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US-20260125468-A1 - CD3-TARGETING ANTIBODY AND USE THEREOF

US20260125468A1US 20260125468 A1US20260125468 A1US 20260125468A1US-20260125468-A1

Abstract

Disclosed herein are CD3-targeting antibodies and bispecific antibodies targeting both CD3 and tumor-associated antigens. Polynucleotides encoding the antibodies, pharmaceutical compositions comprising the antibodies, and methods of producing the antibodies described above are also provided herein. Medical uses of the antibodies described herein are also disclosed.

Inventors

  • Yuexiang YIN
  • Gezi JIA
  • Jian Wang
  • Chengen WANG
  • Qiuming PAN
  • Yuetao Wu

Assignees

  • NONA BIOSCIENCES (SUZHOU) CO., LTD.

Dates

Publication Date
20260507
Application Date
20230918
Priority Date
20220930

Claims (20)

  1. 1 . (canceled)
  2. 2 . A CD3-targeting antibody comprising a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein, the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 17, 41 and 62, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 18, 41 and 63, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 64, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 17, 41 and 65, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 66, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 21, 42 and 64, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 67, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 68, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 69, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 70, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 71, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 72, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 73, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 74, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 75, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 76, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 77, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 22, 42 and 64, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 43 and 64, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 78, respectively; or the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 79, respectively; the CDR regions are defined as Chothia numbering system.
  3. 3 . The antibody according to claim 2 , wherein the heavy chain variable region (VH) comprises the amino acid sequence as set forth in any one of SEQ ID NOs: 107-108 and SEQ ID NOs: 110-132; or, the VH fragment has at least 90%, at least 95%, at least 98%, at least 99% of sequence identity to the amino acid sequence as set forth in any one of SEQ ID NOs: 107-108 and SEQ ID NOs: 110-132.
  4. 4 . The antibody according to claim 2 , wherein the antibody further comprises a heavy chain constant region; preferably, the heavy chain constant region is derived from hIgG1, hIgG2, hIgG3 and hIgG4 and a variant thereof; more preferably, the heavy chain constant region is derived from hIgG1.
  5. 5 . The antibody according to claim 4 , wherein the antibody further comprises one or more mutations at heavy chain constant region; preferably, the mutation could be selected from L234A, L235A, G237A, P329G (Eu numbering) or any combination.
  6. 6 . The antibody according to claim 3 , wherein the antibody is a heavy chain only antibody comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 141-142 and SEQ ID NOs: 144-166.
  7. 7 . A bispecific antibody comprising a first antigen-binding fragment targeting CD3 and a second antigen-binding fragment targeting tumor associated antigen (TAA); wherein the first antigen-binding fragment targeting CD3 is as described in claim 2 ; preferably, the TAA could be any one of CD19, BCMA, TSHR, CD171, CS-1, CLL-1, GD3, Tn Ag, FLT3, CD38, CD123, CD44v6, B7H3, B7H4, KIT, IL-13Ra2, IL-11Ra, PSCA, PSMA, PRSS21, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, MUC1, EGFR, NCAM, CAIX, LMP2, EphA2, sLe, GM3, TGS5, HMWMAA, GD2, FOLR1, FOLR2, TEM1/CD248, TEM7R, CLDN6, CLDN18.2, GPRC5D, CXORF61, CD97, CD179a, ALK, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TAARP, WT1, ETV6-AML, SPA17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, FOSL1, hTERT, ML-IAP, ERG, NA17, PAX3, AR, Cyclin B1, MYCN, RhoC, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLECi2A, BST2, EMR2, LY75, GPC3, FCRL5, IGLL1, CD20, CD30, HER2, ROR1, FLT3, TAAG72, CD22, CD33, GD2, gp100Tn, FAP, TYR, EPCAM, CEA, IGF-1R, EphB2, MSLN, CDH17, CD32b, EGFRvIII, GPNMB, GPR64, HER3, LRP6, LYPD8, NKG2D, SLC34A2, SLC39A6, SLITRK6, GUCY2C and TACSTD2; more preferably, BCMA, B7H4 or ROR1.
  8. 8 . The bispecific antibody according to claim 7 , wherein the second antigen-binding fragment targets B7H4; preferably, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; the CDR regions are defined as Chothia numbering system.
  9. 9 . The bispecific antibody according to claim 7 , wherein the second antigen-binding fragment targets BCMA; preferably, the second antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 12, 36 and 57, respectively; the CDR regions are defined as Chothia numbering system.
  10. 10 . The bispecific antibody according to claim 7 , wherein the second antigen-binding fragment targets ROR1; preferably, the second antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 15, 39 and 60, respectively; the CDR regions are defined as Chothia numbering system.
  11. 11 . The bispecific antibody according to claim 7 , wherein, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 17, 41 and 62, respectively; the second antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 12, 36 and 57, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 18, 41 and 63, respectively; the second antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 12, 36 and 57, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 17, 41 and 62, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 18, 41 and 63, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 64, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 17, 41 and 65, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 66, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 21, 42 and 64, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 67, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 68, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 69, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 70, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 71, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 72, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 73, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 74, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 75, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 76, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 77, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 22, 42 and 64, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 43 and 64, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 78, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 79, respectively; the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises an LCDR1, an LCDR2 and an LCDR3, wherein the LCDR1, LCDR2 and LCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 88, 93 and 98, respectively, the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 14, 38 and 59, respectively; or the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 17, 41 and 62, respectively; the second antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises an HCDR1, an HCDR2 and an HCDR3, wherein the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 15, 39 and 60, respectively; the CDR regions are defined as Chothia numbering system.
