A tumor-targeted immune checkpoint blocker

Significance Current immune checkpoint inhibitors are not tumor specific and induce systemic immune activation in other tissues and organs. Combination immunotherapies further amplify these toxicities, which limit their clinical application. Here, we describe a strategy to direct checkpoint inhibition to the tumor microenvironment while avoiding systemic immune activation. Specifically, we have synthesized a bispecific antibody by conjugating an MSH analog to the αPD-L1 antibody avelumab. This bispecific antibody binds both MC1R and PD-L1 on cancer cells, shows excellent in vitro activities, and has enhanced efficacy in a syngeneic melanoma mouse model as compared to the parental antibody. This work demonstrates that the incorporation of a targeting element into an immune checkpoint blocking antibody could provide a therapeutic advantage.