Janku et al. demonstrated that NJH395, a toll-like receptor 7 (TLR7) agonist conjugated to an anti-HER2 via a non-cleavable linker-payload, activated myeloid cells in the presence of HER2+ cancer cells and significantly inhibited tumor growth in multiple HER2 tumor models. Dose escalation studies in patients with HER2+ non-breast advanced malignancies showed payload detection in HER2+ tumor cells, and increased TLR7 in macrophages. TLR7 induced a type I IFN response that resulted in myeloid cell proliferation and T cell activation. Cytokine release syndrome was a common, but manageable, drug-related adverse event, and anti-drug antibodies (ADA) decreased drug exposure.
Contributed by Shishir Pant
ABSTRACT: Immune-stimulator antibody conjugates (ISACs) 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 via a non-cleavable 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 1, multicenter, open-label study in patients with HER2+ non-breast advanced malignancies (NCT03696771). Data from 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. Anti-drug antibodies and neuroinflammation at high doses represented significant clinical challenges. Data provide proof-of-mechanism and critical insights for novel immunotherapies.
Author Info: (1) The University of Texas MD Anderson Cancer Center, Houston, Texas, United States. (2) Seoul National University Hospital, Seoul, Korea (South), Republic of. (3) National Cancer
Author Info: (1) The University of Texas MD Anderson Cancer Center, Houston, Texas, United States. (2) Seoul National University Hospital, Seoul, Korea (South), Republic of. (3) National Cancer Center Hospital East, Kashiwashi, Chiba, Japan. (4) Grande Ospedale Metropolitano Niguarda, Milano, Italy. (5) The University of Texas MD Anderson Cancer Center, Houston, TX, United States. (6) National Cancer Center Hospital East, Kashiwa, Chiba, Japan. (7) Bristol-Myers Squibb (United States), San Diego, CA, United States. (8) Novartis Institutes for BioMedical Research, Inc.,, San Diego, CA, United States. (9) Novartis (Switzerland), Switzerland. (10) Werewolf Therapeutics, MA, United States. (11) Novartis Institutes for BioMedical Research, East Hanover, New Jersey, United States. (12) Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States. (13) Novartis Institute for BioMedical Research, San Diego, San Diego, United States. (14) Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States. (15) Novartis Institute for Biomedical Research, Cambridge, MA, United States. (16) Novartis Therapeutics, Cambridge, MA, United States. (17) Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States. (18) Universitð degli Studi di Milano, Milan, Italy, Italy.
