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

Abstract Purpose: 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 approach to STING agonism and develop a clinical candidate. Methods: XMT-2056, a HER2-directed STING-agonist antibody-drug conjugate (ADC), was designed, built, and tested in pharmacology and toxicology studies. The ADC was compared to a clinical benchmark intravenously administered STING agonist. Results: XMT-2056 achieved tumor-targeted delivery of the STING agonist upon systemic administration in mice and induced innate anti-tumor immune responses; single dose administration of XMT-2056 induced tumor regression in a variety of tumor models with high and low HER2 expression. Notably, XMT-2056 demonstrated superior efficacy and reduced systemic inflammation compared to 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 heterogenous 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 (T-Dxd) ADC. The combination of XMT-2056 with anti-PD-1 conferred benefit on anti-tumor activity and induced immunological memory. XMT-2056 was well tolerated in nonclinical toxicology studies. Conclusion: These data provide a robust preclinical characterization of XMT-2056 and provide rationale and strategy for its clinical testing.