Preclinical Characterization and Phase I Study of an Anti-HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2+ Malignancies.

Abstract

Immune-stimulator antibody conjugates (ISAC) combining tumor-targeting monoclonal antibodies with immunostimulatory agents allow targeted delivery of immune activators into tumors. NJH395 is a novel, first-in-class ISAC comprising a Toll-like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody via a noncleavable linker payload. Preclinical characterization showed ISAC-mediated activation of myeloid cells in the presence of antigen-expressing cancer cells, with antigen targeting and TLR7 agonism contributing to antitumor activity. Safety, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics were investigated in a phase I, multicenter, open-label study in patients with HER2+ non-breast advanced malignancies (NCT03696771). Data from 18 patients enrolled in single ascending dose escalation demonstrated delivery of the TLR7-agonist payload in HER2+ tumor cells and induction of type I IFN responses, which correlated with immune modulation in the tumor microenvironment. Cytokine release syndrome was a common, but manageable, drug-related adverse event. Antidrug antibodies and neuroinflammation at high doses represented significant clinical challenges. Data provide proof-of-mechanism and critical insights for novel immunotherapies.

• Authors: Filip Janku, Sae-Won Han, Toshihiko Doi, Alessio Amatu, Jaffer A Ajani, Yasutoshi Kuboki, Alex Cortez, Susan E Cellitti, Ping C Mahling, Kulandayan Subramanian, Heidi A Schoenfeld, Sarah M Choi, Lori A Iaconis, Lang Ho Lee, Marc R Pelletier, Glenn Dranoff, Vasileios Askoxylakis, Salvatore Siena
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 10 Issue 12 Pg. 1441-1461 (12 02 2022) ISSN: 2326-6074 [Electronic] United States
• PMID: 36129967 (Publication Type: Clinical Trial, Phase I, Multicenter Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Toll-Like Receptor 7
• Immunoconjugates
• Antineoplastic Agents
• Antineoplastic Agents, Immunological
• Receptor, ErbB-2
• TLR7 protein, human

Topics

• Humans
• Toll-Like Receptor 7 (agonists)
• Immunoconjugates (adverse effects)
• Neoplasms (drug therapy)
• Antineoplastic Agents
• Antineoplastic Agents, Immunological (therapeutic use)
• Receptor, ErbB-2
• Tumor Microenvironment