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CN-122003437-A - Anti-FGFR 2 antibodies and multispecific binding molecules comprising same

CN122003437ACN 122003437 ACN122003437 ACN 122003437ACN-122003437-A

Abstract

An isolated antibody or antigen-binding fragment that specifically binds FGFR2 protein and a multispecific binding molecule comprising an isolated antibody or antigen-binding fragment that specifically binds FGFR2 protein. Also disclosed are nucleic acids encoding the isolated antibodies or antigen binding fragments that specifically bind FGFR2 proteins or the multispecific binding molecules and host cells comprising the isolated antibodies or antigen binding fragments that specifically bind FGFR2 proteins or the multispecific binding molecules or the nucleic acids, and methods of making the isolated antibodies or antigen binding fragments that specifically bind FGFR2 proteins, the multispecific binding molecules. Furthermore, it further relates to diagnostic, prophylactic and/or therapeutic uses of said isolated antibodies or antigen binding fragments or said multispecific binding molecules that specifically bind to FGFR2 proteins.

Inventors

  • DANG YUJIA
  • HUANG XIAO
  • Ni Chengze
  • ZHANG PENG
  • LING HONG

Assignees

  • 南京维立志博生物科技股份有限公司

Dates

Publication Date
20260508
Application Date
20240927
Priority Date
20230928

Claims (20)

