Cleaved CDCP1 marks the spot: a neoepitope for RAS-driven cancers
Katelyn L. Donahue, Marina Pasca di Magliano
Katelyn L. Donahue, Marina Pasca di Magliano
Published February 15, 2022
Citation Information: J Clin Invest. 2022;132(4):e157168. https://doi.org/10.1172/JCI157168.
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Commentary

Cleaved CDCP1 marks the spot: a neoepitope for RAS-driven cancers

Abstract

A challenge in cancer treatment is targeting cancer cells while sparing normal cells. Thus, identifying cancer-specific neoepitopes is an active research area. Neoepitopes are generated by the accumulation of mutations; however, deadly cancer types, including pancreatic cancer, have a low mutational burden and, consequently, a paucity of neoantigens. In this issue of the JCI, Lim, Zhou, and colleagues describe a neoepitope generated upon proteolytic cleavage of the transmembrane CUB domain containing protein 1 (CDCP1). CDCP1 is overexpressed in cancer and portends a worse prognosis; previous attempts to target CDCP1 reduced cancer growth, but adversely affected the host. Here, the authors generated an antibody that specifically targeted cleaved CDCP1 (c-CDCP1) and developed a drug conjugate, a vector for radioactive ions, and a mediator of T cell activation. The therapeutics inhibited pancreatic cancer cell growth in vitro and in vivo. Exploiting proteolytic cleavage-derived neoantigens opens an attractive way for specifically targeting cancer cells.

Authors

Katelyn L. Donahue, Marina Pasca di Magliano

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Figure 1

c-CDCP1 marks pancreatic tumor cells for targeted therapeutics.

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c-CDCP1 marks pancreatic tumor cells for targeted therapeutics. (A) Heal...
(A) Healthy cells express relatively low levels of fl-CDCP1, while pancreatic tumor cells have increased levels of fl-CDCP1 and c-CDCP1. Extracellular proteases cleave CDCP1 between the NTF and CTF. Lim, Zhou, et al. (4) showed that both fragments remain in close association, providing a targetable neoepitope on pancreatic tumor cells. (B) Antibodies that bind both fl-CDCP1 and c-CDCP1 include D1W9N (commercially available), which targets the ectodomain; 4A06 (6), which binds the human NTF; and IgG12, (a murine analog of 4A06, developed by Lim, Zhou, et al.), which binds the NTF. Lim, Zhou, et al. also developed two antibodies that bound specifically to c-CDCP1: CL03 (human) and IgG58 (mouse) both bound the neoepitope exposed on the NTF after proteolytic cleavage. (C) Lim, Zhou, et al. (4) investigated multiple modes of therapeutic action, assessing the ability of antibodies specific for the c-CDCP1 neoepitope to kill tumor cells while sparing healthy cells. Three strategies included an ADC that used the cytotoxin MMAF, targeted radiation that employed 177Lu- IgG58 radioligands, and ligand-dependent T cell activation that created a BiTE molecule through the conjugation of anti-CD3 OKT3 scFV with the c-CDCP1–targeting variable domain.