EP-4736954-A2 - BISPECIFIC BINDING PROTEINS AND USES THEREOF

Abstract

The disclosure generally provides proteins that bind two epitopes (e.g., a first and a second epitope) and that are bivalent for binding to each of the first and second epitopes. The disclosure also provides for specific binding proteins, including antibodies, which bind to a target protein. The disclosure also provides compositions comprising such proteins, nucleic acid molecules encoding such proteins and methods of making such proteins. The disclosure provides methods of inducing an immune response in a subject as well as methods for treating or preventing cancer in a subject by administering the proteins, nucleic acid molecules and/or compositions to the subject.

Inventors

• KASTURIRANGAN, SRINATH
• MAZOR, YARIV
• OBERST, MICHAEL
• HAMMOND, SCOTT A.
• LOBO, BRIAN
• MANIKWAR, Prakash
• SEAMAN, JONATHAN
• HERBST, RONALD
• DOVEDI, Simon
• GAO, CHANGSHOU
• RAINEY, GODFREY
• MORROW, MICHELLE
• DOBSON, CLAIRE LOUISE
• DRABIC, Stacey
• SCHOFIELD, DARREN
• CARLESSO, GIANLUCA
• POLLIZZI, Kristen

Assignees

• MedImmune, LLC

Dates

Publication Date

20260506

Application Date

20170505

Claims (10)

1. A bispecific binding protein that binds to PD-1 and TIM3 comprising a first heavy chain, a first light chain, a second heavy chain, and a second light chain, wherein the first heavy chain comprises the amino acid sequence of SEQ ID NO: 9, wherein the first light chain comprises the amino acid sequence of SEQ ID NO: 7, wherein the second heavy chain comprises the amino acid sequence of SEQ ID NO: 30, and wherein the second light chain comprises the amino acid sequence of SEQ ID NO: 28.
2. The antibody or antigen binding fragment thereof of claim 1, comprising a heavy chain variable region and a light chain variable region, wherein the second heavy chain variable region comprises: SEQ ID NO: 85, and the second light chain variable region comprises: SEQ ID NO: 86.
3. The antibody or antigen binding fragment thereof of claim 1, wherein the second heavy chain comprises SEQ ID NO: 87, and the second light chain comprises: SEQ ID NO: 88.
4. A composition comprising the bispecific binding protein of any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
5. A nucleic acid molecule comprising a nucleotide sequence encoding the bispecific binding protein according to any one of claims 1 to 3.
6. A vector comprising the nucleic acid molecule of claim 5.
7. A host cell comprising the vector of claim 6.
8. A method of treating cancer in a subject, the method comprising administering the bispecific binding protein of any one of claims 1 to 3 to the subject.
9. The method of claim 8, wherein the cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer.
10. A method of enhancing an immune response in a subject, the method comprising administering the bispecific binding protein of any one of claims 1 to 3 to the subject.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 62/332,788 filed May 6, 2016, the disclosure of which is incorporated herein by reference in its entirety. SEQUENCE LISTING The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled IOBS_100_ST25.txt created May 2, 2017, which is 244 kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. BACKGROUND Cancer continues to be a major global health burden. Despite progress in the treatment of cancer, there continues to be an unmet medical need for more effective and less toxic therapies, especially for those patients with advanced disease or cancers that are resistant to existing therapeutics. The role of the immune system, in particular T cell-mediated cytotoxicity, in tumor control is well recognized. There is mounting evidence that T cells control tumor growth and survival in cancer patients, both in early and late stages of the disease. However, tumor-specific T-cell responses are difficult to mount and sustain in cancer patients. The continuing advancement and successes of cancer immunotherapies, which stimulate or enhance innate immune responses against cancer, make such therapeutics an attractive treatment option when compared to therapies that utilize non-specific chemotherapeutics and/or radiation. A number of molecular targets have been identified for their potential utility as immuno-oncology (IO) therapeutics against cancer. Some molecular targets that are being investigated for their therapeutic potential in the area of immuno-oncology therapy include cytotoxic T lymphocyte antigen-4 (CTLA-4 or CD152), programmed death ligand 1 (PD-L1 or B7-H1 or CD274), Programmed Death-1 (PD-1), OX40 (CD134 or TNFRSF4) and T-cell inhibitory receptor T-cell immunoglobulin and mucin-domain containing-3 (TIM3). While some of these targets have been successfully exploited therapeutically (e.g., PD-1 and CTLA-4), many patients have been unresponsive to the therapeutics that have been developed. And, while a therapeutic regimen that includes higher doses and/or a combination of immunotherapies may be considered, such therapies may be associated with increased risk of side effects, which tend to increase with higher doses and cumulative exposure, and appear to be additive when used with combination immunotherapies. Some common side effects include hypophysitis, thyroiditis, adrenal insufficiency, enterocolitis, dermatitis, pneumonitis, hepatitis, pancreatitis, motor and sensory neuropathies, and arthritis. Furthermore, as immunotherapeutics are typically associated with high costs, a therapy that includes a combination of immunotherapeutics can be cost-prohibitive to patients. As such, there remains a need to continue to identify candidate targets for IO therapeutics, develop new therapeutics to the existing targets, and to develop therapeutic strategies that avoid disadvantages of immunotherapies that are currently in use, including the lack of patient response and the increased risk of side effects involved with combination treatment. IO therapeutics (e.g., binding proteins) that are bispecific for a combination of target molecules, particularly those that exhibit greater binding affinity for the target molecules when compared to the binding affinity for a combination of individual monospecific binding proteins, represent a class of particularly desirable molecules for therapeutic potential. SUMMARY OF THE INVENTION The invention provides bispecific molecules or proteins that bind two epitopes (e.g., a first and a second epitope) and that are bivalent for binding to each of the first and second epitopes. The invention also provides methods of inducing an immune response in a subject as well as methods for treating or preventing cancer in a subject (e.g., a human subject) by administering the proteins, nucleic acid molecules and/or compositions to the subject. In one aspect, the invention provides a protein, containing: a first binding domain (BD1) that binds to a first epitope, a second binding domain (BD2) that binds to a second epitope, and an Fc region having CH2 and CH3 domain; where the Fc region includes BD2 at a solvent exposed loop in the CH2 domain, the CH3 domain, or at the interface of the CH2 and CH3 domains; and where the protein is bivalent for binding to each of the first and second epitopes. In another aspect, the invention provides a composition containing a protein or antibody according to any aspect herein and a pharmaceutically acceptable carrier. In another aspect, the invention provides a method of treating or preventing cancer in a subject, the method involving administering the protein or antibody according to any aspect herein to the subject (e.g., a human subject). In various embodiments, the cancer is one or mo