Novel anti-CD3 antibodies and uses thereof

Abstract

Anti-CD3 antibodies or antigen-binding fragments thereof, isolated polynucleotides encoding them, pharmaceutical compositions comprising them, and uses thereof are provided.

Description

[Technical field]

[0001] The present disclosure relates generally to novel anti-CD3 antibodies, antigen-binding fragments thereof, and uses thereof. [Background technology]

[0002] The CD3 (cluster of differentiation 3) T-cell coreceptor is a protein complex, composed of four separate chains, the CD3 gamma chain, the CD3 delta chain, and two CD3 epsilon chains. These chains associate with a molecule known as the T-cell receptor (TCR) and the zeta chain to generate activation signals in T-lymphocytes. The TCR, zeta chain, and CD3 molecule together form the TCR-CD3 complex, with the TCR as a subunit recognizing and binding antigens and the CD3 as a subunit transmitting and transferring antigenic stimulation to signal transduction pathways, ultimately regulating T-cell activity. The CD3 protein is present on virtually all T cells.

[0003] Mouse monoclonal antibodies specific for human CD3, such as OKT3 (Kung et al., (1979) Science 206:347-9), were the first generation CD3 antibodies for treatment. Although OKT3 has strong immunosuppressive potential, its clinical use was hindered by severe side effects related to its immunogenic and mitogenic potential (Chatenoud (2003) Nature Reviews Immunology 3:123-132). OKT3 induces antiglobulin responses and promotes its own rapid clearance and neutralization (Chatenoud et al., (1982) Eur. J. Immunol. 137:830-8). In addition, OKT3 induced T cell proliferation and cytokine production in vitro and led to massive cytokine release in vivo (Hirsch et al., (1989) J. Immunol 142:737-43). Cytokine release (also called "cytokine storm") then led to a "flu-like" syndrome characterized by fever, chills, headache, nausea, vomiting, diarrhea, respiratory distress, bacterial meningitis, and low blood pressure (Chatenoud (2003) Nature Reviews Immunology 3:123-132). Such severe side effects have limited the more widespread use of OKT3 in transplantation as well as the expansion of its use into other clinical areas such as autoimmunity.

[0004] A more recent application of CD3 antibodies is in the form of bispecific antibodies, i.e. antibodies that bind CD3 on the one hand and tumor cell antigens on the other. Such antibodies bind both of their targets simultaneously, resulting in a transient interaction between the target cell and T cells, leading to the activation of any cytotoxic T cells and subsequent lysis of the target cell.

[0005] There remains a need for new anti-CD3 antibodies. Summary of the Invention

[0006] Throughout this disclosure, the articles "a," "an," and "the" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an antibody" means one antibody or more than one antibody.

[0007] In one respect, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to CD3, comprising any one of the heavy chain variable (VH) region sequences selected from the group consisting of SEQ ID NOs: 7, 15, 23, 31, 39, 47, 55, 63, 71, 79, 87, 95, 108, 116, 124, 132, 140, 148, 156, 163, 164, 165, 166, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 213, 202, 203, 204, 205, 206, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, and 245. one or two or three heavy chain complementarity determining regions (HCDR1, HCDR2 and / or HCDR3) contained within any one of the sequences; and / or one or two or three light chain complementarity determining regions (LCDR1, LCDR2 and / or LCDR3) contained within any one of the light chain variable (VL) region sequences selected from the group consisting of SEQ ID NOs: 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 109, 117, 125, 133, 141, 149, 157, 168, 169, 170, 197, 198, 199, 200, 207, 208, 209, 230, 231 and 232. The present invention provides an antibody or antigen-binding fragment thereof comprising:

[0008] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure is selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 13, 14, 17, 18, 19, 20, 21, 22, 25, 26, 27, 28, 29, 30, 33, 34, 35, 36, 37, 38, 41, 42, 43, 44, 45, 46, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109 ...10, 111, 112, 113, 114, 115, 116, 117, 57, 58, 59, 60, 61, 62, 65, 66, 67, 68, 69, 70, 73, 74, 75, 76, 77, 78, 81, 82, 83, 84, 85, 86, 89, 90, 91, 92, 93, 94, 102, 103, 104, 105, 106, 107, 110, 111, 112, 113, 114, 115, 118, 119, 120, 121 , 122, 123, 126, 127, 128, 129, 130, 131, 134, 135, 136, 137, 138, 139, 142, 143, 144, 145, 146, 147, 150, 151, 152, 153, 154, 155, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, and at least one heavy or light chain complementarity determining region (CDR) comprising an amino acid sequence selected from the group consisting of 183, 184, 185, 201, 162, 167, 210, 211, 212, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228 and 229.

[0009] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure is selected from the group consisting of SEQ ID NOs: 1, 2, 3, 9, 10, 11, 17, 18, 19, 25, 26, 27, 33, 34, 35, 41, 42, 43, 49, 50, 51, 57, 58, 59, 65, 66, 67, 73, 74, 75, 81, 82, 83, 89, 90, 91, 102, 103, 104, 110, 111, 112, 118, 119, 120, 126, 127, 128, 134, 135, 136, 142, 143, 144, 150, 151, 152, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 201, 162, 210, 211, 212, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228 and 229.

[0010] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure is selected from the group consisting of SEQ ID NOs: 4, 5, 6, 12, 13, 14, 20, 21, 22, 28, 29, 30, 36, 37, 38, 44, 45, 46, 52, 53, 54, 60, 61, 62, 68, 69, 70, 76, 77, 78, 84, 85, 86, 92, 93, 94, 105, 106, 107, 113, 114, 115, 116, 117, 118, 119, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 30, 36, 37, 38, 44, 45, 46, 52, 53, 54, 60, 61, 62, 68, 69, 70, 76, 77, 78, 84, 85, 86, 92, 93, 94, 105, 106, 107, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, and a VL region comprising one or two or three of LCDR1, LCDR2, and LCDR3 comprising amino acid sequences selected from the group consisting of 15, 121, 122, 123, 129, 130, 131, 137, 138, 139, 145, 146, 147, 153, 154, 155, 182, 183, 184, 185, 167, 214, 215 and 216.

[0011] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises: (a) an HCDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 102, 110, 118, 126, 134, 142, 150, 217, 218, and 219; (b) an HCDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 10, 18, 26, 34, 42, 50, 58, 66, 74, 82, 90, 103, 111, 119, 127, 135, 143, 151, 171, 172, 173, 201, 210, 211, 212, 220 and 222; and (c) an HCDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 11, 19, 27, 35, 43, 51, 59, 67, 75, 83, 91, 104, 112, 120, 128, 136, 144, 152, 174, 175, 176, 177, 178, 179, 180, 181, 221, 223, 224, 225, 226, 227, 228, 229, and 162 Includes.

[0012] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises: (a) an LCDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 105, 113, 121, 129, 137, 145 and 153; (b) an LCDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 13, 21, 29, 37, 45, 53, 61, 69, 77, 85, 93, 106, 114, 122, 130, 138, 146, and 154; and (c) an LCDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 14, 22, 30, 38, 46, 54, 62, 70, 78, 86, 94, 107, 115, 123, 131, 139, 147, 155, 182, 183, 184, 185, 214, 215, 216, and 167 Includes.

[0013] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises: (a) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:3; (b) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; (c) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19; (d) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27; (e) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35; (f) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; (g) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51; (h) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59; (i) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 67; (j) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75; (k) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 81, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 82, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83; (l) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 89, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91; (m) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 102, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 103, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104; (n) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 110, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 111, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; (o) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120; (p) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 126, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 127, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128; (q) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; (r) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 143, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144; (s) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; (t) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 219, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162; (u) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, 217 or 218; HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, 171, 172, 173, 220 or 222; HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, 174, 175, 176, 177, 178, 179, 180, 181, 221, 223, 224, 225, 226, 227, 228 or 229; (v) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 212, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; (w) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 210, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; or (x) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 211, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152 Includes.

[0014] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises: (a) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (b) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (c) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22; (d) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30; (e) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 36, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 37, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 38; (f) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (g) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 53, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 54; (h) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 61, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 62; (i) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; (j) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 76, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 77, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 78; (k) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 85, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 86; (l) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 93, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 94; (m) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 105, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107; (n) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; (o) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 121, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 122, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123; (p) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 129, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 130, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 131; (q) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 137, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 138, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 139; (r) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 145, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 147; (s) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155; (t) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 167; or (u) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14, 182, 183, 184, 185, 214, 215, or 216. Includes.

[0015] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises: (a) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; (b) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (c) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22; (d) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30; (e) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 36, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 37, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 38; (f) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (g) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 53, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 54; (h) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 61, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 62; (i) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 67, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; (j) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 76, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 77, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 78; (k) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 81, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 82, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 85, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 86; (l) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 89, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 93, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 94; (m) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 102, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 103, an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104, an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 105, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107; (n) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 110, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 111, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; (o) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 121, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 122, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123; (p) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 126, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 127, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 129, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 130, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 131; (q) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 137, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 138, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 139; (r) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 143, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 145, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 147; (s) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 151, an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155; (t) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 171, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (u) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 172, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (v) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:173, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (w) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:174, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (x) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (y) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 176, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (z) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (aa) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 178, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (bb) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 179, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (cc) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:180, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (dd) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:181, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (ee) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:182; (ff) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:183; (gg) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:184; or (hh) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185; (ii) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:220, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (jj) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 221, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (kk) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:222, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:180, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (ll) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:172, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:223, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (mm) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:171, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:224, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (nn) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:214; (oo) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 215; (pp) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:216; (qq) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 222, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 180, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 214; (rr) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:222, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:180, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:215; (ss) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:172, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:223, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:214; (tt) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:172, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:223, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:215; (uu) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (vv) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:226, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (ww) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:227, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (xx) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 228, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (yy) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:174, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (zz) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:229, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (aaa) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 217, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (bbb) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 218, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (ccc) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 219, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 167; (ddd) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 212, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155; (eee) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 210, an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155; or (fff) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 211, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155 Includes.

[0016] In some embodiments, an antibody or antigen-binding fragment thereof of the disclosure comprises an amino acid sequence set forth in SEQ ID NO: 7, 15, 23, 31, 39, 47, 55, 63, 71, 79, 87, 95, 108, 116, 124, 132, 140, 148, 156, 163, 164, 165, 166, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 213, 202, 203, 204, 205, 206, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, or 245. or a homologous sequence thereof having at least 80% sequence identity to SEQ ID NO: 7, 15, 23, 31, 39, 47, 55, 63, 71, 79, 87, 95, 108, 116, 124, 132, 140, 148, 156, 163, 164, 165, 166, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 213, 202, 203, 204, 205, 206, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244 or 245.

[0017] In some embodiments, the antibody or antigen-binding fragment thereof of the present disclosure comprises an amino acid sequence set forth in SEQ ID NO: 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 109, 117, 125, 133, 141, 149, 157, 168, 169, 170, 197, 198, 199, 200, 207, 208, 209, 230, 231, or 232. or a homologous sequence thereof having at least 80% sequence identity to SEQ ID NO: 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 109, 117, 125, 133, 141, 149, 157, 168, 169, 170, 197, 198, 199, 200, 207, 208, 209, 230, 231 or 232.

[0018] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure is selected from the group consisting of SEQ ID NOs: 7 / 8, 15 / 16, 23 / 24, 31 / 32, 39 / 40, 47 / 48, 55 / 56, 63 / 64, 71 / 72, 79 / 80, 87 / 88, 95 / 96, 108 / 109, 116 / 117, 124 / 125, 132 / 133, 140 / 141, 148 / 149, 156 / 157, 163 / 164, 170 / 176, 178 / 178, 179 / 179, 180 / 182, 184 / 186, 188 / 189, 190 / 191, 192 / 193, 194 / 195, 196 / 197, 198 / 199, 200 / 201, 202 / 203, 203 / 204, 204 / 205, 205 / 206, 207 / 208, 208 / 209, 210 / 211, 212 / 213, 214 / 215, 216 / 217, 218 / 218, 220 / 221, 222 / 223, 224 / 225, 226 / 227, 228 / 229, 230 / 231, 232 / 233, 234 / 235, 236 / 237, 238 / 239, 240 / 241, 242 / 243, 244 / 245, 246 / 168, 163 / 169, 163 / 170, 164 / 168, 164 / 169, 164 / 170, 165 / 168, 165 / 169, 165 / 170, 166 / 168, 166 / 169, 166 / 170, 186 / 169, 187 / 169, 188 / 169, 189 / 169, 190 / 169, 191 / 169, 192 / 169, 193 / 169, 194 / 16 9, 195 / 169, 196 / 169, 165 / 197, 165 / 198, 165 / 199, 165 / 200, 202 / 207, 202 / 208, 202 / 209, 203 / 207, 203 / 208, 203 / 209, 204 / 207, 205 / 207, 206 / 207, 206 / 208, 206 / 209, 233 / 169, 234 / 169, 235 / 169, 2 The VH / VL amino acid sequence pair is selected from the group consisting of 36 / 169, 237 / 169, 238 / 169, 239 / 169, 240 / 169, 241 / 169, 242 / 169, 243 / 169, 244 / 169, 245 / 169, 165 / 230, 165 / 231, 165 / 232, 235 / 230, 235 / 231, 236 / 230 and 236 / 231.

[0019] In some embodiments, the antibody or antigen-binding fragment of the present disclosure further comprises one or more amino acid residue substitutions or modifications and still retains specific binding affinity to CD3. In some embodiments, at least one of the substitutions or modifications is in one or more of the CDR sequences of the VH or VL region. In some embodiments, at least one of the substitutions or modifications is in one or more of the non-CDR sequences of the VH or VL region. In some embodiments, the antibody or antigen-binding fragment of the present disclosure further comprises one or more non-natural amino acid (NNAA) substitutions. In some embodiments, the NNAA can be conjugated.

[0020] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises: (a) is capable of specifically binding to human CD3 as measured by a FACS assay; (b) having T cell activation capability as measured by a Jurkat NFAT-luciferase activation assay; and (c) having the ability to activate PBMCs as measured by an ELISA assay; and having one or more binding properties for CD3 selected from the group consisting of:

[0021] In another aspect, the disclosure provides an antibody or antigen-binding fragment thereof that competes with the above-described antibody or antigen-binding fragment thereof for binding to CD3.

[0022] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure is a chimeric, humanized, or human antibody or antigen-binding fragment thereof.

[0023] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure is a labeled antibody, a bivalent antibody, an anti-idiotypic antibody, or a fusion protein.

[0024] In some embodiments, an antibody or antigen-binding fragment thereof of the disclosure is a diabody, a Fab, a Fab', a F(ab')2, an Fd, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv-dsFv'), a disulfide stabilized diabody (ds diabody), a single chain antibody molecule (scFv), an scFv dimer (bivalent diabody), a camelized single domain antibody, a nanobody, a domain antibody, or a bivalent domain antibody.

[0025] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure further comprises an Fc region. In some embodiments, the Fc region is an Fc region of a human immunoglobulin (Ig). In some embodiments, the Fc region is an Fc region of a human IgG. In some embodiments, the Fc region is derived from human IgG1, IgG2, IgG3, or IgG4. In some embodiments, the Fc region is derived from human IgG1. In some embodiments, the Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 97-99.

[0026] In some embodiments, the light chain of an antibody or antigen-binding fragment thereof of the present disclosure is a λ light chain or a κ light chain.

[0027] In some embodiments, the antibody or antigen-binding fragment thereof of the present disclosure is a bispecific or multispecific antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof of the present disclosure is capable of specifically binding to one or more additional antigens other than CD3 or a second epitope on CD3.In some embodiments, the one or more additional antigens other than CD3 are: CD16a, CD33, CD38, CD45, CD123, CD146, CD228, CLL-1, FLT3, FLT3L, TAF1, TgPRF, HVCN1, IL-6R, IL-11R, IL17A, IL-23R, IL-33, ILDR2, LAP, TSLP, TREM-1, ANGPT2, APOE, IFNAR, CypA, DOG-1, NKp30, CSF-1R, CCR2, LRRC15, mesothelin, Dickkopf2, DLL3, HER-2 , C10orf54, TrkA, MEKK1, KRAS, ERK, XPO1, mTORC1 / 2, PAK4, NAMPT, ATR, EGFR, FGFR, VEGF, LILRB (e.g., LILRB1, LILRB2, LILRB3, LILRB4, LILRB5) , c-MET, Her2, Her3, CTLA4, GITA, CD112R, CD2, CD7, CD16, CD19, CD20, CD24, CD27, CD30, CD34, CD37, CD39, CD70, CD73, CD83, CD28, CD80(B7-1), C D86 (B7-2), CD40, CD40L (CD154), CD47, SIRPα, CD122, CD137, CD137L, OX40 (CD134), OX40L (CD252), BCMA (e.g. BCMA02), PSMA, CLDN18 (e.g. CLD N18.2), NKG2C, 4-1BB, LIGHT, PVRIG, SLAMF7, HVEM, BAFFR, ICAM-1, 2B4, LFA-1, GITR, ICOS (CD278), ICOSLG (CD275), LAG3 (CD223), A2AR, B7-H3 (CD276), B7-H4 (VTCN1), B7-H5, BTLA (CD272), CD160, CTLA-4 (CD152), GPRC5D, IDO (e.g., IDO1, IDO2), TDO, KIR, LAIR-1, NOX2, PD-1, PD-L1, PD-L2, TIM-3, VISTA, SIGLEC-7 (CD328), SIGLEC-9 (CD329), SIGLEC-15, TIGIT, PVR (CD155), TLR3, CLEC9A, DEC-205, STING, and TGFβ.

[0028] In some embodiments, the antibody or antigen-binding fragment of the present disclosure is linked to one or more conjugate moieties.In some embodiments, the conjugate moiety comprises a clearance modifier, a chemotherapeutic agent, a toxin, a radioisotope, a lanthanide, a detectable label (e.g., a luminescent label, a fluorescent label), an enzyme-substrate label, a DNA alkylating agent, a topoisomerase inhibitor, a tubulin binding agent, a purification moiety or another anticancer agent.In some embodiments, the conjugate moiety is covalently linked, either directly or via a linker.

[0029] In another aspect, the present disclosure provides a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof of the present disclosure and one or more pharma- ceutically acceptable carriers.

[0030] In another aspect, the present disclosure provides a chimeric antigen receptor comprising the antibody or antigen-binding fragment thereof of the present disclosure, a transmembrane domain and an intracellular signal domain. In some embodiments, the transmembrane domain comprises the transmembrane domain of CD3, CD4, CD8, or CD28. In some embodiments, the intracellular signal domain is selected from the group consisting of CD3, FcγRI, CD27, CD28, CD137, CD134, MyD88, CD40, CD278, TLR intracellular signal domain sequence, or a combination thereof. In some embodiments, the antigen-binding fragment of the chimeric antigen receptor is an scFv.

[0031] In another aspect, the present disclosure provides an isolated polynucleotide encoding an antibody or antigen-binding fragment thereof of this disclosure, and / or a chimeric antigen receptor of this disclosure.

[0032] In another aspect, the disclosure provides a vector comprising an isolated polynucleotide of the disclosure.

[0033] In another aspect, the disclosure provides a host expression system comprising a vector of the disclosure or having a polynucleotide of the disclosure incorporated into its genome. In some embodiments, the host expression system of the disclosure is a microorganism, a yeast, or a mammalian cell. In some embodiments, the microorganism is selected from the group consisting of E. coli and B. subtilis. In some embodiments, the yeast is Saccharomyces. In some embodiments, the mammalian cell is selected from the group consisting of COS, CHO-S, CHO-K1, HEK-293, and 3T3 cells.

[0034] In another aspect, the disclosure provides a virus comprising the vector of the disclosure.

[0035] In another aspect, the present disclosure provides a kit comprising an antibody or antigen-binding fragment thereof of this disclosure and / or a pharmaceutical composition of this disclosure and / or a chimeric antigen receptor of this disclosure, and a second therapeutic agent.

[0036] In another aspect, the present disclosure provides a method of expressing an antibody or antigen-binding fragment thereof, or a chimeric antigen receptor of the present disclosure, comprising culturing a host expression system of the present disclosure under conditions in which the antibody or antigen-binding fragment thereof, or the chimeric antigen receptor of the present disclosure is expressed.

[0037] In another aspect, the present disclosure provides a method of treating, preventing, or ameliorating a disease, disorder, or condition in a subject, comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof, and / or a pharmaceutical composition, and / or a chimeric antigen receptor of the present disclosure.

[0038] In another aspect, the present disclosure provides the use of an antibody or antigen-binding fragment thereof, and / or a pharmaceutical composition, and / or a chimeric antigen receptor of the present disclosure in the manufacture of a medicament for treating a CD3-related disease, disorder, or condition in a subject.

[0039] In another aspect, the present disclosure provides the use of an antibody or antigen-binding fragment thereof, and / or a chimeric antigen receptor and / or a pharmaceutical composition of the present disclosure in the manufacture of a diagnostic reagent for diagnosing a CD3-related disease, disorder, or condition.

[0040] In some embodiments, the disease, disorder, or condition is an immune disease, an inflammatory disease, cancer, or a neurological disease. In some embodiments, the cancer is a solid tumor or a hematological tumor. In some embodiments, the disease, disorder, or condition is lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung adenocarcinoma, or lung squamous cell carcinoma), peritoneal cancer, carcinoid cancer, bone cancer, pancreatic cancer, primitive neuroectodermal tumor, skin cancer, gallbladder cancer, head or neck cancer, squamous cell carcinoma, uterine cancer, ovarian cancer, rectal cancer, prostate cancer, bladder cancer (e.g., urothelial carcinoma), cancer of the anal region (e.g., anal squamous cell carcinoma), gastric cancer, or stomach cancer.cancer (e.g., gastrointestinal cancer), esophageal cancer, colon cancer, breast cancer, uterine cancer, liver cancer (e.g., hepatoblastoma, hepatocellular carcinoma / hepatoma, or hepatoma), bile duct cancer, sarcoma, colorectal cancer, fallopian tube cancer, salivary gland cancer, cervical cancer, endometrial or uterine cancer, osteosarcoma, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, nasopharyngeal cancer, soft tissue sarcoma, polycythemia vera, urethral cancer, penile cancer, kidney or ureter cancer (e.g., renal rhabdoid tumor), cutaneous T-cell lymphoma, medulloblastoma, nephroblastoma, myelodysplastic syndromes, chronic and non-chronic bone marrow hyperplasia reproductive disorders, choroid plexus papilloma, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) neoplasms, soft tissue sarcomas (e.g., rhabdomyosarcoma, fibrosarcoma, Kaposi's sarcoma), spinal axis tumors, gliomas (e.g., ependymoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, eye cancer (e.g., retinoblastoma), brain stem glioma, or mixed gliomas, e.g., oligoastrocytoma), brain tumors (e.g., glioblastoma / glioblastoma multiforme (GBM), non-glioblastoma brain tumors, or meningiomas), melanomas (e.g., cutaneous or intraocular melanoma), thrombocytosis, mesothelioma, mycosis fungoides, Sézary syndrome, idiopathic myelofibrosis, isolated MYH-associated polyposis, pituitary adenoma, childhood cancers such as childhood sarcomas (e.g., neuroblastoma, rhabdomyosarcoma, and osteosarcoma), blood cancers, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia (e.g., lymphocytic / lymphoblastic leukemia), chronic or acute leukemia, mast cell leukemia, lymphocytic lymphoma, primary CNS lymphoma, chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), chronic myelomonocytic leukemia (CMML), chronic lymphocytic leukemia (CLM), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLM), acute lymphocytic leukemia (AML), chronic lymphocytic leukemia (CMML), chronic lymphocytic leukemia (CLM), acute ... The tumor is selected from the group consisting of lymphoblastic leukemia, acute lymphoblastic leukemia, hairy cell leukemia (HCL), Burkitt's lymphoma (BL), multiple myeloma (e.g., relapsed or refractory multiple myeloma), T or B cell lymphoma, mantle cell lymphoma (MCL) (e.g., relapsed or refractory mantle cell lymphoma), malignant melanoma, diffuse large B cell lymphoma (DLBCL), DLBCL arising from follicular lymphoma, high-grade B cell lymphoma, primary mediastinal large B cell lymphoma, follicular lymphoma (FL), and primary mediastinal B cell lymphoma.

[0041] In some embodiments, the subject is a human.

[0042] In some embodiments, administration is via parenteral routes, including subcutaneous, intraperitoneal, intravenous, intramuscular, or intradermal injection; or non-parenteral routes, including transdermal, oral, intranasal, intraocular, sublingual, rectal, or topical.

[0043] In some embodiments, the method of treating, preventing, or alleviating a disease, disorder, or condition in a subject further comprises administering an additional therapeutic agent to the subject in need thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of an active agent, an imaging agent, a cytotoxic agent, and an angiogenesis inhibitor, a kinase inhibitor, a costimulatory molecule agonist, a co-inhibitory molecule blocker, an adhesion molecule blocker, an anti-cytokine antibody or a functional fragment thereof, a detectable label or reporter, an antibacterial agent, a gene editing agent, a beta agonist, a viral RNA inhibitor, a polymerase inhibitor, an interferon, and a microRNA. In some embodiments, the additional therapeutic agent is administered to the subject in need thereof before, after, or simultaneously with the antibody or antigen-binding fragment thereof, and / or the pharmaceutical composition, and / or the chimeric antigen receptor of the present disclosure.

[0044] In another aspect, the present disclosure provides a method of activating CD3-expressing T cells in vivo or in vitro, comprising contacting CD3-expressing T cells with an antibody or antigen-binding fragment thereof, and / or a pharmaceutical composition, and / or a chimeric antigen receptor of the present disclosure.

[0045] In another aspect, the present disclosure provides a method of modulating CD3 activity in a CD3-expressing cell, the method comprising exposing the CD3-expressing cell to an antibody or antigen-binding fragment thereof, and / or a pharmaceutical composition, and / or a chimeric antigen receptor of the present disclosure.

