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Preclinical Characterization and Phase I Study of an Anti–HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2+ Malignancies by 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 is a Medicine article available to read on EtoBox.

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## 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.

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Author

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

Publisher

American Association for Cancer Research (AACR)

Published

2022

Language

EN

Field

Medicine (Life Sciences)