  1. An anti-FGFR 2 antibody or antigen-binding fragment thereof comprising I. Three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH as shown in SEQ ID No. 63, 69, 71, 73, 75, 77 or 79, and three complementarity determining regions LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL as shown in SEQ ID No. 81, 86 or 88; Three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH as shown in SEQ ID NO. 2, and three complementarity determining regions LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL as shown in SEQ ID NO. 7; Three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH as set forth in SEQ ID NO. 22, and three complementarity determining regions LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL as set forth in SEQ ID NO. 81; three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH as shown in SEQ ID NO. 37, and three complementarity determining regions LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL as shown in SEQ ID NO. 41; v. three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH as set forth in SEQ ID NO. 27, and three complementarity determining regions LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL as set forth in SEQ ID NO. 32; Three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH as shown in SEQ ID NO. 12, and three complementarity determining regions LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL as shown in SEQ ID NO. 17; Three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH as shown in SEQ ID NO 44 or 104, and three complementarity determining regions LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL as shown in SEQ ID NO 49 or 105; three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH as shown in SEQ ID NO:54 and three complementarity determining regions LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL as shown in SEQ ID NO:58, or Three complementarity determining regions HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region VH as shown in SEQ ID NO. 22, and three complementarity determining regions LCDR1, LCDR2 and LCDR3 contained in the light chain variable region VL as shown in SEQ ID NO. 81.
  2. An anti-FGFR 2 antibody or antigen-binding fragment thereof comprising HCDR1, HCDR2 and HCDR3, and LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 64, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 65 or 66, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 67, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 82, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 83, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 84. HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 3, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 4, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 5, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 8, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 9, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 10; HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 23, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 24, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 25, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 82, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 83, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 84. HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 3, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 38, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 39, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 8, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 42, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 10. HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 28, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 29, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 30, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 33, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 34, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 35; HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 13, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 14, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 15, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 18, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 19, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 20. HCDR1 comprises, consists of, or consists of the amino acid sequence of SEQ ID NO. 45, HCDR2 comprises, consists of, or consists of the amino acid sequence of SEQ ID NO. 46, HCDR3 comprises, consists of, or consists of the amino acid sequence of SEQ ID NO. 47, LCDR1 comprises, consists of, or consists of the amino acid sequence of SEQ ID NO. 50, LCDR2 comprises, consists of, or consists of the amino acid sequence of SEQ ID NO. 51, and LCDR3 comprises, consists of, or consists of the amino acid sequence of SEQ ID NO. 52 HCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 3, HCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 55, HCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 56, LCDR1 comprises or consists of the amino acid sequence of SEQ ID NO. 59, LCDR2 comprises or consists of the amino acid sequence of SEQ ID NO. 60, and LCDR3 comprises or consists of the amino acid sequence of SEQ ID NO. 61.
  3. The antibody or antigen-binding fragment thereof of claim 1 or 2, comprising a heavy chain variable region VH, wherein the heavy chain variable region (I) Comprising or consisting of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO. 2, 12, 22, 27, 37, 44, 54, 63, 69, 71, 73, 75, 77, 79 or 104, or (Ii) Comprising or consisting of the amino acid sequence of SEQ ID NO. 2, 12, 22, 27, 37, 44, 54, 63, 69, 71, 73, 75, 77, 79 or 104.
  4. The antibody or antigen-binding fragment thereof of any one of claims 1-3, comprising a light chain variable region VL, wherein the light chain variable region (I) Comprising or consisting of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO. 7, 17, 32, 41, 49, 58, 81, 86, 88 or 105, or (Ii) Comprising or consisting of the amino acid sequence of SEQ ID NO. 7, 17, 32, 41, 49, 58, 81, 86, 88 or 105.
