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Tumor-Specific Activation of an EGFR-Targeting Probody Enhances Therapeutic Index

A proteolytically activatable EGFR Probody demonstrates antitumor efficacy while alleviating toxicity. Seek and Destroy One of the main problems with current cancer therapies is lack of specificity: Traditional chemotherapeutics target all dividing cells, and even more restricted drugs, like monoclonal antibodies, may have on-target but off-tumor side effects. But what if you had a drug that was only turned on in the presence of the tumor? Desnoyers et al. now report the development of a Probody that targets epidermal growth factor receptor (EGFR) only in the presence of tumor. Cetuximab is a Food and Drug Administration–approved EGFR-targeting antibody used to treat metastatic colorectal cancer and head and neck cancer, but therapy often results in dose-limiting skin rash. The authors modified cetuximab to form a Probody (PB1)—where the antigen-binding sites are masked until the antibody is activated by proteases commonly found in the tumor microenvironment. The authors found that PB1 was largely inert while in circulation in mice, but that it had comparable efficacy to cetuximab in the presence of tumor. In nonhuman primates, PB1 demonstrated safety and decreased toxicity at higher doses than cetuximab. What’s more, ex vivo human primary tumor samples were sufficient to activate PB1. If these data hold true in human trials and for other antibodies, Probodies could be used to target cancer while minimizing treatment side effects. Target-mediated toxicity constitutes a major limitation for the development of therapeutic antibodies. To redirect the activity of antibodies recognizing widely distributed targets to the site of disease, we have applied a prodrug strategy to create an epidermal growth factor receptor (EGFR)–directed Probody therapeutic—an antibody that remains masked against antigen binding until activated locally by proteases commonly active in the tumor microenvironment. In vitro, the masked Probody showed diminished antigen binding and cell-based activities, but when activated by appropriate proteases, it regained full activity compared to the parental anti-EGFR antibody cetuximab. In vivo, the Probody was largely inert in the systemic circulation of mice, but was activated within tumor tissue and showed antitumor efficacy that was similar to that of cetuximab. The Probody demonstrated markedly improved safety and increased half-life in nonhuman primates, enabling it to be dosed safely at much higher levels than cetuximab. In addition, we found that both Probody-responsive xenograft tumors and primary tumor samples from patients were capable of activating the Probody ex vivo. Probodies may therefore improve the safety profile of therapeutic antibodies without compromising efficacy of the parental antibody and may enable the wider use of empowered antibody formats such as antibody-drug conjugates and bispecifics.