US-12622954-B2 - Anti-ICOS agonist antibodies and uses thereof

US12622954B2US 12622954 B2US12622954 B2US 12622954B2US-12622954-B2

Abstract

The present invention provides isolated monoclonal antibodies (e.g., humanized and human monoclonal antibodies) that bind to human Inducible T Cell COStimulator (ICOS) and exhibit therapeutically desirable functional properties, e.g., the ability to stimulate human ICOS activity. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells, and methods for expressing the antibodies of the invention are also provided. Immunoconjugates, bispecific molecules, and pharmaceutical compositions comprising the antibodies of the invention are also provided. The antibodies of the invention can be used, for example, as an agonist to stimulate or enhance an immune response in a subject, e.g., antigen-specific T cell responses against a tumor or viral antigen. The antibodies of the invention can also be used in combination with other antibodies (e.g., PD-1, PD-L1, and/or CTLA-4 antibodies) to treat, for example, cancer. Accordingly, the antibodies can be used in therapeutic applications and methods to detect ICOS protein.

Inventors

John J. ENGELHARDT
Mark J. Selby
Alan J. Korman
Mary Diane Feingersh
Brenda L. Stevens

Assignees

BRISTOL-MYERS SQUIBB COMPANY

Dates

Publication Date: 20260512
Application Date: 20221102

Claims (15)

1 . An isolated humanized monoclonal antibody that binds to human Inducible COStimulator molecule (ICOS), wherein the antibody comprises: a heavy chain variable domain consisting essentially of the amino acid sequence of SEQ ID NO: 5, a light chain variable domain consisting essentially of the amino acid sequence of SEQ ID NO: 6, and wherein the antibody binds to human CD32b with a K D of 170 nM or less as measured by surface plasmon resonance.
2 . An isolated monoclonal antibody that binds to human ICOS, wherein the antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO: 7, and a light chain comprising the amino acid sequence of SEQ ID NO: 8.
3 . An isolated monoclonal antibody that binds to human ICOS, wherein the antibody comprises: a heavy chain consisting essentially of the amino acid sequence of SEQ ID NO: 7, a light chain consisting essentially of the amino acid sequence of SEQ ID NO: 8.
4 . The antibody of claim 1 , wherein the antibody blocks the binding and/or the interaction of ICOS ligand to human ICOS.
5 . The antibody of claim 2 , wherein the antibody blocks the binding and/or the interaction of ICOS ligand to human ICOS.
6 . The antibody of claim 3 , wherein the antibody blocks the binding and/or the interaction of ICOS ligand to human ICOS.
7 . A composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
8 . A composition comprising the antibody of claim 2 and a pharmaceutically acceptable carrier.
9 . A composition comprising the antibody of claim 3 and a pharmaceutically acceptable carrier.
10 . The composition of claim 7 , further comprising an additional therapeutic agent, wherein the additional therapeutic agent is an anti-cancer therapeutic agent, an immunostimulatory therapeutic agent, a chemotherapeutic agent, a radiotherapeutic agent, an immunotherapeutic agent, and/or an immunogenic therapeutic agent.
11 . The composition of claim 8 , further comprising an additional therapeutic agent, wherein the additional therapeutic agent is an anti-cancer therapeutic agent, an immunostimulatory therapeutic agent, a chemotherapeutic agent, a radiotherapeutic agent, an immunotherapeutic agent, and/or an immunogenic therapeutic agent.
12 . The composition of claim 9 , further comprising an additional therapeutic agent, wherein the additional therapeutic agent is an anti-cancer therapeutic agent, an immunostimulatory therapeutic agent, a chemotherapeutic agent, a radiotherapeutic agent, an immunotherapeutic agent, and/or an immunogenic therapeutic agent.
13 . The composition of claim 10 , wherein the additional therapeutic agent is an anti-programmed death protein 1 (PD-1) antibody, anti-programmed death ligand 1 (PD-L1) antibody, and/or an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody.
14 . The composition of claim 11 , wherein the additional therapeutic agent is an anti-programmed death protein 1 (PD-1) antibody, anti-programmed death ligand 1 (PD-L1) antibody, and/or an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody.
15 . The composition of claim 12 , wherein the additional therapeutic agent is an anti-programmed death protein 1 (PD-1) antibody, anti-programmed death ligand 1 (PD-L1) antibody, and/or an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody.