[0046] In another aspect, the present disclosure discloses a method of promoting in vivo or in vitro processing of a second antigen by a CD3-expressing T cell, comprising contacting the CD3-expressing T cell with a bispecific antibody or antigen-binding fragment thereof of the present disclosure, wherein the bispecific antibody or antigen-binding fragment thereof can specifically bind to both the CD3-expressing T cell and the second antigen, thereby bringing them into close proximity.

[0047] In another aspect, the present disclosure provides a method of detecting the presence or amount of CD3 in a sample, the method comprising contacting the sample with an antibody or antigen-binding fragment thereof, and / or a pharmaceutical composition, and / or a chimeric antigen receptor of the present disclosure, and determining the presence or amount of CD3 in the sample.

[0048] In another aspect, the present disclosure provides a method of diagnosing a CD3-related disease or disorder in a subject, the method comprising: a) contacting a sample obtained from the subject with an antibody or antigen-binding fragment thereof, and / or a chimeric antigen receptor and / or a pharmaceutical composition of the present disclosure; b) determining the presence or amount of CD3 in the sample; and c) correlating the presence or amount of CD3 with the presence or status of a CD3-related disease or condition in the subject.

[0049] In another aspect, the present disclosure provides a kit comprising an antibody or antigen-binding fragment thereof and / or a chimeric antigen receptor and / or a pharmaceutical composition of the present disclosure useful in the detection of CD3, optionally recombinant CD3, CD3 expressed on the cell surface, or CD3-expressing cells. [Brief description of the drawings]

[0050] [Figure 1] FIG. 1 shows the activation ability of some selected antibodies in Jurkat-NFAT-Luc cells. [Diagram 2] FIG. 2 shows the results of FACS analysis of the binding affinity of several selected chimeric antibodies and the reference antibody OKT3 to Jurkat cells. [Diagram 3] FIG. 3 shows the results of FACS analysis of the binding affinity of several selected chimeric antibodies and reference antibodies BMK-B219 and BMK-TCB to Jurkat cells. [Figure 4] FIG. 4 shows the binding affinity of some selected chimeric antibodies to 293T-cynoCD3mix cells. [Diagram 5] FIG. 5 shows the activation capacity of some selected chimeric antibodies and the reference antibody OKT3 in Jurkat-NFAT-Luc cells. [Figure 6] FIG. 6 shows IL-2 release induced by some selected chimeric antibodies and the reference antibody OKT3 in a PBMC activation assay. [Figure 7] FIG. 7 shows IFNγ release induced by some selected chimeric antibodies and the reference antibody OKT3 in a PBMC activation assay. [Figure 8] FIG. 8 shows CD25 expression on CD3+ human T cells induced by several selected chimeric antibodies and reference antibodies BMK-B219 and BMK-TCB in a PBMC activation assay. [Figure 9A] FIG. 9A shows the binding affinity of several produced humanized or affinity matured 40-C12-C10-E9 antibodies to Jurkat cells. [Figure 9B] FIG. 9B shows the binding affinity of several produced humanized or affinity matured 40-C12-C10-E9 antibodies to Jurkat cells. [Figure 10] 10A-F show the activation potency of several humanized or affinity matured 40-C12-C10-E9 antibodies and reference antibody BMK-TCB in Jurkat-NFAT-Luc cells. [Figure 11] FIG. 11 shows the activation effects of several humanized or affinity matured 40-C12-C10-E9 antibodies and the reference antibody BMK-TCB in a PBMC activation assay. [Figure 12]FIG. 12 shows the binding affinity of several produced humanized 147E11E2 antibodies to Jurkat cells. [Figure 13] FIG. 13 shows the binding affinity of some produced humanized 147E11E2 antibodies to 293T-cynoCD3mix cells. [Figure 14] 14A-C show the activation ability of several humanized 147E11E2 antibodies and reference antibody BMK-TCB in Jurkat-NFAT-Luc cells. [Figure 15] FIG. 15 shows the activation effects of several humanized 147E11E2 antibodies and reference antibody BMK-TCB in a PBMC activation assay. [Figure 16] 16A and B show the binding affinity of several produced humanized or affinity matured 40-C12-C10-E9 antibodies to Jurkat cells. [Figure 17] 17A-E show the activation potency of several humanized or affinity matured 40-C12-C10-E9 antibodies in Jurkat-NFAT-Luc cells. [Figure 18] FIG. 18 shows the activation effects of several humanized or affinity matured 40-C12-C10-E9 antibodies and reference antibody BMK-TCB in a PBMC activation assay. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] The following description of the present disclosure is intended to merely illustrate various embodiments of the present disclosure. Therefore, the specific modifications discussed should not be interpreted as limitations on the scope of the present disclosure. It is clear to those skilled in the art that various equivalents, changes and modifications can be made without departing from the scope of the present disclosure, and it is understood that such equivalent embodiments are included herein. All references cited in this specification, including publications, patents and patent applications, are incorporated herein by reference in their entirety.

[0052] definition The term "antibody" as used herein includes any immunoglobulin, monoclonal, polyclonal, polyvalent, bivalent, monovalent, multispecific, or bispecific antibody that binds to a specific antigen. A natural intact antibody comprises two heavy (H) chains and two light (L) chains. Mammalian heavy chains are classified as alpha, delta, epsilon, gamma, and mu, each heavy chain comprising a variable region (VH) and a first, second, third, and optionally a fourth constant region (CH1, CH2, CH3, CH4, respectively); mammalian light chains are classified as lambda or kappa, each light chain comprising a variable region (VL) and a constant region. Antibodies have a "Y" shape, with the stem of the Y comprising the second and third constant regions of two heavy chains bound together via disulfide bonds. Each arm of the Y comprises the variable region and first constant region of a single heavy chain bound to the variable and constant region of a single light chain. The variable regions of the light and heavy chains are involved in antigen binding. The variable regions of both chains generally contain three hypervariable loops called complementarity determining regions (CDRs) (light chain CDRs including LCDR1, LCDR2, and LCDR3, heavy chain CDRs including HCDR1, HCDR2, and HCDR3). The three CDRs are interposed between adjacent stretches known as framework regions (FRs) (light chain FRs including LFR1, LFR2, LFR3, and LFR4, heavy chain FRs including HFR1, HFR2, HFR3, and HFR4) that are more highly conserved than the CDRs and form a scaffold that holds the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit various effector functions. Antibodies are assigned to classes based on the amino acid sequence of the constant region of their heavy chains. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, which are characterized by the presence of alpha, delta, epsilon, gamma, and mu heavy chains, respectively. Some of the major antibody classes are divided into subclasses, such as IgG1 (gamma 1 heavy chain), IgG2 (gamma 2 heavy chain), IgG3 (gamma 3 heavy chain), IgG4 (gamma 4 heavy chain), IgA1 (alpha 1 heavy chain), or IgA2 (alpha 2 heavy chain).

[0053] In certain embodiments, the antibodies provided herein encompass any antigen-binding fragment thereof. The term "antigen-binding fragment" as used herein refers to an antibody fragment formed from a portion of an antibody that includes one or more (e.g., 1, 2, 3, 4, 5, or 6) CDRs, or any other antibody fragment that binds to an antigen but does not include an intact native antibody structure. Examples of antigen-binding fragments include, but are not limited to, diabodies, Fab, Fab', F(ab')2, Fd, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (ds diabodies), single-chain antibody molecules (scFv), scFv dimers (bivalent diabodies), bispecific antibodies, multispecific antibodies, camelized single domain antibodies, nanobodies, domain antibodies, or bivalent domain antibodies. An antigen-binding fragment is capable of binding to the same antigen or epitope that the parent antibody binds.

[0054] "Fab" with respect to an antibody refers to that portion of an antibody that consists of a single light chain (both the variable and constant regions) bound by disulfide bonds to the variable region and first constant region of a single heavy chain.

[0055] "Fab'" refers to a Fab fragment that contains part of the hinge region.

[0056] "F(ab')2" refers to a Fab' dimer.

[0057] "Fc" with respect to an antibody (e.g., an antibody of IgG, IgA, or IgD isotype) refers to that portion of an antibody consisting of the second and third constant domains of a first heavy chain linked to the second and third constant domains of a second heavy chain via disulfide bonds. Fc with respect to antibodies of IgM and IgE isotypes further comprises a fourth constant domain. The Fc portion of an antibody is involved in various effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC), but does not function in antigen binding.

[0058] "Fv" with respect to an antibody refers to the minimum fragment of an antibody that contains a complete antigen-binding site. The Fv fragment consists of the variable region of a single light chain bound to the variable region of a single heavy chain.

[0059] A "single-chain Fv antibody" or "scFv" refers to an engineered antibody consisting of a light chain variable region and a heavy chain variable region connected via a linker (e.g., a peptide sequence) or directly to each other (Huston JS et al., Proc Natl Acad Sci USA, 85:5879 (1988)).

[0060] "Single chain Fv-Fc antibody" or "scFv-Fc" refers to an engineered antibody consisting of an scFv connected to the Fc region of an antibody.

[0061] "Camelized single domain antibody", "heavy chain antibody", or "HCAb" refers to an antibody that contains two VH domains and no light chains (Riechmann L. and Muyldermans S., J Immunol Methods. Dec 10; 231(1-2): 25-38 (1999); Muyldermans S., J Biotechnol. Jun; 74(4): 277-302 (2001); WO94 / 04678; WO94 / 25591; U.S. Patent No. 6,005,079). Heavy chain antibodies are originally derived from the Camelidae family (camels, dromedaries, and llamas). Although lacking light chains, camelized antibodies have a bona fide antigen-binding repertoire (Hamers-Casterman C. et al., Nature. Jun 3; 363(6428): 446-8 (1993); Nguyen VK. et al., Immunogenetics. Apr; 54(1): 39-47 (2002); Nguyen VK. et al., Immunology. May; 109(1): 93-101 (2003)). The variable domain of heavy chain antibodies (VHH domain) represents the smallest known antigen-binding unit generated by adaptive immunity (Koch-Nolte F. et al., FASEB J. Nov; 21(13): 3490-8. Epub 2007 Jun 15 (2007)).

[0062] "Nanobody" refers to an antibody fragment consisting of a VHH domain from a heavy chain antibody and two constant domains, CH2 and CH3.

[0063] A "diabody" or "dAb" comprises a small antibody fragment having two antigen-binding sites, the fragment comprising a VH domain connected to a VL domain in the same polypeptide chain (VH-VL or VL-VH) (see, e.g., Holliger P. et al., Proc Natl Acad Sci USA. Jul 15; 90(14):6444-8 (1993); EP 404097; WO 93 / 11161). By using a linker that is too short to allow pairing between the two domains in the same chain, the domains are forced to pair with complementary domains in another chain, thereby creating two antigen-binding sites. The antigen-binding sites may target the same or different antigens (or epitopes). In certain embodiments, a "bispecific ds diabody" is a diabody that targets two different antigens (or epitopes).

[0064] "Domain antibody" refers to an antibody fragment that contains only the variable region of the heavy chain or the variable region of the light chain. In certain instances, two or more VH domains are covalently linked by a peptide linker to create a bivalent or multivalent domain antibody. The two VH domains of a bivalent domain antibody can target the same or different antigens.

[0065] The term "valency" as used herein refers to a specified number of antigen-binding sites present in a given molecule. The term "monovalent" refers to an antibody or antigen-binding fragment that has only one single antigen-binding site; the term "multivalent" refers to an antibody or antigen-binding fragment that has multiple antigen-binding sites. Thus, the terms "bivalent", "tetravalent" and "hexavalent" indicate that two, four and six antigen-binding sites are present in an antigen-binding molecule, respectively. In some embodiments, an antibody or antigen-binding fragment thereof is bivalent.

[0066] As used herein, a "bispecific" antibody refers to an artificial antibody that has fragments derived from two different monoclonal antibodies and is capable of binding to two different epitopes. The two epitopes may be present on the same antigen or they may be present on two different antigens.

[0067] As used herein, a "multispecific" antibody refers to an antibody that specifically binds to at least two distinct antigens or at least two distinct epitopes within the same antigen. A multispecific antibody may, for example, bind to 2, 3, 4, 5, or more distinct antigens or distinct epitopes within the same antigen.

[0068] In certain embodiments, an "scFv dimer" is a bivalent diabody or bispecific scFv (BsFv) that includes a VH-VL (linked by a peptide linker) dimerized with another VH-VL moiety such that the VH of one moiety cooperates with the VL of the other moiety to form two binding sites that can target the same antigen (or epitope) or different antigens (or epitopes). In other embodiments, an "scFv dimer" is a bispecific diabody that includes VH1-VL2 (linked by a peptide linker) associated with VL1-VH2 (linked by a peptide linker) such that VH1 and VL1 cooperate and VH2 and VL2 cooperate, with each coordinated pair having a different antigen specificity.

[0069] "dsFv" refers to a disulfide-stabilized Fv fragment in which the link between the variable region of a single light chain and the variable region of a single heavy chain is a disulfide bond. In some embodiments, "(dsFv)2", or "(dsFv-dsFv')" comprises three peptide chains: two VH portions linked by a peptide linker (e.g., a long flexible linker), each bound to two VL portions via a disulfide bridge. In some embodiments, dsFv-dsFv' is bispecific in that each disulfide-paired heavy and light chain has a different antigen specificity.

[0070] The term "chimeric" as used herein refers to an antibody or antigen-binding fragment having a portion of the heavy and / or light chain derived from one species and the remainder of the heavy and / or light chain derived from a different species. In an illustrative example, a chimeric antibody may contain a constant region derived from a human and a variable region derived from a non-human animal, such as a mouse. In some embodiments, the non-human animal is a mammal, such as a mouse, rat, rabbit, goat, sheep, guinea pig, or hamster.

[0071] The term "humanized" as used herein means that an antibody or antigen-binding fragment contains CDRs derived from a non-human animal, FR regions derived from a human, and optionally constant regions derived from a human. The CDRs of the humanized antibodies provided in this disclosure may contain mutation(s) compared to the CDRs of its parent antibody.

[0072] The term "affinity," as used herein, refers to the strength of the non-covalent interactions between an immunoglobulin molecule (i.e., an antibody) or an antigen-binding fragment thereof and an antigen.

[0073] An antibody or antigen-binding fragment thereof that "specifically binds" or "specifically binds" to a target (e.g., an epitope) is a term well understood in the art, and methods for determining such specific binding are also well known in the art. A molecule is said to exhibit "specific binding" when it reacts or associates with a particular cell or substance more frequently, more rapidly, for a longer period, and / or with greater affinity than it binds to alternative cells or substances. An antibody "specifically binds" to a target when it binds with greater affinity, avidity, more readily, and / or for a longer period than it binds to other substances. For example, an antibody that specifically binds to a CD3 epitope is an antibody that binds to this CD3 epitope with greater affinity, avidity, more readily, and / or for a longer period than it binds to other CD3 epitopes or non-CD3 epitopes. By reading this definition, it is also understood that, for example, an antibody (or moiety or epitope) that specifically binds to a first target may or may not specifically bind to a second target. As such, "specifically binding" or "specifically binding" does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding refers to specific binding.

[0074] The ability to "compete for binding to CD3" as used herein refers to the ability of a first antibody or antigen-binding fragment to inhibit the binding interaction between CD3 and a second anti-CD3 antibody to any detectable extent. In certain embodiments, an antibody or antigen-binding fragment that competes for binding to CD3 inhibits the binding interaction between CD3 and a second anti-CD3 antibody by at least 85%, or at least 90%. In certain embodiments, this inhibition can be greater than 95%, or greater than 99%.

[0075] The term "epitope" as used herein refers to a specific group of atoms or amino acids on an antigen to which an antibody binds. Two antibodies may bind to the same or closely related epitopes in an antigen if they exhibit competitive binding with respect to the antigen. Epitopes may be linear or conformational (i.e., comprise spatially separated amino acid residues). For example, an antibody or antigen-binding fragment may be considered to bind to the same / closely related epitope as a reference antibody if the antibody or antigen-binding fragment blocks at least 85%, or at least 90%, or at least 95% of the binding of the reference antibody to the antigen.

[0076] The term "amino acid" as used herein refers to an organic compound containing an amine (-NH2) and a carboxyl (-COOH) functional group along with a side chain specific for each amino acid. The names of amino acids are represented in this disclosure by standard one-letter or three-letter symbols, which are summarized below.

[0077] [Table A]

[0078] "Conservative substitution" in reference to amino acid sequence refers to replacing an amino acid residue with a different amino acid residue with a side chain having similar physiochemical properties. For example, conservative substitution can be made between amino acid residues with hydrophobic side chains (e.g., Met, Ala, Val, Leu and Ile), neutral hydrophilic side chains (e.g., Cys, Ser, Thr, Asn and Gln), acidic side chains (e.g., Asp, Glu), basic side chains (e.g., His, Lys and Arg), or aromatic side chains (e.g., Trp, Tyr and Phe). As is known in the art, conservative substitution usually does not cause significant changes in the conformation of a protein, and therefore can retain the biological activity of the protein.

[0079] The term "homologous" as used herein refers to a nucleic acid sequence (or its complementary strand) or amino acid sequence that has at least 60% (e.g., at least 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to another sequence when optimally aligned.

[0080] "Percent (%) sequence identity" with respect to an amino acid sequence (or nucleic acid sequence) is defined as the percentage of amino acid (or nucleic acid) residues in a candidate sequence that are identical to the amino acid (or nucleic acid) residues in a reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum number of identical amino acids (or nucleic acids). In other words, the percent (%) sequence identity of an amino acid sequence (or nucleic acid sequence) can be calculated by dividing the number of identical amino acid residues (or bases) compared to the reference sequence to which it is compared by the total number of amino acid residues (or bases) in the shorter of either the candidate or reference sequence. Conservative substitutions of amino acid residues may or may not be considered as identical residues. Alignment for purposes of determining percent amino acid (or nucleic acid) sequence identity can be accomplished, for example, using publicly available tools such as BLASTN, BLASTp (available at the US National Center for Biotechnology Information (NCBI) website, see also Altschul SF et al., J. Mol. Biol., 215:403-410 (1990); Stephen F. et al., Nucleic Acids Res., 25:3389-3402 (1997)), ClustalW2 (available at the European Bioinformatics Institute website, see also Higgins DG et al., Methods in Enzymology, 266:383-402 (1996); Larkin MA et al., Bioinformatics (Oxford, England), 23(21): 2947-8 (2007)), and ALIGN or Megalign (DNASTAR) software. One skilled in the art may use the default parameters provided by the tool or may custom generate parameters that are appropriate for the alignment, for example by selecting a suitable algorithm.

[0081] "Effector function" as used herein refers to the biological activity resulting from the binding of the Fc region of an antibody to its effector, such as the C1 complex and Fc receptor. Exemplary effector functions include complement-dependent cytotoxicity (CDC), which is mediated by the interaction of an antibody with C1q on the C1 complex; antibody-dependent cellular cytotoxicity (ADCC), which is mediated by the binding of the Fc region of an antibody to an Fc receptor on an effector cell; and phagocytosis. Effector function can be evaluated using various assays, such as Fc receptor binding assays, C1q binding assays, and cytolysis assays.

[0082] "Antibody-dependent cellular cytotoxicity" or "ADCC," as used herein, refers to a cell-mediated reaction in which effector cells expressing Fc receptors (FcR) recognize bound antibodies or antigen-binding fragments on target cells and subsequently cause lysis of the target cells. "ADCC activity" or "ADCC effect" refers to the ability of bound antibodies or antigen-binding fragments on target cells to elicit an ADCC response as described above.

[0083] "Complement-dependent cytotoxicity" or "CDC" as used herein refers to the mechanism by which antibodies can mediate specific target cell lysis through activation of an organism's complement system. In CDC, C1q binds to antibodies, which triggers the complement cascade, resulting in the formation of the membrane attack complex (MAC) (C5b to C9) on the surface of target cells as a result of classical pathway complement activation. "CDC activity" or "CDC effect" refers to the ability of an antibody or antigen-binding fragment bound on a target cell to induce a CDC response as described above.

[0084] "Target cells" as used herein refer to cells to which an antibody containing an Fc region specifically binds via a protein moiety that is generally C-terminal to the Fc region. "Effector cells" are white blood cells that express one or more Fc receptors and perform effector functions. Examples of human white blood cells that mediate ADCC include peripheral blood mononuclear cells (PBMCs), natural killer (NK) cells, monocytes, cytotoxic T cells, and neutrophils, with PBMCs and NK cells being preferred. Effector cells can be isolated from natural sources, for example, from blood or PBMCs as known in the art.

[0085] An "isolated" material is altered by the hand of man from its natural state. When an "isolated" composition or material is naturally occurring, it has been altered or removed from its original environment, or both. For example, a polynucleotide or polypeptide that naturally occurs in a living animal is not "isolated", but is "isolated" when it is sufficiently separated from the coexisting materials of its natural state to exist in a substantially pure state. An "isolated nucleic acid sequence" refers to a sequence of an isolated nucleic acid molecule. In certain embodiments, an "isolated antibody or antigen-binding fragment thereof" refers to an antibody or antigen-binding fragment thereof that has a purity of at least 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% as determined by electrophoretic methods (e.g., SDS-PAGE, isoelectric focusing, capillary electrophoresis) or chromatographic methods (e.g., ion exchange chromatography or reverse phase HPLC).

[0086] The term "vector" as used herein refers to a vehicle into which a polynucleotide encoding a protein can be operatively inserted to effect expression of the protein. A vector can be used to transform, transduce, or transfect a host cell to effect expression of the genetic elements it carries in the host cell. Examples of vectors include plasmids, phagemids, cosmids, artificial chromosomes, such as yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), or P1-derived artificial chromosomes (PACs), bacteriophages, such as lambda phage or M13 phage, and animal viruses. Categories of animal viruses used as vectors include retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpes viruses (e.g., herpes simplex viruses), pox viruses, baculoviruses, papilloma viruses, and parvoviruses (e.g., SV40). A vector can contain a variety of elements for controlling expression, including promoter sequences, transcription initiation sequences, enhancer sequences, selectable elements, and reporter genes. In addition, the vector may contain an origin of replication. The vector may also contain materials that aid its entry into cells, including but not limited to viral particles, liposomes, or protein coatings. The vector may be an expression vector or a cloning vector. The present disclosure provides a vector (e.g., an expression vector) that contains the nucleic acid sequence provided herein that encodes an antibody or an antigen-binding fragment thereof, at least one promoter (e.g., SV40, CMV, EF-1α) operably linked to the nucleic acid sequence, and at least one selection marker.Examples of vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpes viruses (e.g., herpes simplex virus), poxviruses, baculoviruses, papilloma viruses, parvoviruses (e.g., SV40), lambda phage, and M13 phage, plasmids pcDNA3.3, pMD18-T, pOptivec, pCMV, pEGFP, pIRES, pQD-Hyg-GSeu, pALTE R, pBAD, pcDNA, pCal, pL, pET, pGEMEX, pGEX, pCI, pEGFT, pSV2, pFUSE, pVITRO, pVIVO, pMAL, pMONO, pSELECT, pUNO, pDUO, Psg5L, pB ABE, pWPXL, pBI, p15TV-L, pPro18, pTD, pRS10, pLexA, pACT2.2, pCMV-SCRIPT.RTM., pCDM8, pCDNA1.1 / amp, pcDNA3.1, pRc / RSV, PCR 2.1, pEF-1, pFB, pSG5, pXT1, pCDEF3, pSVSPORT, pEF-Bos, etc.

[0087] The phrase "host cell," as used herein, refers to a cell into which an exogenous polynucleotide and / or vector can be or has been introduced.

[0088] The term "subject" includes humans and non-human animals. Non-human animals include all vertebrates, such as mammals and non-mammals, such as non-human primates, mice, rats, cats, rabbits, sheep, dogs, cows, chickens, amphibians, and reptiles. Except as noted, the terms "patient," "subject," or "individual" are used interchangeably herein.

[0089] The term "antitumor activity" refers to the reduction of tumor cell proliferation, survival rate, or metastatic activity. For example, antitumor activity can be shown by a decrease in the rate of abnormal cell growth that occurs during treatment, or a stable or reduced tumor size, or a longer survival with treatment compared to a control that does not receive treatment. Such activity can be evaluated using accepted in vitro or in vivo tumor models, including but not limited to xenograft models, allograft models, mouse mammary tumor virus (MMTV) models, and other known models known in the art for investigating antitumor activity.

[0090] "Treating" or "treatment" of a disease, disorder, or condition, as used herein, includes preventing or alleviating the disease, disorder, or condition, slowing the onset or rate of occurrence of the disease, disorder, or condition, reducing the risk of developing a disease, disorder, or condition, preventing or slowing the onset of symptoms associated with the disease, disorder, or condition, reducing or ending symptoms associated with the disease, disorder, or condition, producing complete or partial regression of the disease, disorder, or condition, curing the disease, disorder, or condition, or any combination thereof.

[0091] The term "diagnosis", "diagnose" or "diagnosing" refers to the identification of a pathological condition, disease or condition, such as the identification of a CD3-related disease, or the identification of a subject having a CD3-related disease that may benefit from a particular treatment regimen. In some embodiments, diagnosis includes the identification of an abnormal amount or activity of CD3. In some embodiments, diagnosis refers to the identification of cancer in a subject.

[0092] As used herein, the term "biological sample" or "sample" refers to a biological composition obtained or derived from a subject of interest that contains cellular and / or other molecular entities that are characterized and / or identified based on, for example, physical, biochemical, chemical, and / or physiological characteristics. Biological samples include, but are not limited to, cells, tissues, organs, and / or biological fluids of a subject obtained by any method known to one of skill in the art. In some embodiments, the biological sample is a bodily fluid sample. In some embodiments, the bodily fluid sample is whole blood, plasma, serum, mucus (including nasal mucus and sputum), peritoneal fluid, pleural fluid, chest fluid, saliva, urine, synovial fluid, cerebrospinal fluid (CSF), thoracentesis, abdominal fluid, ascites, or pericardial fluid. In some embodiments, the biological sample is tissue or cells obtained from the stomach, heart, liver, spleen, lungs, kidneys, skin, or blood vessels of a subject.

