Enhancing Tumor Regression: The Impact of EGFR-CD3 Probody Therapeutics on Maximum Tolerated Dose in Preclinical Models

T cell-engaging bispecific antibodies (TCBs) are a potent class of therapeutics that have shown clinical benefits in hematologic malignancies but face challenges in treating solid tumors due to their potential to cause on-target, off-tumor toxicity. This has led to the development of Probody™ therapeutics by CytomX, which are antibody prodrugs that are masked to prevent binding to antigens in healthy tissue and can be unmasked by proteases active in the tumor microenvironment.

A novel T cell-engaging Bispecific Probody therapeutic (Pb-TCB) targeting the Epidermal Growth Factor Receptor (EGFR) and CD3 has been optimized for several characteristics, including affinity, effector function, masking, and cleavability. In vitro, the EGFR-CD3 Pb-TCB showed significantly reduced cytotoxicity under protease-deficient conditions compared to the unmasked TCB. However, in tumor models with active tumor-resident proteases, Pb-TCBs effectively induced tumor regressions.

Preclinical studies in nonhuman primates demonstrated that the maximum tolerated dose (MTD) of the EGFR-CD3 Pb-TCB was more than 60-fold higher than that of the unmasked TCB. Furthermore, the tolerated exposure (AUC) was more than 10,000-fold higher, with transient serum cytokine and AST/ALT increases still lower than those induced by the TCB.

These findings suggest that Pb-TCBs could enhance the therapeutic window of TCBs by concentrating their activity in the tumor microenvironment, thereby potentially expanding their clinical application, especially for solid tumors where existing EGFR-directed therapies have shown limited effectiveness.

The research was presented by Leila M. Boustany, Laurie Wong, and colleagues at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in 2017.