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

Cancer Immunol Res. 2022 Dec 2;10(12):1441-1461. doi: 10.1158/2326-6066.CIR-21-0722.


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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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

Associated data