[0093] "CD3" as used herein refers to cluster of differentiation 3 protein, including any variant, conformation, isoform, and species homologue of CD3 expressed naturally by cells or expressed by cells transfected with the CD3 gene. For example, CD3 as described herein may refer to cluster of differentiation 3 protein from any vertebrate source, including mammals such as primates (e.g., humans, monkeys) and rodents (e.g., mice and rats). In mammals, the CD3 molecule is a six-chain multiprotein complex that includes a homodimer of CD3 gamma chain, CD3 delta chain, two CD3 epsilon chains, and CD3 zeta chain, where the CD3 zeta chain is the intracellular tail of the CD3 molecule, and the CD3 gamma, CD3 delta, and CD3 epsilon chains all contain an extracellular domain (ECD) that is expressed on the surface of T cells. Exemplary sequences of human CD3 include the human CD3 epsilon protein (NCBI Reference SEQ ID NO: NP_000724), the human CD3 delta protein (NCBI Reference SEQ ID NO: NP_000723), and the human CD3 gamma protein (NCBI Reference SEQ ID NO: NP_000064).Exemplary sequences of non-human CD3 include Macaca fascicularis (monkey) CD3 epsilon protein (NCBI Reference SEQ ID NO: NP_001270544), Macaca fascicularis (monkey) CD3 delta protein (NCBI Reference SEQ ID NO: NP_001274617), Macaca fascicularis (monkey) CD3 gamma protein (NCBI Reference SEQ ID NO: NP_001270839); Mus musculus (mouse) CD3 epsilon protein (NCBI Reference SEQ ID NO: NP_031674), Mus musculus (mouse) CD3 delta protein (NCBI Reference SEQ ID NO: NP_038515), Mus musculus domesticus (mouse) CD3 gamma protein (NCBI Reference SEQ ID NO: AAA37400); Rattus norvegicus (rat) CD3 epsilon protein (NCBI Reference SEQ ID NO: NP_001101610), Rattus norvegicus (rat) CD3 delta protein (NCBI reference sequence NP_037301), Rattus norvegicus (rat) CD3 gamma protein (NCBI reference sequence NP_001071114). In certain embodiments, CD3 as used herein may also be recombinant CD3, which may be optionally expressed as a recombinant CD3 complex, for example, recombinant CD3 including recombinant CD3 epsilon protein, recombinant CD3 delta protein, and recombinant CD3 gamma protein. The recombinant CD3 complex may be expressed on the cell surface, or alternatively may be expressed as a soluble form not associated on the cell surface. In certain embodiments, CD3 is human CD3. The terms "CD3", "CD-3", "CD 3", and "cluster of differentiation 3" may be used interchangeably in this disclosure.

[0094] The term "anti-CD3 antibody" refers to an antibody that specifically binds to CD3 (e.g., human CD3). The term "anti-human CD3 antibody" refers to an antibody that specifically binds to human CD3. In some embodiments, the anti-CD3 antibodies provided herein specifically bind to CD3 gamma protein. In some embodiments, the anti-CD3 antibodies provided herein specifically bind to CD3 delta protein. In some embodiments, the anti-CD3 antibodies provided herein specifically bind to CD3 epsilon protein.

[0095] The term "CD3 gamma," as used herein, is intended to encompass any form of CD3 gamma, such as: 1) the native unprocessed CD3 gamma molecule, the "full-length" CD3 gamma chain, or a naturally occurring variant of CD3 gamma, such as a splice variant or allelic variant; 2) any form of CD3 gamma that results from processing in the cell; or 3) a full-length, fragment (e.g., truncated, extracellular / transmembrane domain), or modified (e.g., mutated, glycosylated / PEGylated, His-tag / immunofluorescence fusion) CD3 gamma subunit produced through recombinant methods.

[0096] The term "CD3 delta," as used herein, is intended to encompass any form of CD3 delta, such as: 1) the native unprocessed CD3 delta molecule, the "full-length" CD3 delta chain, or a naturally occurring variant of CD3 delta, such as a splice variant or allelic variant; 2) any form of CD3 delta that results from processing in the cell; or 3) a full-length, fragment (e.g., truncated, extracellular / transmembrane domain), or modified (e.g., mutated, glycosylated / PEGylated, His-tag / immunofluorescence fusion) CD3 delta subunit produced through recombinant methods.

[0097] The term "CD3 epsilon", as used herein, is intended to encompass any form of CD3 epsilon, such as 1) the native unprocessed CD3 epsilon molecule, the "full-length" CD3 epsilon chain, or a naturally occurring variant of CD3 epsilon, such as a splice variant or an allelic variant; 2) any form of CD3 epsilon that results from processing in the cell; or 3) a full-length, a fragment (e.g., truncated, extracellular / transmembrane domain), or modified (e.g., mutated, glycosylated / PEGylated, His-tag / immunofluorescence fusion) of the CD3 epsilon subunit produced through recombinant methods.

[0098] In some embodiments, the anti-CD3 antibodies provided herein specifically bind to CD3 epsilon but do not bind to CD3 gamma (or CD3 delta) or bind weaker to CD3 gamma (or CD3 delta), for example, the binding affinity to CD3 epsilon is at least 10 times lower than the binding affinity to CD3 gamma (or CD3 delta), or at least 50 times lower than the binding affinity to CD3 gamma (or CD3 delta), or at least 100 times lower, or at least 200 times lower. In some embodiments, the anti-CD3 antibodies provided herein do not have detectable binding affinity to CD3 gamma (or CD3 delta). In some embodiments, the binding affinity is determined by FACS assay. In some embodiments, the binding affinity is determined by the mean fluorescence intensity (MFI) detected by FACS assay.

[0099] "CD3-associated" or "CD3-associated" disease, disorder, or condition, as used herein, refers to any disease, disorder, or condition caused by, exacerbated by, or otherwise associated with increased or decreased expression or activity of CD3. In some embodiments, the CD3-associated disease, disorder, or condition is a disorder associated with excessive cell proliferation, such as cancer. In certain embodiments, the CD3-associated disease or condition is characterized by expressing or overexpressing CD3 and / or CD3-associated genes.

[0100] The term "pharmaceutical acceptable" indicates that the specified carrier, vehicle, diluent, excipient(s), and / or salt is generally chemically and / or physically compatible with the other ingredients that make up the formulation and physiologically compatible with the recipient thereof.

[0101] The term "CD3-expressing cell," as used herein, refers to a cell that expresses CD3 on its surface.

[0102] Anti-CD3 antibody The present disclosure provides anti-CD3 antibodies and antigen-binding fragments thereof. The anti-CD3 antibodies and antigen-binding fragments provided herein are capable of binding (e.g., specifically binding) to CD3 (e.g., human CD3).

[0103] The binding affinity of an antibody or antigen-binding fragment thereof provided herein is the ratio of the dissociation rate to the association rate when binding between an antigen and an antigen-binding molecule reaches equilibrium (k off / k on ) D Antigen binding affinity (e.g., K D) can be suitably determined using a suitable method known in the art, including, for example, flow cytometry assays. In some embodiments, binding of different concentrations of an antibody or antigen-binding fragment thereof to an antigen can be determined by flow cytometry, and the determined mean fluorescence intensity (MFI) can first be plotted against the antibody concentration, and then K D Values ​​were analyzed using Prism version 5 (GraphPad Software, San Diego, CA) to determine the dependence of specific binding fluorescence intensity (Y) and antibody concentration (X) using a one-site saturation equation: Y = B max * X / (K D +X), where B max refers to the maximum specific binding of a test antibody to an antigen.

[0104] The binding of an antibody or antigen-binding fragment thereof provided herein to CD3 may also be referred to as the "half maximal effective concentration" (EC 50 ) value, which refers to the antibody concentration at which 50% of its maximum binding is observed. 50 The value can be measured by binding assays known in the art, such as direct or indirect binding assays, such as enzyme-linked immunosorbent assay (ELISA), FACS assay, and other binding assays. In certain embodiments, the antibody or antigen-binding fragment thereof provided herein can specifically bind to human CD3 (e.g., as measured by FACS assay). In certain embodiments, the antibody or antigen-binding fragment thereof provided herein can bind to both human and cynomolgus CD3 (e.g., as measured by FACS assay).

[0105] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein has T cell activation ability. In certain embodiments, the antibody or antigen-binding fragment thereof provided herein has higher T cell activation ability than OKT3. OKT3 is the first monoclonal antibody drug with specificity for human CD3 antigen, approved by the US FDA in 1986. It has been described in the prior art that OKT3 is a potent T cell mitogen (Van Wauve, J.Immunol.124(1980),2708-18) as well as a potent T cell killer (Wong et al., Transplantation 50(1990),683-9). In certain embodiments, the antibody or antigen-binding fragment thereof provided herein has higher or at least equal T cell activation ability compared to BMK-B219 or BMK-TCB. BMK-B219 is an anti-CD3 antibody developed by Johnson&Johnson, and information about it can be found, for example, in WO2019224717A2. BMK-TCB is an anti-CD3 antibody developed by Roche, information about which can be found, for example, in WO2019154890A1.

[0106] The T cell activation ability of anti-CD3 antibodies can be measured by methods well known in the art, for example, by Jurkat NFAT-luciferase activation assay. In certain embodiments, the T cell activation ability is measured by the methods described in Example 2.3, Example 3.2 and Example 4.4 of the present disclosure.

[0107] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein have the ability to activate PBMCs. In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein have a higher ability to activate PBMCs than OKT3, BMK-B219 and / or BMK-TCB. The ability of anti-CD3 antibodies to activate PBMCs can be determined by methods well known in the art, for example, by ELISA assays, for example, measuring IL-2 and / or IFNγ release levels, and can be used to determine the ability of anti-CD3 antibodies to activate PBMCs.+ CD25 expression on T cells can be measured. In certain embodiments, PBMC activation capacity is measured by the method described in Example 3.6 of the present disclosure.

[0108] Exemplary Anti-CD3 Antibodies In certain embodiments, the present disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to CD3, SEQ ID NOs: 7, 15, 23, 31, 39, 47, 55, 63, 71, 79, 87, 95, 108, 116, 124, 132, 140, 148, 156, 163, 164, 165, 166, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 213, 202, 203, 204, 205, 206 , 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244 and 245; and / or one or two or three heavy chain complementarity determining regions (HCDR1, HCDR2 and / or HCDR3) contained within any one of the heavy chain variable (VH) region sequences selected from the group consisting of: One or two or three light chain complementarity determining regions (LCDR1, LCDR2 and / or LCDR3) contained within any one of the light chain variable (VL) region sequences selected from the group consisting of SEQ ID NOs: 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 109, 117, 125, 133, 141, 149, 157, 168, 169, 170, 197, 198, 199, 200, 207, 208, 209, 230, 231 and 232. The present invention provides an antibody or antigen-binding fragment thereof comprising:

[0109] A person skilled in the art can define or identify the CDR boundaries of a VH or VL region by methods well known in the art, provided the amino acid sequence of the VH or VL region is known. For example, the CDR boundaries of an antibody or antigen-binding fragment thereof may be defined or identified by the conventions of Kabat, IMGT, Chothia, or Al-Lazikani (Al-Lazikani, B., Chothia, C., Lesk, A. M., J. Mol. Biol., 273(4), 927 (1997); Chothia, C. et al., J Mol Biol. Dec 5; 186(3):651-63 (1985); Chothia, C. and Lesk, A. M., J. Mol. Biol., 196, 901 (1987); Chothia, C. et al., Nature. Dec 21-28; 342(6252):877-83 (1989); Kabat EA et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991); Marie-Paule Lefranc et al., Developmental and Comparative Immunology, 27: 55-77 (2003); Marie-Paule Lefranc et al., Immunome Research, 1(3), (2005); Marie-Paule Lefranc, Molecular Biology of B cells (second edition), chapter 26, 481-514, (2015)). In some embodiments, the CDR boundaries of the antibodies or antigen-binding fragments thereof provided herein are identified according to the Kabat convention. In some embodiments, the CDR boundaries of the antibodies or antigen-binding fragments thereof provided herein are identified according to the IMGT convention. In some embodiments, the CDR boundaries of the antibodies or antigen-binding fragments thereof provided herein are identified according to the Chothia convention.In some embodiments, the CDR boundaries of an antibody or antigen-binding fragment thereof provided herein are identified according to the Al-Lazikani convention.

[0110] In certain embodiments, the present disclosure provides anti-CD3 antibodies 25-G12-G6-C12, 40-C12-C10-E9, 8-B12-F9-B11, 31-F8-F5-C5, 16-F2-C11-D9, 20-E11-E11-C2, 7-D9-G10-H2, 7-D8-G12-E4, 2-F12-A6-G2, 3-C6-C11-F12, 4 The present invention provides an antibody or antigen-binding fragment thereof that specifically binds to CD3, comprising one or more (e.g., one, two, three, four, five, or six) CDR sequences of -F12-F1-A4, 3-F3-G12-E2, 124E3D6, 126A11A4, 127E2D3, 133B4C7, 140D2B10, 147C6F3, or 147E11E2.

[0111] The antibody "25-G12-G6-C12," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:7, and a light chain variable region having the sequence of SEQ ID NO:8.

[0112] The antibody "40-C12-C10-E9," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:15, and a light chain variable region having the sequence of SEQ ID NO:16.

[0113] The antibody "8-B12-F9-B11," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:23, and a light chain variable region having the sequence of SEQ ID NO:24.

[0114] The antibody "31-F8-F5-C5," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:31, and a light chain variable region having the sequence of SEQ ID NO:32.

[0115] The antibody "16-F2-C11-D9," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:39, and a light chain variable region having the sequence of SEQ ID NO:40.

[0116] The antibody "20-E11-E11-C2," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:47, and a light chain variable region having the sequence of SEQ ID NO:48.

[0117] The antibody "7-D9-G10-H2," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:55 and a light chain variable region having the sequence of SEQ ID NO:56.

[0118] The antibody "7-D8-G12-E4," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:63 and a light chain variable region having the sequence of SEQ ID NO:64.

[0119] The antibody "2-F12-A6-G2," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:71 and a light chain variable region having the sequence of SEQ ID NO:72.

[0120] The antibody "3-C6-C11-F12," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:79 and a light chain variable region having the sequence of SEQ ID NO:80.

[0121] The antibody "4-F12-F1-A4" as used herein refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:87 and a light chain variable region having the sequence of SEQ ID NO:88.

[0122] The antibody "3-F3-G12-E2," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:95 and a light chain variable region having the sequence of SEQ ID NO:96.

[0123] The antibody "124E3D6," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:108, and a light chain variable region having the sequence of SEQ ID NO:109.

[0124] The antibody "126A11A4," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:116, and a light chain variable region having the sequence of SEQ ID NO:117.

[0125] The antibody "127E2D3," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:124 and a light chain variable region having the sequence of SEQ ID NO:125.

[0126] The antibody "133B4C7," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:132, and a light chain variable region having the sequence of SEQ ID NO:133.

[0127] The antibody "140D2B10," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:140, and a light chain variable region having the sequence of SEQ ID NO:141.

[0128] The antibody "147C6F3," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:148 and a light chain variable region having the sequence of SEQ ID NO:149.

[0129] The antibody "147E11E2," as used herein, refers to a murine monoclonal antibody comprising a heavy chain variable region having the sequence of SEQ ID NO:156, and a light chain variable region having the sequence of SEQ ID NO:157.

[0130] The specific amino acid sequences of the heavy and light chain variable regions of each of the above exemplary antibodies are shown in Table 3 below.

[0131] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO:7, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO:8.

[0132] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 15, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 16.

[0133] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO:23, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO:24.

[0134] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 31, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 32.

[0135] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 39, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 40.

[0136] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 47, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 48.

[0137] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO:55, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO:56.

[0138] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO:63, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO:64.

[0139] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 71, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 72.

[0140] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO:79, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO:80.

[0141] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 87, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 88.

[0142] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 95, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 96.

[0143] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 108, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 109.

[0144] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 116, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 117.

[0145] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 124, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 125.

[0146] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 132, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 133.

[0147] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 140, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 141.

[0148] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 148, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 149.

[0149] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 156, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 157.

[0150] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 163, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 168.

[0151] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 163, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0152] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 163, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 170.

[0153] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 164, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 168.

[0154] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 164, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0155] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 164, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 170.

[0156] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 165, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 168.

[0157] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 165, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0158] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 165, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 170.

[0159] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 166, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 168.

[0160] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 166, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0161] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 166, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 170.

[0162] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 186, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0163] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 187, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0164] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 188, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0165] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 189, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0166] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 190, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0167] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 191, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0168] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 192, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0169] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 193, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0170] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 194, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0171] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 195, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0172] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 196, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0173] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 165, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 197.

[0174] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 165, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 198.

[0175] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 165, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 199.

[0176] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 165, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 200.

[0177] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 202, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 207.

[0178] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 202, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 208.

[0179] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 202, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 209.

[0180] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 203, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 207.

[0181] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 203, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 208.

[0182] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 203, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 209.

[0183] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 204, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 207.

[0184] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 205, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 207.

[0185] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 206, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 207.

[0186] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 206, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 208.

[0187] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 206, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 209.

[0188] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 233, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0189] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 234, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0190] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 235, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0191] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 236, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0192] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 237, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0193] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 238, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0194] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 239, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0195] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 240, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0196] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 241, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0197] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 242, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0198] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 243, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0199] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 244, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0200] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 245, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 169.

[0201] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 165, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 230.

[0202] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 165, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 231.

[0203] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 165, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 232.

[0204] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 235, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 230.

[0205] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 235, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 231.

[0206] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 236, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 230.

[0207] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within the VH region sequence set forth in SEQ ID NO: 236, and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the VL region sequence set forth in SEQ ID NO: 231.

[0208] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein are selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 13, 14, 17, 18, 19, 20, 21, 22, 25, 26, 27, 28, 29, 30, 33, 34, 35, 36, 37, 38, 41, 42, 43, 44, 45, 46, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 102, 103, 104, 105, 106, 107, 108, 109, 109, 110, 111, 112, 113, 114, 115, 1 3, 54, 57, 58, 59, 60, 61, 62, 65, 66, 67, 68, 69, 70, 73, 74, 75, 76, 77, 78, 81, 82, 83, 84, 85, 86, 89, 90, 91, 92, 93, 94, 102, 103, 104, 105, 106, 107, 110, 111, 112, 113, 114, 115, 118, 119, 120, 12 1, 122, 123, 126, 127, 128, 129, 130, 131, 134, 135, 136, 137, 138, 139, 142, 143, 144, 145, 146, 147, 150, 151, 152, 153, 154, 155, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 24 3, 184, 185, 201, 162, 167, 210, 211, 212, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228 and 229.

[0209] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein are selected from the group consisting of SEQ ID NOs: 1, 2, 3, 9, 10, 11, 17, 18, 19, 25, 26, 27, 33, 34, 35, 41, 42, 43, 49, 50, 51, 57, 58, 59, 65, 66, 67, 73, 74, 75, 81, 82, 83, 89, 90, 91, 102, 103, 104, 110, 111, 112, 118, 119, 120, 126, 127, 128, 134, 135, 136, 137, 138, 139, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 25 42, 143, 144, 150, 151, 152, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 201, 162, 210, 211, 212, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228 and 229.

[0210] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein are selected from the group consisting of SEQ ID NOs: 4, 5, 6, 12, 13, 14, 20, 21, 22, 28, 29, 30, 36, 37, 38, 44, 45, 46, 52, 53, 54, 60, 61, 62, 68, 69, 70, 76, 77, 78, 84, 85, 86, 92, 93, 94, 105, 106, 107, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 200, 201, 202, 203, 204, 205, 206, 207, 2 and a VL region comprising one or two or three of LCDR1, LCDR2 and LCDR3 comprising amino acid sequences selected from the group consisting of 14, 115, 121, 122, 123, 129, 130, 131, 137, 138, 139, 145, 146, 147, 153, 154, 155, 182, 183, 184, 185, 167, 214, 215 and 216.

[0211] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises an HCDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 102, 110, 118, 126, 134, 142, 150, 217, 218, and 219; , 201, 210, 211, 212, 220 and 222; and an HCDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 11, 19, 27, 35, 43, 51, 59, 67, 75, 83, 91, 104, 112, 120, 128, 136, 144, 152, 174, 175, 176, 177, 178, 179, 180, 181, 221, 223, 224, 225, 226, 227, 228, 229 and 162.

[0212] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein comprises an LCDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 105, 113, 121, 129, 137, 145, and 153; and an LCDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 14, 22, 30, 38, 46, 54, 62, 70, 78, 86, 94, 107, 115, 123, 131, 139, 147, 155, 182, 183, 184, 185, 214, 215, 216 and 167.

[0213] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein are (a) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:3; (b) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11; (c) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19; (d) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27; (e) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35; (f) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43; (g) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51; (h) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59; (i) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 67; (j) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75; (k) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 81, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 82, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83; (l) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 89, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91; (m) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 102, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 103, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104; (n) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 110, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 111, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112; (o) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120; (p) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 126, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 127, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128; (q) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136; (r) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 143, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144; (s) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 151, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; (t) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 219, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162; (u) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, 217 or 218; HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, 171, 172, 173, 220 or 222; HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, 174, 175, 176, 177, 178, 179, 180, 181, 221, 223, 224, 225, 226, 227, 228 or 229; (v) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 212, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; (w) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 210, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152; or (x) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 211, and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152 Includes.

[0214] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein are (a) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (b) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (c) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22; (d) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30; (e) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 36, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 37, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 38; (f) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (g) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 53, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 54; (h) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 61, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 62; (i) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; (j) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 76, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 77, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 78; (k) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 85, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 86; (l) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 93, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 94; (m) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 105, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107; (n) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; (o) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 121, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 122, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123; (p) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 129, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 130, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 131; (q) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 137, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 138, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 139; (r) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 145, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 147; (s) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155; (t) an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 167; or (u) LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14, 182, 183, 184, 185, 214, 215, or 216. Includes.

[0215] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein are (a) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:1, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:2, an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:3, an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:5, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:6; (b) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (c) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22; (d) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30; (e) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 33, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 36, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 37, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 38; (f) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 41, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 42, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 43, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 45, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 46; (g) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 49, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 50, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 51, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 53, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 54; (h) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 57, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 58, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 60, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 61, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 62; (i) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 65, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 67, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 68, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 69, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; (j) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 73, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 75, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 76, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 77, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 78; (k) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 81, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 82, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 85, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 86; (l) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 89, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 90, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 91, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 93, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 94; (m) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 102, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 103, an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104, an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 105, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 107; (n) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 110, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 111, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 113, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 115; (o) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 120, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 121, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 122, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 123; (p) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 126, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 127, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 129, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 130, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 131; (q) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 137, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 138, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 139; (r) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 143, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 145, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 147; (s) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 151, an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155; (t) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 171, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (u) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 172, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (v) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:173, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (w) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:174, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (x) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (y) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 176, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (z) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 177, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (aa) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 178, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (bb) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 179, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (cc) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:180, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (dd) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:181, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (ee) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:182; (ff) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:183; (gg) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 184; (hh) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185; (ii) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:220, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (jj) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 221, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (kk) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:222, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:180, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (ll) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:172, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:223, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (mm) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:171, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:224, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (nn) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:214; (oo) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 215; (pp) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:216; (qq) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 222, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 180, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 214; (rr) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:222, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:180, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:215; (ss) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:172, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:223, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:214; (tt) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:172, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:223, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:215; (uu) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (vv) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:226, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (ww) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:227, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (xx) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 228, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (yy) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:174, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (zz) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:9, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:229, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:14; (aaa) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 217, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (bbb) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 218, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (ccc) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 219, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 167; (ddd) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 212, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155; (eee) an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 210, an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155; or (fff) HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 211, HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152, LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 153, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 154, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 155 Includes.

[0216] The sequence numbers of the heavy chain (designated as "H") variable region, light chain (designated as "L") variable region, HCDR and LCDR of each of the above 19 monoclonal antibodies are set forth in Table 1 below. Unless otherwise indicated, the CDR boundaries described herein were defined or identified according to the Kabat convention. The amino acid sequences of each CDR of the 19 exemplary monoclonal antibodies are set forth in Table 2 below. The amino acid sequences of each VH and VL of the 19 exemplary monoclonal antibodies are set forth in Table 3 below.

[0217] [Table 1]

[0218] [Table 2-1] [Table 2-2] [Table 2-3]

[0219] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0220] Assuming that each of the 19 exemplary monoclonal antibodies binds to CD3 and that antigen-binding specificity is provided primarily by the CDR1, CDR2 and CDR3 regions, the HCDR1, HCDR2 and HCDR3 sequences and LCDR1, LCDR2 and LCDR3 sequences of each of the 19 exemplary monoclonal antibodies can be "mixed and matched" (i.e., CDRs from different antibodies can be mixed and matched, but each antibody must contain HCDR1, HCDR2 and HCDR3 and LCDR1, LCDR2 and LCDR3) to generate an anti-CD3 antibody or antigen-binding fragment thereof of the present disclosure. The CD3 binding of such "mixed and matched" antibodies can be tested using the binding assays described above and in the Examples. Preferably, when VH CDR sequences are mixed and matched, the HCDR1, HCDR2 and / or HCDR3 sequences from a particular VH sequence are replaced with a structurally similar CDR sequence(s). Similarly, when VL CDR sequences are mixed and matched, the LCDR1, LCDR2 and / or LCDR3 sequences from a particular VL sequence are preferably replaced with structurally similar CDR sequence(s).For example, the HCDR1 of antibodies 25-G12-G6-C12 and 40-C12-C10-E9 share some structural similarity and are therefore amenable to mix and match.It will be readily apparent to those skilled in the art that new VH and VL sequences can be created by replacing one or more VH and / or VL CDR sequences with structurally similar sequences from the CDR sequences disclosed herein for the 19 exemplary monoclonal antibodies.

