Abstract
Targeting the proteolytically cleaved form of CDCP1 showed antitumor activity in solid tumor models.
Major Finding: Targeting the proteolytically cleaved form of CDCP1 showed antitumor activity in solid tumor models.
Concept: Cleaved CDCP1 is more abundant in cancer cells than normal cells and represents a potential therapeutic target.
Impact: Targeting tumor-specific proteolytic neoepitopes versus full-length proteins may be safer and more effective.
Selective targeting of cancer cells over normal cells is key to safe and effective cancer treatments. The targeting of differentially expressed antigens as well as disease-associated alternative splice forms has been attempted, with more recent efforts focusing on targeting novel epitopes produced by proteases on tumor cells. Lim, Zhou, and colleagues took this approach by generating recombinant antibodies against CUB domain containing protein 1 (CDCP1), which is highly expressed in many solid tumor types and is critical in KRAS-transformed cells. CDCP1 is proteolytically cleaved into an N-terminal fragment and a C-terminal fragment (NTF and CTF, respectively), with cancer cells exhibiting a higher proportion of cleaved CDCP1 (c-CDCP1). The NTF of CDCP1 was found to be retained on the membrane following proteolysis, and overexpression of either c-CDCP1 or full-length CDCP1 was able to induce downstream signaling. A unique antibody clone that was selective for c-CDCP1 and bound all three c-CDCP1 antigens was developed, with additional analyses indicating that the epitope for this antibody was located toward the C-terminal portion of the NTF and is inaccessible in the uncleaved state. Specific antibody binding to pancreatic ductal adenocarcinoma (PDAC) cell lines was observed, with use of a c-CDCP1 antibody–drug conjugate showing delivery of cytotoxic payloads to c-CDCP1–expressing PDAC cells. Similar results were observed with use of this clone as a bispecific T-cell engager. Furthermore, strong tumor localization of this antibody was revealed in murine models, with a superior safety profile compared to a pan-CDCP1 targeting approach. Use of this antibody as a radioligand therapeutic in these mouse models significantly reduced tumor volume and increased the survival of treated mice compared with vehicle control. This study defines a c-CDCP1–specific antibody that demonstrates effective antitumor activity as well as a favorable safety profile and supports further use of an antibody-based strategy to target cancer-specific neoepitopes created by proteolytic cleavage.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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