JP-7856818-B2 - Claudin 6 bispecific antibody

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 (20)

1. A bispecific antigen-binding protein that binds to human claudin 6 (CLDN6) protein (SEQ ID NO: 200) and a second antigen which is CD3 or CD16A, Antigen-binding proteins, (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) f. LC CDR3 containing the amino acid sequence QHHYTVPWT (SEQ ID NO: 22) The bispecific antigen-binding protein contains and binds to human claudin 6 (CLDN6) protein (SEQ ID NO: 200).
2. The bispecific antigen-binding protein according to claim 1, wherein the X at position 8 in formula (iii) is S.
3. The bispecific antigen-binding protein according to claim 1, wherein the X at position 8 in formula (iii) is T.
4. The bispecific antigen-binding protein according to claim 1, wherein the X at position 8 in formula (iii) is A.
5. The bispecific antigen-binding protein according to claim 1, wherein the X at position 8 in formula (iii) is C.
6. The bispecific antigen-binding protein according to claim 1, wherein the X at position 8 in formula (iii) is Y.
7. The bispecific antigen-binding protein according to any one of claims 1 to 6, wherein the antigen-binding protein is an antigen-binding fragment of an antibody selected from the group consisting of scFv, F(ab') 2 , Fab, and Fv.
8. The bispecific antigen-binding protein according to any one of claims 1 to 6, wherein the antigen-binding protein is an antibody.
9. Antibodies, (i) Monoclonal antibodies, and (ii) Human antibodies, humanized antibodies, or chimeric antibodies, The bispecific antigen-binding protein according to claim 8, which is any one of the following.
10. The bispecific antigen-binding protein according to claim 8, wherein the antibody is an IgG antibody.
11. The bispecific antigen-binding protein according to claim 10, wherein IgG is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.
12. The bispecific antigen-binding protein according to claim 11, wherein IgG is IgG1.
13. The bispecific antigen-binding protein according to claim 2, wherein the bispecific antigen-binding protein that binds to the human claudin 6 (CLDN6) protein has the heavy chain variable domain sequence of SEQ ID NO: 387 and the light chain variable domain sequence of SEQ ID NO: 389.
14. The bispecific antigen-binding protein according to any one of claims 1 to 6, wherein the bispecific antigen-binding protein is a bispecific antibody or a bispecific antigen-binding antibody fragment.
15. The bispecific antigen-binding protein according to claim 14, wherein the bispecific antigen-binding protein is a bispecific monoclonal antibody.
16. The bispecific antigen-binding protein according to claim 14 or 15, wherein the bispecific antigen-binding protein is a chimeric or humanized bispecific antibody.
17. The bispecific antigen-binding protein according to any one of claims 1 to 6, wherein the bispecific antigen-binding protein is a bispecific T cell engager or a tandem diabody.
18. (a) A bispecific antigen-binding protein according to any one of claims 1 to 17, and (b) A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient.
19. A bispecific antigen-binding protein according to any one of claims 1 to 17, or a pharmaceutical composition according to claim 18, for use in the treatment of cancer, inhibition of tumor growth, reduction of tumor size, or prevention of cancer recurrence.
20. A method for manufacturing a pharmaceutical composition, pharmaceutically acceptable carriers, diluents and/or excipients, a. The bispecific antigen-binding protein according to claim 1, b. A complex comprising the bispecific antigen-binding protein described in claim 1, c. A fusion protein comprising the bispecific antigen-binding protein described in claim 1, d. A nucleic acid encoding a bispecific antigen-binding protein as described in claim 1, e. A vector containing the nucleic acid of (d) above, f. A host cell containing the nucleic acid of (d) or the vector of (e), or g. A combination of a. to f. above, The method, which includes combining the following.

Description

Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 62/821,399, 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 344,064 ASCII (text) file named "54086P2_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) and bispecific forms thereof. 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. This specification further provides antigen-binding proteins conjugated to heterologous moieties (e.g., any chemotherapeutic agent, drug, or toxic moiety) that inhibit tumor growth in a target, such as in humans. In various cases, the conjugated antigen-binding protein is a monoclonal antibody. In various cases, the antibody is conjugated to a drug that alters microtubule dynamics, such as MMAE. In various cases, the complex includes a cleavable linker, such as MC-VC-PAB. In various embodiments, the complex is a homogeneous or heterogeneous complex. In various embodiments, the heterologous moiety is conjugated at a specific site on the antigen-binding protein. In various cases, the conjugated antigen-binding protein is a bispecific antigen-binding protein. In various embodiments, bispecific antigen-binding proteins bind to CLDN6 expressed by human cancer cells. In various embodiments, antigen-binding proteins inhibit the binding interaction between human CLDN6 and an anti-CLDN6 reference antibody. Without being bound by any particular theory, the inhibitory effect of the antigen-binding proteins provided herein makes such entities useful in methods of suppressing tumor growth and treating tumors or cancerous subjects. As further discussed herein, in various embodiments, the antigen-binding protein is an antibody, its antigen-binding antibody fragment, or an antibody protein product. This disclosure also provides bispecific antigen-binding proteins comprising at least three, four, five, or all of the amino