Research Papers:
Next-generation cell-penetrating antibodies for tumor targeting and RAD51 inhibition
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Abstract
Madison Rackear1,2, Elias Quijano1,2, Zaira Ianniello1, Daniel A. Colón-Ríos1,2, Adam Krysztofiak1, Rashed Abdullah3, Yanfeng Liu1, Faye A. Rogers1, Dale L. Ludwig3, Rohini Dwivedi1,4, Franziska Bleichert4 and Peter M. Glazer1,2
1 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA
2 Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
3 Gennao Bio, Hopewell, NJ 08525, USA
4 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA
Correspondence to:
Peter M. Glazer, | email: | [email protected] |
Keywords: 3E10; cell penetration; nucleic acid binding; nucleic acid delivery; RAD51
Received: June 03, 2024 Accepted: September 17, 2024 Published: October 01, 2024
ABSTRACT
Monoclonal antibody therapies for cancer have demonstrated extraordinary clinical success in recent years. However, these strategies are thus far mostly limited to specific cell surface antigens, even though many disease targets are found intracellularly. Here we report studies on the humanization of a full-length, nucleic acid binding, monoclonal lupus-derived autoantibody, 3E10, which exhibits a novel mechanism of cell penetration and tumor specific targeting. Comparing humanized variants of 3E10, we demonstrate that cell uptake depends on the nucleoside transporter ENT2, and that faster cell uptake and superior in vivo tumor targeting are associated with higher affinity nucleic acid binding. We show that one human variant retains the ability of the parental 3E10 to bind RAD51, serving as a synthetically lethal inhibitor of homology-directed repair in vitro. These results provide the basis for the rational design of a novel antibody platform for therapeutic tumor targeting with high specificity following systemic administration.
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PII: 28651