Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate

Shweta Singh, Laura Serwer, Amy DuPage, Kristi Elkins, Niharika Chauhan, Matthew Ravn, Fritz Buchanan, Leyu Wang, Michael Krimm, Ken Wong, Jason Sagert, Kimberly Tipton, Stephen J. Moore, Yuanhui Huang, Andrew Jang, Eric Ureno, Adam Miller, Sarah Patrick, Shanti Duvur, Shouchun Liu, Olga Vasiljeva, Yingchun Li, Tracy Henriques, Ilaria Badagnani, Shawn Jeffries, Siew Schleyer, Rob Leanna, Claus Krebber, Sridhar Viswanathan, Luc Desnoyers, Jonathan Terrett, Marcia Belvin, Susan Morgan-Lappe, W. Michael Kavanaugh, Jennifer Richardson

Probody® therapeutics(Pb-Tx) are conditionally activated antibody-drug conjugates designed to remain inactive until proteolytically activated in the tumor microenvironment, enabling safer targeting of antigens expressed in both tumor and normal tissue. Previous attempts to target CD71, a highly expressed tumor antigen, have failed to establish an acceptable therapeutic window due to widespread normal tissue expression. This study evaluated whether a Probody-drug conjugate targeting CD71 can demonstrate a favorable efficacy and tolerability profile in preclinical studies for the treatment of cancer. CX-2029, a Pb-Tx conjugated to vcMMAE, was developed as a novel cancer therapeutic targeting CD71. Preclinical studies were performed to evaluate the efficacy and safety of this anti-CD71 PDC in mouse patient-derived xenograft(PDX) models and cynomolgus monkeys, respectively. CD71 expression was detected at high levels by IHC across a broad range of tumor and normal tissues. In vitro, the masked Pb-Tx form of the anti-CD71 PDC displayed >50-fold reduced affinity for binding to CD71 on cells compared with protease-activated, unmasked anti-CD71 PDC. Potent in vivo tumor growth inhibition (stasis or regression) was observed in >80% of PDX models(28/34) at 3 or 6mg/kg. Anti-CD71 PDC remained mostly masked(>80%) in circulation throughout dosing in cynomolgus monkeys at 2, 6, and 12mg/kg and displayed a 10-fold improvement in tolerability compared with an anti-CD71 ADC, which was lethal. Preclinically, anti-CD71 PDC exhibits a highly efficacious and acceptable safety profile that demonstrates the utility of the Pb-Tx platform to target CD71, an otherwise undruggable target. These data support further clinical development of the anti-CD71 PDC CX-2029 as a novel cancer therapeutic.