Anti-HER2 antibody or antigen-binding fragment thereof, and chimeric antigen receptor comprising same
The present disclosure relates to a novel anti-HER2 antibody or an antigen-binding fragment thereof used in the prevention or treatment of cancer, a chimeric antigen receptor including the same, and uses thereof. The antibody of the present disclosure is an antibody that specifically binds to HER2 which is highly expressed in cancer cells (particularly, breast cancer or gastric cancer cells), and binds to an epitope that is different from an epitope to which trastuzumab binds. When compared with trastuzumab, the antibody of the present disclosure exhibits better killing ability for HER2-unexpressed cancer cells which have non-reactivity (or resistance) to the trastuzumab antibody or have reduced sensitivity. In addition, when the anti-HER2 antibody of the present disclosure is administered in combination with trastuzumab, a synergistic killing ability is achieved for cancer cells on which the trastuzumab antibody acts. Therefore, a composition of the present disclosure can be very usefully used for combined administration with the trastuzumab antibody for the treatment of cancer, or for the treatment of cancer not treated with trastuzumab.
1. An antibody against human epidermal growth factor receptor 2 (HER2), or an antigen-binding fragment thereof, comprising:
(a) a heavy chain variable region comprising CDRH1 of SEQ ID NO: 7, CDRH2 of SEQ ID NO: 8 and CDRH3 of SEQ ID NO: 9, and a light chain variable region comprising CDRL1 of SEQ ID NO: 10, CDRL2 of SEQ ID NO: 11 and CDRL3 of SEQ ID NO: 12;
(b) a heavy chain variable region comprising CDRH1 of SEQ ID NO: 7, CDRH2 of SEQ ID NO: 8 and CDRH3 of SEQ ID NO: 71, and a light chain variable region comprising CDRL1 of SEQ ID NO: 10, CDRL2 of SEQ ID NO: 11 and CDRL3 of SEQ ID NO: 12;
(c) a heavy chain variable region comprising CDRH1 of SEQ ID NO: 7, CDRH2 of SEQ ID NO: 8 and CDRH3 of SEQ ID NO: 72, and a light chain variable region comprising CDRL1 of SEQ ID NO: 10, CDRL2 of SEQ ID NO: 11 and CDRL3 of SEQ ID NO: 73; or
(d) a heavy chain variable region comprising CDRH1 of SEQ ID NO: 7, CDRH2 of SEQ ID NO: 8 and CDRH3 of SEQ ID NO: 72, and a light chain variable region comprising CDRL1 of SEQ ID NO: 10, CDRL2 of SEQ ID NO: 11 and CDRL3 of SEQ ID NO: 74.
2. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein:
the heavy chain variable region of (a) comprises amino acid sequence of SEQ ID NO: 39;
the heavy chain variable region of (b) comprises amino acid sequence of SEQ ID NO: 87;
the heavy chain variable region of (c) comprises amino acid sequence of SEQ ID NO: 95; and
the heavy chain variable region of (d) comprises amino acid sequence of SEQ ID NO: 103.
3. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein:
the light chain variable region of (a) comprises amino acid sequence of SEQ ID NO: 43;
the light chain variable region of (b) comprises amino acid sequence of SEQ ID NO: 91;
the light chain variable region of (c) comprises amino acid sequence of SEQ ID NO: 99; and
the light chain variable region of (d) comprises amino acid sequence of SEQ ID NO: 107.
4. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein
the antibody or the antigen-binding fragment thereof comprising (a) comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 41;
the antibody or the antigen-binding fragment thereof comprising (b) comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 89;
the antibody or the antigen-binding fragment thereof comprising (c) comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 97; and
the antibody or the antigen-binding fragment thereof comprising (d) comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 105.
5. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein
the antibody or the antigen-binding fragment thereof comprising (a) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 45;
the antibody or the antigen-binding fragment thereof comprising (b) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 93;
the antibody or the antigen-binding fragment thereof comprising (c) comprises a light chain comprising an amino acid sequence of SEQ ID NO: 101; and
the antibody or the antigen-binding fragment thereof comprising (d) comprises a light chain comprising the amino acid sequence of SEQ ID NO: 109.
