) of 4 x 1041 / s to about 2 x 1021 / s at pH 5.0 to 6.8, optionally at pH 6.0 or pH 5.0.

27. A conjugate, comprising the anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-26 and a heterologous molecule or moiety.

28. The conjugate of claim 27, wherein the heterologous molecule or moiety is a cytotoxic agent, a drug, enzymatically active toxin or fragment thereof, or a radioactive atom.

29. A bispecific antibody, comprising the anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-26.

30. A PD-1 directed chimeric antigen receptor (CAR) comprising an extracellular antigenbinding domain comprising the anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-26, a transmembrane region and an intracellular signaling region.

31. A polynucleotide or polynucleotides comprising a nucleic acid sequence encoding the anti-PD-1 antibody or antigen-binding domain thereof of any of claims 1-26 or a heavy or light chain thereof.

32. A polynucleotide comprising a nucleic acid encoding the PD-1 directed chimeric antigen receptor of claim 30.

33. A vector, comprising the polynucleotide of claim 31 or 32.

34. The vector of claim 33, wherein the vector is a viral vector.

35. The vector of claim 34, wherein the viral vector is a retroviral vector or a lentiviral vector.

36. An engineered cell comprising the anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-26, the bispecific antibody of claim 29, or the conjugate of claim 27 or 28.

37. An engineered cell comprising the PD-1 directed chimeric antigen receptor of claim 30.

38. The engineered cell of claim 36 or 37, wherein the cell is a lymphocyte.

39. The engineered cell of claim 38, wherein the lymphocyte is a natural killer (NK) cell or a T cell.

40. The engineered cell of any of claims 36-39, wherein the cell is a T cell and the T cell is a CD4+ T cell or a CD8+ T cell.

41. A cell comprising the polynucleotide of claim 31 or 32, or the vector of any of claims 33-35.

42. The cell of claim 41, wherein the cell is a mammalian cell.

43. A method of producing an antibody comprising culturing the cell of claim 41 or 42 under a condition that produces the antibody.

44. The method of claim 43, further comprising recovering the antibody produced by the cell.

45. An antibody or antigen-binding fragment thereof produced by the method of claim 43 or claim 44.

46. A composition comprising the cell of any of claims 36-42.

47. A composition comprising the anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-26 and 45, the conjugate of claim 27 or 28, the bispecific antibody of claim 29, or the PD-1 directed chimeric antigen receptor of claim 30.

48. The composition of claim 46 or claim 47, further comprising a pharmaceutically acceptable excipient.

49. A method of treatment, comprising administering the cell of any of claims 36-42 or the composition of any of claims 46-48 to a subject having a disease or disorder associated with PD-1.

50. A method of increasing the activity of an immune cell, comprising contacting an immune cell with the anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-26 and 42, the conjugate of claim 27 or 28, or the bispecific antibody of claim 29.

51. A method of increasing the activity of an immune cell, comprising administering to a subject in need thereof a therapeutically effective amount of the anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1-26 and 42, the conjugate of claim 27 or 28, the bispecific antibody of claim 29.

52. The method of claim 50 or claim 51, wherein the method is used for an ex vivo treatment of a disease or disorder in a subject.

53. The method of claim 49 or claim 52, wherein the disease or disorder is a cancer or an infection or infectious disease.

54. A binding molecule comprising a PD-1 binding domain that binds PD-1, and a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) binding domain that binds CTLA-4, wherein:(a) the PD-1 binding domain comprises a heavy chain and a light chain comprising the heavy chain variable (VH) region (PD-1 VH ) and the light chain variable (VL) region (PD-1 VL), respectively, of the anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1- 26, and(b) the CTLA-4 binding domain comprises a heavy chain comprising a heavy chain variable (CTLA-4 VH) region and a light chain comprising a light chain variable (CTLA-4 VL) region, wherein:(i) the CTLA-4 VH region comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the sequence set forth in any one of SEQ ID NOs: 278-285, a heavy chain complementarity determining region 2 (CDR-H2) comprising the sequence set forth in any one of SEQ ID NOs: 286-296, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the sequence set forth in any one of SEQ ID NOs: 297-302; and the CTLA-4 VL region comprises a light chain complementarity determining region 1 (CDR-L1) comprising the sequence set forth in any one of SEQ ID NOs: 303-317, a light chain complementarity determining region 2 (CDR-L2) comprising the sequence set forth in any one of SEQ ID NOs: 318-326, and a light chain complementarity determining region 3 (CDR-L3) comprising the sequence set forth in any one of SEQ ID NOs: 327- 329, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 278, 286, 297,303, 318, and 327, respectively; or(ii) the CTLA-4 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: 230-256, and 341, and the CTLA-4 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: 257, 277, and 347, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 278, 286, 297,303, 318, and 327, respectively.

