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

Shion A Lim1, Jie Zhou1, Alexander J Martinko1

  • 1Department of Pharmaceutical Chemistry.

The Journal of Clinical Investigation
|February 15, 2022
PubMed

Insights

Antibodies targeting a specific cleavage neoepitope on CUB domain containing protein 1 (CDCP1) offer safer and more effective treatments for solid tumors by selectively targeting cancer cells. This approach enhances therapeutic precision and antitumor activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Extracellular proteolysis dysregulation in disease generates unique neoepitopes.
  • CUB domain containing protein 1 (CDCP1) is overexpressed in RAS-driven cancers and cleaved by proteases.
  • Proteolytic neoepitopes present opportunities for targeted therapies.

Purpose of the Study:

  • To develop highly selective antibodies against a proteolytic neoepitope on cleaved CDCP1.
  • To evaluate the therapeutic potential of these antibodies in solid tumors.
  • To compare the safety and efficacy of targeting cleaved CDCP1 versus pan-CDCP1.

Main Methods:

  • Biochemical, biophysical, and structural characterization of cleaved CDCP1.
  • Generation of recombinant antibodies using differential phage display.
  • In vitro and in vivo evaluation of antibody-drug conjugates, antibody-radionuclide conjugates, and bispecific T cell engagers in a pancreatic tumor model.

Main Results:

  • Recombinant antibodies showed exquisite selectivity for cleaved CDCP1 over uncleaved forms.
  • Targeting cleaved CDCP1-expressing cancer cells demonstrated potent efficacy in various formats.
  • Cleaved-specific antibodies exhibited tumor-specific localization and significant antitumor activity with improved safety in a pancreatic tumor model.

Conclusions:

  • Antibodies targeting CDCP1 proteolytic neoepitopes enable precise cancer cell targeting.
  • This strategy offers a superior therapeutic index compared to targeting all CDCP1 forms.
  • Targeting proteolytic neoepitopes represents a promising approach for developing safer and more effective cancer therapeutics.
Keywords:
AntigenCancer immunotherapyProteasesTherapeutics

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