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

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.

DSP-0509, a systemically available TLR7 agonist, exhibits combination effect with immune checkpoint blockade by activating anti-tumor immune effects

“…Since the intensity of TCR stimulation on CTLs has been reported to be critical in inducing differentiation of memory T cells ( 54 ), it is conceivable that the combination of DSP-0509 with anti-CTLA-4 antibody increased the antigen-presenting ability of DCs, resulting in increased TCR signal on CTL. Recent approach in TLR7 agonist drug discovery is focusing on tumor targeting modality including ADC and nanoparticle and so on ( 55 – 58 ). However, these approaches are not always succeeded so far.…”

Trial watch: Toll-like receptor ligands in cancer therapy

“…Data from 18 patients enrolled in the single ascending dose escalation (part I) demonstrated that NJH395 could efficiently deliver the TLR7 agonist moiety in HER2 + cancer cells. 25 , 26 Additionally, NJH395 induced IFN-I responses, which correlated with immune modulation in the tumor microenvironment. 25 , 26 Although cytokine release syndrome was common, it remained manageable.…”

“… 25 , 26 Additionally, NJH395 induced IFN-I responses, which correlated with immune modulation in the tumor microenvironment. 25 , 26 Although cytokine release syndrome was common, it remained manageable. On the other hand, antidrug antibodies and neuroinflammation at high doses represent significant clinical challenges.…”

“…On the other hand, antidrug antibodies and neuroinflammation at high doses represent significant clinical challenges. 25 , 26 …”

Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer

“…Intravenous NJH395 is an immune-stimulating antibody conjugate (ISAC) that combines an unspecified TLR7 agonist with a monoclonal antibody against human epidermal growth factor receptor-2 (HER2) 40 . Despite its systemic distribution, the HER2 component directs the TLR7 agonist specifically to HER2expressing cells, enabling it to act locally and theoretically limit its off-target effects.…”