55. The binding molecule of claim 54, wherein: the CTLA-4 VH region comprises a CDR-H1 comprising the sequence set forth in any one of SEQ ID NOs: 278-285, a CDR-H2 comprising the sequence set forth in any one of SEQ ID NOs: 286- 296, and a CDR-H3 comprising the sequence set forth in any one of SEQ ID NOs: 297-302; and the CTLA-4 VL region comprises a CDR-L1 comprising the sequence set forth in any one of SEQ ID NOs: 303-317, a CDR-L2 comprising the sequence set forth in any one of SEQ ID NOs: 318- 326, and a CDR-L3 comprising the sequence set forth in any one of SEQ ID NOs: 327-329, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 are not set forth in SEQ ID NOS: 278, 286, 297,303, 318, and 327, respectively.

56. The binding molecule of claim 54 or claim 55, wherein: the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 230, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 231, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 232, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR- H1 , a CDR-H2, and a CDR-H3 contained within SEQ ID NO:233, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:234, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1 , a CDR-H2, and a CDR-H3 contained within SEQ ID NO:235, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:236, and the CTLA-4 VL region comprises a CDR-L1 , a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:237, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2,and a CDR-H3 contained within SEQ ID NO:238, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR- H1 , a CDR-H2, and a CDR-H3 contained within SEQ ID NO:239, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:240, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1 , a CDR-H2, and a CDR-H3 contained within SEQ ID NO:241 , and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:242, and the CTLA-4 VL region comprises a CDR-L1 , a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:243, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:244, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR- H1 , a CDR-H2, and a CDR-H3 contained within SEQ ID NO:245, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:246, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1 , a CDR-H2, and a CDR-H3 contained within SEQ ID NO:247, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:248, and the CTLA-4 VL region comprises a CDR-L1 , a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:249, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO:250, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR- H1 , a CDR-H2, and a CDR-H3 contained within SEQ ID NO:251 , and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 347; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 257; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3contained within SEQ ID NO: 259; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 260; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 261; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 262; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 263; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 264; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 265; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 266; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 267; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 269; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 271; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 272; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 273; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 274; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 341, and the CTLA-4 VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 275 the CTLA-4 VH region comprises a CDR-H1, aCDR-H2, and a CDR-H3 contained within SEQ ID NO: 252, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 253, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 254, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 255, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 251, and the CTLA-4 VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 256, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 270; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 252, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 253, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 254, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 255, and the CTLA-4 VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 251, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 256, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 276; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 252, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258 the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 253, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 254, and the CTLA-4 VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 255, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 251, and the CTLA-4VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 256, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 258; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 252, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 253, and the CTLA-4 VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 254, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 255, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 251, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 256, and the CTLA-4 VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 268; or the CTLA-4 VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 234, and the CTLA-4 VL region comprises a CDR-L1, a CDR- L2, and a CDR-L3 contained within SEQ ID NO: 277.