[0221] It is known that CDR is involved in antigen binding.However, it has been found that not all six CDRs are essential or irreplaceable.In other words, it is possible to replace, change or modify one or more CDRs of each of the 19 exemplary monoclonal antibodies, and still retain the specific binding affinity to CD3.

[0222] In certain embodiments, the anti-CD3 antibodies and antigen-binding fragments provided herein comprise the heavy chain CDR3 sequence of one of the anti-CD3 antibodies 25-G12-G6-C12, 40-C12-C10-E9, 8-B12-F9-B11, 31-F8-F5-C5, 16-F2-C11-D9, 20-E11-E11-C2, 7-D9-G10-H2, 7-D8-G12-E4, 2-F12-A6-G2, 3-C6-C11-F12, 4-F12-F1-A4, 3-F3-G12-E2, 124E3D6, 126A11A4, 127E2D3, 133B4C7, 140D2B10, 147C6F3, and 147E11E2. In certain embodiments, the anti-CD3 antibodies and antigen-binding fragments provided herein comprise heavy chain CDR3 sequences selected from the group consisting of SEQ ID NOs: 3, 11, 19, 27, 35, 43, 51, 59, 67, 75, 83, 91, 104, 112, 120, 128, 136, 144 and 152. The heavy chain CDR3 region is located at the center of the antigen-binding site, and is therefore considered to have the most contact with the antigen and provide the most free energy for the affinity of the antibody to the antigen. Similarly, the heavy chain CDR3 is considered to be the most diverse CDR of the antigen-binding site in terms of length, amino acid composition and conformation through multiple diversification mechanisms (Tonegawa S.Nature.302:575-81). Diversity in the heavy chain CDR3 is sufficient to generate most antibody specificities (Xu JL, Davis MM. Immunity. 13:37-45) as well as desired antigen binding affinities (Schier R, et al., J Mol Biol. 263:551-67).

[0223] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein are selected from the group consisting of SEQ ID NOs: 7, 15, 23, 31, 39, 47, 55, 63, 71, 79, 87, 95, 108, 116, 124, 132, 140, 148, 156, 163, 164, 165, 166, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 300, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 3, 194, 195, 196, 213, 202, 203, 204, 205, 206, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244 or 245, or a VH region having the amino acid sequence set forth in SEQ ID NO: 7, 15, 23, 31, 39, 47, 55, 63, 71, 79, 87, 95 , 108, 116, 124, 132, 140, 148, 156, 163, 164, 165, 166, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 213, 202, 203, 204, 205, 206, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244 or 245 and its homologous sequences having at least 80% (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity to said sequence.

[0224] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein comprise a VL region having an amino acid sequence set forth in SEQ ID NO: 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 109, 117, 125, 133, 141, 149, 157, 168, 169, 170, 197, 198, 199, 200, 207, 208, 209, 230, 231, or 232, or a VL region having an amino acid sequence set forth in SEQ ID NO: 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96 , 109, 117, 125, 133, 141, 149, 157, 168, 169, 170, 197, 198, 199, 200, 207, 208, 209, 230, 231 or 232 and its homologous sequences having at least 80% (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) sequence identity.

[0225] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein are selected from the group consisting of SEQ ID NOs: 7 / 8, 15 / 16, 23 / 24, 31 / 32, 39 / 40, 47 / 48, 55 / 56, 63 / 64, 71 / 72, 79 / 80, 87 / 88, 95 / 96, 108 / 109, 116 / 117, 124 / 125, 132 / 133, 140 / 141, 148 / 149, 156 / 1 57, 163 / 168, 163 / 169, 163 / 170, 164 / 168, 164 / 169, 164 / 170, 165 / 168, 165 / 169, 165 / 170, 166 / 168, 166 / 169, 166 / 170, 186 / 169, 187 / 169, 188 / 169, 189 / 169, 190 / 169, 191 / 169, 192 / 169, 193 / 169, 19 4 / 169, 195 / 169, 196 / 169, 165 / 197, 165 / 198, 165 / 199, 165 / 200, 202 / 207, 202 / 208, 202 / 209, 203 / 207, 203 / 208, 203 / 209, 204 / 207, 205 / 207, 206 / 207, 206 / 208, 206 / 209, 233 / 169, 234 / 169, 235 / 169 , 236 / 169, 237 / 169, 238 / 169, 239 / 169, 240 / 169, 241 / 169, 242 / 169, 243 / 169, 244 / 169, 245 / 169, 165 / 230, 165 / 231, 165 / 232, 235 / 230, 235 / 231, 236 / 230 and 236 / 231.

[0226] In certain embodiments, the antibodies and antigen-binding fragments thereof provided herein comprise suitable framework region (FR) sequences, so long as the antibodies and antigen-binding fragments thereof can specifically bind to CD3. The CDR sequences provided in Table 2 above are derived from mouse antibodies, but they can be grafted into any suitable FR sequence of any suitable species, such as mouse, human, rat, rabbit, among others, using suitable methods known in the art, such as recombinant techniques.

[0227] In certain embodiments, the antibody and its antigen-binding fragments provided herein are humanized. Humanized antibodies or their antigen-binding fragments are desirable due to their reduced immunogenicity in humans. Humanized antibodies are chimeric in their variable regions because non-human CDR sequences are grafted into human or substantially human FR sequences. Humanization of antibodies or antigen-binding fragments can essentially be performed by substituting non-human (e.g., murine) CDR genes for the corresponding human CDR genes in human immunoglobulin genes (see, for example, Jones et al., (1986) Nature 321:522-525; Riechmann et al., (1988) Nature 332:323-327; Verhoeyen et al., (1988) Science 239:1534-1536).

[0228] Suitable human heavy and light chain variable domains can be selected to achieve this goal using methods known in the art. In an illustrative example, a "best fit" approach can be used, where a non-human (e.g., rodent) antibody variable domain sequence is screened or BLASTed against a database of known human variable domain sequences, and the human sequence that is closest to the non-human query sequence is identified and used as a human scaffold for grafting the non-human CDR sequence (see, for example, Sims et al., (1993) J.Immunol.151:2296; Chothia et al., (1987) J.Mot.Biol.196:901). Alternatively, a framework derived from the consensus sequence of all human antibodies may be used to graft non-human CDRs (see, e.g., Carter et al., (1992) Proc. Natl. Acad. Sci. USA, 89:4285; Presta et al., (1993) J. Immunol., 151:2623).

[0229] In some embodiments, the anti-CD3 antibody or antigen-binding fragment thereof provided herein is humanized. In certain embodiments, the humanized antibody or antigen-binding fragment thereof provided herein is composed of substantially all human sequences, except for the CDR sequences, which are non-human. In some embodiments, the variable region, FR, and, if present, the constant region are derived entirely or substantially from human immunoglobulin sequences. The human FR sequences and the human constant region sequences may be derived from different human immunoglobulin genes, for example, the FR region may be derived from one human antibody and the constant region may be derived from another human antibody. In some embodiments, the humanized antibody or antigen-binding fragment thereof comprises human heavy chains HFR1, HFR2, HFR3 and HFR4, and / or light chains LFR1, LFR2, LFR3 and LFR4.

[0230] In some embodiments, the FR region derived from a human may contain the same amino acid sequence as the human immunoglobulin from which it is derived. In some embodiments, one or more amino acid residues of the human FR are replaced with the corresponding residues from the parent non-human antibody. This may be desirable in certain embodiments to make the humanized antibody or fragment thereof more closely resemble the non-human parent antibody structure and optimize the binding characteristics (e.g., increase binding affinity). In certain embodiments, the humanized antibody or antigen-binding fragment thereof provided herein contains no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid residue substitutions in each of the human FR sequences, or no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid residue substitutions in all of the FR sequences of the heavy or light chain variable domains. In some embodiments, such changes in amino acid residues may be present only in the heavy chain FR region, only in the light chain FR region, or in both chains. In certain embodiments, one or more amino acids of the human FR sequence are randomly mutated to increase binding affinity. In certain embodiments, one or more amino acids of the human FR sequences are backmutated to the corresponding amino acid(s) of the parent non-human antibody to increase binding affinity.

[0231] In some embodiments, one, two, three, or four amino acids at positions selected from the group consisting of 45, 46, 48, and 70 (corresponding to positions 46, 47, 49, and 71, respectively, according to the Kabat numbering, or 52, 53, 55, and 87, respectively, according to the IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein compared to SEQ ID NO: 168 are backmutated to the corresponding amino acid(s) of the parent murine antibody.

[0232] For example, one amino acid at position 45 (corresponding to position 46 according to Kabat numbering or position 52 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid(s) of the parent mouse antibody compared to SEQ ID NO: 168. In one embodiment, the leucine at position 45 (corresponding to position 46 according to Kabat numbering or position 52 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody. In another embodiment, the leucine at position 45 (corresponding to position 46 according to Kabat numbering or position 52 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to arginine (i.e., L45R).

[0233] In another example, one amino acid at position 46 (corresponding to position 47 according to Kabat numbering or position 53 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 168. In one embodiment, the leucine at position 46 (corresponding to position 47 according to Kabat numbering or position 53 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 168. In another embodiment, the leucine at position 46 (corresponding to position 47 according to Kabat numbering or position 53 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to tryptophan (i.e., L46W).

[0234] In yet another example, one amino acid at position 48 (corresponding to position 49 according to Kabat numbering or position 55 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 168. In one embodiment, a lysine at position 48 (corresponding to position 49 according to Kabat numbering or position 55 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 168. In another embodiment, a lysine at position 48 (corresponding to position 49 according to Kabat numbering or position 55 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to a tyrosine (i.e., K48Y).

[0235] In yet another example, one amino acid at position 70 (corresponding to position 71 according to Kabat numbering or position 87 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 168. In one embodiment, the phenylalanine at position 70 (corresponding to position 71 according to Kabat numbering or position 87 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 168. In another embodiment, the phenylalanine at position 70 (corresponding to position 71 according to Kabat numbering or position 87 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to tyrosine (i.e., F70Y).

[0236] In yet another example, one amino acid at position 45 (corresponding to position 46 according to Kabat numbering or position 52 according to IMGT numbering) and one amino acid at position 48 (corresponding to position 49 according to Kabat numbering or position 55 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are back-mutated to the corresponding amino acid of the parent mouse antibody. In one embodiment, a leucine at position 45 (corresponding to position 46 according to Kabat numbering or position 52 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein and a lysine at position 48 (corresponding to position 49 according to Kabat numbering or position 55 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are back-mutated to the corresponding amino acid of the parent mouse antibody. In another embodiment, the leucine at position 45 compared to SEQ ID NO: 168 (corresponding to position 46 according to Kabat numbering, or position 52 according to IMGT numbering) and the lysine at position 48 compared to SEQ ID NO: 168 (corresponding to position 49 according to Kabat numbering, or position 55 according to IMGT numbering) of the human light chain FR sequence of a humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are back-mutated to arginine and tyrosine, respectively (i.e., L45R+K48Y).

[0237] In yet another example, the amino acids at positions 45, 46, 48 and 70 (corresponding to positions 46, 47, 49 and 71, respectively, according to Kabat numbering, or corresponding to positions 52, 53, 55 and 87, respectively, according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are backmutated to the corresponding amino acids of the parent mouse antibody, as compared to SEQ ID NO: 168. In one embodiment, the leucine, leucine, lysine and phenylalanine at positions 45, 46, 48 and 70 (corresponding to positions 46, 47, 49 and 71, respectively, according to Kabat numbering, or corresponding to positions 52, 53, 55 and 87, respectively, according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are backmutated to the corresponding amino acids of the parent mouse antibody, as compared to SEQ ID NO: 168. In another embodiment, the leucine, leucine, lysine and phenylalanine at positions 45, 46, 48 and 70 (corresponding to positions 46, 47, 49 and 71, respectively, according to Kabat numbering, or 52, 53, 55 and 87, respectively, according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment provided herein are mutated to arginine, tryptophan, tyrosine and tyrosine, respectively, compared to SEQ ID NO: 168 (i.e., L45R+L46W+K48Y+F70Y).

[0238] In some embodiments, one, two, three, four, or five amino acids at a position(s) selected from the group consisting of 27, 48, 68, 70, and 72 (corresponding to positions 27, 48, 67, 69, and 71, respectively, according to the Kabat numbering, or 28, 53, 76, 78, and 80, respectively, according to the IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein compared to SEQ ID NO: 163 are backmutated to the corresponding amino acid(s) of the parent murine antibody.

[0239] For example, one amino acid at position 27 (corresponding to position 27 according to Kabat numbering or corresponding to position 28 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 163. In one embodiment, the glycine at position 27 (corresponding to position 27 according to Kabat numbering or corresponding to position 28 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 163. In another embodiment, the glycine at position 27 (corresponding to position 27 according to Kabat numbering or corresponding to position 28 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to tyrosine (i.e., G27Y).

[0240] In another example, one amino acid at position 48 (corresponding to position 48 according to Kabat numbering or corresponding to position 53 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 163. In one embodiment, the methionine at position 48 (corresponding to position 48 according to Kabat numbering or corresponding to position 53 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 163. In another embodiment, the methionine at position 48 (corresponding to position 48 according to Kabat numbering or corresponding to position 53 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to isoleucine (i.e., M48I).

[0241] In another example, one amino acid at position 68 (corresponding to position 67 according to Kabat numbering or corresponding to position 76 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 163. In one embodiment, a valine at position 68 (corresponding to position 67 according to Kabat numbering or corresponding to position 76 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 163. In another embodiment, a valine at position 68 (corresponding to position 67 according to Kabat numbering or corresponding to position 76 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to alanine (i.e., V68A).

[0242] In another example, one amino acid at position 70 (corresponding to position 69 according to Kabat numbering or corresponding to position 78 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 163. In one embodiment, the isoleucine at position 70 (corresponding to position 69 according to Kabat numbering or corresponding to position 78 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 163. In another embodiment, the isoleucine at position 70 (corresponding to position 69 according to Kabat numbering or corresponding to position 78 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to leucine (i.e., I70L).

[0243] In another example, one amino acid at position 72 (corresponding to position 71 according to Kabat numbering or corresponding to position 80 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 163. In one embodiment, the alanine at position 72 (corresponding to position 71 according to Kabat numbering or corresponding to position 80 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 163. In another embodiment, the alanine at position 72 (corresponding to position 71 according to Kabat numbering or corresponding to position 80 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to serine (i.e., A72S).

[0244] In yet another example, the amino acids at positions 27, 70 and 72 (corresponding to positions 27, 69 and 71, respectively, according to Kabat numbering, or corresponding to positions 28, 78 and 80, respectively, according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are back-mutated to the corresponding amino acids of the parent mouse antibody, compared to SEQ ID NO: 163. In one embodiment, the glycine, isoleucine and alanine at positions 27, 70 and 72 (corresponding to positions 27, 69 and 71, respectively, according to Kabat numbering, or corresponding to positions 28, 78 and 80, respectively, according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are mutated to tyrosine, leucine and serine, respectively (i.e., G27Y+I70L+A72S).

[0245] In yet another example, the amino acids at positions 27, 48, 68, 70 and 72 (corresponding to positions 27, 48, 67, 69 and 71, respectively, according to the Kabat numbering, or 28, 53, 76, 78 and 80, respectively, according to the IMGT numbering) of the human heavy chain FR sequence of a humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein, compared to SEQ ID NO: 163, are backmutated to the corresponding amino acids of the parent mouse antibody. In one embodiment, the glycine, methionine, valine, isoleucine and alanine at positions 27, 48, 68, 70 and 72 (corresponding to positions 27, 48, 67, 69 and 71, respectively, according to the Kabat numbering, or 28, 53, 76, 78 and 80, respectively, according to the IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are mutated to tyrosine, isoleucine, alanine, leucine and serine, respectively, compared to SEQ ID NO: 163 (i.e., G27Y+M48I+V68A+I70L+A72S).

[0246] In some embodiments, one, two, three, four, five, or six amino acids at a position(s) selected from the group consisting of 27, 30, 48, 68, 70, and 72 (corresponding to positions 27, 30, 48, 67, 69, and 71, respectively, according to the Kabat numbering, or 28, 35, 53, 76, 78, and 80, respectively, according to the IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein compared to SEQ ID NO:213 are backmutated to the corresponding amino acid(s) of the parent murine antibody.

[0247] For example, one amino acid at position 27 (corresponding to position 27 according to Kabat numbering or corresponding to position 28 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 213 (corresponding to position 27 according to Kabat numbering or corresponding to position 28 according to IMGT numbering). In one embodiment, the glycine at position 27 (corresponding to position 27 according to Kabat numbering or corresponding to position 28 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 213. In another embodiment, the glycine at position 27 (corresponding to position 27 according to Kabat numbering or corresponding to position 28 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to tyrosine (i.e., G27Y).

[0248] For another example, one amino acid at position 30 (corresponding to position 30 according to Kabat numbering or corresponding to position 35 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody compared to SEQ ID NO: 213 (corresponding to position 30 according to Kabat numbering or corresponding to position 35 according to IMGT numbering). In one embodiment, a serine at position 30 (corresponding to position 30 according to Kabat numbering or corresponding to position 35 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody compared to SEQ ID NO: 213. In another embodiment, a serine at position 30 (corresponding to position 30 according to Kabat numbering or corresponding to position 35 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to threonine (i.e., S30T).

[0249] As another example, one amino acid at position 48 (corresponding to position 48 according to Kabat numbering or corresponding to position 53 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 213 (corresponding to position 48 according to Kabat numbering or corresponding to position 53 according to IMGT numbering). In one embodiment, the methionine at position 48 (corresponding to position 48 according to Kabat numbering or corresponding to position 53 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 213. In another embodiment, the methionine at position 48 (corresponding to position 48 according to Kabat numbering or corresponding to position 53 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to isoleucine (i.e., M48I).

[0250] As another example, one amino acid at position 68 (corresponding to position 67 according to Kabat numbering or corresponding to position 76 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 213. In one embodiment, a valine at position 68 (corresponding to position 67 according to Kabat numbering or corresponding to position 76 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 213. In another embodiment, a valine at position 68 (corresponding to position 67 according to Kabat numbering or corresponding to position 76 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to alanine (i.e., V68A).

[0251] As another example, one amino acid at position 70 (corresponding to position 69 according to Kabat numbering or corresponding to position 78 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 213 (corresponding to position 69 according to Kabat numbering or corresponding to position 78 according to IMGT numbering). In one embodiment, the isoleucine at position 70 (corresponding to position 69 according to Kabat numbering or corresponding to position 78 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 213. In another embodiment, the isoleucine at position 70 (corresponding to position 69 according to Kabat numbering or corresponding to position 78 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to leucine (i.e., I70L).

[0252] As another example, one amino acid at position 72 (corresponding to position 71 according to Kabat numbering or corresponding to position 80 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 213. In one embodiment, an alanine at position 72 (corresponding to position 71 according to Kabat numbering or corresponding to position 80 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 213. In another embodiment, an alanine at position 72 (corresponding to position 71 according to Kabat numbering or corresponding to position 80 according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to valine (i.e., A72V).

[0253] As yet another example, the amino acids at positions 27 and 30 (corresponding to positions 27 and 30, respectively, according to Kabat numbering, or corresponding to positions 28 and 35, respectively, according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein compared to SEQ ID NO: 213 are backmutated to the corresponding amino acids of the parent mouse antibody. In one embodiment, the glycines and serine at positions 27 and 30 (corresponding to positions 27 and 30, respectively, according to Kabat numbering, or corresponding to positions 28 and 35, respectively, according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein compared to SEQ ID NO: 213 are backmutated to the corresponding amino acids of the parent mouse antibody, respectively. In another embodiment, the glycine and serine at positions 27 and 30 (corresponding to positions 27 and 30, respectively, according to the Kabat numbering, or positions 28 and 35, respectively, according to the IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are mutated to tyrosine and threonine, respectively, compared to SEQ ID NO: 213 (i.e., G27Y+S30T).

[0254] As yet another example, the amino acids at positions 27, 30, 70, and 72 (corresponding to positions 27, 30, 69, and 71, respectively, according to Kabat numbering, or corresponding to positions 28, 35, 78, and 80, respectively, according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are backmutated to the corresponding amino acids of the parent mouse antibody, as compared to SEQ ID NO: 213. In one embodiment, the glycine, serine, isoleucine, and alanine at positions 27, 30, 70, and 72 (corresponding to positions 27, 30, 69, and 71, respectively, according to Kabat numbering, or corresponding to positions 28, 35, 78, and 80, respectively, according to IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are backmutated to the corresponding amino acids of the parent mouse antibody, as compared to SEQ ID NO: 213. In another embodiment, the glycine, serine, isoleucine and alanine at positions 27, 30, 70 and 72 (corresponding to positions 27, 30, 69 and 71, respectively, according to the Kabat numbering, or positions 28, 35, 78 and 80, respectively, according to the IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein compared to SEQ ID NO: 213 are mutated to tyrosine, threonine, leucine and valine, respectively (i.e., G27Y+S30T+I70L+A72V).

[0255] As yet another example, the amino acids at positions 27, 30, 48, 68, 70, and 72 (corresponding to positions 27, 30, 48, 67, 69, and 71, respectively, according to the Kabat numbering, or positions 28, 35, 53, 76, 78, and 80, respectively, according to the IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein, compared to SEQ ID NO: 213, are backmutated to the corresponding amino acids of the parent mouse antibody. In one embodiment, the glycine, serine, methionine, valine, isoleucine and alanine at positions 27, 30, 48, 68, 70, and 72 (corresponding to positions 27, 30, 48, 67, 69, and 71, respectively, according to the Kabat numbering, or positions 28, 35, 53, 76, 78, and 80, respectively, according to the IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein compared to SEQ ID NO: 213 are back-mutated to the corresponding amino acids of the parent mouse antibody, respectively. In another embodiment, the glycine, serine, methionine, valine, isoleucine, and alanine at positions 27, 30, 48, 68, 70, and 72 (corresponding to positions 27, 30, 48, 67, 69, and 71, respectively, according to the Kabat numbering, or positions 28, 35, 53, 76, 78, and 80, respectively, according to the IMGT numbering) of the human heavy chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein are mutated to tyrosine, threonine, isoleucine, alanine, leucine, and valine, respectively, compared to SEQ ID NO: 213 (i.e., G27Y+S30T+M48I+V68A+I70L+A72V).

[0256] In some embodiments, one amino acid at position 49 (corresponding to position 43 according to Kabat numbering or corresponding to position 49 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 207. In one embodiment, the proline at position 49 (corresponding to position 43 according to Kabat numbering or corresponding to position 49 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to the corresponding amino acid of the parent mouse antibody, as compared to SEQ ID NO: 207. In another embodiment, the proline at position 49 (corresponding to position 43 according to Kabat numbering or corresponding to position 49 according to IMGT numbering) of the human light chain FR sequence of the humanized anti-CD3 antibody or antigen-binding fragment thereof provided herein is back-mutated to serine (i.e., P49S).

[0257] In some embodiments, the present disclosure provides a humanized antibody or antigen-binding fragment thereof of clone 40-C12-C10-E9 (also referred to in the present disclosure as "humanized 40-C12-C10-E9"). In some embodiments, the present disclosure provides twelve humanized 40-C12-C10-E9s designated as hu40E9-L1H1, hu40E9-L1H2, hu40E9-L1H3, hu40E9-L1H4, hu40E9-L2H1, hu40E9-L2H2, hu40E9-L2H3, hu40E9-L2H4, hu40E9-L3H1, hu40E9-L3H2, hu40E9-L3H3, and hu40E9-L3H4, respectively. The SEQ ID NOs for the heavy and light chain variable regions of each humanized 40-C12-C10-E9 are shown below in Table 20 (CDR sequences identified by the Kabat convention are underlined). Each of the 12 humanized 40-C12-C10-E9 clones contains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, which contain the amino acid sequences set forth in SEQ ID NOs: 9, 10, 11, 12, 13 and 14, respectively.

[0258] In some embodiments, the present disclosure provides a humanized antibody or antigen-binding fragment thereof of clone 147E11E2 (also referred to in the present disclosure as "humanized 147E11E2"). In some embodiments, the present disclosure provides eleven humanized 147E11E2s designated as hu147E2-L1H2, hu147E2-L1H3, hu147E2-L1H3a, hu147E2-L1H3b, hu147E2-L1H4, hu147E2-L2H2, hu147E2-L2H3, hu147E2-L2H4, hu147E2-L3H2, hu147E2-L3H3 and hu147E2-L3H4, respectively. The SEQ ID NOs for the heavy and light chain variable regions of each humanized 147E11E2 are shown below in Table 20 (CDR sequences identified by the Kabat convention are underlined). Each of the eleven humanized 147E11E2 clones contains HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 that contain the amino acid sequences set forth in SEQ ID NOs: 150, 212, 152, 153, 154 and 155, respectively.

