Balancing efficacy and safety of an anti-DLL4 antibody through pharmacokinetic modulation.

Purpose: Although agents targeting Delta-like ligand 4 (DLL4) have shown great promise for angiogenesis-based cancer therapy, findings in recent studies have raised serious safety concerns. To further evaluate the potential for therapeutic targeting of the DLL4 pathway, we pursued a novel strategy to reduce toxicities related to DLL4 inhibition by modulating the pharmacokinetic (PK) properties of an anti-DLL4 antibody. Experimental Design: The F(ab')(2) fragment of anti-DLL4 antibody (anti-DLL4 F(ab')(2)) was generated and assessed in efficacy and toxicity studies. Results: Anti-DLL4 F(ab')(2) enables greater control over the extent and duration of DLL4 inhibition, such that intermittent dosing of anti-DLL4 F(ab')(2) can maintain significant antitumor activity while markedly mitigating known toxicities associated with continuous pathway inhibition. Conclusions: PK modulation has potentially broad implications for development of antibody-based therapeutics. Our safety studies with anti-DLL4 F(ab')(2) also provide new evidence reinforcing the notion that the DLL4 pathway is extremely sensitive to pharmacologic perturbation, further underscoring the importance of exercising caution to safely harness this potent pathway in humans. (C) 2015 AACR.