57. The binding molecule of any one of claims 54-56, wherein: the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 287, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 298, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 280, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 279, 288, and 297, respectively, and the -LI, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 290, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise thesequences set forth in SEQ ID NOS: 280, 291, 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 279, 292, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 279, 286, and 298, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 282, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 282, 286, and 299, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 283, 286, and 300, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 284, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 285, 286, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 293, 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 289, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 295, and 297, respectively, and the CDR-L1, a CDR-L2, and a CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 300, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 302, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278,286, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 304, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 306, 318, 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 307, 319, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 307, 319, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR- L3 comprise the sequences set forth in SEQ ID NOS: 310, 320, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 307, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 310, 321, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 311, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 311, 322, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 312, 321, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 329, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and theCDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 315, 323, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 316, 324, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 325, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 317, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 297, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 303, 326, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 302, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 314, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 302, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 302, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, and 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 305, 318, 327, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 302, respectively, and the CDR-L1, the CDR- L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 296, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 286, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise thesequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 278, 294, and 301, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 313, 318, and 328, respectively; or the CDR-H1, the CDR-H2, and the CDR-H3 comprise the sequences set forth in SEQ ID NOS: 281, 289, and 297, respectively, and the CDR-L1, the CDR-L2, and the CDR-L3 comprise the sequences set forth in SEQ ID NOS: 317, 318, 329, respectively.

58. The binding molecule of any one of claims 54-57, wherein: the CTLA-4 VH region and the CTLA-4 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: 230 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 231 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 232 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 233 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 234 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 235 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 236 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 237 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 238 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 239 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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 IDNO: 240 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 241 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 242 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 243 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 244 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 245 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 246 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 247 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 248 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 249 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 250 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 251 and SEQ ID NO: 347, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 257, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 VL 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: 341 and SEQ ID NO: 259, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 260, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 261, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 262, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 263, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 264, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 265, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 266, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 267, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 26, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 271, respectively; the CTLA-4 VH region and the CTLA-4 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 IDNO: 341 and SEQ ID NO: 272, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 273, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 274, respectively; the CTLA-4 VH region and the CTLA-4 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: 341 and SEQ ID NO: 275, respectively; the CTLA-4 VH region and the CTLA-4 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: 252 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 253 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 255 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 251 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 256 and SEQ ID NO: 270, respectively; the CTLA-4 VH region and the CTLA-4 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: 252 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 253 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 255 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 VL 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: 251 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 256 and SEQ ID NO: 276, respectively; the CTLA-4 VH region and the CTLA-4 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: 252 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 253 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 255 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 251 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 256 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 252 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 253 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 255 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 251 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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 IDNO: 256 and SEQ ID NO: 268, respectively; or the CTLA-4 VH region and the CTLA-4 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: 234 and SEQ ID NO: 277, respectively.