[0259] In some embodiments, some motifs susceptible to deamination (e.g., N55G56 motif) may be identified in one or more CDRs (e.g., HCDR2) of a humanized antibody or antigen-binding fragment thereof. Different mutations can be introduced into the motif to remove such deamidation sites, and still retain specific binding to CD3. In some embodiments, the deamidation site is identified in the amino acid sequence of hu147E2-H3 (i.e., SEQ ID NO: 203), which has the same CDRs as the heavy chain of clone 147E11E2. In some embodiments, one or more amino acids in one or more CDRs of the candidate antibody are mutated to remove the deamidation site. In some embodiments, the mutation occurs in the HCDR2 of the candidate antibody (e.g., at position 55 compared to SEQ ID NO: 213). Thus, the present disclosure provides an anti-CD3 antibody or antigen-binding fragment thereof, which has the same CDRs as clone 147E11E2, except that the amino acid sequence of HCDR2 is different. For example, an anti-CD3 antibody or antigen-binding fragment thereof provided herein comprises an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 212. In some embodiments, the disclosure provides humanized antibody hu147E2-L1H3a comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 210, which has a single mutation (i.e., N55Q) compared to the parent HCDR2 (i.e., SEQ ID NO: 151) to remove the deamination site NG motif. In some embodiments, the disclosure provides humanized antibody hu147E2-L1H3b comprising an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 211, which has a single mutation (i.e., N55S) compared to the parent HCDR2 (i.e., SEQ ID NO: 151) to remove the deamination site NG motif.

[0260] In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 212, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 152. In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 150, 212, 152, 153, 154, and 155, respectively. In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 150, 210, 152, 153, 154, and 155, respectively. In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 150, 211, 152, 153, 154 and 155, respectively. The amino acid sequences of SEQ ID NOs: 210, 211 and 212 are set forth in Table 22 below.

[0261] In some embodiments, the humanized antibody or antigen-binding fragment thereof provided herein comprises a VH region having an amino acid sequence set forth in SEQ ID NO: 163, 164, 165, 166, 213, 202, 203, 204, 205, 206, or a homologous sequence thereof having at least 80% (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identity to SEQ ID NO: 163, 164, 165, 166, 213, 202, 203, 204, 205 or 206. In some embodiments, the humanized antibody or antigen-binding fragment thereof provided herein comprises a VL region having an amino acid sequence set forth in SEQ ID NO: 168, 169, 170, 207, 208, 209, or a homologous sequence thereof having at least 80% (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identity to SEQ ID NO: 168, 169, 170, 207, 208 or 209.

[0262] The present disclosure also provides 1) "hu40E9-L1H1", which contains the heavy chain variable region of hu40E9-H1 (SEQ ID NO: 163) and the light chain variable region of hu40E9-L1 (SEQ ID NO: 168); 2) "hu40E9-L1H2" comprising the heavy chain variable region of hu40E9-H2 (SEQ ID NO: 164) and the light chain variable region of hu40E9-L1 (SEQ ID NO: 168); 3) "hu40E9-L1H3" comprising the heavy chain variable region of hu40E9-H3 (SEQ ID NO: 165) and the light chain variable region of hu40E9-L1 (SEQ ID NO: 168); 4) "hu40E9-L1H4" comprising the heavy chain variable region of hu40E9-H4 (SEQ ID NO: 166) and the light chain variable region of hu40E9-L1 (SEQ ID NO: 168); 5) "hu40E9-L2H1" comprising the heavy chain variable region of hu40E9-H1 (SEQ ID NO: 163) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 6) "hu40E9-L2H2" comprising the heavy chain variable region of hu40E9-H2 (SEQ ID NO: 164) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 7) "hu40E9-L2H3" comprising the heavy chain variable region of hu40E9-H3 (SEQ ID NO: 165) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 8) "hu40E9-L2H4" comprising the heavy chain variable region of hu40E9-H4 (SEQ ID NO: 166) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 9) "hu40E9-L3H1" comprising the heavy chain variable region of hu40E9-H1 (SEQ ID NO: 163) and the light chain variable region of hu40E9-L3 (SEQ ID NO: 170); 10) "hu40E9-L3H2" comprising the heavy chain variable region of hu40E9-H2 (SEQ ID NO: 164) and the light chain variable region of hu40E9-L3 (SEQ ID NO: 170); 11) "hu40E9-L3H3" comprising the heavy chain variable region of hu40E9-H3 (SEQ ID NO: 165) and the light chain variable region of hu40E9-L3 (SEQ ID NO: 170); or 12) "hu40E9-L3H4" comprising the heavy chain variable region of hu40E9-H4 (SEQ ID NO: 166) and the light chain variable region of hu40E9-L3 (SEQ ID NO: 170) Also provided is an exemplary humanized antibody of clone 40-C12-C10-E9, comprising:

[0263] The present disclosure also provides 1) "hu14E2-L1H2," comprising the heavy chain variable region of hu14E2-H2 (SEQ ID NO: 202) and the light chain variable region of hu14E2-L1 (SEQ ID NO: 207); 2) "hu14E2-L1H3," comprising the heavy chain variable region of hu14E2-H3 (SEQ ID NO: 203) and the light chain variable region of hu14E2-L1 (SEQ ID NO: 207); 3) "hu14E2-L1H3a," comprising the heavy chain variable region of hu14E2-H3a (SEQ ID NO: 204) and the light chain variable region of hu14E2-L1 (SEQ ID NO: 207); 4) "hu14E2-L1H3b" comprising the heavy chain variable region of hu14E2-H3b (SEQ ID NO: 205) and the light chain variable region of hu14E2-L1 (SEQ ID NO: 207); 5) "hu14E2-L1H4" comprising the heavy chain variable region of hu14E2-H4 (SEQ ID NO: 206) and the light chain variable region of hu14E2-L1 (SEQ ID NO: 207); 6) "hu14E2-L2H2" comprising the heavy chain variable region of hu14E2-H2 (SEQ ID NO: 202) and the light chain variable region of hu14E2-L2 (SEQ ID NO: 208); 7) "hu14E2-L2H3" comprising the heavy chain variable region of hu14E2-H3 (SEQ ID NO: 203) and the light chain variable region of hu14E2-L2 (SEQ ID NO: 208); 8) "hu14E2-L2H4" comprising the heavy chain variable region of hu14E2-H4 (SEQ ID NO: 206) and the light chain variable region of hu14E2-L2 (SEQ ID NO: 208); 9) "hu14E2-L3H2" comprising the heavy chain variable region of hu14E2-H2 (SEQ ID NO: 202) and the light chain variable region of hu14E2-L3 (SEQ ID NO: 209); 10) "hu14E2-L3H3" comprising the heavy chain variable region of hu14E2-H3 (SEQ ID NO: 203) and the light chain variable region of hu14E2-L3 (SEQ ID NO: 209); or 11) "hu14E2-L3H4" comprising the heavy chain variable region of hu14E2-H4 (SEQ ID NO: 206) and the light chain variable region of hu14E2-L3 (SEQ ID NO: 209) Also provided is an exemplary humanized antibody of clone 147E211E2 comprising:

[0264] [Table 20-1] [Table 20-2] [Table 20-3]

[0265] The present disclosure also provides a humanized, affinity-improved antibody or antigen-binding fragment thereof that specifically binds to CD3. In some embodiments, affinity maturation is performed based on the sequences of hu40E9-H3 and hu40E9-L2, which have the same CDRs as clone 40-C12-C10-E9. In some embodiments, one or more amino acids within one or more CDRs of the candidate antibody are mutated to improve affinity, for example, the mutations occur within HCDR1 (e.g., positions 31-33 compared to SEQ ID NO: 165), HCDR2 (e.g., positions 54-56 compared to SEQ ID NO: 165), HCDR3 (e.g., positions 99-106 compared to SEQ ID NO: 165), or LCDR3 (e.g., positions 91-93 compared to SEQ ID NO: 169) of the candidate antibody. Thus, the present disclosure provides an anti-CD3 antibody or antigen-binding fragment thereof that has the same CDRs as clone 40-C12-C10-E9, except that the amino acid sequences of HCDR1, HCDR2, HCDR3 and / or LCDR3 are different.

[0266] In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 219. In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, 217 or 218.

[0267] In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201. In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, 171, 172, 173, 220 or 222.

[0268] In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162. In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, 174, 175, 176, 177, 178, 179, 180, 181, 221, 223, 224, 225, 226, 227, 228, or 229.

[0269] In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14, 182, 183, 184, 185, 214, 215, or 216.

[0270] In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 219, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 201, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162. In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences set forth in SEQ ID NOs: 219, 201, 162, 12, 13, and 167, respectively.

[0271] In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, 217 or 218; an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, 171, 172, 173, 220 or 222; and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, 174, 175, 176, 177, 178, 179, 180, 181, 221, 223, 224, 225, 226, 227, 228 or 229. In some embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14, 182, 183, 184, 185, 214, 215 or 216. In some embodiments, an anti-CD3 antibody or antigen-binding fragment thereof provided herein comprises an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, 217 or 218; an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, 171, 172, 173, 220 or 222; an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, 174, 175, 176, 177, 178, 179, 180, 181, 221, 223, 224, 225, 226, 227, 228 or 229; an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14, 182, 183, 184, 185, 214, 215 or 216.

[0272] The amino acid sequences of SEQ ID NOs: 171-185, 201, 162, 167 and 214-229 are shown in Table 22 below. As shown in Table 22 below, each of the hu40E9 HCDRs contains one or more mutations compared to its corresponding HCDR contained in hu40E9-H3 (i.e., SEQ ID NO: 165), and the mutated amino acid(s) are underlined; similarly, each of the hu40E9 LCDR3s contains one or more mutations compared to the LCDR3 contained in hu40E9-L2 (i.e., SEQ ID NO: 169), and the mutated amino acid(s) are also underlined; similarly, each of the hu147E2 HCDR2s contains one mutation compared to the HCDR2 contained in hu40E9-H3 (i.e., SEQ ID NO: 165), and the mutated amino acid(s) are also underlined.

[0273] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to CD3, the antibody or antigen-binding fragment thereof comprising one or two or three HCDRs contained within any one of the VH region sequences selected from the group consisting of SEQ ID NOs: 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244 and 245; and / or one or two or three LCDRs contained within any one of the VL region sequences selected from the group consisting of SEQ ID NOs: 197, 198, 199, 200, 230, 231 and 232. In some embodiments, the disclosure also provides an anti-CD3 antibody or antigen-binding fragment thereof comprising an HCDR1, HCDR2 and HCDR3 contained within any one of the VH region sequences selected from the group consisting of SEQ ID NOs: 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244 and 245; and an LCDR1, LCDR2 and LCDR3 contained within any one of the VL region sequences selected from the group consisting of SEQ ID NOs: 197, 198, 199, 200, 230, 231 and 232.

[0274] In some embodiments, the disclosure provides an antibody or antigen-binding fragment thereof that specifically binds to CD3, comprising one or two or three HCDRs contained within any one of the VH region sequences selected from the group consisting of SEQ ID NOs: 213, 202, 203, 204, 205, and 206; and / or one or two or three LCDRs contained within any one of the VL region sequences selected from the group consisting of SEQ ID NOs: 207, 208, and 209. In some embodiments, the disclosure also provides an anti-CD3 antibody or antigen-binding fragment thereof that comprises HCDR1, HCDR2, and HCDR3 contained within any one of the VH region sequences selected from the group consisting of SEQ ID NOs: 213, 202, 203, 204, 205, and 206; and LCDR1, LCDR2, and LCDR3 contained within any one of the VL region sequences selected from the group consisting of SEQ ID NOs: 207, 208, and 209.

[0275] The amino acid sequences of SEQ ID NOs: 186-200 and 230-245 are shown in Table 21 below. As shown in Table 21 below, each of the VH regions contains one, two, or three mutations compared to the amino acid sequence of hu40E9-H3 (i.e., SEQ ID NO: 165), with the mutated amino acid(s) underlined; similarly, each of the VL regions contains one or two mutations compared to the amino acid sequence of hu40E9-L2 (i.e., SEQ ID NO: 169), with the mutated amino acid(s) underlined.

[0276] [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4] [Table 21-5]

[0277] [Table 22-1] [Table 22-2] [Table 22-3]

[0278] The present disclosure relates to 1) "hu40E9-L2H3-N55S.H" comprising the heavy chain variable region of hu40E9-H3-N55S.H (SEQ ID NO: 186) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 2) "hu40E9-L2H3-D99E.H," comprising the heavy chain variable region of hu40E9-H3-D99E.H (SEQ ID NO: 187) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 3) "hu40E9-L2H3-Y101F.H," comprising the heavy chain variable region of hu40E9-H3-Y101F.H (SEQ ID NO: 188) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 4) "hu40E9-L2H3-D105E.H," comprising the heavy chain variable region of hu40E9-H3-D105E.H (SEQ ID NO: 189) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 5) "hu40E9-L2H3-G106A.H," comprising the heavy chain variable region of hu40E9-H3-G106A.H (SEQ ID NO: 190) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 6) "hu40E9-L2H3-Y54G.H" comprising the heavy chain variable region of hu40E9-H3-Y54G.H (SEQ ID NO: 191) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 7) "hu40E9-L2H3-D56G.H" comprising the heavy chain variable region of hu40E9-H3-D56G.H (SEQ ID NO: 192) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 8) "hu40E9-L2H3-D99R.H" comprising the heavy chain variable region of hu40E9-H3-D99R.H (SEQ ID NO: 193) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 9) "hu40E9-L2H3-S100R.H" comprising the heavy chain variable region of hu40E9-H3-S100R.H (SEQ ID NO: 194) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 10) "hu40E9-L2H3-Y102S.H" comprising the heavy chain variable region of hu40E9-H3-Y102S.H (SEQ ID NO: 195) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 11) "hu40E9-L2H3-D105R.H" comprising the heavy chain variable region of hu40E9-H3-D105R.H (SEQ ID NO: 196) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 12) "hu40E9-L2H3-N93S.L" comprising the heavy chain variable region of hu40E9-H3 (SEQ ID NO: 165) and the light chain variable region of hu40E9-L2-N93S.L (SEQ ID NO: 197); 13) "hu40E9-L2H3-S91R.L" comprising the heavy chain variable region of hu40E9-H3 (SEQ ID NO: 165) and the light chain variable region of hu40E9-L2-S91R.L (SEQ ID NO: 198); 14) "hu40E9-L2H3-N93R.L" comprising the heavy chain variable region of hu40E9-H3 (SEQ ID NO: 165) and the light chain variable region of hu40E9-L2-N93R.L (SEQ ID NO: 199); 15) "hu40E9-L2H3-N93W.L" comprising the heavy chain variable region of hu40E9-H3 (SEQ ID NO: 165) and the light chain variable region of hu40E9-L2-N93W.L (SEQ ID NO: 200); 16) "hu40E9-L2H5" comprising the heavy chain variable region of hu40E9-H5 (SEQ ID NO: 233) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 17) "hu40E9-L2H6" comprising the heavy chain variable region of hu40E9-H6 (SEQ ID NO: 234) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 18) "hu40E9-L2H7" comprising the heavy chain variable region of hu40E9-H7 (SEQ ID NO: 235) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 19) "hu40E9-L2H8" comprising the heavy chain variable region of hu40E9-H8 (SEQ ID NO: 236) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 20) "hu40E9-L2H9" comprising the heavy chain variable region of hu40E9-H9 (SEQ ID NO: 237) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 21) "hu40E9-L2H10" comprising the heavy chain variable region of hu40E9-H10 (SEQ ID NO: 238) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 22) "hu40E9-L2H11" comprising the heavy chain variable region of hu40E9-H11 (SEQ ID NO: 239) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 23) "hu40E9-L2H12" comprising the heavy chain variable region of hu40E9-H12 (SEQ ID NO: 240) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 24) "hu40E9-L2H13" comprising the heavy chain variable region of hu40E9-H13 (SEQ ID NO: 241) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 25) "hu40E9-L2H14" comprising the heavy chain variable region of hu40E9-H14 (SEQ ID NO: 242) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 26) "hu40E9-L2H15" comprising the heavy chain variable region of hu40E9-H15 (SEQ ID NO: 243) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 27) "hu40E9-L2H16" comprising the heavy chain variable region of hu40E9-H16 (SEQ ID NO: 244) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 28) "hu40E9-L2H17" comprising the heavy chain variable region of hu40E9-H17 (SEQ ID NO: 245) and the light chain variable region of hu40E9-L2 (SEQ ID NO: 169); 29) "hu40E9-L4H3" comprising the heavy chain variable region of hu40E9-H3 (SEQ ID NO: 165) and the light chain variable region of hu40E9-L4 (SEQ ID NO: 230); 30) "hu40E9-L5H3" comprising the heavy chain variable region of hu40E9-H3 (SEQ ID NO: 165) and the light chain variable region of hu40E9-L5 (SEQ ID NO: 231); 31) "hu40E9-L6H3" comprising the heavy chain variable region of hu40E9-H3 (SEQ ID NO: 165) and the light chain variable region of hu40E9-L6 (SEQ ID NO: 232); 32) "hu40E9-L4H7" comprising the heavy chain variable region of hu40E9-H7 (SEQ ID NO: 235) and the light chain variable region of hu40E9-L4 (SEQ ID NO: 230); 33) "hu40E9-L4H8" comprising the heavy chain variable region of hu40E9-H8 (SEQ ID NO: 236) and the light chain variable region of hu40E9-L4 (SEQ ID NO: 230); 34) "hu40E9-L5H7" comprising the heavy chain variable region of hu40E9-H7 (SEQ ID NO: 235) and the light chain variable region of hu40E9-L5 (SEQ ID NO: 231); or 35) "hu40E9-L5H8" comprising the heavy chain variable region of hu40E9-H8 (SEQ ID NO: 236) and the light chain variable region of hu40E9-L5 (SEQ ID NO: 231) Further provided are exemplary humanized and affinity-improved antibodies of clone 40-C12-C10-E9, including:

[0279] In some embodiments, the anti-CD3 antibodies and antigen-binding fragments provided herein comprise all or a portion of the heavy chain variable domain and / or all or a portion of the light chain variable domain. In one embodiment, the anti-CD3 antibodies or antigen-binding fragments provided herein are single-domain antibodies consisting of all or a portion of the heavy chain variable domain provided herein. More information on such single-domain antibodies is available in the art (see, for example, U.S. Patent No. 6,248,516).

[0280] In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein further comprise an Fc region. In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein further comprise an Fc region of a human immunoglobulin (Ig). In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein further comprise a constant region, optionally further comprising a heavy chain and / or a light chain constant region. In certain embodiments, the heavy chain constant region comprises a CH1, hinge, and / or a CH2-CH3 region (or optionally a CH2-CH3-CH4 region). In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise a heavy chain constant region of a human IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, or IgM. In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise a lambda (λ) light chain or a kappa (κ) light chain. The constant regions of the anti-CD3 antibodies or antigen-binding fragments thereof provided herein may be identical to the wild-type constant region sequences or may differ by one or more mutations.

[0281] In certain embodiments, the heavy chain constant region comprises an Fc region. The Fc region is known to mediate effector functions such as ADCC and complement-dependent cytotoxicity (CDC) of antibodies. The Fc regions of different Ig isotypes have different abilities to induce effector functions. For example, it is recognized that the Fc regions of IgG1 and IgG3 induce both ADCC and CDC more effectively than the Fc regions of IgG2 and IgG4. In certain embodiments, the anti-CD3 antibodies and antigen-binding fragments thereof provided herein comprise an Fc region of an IgG1 or IgG3 isotype that can induce ADCC or CDC; or alternatively, a constant region of an IgG4 or IgG2 isotype that reduces or depletes effector functions. In some embodiments, the Fc region was derived from human IgG1. In some embodiments, the Fc region was derived from human IgG1 with enhanced effector functions. In some embodiments, the Fc region comprises the amino acid sequence set forth in SEQ ID NO:97. [ka]

[0282] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein have sufficient specific binding affinity for human CD3 to provide diagnostic and / or therapeutic uses.

[0283] The antibodies or antigen-binding fragments thereof provided herein can be monoclonal, polyclonal, humanized, human, chimeric, recombinant, bispecific, multispecific, labeled, bivalent, anti-idiotypic, or fusion proteins. Recombinant antibodies are antibodies prepared in vitro using recombinant methods, rather than in animals.

[0284] In certain embodiments, the present disclosure provides anti-CD3 antibodies or antigen-binding fragments thereof that compete with the antibodies or antigen-binding fragments thereof provided herein for binding to CD3. In certain embodiments, the present disclosure provides antibodies 25-G12-G6-C12, 40-C12-C10-E9, 8-B12-F9-B11, 31-F8-F5-C5, 16-F2-C11-D9, 20-E11-E11-C2, 7-D9-G10-H2, 7-D8-G12-E4, 2-F12-A6-G2, 3-C6-C11-F12, 4-F12- F1-A4, 3-F3-G12-E2, 124E3D6, 126A11A4, 127E2D3, 133B4C7, 140D2B10, 147C6F3, 147E11E2, hu40E9-L 1H1, hu40E9-L1H2, hu40E9-L1H3, hu40E9-L1H4, hu40E9-L2H1, hu40E9-L2H2, hu40E9-L2H3, hu40E9-L2 H4, hu40E9-L3H1, hu40E9-L3H2, hu40E9-L3H3, hu40E9-L3H4, hu40E9-L2H3-N55S.H, hu40E9-L2H3-D99 E.H, hu40E9-L2H3-Y101F.H, hu40E9-L2H3-D105E.H, hu40E9-L2H3-G106A.H, hu40E9-L2H3-Y54G.H, hu 40E9-L2H3-D56G.H, hu40E9-L2H3-D99R.H, hu40E9-L2H3-S100R.H, hu40E9-L2H3-Y102S.H, hu40E9-L2 H3-D105R.H, hu40E9-L2H3-N93S.L, hu40E9-L2H3-S91R.L, hu40E9-L2H3-N93R.L, hu40E9-L2H3-N93W.L, hu40E9-L2H5, hu40E9-L2H6, hu40E9-L2H7, hu40E9-L2H8, hu40E9-L2H9, hu40E9-L2H10, hu40E9-L2H11, hu40E9-L2H12, hu40E9- L2H13, hu40E9-L2H14, hu40E9-L2H15, hu40E9-L2H16, hu40E9-L2H17, hu40E9-L4H3, hu40E9-L5H3, hu40E9-L6H3, hu40E9-L4H7, hu In some embodiments, the present disclosure provides an anti-CD3 antibody or antigen-binding fragment thereof that competes with any one of the following antibodies or antigen-binding fragments: 40E9-L4H8, hu40E9-L5H7, hu40E9-L5H8, hu147E2-L1H2, hu147E2-L1H3, hu147E2-L1H3a, hu147E2-L1H3b, hu147E2-L1H4, hu147E2-L2H2, hu147E2-L2H3, hu147E2-L2H4, hu147E2-L3H2, hu147E2-L3H3, and hu147E2-L3H4. In some embodiments, the present disclosure provides an anti-CD3 antibody or antigen-binding fragment thereof that competes with an antibody or antigen-binding fragment thereof provided herein for the same epitope.

[0285] The ability to "block binding" or "compete for binding", as used herein, refers to the ability of an antibody or antigen-binding fragment to inhibit the binding interaction between two molecules (e.g., human CD3 and an anti-CD3 antibody) to any detectable degree. In certain embodiments, the antibody or antigen-binding fragment thereof blocks the binding between the two molecules and inhibits the binding interaction between the two molecules by at least 85% or at least 90%. In certain embodiments, the inhibition may be greater than 85% or greater than 90%.

[0286] Those of skill in the art will appreciate that human monoclonal antibodies may be used in combination with the antibodies of the present disclosure (e.g., murine monoclonal antibodies 25-G12-G6-C12, 40-C12-C10-E9, 8-B12-F9-B11, 31-F8-F5-C5, 16-F2-C11-D9, 20-E11-E11-C2, 7-D9-G10-H2, 7-D8-G12-E4, 2-F12-A6-G2, 3-C6-C11-F12, 4 -F12-F1-A4, 3-F3-G12-E2, 124E3D6, 126A11A4, 127E2D3, 133B4C7, 140D2B10, 147C6F3, 147E11E2, hu40 E9-L1H1, hu40E9-L1H2, hu40E9-L1H3, hu40E9-L1H4, hu40E9-L2H1, hu40E9-L2H2, hu40E9-L2H3, hu40E9 -L2H4, hu40E9-L3H1, hu40E9-L3H2, hu40E9-L3H3, hu40E9-L3H4, hu40E9-L2H3-N55S.H, hu40E9-L2H3- D99E.H, hu40E9-L2H3-Y101F.H, hu40E9-L2H3-D105E.H, hu40E9-L2H3-G106A.H, hu40E9-L2H3-Y54G.H, hu40E9-L2H3-D56G.H, hu40E9-L2H3-D99R.H, hu40E9-L2H3-S100R.H, hu40E9-L2H3-Y102S.H, hu40E9-L 2H3-D105R.H, hu40E9-L2H3-N93S.L, hu40E9-L2H3-S91R.L, hu40E9-L2H3-N93R.L, hu40E9-L2H3-N93W.L,hu40E9-L2H5,hu40E9-L2H6,hu40E9-L2H7,hu40E9-L2H8,hu40E9-L2H9,hu40E9-L2H10,hu40E9-L2H11,hu40E9-L2H12,hu40E9-L2H13,hu40E9-L2 H14, hu40E9-L2H15, hu40E9-L2H16, hu40E9-L2H17, hu40E9-L4H3, hu40E9-L5H3, hu40E9-L6H3, hu40E9-L4H7, hu40E9-L4H8, hu40E9-L5H7, hu40E9-L It will be appreciated that if a test antibody binds to the same epitope as an antibody of the present disclosure (e.g., 5H8, hu147E2-L1H2, hu147E2-L1H3, hu147E2-L1H3a, hu147E2-L1H3b, hu147E2-L1H4, hu147E2-L2H2, hu147E2-L2H3, hu147E2-L2H4, hu147E2-L3H2, hu147E2-L3H3 and hu147E2-L3H4), this can be determined without undue experimentation by determining whether the former prevents the latter from binding to a CD3 antigen polypeptide. If the test antibody competes with an antibody of the present disclosure, as indicated by a decrease in binding to a CD3 antigen polypeptide by the antibody of the present disclosure, then the two antibodies bind to the same or closely related epitopes. Or, if binding of the test antibody to the CD3 antigen polypeptide is inhibited by an antibody of the present disclosure, then the two antibodies bind to the same or closely related epitopes.

