TY - JOUR
T1 - Preclinical Characterization and Phase I Study of an Anti-HER2-TLR7 Immune-Stimulator Antibody Conjugate in Patients with HER2+ Malignancies
AU - Janku, Filip
AU - Han, Sae Won
AU - Doi, Toshihiko
AU - Amatu, Alessio
AU - Ajani, Jaffer A.
AU - Kuboki, Yasutoshi
AU - Cortez, Alex
AU - Cellitti, Susan E.
AU - Mahling, Ping C.
AU - Subramanian, Kulandayan
AU - Schoenfeld, Heidi A.
AU - Choi, Sarah M.
AU - Iaconis, Lori A.
AU - Lee, Lang Ho
AU - Pelletier, Marc R.
AU - Dranoff, Glenn
AU - Askoxylakis, Vasileios
AU - Siena, Salvatore
N1 - Publisher Copyright:
©2022 American Association for Cancer Research.
PY - 2022/12/2
Y1 - 2022/12/2
N2 - 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.
AB - 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.
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U2 - 10.1158/2326-6066.CIR-21-0722
DO - 10.1158/2326-6066.CIR-21-0722
M3 - Article
C2 - 36129967
AN - SCOPUS:85143197691
SN - 2326-6066
VL - 10
SP - 1441
EP - 1461
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 12
ER -