https://orcid.org/0000-0003-2086-4853
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ABSTRACT
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein that plays several roles in cancer biology. EpCAM is an attractive therapeutic target because of its expression in most solid tumors. However, targeting EpCAM has been challenging because it is also highly expressed in normal epithelial tissues. Initial attempts to develop EpCAM-specific T-cell engagers were unsuccessful due to severe cytokine release effects, as well as serious on-target, off-tumor drug-related toxicities. We developed novel, conditionally active biological (CAB) bispecific antibodies that bind to both EpCAM and CD3 in an acidic tumor microenvironment. In healthy tissues, binding to EpCAM and CD3 is greatly reduced by a novel, dual CAB selection, where each binding domain is independently blocked by the presence of physiological chemicals known as Protein-associated Chemical Switches (PaCS). The CAB anti-EpCAM T-cell engagers displayed the anticipated bispecific binding properties and mediated the potent lysis of EpCAM-positive cancer cell lines through the recruitment of T cells in the tumor microenvironment. Xenograft studies showed that the efficacy of CAB bispecific antibodies is similar to that of a non-CAB anti-EpCAM bispecific antibody, but they have markedly reduced toxicity in non-human primates, indicating an unprecedentedly widened therapeutic index of over 100-fold. These preclinical results indicate that the dual CAB bispecific antibody is potentially both a powerful and safe therapeutic platform and a promising T cell-engaging treatment for patients with EpCAM-expressing tumors.
SUMMARY
Development of a novel conditionally active EpCAM-specific T-cell engager with enhanced safety and tolerability for treatment of solid tumors.
Abbreviations
| ADA | = | anti-drug antibodies |
| CAB | = | conditionally active biologic |
| CDX | = | cell line derived xenograft |
| CRS | = | cytokine release syndrome |
| cyno | = | cynomolgus |
| ECD | = | extracellular domain |
| EpCAM | = | epithelial cell adhesion molecule |
| GLP | = | good laboratory practice |
| hu | = | human |
| i.v. | = | intravenously |
| MTD | = | maximum tolerated dose |
| mpk | = | milligram per kilogram |
| PaCS | = | protein-associated chemical switches |
| PBMC | = | peripheral blood mononuclear cells |
| TAA | = | tumor-associated antigen |
| TCE | = | T-cell engager |
| TGI | = | tumor growth inhibition |
| TME | = | tumor microenvironment |
| WT | = | wild type |
Acknowledgments
We thank the BioDuro-Sundia Discovery Biology team for their valuable technical assistance and R&D support and Monica Sullivan and James Butler for critical reading of the manuscript.
Disclosure statement
All authors are shareholders of BioAtla, Inc., which owns intellectual property rights to CABs- and PaCS-related technology. HWC, GF, and JMS are inventors of relevant patents. JMS serve as Director of BioAtla.
Author contributions
Conceptualization: GF, HWC, JMS; Investigation and Data Analysis: GF, APGC, HL, CX, CW, HWC, WJB, and JMS; Visualization: GF, APGC, HL, CX, CW; Writing (original draft), review, and editing): GF, APGC, HL, CX, and HWC; Writing (review and editing): GF, APGC, HL, HWC, WJB, and JMS.
Data availability satement
All data are available in the main text or the supplementary materials.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19420862.2024.2322562