[0287] In certain embodiments, the present disclosure provides anti-CD3 antibodies or antigen-binding fragments thereof that have higher or equivalent binding affinity to CD3 (e.g., human CD3 or cynomolgus CD3) compared to OKT3, BMK-B219 and / or BMK-TCB.

[0288] In certain embodiments, an anti-CD3 antibody or antigen-binding fragment that competes with an antibody or antigen-binding fragment thereof provided herein for binding to CD3 is not OKT3, BMK-B219, or BMK-TCB.

[0289] "OKT3," as used herein, refers to an antibody or antigen-binding fragment thereof comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 100 and a light chain variable region having the amino acid sequence of SEQ ID NO: 101. The CDR sequences are underlined in SEQ ID NO: 100 and SEQ ID NO: 101, respectively. [ka]

[0290] "BMK-B219" as used herein refers to an antibody or antigen-binding fragment thereof comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 158 and a light chain variable region having the amino acid sequence of SEQ ID NO: 159. The CDR sequences are underlined in SEQ ID NO: 158 and SEQ ID NO: 159, respectively. [ka]

[0291] "BMK-TCB" as used herein refers to an antibody or antigen-binding fragment thereof comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 160 and a light chain variable region having the amino acid sequence of SEQ ID NO: 161. The CDR sequences are underlined in SEQ ID NO: 160 and SEQ ID NO: 161, respectively. [ka]

[0292] Antibody variants The antibodies and antigen-binding fragments thereof provided herein also encompass various variants of the antibody sequences provided herein.

[0293] In certain embodiments, the antibody variant comprises one or more amino acid residue substitutions or modifications, but still retains specific binding affinity to CD3. In certain embodiments, at least one of the substitutions or modifications is present in one or more of the CDR sequences of the VH or VL region. In certain embodiments, at least one of the substitutions or modifications is present in one or more of the non-CDR sequences of the VH or VL region. In certain embodiments, the antibody or antigen-binding fragment thereof provided herein further comprises one or more non-natural amino acid (NNAA) substitutions. In certain embodiments, the NNAA can be conjugated.

[0294] For example, an antibody variant comprises one or more amino acid residue substitutions or modifications in one or more of the CDR sequences provided in Table 2 above, one or more non-CDR sequences of the heavy or light chain variable regions provided in Table 3 above, and / or in the constant region (e.g., Fc region). Such variants retain the binding specificity for CD3 of their parent antibody, but have one or more desired properties conferred by the modification(s) or substitution(s). For example, an antibody variant may have improved antigen binding affinity, improved glycosylation pattern, reduced glycosylation risk, reduced deamination, enhanced effector function(s), improved FcRn receptor binding, increased pharmacokinetic half-life, pH sensitivity, and / or suitability for conjugation (e.g., one or more introduced cysteine ​​residues), etc.

[0295] The parent antibody sequence may be screened using methods known in the art, such as "alanine scanning mutagenesis," to identify suitable or preferred residues for modification or substitution (see, e.g., Cunningham and Wells (1989) Science, 244:1081-1085). Briefly, target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) can be identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine), and modified antibodies are produced and screened for the desired properties. If substitutions at a particular amino acid position demonstrate the desired functional change, that position can be identified as a potential residue for modification or substitution. Potential residues may be further evaluated by substituting different types of residues (e.g., cysteine ​​residues, positively charged residues, etc.).

[0296] Affinity variants The affinity variants of the antibody may contain modifications or substitutions in one or more CDR sequences, one or more FR sequences, or the heavy or light chain variable region sequences provided in Table 3 above. Since it is well known in the art that a CDR region is adjacent to two FR regions in the variable region, the FR sequences can be easily identified by those skilled in the art based on the CDR sequences in Table 2 above and the variable region sequences in Table 3 above. The affinity variants retain the specific binding affinity to CD3 of the parent antibody, or even have improved CD3 specific binding affinity compared to the parent antibody. In certain embodiments, at least one (or all) of the substitution(s) in the CDR sequences, FR sequences, or variable region sequences comprises a conservative substitution.

[0297] Those skilled in the art will understand that one or more amino acid residues may be substituted in the CDR sequences provided in Table 2 above, and the variable region sequences provided in Table 3 above, and the resulting antibody or antigen-binding fragment still retains or even retains improved binding affinity or ability to bind CD3. Various methods known in the art can be used to achieve this goal. For example, a library of antibody variants (e.g., Fab or scFv variants) can be generated and expressed by phage display technology, and then screened for binding affinity to human CD3. In another example, computer software can be used to virtually simulate the binding of an antibody to human CD3, and identify amino acid residues on the antibody that form the binding interface. Such residues may be avoided in substitutions to prevent a reduction in binding affinity, or may be targeted for substitution to provide stronger binding.

[0298] In certain embodiments, the humanized antibody or antigen-binding fragment thereof provided herein comprises one or more amino acid residue substitutions in one or more of the CDR sequences and / or in one or more of the FR sequences. In certain embodiments, the affinity variant comprises no more than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 substitutions in total in the CDR and / or FR sequences.

[0299] In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise one, two, or three CDR sequences that have at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to a sequence (or sequences) set forth in Table 2 above, yet retain a specific binding affinity for CD3 at a similar or even higher level than its parent antibody.

[0300] In certain embodiments, the anti-CD3 antibody or antigen-binding fragment thereof comprises one or more variable region sequences that have at least 80% (e.g., at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to a sequence (or sequences) set forth in Table 3 above, yet retain a specific binding affinity for CD3 at a similar or higher level than its parent antibody. In some embodiments, a total of 1-10 amino acids are substituted, inserted, or deleted in the variable region sequences set forth in Table 3 above. In some embodiments, the substitutions, insertions, or deletions are in regions outside of the CDRs (e.g., FRs).

[0301] Glycosylation variants The anti-CD3 antibodies or antigen-binding fragments thereof provided herein also encompass glycosylation variants that can be obtained to increase or decrease the extent of glycosylation of the antibodies or antigen-binding fragments thereof.

[0302] The antibody or antigen-binding fragment thereof provided herein may contain one or more modifications that introduce or remove glycosylation sites. A glycosylation site is an amino acid residue that has a side chain to which a carbohydrate moiety (e.g., an oligosaccharide structure) can be attached. Glycosylation of an antibody is typically either N-linked or O-linked. N-linked refers to the attachment of a carbohydrate moiety to the side chain of an aspartic acid residue, for example, an asparagine residue in a tripeptide sequence such as asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine. Removal of a native glycosylation site can be conveniently accomplished, for example, by altering the amino acid sequence so as to substitute one of the above-mentioned tripeptide sequences (for N-linked glycosylation sites), or serine or threonine residues (for O-linked glycosylation sites) present in the sequence. New glycosylation sites can be similarly created by introducing such tripeptide sequences or serine or threonine residues.

[0303] Cysteine ​​engineered variants The anti-CD3 antibodies or antigen-binding fragments thereof provided herein also encompass cysteine ​​engineered variants that contain one or more introduced free cysteine ​​amino acid residues.

[0304] A free cysteine ​​residue is a residue that is not part of a disulfide bridge. Cysteine ​​engineered variants are useful for conjugating, for example, cytotoxic compounds and / or imaging compounds, labels, or radioisotopes, among others, at the site of engineered cysteine, for example, through maleimide or haloacetyl. Methods for engineering antibodies or antigen-binding fragments thereof to introduce free cysteine ​​residues are known in the art, see, for example, WO2006 / 034488.

[0305] Fc variants The anti-CD3 antibodies and antigen-binding fragments provided herein also encompass Fc variants comprising one or more amino acid residue modifications or substitutions in the Fc region and / or hinge region.

[0306] In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein contain one or more amino acid substitution(s) that improve pH-dependent binding to the neonatal Fc receptor (FcRn). Such variants may have an extended pharmacokinetic half-life because they bind to FcRn at an acidic pH that allows them to escape lysosomal degradation and subsequently translocate and be released from the cell. Methods for engineering antibodies or antigen-binding fragments thereof to improve binding affinity to FcRn are well known in the art, see, e.g., Vaughn, D. et al., Structure, 6(1):63-73, 1998; Kontermann, R. et al., Antibody Engineering, Volume 1, Chapter 27: Engineering of the Fc region for improved PK, published by Springer, 2010; Yeung, Y. et al., Cancer Research, 70:3269-3277(2010); and Hinton, P. et al., J. Immunology, 176:346-356(2006).

[0307] In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein contain one or more amino acid substitution(s) that alter ADCC. Certain amino acid residues in the CH domain of the Fc region can be substituted to provide enhanced ADCC activity. Alternatively or additionally, the carbohydrate structure of the antibody can be altered to enhance ADCC activity. Methods for engineering antibodies to alter ADCC activity have been described in the art, e.g., Shields RL.et al., J Biol Chem.2001.276(9):6591-604; Idusogie EE.et al., J Immunol.2000.164(8):4178-84; Steurer W.et al., J Immunol.1995,155(3):1165-74; Idusogie EE.et al., J Immunol.2001,166(4):2571-5; Lazar GA.et al., PNAS,2006,103(11):4005-4010; Ryan MC.et al., Mol.Cancer Ther.,2007,6:3009-3018; Richards JO,.et al., Mol Cancer See Ther. 2008, 7(8):2517-27; Shields R Let al., J. Biol. Chem, 2002, 277:26733-26740; Shinkawa T. et al., J. Biol. Chem, 2003, 278:3466-3473.

[0308] In certain embodiments, the anti-CD3 antibody or antigen-binding fragment thereof comprises one or more amino acid substitution(s) that alter CDC, for example by improving or impairing C1q binding and / or CDC (see, for example, WO99 / 51642; Duncan & Winter Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO94 / 29351 for other examples of Fc region variants). One or more amino acids selected from amino acid residues 329, 331 and 322 of the Fc region can be replaced with different amino acid residues to alter Clq binding and / or enhance CDC (see U.S. Patent No. 6,194,551 by Idusogie et al.). One or more amino acid substitution(s) can also be introduced to alter the complement fixation ability of the antibody (see PCT application WO94 / 29351 by Bodmer et al.).

[0309] In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise one or more amino acid substitution(s) at positions 234 and / or 235 (according to EU numbering) of a human immunoglobulin. In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise two amino acid substitutions at positions 234 and 235 (according to EU numbering) of a human immunoglobulin (e.g., IgG1). In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise L234A and L235A (according to EU numbering) amino acid substitutions.

[0310] In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise one or more amino acid substitution(s) at position 228 (according to EU numbering) of a human immunoglobulin (e.g., IgG4). In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein comprise an S228P (according to EU numbering) amino acid substitution.

[0311] In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein contain one or more amino acid substitution(s) at the interface of the Fc region to facilitate and / or promote heterodimerization. These modifications include the introduction of a protuberance into a first Fc polypeptide and a cavity into a second Fc polypeptide, where the protuberance may be located in the cavity to promote interaction of the first and second Fc polypeptides to form a heterodimer or complex. Methods for generating antibodies with these modifications are known in the art, for example, as described in U.S. Pat. No. 5,731,168.

[0312] In certain embodiments, an anti-CD3 antibody or antigen-binding fragment thereof provided herein comprises an amino acid substitution at position 366 (according to EU numbering) of a first Fc polypeptide and one, two, or three amino acid substitutions at one, two, or three positions at positions 366, 368, and 407 (according to EU numbering) of a second Fc polypeptide. In certain embodiments, an anti-CD3 antibody or antigen-binding fragment thereof provided herein comprises a T366W substitution (according to EU numbering) of a first Fc polypeptide and a T366S+L368A+Y407V substitution (according to EU numbering) of a second Fc polypeptide.

[0313] In certain embodiments, the anti-CD3 antibody or antigen-binding fragment thereof provided herein further comprises one or more amino acid substitution(s) in the first Fc polypeptide and comprises one or more amino acid substitution(s) in the second Fc polypeptide to introduce a non-natural disulfide bond between the two Fc polypeptides. For example, the anti-CD3 antibody or antigen-binding fragment thereof provided herein comprises an amino acid substitution at position 354 (according to EU numbering) in the first Fc polypeptide and an amino acid substitution at position 349 (according to EU numbering) in the second Fc polypeptide. In certain embodiments, the anti-CD3 antibody or antigen-binding fragment thereof provided herein comprises an S354C substitution (according to EU numbering) in the first Fc polypeptide and comprises a Y349C substitution (according to EU numbering) in the second Fc polypeptide.

[0314] In certain embodiments, the anti-CD3 antibody or antigen-binding fragment thereof provided herein comprises a first Fc polypeptide comprising the amino acid sequence set forth in SEQ ID NO:98 and a second Fc polypeptide comprising the amino acid sequence set forth in SEQ ID NO:99. [ka]

[0315] antigen-binding fragment Also provided herein are anti-CD3 antigen-binding fragments. Various types of antigen-binding fragments are known in the art and can be developed based on the anti-CD3 antibodies provided herein, including, for example, the exemplary antibodies whose CDRs are shown in Table 2 above and whose variable sequences are shown in Table 3 above, and different variants thereof (e.g., affinity variants, glycosylation variants, Fc variants, cysteine ​​engineered variants, etc.).

[0316] In certain embodiments, an anti-CD3 antigen-binding fragment provided herein is a diabody, a Fab, a Fab', a F(ab')2, an Fd, an Fv fragment, a disulfide-stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv-dsFv'), a disulfide-stabilized diabody (ds diabody), a single-chain antibody molecule (scFv), an scFv dimer (bivalent diabody), a multispecific antibody, a camelized single domain antibody, a nanobody, a domain antibody, or a bivalent domain antibody.

[0317] A variety of techniques can be used to produce such antigen-binding fragments. Exemplary methods include enzymatic digestion of intact antibodies (e.g., Morimoto et al., Journal of Biochemical and Biophysical Methods 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)), recombinant expression by host cells such as E. coli (e.g., for Fab, Fv and ScFv antibody fragments), screening from phage display libraries as discussed above (e.g., for ScFv), and chemical coupling of two Fab'-SH fragments to form F(ab')2 fragments (Carter et al., Bio / Technology 10:163-167 (1992)). Other techniques for producing antibody fragments will be apparent to those skilled in the art.

[0318] In certain embodiments, the antigen-binding fragment is an scFv. The generation of scFv is described, for example, in WO93 / 16185; U.S. Patent No. 5,571,894; and U.S. Patent No. 5,587,458. The scFv can be fused to an effector protein at either the amino or carboxyl terminus to provide a fusion protein (see, for example, Antibody Engineering, ed. Borrebaeck).

[0319] In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein are bivalent, tetravalent, hexavalent, or multivalent. Any molecule that is more than bivalent is considered to be multivalent, including, for example, trivalent, tetravalent, hexavalent, etc.

[0320] A bivalent molecule can be monospecific when both binding sites are specific for binding to the same antigen or epitope. In certain embodiments, it provides stronger binding to antigen or epitope than its monovalent counterpart. Similarly, a multivalent molecule can also be monospecific. In certain embodiments, in a bivalent or multivalent antigen-binding moiety, the first valency of the binding site and the second valency of the binding site are structurally identical (i.e., have the same sequence) or structurally different (i.e., have different sequences, despite having the same specificity).

[0321] Bivalent can also be bispecific, when two binding sites are specific for different antigens or epitopes. This also applies to multivalent molecules. For example, a trivalent molecule can be bispecific, when two binding sites are monospecific for a first antigen (or epitope) and the third binding site is specific for a second antigen (or epitope).

[0322] Bispecific or multispecific antibodies In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein are bispecific or multispecific. In certain embodiments, the anti-CD3 antibodies or antigen-binding fragments thereof provided herein are further linked to a second functional moiety having a binding specificity different from that of the anti-CD3 antibodies or antigen-binding fragments thereof. In some embodiments, the bispecific or multispecific antibodies and antigen-binding fragments thereof provided herein have a first specificity for CD3 and a second specificity. In some embodiments, the second specificity is for CD3 but a different epitope. In some embodiments, the second specificity is for a second antigen different from CD3, and its presence in proximity to CD3-expressing T cells is desirable for the second antigen to be recognized by the immune system. For example, bringing CD3-expressing T cells in proximity to tumor or pathogen antigens facilitates the recognition or elimination of such antigens by the immune system.

[0323] In certain embodiments, the second specificity is for a tumor-associated antigen or an epitope thereof. The term "tumor-associated antigen" refers to an antigen that is present or may be present on the tumor cell surface and is located on or within a tumor cell. In some embodiments, only tumor cells can present tumor-associated antigens, and normal cells, i.e., non-tumor cells, cannot. In some other embodiments, tumor-associated antigens may be exclusively expressed on tumor cells or may represent tumor-specific mutations compared to non-tumor cells. In some other embodiments, tumor-associated antigens may be found in both tumor cells and non-tumor cells, but are overexpressed in tumor cells compared to non-tumor cells, or are accessible for antibody binding in tumor cells due to less compact tumor tissue structure compared to non-tumor tissue. In some embodiments, tumor-associated antigens are located in the vasculature of tumors.

[0324] In certain embodiments, the bispecific or multispecific antibodies or antigen-binding fragments thereof provided herein are capable of specifically binding to one or more (e.g., 1, 2, 3, 4, 5 or more) additional antigens other than CD3 or a second epitope on CD3.In certain embodiments, the one or more additional antigens other than CD3 are CD16a, CD33, CD38, CD45, CD123, CD146, CD228, CLL-1, FLT3, FLT3L, TAF1, TgPRF, HVCN1, IL-6R, IL-11R, IL17A, IL-23R, IL-33, ILDR2, LAP, TSLP, TREM-1, ANGPT2, APOE, IFNAR, CypA, DOG-1, NKp30, CSF-1R, CCR2, LRRC15, mesothelin, Dickkopf2, DLL3, HER- 2, C10orf54, TrkA, MEKK1, KRAS, ERK, ), c-MET, Her2, Her3, CTLA4, GITA, CD112R, CD2, CD7, CD16, CD19, CD20, CD24, CD27, CD30, CD34, CD37, CD39, CD70, CD73, CD83, CD28, CD80 (B7-1), CD86 (B7-2), CD40, CD40L (CD154), CD47, SIRPα, CD122, CD137, CD137L, OX40 (CD134), OX40L (CD252), BCMA (e.g. BCMA02), PSMA, CLDN18 (e.g. CL DN18.2), NKG2C, 4-1BB, LIGHT, PVRIG, SLAMF7, HVEM, BAFFR, ICAM-1, 2B4, LFA-1, GITR, ICOS (CD278), ICOSLG (CD275), LAG3 (CD223), A2AR, B7-H3 (CD276), B7-H4 (VTCN1), B7-H5, BTLA (CD272), CD160, CTLA-4 (CD152), GPRC5D, IDO (e.g., IDO1, IDO2), TDO, KIR, LAIR-1, NOX2, PD-1, PD-L1, PD-L2, TIM-3, VISTA, SIGLEC-7 (CD328), SIGLEC-9 (CD329), SIGLEC-15, TIGIT, PVR (CD155), TLR3, CLEC9A, DEC-205, STING, and TGFβ.

[0325] In certain embodiments, the bispecific antibodies or antigen-binding fragments provided herein are capable of specifically binding to CD3 and CD19. In certain embodiments, the bispecific antibodies or antigen-binding fragments provided herein are capable of specifically binding to CD3 and CLDN18 (e.g., CLDN18.2). In certain embodiments, the bispecific antibodies or antigen-binding fragments provided herein are capable of specifically binding to CD3 and PD-L1. In certain embodiments, the bispecific antibodies or antigen-binding fragments provided herein are capable of specifically binding to CD3 and BCMA. In certain embodiments, the bispecific antibodies or antigen-binding fragments provided herein are capable of specifically binding to CD3 and GPRC5D.

[0326] Conjugates In some embodiments, the anti-CD3 antibody or antigen-binding fragment thereof provided herein further comprises one or more conjugate moieties. The conjugate moiety can be linked to the antibody or antigen-binding fragment thereof. The conjugate moiety is a moiety that can bind to the antibody or antigen-binding fragment thereof. It is contemplated that a variety of conjugate moieties can be linked to the antibody or antigen-binding fragment thereof provided herein (see, for example, "Conjugate Vaccines", Contributions to Microbiology and Immunology, JM Cruse and RE Lewis, Jr. (eds.), Carger Press, New York, (1989)). These conjugate moieties can be linked to the antibody or antigen-binding fragment thereof by covalent bonds (e.g., disulfide bonds), affinity binding, intercalation, cooperative binding, complex formation, association, admixture, or addition, among other methods. In some embodiments, the antibody or antigen-binding fragment thereof can be linked to one or more conjugates via a linker or crosslinker. The linker or crosslinker comprises a reactive chemical group that can react with the anti-CD3 antibody or antigen-binding fragment thereof. The reactive chemical groups can be N-succinimidyl esters and N-sulfosuccinimidyl esters. In addition, the linker contains a reactive chemical group that can be a dithiopyridyl group that can react with a drug to form a disulfide bond.Linker molecules include, for example, N-succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC), N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) (see, for example, Carlsson et al. al., Biochem. J., 173:723-737 (1978)), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) (see, e.g., U.S. Pat. No. 4,563,304), N-succinimidyl 4-(2-pyridyldithio)2-sulfobutanoate (sulfo-SPDB) (see, U.S. Patent Application Publication No. 20090274713), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP) (see, e.g., CAS Registry No. 341498-08-6), 2-iminothiolane, or acetylsuccinic anhydride. For example, an antibody or cell-binding agent can be modified with a cross-linking reagent, and the antibody or cell-binding agent thus derivatized containing a free or protected thiol group can be reacted with a disulfide or thiol-containing maytansinoid to produce a conjugate. The conjugate can be purified by chromatography, including but not limited to HPLC, size exclusion, adsorption, ion exchange and affinity capture, dialysis, or tangential flow filtration.

[0327] In certain embodiments, the antibodies or antigen-binding fragments thereof provided herein may be engineered to contain specific sites outside the epitope-binding moiety that can be utilized to bind to one or more conjugate moieties. For example, such sites may contain one or more reactive amino acid residues, such as cysteine ​​or histidine residues, to facilitate covalent binding to the conjugate moiety.

[0328] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein may be indirectly linked to the conjugate moiety or linked through another conjugate moiety. For example, the antibody or antigen-binding fragment thereof provided herein may be conjugated to biotin and then indirectly conjugated to a second conjugate conjugated to avidin. In some embodiments, the conjugate moiety comprises a clearance modifier (e.g., a polymer, e.g., PEG, which extends half-life), a chemotherapeutic agent, a toxin, a radioisotope, a lanthanide, a detectable label (e.g., a luminescent label, a fluorescent label, an enzyme-substrate label), a DNA alkylating agent, a topoisomerase inhibitor, a tubulin binding agent, a purification moiety or other anti-cancer agent (e.g., an agonist of toll-like receptor 7 (TLR-7), TLR-8 and / or TLR-9, an siRNA, an antibody or antigen-binding fragment thereof, a peptide (e.g., a small peptide), etc.).

[0329] A "toxin" can be any agent that is harmful to a cell or that can damage or kill a cell. Examples of toxins include, but are not limited to, taxol, taxoids, CC-1065 and CC-1065 analogs, duocarmycins and duocarmycin analogs, enediynes, dolastatin analogs, including calicheamicins, dolastatins and auristatins, tomamycin derivatives, leptomycin derivatives, cisplatin, carboplatin, daunorubicin, doxorubicin, vincristine, vinblastine, melphalan, mitomycin, cyclosporine ... C, chlorambucil and morpholinodoxorubicin, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, MMAE, MMAF, DM1, DM4, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, theophylline, Tracaine, lidocaine, propranolol, puromycin and its analogs, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil, dacarbazine), alkylating agents (e.g., mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mycobacterial tomycin C, and cis-dichlorodiamineplatinum(II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), mitotic inhibitors (e.g., vincristine and vinblastine), topoisomerase inhibitors, and tubulin binding agents.

[0330] Examples of detectable labels include fluorescent labels (e.g., fluorescein, rhodamine, dansyl, phycoerythrin, or Texas Red), enzyme-substrate labels (e.g., horseradish peroxidase, alkaline phosphatase, luciferase, glucoamylase, lysozyme, saccharide oxidase, or β-D-galactosidase), radioisotopes (e.g., 123 I, 124 I, 125 I, 131 I, 35 S, 3 H, 111 In, 112 In, 14 C. 64 Cu, 67 Cu, 86 Y, 88 Y, 90 Y, 177 Lu, 211 At, 186 Re, 188 Re, 153 Sm, 212 Bi, and 32 P, other lanthanides), luminescent labels, chromophore moieties, digoxigenin, biotin / avidin, DNA molecules or gold for detection.

[0331] In certain embodiments, the conjugate moiety can be a clearance modifier that helps to increase the half-life of the antibody. Illustrative examples include water-soluble polymers such as PEG, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, ethylene glycol / propylene glycol copolymers and the like. The polymer can be any molecular weight polymer, and can be branched or unbranched. The number of polymers attached to the antibody can vary, and when more than one polymer is attached, they can be the same or different molecules.

[0332] In certain embodiments, the conjugate moiety may be a purification moiety, such as a magnetic bead.

[0333] In certain embodiments, an antibody or antigen-binding fragment thereof provided herein is used as a base for a conjugate.