6. The antibody or antigen-binding fragment thereof according to claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising CDRH1 of SEQ ID NO: 7, CDRH2 of SEQ ID NO: 8, and CDRH3 of SEQ ID NO: 9, and a light chain variable region comprising CDRL1 of SEQ ID NO: 10, CDRL2 of SEQ ID NO: 11, and CDRL3 of SEQ ID NO: 12.
7. The antibody or antigen-binding fragment thereof according to claim 1 , wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO: 39 and the light chain variable region comprises an amino acid sequence of SEQ ID NO: 43.
8. The antibody or antigen-binding fragment thereof according to claim 1 , wherein the heavy chain comprises an amino acid sequence of SEQ ID NO: 41 and the light chain comprises the amino acid sequence of SEQ ID NO: 45.
9. A fusion protein comprising the antibody or antigen-binding fragment thereof according to claim 1 .
10. A fusion protein comprising the antibody or antigen-binding fragment thereof according to claim 6 .
11. A chimeric antigen receptor polypeptide comprising:
(a) an HER2-binding domain comprising the antibody or antigen-binding fragment thereof according to claim 1 ;
(b) a transmembrane domain (TM);
(c) a costimulatory domain; and
(d) an intracellular signaling domain (ICD).
12. A chimeric antigen receptor polypeptide comprising:
(a) an HER2-binding domain comprising the antibody or antigen-binding fragment thereof according to claim 6 ;
(b) a transmembrane domain (TM);
(c) a costimulatory domain; and
(d) an intracellular signaling domain (ICD).
13. The chimeric antigen receptor polypeptide according to claim 12 , wherein the transmembrane domain is a transmembrane domain of a protein selected from a group consisting of T-cell receptor alpha, beta or zeta chain, CD28, CD3 epsilon, CD45, CD4, CDS, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154.
14. The chimeric antigen receptor polypeptide according to claim 12 , wherein the costimulatory domain is a functional signaling domain obtained from a protein selected from a group consisting of MHC class I molecule, TNF receptor protein, immunoglobulin-like protein, cytokine receptor, integrin, signaling lymphocytic activation molecule (SLAM), activating NK cell receptor, BTLA (B- and T-lymphocyte attenuator), Toll-like ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CD1 1a/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11le, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAMI (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGLI, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG(CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand binding specifically to CD83.
15. The chimeric antigen receptor polypeptide according to claim 12 , wherein the intracellular signaling domain comprises a functional signaling domain of 4-1BB, CD28, OX40 or CD3 zeta, or a combination thereof.
16. A nucleic acid molecule encoding the anti-HER2 antibody or the antigen-binding fragment thereof according to claim 6 .
17. A nucleic acid molecule encoding the chimeric antigen receptor polypeptide according to claim 12 .
18. A recombinant vector comprising the nucleic acid molecule according to claim 17 .
19. A host cell transformed with the recombinant vector according to claim 18 .
20. An effector cell expressing the chimeric antigen receptor polypeptide according to claim 12 .
21. The effector cell according to claim 20 , wherein the effector cell is selected from a group consisting of a dendritic cell, a killer dendritic cell, a mast cell, a natural killer cell, a B lymphocyte, a T lymphocyte, a macrophage and precursor cells thereof.
22. A pharmaceutical composition for treating cancer, comprising: (a) a pharmaceutically effective amount of the anti-HER2 antibody or the antigen-binding fragment thereof according to claim 6 ; and (b) a pharmaceutically acceptable carrier.
23. A pharmaceutical composition for treating cancer, comprising the effector cell expressing the chimeric antigen receptor polypeptide according to claim 20 .
24. A kit for diagnosing cancer, comprising the anti-HER2 antibody or the antigen-binding fragment thereof according to claim 6 .