59. The binding molecule of any one of claims 54-58, wherein: the CTLA-4 VH region and the CTLA-4 VL region are or comprise: the sequence set forth in SEQ ID NO: 230 and 347, respectively; the sequence set forth in SEQ ID NO: 231 and 347, respectively; the sequence set forth in SEQ ID NO: 232 and 347, respectively; the sequence set forth in SEQ ID NO: 233 and 347, respectively; the sequence set forth in SEQ ID NO: 234 and 347, respectively; the sequence set forth in SEQ ID NO: 235 and 347, respectively; the sequence set forth in SEQ ID NO: 236 and 347, respectively; the sequence set forth in SEQ ID NO: 237 and 347, respectively; the sequence set forth in SEQ ID NO: 238 and 347, respectively; the sequence set forth in SEQ ID NO: 239 and 347, respectively; the sequence set forth in SEQ ID NO: 240 and 347, respectively; the sequence set forth in SEQ ID NO: 241 and 347, respectively; the sequence set forth in SEQ ID NO: 242 and 347, respectively; the sequence set forth in SEQ ID NO: 243 and 347, respectively; the sequence set forth in SEQ ID NO: 244 and 347, respectively; the sequence set forth in SEQ ID NO: 245 and 347, respectively; the sequence set forth in SEQ ID NO: 246 and 347, respectively; the sequence set forth in SEQ ID NO: 247 and 347, respectively; the sequence set forth in SEQ ID NO: 248 and 347, respectively; the sequence set forth in SEQ ID NO: 249 and 347, respectively; the sequence set forth in SEQ ID NO: 250 and 347, respectively; the sequence set forth in SEQ ID NO: 251 and 347, respectively; the sequence set forth in SEQ ID NO: 341 and 257, respectively; the sequence set forth in SEQ ID NO: 341 and 258, respectively; the sequence set forth in SEQ ID NO: 341 and 259, respectively; the sequence set forth in SEQ ID NO: 341 and 260, respectively; the sequence set forth in SEQ ID NO: 341 and 261, respectively; the sequence set forth in SEQ ID NO: 341 and 262, respectively; the sequence set forth in SEQ ID NO: 341 and 263, respectively; the sequence set forth in SEQ ID NO: 341 and 264, respectively; the sequence set forth in SEQ ID NO: 341 and 265, respectively; the sequence set forth in SEQ ID NO: 341 and 266, respectively; the sequence set forth in SEQ ID NO: 341 and 267, respectively; the sequence set forth in SEQ ID NO: 341and 268, respectively; the sequence set forth in SEQ ID NO: 341 and 269, respectively; the sequence set forth in SEQ ID NO: 341and 270, respectively; the sequence set forth in SEQ ID NO: 341and 271, respectively; the sequence set forth in SEQ ID NO: 341and 272, respectively; the sequence set forth in SEQ ID NO: 341and 273, respectively; the sequence set forth in SEQ ID NO: 341and 274, respectively; the sequence set forth in SEQ ID NO: 341and 275, respectively; the sequence set forth in SEQ ID NO: 252 and 270, respectively; the sequence set forth in SEQ ID NO: 253 and 270, respectively; the sequence set forth in SEQ ID NO: 254 and 270, respectively; the sequence set forth in SEQ ID NO: 255 and 270, respectively; the sequence set forth in SEQ ID NO: 251 and 270,respectively; the sequence set forth in SEQ ID NO: 256 and 270, respectively; the sequence set forth in SEQ ID NO: 252 and 276, respectively; the sequence set forth in SEQ ID NO: 253 and 276, respectively; the sequence set forth in SEQ ID NO: 254 and 276, respectively; the sequence set forth in SEQ ID NO: 255 and 276, respectively; the sequence set forth in SEQ ID NO: 251 and 276, respectively; the sequence set forth in SEQ ID NO: 256 and 276, respectively; the sequence set forth in SEQ ID NO: 252 and 258, respectively; the sequence set forth in SEQ ID NO: 253 and 258, respectively; the sequence set forth in SEQ ID NO: 254 and 258, respectively; the sequence set forth in SEQ ID NO: 255 and 258, respectively; the sequence set forth in SEQ ID NO: 251 and 258, respectively; the sequence set forth in SEQ ID NO: 256 and 258, respectively; the sequence set forth in SEQ ID NO: 252 and 268, respectively; the sequence set forth in SEQ ID NO: 253 and 268, respectively; the sequence set forth in SEQ ID NO: 254 and 268, respectively; the sequence set forth in SEQ ID NO: 255 and 268, respectively; the sequence set forth in SEQ ID NO: 251 and 268, respectively; the sequence set forth in SEQ ID NO: 256 and 268, respectively; the sequence set forth in SEQ ID NO: 234 and 277, respectively.

60. A binding molecule comprising a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) binding domain that binds CTLA-4, and a PD-1 binding domain that binds PD-1, wherein:(a) the PD-1 binding domain comprises a heavy chain and a light chain comprising the heavy chain variable (VH) region (PD-1 VH ) and the light chain variable (VL) region (PD-1 VL), respectively, of the anti-PD-1 antibody or antigen-binding fragment thereof of any of claims 1- 26; and(b) the CTLA-4 binding domain comprises a heavy chain variable (CTLA-4 VH) region and a light chain variable (CTLA-4 VL) region, wherein: the CTLA-4 VH region comprises the sequence set forth in: QVQLVESGGGVVQPGRSLRLSCAASGFTFSX , YTMHW VRQAPGKGLEWVTFIS YX2GNNKX3YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGX4X5GPFDYWGQGTLVTVSS, wherein X, is S or R; X2is E or H; X3is H or Y; X4is W or H; and X5is L or H (SEQ ID NO: 407); and the CTLA-4 VL region comprises the sequence set forth in: EIVLTQSPGTLSLSPGERATLSCRASQX1VGHX2YLAWYQQKPGQAPRLLIYGAFSRATGIPD RFSGSGSGTDFTLTISRLEPEDFAVYYCQX3YGSSPWTFGQGTKVEIK, wherein X, is H or S; X2is H or S; and X3is Q or H (SEQ ID NO: 408).

