Anti-Claudin18.2-IL-21 fusion protein bifunctional molecule has more powerful anti-tumor effect and better safety

Abstract

Antibody or antibody-like protein drugs related to tumor immunotherapy are now widely used. Here, we describe an antibody-fusion protein drug IMAB362-mIL-21 with mouse IL-21 (mIL-21) fused into the C-terminal domain of IMAB362 (a clinical antibody drug against Claudin18.2), that we expect can achieve tumor targeting and activate local anti-tumor immune response more effectively, while reducing the systemic side effects of individual cytokines. In vitro assays comparing the fusion protein IMAB362-mIL-21 to IMAB362 and mIL-21, IMAB362-mIL-21 was able to recognize its cognate antigen Claudin18.2 and natural receptor mIL-21R with similar binding affinities, mediate equivalent ADCC activity and activate IL-21R-mediated downstream signal pathway. In in vivo assays, IMAB362-mIL-21 produced stronger anti-tumor effects compared with IMAB362 or mIL-21 or their combination at equimolar concentrations. Moreover, according to routine blood indicators, mIL-21-Fc and the combined treatment group had significant decreases (P<0.01) in red blood cells (RBC), hemoglobin (HGB) and hematocrit (HCT), while the IMAB362-mIL-21 group did not. The above results have shown that IMAB362-mIL-21 can produce better anti-tumor effects without obvious hematological toxicity, which is sufficient to show that this kind of antibody-cytokine protein has better application value than IMAB362 or IL-21 as single drugs or in combination. Therefore, this bifunctional molecule combined tumor-targeting and immune activation effectively and has good application prospects.