JP-7856817-B2 - Claudin 6 antibody and drug conjugate

Inventors

• コンクリン，ディラン
• マクダーモット，マルティナ，エス．
• オブライエン，ニール，エー．
• パラッツォロ，マイケル，ジェイ．
• スレイモン，デニス
• ボン エウウ，エリカ
• バウワーズ，ピーター

Assignees

• ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア

Dates

Publication Date

20260511

Application Date

20250514

Priority Date

20190320

Claims (15)

1. A complex comprising monomethyl auristatin E (MMAE), a chemotherapy drug, and an isolated antigen-binding protein or its antigen-binding fragment that binds to claudin 6 (CLDN6), wherein the antigen-binding protein or its antigen-binding fragment is (i) HC CDR1 containing the amino acid sequence GTFFSNYW (SEQ ID NO: 23), (ii) HC CDR2 containing the amino acid sequence IRLKSDNYAT (SEQ ID NO: 24), (iii) HC CDR3 containing the amino acid sequence XDGPPSGX (Sequence ID: 457), wherein the X at position 1 is N and the X at position 8 is S, T, A, C, or Y. (iv) LC CDR1 containing amino acid sequence ENIYSY (SEQ ID NO: 20), (v) LC CDR2 containing the amino acid sequence NAK (SEQ ID NO: 21), (vi) LC CDR3 containing the amino acid sequence QHHYTVPWT (SEQ ID NO: 22) The antigen-binding protein or its antigen-binding fragment has the chemical structure of the following formula I. (Maleimidocaproyl (MC)) It is linked to this, and this is the chemical structure of formula II below. (Valine-Citrulline (VC)) It is connected to this, and this is the chemical structure of formula III below. (Para-aminobenzyloxycarbonyl having a para-aminobenzyl (PAB) group) The composite is connected to the MMAE.
2. The composite according to claim 1, wherein the X at position 8 in formula (iii) is S.
3. The composite according to claim 1, wherein the X at position 8 in formula (iii) is T.
4. The composite according to claim 1, wherein the X at position 8 in formula (iii) is A.
5. The complex according to claim 1, wherein the X at position 8 in formula (iii) is C, or the complex has HC CDR3 as shown in Sequence ID No. 25.
6. The composite according to claim 1, wherein the X at position 8 in formula (iii) is Y.
7. The complex according to claim 1, wherein the linked group is linked to the antigen-binding protein via a Cys residue of the antigen-binding protein.
8. The complex according to any one of claims 1 to 7, wherein the antigen-binding protein is either an antigen-binding fragment of an antibody or selected from the group consisting of scFv, F(ab') 2 , Fab, and Fv.
9. The complex according to any one of claims 1 to 7, wherein the antigen-binding protein is an antibody.
10. Antibodies, (i) Monoclonal antibodies, and (ii) Human antibodies, humanized antibodies, or chimeric antibodies, The composite according to claim 9, which is any of the following.
11. The complex according to claim 9, wherein the antibody is an IgG antibody.
12. The complex according to claim 11, wherein IgG is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.
13. The complex according to claim 12, wherein IgG is IgG1.
14. (a) The composite according to any one of claims 1 to 13, and (b) A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient.
15. A complex according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14, for use in the treatment of cancer.

Description

Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 62/821,391, filed on March 20, 2019, and the entire contents of the said application are incorporated in their entirety by this reference. Incorporation by reference of electronically submitted materials The entirety of which is incorporated by reference is a computer-readable nucleotide/amino acid sequence listing, identified as a 338,714 ASCII (text) file named "54086P1_Seqlisting.txt" created on March 20, 2019, which was submitted at the same time as the application. Antibodies constitute potent therapeutic agents characterized by limited side effects due to their ability to specifically target different antigens on cells, bacteria, viruses, or toxins. In 1986, Orthoclone OKT3, the first therapeutic monoclonal antibody, was introduced to the market. Since then, this class of biopharmaceuticals has grown significantly. In late 2014, 47 monoclonal antibody products were approved in the United States or Europe for the treatment of cancer, as well as a variety of other diseases, including inflammatory diseases, cardiovascular diseases, respiratory diseases, and infections. More than 12 monoclonal antibodies are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer. These include alemtuzumab (Campath®), indicated for chronic lymphocytic leukemia (CLL), and trastuzumab (Herceptin®), used to treat breast cancer. Some antibodies are labeled with chemotherapy drugs, such as brentuximab vedotin (Adcetris®) and trastuzumab emtansine (Kadcyla®). Other antibody products, such as blinatumomab (Blincyto), are designed to recognize and bind to two different antigens. Despite the availability of such antibody products, current cancer incidence and mortality rates remain high. The cancer incidence rate is reported to be over 450 cases per 100,000 person-years for both men and women, and the cancer mortality rate is slightly over 170 cases per 100,000 person-years for both men and women. This specification provides antigen-binding proteins that bind to claudin 6 (CLDN6). In various embodiments, the antigen-binding proteins of this disclosure bind to human CLDN6 and, optionally, to mouse CLDN6. In various embodiments, the antigen-binding proteins bind to the extracellular domain (ECD) of CLDN6. In various embodiments, the antigen-binding proteins bind to the extracellular loop 2 (EL2) of the ECD of CLDN6. In various embodiments, the antigen-binding proteins bind to EL2 but not to the extracellular loop 1 (EL1) of the ECD of CLDN6. In various embodiments, the antigen-binding proteins bind to additional members of the human claudin family, such as claudin 3 (CLDN3), claudin 4 (CLDN4), and claudin 9 (CLDN9), etc. In various embodiments, the antigen-binding proteins bind to CLDN6 and at least one of CLDN4 and CLDN9. In various cases, the antigen-binding protein binds to CLDN6 and not to any other member of the claudin family. In various embodiments, the antigen-binding protein binds to CLDN6 endogenously expressed by human ovarian cancer cells, e.g., OVCA429 cells, and exhibits an IC50 of less than approximately 1200 nM in FACS affinity assays using OVCA429 cells. In various cases, the antigen-binding protein of this disclosure inhibits tumor growth in a subject, e.g., human, without including any other portion bound to this antigen-binding protein. In various embodiments, the antigen-binding protein may be: (a) the heavy chain CDR1 amino acid sequence of SEQ ID NO: 504 or SEQ ID NO: 507, or a variant thereof, differing by only one or two amino acids, or having approximately or at least 70% sequence identity; (b) the heavy chain CDR2 amino acid sequence of SEQ ID NO: 505 or SEQ ID NO: 508, or a variant thereof, differing by only one or two amino acids, or having approximately or at least 70% sequence identity; (c) the heavy chain CDR3 amino acid sequence of SEQ ID NO: 506 or SEQ ID NO: 509, or a variant thereof, differing by only one or two amino acids, or having approximately or at least 70% sequence identity; or (d) SEQ ID NO: 44 (a) The light chain CDR1 amino acid sequence of sequence number 9 or sequence number 476, or a variant thereof, which differs by only one or two amino acids, or has approximately or at least 70% sequence identity; (e) The light chain CDR2 amino acid sequence of sequence number 450 or sequence number 477, or a variant thereof, which differs by only one or two amino acids, or has approximately or at least 70% sequence identity; (f) The light chain CDR3 amino acid sequence of sequence number 451 or sequence number 454, or a variant thereof, which differs by only one or two amino acids, or has approximately or at least 70% sequence identity; and/or (g) any two or more combinations of (a) to (f). In various embodiments, the antigen-binding protein may include (a) any one heavy chain variable region amino acid sequence from sequence numbers 490-503, or the