RT Journal Article
SR Electronic
T1 Targeting a proteolytic neo-epitope of CUB-domain containing protein 1 in RAS-driven cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.14.448427
DO 10.1101/2021.06.14.448427
A1 Shion A. Lim
A1 Jie Zhou
A1 Alexander J. Martinko
A1 Yung-Hua Wang
A1 Ekaterina V. Filippova
A1 Veronica Steri
A1 Donghui Wang
A1 Soumya G. Remesh
A1 Jia Liu
A1 Byron Hann
A1 Anthony A. Kossiakoff
A1 Michael J. Evans
A1 Kevin K. Leung
A1 James A. Wells
YR 2021
UL http://biorxiv.org/content/early/2021/06/15/2021.06.14.448427.abstract
AB A central challenge for any therapeutic is targeting diseased over normal cells. Proteolysis is frequently upregulated in disease and can generate proteoforms with unique neo-epitopes. We hypothesize that targeting proteolytic neo-epitopes can enable more effective and safer treatments, reflecting a conditional layer of disease-specific regulation. Here, we characterized the precise proteolytic isoforms of CUB domain containing protein 1 (CDCP1), a protein overexpressed and specifically cleaved in RAS-driven cancers. We validated that the N-terminal and C-terminal fragments of CDCP1 remain associated after proteolysis in vitro and on the surface of pancreatic cancer cells. Using a differential phage display strategy, we generated exquisitely selective recombinant antibodies that target cells harboring cleaved CDCP1 and not the full-length form using antibody-drug conjugates or a bi-specific T-cell engagers. We show tumor-specific localization and anti-tumor activity in a syngeneic pancreatic tumor model having superior safety profiles compared to a pan-CDCP1-targeting antibody. Our studies show proteolytic neo-epitopes can provide an orthogonal “AND” gate for disease-specific targeting.One-Sentence Summary Antibody-based targeting of neo-epitopes generated by disease-associated proteolysis improves the therapeutic indexCompeting Interest StatementSAL, JZ, AJM, JL, KKL, JAW are inventors on a provisional patent filed on the composition of matter for the antibodies described in this study.