The primary objective of this project is to establish the in vivo therapeutic potential for a new approach to treating melanoma. Malignant melanoma is a lethal form of skin cancer resulting from the uncontrolled proliferation of melanocytes. Melanoma is an aggressive malignancy that frequently metastasizes beyond its primary site, making the disease more difficult to treat. Prognosis following metastasis is grim and median survival, even with state-of-the-art immunotherapy treatment is less than one year. The current FDA-approved immune checkpoint inhibitors nivolumab and ipilimumab have produced compelling results, however they are known to cause significant adverse effects and only produce clinical benefit in a subset of patients. Barriers to advancing safer and more effective stand-alone or adjuvant immune checkpoint therapies include difficulty identifying appropriate target molecules with the potency and specificity to mount an immune response against cancer cells without triggering of tumor escape. Abcuro has identified and characterized a protein cell surface marker for T cells exhibited in the tumor microenvironment that aligns directly with the degree of T cell differentiation and is highly exhibited in melanoma-derived tumor infiltrating lymphocytes. We have developed a monoclonal antibody against this inhibitory receptor which we postulate is capable of precipitating an immune checkpoint blockade on natural killer and T cells to reactivate effector T cell response against cancer cells. In this proposal we aim to test whether two lead antibodies against the inhibitory receptor will result in amelioration of tumor pathology in an animal model relevant to clinical human melanoma. To accomplish this, we will produce and characterize recombinant humanized antibodies and measure the effect of antibody blockade of the target in a human peripheral blood cell reconstituted immunodeficient murine melanoma model. In this way we are able to test the efficacy of antibodies in reducing tumor growth and increasing survival in vivo using human lymphocytes. The proposed project will establish animal proof of concept for Abcuros engineered antibodies in a murine humanized melanoma model. If successful, we will have produced direct proof-of-concept evidence of the effect of targeted blockade of this T cell activating co-inhibitory receptor for the treatment of melanoma, allowing us to further develop our fully characterized lead antibody for clinical trials in human patients.
Public Health Relevance Statement: NARRATIVE Malignant melanoma is a type of skin cancer that results from overgrowth of pigment-producing cells and which carries an extremely poor prognosis. We propose to develop a therapeutic antibody capable of modulating T cells to reactivate the immune response against tumor growth. We will test our antibodies in an animal model of melanoma that mimics the human immune system. This work will establish the potential of a novel antibody capable of blocking mechanisms of tumor escape, opening new possibilities for cancer patients unresponsive to currently available treatments.
Project Terms: Address; Advanced Development; Adverse effects; Animal Model; Animals; anti-PD1 therapy; Antibodies; antibody engineering; Binding; Biological Assay; Biophysics; Blocking Antibodies; Blood Cells; Bypass; cancer cell; Cancer Model; Cancer Patient; CD8-Positive T-Lymphocytes; Cell Line; Cell Surface Proteins; Cells; checkpoint therapy; Clinical; Clinical Trials; combat; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Diagnosis; Disease; Drug Kinetics; E-Cadherin; effector T cell; efficacy testing; Endotoxins; Ensure; Exhibits; experience; experimental study; FDA approved; Funding; Future; glycosylation; Human; humanized antibody; humanized mouse; immune checkpoint; immune checkpoint blockade; Immune checkpoint inhibitor; Immune response; Immune system; Immune Targeting; Immunologic Adjuvants; Immunotherapy; in vivo; Individual; Lead; Ligands; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Measures; melanocyte; melanoma; Melanoma Cell; Metastatic Melanoma; Modeling; Monoclonal Antibodies; mouse model; Mus; N-Cadherin; Natural Killer Cells; Neoplasm Metastasis; Nivolumab; nonhuman primate; novel; novel strategies; outcome forecast; Pathway interactions; patient subsets; Patients; Peripheral Blood Mononuclear Cell; Phase; Phase III Clinical Trials; Pigments; receptor; Recombinants; reconstitution; Resistance; resistance mechanism; scale up; Scientist; Site; Skin Cancer; Small Business Innovation Research Grant; Specificity; success; Survival Rate; synergism; System; T cell differentiation; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic antibodies; Therapeutic Monoclonal Antibodies; tool; Toxicology; Tumor Escape; tumor growth; tumor microenvironment; Tumor Pathology; Tumor-Derived; Tumor-Infiltrating Lymphocytes; tumorigenesis; United States; Variant; Work
