Enhancing Probody Therapeutics: CD71-Targeted PDCs for Solid Tumors and Lymphoma with Primate Tolerability

Probody therapeutics are a type of antibody prodrug that become active only when activated by proteolysis in the tumor microenvironment, which can be beneficial for targeting antigens that are expressed in both cancerous and normal tissues. CD71, also known as the transferrin receptor, is identified as a suitable target for Probody Drug Conjugates (PDCs) due to its high expression in various tumor types and in proliferating normal cells, and its ability to internalize and deliver cytotoxic substances.

Our research has shown that while an anti-CD71 antibody drug conjugate is highly toxic, a PDC targeting CD71 is both effective in mouse tumor models and safe in nonhuman primates. The effectiveness and specificity of Probody therapeutics are enhanced by two main features: a masking element that inhibits the antibody's binding to the target antigen in normal tissues, and a protease-activatable substrate that is cleaved in the tumor microenvironment to remove the mask.

We have found that adjusting the strength of the mask and the cleavability of the substrate can improve the efficacy and safety of a CD71-targeting PDC. Our lead molecule, CX-2029, is a PDC conjugated to vcMMAE with a Drug to Probody Ratio (DPR) of 2. It has been optimized to have a stronger mask and a less cleavable substrate, which contributes to its improved therapeutic index and tolerability in nonhuman primates.

In preclinical models, CX-2029 has demonstrated complete tumor regressions and sustained responses at doses that are expected to be safe for humans. The use of a LC/MS/MS method has also confirmed that the lead molecule CX-2029 has lower levels of circulating activated drug compared to an earlier version, which correlates with its enhanced tolerability.

CX-2029 is currently in development, with an Investigational New Drug (IND) application anticipated in 2018. The term "Probody" is a registered trademark of CytomX Therapeutics, Inc.

Citation: Singh S, Serwer L, Chauhan N, et al. Optimizing a CD71-targeting Probody drug conjugate (PDC) for activity in multiple solid tumor and lymphoma models and for tolerability in nonhuman primates [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; Philadelphia, PA; 2017 Oct 26-30. Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B116.