  5. The antibody or antigen-binding fragment thereof of claim 1 or 2, comprising a heavy chain variable region VH and a light chain variable region VL, wherein I. The VH comprises or consists of an amino acid sequence shown in SEQ ID No. 63, 69, 71, 73, 75, 77 or 79, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the VL comprises or consists of an amino acid sequence shown in SEQ ID No. 81, 86 or 88, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; the VH comprises or consists of the amino acid sequence shown in SEQ ID No. 63 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the VL comprises or consists of the amino acid sequence shown in SEQ ID No. 81 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; said VH comprises or consists of the amino acid sequence shown in SEQ ID NO 69 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said VL comprises or consists of the amino acid sequence shown in SEQ ID NO86 or 88 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; The VH comprises or consists of an amino acid sequence shown in SEQ ID NO 71 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the VL comprises or consists of an amino acid sequence shown in SEQ ID NO86 or 88 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; v. the VH comprises or consists of an amino acid sequence shown in SEQ ID NO 73 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the VL comprises or consists of an amino acid sequence shown in SEQ ID NO86 or 88 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; the VH comprises or consists of an amino acid sequence shown in SEQ ID NO 75 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the VL comprises or consists of an amino acid sequence shown in SEQ ID NO86 or 88 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; Said VH comprises or consists of the amino acid sequence shown in SEQ ID No. 77 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said VL comprises or consists of the amino acid sequence shown in SEQ ID No. 86 or 88 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; Said VH comprises or consists of an amino acid sequence shown in SEQ ID No. 79 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said VL comprises or consists of an amino acid sequence shown in SEQ ID No. 86 or 88 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; The VH comprises or consists of an amino acid sequence shown in SEQ ID No. 2 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the VL comprises or consists of an amino acid sequence shown in SEQ ID No. 7 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; x. said VH comprises or consists of the amino acid sequence shown in SEQ ID No. 22 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said VL comprises or consists of the amino acid sequence shown in SEQ ID No. 81 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; said VH comprises or consists of the amino acid sequence shown in SEQ ID No. 37 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said VL comprises or consists of the amino acid sequence shown in SEQ ID No. 41 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; Said VH comprises or consists of the amino acid sequence shown in SEQ ID No. 27 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said VL comprises or consists of the amino acid sequence shown in SEQ ID No. 32 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; Said VH comprises or consists of the amino acid sequence shown in SEQ ID No. 12 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said VL comprises or consists of the amino acid sequence shown in SEQ ID No. 17 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; The VH comprises or consists of the amino acid sequence shown in SEQ ID NO 44 or 104 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the VL comprises or consists of the amino acid sequence shown in SEQ ID NO 49 or 105 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, the VH comprises or consists of the amino acid sequence shown in SEQ ID NO 44 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the VL comprises or consists of the amino acid sequence shown in SEQ ID NO 49 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; xv. said VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 104 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 105 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, or Xvi. the VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 54 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 58 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto.
  6. The antibody or antigen-binding fragment thereof of claim 1 or 2, comprising a heavy chain variable region VH and a light chain variable region VL, wherein I. The VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 63, 69, 71, 73, 75, 77 or 79, and the VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 81, 86 or 88; The VH contains or consists of the amino acid sequence shown in SEQ ID NO. 63, and the VL contains or consists of the amino acid sequence shown in SEQ ID NO. 81; The VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 69, and the VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 86 or 88; The VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 71, and the VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 86 or 88; v. said VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 73 and said VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 86 or 88; The VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 75, and the VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 86 or 88; Said VH comprises or consists of the amino acid sequence shown in SEQ ID No. 77, and said VL comprises or consists of the amino acid sequence shown in SEQ ID No. 86 or 88; Said VH comprises or consists of the amino acid sequence shown in SEQ ID No. 79 and said VL comprises or consists of the amino acid sequence shown in SEQ ID No. 86 or 88; The VH contains or consists of the amino acid sequence shown in SEQ ID NO. 2, and the VL contains or consists of the amino acid sequence shown in SEQ ID NO. 7; x. said VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 22, and said VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 81; The VH contains or consists of the amino acid sequence shown in SEQ ID NO. 37, and the VL contains or consists of the amino acid sequence shown in SEQ ID NO. 41; Said VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 27 and said VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 32; said VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 12 and said VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 17; Said VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 44 or 104 and said VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 49 or 105; the VH contains or consists of the amino acid sequence shown in SEQ ID NO. 44, and the VL contains or consists of the amino acid sequence shown in SEQ ID NO. 49; xv. said VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 104 and said VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 105, or Xvi. The VH comprises or consists of the amino acid sequence shown in SEQ ID NO. 54 and the VL comprises or consists of the amino acid sequence shown in SEQ ID NO. 58.
  7. The antibody or antigen-binding fragment thereof of any one of claims 1-6, further comprising a heavy chain constant region HC, e.g., the heavy chain constant region HC of an IgG1, igG2, igG3, or IgG4, preferably the heavy chain constant region of IgG 1.
  8. The antibody or antigen-binding fragment thereof of claim 7, wherein the heavy chain constant region (I) Comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%,97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO. 91, or (Ii) Comprising or consisting of the amino acid sequence of SEQ ID NO. 91.
  9. The antibody or antigen-binding fragment thereof of any one of claims 1-8, comprising a light chain constant region, e.g., the light chain constant region is a lambda or kappa light chain constant region.
