SUMMARY OF INVENTION
Dysregulated protein phosphorylation is a shared molecular driver frequently contributing to oncogenesis. Phosphorylation of the insulin receptor substrate (pIRS) has been shown to link signaling from growth factor/cytokine receptors to drive cell growth, metabolism, and the survival of cells. Indeed, aberrant IRS2 phosphorylation has been frequently observed in a host of leukemias and solid tumors.
To address the intracellular phosphorylated cancer targets, MSK investigators developed a TCR mimic (TCRm) monoclonal antibody against the “public” phospho-neoantigen pIRS2. Phosphopeptides are emerging as a new class of targetable tumor antigens that appear in cancer cells with dysregulated kinase activity. The pIRS2 phosphopeptide previously has been shown to be presented by HLA-A*02:01, recognized by CD8+ T-cells, and a pIRS2 cancer vaccine has been evaluated in high-risk melanoma patients.
TCR mimic monoclonal antibodies were generated against the pIRS2/HLA-A*02:01 complex with lead antibody 6B1 capable of discriminating between phosphorylated and unphosphorylated IRS2 peptides. The 6B1 antibody was reformatted into different bispecific antibody formats with the 1+1 and H2+2 format demonstrating the greatest cytotoxicity against tumor cell lines.
The TCRm binder is available to license and could be developed as a bispecific antibody or in another format (ex: TCRm CAR T-cell) to achieve therapeutic activity.
ADVANTAGES
- Therapeutics against “public” phosphopeptides represent a highly promising class of tumor specific neoantigens that are widely expressed in malignant cells and hence, not patient specific—unlike other “neoantigens.”
- The 6B1 antibody did not bind hematopoietic cells (neutrophils, monocytes/macrophages, and lymphocytes), human cardiac and thymic fibroblasts, or human cardiomyocytes, minimizing potential side effects.
MARKET OPPORTUNITY
pIRS2 has been observed in a number of cancers including hepatocellular carcinoma, melanoma, ovarian cancer, and colon cancer. HLA-A*02:01 is among the most frequently presented HLA alleles in the U.S. (~40% of the population; Pearlman et al., 2021).
PATENT INFORMATION
PCT application (PCT/US2022/029974) filed in May 2022.
PUBLICATIONS
Dao et al., A TCR mimic monoclonal antibody reactive with the “public” phospho-neoantigen pIRS2/HLA-A*02:01 complex. JCI Insight. 2022 (link)
LEAD INVESTIGATOR
David Scheinberg, PhD, MD, Vincent Astor Chair; Chairman, Center for Therapeutics Center; and Deputy Director, Therapeutic Discovery, Sloan Kettering Institute, MSK
CONTACT INFORMATION
James Delorme, Ph.D.
Licensing Manager
E-mail: [email protected]