Description

RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 16/601,231 (allowed), filed on Oct. 14, 2019, which is a divisional of U.S. patent application Ser. No. 15/946,625 (U.S. Pat. No. 10,898,556 B2), filed on Apr. 5, 2018, which claims the benefit of priority of U.S. Provisional Application Nos. 62/483,158 (filed on Apr. 7, 2017), 62/514,151 (filed on Jun. 2, 2017), 62/545,732 (filed on Aug. 15, 2017) and 62/581,412 (filed on Nov. 3, 2017). The contents of the aforementioned applications are hereby incorporated by reference in their entireties. TECHNICAL FIELD This invention relates to anti-Inducible T Cell COStimulator (ICOS) agonist antibodies and pharmaceutical compositions thereof, and methods for using such antibodies, e.g., for treating cancer by administering the anti-ICOS agonist antibodies and pharmaceutical compositions. SEQUENCE LISTING The instant application contains a Sequence Listing which has been filed electronically in xml format and is hereby incorporated by reference in its entirety. Said xml copy, created on Nov. 2, 2022, is named MXI-556DV4CN_Sequence_Listing.xml and is 281 bytes in size. BACKGROUND A need exists to combat the global epidemic of cancer. Cancer is one of the leading causes of disease and the second leading cause of death worldwide. Cancer accounted for 8.8 million deaths in 2015. Globally, nearly one in six deaths is due to cancer. In 2018, there will be an estimated 1,735,350 new cancer cases diagnosed and 609,640 cancer deaths in the United States. In 2012, there were an estimated 3.5 million new cancer cases and 1.9 million cancer deaths in Europe. The World Health Organization estimates in 2018 that the number of new cases of cancer is expected to rise by about 70% over the next two decades. Traditional cancer treatments include surgery, radiation therapy, and chemotherapy, amongst other therapies. In recent years, immuno-oncology has emerged as a new option to treat cancer. Immuno-oncology is different from traditional cancer treatments, which, for example, has tried to target tumors directly or to disrupt the tumor blood supply. Instead, immuno-oncology is designed to use the patient's own immune response to treat cancer. Understanding how the immune system affects cancer development and how it can be used to treat cancer has been a challenging, complicated problem. For example, patients may not respond to certain immuno-oncology drugs, and some develop resistance mechanisms, such as T cell exhaustion, which is when a T cell, a specific type of white blood cell, no longer functions properly. (Dempke et al., Eur. J. of Cancer, 74 55-72 (2017)). An important role of the immune system is its ability to differentiate between normal cells and “foreign” cells. The immune system can thus attack the foreign cells and leave normal cells alone. To do this, the immune system uses “checkpoints,” which are molecules on certain immune cells that need to be activated or inactivated to begin an immune response. Tumor cells can sometimes use these checkpoints to avoid being attacked by the immune system. Some immuno-oncology drugs target these checkpoints by acting as checkpoint inhibitors. Programmed death protein 1 (PD-1) is a checkpoint inhibitor that typically acts as a brake to prevent T cells from attacking other cells in the body. PD-1 does this when it binds to programmed death ligand 1 (PD-L1), a protein on some normal (and cancer) cells. When PD-1 binds to PD-L1, this interaction tells the T cell to not attack other cells. Some cancer cells have large amounts of PD-L1, which helps them evade immune attack. Therapeutic agents such as monoclonal antibodies that target this PD-1/PD-L1 interaction, such as nivolumab (Opdivo), can block the PD-1/PD-L1 binding to increase the body's immune response against tumor cells. A need exists for drugs that target different mechanisms of action that work either alone or in combination with checkpoint inhibitors to safely and effectively treat cancer and other diseases or conditions. T cell activation and function are regulated by the innate immune system through costimulatory molecules in the CD28-superfamily (e.g., positive and negative costimulatory molecules that promote or inhibit activation of the T cell receptor signal, respectively). Inducible COStimulator molecule (ICOS), also known as CD278, is an immune checkpoint protein that is a member of this CD28-superfamily. ICOS is a 55-60 kDa type I transmembrane protein that is expressed on T cells after T cell activation and costimulates T-cell activation after binding its ligand, ICOS-L (B7H2). ICOS is expressed by CD4+ cells, CD8+ cells, and regulatory T cells (Treg). ICOS also has been shown to be a key player in the function of follicular helper T cells (Tfhs) and the humoral immune response. The magnitude and quality of a T cell's immune response depends in part on the complicated balance between co-stimulatory and inhibitory signals to the