Invented by John J. ENGELHARDT, Mark J. Selby, Alan J. Korman, Mary Diane Feingersh, Brenda L. Stevens, Bristol Myers Squibb Co

The Market for Anti-ICOS Agonist Antibody and Its Uses In recent years, the field of immunotherapy has witnessed remarkable advancements in the treatment of various diseases, particularly cancer. One such breakthrough is the development of anti-ICOS agonist antibodies, which have shown promising results in enhancing the immune system’s response against cancer cells. The market for these antibodies is rapidly growing, driven by the increasing demand for effective and targeted cancer therapies. ICOS, or Inducible T-cell CO-stimulator, is a protein found on the surface of certain immune cells called T-cells. It plays a crucial role in regulating the immune response by promoting the activation and proliferation of T-cells. However, cancer cells can exploit this pathway to suppress the immune system and evade detection. Anti-ICOS agonist antibodies work by blocking the inhibitory signals and activating the immune system to recognize and attack cancer cells more effectively. The potential applications of anti-ICOS agonist antibodies extend beyond cancer treatment. They have also shown promise in treating autoimmune diseases, such as rheumatoid arthritis and lupus, where the immune system mistakenly attacks healthy tissues. By modulating the immune response, these antibodies can help restore the balance and alleviate the symptoms associated with these conditions. The market for anti-ICOS agonist antibodies is expected to witness significant growth in the coming years. Several pharmaceutical companies are investing heavily in research and development to bring these therapies to the market. The increasing prevalence of cancer and autoimmune diseases, coupled with the limitations of existing treatment options, has created a strong demand for innovative therapies like anti-ICOS agonist antibodies. Moreover, the favorable regulatory environment and the growing acceptance of immunotherapy as a viable treatment option have further fueled the market’s growth. Regulatory agencies, such as the U.S. Food and Drug Administration (FDA), have granted breakthrough therapy designations to certain anti-ICOS agonist antibodies, expediting their development and approval process. The market for anti-ICOS agonist antibodies is highly competitive, with several players vying for a share of the market. Key pharmaceutical companies, including Bristol Myers Squibb, AstraZeneca, and Merck, have made significant investments in this field. These companies are not only developing their proprietary anti-ICOS agonist antibodies but also exploring potential combination therapies with other immunotherapies to enhance their efficacy. Despite the immense potential, there are certain challenges that the market for anti-ICOS agonist antibodies faces. One of the primary concerns is the high cost associated with these therapies. The development and production of monoclonal antibodies are complex and expensive processes, which ultimately impact the final pricing. However, with the increasing competition and advancements in manufacturing technologies, it is expected that the cost of these therapies will gradually decrease, making them more accessible to patients. Another challenge is the identification of suitable biomarkers to predict patient response to anti-ICOS agonist antibodies. As with any targeted therapy, not all patients will respond equally to treatment. Therefore, the development of reliable biomarkers can help identify patients who are more likely to benefit from these therapies, enabling personalized treatment approaches. In conclusion, the market for anti-ICOS agonist antibodies is witnessing rapid growth, driven by the increasing demand for effective and targeted cancer therapies. These antibodies have shown promising results in enhancing the immune system’s response against cancer cells and have the potential to revolutionize cancer treatment. Additionally, their applications in autoimmune diseases further expand their market potential. While challenges exist, such as high costs and the need for biomarker identification, ongoing research and development efforts are expected to overcome these hurdles, paving the way for a brighter future in immunotherapy.

The Bristol Myers Squibb Co invention works as follows

The present invention provides monoclonal monoclonal antibody (e.g. humanized and human monoclonal antigens) that bind human Inducible T Cell COStimulator(ICOS) with therapeutically desired functional properties. For example, they can stimulate human ICOS. The invention also provides nucleic acid molecule encoding antibodies, expression vectors and host cells as well as methods of expressing antibodies. The invention also includes immunoconjugates and bispecific molecules. Pharmaceutical compositions containing the antibodies are also included. The antibodies of this invention can also be used as an agonist in order to enhance or stimulate an immune response, such as antigen-specific responses by T cells against a viral or tumor antigen. The antibodies of this invention can be combined with other antibodies to treat cancer, such as PD-1 antibodies, PDL1 antibodies, and/or CTLA-4 antibody. The antibodies can also be used to detect ICOS proteins in therapeutic applications.

