Anti-TLR7 antibody(BioLegend)

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.

Blocking immune cell gut homing via α4β7 integrin with the monoclonal antibody vedolizumab is an established therapeutic strategy in inflammatory bowel disease. However, despite promising preclinical and phase 2 clinical data, the anti-β7 antibody etrolizumab yielded disappointing results in a large phase 3 trial program in UC. Mechanistic explanations are still lacking. We have recently shown that vedolizumab is associated with residual homing of regulatory T (Treg) cells in a certain exposure range and aimed to investigate whether a similar mechanism applies for etrolizumab.

We used flow cytometry, competitive dynamic adhesion, and transmigration assays to assess binding of the etrolizumab surrogate (etrolizumab-s) antibody FIB504 to Treg and effector T cells (Teff) and to explore the impact on cell trafficking.

We observed only minimal differences in the binding of etrolizumab-s to Treg and Teff cells. Dynamic adhesion and transmigration of Treg and Teff cells was not substantially differentially affected at relevant concentrations. The β1+ and PI16+ Treg cells were only resistant to etrolizumab-s at low concentrations.

Etrolizumab does not seem to induce notable residual trafficking of Treg cells. Thus, the Teff overweight in the inflamed gut might persist despite reduced overall T cell recruitment. This might be one piece of the puzzle to explain recent clinical results in phase 3.