  12. 12 . The bispecific antibody according to claim 7 , wherein, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 107, the second antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 101; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 108, the second antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 101; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 107, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 108, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 110, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 111, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 112, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 113, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 114, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 115, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 116, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 117, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 118, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 119, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 120, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 121, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 122, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 123, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 124, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 125, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 126, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 127, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 128, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 129, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 130, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 131, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 132, the second antigen-binding fragment comprises one light chain variable region (VL) and one heavy chain variable region (VH), the VL region comprises the amino acid sequence set forth in SEQ ID NO: 134, the VH region comprises the amino acid sequence set forth in SEQ ID NO: 103; or, the first antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 107, the second antigen-binding fragment comprises one heavy chain variable region (VH), the VH region comprises the amino acid sequence set forth in SEQ ID NO: 105.
  13. 13 . The bispecific antibody according to claim 7 , comprising one polypeptide with the amino acid sequence set forth in SEQ ID NO: 172; or comprising one polypeptide with the amino acid sequence set forth in SEQ ID NO: 173; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 175, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 170; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 176, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 170; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 177, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 179, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 180, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 181, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 182, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 183, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 185, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 186, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 187, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 188, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 189, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 190, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 191, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 192, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 193, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 194, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 195, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 196, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 197, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 198, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 199, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 200, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising two polypeptides, wherein, the first polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 201, the second polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 178; or comprising one polypeptide with the amino acid sequence set forth in SEQ ID NO: 184.
  14. 14 . A polynucleotide encoding the CD3-targeting antibody of claim 2 or a bispecific antibody; wherein the bispecific antibody comprises a first antigen-binding fragment targeting CD3 and a second antigen-binding fragment targeting tumor associated antigen (TAA); wherein the first antigen-binding fragment targeting CD3 is the CD3-targeting antibody; preferably, the polynucleotide is selected from DNA or RNA; more preferably, the polynucleotide is mRNA.
  15. 15 . A vector comprising the polynucleotide of claim 14 .
  16. 16 . A cell comprising the CD3-targeting antibody of claim 2 , or a bispecific antibody, a polynucleotide encoding the CD3-targeting antibody or the bispecific antibody, or a vector comprising the polynucleotide; wherein the bispecific antibody comprises a first antigen-binding fragment targeting CD3 and a second antigen-binding fragment targeting tumor associated antigen (TAA); wherein the first antigen-binding fragment targeting CD3 is the CD3-targeting antibody.
  17. 17 . A method for preparing the CD3-targeting antibody of claim 2 or a bispecific antibody, comprising a step of cultivating a cell comprising a polynucleotide encoding the CD3-targeting antibody or the bispecific antibody or a vector comprising the polynucleotide to obtain the CD3-targeting antibody or the bispecific antibody from culture; wherein the bispecific antibody comprises a first antigen-binding fragment targeting CD3 and a second antigen-binding fragment targeting tumor associated antigen (TAA); wherein the first antigen-binding fragment targeting CD3 is the CD3-targeting antibody.
  18. 18 . A pharmaceutical composition comprising the CD3-targeting antibody of claim 2 or a bispecific antibody or a polynucleotide encoding the CD3-targeting antibody or the bispecific antibody, or a vector comprising the polynucleotide, or a cell comprising the CD3-targeting antibody, the bispecific antibody, the polynucleotide or the vector, and optionally a pharmaceutically acceptable carrier; wherein the bispecific antibody comprises a first antigen-binding fragment targeting CD3 and a second antigen-binding fragment targeting tumor associated antigen (TAA); wherein the first antigen-binding fragment targeting CD3 is the CD3-targeting antibody.
  19. 19 . (canceled)
  20. 20 . (canceled)