61. The binding molecule of claim 54-60, wherein: the CTLA-4 VH region comprises a CDR-H1 comprising the sequence set forth in SEQ ID NO: 278 or SEQ ID NO: 281, a CDR-H2 comprising the sequence set forth in SEQ ID NO: 289 or SEQ ID NO: 296, and a CDR-H3 comprising the sequence set forth in SEQ ID NO: 297 or SEQ ID NO: 301; andthe CTLA-4 VL region comprises a CDR-L1 comprising the sequence set forth in SEQ ID NO: 305 or SEQ ID NO: 313; a CDR-L2 comprising the sequence set forth in SEQ ID NO: 318, and a CDR- L3 comprising the sequence set forth in SEQ ID NO: 327 or SEQ ID NO: 328.

62. The binding molecule of any one of claims 54-61, wherein the CTLA-4 VH region comprises:(a) a serine (S) at position 31, a glutamic acid (E) at position 54, a histidine (H) at position 59, a tryptophan (W) at position 101, and a leucine (L) at position 102, wherein the numbering is relative to SEQ ID NO: 407, or (b) a arginine (R) at position 31, a glutamic acid (E) at position 54, a tyrosine (Y) at position 59, a tryptophan (W) at position 101, and a histidine (H) at position 102, wherein the numbering is relative to SEQ ID NO: 408.

63. The binding molecule of any one of claims 54-62, wherein the CTLA-4 VL region comprises:(a) a histidine (H) at position 28, a serine (S) at position 32, and a glutamine (Q) at position 91, wherein the numbering is relative to SEQ ID NO: 407, or(b) a serine (S) at position 28, a serine (S) at position 32, and a histidine (H) at position 91, wherein the numbering is relative to SEQ ID NO: 408.

64. The binding molecule of any one of claims 54-62, wherein: the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 258, respectively; the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 268, respectively; the CTLA-4 VH region and the CTLA-4 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: 252 and SEQ ID NO: 268, respectively.

65. The binding molecule of any one of claims 54-64, wherein: the CTLA-4 VH region and the CTLA-4 VL region are or comprise: the sequence set forth in SEQ ID NO: 254 and 258, respectively; the sequence set forth in SEQ ID NO: 254 and 268, respectively; the sequence set forth in SEQ ID NO: 252 and 268, respectively.

66. The binding molecule of any one of claims 54-65, wherein: the CTLA-4 VH region and the CTLA-4 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: 254 and SEQ ID NO: 268, respectively.

67. The binding molecule of any one of claims 54-66, wherein:the PD-1 VH region and the PD-1 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: 168 and SEQ ID NO: 172, respectively.

68. The binding molecule of any one of claims 54-67, wherein: the PD-1 VH region is or comprises an amino acid sequence set forth in SEQ ID NO: 168, and the PD-1 VL region is or comprises an amino acid sequence set forth in SEQ ID NO: 172.

69. The binding molecule of any one of claims 54-68 , wherein the CTLA-4 binding domain and the PD-1 binding domain are Fab fragments each comprising a VH region and a VL region, wherein one of the Fab fragments is a crossover Fab such that the VH region and the VL region of such Fab are replaced by each other.

70. The binding molecule of any one of claims 54-69, wherein the CTLA-4 binding domain is a crossover CTLA-4 Fab and the PD-1 binding domain is a Fab, wherein: the crossover CTEA-4 Fab comprises: (a) a heavy chain (HC1) comprising the CTEA-4 VL region and a heavy chain constant region 1 (CHI), designated CTEA-4 VL-CH1 ; and (b) a light chain (ECI) comprising the CTLA-4 VH region and a light chain constant region (CL), designated CTLA-4 VH-CL; and the PD-1 binding domain comprises (a) a heavy chain 2 (HC2) comprising the PD-1 VH region and a heavy chain constant region 1 (CHI), designated PD-1 VH-CH1 ; and (b) a light chain 2 (LC2) comprising the PD-1 VL region and a light chain constant region (CL), designated PD-1 VL-CL.

