Antibody Reengineering Improves Therapeutic Index in Preclinical Models

The efficacy of therapeutic monoclonal antibodies is often limited by the expression of antigens in both tumor and normal tissue, resulting in dose-limiting, on-target toxicities. For example, the anti-EGF receptor (EGFR) antibody cetuximab induces severe skin reactions that reduce its therapeutic index in patients with solid tumors. As an alternative approach, Desnoyers and colleagues engineered an EGFR-targeting proantibody, or Probody, based on cetuximab and the concept of prodrugs, which remain inert until locally activated at the disease site. The Probody PB1 consists of an N-terminal masking peptide that prevents EGFR binding connected to a linker sequence that is selectively cleavable by proteases known to be upregulated in human tumors, thereby enabling local PB1 activation in the tumor microenvironment. PB1 activation in vitro or by proteases within non–small cell lung cancer (NSCLC) xenograft tumors facilitated binding to EGFR, inhibition of tumor cell proliferation, and PB1 accumulation at the tumor site, similar to cetuximab. Moreover, treatment with PB1 inhibited EGFR-mediated signaling and suppressed NSCLC xenograft growth in mice with comparable efficacy to that of cetuximab. However, in contrast with cetuximab, PB1 treatment was associated with decreased cutaneous toxicity in nonhuman primates, even at higher doses, and PB1 remained inactive in the plasma and skin of treated monkeys despite increased exposure and an extended half-life, indicating that the masking effect improves the safety profile of PB1. Furthermore, PB1 activation was detected in EGFR-positive primary human NSCLC and colorectal tumor samples ex vivo, suggesting that PB1 may be used to measure proteolytic activity and select patients likely to respond. These results establish Probodies as a strategy to enhance the efficacy and alleviate the on-target toxicity of monoclonal antibodies and suggest that PB1 may allow for broader use of anti-EGFR antibodies in cancer therapy.

Desnoyers LR, Vasiljeva O, Richardson JH, Yang A, Menendez EE, Liang TW, et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci Transl Med 2013;5:207ra144.

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