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