Background for Anti-ICOS agonist antibody and its uses

It is urgent to fight the global cancer epidemic. Cancer is the second-leading cause of death and one of the most common diseases in the world. In 2015, cancer was responsible for 8.8 millions deaths. Nearly one out of six deaths worldwide is caused by cancer. In the United States, there are estimated to be 1,735,350 cancer cases in 2018 and 609 640 cancer deaths. In Europe, in 2012 there were estimated 3.5 millions new cancer cases. In 2018, the World Health Organization estimated that new cancer cases would increase by 70% in the next 20 years.

Traditional cancer treatment includes surgery, chemotherapy, and radiation therapy. Immuno-oncology is a relatively new treatment option for cancer. Immuno-oncology differs from other cancer treatments that, for instance, have tried to directly target tumors or disrupt the blood supply to tumors. Immuno-oncology uses the patient’s immune system to fight cancer. It has been difficult to understand how the immune system influences cancer growth and how it could be used in cancer treatment. Patients may not respond well to immuno-oncology treatments, while others develop resistance mechanisms. One example is T cell exhaustion. This occurs when T cells, a type of white blood cell that no longer function properly, are exhausted. (Dempke et al., Eur. J. of Cancer 74, 55-72 (2017 )).

There is a need for drugs that target multiple mechanisms of action, either in isolation or combined with checkpoint inhibitors, to effectively and safely treat cancer or other diseases and conditions. The innate immune system regulates T cell activation by using costimulatory molecule members of the CD28 superfamily. (e.g. positive and negative costimulatory peptides that either promote or inhibit the activation signal from the T cell receptor). The immune checkpoint protein, Inducible COStimulator molecule or CD278, belongs to the CD28-superfamily. ICOS, also known as CD278, is a type I transmembrane 55-60 kDa protein expressed on T-cells after activation. It costimulates activation of T-cells after binding to its ligand ICOS-L(B7H2). ICOS is expressed on CD4+, CD8+, and regulatory T-cells (Treg). ICOS has also been shown to play a major role in the function of follicular Tfhs (Tfhs), and the humoral immunity response.

The balance between co-stimulatory signals and inhibitory ones to the T cell is crucial in determining the magnitude and quality a T cell’s response. Novel immuno-oncology treatments are needed to improve the response rate of patients after immunotherapy, and overcome drug resistance.

The present invention provides monoclonal anti-huICOS antibody (e.g. humanized or human monoclonal) that binds to human ICOS, i.e. anti-huICOS, and has therapeutically desired functional properties. The antibodies of this invention can be used to enhance or stimulate an immune response, e.g. to stimulate the human ICOS and/or provide antigen-specific responses to a viral or tumor antigen. The antibodies of this invention can be used with other antibodies, such as PD-1 antibodies, PDL1 antibodies, and/or CTLA-4 antibody, to treat different conditions. The antibodies described herein can be used alone or in combination to treat various diseases or conditions, including cancer. The antibodies disclosed herein may also be used to detect ICOS proteins in other embodiments.

In one aspect of the isolated antibody, it is a humanized isolate antibody (or an antigen-binding portion thereof) which binds to the human ICOS, and blocks the binding or interaction between ICOS ligands (e.g. human ICOS L) and human ICOS, and

(a), induces proliferation and IFN-gamma? “(a) induces proliferation and interferon-gamma (IFN-?) “CD4+ T cells that have an EC50 between 0.01 and about 16.16 nM when tested in an in vitro CHO OKT3-CD32A assay

(b), induces IFN? “(b) induces IFN-? CD4+ T-cells with an EC50 ranging from 0.002 nM – 0.4 nM for a staphylococcal EnterotoxinB in a CD25 test. “Assay for co-culture of CD4+ T cells and B cells.

The antibody or antigen-binding portion of the antibody exhibits the following characteristics:

(a), binds human T-cells with an EC50 value of approximately 0.7 nM, and cynomolgus cells with an EC50 value of approximately 0.3 nM

(b), binds human activated CD4+T cells;

(c), does not bind human CD28 or human CTLA-4

(d), activates at lease one primary T-lymphocyte, such as CD4+ effector (Teff), a follicular (Tfh) helper (Tfh), and a regulatory (Treg);

(e), induces phosphorylation by protein kinase B in an in vitro signaling assay of primary T cells with an EC50 value of approximately 30 nM

(f), induces interleukin-10 production in response staphylococcal Enterotoxin-B in a co-culture of Tfh cells and naive b-cells;

(g), induces a higher proliferation increase of CD3 stimulated Teffs than CD45RA+ and CD45RO+Tregs in an In vitro assay.

(h), reduces Teff suppression by Tregs

(i), does not increase cytokine in a whole-blood cell assay when 10?g/mL is used;

(j), increases the secretion of IFN-g and IL-10 by Tfh cell in vitro.

(k), stimulates ICOSmediated signaling

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