Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers

Lim, Shion A.; Zhou, Jie; Martinko, Alexander J.; Wang, Yung-Hua; Filippova, Ekaterina V.; Steri, Veronica; Wang, Donghui; Remesh, Soumya G.; Liu, Jia; Hann, Byron; Kossiakoff, Anthony A.; Evans, Michael J.; Leung, Kevin K.; Wells, James A.

doi:10.1172/jci154604

Title: Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers

Journal Article · 14 February 2022 · Journal of Clinical Investigation

DOI: https://doi.org/10.1172/jci154604 · OSTI ID:1903835

^[1];

^[2];

^[2]; Wang, Yung-Hua ^[2];

^[3];

^[2]; Wang, Donghui ^[2]; Remesh, Soumya G. ^[2]; Liu, Jia ^[2];

^[2]; Kossiakoff, Anthony A. ^[3];

^[2];

^[2]; Wells, James A. ^[4]

University of California, San Francisco, CA (United States); OSTI
University of California, San Francisco, CA (United States)
University of Chicago, IL (United States)
University of California, San Francisco, CA (United States); Chan Zuckerberg Biohub, San Francisco, CA (United States)

Extracellular proteolysis is frequently dysregulated in disease and can generate proteoforms with unique neoepitopes not found in healthy tissue. Here, we demonstrate that Abs that selectively recognize a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) could enable more effective and safer treatments for solid tumors. CDCP1 is highly overexpressed in RAS-driven cancers, and its ectodomain is cleaved by extracellular proteases. Biochemical, biophysical, and structural characterization revealed that the 2 cleaved fragments of CDCP1 remain tightly associated with minimal proteolysis-induced conformational change. Using differential phage display, we generated recombinant Abs that are exquisitely selective to cleaved CDCP1 with no detectable binding to the uncleaved form. These Abs potently targeted cleaved CDCP1-expressing cancer cells as an Ab-drug conjugate, an Ab-radionuclide conjugate, and a bispecific T cell engager. In a syngeneic pancreatic tumor model, these cleaved-specific Abs showed tumor-specific localization and antitumor activity with superior safety profiles compared with a pan-CDCP1 approach. Targeting proteolytic neoepitopes could provide an orthogonal "AND" gate for improving the therapeutic index.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); U.S. Department of Defense (USDOD); Prostate Cancer Foundation; Bristol Myers Squibb

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1903835

Journal Information:: Journal of Clinical Investigation, Journal Name: Journal of Clinical Investigation Journal Issue: 4 Vol. 132; ISSN 1558-8238

Publisher:: American Society for Clinical InvestigationCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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Title: Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers

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