71. The binding molecule of claim 70, wherein the CHI of the CTLA-4 VL-CH1 comprises the amino acid sequence set forth in SEQ ID NO: 363 and the CE of the CTEA-4 VH-CL comprises the amino acid sequence set forth in SEQ ID NO: 367.

72. The binding molecule of claim 70 and claim 71, wherein the CHI of the PD-1 VH-CH1 comprises the amino acid sequence set forth in SEQ ID NO: 371 and the CE of the PD-1 VL-CE comprises the amino acid sequence set forth in SEQ ID NO: 175.

73. The binding molecule of any one of claims 54-69, wherein the CTLA-4 binding domain is a CTLA-4 Fab and the PD-1 binding domain is a crossover Fab, wherein: the CTEA-4 Fab comprises: (a) a heavy chain (HC1) comprising the CTEA-4 VH region and a heavy chain constant region 1 (CHI), designated CTLA-4 VH-CH1 ; and (b) a light chain (LC1) comprising the CTLA-4 VL region and a light chain constant region (CL), designated CTLA-4 VL-CL; and the PD-1 binding domain comprises (a) a heavy chain 2 (HC2) comprising the PD-1 VL region and a heavy chain constant region 1 (CHI), designated PD-1 VL-CH1 ; and (b) a light chain 2 (LC2) comprising the PD-1 VH region and a light chain constant region (CL), designated PD-1 VH-CL.

74. The binding molecule of claim 73, wherein the CHI of the PD-1 VL-CH1 comprises the amino acid sequence set forth in SEQ ID NO: 363 and the CL of the PD-1 VH-CL comprises the amino acid sequence set forth in SEQ ID NO: 367.

75. The binding molecule of claim 73 and claim 74, wherein the CHI of the CTLA-4 VH- CH1 comprises the amino acid sequence set forth in SEQ ID NO: 371 and the CL of the CTLA-4 VL- CL comprises the amino acid sequence set forth in SEQ ID NO: 175.

76. The binding molecule of any of claims 69-75, wherein: the CTLA-4 VH comprises the sequence of amino acids set forth in SEQ ID NO: 254 and the CTLA-4 VL comprises the sequence of amino acids set forth in SEQ ID NO: 268; and the PD-1 VH comprises the sequence of amino acids set forth in SEQ ID NO: 168 and the PD- 1 VL comprise the sequence of amino acids set forth in SEQ ID NO: 172.

77. The binding molecule of any one of claims 54-76, further comprising an Fc region comprising a first and second polypeptide each comprising a hinge-CH2-CH3, wherein one of the first polypeptide and second polypeptide is linked to the CHI of the CTLA-4 Fab and the other of the first polypeptide and second polypeptide is linked to the CHI of the PD-1 Fab.

78. The binding molecule of claim 77, wherein the Fc region is a heterodimeric Fc region.

79. The binding molecule of claim 78, wherein each of the first and second polypeptide of the heterodimeric Fc comprises one or more amino acid substitutions in a wild-type Fc polypeptide region to effect heterodimer formation between the first polypeptide and the second polypeptide.

80. The binding molecule of claim 79, wherein the wild-type Fc region is an IgGl Fc region.

81. The binding molecule of claim 79 or claim 80, wherein the wild-type Fc region comprises the sequence set forth in SEQ ID NO:407 or SEQ ID NO: 408.

82. The binding molecule of any of claims 79-81, wherein the one more amino acid substitutions are a knob-into-hole modification, a charge mutation to reduce or prevent selfassociation due to charge repulsion, or disulfide bonding pairing mutation.

83. The binding molecule of any of claims 79-82, wherein the one or more amino acid substitutions are: (i) amino acid substitution T366W in the first polypeptide of the heterodimeric Fc and amino acid substitutions T366S, E368A and Y407V in the second polypeptide of the heterodimeric Fc; (ii) amino acid substitution E356K, E357K and D399K in the first polypeptide of the heterodimeric Fc and amino acid substitutions K439E, K370E and K409D in the second polypeptide of the heterodimeric Fc; or (iii) amino acid substitution S354C on the first polypeptide of the heterodimeric Fc and amino acid substitution Y349C on the second polypeptide of the heterodimeric Fc.