  10. The antibody or antigen-binding fragment thereof of claim 9, wherein the light chain constant region (I) Comprising or consisting of an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%,97%, 98% or 99% identity to an amino acid sequence selected from SEQ ID NO. 92, or (Ii) Comprising or consisting of an amino acid sequence selected from SEQ ID NO. 92.
  11. The antibody or antigen-binding fragment thereof of any one of claims 1-10, wherein the antibody comprises a heavy chain that (I) Comprising or consisting of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO. 1, 11, 21, 26, 36, 43, 53, 62, 68, 70, 72, 74, 76, 78 or 106, or (Ii) An amino acid sequence comprising or consisting of SEQ ID NO 1, 11, 21, 26, 36, 43, 53, 62, 68, 70, 72, 74, 76, 78 or 106, or (Iii) The heavy chain of (ii), wherein the lysine of the heavy chain at the C-terminus is substituted with alanine.
  12. The antibody or antigen-binding fragment thereof of any one of claims 1-11, wherein the antibody comprises a light chain that (I) Comprising or consisting of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO. 6, 16, 31, 40, 48, 57, 80, 85, 87 or 107, or (Ii) Comprising or consisting of the amino acid sequence of SEQ ID NO. 6, 16, 31, 40, 48, 57, 80, 85, 87 or 107.
  13. The antibody or antigen-binding fragment thereof of any one of claims 1-12, comprising a heavy chain and a light chain, wherein I. the heavy chain comprises or consists of an amino acid sequence as set forth in SEQ ID No. 62, 68, 70, 72, 74, 76 or 78, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of an amino acid sequence as set forth in SEQ ID No. 80, 85 or 87, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; the heavy chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 62 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 80 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; The heavy chain comprises or consists of the amino acid sequence shown in SEQ ID No. 68 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of the amino acid sequence shown in SEQ ID No. 85 or 87 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; The heavy chain comprises or consists of the amino acid sequence shown in SEQ ID No. 70 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of the amino acid sequence shown in SEQ ID No. 85 or 87 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; v. the heavy chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 72 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 85 or 87 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; The heavy chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 74 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 85 or 87 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; said heavy chain comprises or consists of the amino acid sequence shown in SEQ ID No. 76 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said light chain comprises or consists of the amino acid sequence shown in SEQ ID No. 85 or 87 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; Said heavy chain comprises or consists of the amino acid sequence shown in SEQ ID No. 78 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said light chain comprises or consists of the amino acid sequence shown in SEQ ID No. 85 or 87 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; The heavy chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 1 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 6 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; x. the heavy chain comprises or consists of the amino acid sequence shown in SEQ ID No. 21 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of the amino acid sequence shown in SEQ ID No. 80 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; Said heavy chain comprises or consists of the amino acid sequence shown in SEQ ID No. 36 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said light chain comprises or consists of the amino acid sequence shown in SEQ ID No. 40 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; Said heavy chain comprises or consists of the amino acid sequence shown in SEQ ID No. 26 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said light chain comprises or consists of the amino acid sequence shown in SEQ ID No. 31 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; Said heavy chain comprises or consists of the amino acid sequence shown in SEQ ID No. 11 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said light chain comprises or consists of the amino acid sequence shown in SEQ ID No. 16 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; Said heavy chain comprises or consists of an amino acid sequence as set forth in SEQ ID No. 43 or 106 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and said light chain comprises or consists of an amino acid sequence as set forth in SEQ ID No. 48 or 107 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; xv. the heavy chain comprises or consists of an amino acid sequence shown as SEQ ID No. 43 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of an amino acid sequence shown as SEQ ID No. 48 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; xvi. the heavy chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 106 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 107 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto; xvii. The heavy chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 53 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and the light chain comprises or consists of the amino acid sequence shown in SEQ ID NO. 57 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, or The heavy and light chain of any one of claims xviii-xvii, wherein a lysine of the heavy chain at the C-terminus is substituted with alanine.
  14. The antibody or antigen-binding fragment thereof of any one of claims 1-13, wherein the antibody is a humanized antibody.
  15. The antibody or antigen-binding fragment thereof of any one of claims 1-14, wherein the antibody is a monoclonal antibody.
  16. The antibody or antigen-binding fragment thereof of any one of claims 1-15, wherein the antigen-binding fragment is an antibody fragment selected from the group consisting of Fab, fab '-SH, fv, single chain antibody, (Fab') 2 , single domain antibodies such as heavy chain variable region VHH, dAb (domainantibody), heavy chain antibody, or linear antibody.
  17. The antibody or antigen-binding fragment thereof of claim 16, wherein the single chain antibody is an scFv.
  18. A multispecific binding molecule comprising the antibody or antigen-binding fragment thereof of any one of claims 1-17.
  19. The multispecific binding molecule of claim 18, which is a bispecific binding molecule.
  20. The multispecific binding molecule of claim 19, which is a bispecific binding molecule, such as a fusion protein, that specifically binds FGFR2 and VEGF, such as VEGFA, such as VEGF 165.

