| Autor: |
Salvatore Siena, Vasileios Askoxylakis, Glenn Dranoff, Marc R. Pelletier, Lang Ho Lee, Lori A. Iaconis, Sarah M. Choi, Heidi A. Schoenfeld, Kulandayan Subramanian, Ping C. Mahling, Susan E. Cellitti, Alex Cortez, Yasutoshi Kuboki, Jaffer A. Ajani, Alessio Amatu, Toshihiko Doi, Sae-Won Han, Filip Janku |
| Rok vydání: |
2023 |
| DOI: |
10.1158/2326-6066.c.6551021.v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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