Targeting a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) for RAS-driven cancers
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 a...
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Published in | The Journal of clinical investigation Vol. 132; no. 4 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Clinical Investigation
15.02.2022
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Subjects | |
Online Access | Get full text |
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Summary: | 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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Bibliography: | U.S. Department of Defense (USDOD) Prostate Cancer Foundation AC02-05CH11231; F32 5F32CA236151; PC200407; R01EB025207; 1P41CA196276; CA191018; GM097316; P30 GM124169; S10OD018483 Bristol Myers Squibb National Institutes of Health (NIH) USDOE Office of Science (SC), Biological and Environmental Research (BER) Authorship note: SAL and JZ are co–first authors and contributed equally to the study. |
ISSN: | 1558-8238 0021-9738 1558-8238 |
DOI: | 10.1172/JCI154604 |