[0334] In certain embodiments, the antibody or antigen-binding fragment thereof provided herein is conjugated to a signal peptide. A signal peptide (sometimes referred to as a signal sequence, leader sequence, or leader peptide) can be used to facilitate secretion and isolation of the antibody or antigen-binding fragment thereof provided herein. A signal peptide is typically characterized by a core of hydrophobic amino acids that are generally cleaved from the mature protein during secretion in one or more cleavage events. Such signal peptides contain processing sites that allow for cleavage of the signal sequence from the mature protein as they pass through the secretory pathway. Thus, the present invention relates to the described polypeptides having a signal sequence, as well as polypeptides in which the signal sequence has been proteolytically cleaved (i.e., cleavage products). In one embodiment, a nucleic acid sequence encoding a signal sequence can be operably linked to a protein of interest in an expression vector, such as a protein that is not normally secreted or is otherwise difficult to isolate. The signal sequence directs the secretion of the protein, for example, from a eukaryotic host into which the expression vector is transformed, and the signal sequence is subsequently or simultaneously cleaved. The protein can then be readily purified from the extracellular medium by art-recognized methods. Alternatively, a signal sequence can be linked to the protein of interest using a sequence that facilitates purification, such as a GST domain.

[0335] Chimeric Antigen Receptor In certain embodiments, the present disclosure provides a chimeric antigen receptor comprising an antibody or antigen-binding fragment thereof provided herein, a transmembrane domain, and an intracellular signaling domain.

[0336] The term "chimeric antigen receptor" or "CAR" or "CARs," as used herein, refers to an engineered receptor that grafts antigen specificity onto a cell (e.g., a T cell, such as a naive T cell, a central memory T cell, an effector memory T cell, a regulatory T cell, a natural killer cell, or a combination thereof). A CAR is also known as an artificial T cell receptor, a chimeric T cell receptor, or a chimeric immune receptor. In some embodiments, a CAR comprises an antigen-specific targeting region (e.g., an antigen-binding fragment of an anti-CD3 antibody provided herein), an extracellular region, a transmembrane region, one or more costimulatory regions, and an intracellular signaling region.

[0337] In some embodiments, the antigen-specific targeting region is an scFv. In some embodiments, the transmembrane region comprises the transmembrane region of CD3, CD4, CD8 or CD28. In some embodiments, the costimulatory region comprises the costimulatory domain of CD28, ICOS, CD27, 4-1BB, OX40 and CD40L. In some embodiments, the intracellular signal region is selected from the group consisting of CD3, FcγRI, CD27, CD28, CD137, CD134, MyD88, CD40, CD278, TLR intracellular signal region sequences, or combinations thereof.

[0338] CARs can be grafted onto a variety of cells, for example, allogeneic, autologous or xenogeneic cells.

[0339] The term "allogeneic cells," as used herein, refers to any cells derived from a different subject of the same species.

[0340] The term "autologous cells," as used herein, refers to any cells derived from the same subject that are subsequently reintroduced into the subject.

[0341] The term "xenogeneic cell," as used herein, refers to any cell derived from a different subject of a different species.

[0342] In some embodiments, the CAR is grafted onto an immune effector cell, such as a T cell, a natural killer cell, a macrophage cell, a tumor-infiltrating lymphocyte, etc.

[0343] Polynucleotides and Recombinant Methods The present disclosure provides isolated polynucleotides encoding the anti-CD3 antibody or its antigen-binding fragment and / or chimeric antigen receptor provided herein. The term "nucleic acid" or "polynucleotide" as used herein refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and polymers thereof in single-stranded or double-stranded form. Unless otherwise indicated, a particular polynucleotide sequence also implicitly encompasses its conservatively modified variants (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (see Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)).

[0344] The DNA encoding the antibody or its antigen-binding fragment, or chimeric antigen receptor provided herein can be easily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of the antibody). The encoding DNA can also be obtained by synthetic methods.

[0345] The isolated polynucleotides encoding the anti-CD3 antibodies or antigen-binding fragments thereof provided herein and / or the chimeric antigen receptors provided herein can be inserted into vectors for further cloning (amplification of DNA) or expression using recombinant techniques known in the art. Many vectors are available. Vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter (e.g., SV40, CMV, EF-1α), and a transcription termination sequence.

[0346] The present disclosure provides a vector comprising the isolated polynucleotide provided herein. In certain embodiments, the polynucleotide provided herein encodes the antibody or antigen-binding fragment thereof and / or chimeric antigen receptor provided herein, at least one promoter (e.g., SV40, CMV, EF-1α) operably linked to the nucleic acid sequence, and at least one selection marker. Examples of vectors include, but are not limited to, retroviruses (including lentiviruses), adenoviruses, adeno-associated viruses, herpes viruses (e.g., herpes simplex viruses), poxviruses, baculoviruses, papilloma viruses, papova viruses (e.g., SV40), lambda phage, and M13 phage, plasmids pcDNA3.3, pMD18-T, pOptivec, pCMV, pEGFP, pIRES, pQD-Hyg-GSeu, pALTE R, pBAD, pcDNA, pCal, pL, pET, pGEMEX, pGEX, pCI, pEGFT, pSV2, pFUSE, pVITRO, pVIVO, pMAL, pMONO, pSELECT, pUNO, pDUO, Psg5L, pB ABE, pWPXL, pBI, p15TV-L, pPro18, pTD, pRS10, pLexA, pACT2.2, pCMV-SCRIPT.RTM., pCDM8, pCDNA1.1 / amp, pcDNA3.1, pRc / RSV, PCR 2.1, pEF-1, pFB, pSG5, pXT1, pCDEF3, pSVSPORT, pEF-Bos, etc.

[0347] A vector comprising a polynucleotide sequence encoding an antibody or antigen-binding fragment thereof and / or a chimeric antigen receptor provided herein can be introduced into a host expression system (e.g., a host cell) for cloning or gene expression. In certain embodiments, the host expression system provided herein is a microorganism, yeast, or mammalian cell. In certain embodiments, the microorganism is selected from the group consisting of Escherichia coli and Bacillus subtilis. In certain embodiments, the yeast is Saccharomyces. In certain embodiments, the mammalian cell is selected from the group consisting of COS, CHO-S, CHO-K1, HEK-293, and 3T3 cells.

[0348] Suitable host cells for cloning or expressing the DNA in the vectors herein are the prokaryotic cells, yeast, or higher eukaryotic cells described above. Suitable prokaryotic cells for this purpose include eubacteria, such as gram-negative or gram-positive organisms, such as Enterobacteriaceae, Escherichia, such as E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, such as Salmonella typhimurium, Serratia, such as Serratia marcescans, and Shigella, as well as Bacillus, such as Bacillus subtilis and B. licheniformis, Pseudomonas, such as P. aeruginosa, and Streptomyces.

[0349] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for anti-CD3 antibody-encoding vectors. Saccharomyces cerevisiae, or common baker's yeast, is the most commonly used among lower eukaryotic host microorganisms. However, many other genera, species, and strains, such as Schizosaccharomyces pombe; Kluyveromyces hosts, such as K. lactis, K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906), K. thermotolerans, and K. marxianus; Yarrowia (EP 402,226); Pichia pastoris; pastoris (EP 183,070); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa; Schwanniomyces, such as Schwanniomyces occidentalis; and filamentous fungi, such as Neurospora, Penicillium, Tolypocladium, and Aspergillus hosts, such as A. nidulans and A. niger, are commonly available and useful herein.

[0350] Suitable host cells for expressing the glycosylated antibodies or antigen-binding fragments thereof provided herein are derived from multicellular organisms. Examples of invertebrates include plants and insect cells. Multiple baculovirus strains and variants have been identified, as well as corresponding permissive insect host cells from hosts such as Spodoptera frugiperda (caterpillar), Aedes aegypti (mosquito), Aedes albopictus (mosquito), Drosophila melanogaster (fruit fly), and Bombyx mori (silkworm). Various virus strains for transfection have been published, such as the L-1 variant of Autographa californica NPV and the Bm-5 variant of silkworm NPV, and such viruses can be used as viruses herein in accordance with the present invention, particularly for transfection of Spodoptera frugiperda cells. Plant cell cultures of cotton, corn, potato, soybean, petunia, tomato, and tobacco can also be utilized as host cells.

[0351] However, most interest has been in vertebrate cells, and propagating vertebrate cells in culture (tissue culture) has become a routine procedure. Examples of useful mammalian host cell lines are the SV40 transformed monkey kidney CV1 line (COS-7, ATCC CRL 1651); human embryonic kidney cell line (293 or 293 cells subcloned to grow in suspension culture, Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK, ATCC CCL 10); Chinese hamster ovary cells / -DHFR (CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); mouse Sertoli cells (TM4, Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1 ATCC CCL 70); African green monkey kidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo rat hepatocytes (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL 75); human hepatocytes (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TRI cells (Mather et al., Annals NYAcad. Sci. 383:44-68 (1982)); MRC5 cells; FS4 cells; mouse forestomach carcinoma cells (MFC), SNU620 cells, and human hepatoma cell line (HepG2). In some embodiments, the host cell is a mammalian cultured cell line, such as CHO, BHK, NS0, 293, MFC, SNU620 and derivatives thereof.

[0352] The host cell is transformed with the above expression or cloning vector for anti-CD3 antibody production, and cultured in a conventional nutrient medium modified appropriately to induce promoters, select transformants, or amplify genes encoding desired sequences. In another embodiment, the antibody may be produced by homologous recombination as known in the art. In certain embodiments, the host cell is capable of producing the antibody or antigen-binding fragment thereof provided herein.

[0353] The present disclosure also provides a method of expressing the antibody or antigen-binding fragment thereof and / or chimeric antigen receptor provided herein, comprising culturing the host expression system provided herein under conditions in which the antibody or antigen-binding fragment thereof and / or chimeric antigen receptor is expressed. The host expression system used to produce the antibody or antigen-binding fragment thereof and / or chimeric antigen receptor provided herein can be cultured in a variety of media. Commercially available media, such as Ham's F10 (Sigma), minimal essential medium (MEM) (Sigma), RPMI-1640 (Sigma), and Dulbecco's modified Eagle's medium (DMEM) (Sigma), are suitable for culturing host cells. In addition, any medium described in Ham et al., Meth. Enz. 58:44 (1979), Barnes et al., Anal. Biochem. 102:255 (1980), U.S. Pat. Nos. 4,767,704; 4,657,866; 4,927,762; 4,560,655; or 5,122,469; WO 90 / 03430; WO 87 / 00195; or U.S. Pat. No. 30,985 may be used as a culture medium for the host cells. Any of these media may be supplemented as necessary with hormones and / or other growth factors (e.g., insulin, transferrin, or epidermal growth factor), salts (e.g., sodium chloride, calcium, magnesium, and phosphate), buffers (e.g., HEPES), nucleotides (e.g., adenosine and thymidine), antibiotics (e.g., GENTAMYCIN™ drug), trace elements (usually defined as inorganic compounds present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations known to those of skill in the art. Culture conditions, such as temperature, pH, and the like, will be those previously used for the host cell selected for expression and will be apparent to those of skill in the art.

[0354] Using recombinant techniques, antibodies can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, the first step is to remove particulate debris, either host cells or lysed fragments, for example, by centrifugation or ultracentrifugation. Carter et al., Bio / Technology 10:163-167 (1992) describes a procedure for isolating antibodies secreted into the periplasmic space of E. coli. Briefly, cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonyl fluoride (PMSF) for about 30 minutes. Cell debris can be removed by centrifugation. If the antibody is secreted into the medium, the supernatant from such expression systems is typically first concentrated using a commercially available protein concentration filter, such as an Amicon or Millipore Pellicon ultracentrifugation unit. Protease inhibitors, such as PMSF, may be included in any of the aforementioned steps to inhibit proteolysis, and antibiotics may be included to prevent the growth of adventitious contaminants.

[0355] The anti-CD3 antibody or antigen-binding fragment thereof and / or chimeric antigen receptor prepared from the host expression system can be purified using, for example, hydroxylapatite chromatography, gel electrophoresis, dialysis, DEAE-cellulose ion exchange chromatography, ammonium sulfate precipitation, salting out, and affinity chromatography, with affinity chromatography being the preferred purification technique.

[0356] In certain embodiments, protein A immobilized on a solid phase is used for immunoaffinity purification of the antibodies and their antigen-binding fragments and / or chimeric antigen receptors provided herein. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain present in the antibody. Protein A can be used to purify antibodies based on human gamma 1, gamma 2, or gamma 4 heavy chains (Lindmark et al., J. Immunol. Meth. 62:1-13 (1983)). Protein G is recommended for all mouse isotypes and human gamma 3 (Guss et al., EMBO J. 5:1567 1575 (1986)). The matrix to which the affinity ligand is attached is most often agarose, although other matrices are available. Mechanically stable matrices, such as porous glass or poly(styrenedivinyl)benzene, allow for faster flow rates and shorter processing times than can be achieved with agarose. If the antibody contains a CH3 domain, Bakerbond ABX™ resin (JT Baker, Phillipsburg, NJ) is useful for purification. Other techniques for protein purification, such as fractionation on ion exchange columns, ethanol precipitation, reverse-phase HPLC, chromatography on silica, heparin chromatography, SEPHAROSE™ chromatography on anion or cation exchange resins (e.g., polyaspartic acid columns), chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation, are also available depending on the antibody to be recovered.

[0357] After any preliminary purification step(s), the mixture containing the antibody of interest and contaminants may be subjected to low pH hydrophobic interaction chromatography, preferably performed at a low salt concentration (e.g., about 0-0.25 M salt), using an elution buffer with a pH between about 2.5-4.5.

[0358] Pharmaceutical Compositions The present disclosure further provides pharmaceutical compositions comprising an anti-CD3 antibody or an antigen-binding fragment thereof and / or a chimeric antigen receptor provided herein, and one or more pharma- ceutically acceptable carriers.

[0359] Pharmaceutically acceptable carriers for use in the pharmaceutical compositions disclosed herein may include, for example, pharma- ceutically acceptable liquid, gel, or solid carriers, aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonic agents, buffers, antioxidants, anesthetics, suspending / dispersing agents, sequestering or chelating agents, diluents, adjuvants, excipients, or other non-toxic auxiliary substances, or various combinations thereof known in the art.

[0360] Suitable components may include, for example, antioxidants, bulking agents, binders, disintegrants, buffers, preservatives, lubricants, flavorings, thickeners, coloring agents, emulsifiers, or stabilizers, such as sugars and cyclodextrins.Suitable antioxidants may include, for example, methionine, ascorbic acid, EDTA, sodium thiosulfate, platinum, catalase, citric acid, cysteine, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxyanisole, butylated hydroxytoluene, and / or propyl gallate.As disclosed herein, the inclusion of one or more antioxidants, such as methionine, in compositions comprising the antibodies or antigen-binding fragments thereof and conjugates provided herein reduces the oxidation of the antibodies or antigen-binding fragments thereof. This reduction in oxidation prevents or reduces the loss of binding affinity, thereby improving the stability of the antibodies and maximizing their shelf life.Thus, in certain embodiments, pharmaceutical compositions are provided that include one or more antibodies or antigen-binding fragments thereof disclosed herein and one or more antioxidants, such as methionine. Further provided are methods of preventing oxidation, extending the shelf life, and / or improving the effectiveness of the antibodies or antigen-binding fragments provided herein by combining the antibodies or antigen-binding fragments with one or more antioxidants, such as methionine.

[0361] To further illustrate, pharma- ceutically acceptable carriers may include, for example, Sodium Chloride Injection, Ringer's Injection, Isotonic Dextrose Injection, Sterile Water Injection, or Dextrose and Lactated Ringer's Injection, non-aqueous vehicles such as fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, or peanut oil, antibacterial agents in bacteriostatic or fungistatic concentrations, isotonic agents such as sodium chloride or dextro...

Claims

1. An antibody or its antigen-binding fragment that specifically binds to CD3, Sequence numbers 165, 196, 192, 186, 188, 205, 234, 235, 237, 238, 239, 242, 244, 7, 15, 23, 31, 39, 47, 55, 63, 71, 79, 87, 95, 108, 116, 124, 132, 140, 148, 156, 163, 164, 166, 187, 189, 190, 191, 193 , one, two, or three heavy chain complementarity determining regions (HCDR1, HCDR2, and / or HCDR3) contained within any one of the heavy chain variable (VH) region sequences selected from the group consisting of 194, 195, 213, 202, 203, 204, 206, 233, 236, 240, 241, 243, and 245; and / or One, two, or three light chain complementarity-determining regions (LCDR1, LCDR2, and / or LCDR3) contained within any one of the light chain variable (VL) region sequences selected from the group consisting of SEQ ID NOs: 169, 207, 231, 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 109, 117, 125, 133, 141, 149, 157, 168, 170, 197, 198, 199, 200, 208, 209, 230, and 232. An antibody containing an antigen-binding fragment thereof.

2. Sequence numbers 219, 201, 162, 167, 9, 10, 11, 12, 13, 14, 181, 173, 171, 175, 150, 212, 152, 153, 154, 155, 221, 222, 180, 224, 225, 226, 174, 217, 215, 211, 1, 2, 3, 4, 5, 6, 17, 18, 19, 20, 21, 22, 25, 2 6, 27, 28, 29, 30, 33, 34, 35, 36, 37, 38, 41, 42, 43, 44, 45, 46, 49, 50, 51, 52, 53, 54, 57, 58, 59, 60, 61, 62, 65, 66, 67, 68, 69, 70, 73, 74, 75, 76, 77, 78, 81, 82, 83, 84, 85, 86, 89, 90, 91, 92 ,93,94,102,103,104,105,106,107,110,111,112,113,114,115,118,119,120,121,122,123,126,127,128,129,130,131,134,135,136,137,138,139,142,143,144,145,146,147, The antibody or antigen-binding fragment according to claim 1, comprising at least one heavy chain or light chain complementarity-determining region (CDR) containing an amino acid sequence selected from the group consisting of 151, 172, 176, 177, 178, 179, 182, 183, 184, 185, 210, 214, 216, 218, 220, 223, 227, 228, and 229.

3. a) Sequence numbers 219, 201, 162, 9, 10, 11, 181, 173, 171, 175, 150, 212, 152, 221, 222, 180, 224, 225, 226, 174, 217, 211, 1, 2, 3, 17, 18, 19, 25, 26, 27, 33, 34, 35, 41, 42, 43, 49, 50, 51, 57, 58, 59, 65, 66, 67, 73, 74, 75, 81, 82, 83, 89, 90, 91, 102, A VH region containing one, two, or three HCDR1, HCDR2, and HCDR3 amino acid sequences selected from the group consisting of 103, 104, 110, 111, 112, 118, 119, 120, 126, 127, 128, 134, 135, 136, 142, 143, 144, 151, 172, 176, 177, 178, 179, 210, 218, 220, 223, 227, 228, and 229, and / or b) Sequence numbers 167, 12, 13, 14, 153, 154, 155, 215, 4, 5, 6, 20, 21, 22, 28, 29, 30, 36, 37, 38, 44, 45, 46, 52, 53, 54, 60, 61, 62, 68, 69, 70, 76, 77, 78, 84, 85, 86, 92, 93, 94, 105, 106, 107, 1 A VL region containing one, two, or three LCDR1, LCDR2, and LCDR3, each containing an amino acid sequence selected from the group consisting of 13, 114, 115, 121, 122, 123, 129, 130, 131, 137, 138, 139, 145, 146, 147, 182, 183, 184, 185, 214, and 216. The antibody or antigen-binding fragment thereof according to claim 1 or 2, comprising:

4. i. HCDR1 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 219, 9, 150, 217, 1, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 102, 110, 118, 126, 134, 142, and 218; ii. HCDR2 containing an amino acid sequence selected from the group consisting of SEQ ID NOs. 201, 10, 173, 171, 212, 222, 211, 2, 18, 26, 34, 42, 50, 58, 66, 74, 82, 90, 103, 111, 119, 127, 135, 143, 151, 172, 210 and 220; and iii. HCDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 11, 19, 27, 35, 43, 51, 59, 67, 75, 83, 91, 104, 112, 120, 128, 136, 144, 152, 174, 175, 176, 177, 178, 179, 180, 181, 221, 223, 224, 225, 226, 227, 228, 229 and 162, and / or i. LCDR1 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 153, 4, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 105, 113, 121, 129, 137, and 145; ii. LCDR2 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 154, 5, 21, 29, 37, 45, 53, 61, 69, 77, 85, 93, 106, 114, 122, 130, 138 and 146; and iii. LCDR3 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 167, 14, 155, 215, 6, 22, 30, 38, 46, 54, 62, 70, 78, 86, 94, 107, 115, 123, 131, 139, 147, 182, 183, 184, 185, 214, and 216. preferably includes, i. HCDR1 containing the amino acid sequence described in SEQ ID NO: 219, HCDR2 containing the amino acid sequence described in SEQ ID NO: 201, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 162; ii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 11; iii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 10; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 181; iv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 173; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 11; v. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 171; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 11; vi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 10; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 175; vii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 150, HCDR2 containing the amino acid sequence described in SEQ ID NO: 212, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 152; viiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 10; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 211; ix. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 222; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 180; x. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 171; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 224; xi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 10; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 225; xii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 10; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 226; xiiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 10; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 174; xiv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 217; HCDR2 containing the amino acid sequence described in SEQ ID NO: 10; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 11; xv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9; HCDR2 containing the amino acid sequence described in SEQ ID NO: 222; and HCDR3 containing the amino acid sequence described in SEQ ID NO: 180; xvi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 150, HCDR2 containing the amino acid sequence described in SEQ ID NO: 211, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 152; xvii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 1, HCDR2 containing the amino acid sequence described in SEQ ID NO: 2, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 3; xviiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 17, HCDR2 containing the amino acid sequence described in SEQ ID NO: 18, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 19; xix. HCDR1 containing the amino acid sequence described in SEQ ID NO: 25, HCDR2 containing the amino acid sequence described in SEQ ID NO: 26, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 27; xx. HCDR1 containing the amino acid sequence described in SEQ ID NO: 33, HCDR2 containing the amino acid sequence described in SEQ ID NO: 34, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 35; xxi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 41, HCDR2 containing the amino acid sequence described in SEQ ID NO: 42, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 43; xxii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 49, HCDR2 containing the amino acid sequence described in SEQ ID NO: 50, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 51; xxiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 57, HCDR2 containing the amino acid sequence described in SEQ ID NO: 58, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 59; xxiv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 65, HCDR2 containing the amino acid sequence described in SEQ ID NO: 66, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 67; xxv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 73, HCDR2 containing the amino acid sequence described in SEQ ID NO: 74, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 75; xxvi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 81, HCDR2 containing the amino acid sequence described in SEQ ID NO: 82, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 83; xxvii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 89, HCDR2 containing the amino acid sequence described in SEQ ID NO: 90, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 91; xxviiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 102, HCDR2 containing the amino acid sequence described in SEQ ID NO: 103, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 104; xxx. HCDR1 containing the amino acid sequence described in SEQ ID NO: 110, HCDR2 containing the amino acid sequence described in SEQ ID NO: 111, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 112; xxx. HCDR1 containing the amino acid sequence described in SEQ ID NO: 118, HCDR2 containing the amino acid sequence described in SEQ ID NO: 119, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 120; xxxi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 126, HCDR2 containing the amino acid sequence described in SEQ ID NO: 127, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 128; xxxii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 134, HCDR2 containing the amino acid sequence described in SEQ ID NO: 135, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 136; xxxiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 142, HCDR2 containing the amino acid sequence described in SEQ ID NO: 143, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 144; xxxiv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 150, HCDR2 containing the amino acid sequence described in SEQ ID NO: 151, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 152; xxxv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, 217, or 218; HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, 171, 172, 173, 220, or 222; HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, 174, 175, 176, 177, 178, 179, 180, 181, 221, 223, 224, 225, 226, 227, 228, or 229; or xxxvi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 150, HCDR2 containing the amino acid sequence described in SEQ ID NO: 210, and HCDR3 containing the amino acid sequence described in SEQ ID NO: 152; and / or i. LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 167; ii. LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; iii. LCDR1 containing the amino acid sequence described in SEQ ID NO: 153, LCDR2 containing the amino acid sequence described in SEQ ID NO: 154, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 155; iv. LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 215; v. LCDR1 containing the amino acid sequence described in SEQ ID NO: 4, LCDR2 containing the amino acid sequence described in SEQ ID NO: 5, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 6; vi. LCDR1 containing the amino acid sequence described in SEQ ID NO: 20, LCDR2 containing the amino acid sequence described in SEQ ID NO: 21, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 22; vii. LCDR1 containing the amino acid sequence described in SEQ ID NO: 28, LCDR2 containing the amino acid sequence described in SEQ ID NO: 29, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 30; viiii. LCDR1 containing the amino acid sequence described in SEQ ID NO: 36, LCDR2 containing the amino acid sequence described in SEQ ID NO: 37, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 38; ix. LCDR1 containing the amino acid sequence described in SEQ ID NO: 44, LCDR2 containing the amino acid sequence described in SEQ ID NO: 45, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 46; x. LCDR1 containing the amino acid sequence described in SEQ ID NO: 52, LCDR2 containing the amino acid sequence described in SEQ ID NO: 53, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 54; xi. LCDR1 containing the amino acid sequence described in SEQ ID NO: 60, LCDR2 containing the amino acid sequence described in SEQ ID NO: 61, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 62; xi. LCDR1 containing the amino acid sequence described in SEQ ID NO: 68, LCDR2 containing the amino acid sequence described in SEQ ID NO: 69, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 70; xiiii. LCDR1 containing the amino acid sequence described in SEQ ID NO: 76, LCDR2 containing the amino acid sequence described in SEQ ID NO: 77, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 78; xiv. LCDR1 containing the amino acid sequence described in SEQ ID NO: 84, LCDR2 containing the amino acid sequence described in SEQ ID NO: 85, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 86; xv. LCDR1 containing the amino acid sequence described in SEQ ID NO: 92, LCDR2 containing the amino acid sequence described in SEQ ID NO: 93, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 94; xvi. LCDR1 containing the amino acid sequence described in SEQ ID NO: 105, LCDR2 containing the amino acid sequence described in SEQ ID NO: 106, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 107; xvii. LCDR1 containing the amino acid sequence described in SEQ ID NO: 113, LCDR2 containing the amino acid sequence described in SEQ ID NO: 114, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 115; xviiii. LCDR1 containing the amino acid sequence described in SEQ ID NO: 121, LCDR2 containing the amino acid sequence described in SEQ ID NO: 122, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 123; xix. LCDR1 containing the amino acid sequence described in SEQ ID NO: 129, LCDR2 containing the amino acid sequence described in SEQ ID NO: 130, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 131; xx. LCDR1 containing the amino acid sequence described in SEQ ID NO: 137, LCDR2 containing the amino acid sequence described in SEQ ID NO: 138, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 139; xxi. LCDR1 containing the amino acid sequence described in SEQ ID NO: 145, LCDR2 containing the amino acid sequence described in SEQ ID NO: 146, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 147; or xxii. LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NOs: 14, 182, 183, 184, 185, 214, 215, or 216. An antibody or antigen-binding fragment thereof according to any one of the prior claims, comprising:

