Identification of a hotspot on PD-L1 for pH-dependent binding by monoclonal antibodies for tumor therapy

Dear Editor,Monoclonal antibody(mAb)-based tumor immune checkpoint therapy(ICT)has gained particular interest in recent years.1 The molecular basis of binding between mAbs and PD-1 or PD-L1 has been reported,providing clear information of the binding“hotspots”for mAbs.2,3 Tumor suppression efficacy of PD-L1 specific mAbs relies on not only the blocking of PD-1/PD-L1 interaction to restore T cell reactivity,but also Fc-mediated tumor cell cytotoxity.PD-L1 antibody drug conjugate(ADC)for selective chemo-guided immune modulation of tumor has also been developed which has shown promising tumor suppression potency.4 MAbs that could bind to antigen in a pH-dependent manner would improve recycling of the antibodies and engineered IL-6R mAbs with pH-dependent binding properties have displayed increased lysosomal delivery and therapeutic potency.5 However,no PD-L1 specific mAb with pH-dependent binding property has been reported,and whether the binding to a specific region on PD-L1 would induce pH-dependent interaction remains unknown.