CLDN18.2 antibody and use thereof
Provided are a CLDN18.2-combined antibody and an unfucosylated form thereof. Further provided are a preparation method for the antibody, a conjugate, and a composition containing the antibody, and use thereof in the treatment of a disease such as cancer.
1 . An antibody that binds to CLDN18.2, or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising heavy chain CDRs (CDRHs) and a light chain variable region (VL) comprising light chain CDRs (CDRLs), wherein the CDRHs and the CDRLs are selected from the group consisting of:
a. CDRH1, CDRH2 and CDRH3 as shown in SEQ ID NOs: 3-5; and CDRL1, CDRL2 and CDRL3 as shown in SEQ ID NOs: 8-10;
b. CDRH1, CDRH2 and CDRH3 as shown in SEQ ID NOs: 13-15; and CDRL1, CDRL2 and CDRL3 as shown in SEQ ID NOs: 18-20;
c. CDRH1, CDRH2 and CDRH3 as shown in SEQ ID NOs: 23-25; and CDRL1, CDRL2 and CDRL3 as shown in SEQ ID NOs: 28-30;
d. CDRH1, CDRH2 and CDRH3 as shown in SEQ ID NOs: 33-35; and CDRL1, CDRL2 and CDRL3 as shown in SEQ ID NOs: 38-40;
e. CDRH1, CDRH2 and CDRH3 as shown in SEQ ID NOs: 43-45; and CDRL1, CDRL2 and CDRL3 as shown in SEQ ID NOs: 48-50; and
f. CDRH1, CDRH2 and CDRH3 as shown in SEQ ID NOs: 57-59; and CDRL1, CDRL2 and CDRL3 as shown in SEQ ID NOs: 62-64.
2 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody has the following VH and VL:
a. a VH comprising the amino acid sequence of SEQ ID NO: 1, and a VL comprising the amino acid sequence of SEQ ID NO: 6;
b. a VH comprising the amino acid sequence of SEQ ID NO: 11, and a VL comprising the amino acid sequence of SEQ ID NO: 16;
c. a VH comprising the amino acid sequence of SEQ ID NO: 21, and a VL comprising the amino acid sequence of SEQ ID NO: 26;
d. a VH comprising the amino acid sequence of SEQ ID NO: 31, and a VL comprising the amino acid sequence of SEQ ID NO: 36;
e. a VH comprising the amino acid sequence of SEQ ID NO: 41, and a VL comprising the amino acid sequence of SEQ ID NO: 46; or
f. a VH comprising the amino acid sequence of SEQ ID NO: 55, and a VL comprising the amino acid sequence of SEQ ID NO: 60.
3 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody has an Fc region.
4 . The antibody or antigen-binding fragment thereof of claim 3 , wherein the antibody has a glycosyl structure modification at Asn297, wherein the numbering is according to the EU numbering system.
5 . The antibody or antigen-binding fragment thereof of claim 4 , wherein the ratio of glycosyl structures having fucose to total glycosyl structures is 50% or less.
6 . The antibody or antigen-binding fragment thereof of claim 5 , wherein the ratio of glycosyl structures having fucose to total glycosyl structures is 0%-1%.
7 . The antibody or antigen-binding fragment thereof of claim 5 , wherein the antibody is produced by a cell with Fut8 gene knockout.
8 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is a monoclonal antibody, a bispecific antibody or a multispecific antibody.
9 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is selected from a group consisting of IgG, IgA, IgM, IgE, and IgD isotypes.
10 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is selected from a group consisting of IgG1, IgG2, IgG3, and IgG4 subclasses.
11 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antigen-binding fragment is selected from a group consisting of Fab fragment, Fab′ fragment, F(ab′) 2 fragment, Fd fragment, Fd′ fragment, Fv fragment, scFv fragment, ds-scFv fragment, dAb fragment, single chain fragment, diabody and linear antibody.
12 . A nucleic acid molecule comprising a nucleotide sequence encoding the antibody or antigen-binding fragment thereof of claim 1 .
13 . A conjugate comprising the antibody or antigen-binding fragment thereof of claim 1 conjugated to a therapeutic agent, a diagnostic agent or an imaging agent.
14 . A composition comprising the antibody or antigen-binding fragment thereof of claim 1 and one or more pharmaceutically acceptable carriers, excipients and/or diluents.
15 . The composition of claim 14 , wherein the composition further comprises one or more additional therapeutic agents selected from a group consisting of antibody, chemotherapeutic, and small molecule drug.
16 . The composition of claim 15 , wherein the chemotherapeutic is selected from one or more of epirubicin, oxaliplatin, and 5-fluorouracil (5-FU).
17 . A method for treating a cancer associated with the expression of CLDN18.2 in a subject, wherein the method comprises a step of administering to the subject the antibody or antigen-binding fragment thereof of claim 1 .
18 . The method of claim 17 , wherein the cancer is selected from a group consisting of gastric cancer, cholangiocarcinoma, esophageal cancer, and pancreatic cancer.
19 . The method of claim 17 , wherein the method further comprises a step of administering one or more additional therapies to the subject.
20 . The method of claim 19 , wherein the additional therapy is selected from a group consisting of chemotherapy, radiation therapy, immunotherapy, and surgery.
21 . The method of claim 20 , wherein the immunotherapy is selected from a group consisting of therapy targeting an immune checkpoint molecule, CAR-T cell therapy, and CAR-NK cell therapy.
22 . The method of claim 20 , wherein the chemotherapy is selected from a combined chemotherapy regimen comprising epirubicin, oxaliplatin, and 5-fluorouracil.
23 . An antibody that binds to CLDN18.2, or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 6.
24 . A method for treating a cancer associated with the expression of CLDN18.2 in a subject, wherein the method comprises a step of administering to the subject the antibody or antigen-binding fragment thereof of claim 23 .