IGI and NCI Partner to Test Oral Cbl/b Inhibitor for Triple-Negative Breast Cancer

Ichnos Glenmark Innovation (IGI), a collaboration between Ichnos Sciences Inc. and Glenmark Pharmaceuticals Ltd., has embarked on a significant Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the United States. This partnership aims to explore and develop IGI's proprietary small molecule, GRC 65327, specifically targeting Casitas B-lineage lymphoma b (Cbl/b), an E3 ubiquitin ligase crucial for regulating T and natural killer (NK) cell activation.

GRC 65327 is heralded as a best-in-class, selective, and orally bioavailable Cbl/b inhibitor with notable in vitro potency and in vivo efficacy. It has shown an acceptable non-clinical toxicity profile, making it a promising candidate for further research and development. Dr. Nagaraj Gowda, Vice-President and Head of Small Molecule Research at IGI, expressed optimism about the compound's potential, emphasizing its unique properties and promising preclinical results.

Under the terms of the CRADA, the NCI will characterize and test GRC 65327 in immune-competent models of triple-negative breast cancer (TNBC). The primary goal is to generate robust preclinical data that could pave the way for clinical trials in late-stage TNBC, a form of cancer that currently has limited effective treatment options. Dr. Stan Lipkowitz, Chief of the Women's Malignancies Branch and Deputy Director of the Center for Cancer Research at the NCI, will lead the efforts. His team brings a wealth of experience in Cbl/b research, having initially cloned the gene and identified its significant role as a negative regulator in the adaptive immune system.

Dr. Lipkowitz's team will evaluate GRC 65327 in various models, including in vitro, cell-based, and in vivo mammary cancer models, to assess its efficacy as a Cbl/b inhibitor and its ability to modulate adaptive and innate immune responses to breast cancers. The collaboration aims to harness the potential of small molecule inhibitors of Cbl/b to enhance anti-tumor activity by improving signaling through the costimulatory pathway in T cells and boosting NK cell activity, thereby potentially offering new therapeutic avenues for cancer patients.

IGI's President, Executive Director, and CEO, Dr. Cyril Konto, expressed confidence in the power of collaboration to foster innovation. He highlighted that partnering with Dr. Lipkowitz and the NCI is expected to accelerate the development of GRC 65327, particularly in TNBC. This collaboration complements IGI's broader program to advance GRC 65327 in other solid tumors, aiming to provide new hope for patients battling various forms of cancer.

IGI's GRC 65327 program focuses on the inhibition of Cbl/b, an E3 ubiquitin ligase that acts as a key inhibitor in the activation of T and NK cells in the absence of CD28 costimulation. Cbl/b regulates immune cell activity in PD-1, CTLA4, and TIGIT positive cells, serving as an intracellular master regulator. Inhibiting Cbl/b can lead to robust immune cell activation in immune-suppressed tumor microenvironments, potentially inducing strong single-agent activity. A first-in-human clinical trial for patients with relapsed or refractory solid tumor indications is anticipated to commence in early 2025. IGI plans to present the preclinical data package for GRC 65327 at an upcoming scientific conference.

Ichnos Glenmark Innovation combines the strengths of Ichnos Sciences Inc. and Glenmark Pharmaceuticals Ltd. to accelerate drug discovery in oncology. This alliance leverages Ichnos' expertise in novel biologics and Glenmark's proficiency in new small molecules to create innovative cancer therapies. With over 150 scientists and a robust pipeline of novel molecules, IGI operates from three global centers of innovation located in the USA, Switzerland, and India, all dedicated to advancing cancer treatment options.