Description

TECHNICAL FIELD The present disclosure relates to molecular biology and immunology. Provided herein include anti-CD3 antibodies comprising a VHH fragment (single variable domain VH of heavy chain antibodies), bispecific antibodies comprising the same, as well as uses thereof in treating diseases. BACKGROUND CD3 targeted bispecific antibodies are an emerging treatment modality in the field of cancer immunotherapy. In 2014, FDA approved the anti-CD3xCD19 bispecific T-cell engager blinatumomab for the treatment of patients with Philadelphia chromosome-negative B cell acute lymphoblastic leukemia. More than 100 clinical trials have been initiated for CD3 bispecific T cell redirection in cancer, and some of them show promising outcome in both hematological and solid tumor. CD3 bispecific antibodies can simultaneously target CD3 on T cells and tumor-associated antigens (TAA) expressed on cancer cells. Crosslinking of these two cell types by CD3 bispecific antibodies allows the formation of an immunological synapse similar to that of a natural TCR-MHC complex. This synapse results in T cell activation and thereby secreting inflammatory cytokines and cytolytic molecules which are able to kill the cancer cells in the process. Unlike the TCR, CD3 bispecific antibodies are capable of inducing redirected lysis of cancer cells by polyclonal T cells in an MHC-peptide complex independent manner. Therefore, CD3 bispecific antibodies can engage all available T cells, not restricted to tumor specific T cells, to target and to lyse the tumor by the redirection of the other anti-TAA arm. As new insights in cancer biology accumulate and the antibody technology advances, many different formats of CD3 bispecific have been generated. However, so far, there is still no bispecific utilizing anti-CD3 single domain antibodies reported. VHH antibodies, derived from heavy chain antibodies in llama or alpaca, retain their binding activity in a monomeric manner. This brings the merits for multi-specific antibody construction: first, using VHH instead of VH and VL can reduce the overall chain numbers and obviates the mismatch of unpaired chains; second, due to the strictly monomeric nature, the VHH can be easily grafted onto various parts of multivalent antibodies without compromising qualified biophysical and biochemical properties. As more and more evidences indicate that only first signal or second signal with TAA redirection by bispecific antibodies are far from sufficient to treat solid tumor, there is great demand for trispecific antibodies including one arm targeting CD3 for T cell activation and engagement of tumor lysing, one arm targeting second signal for immune cell proliferation and anti-apoptosis, and the third arm for tumor targeting. Under such circumstances, anti-CD3 VHH antibodies that could be conveniently grafted onto existent costimulatory or immune check point inhibitory bispecific antibodies are of invaluable importance and extreme urgency. SUMMARY Provided herein are antibodies that specifically bind to CD3, bispecific antibodies that further bind to tumor-associated antigens, related pharmaceutical compositions, polynucleotides, vectors, and recombinant cells. Methods of producing the antibodies and uses thereof are also provided herein. Here we demonstrate the discovery of anti-CD3 VHH antibodies. These anti-CD3 VHHs can bind to human CD3 proteins, can specifically bind to human T lymphocyte cell line Jurkat while not to CD3/TCR knockout Jurkat variant cell line, and can activate Jurkat-NFAT-luciferase cells. Most importantly, when constructed into tumor targeting bispecific antibody with anti-BCMA or anti-B7H4 or anti-ROR1 antibodies, the anti-CD3 VHH can engage T cells for tumor cell lysing. This functional anti-CD3 VHH may play indispensable role in future T cell engaging cancer therapy. The first aspect of the present disclosure provides a CD3-targeting antibody comprising a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3, wherein the HCDR1 comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 17-18 and 20-22, the HCDR2 comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 41-43, and the HCDR3 comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 62-79. In some embodiments, the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 17, 41 and 62, respectively. In some other embodiments, the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 18, 41 and 63, respectively. In some other embodiments, the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 64, respectively. In some other embodiments, the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 17, 41 and 65, respectively. In some other embodiments, the HCDR1, HCDR2 and HCDR3 comprise the amino acid sequence set forth in SEQ ID NOs: 20, 42 and 66, respectively. In s