84. The binding molecule of any of claims 79-82, wherein the one or more substitutions are a knob-into-hole modification.

85. The binding molecule of any of claims 79-84, wherein the one or more amino acid substitutions of the first Fc polypeptide comprises Thr366Trp and the one or more amino acid substitutions of the second Fc polypeptide of the heterodimeric Fc comprises the Thr366Ser, Leu368Ala and Tyr407Val.

86. The binding molecule of any of claims 79-85, wherein the first and / or second Fc polypeptide further comprises the amino acid substitution H435R.

87. The binding molecule of any of claims 79-86, wherein the heterodimeric Fc region comprises one or more amino acid substitutions to reduce binding affinity to an Fc receptor and / or to reduce effector function, optionally as compared to a wild-type IgGl Fc domain.

88. The binding molecule of claim 87, wherein the one or more amino acid substitutions are selected from L234A, L234V, L235A, L235E, G237A, D265S, S267K, R292C, N297G, V302C, and P329G by EU numbering.

89. The binding molecule of claim 87 or claim 88, wherein the one or more amino acid substitutions comprises L234A and L235A.

90. The binding molecule of any of claims 87-89, wherein the one or more amino acid substitutions comprises L234A, L235A, and D265S.

91. The binding molecule of any of claims 87-90, wherein the one or more amino acid substitutions comprises L234A, L235A, and P329G.

92. The binding molecule of any of claims 79-91, wherein one or both polypeptides of the heterodimeric Fc lacks Lys447.

93. The binding molecule of any of claims 79-92, wherein: one of the first polypeptide and the second polypeptide of the heterodimeric Fc region 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% sequence identity SEQ ID NO:364; and the other of the first polypeptide and second polypeptide of the heterodimeric Fc region 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% sequence identity SEQ ID NO: 373.

94. The binding molecule of any of claims 79-93, wherein: one of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 364; and the other of the first polypeptide and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 373.

95. The binding molecule of any of claims 79-94, wherein the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 364 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO:373.

96. The binding molecule of any of claims 79-94, wherein the first polypeptide of the heterodimeric Fc region comprise the amino acid sequence set forth in SEQ ID NO: 373 and the second polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ IDNO:364.

97. The binding molecule of any of claims 54-96, comprising:(a) a heavy chain 1 (HC1) polypeptide comprising a VL sequence set forth in SEQ ID NO:268, a CHI sequence set forth in SEQ ID NO: 363, and a hinge-CH2-CH3 sequence set forth in SEQ ID NO: 364; (b) a light chain 1 (LC1) polypeptide comprising a VH sequence set forth in SEQ ID NO:254 and a CL sequence set forth in SEQ ID NO: 367; (c) a HC2 polypeptide comprising a VH sequence set forth in SEQ ID NO: 168, a CHI sequence set forth in SEQ ID NO:371, and a hinge-CH2-CH3 sequence set forth in SEQ ID NO:373; and (d) a LC2 polypeptide comprising a VL sequence set forth in SEQ ID NO: 172 and a CL sequence set forth in SEQ ID NO: 175.

98. The binding molecule of claim 97, comprising:(a) a HC1 polypeptide that 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: 378; (b) a HC2 polypeptide that 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: 387; (c) a LC1 polypeptide that 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: 381; and (d) a LC2 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: 389.

99. The binding molecule of claim 97 or 98, comprising:(a) a HC1 polypeptide that is or comprises the amino acid sequence set forth in SEQ ID NO: 378; (b) a HC2 polypeptide that is or comprises the amino acid sequence set forth in SEQ ID NO: 387;(c) a LC1 polypeptide that is or comprises the amino acid sequence set forth in SEQ ID NO: 381; and(d) a LC2 polypeptide that is or comprises the amino acid sequence set forth in SEQ ID NO: 389.