Description

Anti-FGFR 2 antibodies and multispecific binding molecules comprising same Technical Field The present invention relates generally to binding molecules and uses thereof. More specifically, the invention relates to isolated antibodies or antigen-binding fragments that specifically bind FGFR2, as well as multispecific binding molecules (e.g., comprising the antibodies or antigen-binding fragments thereof). The invention also relates to diagnostic, prophylactic and/or therapeutic uses of the isolated antibodies or antigen binding fragments, multispecific binding molecules that specifically bind FGFR 2. Background Fibroblast growth factor receptor 2 (FGFR 2) is a tyrosine kinase receptor that exists in a variety of forms as a variable variant. FGFR2 extracellular domains are subject to alternative splicing, thereby producing variants [Toshiyuki Ishiwata,Role of fibroblast growth factor receptor-2splicing in normal and cancer cells.Frontiers In Bioscience,Landmark,23,626-639,January1,2018]. comprising all three Ig-like domains (alpha isotype) or only two Ig-like domains (beta isotype), FGFR2 being again divided into two classes, FGFR2IIIb and FGFR2IIIc, depending on the source of the exons. When the C-terminal latter half amino acid of the extracellular third domain is encoded by exon 8, a FGFR2IIIb variant is produced, whereas when its C-terminal latter half amino acid is encoded by exon 9, a FGFR2IIIc variant [Toshiyuki Ishiwata,Role of fibroblast growth factor receptor-2splicing in normal and cancer cells.Frontiers In Bioscience,Landmark,23,626-639,January 1,2018].FGFR2IIIb is produced that is predominantly expressed in epithelial cells, its ligand FGF7, while also binding FGF10, FGF22, etc. Binding of FGFR2 to the ligand causes receptor dimerization, followed by phosphorylation of the kinase domain, leading to docking of the linker protein and activation of four key downstream pathways, RAS-RAF-MAPK, PI3K-AKT, signal transduction and transcription activator (STAT) and phospholipase Cγ(PLCγ)[Nicholas Turner and Richard Grose,Fibroblast growth factor signalling:from development to cancer.DOI:10.1038/nrc2780],, thereby affecting cell proliferation, survival, migration and invasion. FGFR2IIIb is overexpressed in a variety of cancers, including gastric, breast, lung, esophageal, pancreatic, colorectal, and the like. Gastric cancer is the fifth most diagnosed malignancy worldwide, with over 100 new cases annually, 78.4 deaths worldwide in 2018 [ Elizabeth CSmyth, et al, gastric cancer.Lancet 2020;396:635-48]. Stomach cancer can be classified into early stomach cancer and late stomach cancer, and since stomach cancer is often in late stage at the time of diagnosis, mortality is very high, and is the third most common cause of cancer-related death. Although there are a variety of targeted therapies for gastric cancer, the current clinical treatment of gastric cancer is mainly surgery, and there is a great unmet clinical need. Bemarituzumab targeting FGFR2IIIb is a humanized defucosa monoclonal antibody against FGFR2 b. There are 2 demonstrated mechanisms of action that inhibit FGF blocking FGF 2b signaling by competitive binding, and antibody-dependent cell-mediated cytotoxicity (ADCC) against FGFR2b overexpressed tumor cells, which is currently in clinical stage III, in animals' potency to inhibit growth [Hong Xiang et al.,Preclinical characterization of bemarituzumab,an anti-FGFR2b antibody for the treatment of cancer.MABS,2021,VOL.13,NO.1,e1981202(16pages).DOI:10.1080/19420862.2021.1981202], of FGFR2b gene-amplified gastric cancer tumor cells, combined with mFOLFOX6 for therapeutic studies of advanced gastric and gastroesophageal junction cancer. RLY-4008 is a highly selective FGFR2 inhibitor, can inhibit the growth of various FGFR2 mutant tumors in vivo, is currently in clinical stage I, and is used for unresectable or metastatic cholangiocarcinoma or other solid tumors [Jessica Casaletto et al.,：RLY-4008,a Novel Precision Therapy for FGFR2-Driven Cancers Designed to Potently and Selectively Inhibit FGFR2 and FGFR2 Resistance Mutations.AACR,2021,Poster1455]., and part of the FGFR inhibitors are marketed. ERDAFITINID (erdastinib) is the first FDA approved oral FGFR inhibitor, which can be directed against FGFR subtype 1/2/3, for treating adult patients with locally advanced or metastatic bladder cancer with disease progression after platinum chemotherapy carrying FGFR3 or FGFR2 mutations, and the clinical indications currently under investigation are non-small cell lung cancer, stomach cancer, esophageal cancer, cholangiocarcinoma, multiple myeloma, etc. Vascular Endothelial Growth Factor A (VEGFA) is a homodimeric glycoprotein which binds to heparin and has a molecular weight of 40-45kDa, belonging to the family of growth factors, and also comprises VEGFB, VEGFC, VEGFD and placental growth factor (PlGF). The human VEGFA gene is located on chromosome 6p21.1, consisting of 8 exons and 7 introns. Vascular endotheli