On October 4, 2023 AbbVie (NYSE: ABBV), the Broad Institute of MIT and Harvard, and Calico Life Sciences reported the publication in Nature of the discovery and preclinical data that demonstrate investigational ABBV-CLS-484 is a potential first-in-class, orally bioavailable, PTPN2/N1 phosphatase inhibitor that enhances anti-tumor immunity (Press release, AbbVie, OCT 4, 2023, View Source [SID1234635631]). The findings, based on research conducted by AbbVie in collaboration with the Broad Institute and Calico, support the development of ABBV-CLS-484 as a promising new strategy for cancer immunotherapy.

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Titled "The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity," the paper highlights the novel structural insights and design that led to the discovery of ABBV-CLS-484 and its dual mechanism of action that targets tumor cells and suppresses their growth, as well as promotes the activation of several immune cell types to increase their anti-tumor activity.1

Researchers at the Broad previously identified protein tyrosine phosphatase non-receptor type 2 (PTPN2) and its closely related paralog PTPN1 as potential targets for cancer immunotherapy through an in vivo CRISPR screen.2 However, this challenging target class had previously been deemed "undruggable". AbbVie researchers overcame the challenges and discovered the dual PTPN2/N1 inhibitor, ABBV-CLS-484, through structure-based drug design and optimization of drug-like properties.

Discovery scientists at AbbVie, the Broad, and Calico further uncovered the biology and mechanism of action of ABBV-CLS-484. Preclinical findings presented demonstrate that ABBV-CLS-484 treatment amplifies the tumor intrinsic response to interferon and increases the activation and function of several immune cell subsets promoting cellular pathways including JAK-STAT signaling in animal models. In murine cancer models resistant to PD-1 blockade, monotherapy ABBV-CLS-484 treatment generates robust anti-tumor immunity. Through in vivo studies and single cell transcriptional profiling of tumor-infiltrating lymphocytes from ABBV-CLS-484 treated mice, the team revealed that ABBV-CLS-484 inflames the tumor microenvironment and promotes NK and CD8+ T-cell function. In T cells, mechanistically, ABBV-CLS-484 induces epigenetic and metabolic changes resulting in a unique functional state causing increased cytotoxicity and reduced T-cell exhaustion and dysfunction.

"Immunotherapies like PD-1 blockade have revolutionized cancer treatment; however, many patients do not respond well to them, and a significant unmet need remains," said Christina Baumgartner, Ph.D., co-first author and senior principal research scientist, AbbVie. "Through the extraordinary efforts of AbbVie’s medicinal chemistry team to drug the undruggable, we now have a potential first-in-class PTPN2/N1 inhibitor. We’re excited to share its biology and mechanism of action, and look forward to further evaluating it in the clinic."

"This study is a powerful demonstration of how collaboration can bring together diverse expertise to advance our understanding of disease biology and lead to discoveries that support new treatment strategies for people living with cancer," said Marcia Paddock, M.D., Ph.D., co-author and director of oncology new target development at Calico. "We are proud to be working with both AbbVie and the Broad Institute and look forward to sharing additional progress from our clinical studies of this novel immunotherapy."

ABBV-CLS-484 is the first active-site phosphatase inhibitor to enter clinical evaluation as a cancer therapy and is currently in an AbbVie and Calico-led Phase 1 clinical trial in solid tumors (NCT04777994).

"This is an unprecedented opportunity to evaluate how immune responses work," said Robert Manguso, Ph.D., co-senior author on the study, associate member at the Broad, and assistant professor at the Massachusetts General Hospital Center for Cancer Research and Harvard Medical School. "The ability to further explore this signaling pathway in clinical studies is really important."