Preclinical characterization of IMAB362-vcMMAE, an anti-CLDN18.2 antibody–drug conjugate

Abstract

Background Antibody–drug conjugates combine the specific targeting and antitumor activity of monoclonal antibodies with the potent cell killing activity of cytotoxic small molecule drugs. IMAB362 is a monoclonal antibody specific for the tight junction protein Claudin 18.2 (CLDN18.2). In normal tissue, CLDN18.2 is exclusively expressed in the gastric mucosa. In the context of malignant transformation, CLDN18.2 can be found in gastric tumors as well as tumors from organs that do not normally express CLDN18.2 (eg, pancreas). Preclinical characterization of IMAB362 conjugated to the antimitotic molecule, monomethyl auristatin E, with a valine–citrulline linker (IMAB362–vcMMAE) is presented here. Methods IMAB362–vcMMAE binding characteristics and internalization were assessed in CLDN18.2-expressing human cell lines. Cell viability and IMAB362–vcMMAE-mediated cytotoxic effects (direct and indirect [bystander]) were also assessed in CLDN18.2 in vitro models. Xenograft mouse models of pancreatic and gastric cancers were developed to assess the cytotoxic and antitumor effects of IMAB362–vcMMAE in vitro. Results IMAB362–vcMMAE showed a slightly decreased relative binding affinity on CLDN18.2-transfected cells and cells that endogenously express CLDN18.2 compared with unconjugated IMAB362. In cell lines that internalized IMAB362–vcMMAE, cell viability was reduced by 45–90%; EC50 negatively correlated with CLDN18.2 expression level, with the lowest EC50 being Conclusions IMAB362–vcMMAE is a highly specific and potent antibody-drug conjugate against in vivo and in vitro models of gastric and pancreatic cancers.