On March 25, 2021 Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported the peer-reviewed publication of preclinical data of the company’s investigational novel MDM2-p53 inhibitor APG-115 in the journal Nature Immunology unveiling the role of mouse double minute 2 homolog (MDM2) in CD8⁺ T-cell- mediated immunity (Press release, Ascentage Pharma, MAR 25, 2021, View Source [SID1234577179]).

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Titled "The ubiquitin ligase MDM2 sustains STAT5 stability to control T-cell mediated antitumor immunity," the report is published in today’s Nature Immunology. Shaomeng Wang, PhD, cofounder of Ascentage Pharma, Chairman of the company’s Scientific Advisory Board, and the Warner-Lambert/Parke-Davis Professor of Internal Medicine, Pharmacology, and Medicinal Chemistry at the University of Michigan School of Medicine is a co-author of this study. Weiping Zou, MD, PhD, Charles B. de Nancrede Professor of Pathology, Surgery, Immunology and Biology, and Director, Center of Excellence for Cancer Immunology and Immunotherapy at the University of Michigan is the senior and corresponding author of the study.

The MDM2-p53 complex has a proven role in the development and progression of cancer, opening a potential avenue for therapeutic approaches seeking to disrupt the interaction and increase p53-mediated tumor cell death (apoptosis). However, a major challenge is that there are as yet no approved therapies targeting MDM2-p53.

"Before our study, it was unclear whether the MDM2-p53 axis affects CD8⁺ (cytotoxic or cancer-killing) T-cell-mediated antitumor immunity," said Dr. Wang. "Through a series of biochemical, genetic, and functional studies, we have demonstrated that MDM2 plays a pivotal biological role in T-cell stability, survival, and antitumor immunity, potentially laying a foundation for synergistic effects between MDM2-targeted agents such as APG-115 and cancer immunotherapy."

Using in vivo and other experimental models, the authors demonstrated that mice lacking MDM2 in T cells exhibit more rapidly growing tumors with diminished numbers of tumor-infiltrating CD8⁺ T-cells. The authors also showed that MDM2 stabilizes signal transducer and activator of transcription 5 (STAT5), a protein essential for T-cell function and survival. This is an important finding, in part because Ascentage’s drug candidate APG-115 disrupts the MDM2-p53 complex, potentially acting as an "MDM2 enhancer" to stabilize STAT5 and hence augment T-cell immunity.

APG-115 is a novel, orally active molecule that activates p53-mediated apoptosis in tumor cells with wild-type p53 and/or MDM2 amplification. APG-115 is the first MDM2-p53 inhibitor entering clinical development in China, and is currently being investigated in multiple Phase Ib/II clinical studies in solid tumors and hematologic malignancies in China and the US.

"This is truly uncharted territory," said Dr. Dajun Yang, Chairman & CEO of Ascentage Pharma. "There is a significant unmet clinical need for targeted therapies that disrupt the MDM2-p53 complex and not only eradicate tumor cells but also enhance T-cell-mediated immunity. This publication will bring about the incentives and support that will enable us to further accelerate global development and commercialization of this drug candidate," he said. "Given the promising safety and efficacy data obtained thus far, we will expedite development and are hopeful that APG-115 will soon benefit patients worldwide."

Now underway is a phase 2 clinical trial of APG-115 together with the immune checkpoint inhibitor pembrolizumab in patients with PD-1-inhibitor-refractory or relapsed cancers. These include solid tumor, liposarcoma, urothelial carcinoma, and malignant peripheral nerve sheath tumor, which affects the connective tissues surrounding nerves.