5. i. HCDR1 comprising the amino acid sequence described in SEQ ID NO: 219, HCDR2 comprising the amino acid sequence described in SEQ ID NO: 201, HCDR3 comprising the amino acid sequence described in SEQ ID NO: 162, LCDR1 comprising the amino acid sequence described in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence described in SEQ ID NO: 13, and LCDR3 comprising the amino acid sequence described in SEQ ID NO: 167; ii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; iii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 181, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; iv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 173, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; v. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 171, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; vi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 175, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; vii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 150, HCDR2 containing the amino acid sequence described in SEQ ID NO: 212, HCDR3 containing the amino acid sequence described in SEQ ID NO: 152, LCDR1 containing the amino acid sequence described in SEQ ID NO: 153, LCDR2 containing the amino acid sequence described in SEQ ID NO: 154, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 155; viiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 221, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; ix. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 222, HCDR3 containing the amino acid sequence described in SEQ ID NO: 180, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; x. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 171, HCDR3 containing the amino acid sequence described in SEQ ID NO: 224, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 225, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 226, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xiiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 174, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xiv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 217, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 222, HCDR3 containing the amino acid sequence described in SEQ ID NO: 180, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 215; xvi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 150, HCDR2 containing the amino acid sequence described in SEQ ID NO: 211, HCDR3 containing the amino acid sequence described in SEQ ID NO: 152, LCDR1 containing the amino acid sequence described in SEQ ID NO: 153, LCDR2 containing the amino acid sequence described in SEQ ID NO: 154, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 155; xvii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 1, HCDR2 containing the amino acid sequence described in SEQ ID NO: 2, HCDR3 containing the amino acid sequence described in SEQ ID NO: 3, LCDR1 containing the amino acid sequence described in SEQ ID NO: 4, LCDR2 containing the amino acid sequence described in SEQ ID NO: 5, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 6; xviiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 17, HCDR2 containing the amino acid sequence described in SEQ ID NO: 18, HCDR3 containing the amino acid sequence described in SEQ ID NO: 19, LCDR1 containing the amino acid sequence described in SEQ ID NO: 20, LCDR2 containing the amino acid sequence described in SEQ ID NO: 21, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 22; xix. HCDR1 containing the amino acid sequence described in SEQ ID NO: 25, HCDR2 containing the amino acid sequence described in SEQ ID NO: 26, HCDR3 containing the amino acid sequence described in SEQ ID NO: 27, LCDR1 containing the amino acid sequence described in SEQ ID NO: 28, LCDR2 containing the amino acid sequence described in SEQ ID NO: 29, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 30; xx. HCDR1 containing the amino acid sequence described in SEQ ID NO: 33, HCDR2 containing the amino acid sequence described in SEQ ID NO: 34, HCDR3 containing the amino acid sequence described in SEQ ID NO: 35, LCDR1 containing the amino acid sequence described in SEQ ID NO: 36, LCDR2 containing the amino acid sequence described in SEQ ID NO: 37, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 38; xxi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 41, HCDR2 containing the amino acid sequence described in SEQ ID NO: 42, HCDR3 containing the amino acid sequence described in SEQ ID NO: 43, LCDR1 containing the amino acid sequence described in SEQ ID NO: 44, LCDR2 containing the amino acid sequence described in SEQ ID NO: 45, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 46; xxii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 49, HCDR2 containing the amino acid sequence described in SEQ ID NO: 50, HCDR3 containing the amino acid sequence described in SEQ ID NO: 51, LCDR1 containing the amino acid sequence described in SEQ ID NO: 52, LCDR2 containing the amino acid sequence described in SEQ ID NO: 53, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 54; xxiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 57, HCDR2 containing the amino acid sequence described in SEQ ID NO: 58, HCDR3 containing the amino acid sequence described in SEQ ID NO: 59, LCDR1 containing the amino acid sequence described in SEQ ID NO: 60, LCDR2 containing the amino acid sequence described in SEQ ID NO: 61, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 62; xxiv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 65, HCDR2 containing the amino acid sequence described in SEQ ID NO: 66, HCDR3 containing the amino acid sequence described in SEQ ID NO: 67, LCDR1 containing the amino acid sequence described in SEQ ID NO: 68, LCDR2 containing the amino acid sequence described in SEQ ID NO: 69, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 70; xxv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 73, HCDR2 containing the amino acid sequence described in SEQ ID NO: 74, HCDR3 containing the amino acid sequence described in SEQ ID NO: 75, LCDR1 containing the amino acid sequence described in SEQ ID NO: 76, LCDR2 containing the amino acid sequence described in SEQ ID NO: 77, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 78; xxvi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 81, HCDR2 containing the amino acid sequence described in SEQ ID NO: 82, HCDR3 containing the amino acid sequence described in SEQ ID NO: 83, LCDR1 containing the amino acid sequence described in SEQ ID NO: 84, LCDR2 containing the amino acid sequence described in SEQ ID NO: 85, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 86; xxvii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 89, HCDR2 containing the amino acid sequence described in SEQ ID NO: 90, HCDR3 containing the amino acid sequence described in SEQ ID NO: 91, LCDR1 containing the amino acid sequence described in SEQ ID NO: 92, LCDR2 containing the amino acid sequence described in SEQ ID NO: 93, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 94; xxviiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 102, HCDR2 containing the amino acid sequence described in SEQ ID NO: 103, HCDR3 containing the amino acid sequence described in SEQ ID NO: 104, LCDR1 containing the amino acid sequence described in SEQ ID NO: 105, LCDR2 containing the amino acid sequence described in SEQ ID NO: 106, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 107; xxix. HCDR1 containing the amino acid sequence described in SEQ ID NO: 110, HCDR2 containing the amino acid sequence described in SEQ ID NO: 111, HCDR3 containing the amino acid sequence described in SEQ ID NO: 112, LCDR1 containing the amino acid sequence described in SEQ ID NO: 113, LCDR2 containing the amino acid sequence described in SEQ ID NO: 114, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 115; xxx. HCDR1 containing the amino acid sequence described in SEQ ID NO: 118, HCDR2 containing the amino acid sequence described in SEQ ID NO: 119, HCDR3 containing the amino acid sequence described in SEQ ID NO: 120, LCDR1 containing the amino acid sequence described in SEQ ID NO: 121, LCDR2 containing the amino acid sequence described in SEQ ID NO: 122, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 123; xxxi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 126, HCDR2 containing the amino acid sequence described in SEQ ID NO: 127, HCDR3 containing the amino acid sequence described in SEQ ID NO: 128, LCDR1 containing the amino acid sequence described in SEQ ID NO: 129, LCDR2 containing the amino acid sequence described in SEQ ID NO: 130, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 131; xxxii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 134, HCDR2 containing the amino acid sequence described in SEQ ID NO: 135, HCDR3 containing the amino acid sequence described in SEQ ID NO: 136, LCDR1 containing the amino acid sequence described in SEQ ID NO: 137, LCDR2 containing the amino acid sequence described in SEQ ID NO: 138, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 139; xxxiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 142, HCDR2 containing the amino acid sequence described in SEQ ID NO: 143, HCDR3 containing the amino acid sequence described in SEQ ID NO: 144, LCDR1 containing the amino acid sequence described in SEQ ID NO: 145, LCDR2 containing the amino acid sequence described in SEQ ID NO: 146, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 147; xxxiv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 150, HCDR2 containing the amino acid sequence described in SEQ ID NO: 151, HCDR3 containing the amino acid sequence described in SEQ ID NO: 152, LCDR1 containing the amino acid sequence described in SEQ ID NO: 153, LCDR2 containing the amino acid sequence described in SEQ ID NO: 154, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 155; xxxv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 172, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xxxvi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 176, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xxxvii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 177, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xxxviiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 178, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xxxix. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 179, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xl. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 180, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xli. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 182; xlii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 183; xliiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 184; xlv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 185; xlv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 220, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xlvi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 172, HCDR3 containing the amino acid sequence described in SEQ ID NO: 223, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; xlvii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 214; xlviiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 215; xlix. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 216; l. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 172, HCDR3 containing the amino acid sequence described in SEQ ID NO: 223, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 214; i. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 172, HCDR3 containing the amino acid sequence described in SEQ ID NO: 223, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 215; li. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 227, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; liiii. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 228, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; liv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 9, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 229, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; lv. HCDR1 containing the amino acid sequence described in SEQ ID NO: 218, HCDR2 containing the amino acid sequence described in SEQ ID NO: 10, HCDR3 containing the amino acid sequence described in SEQ ID NO: 11, LCDR1 containing the amino acid sequence described in SEQ ID NO: 12, LCDR2 containing the amino acid sequence described in SEQ ID NO: 13, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 14; or lvi. HCDR1 containing the amino acid sequence described in SEQ ID NO: 150, HCDR2 containing the amino acid sequence described in SEQ ID NO: 210, HCDR3 containing the amino acid sequence described in SEQ ID NO: 152, LCDR1 containing the amino acid sequence described in SEQ ID NO: 153, LCDR2 containing the amino acid sequence described in SEQ ID NO: 154, and LCDR3 containing the amino acid sequence described in SEQ ID NO: 155; An antibody or antigen-binding fragment thereof according to any one of the prior claims, comprising:

6. a) A VH region having the amino acid sequence described in SEQ ID NOs: 165, 196, 192, 186, 188, 234, 235, 237, 238, 239, 242, 244, 205, 7, 15, 23, 31, 39, 47, 55, 63, 71, 79, 87, 95, 108, 116, 124, 132, 140, 148, 156, 163, 164, 166, 187, 189, 190, 191, 193, 194, 195, 213, 202, 203, 204, 206, 233, 236, 240, 241, 243 or 245, or SEQ ID NOs: 1 Homologous sequences having at least 80% sequence identity with 65, 196, 192, 186, 188, 234, 235, 237, 238, 239, 242, 244, 205, 7, 15, 23, 31, 39, 47, 55, 63, 71, 79, 87, 95, 108, 116, 124, 132, 140, 148, 156, 163, 164, 166, 187, 189, 190, 191, 193, 194, 195, 213, 202, 203, 204, 206, 233, 236, 240, 241, 243 or 245, and / or b) A VL region having the amino acid sequence described in SEQ ID NOs: 169, 231, 207, 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 109, 117, 125, 133, 141, 149, 157, 168, 170, 197, 198, 199, 200, 208, 209, 230 or 232, or homologous sequences having at least 80% sequence identity with sequence numbers 169, 231, 207, 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 109, 117, 125, 133, 141, 149, 157, 168, 170, 197, 198, 199, 200, 208, 209, 230, or 232. An antibody or antigen-binding fragment thereof according to any one of the prior claims, comprising:

7. Sequence numbers 165 / 169, 196 / 169, 192 / 169, 186 / 169, 188 / 169, 234 / 169, 235 / 169, 237 / 169, 238 / 169, 239 / 169, 242 / 169, 244 / 169, 235 / 231, 205 / 207, 7 / 8, 15 / 16, 23 / 24, 31 / 32, 39 / 40, 47 / 48, 55 / 56, 63 / 64, 7 1 / 72, 79 / 80, 87 / 88, 95 / 96, 108 / 109, 116 / 117, 124 / 125, 132 / 133, 140 / 141, 148 / 149, 156 / 157, 163 / 168, 163 / 169, 163 / 170, 164 / 168, 164 / 169, 164 / 170, 165 / 168, 165 / 170, 166 / 168, 166 / 169, 166 / 1 70, 187 / 169, 189 / 169, 190 / 169, 191 / 169, 193 / 169, 194 / 169, 195 / 169, 165 / 197, 165 / 198, 165 / 199, 165 / 200, 202 / 207, 202 / 208, 202 / 209, 203 / 207, 203 / 208, 203 / 209, 204 / 207, 206 / 207, 206 / 208, An antibody or antigen-binding fragment according to any one of the prior claims, comprising a VH / VL amino acid sequence pair selected from the group consisting of 206 / 209, 233 / 169, 236 / 169, 240 / 169, 241 / 169, 243 / 169, 245 / 169, 165 / 230, 165 / 231, 165 / 232, 235 / 230, 236 / 230, and 236 / 231.

8. a) further comprising one or more amino acid residue substitutions or modifications, but still retaining specific binding affinity to CD3, optionally, i) At least one of the substitutions or modifications is present in one or more CDR sequences of the VH region or VL region, ii) At least one of the substitutions or modifications is present in one or more non-CDR sequences in the VH region or VL region, and / or b) further comprising one or more non-natural amino acid (NNAA) substitutions, optionally, The aforementioned NNAA can be conjugated, and / or c) i. It is capable of specifically binding to human CD3 (e.g., as measured by a FACS assay); ii. Capable of binding to both human and cynomolgus monkey CD3 (e.g., as measured by FACS assay); iii. Having T cell activation ability (e.g., as measured by the Jurkat NFAT-luciferase activation assay); and iv. Possessing PBMC activating ability (e.g., as measured by ELISA assay) Having one or more characteristics for CD3 selected from the group consisting of and / or d) A chimeric, humanized, or human antibody or its antigen-binding fragment, and / or e) A labeled antibody, a bivalent antibody, an anti-idiotype antibody or a fusion protein, and / or f) Diabody, Fab, Fab', F(ab')², Fd, Fv fragment, disulfide-stabilized Fv fragment (dsFv), a(dsFv)², bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabody (dsdiabody), single-chain antibody molecule (scFv), scFv dimer (bivalent diabody), camelized single-domain antibody, nanobody, domain antibody, or bivalent domain antibody, and / or g) Fc region, optionally further comprising the Fc region of human immunoglobulin (Ig), or optionally the Fc region of human IgG, preferably, The Fc region is optionally derived from human IgG1, IgG2, IgG3, or IgG4. The Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 97 to 99, and / or h) The light chain is a λ light chain or a κ light chain, and / or i) A bispecific or polyspecific antibody or its antigen-binding fragment, optionally, It is preferably capable of specifically binding to one or more additional antigens other than CD3, or to a second epitope on CD3. One or more of the additional antigens other than CD3 are CD16a, CD33, CD38, CD45, CD123, CD146, CD228, CLL-1, FLT3, FLT3L, TAF1, TgPRF, HVCC1, IL-6R, IL-11R, IL17A, IL-23R, IL-33, ILDR2, LAP, TSLP, TREM-1, ANGPT2, APOE, IFNAR, CypA, DOG-1, NKp30, CSF-1R, CCR2, LRRC15, Mesothelin, Dickkopf2, DLL3, HER-2, C10orf54 , TrkA, MEKK1, KRAS, ERK, XPO1, mTORC1 / 2, PAK4, NAMPT, ATR, EGFR, FGFR, VEGF, LILRB (e.g. LILRB1, LILRB2, LILRB3, LILRB4, LILRB5), c-MET, Her 2, Her3, CTLA4, GITA, CD112R, CD2, CD7, CD16, CD19, CD20, CD24, CD27, CD 30, CD34, CD37, CD39, CD70, CD73, CD83, CD28, CD80 (B7-1), CD86 (B7-2), CD40, CD40L (CD154), CD47, SIRPα, CD122, CD137, CD137L, OX40 (CD134), OX40L (CD252), BCMA (e.g. BCMA02), PSMA, CLDN18 (e.g. CLDN18.2), NKG2 C, 4-1BB, LIGHT, PVRIG, SLAMF7, HVEM, BAFFR, ICAM-1, 2B4, LFA-1, GITR, ICOS (CD278), ICOSLG (CD275), LAG3 (CD223), A2AR, B7-H3 (CD276), B7-H Selected from the group consisting of 4 (VTCN1), B7-H5, BTLA (CD272), CD160, CTLA-4 (CD152), GPRC5D, IDO (e.g., IDO1, IDO2), ILT3, TDO, KIR, LAIR-1, NOX2, PD-1, PD-L1, PD-L2, TIM-3, VISTA, SIGLEC-7 (CD328), SIGLEC-9 (CD329), SIGLEC-15, TIGIT, PVR (CD155), TLR3, CLEC9A, DEC-205, STING, and TGFβ, and / or j) Connected to one or more conjugate portions, preferably, The conjugate portion preferably comprises a clearance modifier, a chemotherapeutic agent, a toxin, a radioisotope, a lantanide, a detectable label, a DNA alkylating agent, a topoisomerase inhibitor, a tubulin binder, a purified portion, or other anticancer agents. The conjugate portion is covalently linked directly or via a linker. An antibody or its antigen-binding fragment according to any one of the prior claims.

9. An antibody or antigen-binding fragment thereof that competes with the antibody or antigen-binding fragment thereof described in any one of the prior claims with respect to binding to CD3.

10. A chimeric antigen receptor comprising an antibody or its antigen-binding fragment, a transmembrane region and an intracellular signaling region according to any one of claims 1 to 9, wherein optionally, A) The transmembrane region includes the transmembrane region of CD3, CD4, CD8 or CD28, and / or B) The intracellular signaling region is selected from the group consisting of intracellular signaling region sequences of CD3, FcγRI, CD27, CD28, CD137, CD134, MyD88, CD40, CD278, TLR, or combinations thereof, and / or C) The antigen-binding fragment is scFv, and / or D) Grafted onto allogeneic cells, autologous cells, or heterogeneous cells, and / or E) Grafted onto immune effector cells, and / or F) Chimeric antigen receptors grafted onto T cells, natural killer cells, macrophages, or tumor-infiltrating lymphocytes.

11. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 9, or a chimeric antigen receptor according to claim 10, and one or more pharmaceutically acceptable carriers.

12. An isolated polynucleotide encoding an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 9, and / or a chimeric antigen receptor according to claim 10.

13. A vector comprising an isolated polynucleotide as described in claim 12.

14. A host expression system comprising the vector described in claim 13, or having the polynucleotide described in claim 12 incorporated into its genome, preferably, A host expression system comprising a microorganism, yeast, or mammalian cell, wherein the microorganism is optionally selected from the group consisting of Escherichia coli and Bacillus subtilis, the yeast is optionally selected to be Saccharomyces, and the mammalian cell is optionally selected from the group consisting of COS, CHO-S, CHO-K1, HEK-293, and 3T3 cells.

15. A virus comprising the vector described in claim 13.

16. a) comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, and / or a chimeric antigen receptor according to claim 10, and / or a pharmaceutical composition according to claim 11, and a second therapeutic agent, b) comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, and / or a chimeric antigen receptor according to claim 10, and / or a pharmaceutical composition according to claim 11, which is useful for detecting CD3, optionally recombinant CD3, CD3 expressed on the cell surface, or CD3-expressing cells. kit.

17. A method for expressing an antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, or a chimeric antigen receptor according to claim 10, comprising culturing the host expression system according to claim 14 under conditions in which the antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, or the chimeric antigen receptor according to claim 10, is expressed.

18. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, and / or a chimeric antigen receptor according to claim 10, and / or a pharmaceutical composition according to claim 11, for use in a method of treating, preventing, or alleviating a disease, disorder, or condition in a subject, The method comprises administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, and / or a chimeric antigen receptor according to claim 10, and / or a pharmaceutical composition according to claim 11, optionally, A) The disease, disorder, or condition is an immune disease, inflammatory disease, cancer, or neurological disease, preferably, The cancer is a solid tumor or a hematological malignancy, or The aforementioned disease, disorder, or condition is lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), lung adenocarcinoma, or lung squamous cell carcinoma), abdominal cancer, carcinoid cancer, bone cancer, pancreatic cancer, undifferentiated neuroectodermal tumor, skin cancer, gallbladder cancer, head or neck cancer, squamous cell carcinoma, uterine cancer, ovarian cancer, rectal cancer, prostate cancer, bladder cancer (e.g., urothelial carcinoma), anal cancer (e.g., anal squamous cell carcinoma), gastric cancer, or stomach cancer.Cancer (e.g., gastrointestinal cancer), esophageal cancer, colon cancer, breast cancer, uterine cancer, liver cancer (e.g., hepatoblastoma, hepatocellular carcinoma / hepatoma, or liver cancer), cholangiocarcinoma, sarcoma, colorectal cancer, fallopian tube cancer, salivary gland cancer, cervical cancer, endometrial cancer or uterine cancer, osteosarcoma, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, nasopharyngeal cancer, soft tissue sarcoma, polycythemia vera, urethral cancer, penile cancer, kidney cancer or ureteral cancer (e.g., renal rhabdoid tumor), cutaneous T-cell lymphoma, medulloblastoma, nephroblastoma, myelodysplastic syndrome, chronic and non-chronic myeloplasty Progenitor dysfunction, choroid plexus papilloma, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, soft tissue sarcomas (e.g., rhabdomyosarcoma, fibrosarcoma, Kaposi's sarcoma), spinal axial tumors, gliomas (e.g., ependymoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ocular cancer (e.g., retinoblastoma), brainstem glioma, or mixed glioma, e.g., oligodendroglioma), brain tumors (e.g., glioblastoma / glioblastoma multiforme (GBM), non-glioblastomatous brain tumor, or meningioma), melanoma (e.g., cutaneous or intraocular melanoma), thrombocytosis, mesothelioma, mycosis fungoides, Sézary syndrome, idiopathic myelofibrosis, solitary Plasmacytoma, vestibular schwannoma, Ewing's sarcoma, chondrosarcoma, MYH-associated polyposis, pituitary adenoma, childhood cancers, e.g., childhood sarcomas (e.g., neuroblastoma, rhabdomyosarcoma, and osteosarcoma), hematological cancers, Hodgkin lymphoma, non-Hodgkin lymphoma, leukemia (e.g., lymphocytic / lymphoblastic leukemia), chronic or acute leukemia, mast cell leukemia, lymphocytic lymphoma, primary CNS lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), chronic lymphoblastic leukemia A selection from the group consisting of cystic leukemia, acute lymphoblastic leukemia, hairy cell leukemia (HCL), Burkitt lymphoma (BL), multiple myeloma (e.g., relapsed or refractory multiple myeloma), T or B cell lymphoma, mantle cell lymphoma (MCL) (e.g., relapsed or refractory mantle cell lymphoma), malignant melanoma, diffuse large B cell lymphoma (DLBCL), DLBCL resulting from follicular lymphoma, high-grade B cell lymphoma, primary mediastinal large B cell lymphoma, follicular lymphoma (FL), and primary mediastinal B cell lymphoma, or B) The subject is a human, or C) The administration is carried out via parenteral routes including subcutaneous, intraperitoneal, intravenous, intramuscular, or intradermal injection; or via routes other than parenteral routes including transdermal, oral, intranasal, intraocular, sublingual, rectal, or topical surface, or D) Optionally, further comprising administering an additional therapeutic agent to the subject in need thereof, The additional therapeutic agent is selected from the group consisting of activators, contrast agents, cytotoxic agents, angiogenesis inhibitors, kinase inhibitors, costimulatory molecule agonists, co-inhibitory molecule blockers, adhesion molecule blockers, anti-cytokine antibodies or their functional fragments, detectable labels or reporters, antibacterial agents, gene editing agents, beta-agonists, viral RNA inhibitors, polymerase inhibitors, interferons, and microRNAs, or The additional therapeutic agent is administered to the subject in need before, after, or concurrently with the antibody or antigen-binding fragment thereof described in any one of claims 1 to 9, and / or the chimeric antigen receptor described in claim 10, and / or the pharmaceutical composition described in claim 11. An antibody or an antigen-binding fragment thereof according to any one of claims 1 to 9, and / or a chimeric antigen receptor according to claim 10, and / or a pharmaceutical composition according to claim 11.

19. A method, I) A method for activating CD3-expressing T cells in vivo or in vitro, comprising contacting CD3-expressing T cells with an antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, and / or a chimeric antigen receptor according to claim 10, and / or a pharmaceutical composition according to claim 11. II) A method for modulating CD3 activity in CD3-expressing cells, comprising exposing CD3-expressing cells to an antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, and / or a chimeric antigen receptor according to claim 10, and / or a pharmaceutical composition according to claim 11. III) A method for promoting in vivo or in vitro processing of a second antigen by CD3-expressing T cells, comprising contacting CD3-expressing T cells with a bispecific or multispecific antibody or its antigen-binding fragment as described in claim 8, wherein the bispecific or multispecific antibody or its antigen-binding fragment can bind to both the CD3-expressing T cells and the second antigen, thereby bringing them into close proximity. IV) A method for detecting the presence or amount of CD3 in a sample, comprising contacting the sample with an antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, and / or a chimeric antigen receptor according to claim 10, and / or a pharmaceutical composition according to claim 11, and determining the presence or amount of CD3 in the sample, or V) a) a method for diagnosing a CD3-related disease or condition in a subject, comprising: a) contacting a sample obtained from the subject with an antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, and / or a chimeric antigen receptor according to claim 10, and / or a pharmaceutical composition according to claim 11; b) determining the presence or amount of CD3 in the sample; and c) relating the presence or amount of CD3 to the presence or condition of a CD3-related disease or condition in the subject.

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