Background: Probody™ therapeutics (Pb-Txs) are recombinant, proteolytically-activatable antibody prodrugs, designed to remain inactive until activated locally by tumor-associated proteases. A peptide mask is attached to the antibody light chain that blocks the antibody from binding to its target in normal tissue and that can be removed by protease(s) preferentially localized or overexpressed in cancer tissue. In this way, Pb-Txs maintain anti-tumor activity while avoiding on-target toxicity.
Methods: Pb-Txs targeting PD-L1 were developed and tested for target engagement by imaging, activation in tumor and normal tissues, anti-tumor efficacy, and the ability to induce autoimmunity.
Results: In vivo imaging demonstrated tumor-specific, protease-dependent activation of the PD-L1 Pb-Tx. Preferential activation of the PD-L1 Pb-Tx in xenograft tumors as compared to peripheral normal tissue and plasma was demonstrated using capillary electrophoresis coupled with immunodetection. Pb-Txs provided equivalent anti-tumor activity to that of their unmasked parental Abs and reduced induction of autoimmunity in mouse models.
Conclusions: Anti-PD-L1 Probody therapeutics offer the potential to preserve anti-cancer activity while reducing systemic toxicities, particularly in combination with other checkpoint inhibitors. An ongoing clinical study is exploring the safety and activity of the PD-L1-directed Probody CX-072, both as monotherapy and in combination with other therapeutic agents in advanced solid tumor malignancies. Biomarker studies will be employed to investigate mechanistic aspects of Probody technology, including target engagement and Probody activation by proteases in tumor tissue.
PROBODYTM is a trademark of CytomX Therapeutics, Inc.