PROxAb Shuttle: A non-covalent plug-and-play platform for the rapid generation of tumor-targeting antibody-PROTAC conjugates

Schneider, H.; Jaeger, S.; Koenning, D.; Rasche, N.; Schroeter, C.; Elter, D.; Evers, A.; Lecomte, M.; Riccardi Sirtori, F.; Schwarz, D.; Wegener, A.; Hartung, I.; Rieker, M.

doi:10.1101/2023.09.29.558399

bioRxiv · 10.1101/2023.09.29.558399

PROxAb Shuttle: A non-covalent plug-and-play platform for the rapid generation of tumor-targeting antibody-PROTAC conjugates

Schneider, H.·Jaeger, S.·Koenning, D.·Rasche, N.·Schroeter, C.·Elter, D.·Evers, A.·Lecomte, M.·Riccardi Sirtori, F.·Schwarz, D.·Wegener, A.·Hartung, I.·Rieker, M.

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Abstract

Proteolysis-targeting chimeras (PROTACs) have evolved in recent years from an academic idea to a therapeutic modality with more than 25 active clinical programs. However, achieving oral bioavailability and cell-type specificity remains a challenge, especially for PROTACs recruiting the von Hippel-Lindau (VHL) E3 ligase. Herein, we present an unprecedented, plug- and-play platform for VHL-recruiting PROTACs to overcome these limitations. Our platform allows for the generation of non-covalent antibody-PROTAC complexes within minutes and obviates the need for prior PROTAC modification, antibody-drug linker chemistry optimization or bioconjugation. Our technology relies on camelid-derived antibody domains (VHHs) which can easily be engineered into existing therapeutic antibody scaffolds. The resulting targeted, bispecific fusion proteins can be complexed with PROTACs at defined PROTAC-to-antibody ratios and have been termed PROxAb Shuttles. PROxAb Shuttles can prolong the half-life of PROTACs from hours to days, demonstrate anti-tumor efficacy in vivo and have the potential for reloading in vivo to further boost efficacy.

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Schneider, H., Jaeger, S., Koenning, D., Rasche, N., Schroeter, C., Elter, D., Evers, A., Lecomte, M., Riccardi Sirtori, F., Schwarz, D., Wegener, A., Hartung, I., Rieker, M.. 2023-09-29. PROxAb Shuttle: A non-covalent plug-and-play platform for the rapid generation of tumor-targeting antibody-PROTAC conjugates. https://doi.org/10.1101/2023.09.29.558399

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