CD3 antibody and pharmaceutical use thereof
The present disclosure relates to a CD3 antibody and a pharmaceutical use thereof. Specifically, the present disclosure relates to forming a multi-specificity antibody by using CD3 antibody and binding molecules of another target. The multi-specificity antibody may simultaneously bind to CD3 and another tumor-associated antigen, and bind and activate CD3-positive T cells while binding tumor-associated antigen-expressing cells, thereby promoting T cells specifically killing tumor cells that express tumor-associated antigens. In addition, the present disclosure also provides a preparation and application of a multi-specific antibody.
1. An antibody or antigen-binding fragment thereof specifically binding to human CD3, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, wherein:
the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NOs: 48, 49 and 50, respectively, and
the heavy chain variable region is any one selected from the group consisting of the following i) to v):
i) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NOs: 37, 40 and 42, respectively;
ii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NOs: 37, 47 and 45, respectively;
iii) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NOs: 37, 38 and 39, respectively;
iv) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NOs: 37, 40 and 43, respectively; and
v) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NOs: 37, 40 and 41, respectively.
2. The antibody or antigen-binding fragment thereof specifically binding to human CD3 according to claim 1 , wherein the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof.
3. The antibody or antigen-binding fragment thereof specifically binding to human CD3 according to claim 2 , comprising a light chain variable region as shown in SEQ ID NO: 36, and/or a heavy chain variable region as shown in any one selected from the group consisting of SEQ ID NOs: 29, 30, 31, 32, and 35.
4. The antibody or antigen-binding fragment thereof specifically binding to human CD3 according to claim 3 , further comprising an antibody light chain constant region and/or a heavy chain constant region;
optionally, the light chain constant region is a light chain constant region of a human kappa, lambda chain or variant thereof, and the heavy chain constant region is a heavy chain constant region of a human IgG1, IgG2, IgG3, IgG4 or variant thereof.
5. The antibody or antigen-binding fragment thereof specifically binding to human CD3 according to claim 1 , wherein the antigen-binding fragment is selected from Fab, Fab′, F(ab′)2, dimerized V region (diabody) and disulfide-stabilized V region (dsFv).
6. A single-chain antibody, comprising the light chain variable region and the heavy chain variable region of the antibody or antigen-binding fragment thereof specifically binding to human CD3 according to claim 1 .
7. The single-chain antibody according to claim 6 , wherein the sequence of the single-chain antibody is as shown in SEQ ID NO: 55, 56, 57, 58, 61, 62, 63, 64, 65 or 68.
8. A multispecific antibody specifically binding to human CD3 and tumor-associated antigen(s), the multispecific antibody comprising the single-chain antibody according to claim 6 .
9. The multispecific antibody according to claim 8 , wherein the tumor-associated antigen is selected from the group consisting of AFP, ALK, B7H3, BAGE protein, BCMA, BIRC5, BIRC7, β-catenin, brc-abl, BRCA1, BORIS, CA9, CA125, carbonic anhydrase IX, caspase-8, CALR, CCR5, CD19, CD20, CD22, CD30, CD33, CD38, CD40, CD123, CD133, CD138, CDK4, CEA, Claudin 18.2, cyclin-B1, CYP1B1, EGFR, EGFRvIII, ErbB2/Her2, ErbB3, ErbB4, ETV6-AML, EpCAM, EphA2, Fra-1, FOLR1, GAGE protein, GD2, GD3, GloboH, Glypican-3, GM3, gp100, Her2, HLA/B-raf, HLA/k-ras, HLA/MAGE-A3, hTERT, IL13Rα2, LMP2, κ-Light, LeY, MAGE protein, MART-1, Mesothelin, ML-IAP, MOv-γ, Muc1, Muc2, Muc3, Muc4, Muc5, CA-125, MUM1, NA17, NKG2D, NY-BR1, NY-BR62, NY-BR85, NY-ESO1, OX40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1, PRLR, PRAME, PSMA, RAGE protein, Ras, RGS5, Rho, ROR1, SART-1, SART-3, STEAP1, STEAP2, TAG-72, TGF-β, TMPRSS2, Thompson-nouvelle antigen, TRP-1, TRP-2, tyrosinase, uroplakin-3 and 5T4.
10. A pharmaceutical composition, comprising a therapeutically effective amount of the antibody or antigen-binding fragment thereof specifically binding to human CD3 according to claim 1 , and one or more pharmaceutically acceptable carriers, diluents, buffers or excipients.
11. An isolated nucleic acid molecule, encoding the antibody or antigen-binding fragment thereof specifically binding to human CD3 according to claim 1 .
12. A recombinant vector, comprising the isolated nucleic acid molecule according to claim 11 .
13. A host cell transformed with the recombinant vector of claim 12 , wherein said host cell is a prokaryotic cell or a eukaryotic cell.
14. A method for producing the antibody or antigen-binding fragment thereof specifically binding to human CD3 according to claim 1 , the method comprising transforming the recombinant vector into a host cell and culturing a host cell in a culture medium to express and accumulate the antibody or antigen-binding fragment thereof specifically binding to human CD3, and recovering the antibody or antigen-binding fragment thereof.