100. The binding molecule of any of claims 54-96, comprising:(a) a heavy chain 1 (HC1) polypeptide comprising a VL sequence set forth in SEQ ID NO: 172, a CHI sequence set forth in SEQ ID NO: 363, and a hinge-CH2-CH3 sequence set forth in SEQ ID NO: 364; (b) a LC1 polypeptide comprising a VH sequence set forth in SEQ ID NO: 168, and a CL sequence set forth in SEQ ID NO:367; and (c) a HC2 polypeptide comprising a VH sequence set forth in SEQ ID NO:254, a CHI sequence set forth in SEQ ID NO:371, and a hinge-CH2-CH3 sequence set forth in SEQ ID NO: 373; and (d) a LC2 polypeptide comprising a VL sequence set forth in SEQ ID NO:268, and a CL sequence set forth in SEQ ID NO: 175.

101. The binding molecule of claim 100, comprising:(a) a HC1 polypeptide that 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: 360; (b) a HC2 polypeptide that 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: 370; (c) a LC1 polypeptide that 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: 366; and (d) a LC2 that 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: 375.

102. The binding molecule of claim 100-101, comprising:(a) a HC1 polypeptide that is or comprises an amino acid sequence set forth in SEQ ID NO: 360; (b) a HC2 polypeptide that is or comprises an amino acid sequence set forth in SEQ ID NO: 370;(c) a LC1 polypeptide that is or comprises an amino acid sequence set forth in SEQ ID NO: 366; and(d) a LC2 polypeptide that is or comprises an amino acid sequence set forth in SEQ ID NO: 375.

103. The binding molecule of any of claims 54-102, wherein the heavy chain and / or the light chain further comprising a signal peptide.

104. A polynucleotide or polynucleotides comprising a nucleic acid sequence encoding the binding molecule of any one of claims 54-103 or a heavy or light chain thereof.

105. A vector comprising the polynucleotide of claim 104.

106. The vector of claim 105, wherein the vector is a viral vector.

107. The vector of claim 106, wherein the viral vector is a retroviral vector or a lentiviral vector.

108. A cell comprising the polynucleotide or polynucleotides of claim 104, or the vector of any of claims 105-107.

109. The cell of claim 108, wherein the cell is a mammalian cell.

110. A method of producing a binding molecule comprising culturing the cell of claim 108 or claim 109 under a condition that produces the binding molecule, optionally wherein the binding molecule is bispecific antibody binding molecule.

111. The method of claim 110, further comprising recovering the binding molecule produced by the cell.

112. A binding molecule produced by the method of claim 110 or claim 111.

113. A composition comprising the binding molecule of any one of claims 54-103 and claim 112.

114. The composition of claim 113, further comprising a pharmaceutically acceptable excipient.

115. A method for treating a subject with a disease or condition, the method comprising administering a therapeutically effective amount of the binding molecule of any one of claims 54-103 and 112 or the composition of claim 113 or claim 114.

116. The method of claim 115, wherein the disease or condition is a cancer.

117. A method of cancer immunotherapy, the method comprising administering to a subject in need thereof a therapeutically effective amount of the binding molecule of any one of claims 54-103 and 112 or composition of claim 113 or claim 114.

118. The method of claim 117, wherein the cancer is a solid tumor.

119. The method of any of claims 116-118, wherein the cancer is a melanoma, breast carcinoma, HCC, Renal cell carcinoma, Colorectal carcinoma, non-small-cell lung carcinoma, Cervical cancer or Mesothelioma.

120. The method of any of claims 115-119, wherein administering the binding molecule to the subject results in higher Teff-to-suppressor cells (myeloid-derived suppressor cell and Treg) ratios.

121. The method of any of claims 115-120, wherein administering the binding molecule to the subject results in increased pro-inflammatory cytokines, optionally interferon-gamma (IFN-y) and / or tumor necrosis factor-alpha (TNF-a).

122. The method of any one of claims 115-121, wherein the method comprises administering to the subject an effective amount of the binding molecule of any one of claims 54-103 and 112 or the composition of claim 113 or claim 114 prior to a surgery or after a surgery to remove a solid tumor in the subject.