XMT-2056, a HER2-Directed STING Agonist Antibody–Drug Conjugate, Induces Innate Antitumor Immune Responses by Acting on Cancer Cells and Tumor-Resident Immune Cells

• Published in: Clinical cancer research Vol. 31; no. 9; pp. 1766 - 1782
• Main Authors: Bukhalid, Raghida A., Duvall, Jeremy R., Lancaster, Kelly, Catcott, Kalli C., Malli Cetinbas, Naniye, Monnell, Travis, Routhier, Caitlin, Thomas, Joshua D., Bentley, Keith W., Collins, Scott D., Ditty, Elizabeth, Eitas, Timothy K., Kelleher, Eugene W., Shaw, Pamela, Soomer-James, Jahna, Ter-Ovanesyan, Elena, Xu, Ling, Zurita, Jeffrey, Toader, Dorin, Damelin, Marc, Lowinger, Timothy B.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.05.2025
• Subjects: Animals; Antibodies, Monoclonal, Humanized; Biological Agents & Therapies; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Immunity, Innate - drug effects; Immunoconjugates - administration & dosage; Immunoconjugates - pharmacology; Immunology; Membrane Proteins - agonists; Mice; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - immunology; Translational Cancer Mechanisms and Therapy; Trastuzumab; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-24-2449

Targeted tumor delivery may be required to potentiate the clinical benefit of innate immune modulators. The objective of the study was to apply an antibody-drug conjugate (ADC) approach to STING agonism and develop a clinical candidate. XMT-2056, a HER2-directed STING agonist ADC, was designed, synthesized, and tested in pharmacology and toxicology studies. The ADC was compared with a clinical benchmark intravenously administered a STING agonist. XMT-2056 achieved tumor-targeted delivery of the STING agonist upon systemic administration in mice and induced innate antitumor immune responses; single dose administration of XMT-2056 induced tumor regression in a variety of tumor models with high and low HER2 expressions. Notably, XMT-2056 demonstrated superior efficacy and reduced systemic inflammation compared with a free STING agonist. XMT-2056 exhibited concomitant immune-mediated killing of HER2-negative cells specifically in the presence of HER2-positive cancer cells, supporting the potential for activity against tumors with heterogeneous HER2 expression. The antibody does not compete for binding with trastuzumab or pertuzumab, and a benefit was observed when combining XMT-2056 with each of these therapies as well as with trastuzumab deruxtecan ADC. The combination of XMT-2056 with anti-PD-1 conferred benefit on antitumor activity and induced immunologic memory. XMT-2056 was well tolerated in nonclinical toxicology studies. These data provide a robust preclinical characterization of XMT-2056 and provide rationale and strategy for its clinical evaluation.