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Theranostics 2022; 12(16):6915-6930. doi:10.7150/thno.78171 This issue Cite

Research Paper

CUB Domain-Containing Protein 1 (CDCP1) is a rational target for the development of imaging tracers and antibody-drug conjugates for cancer detection and therapy

Tashbib Khan^1*, Nicholas J. Lyons^1*, Madeline Gough¹, Kayden K.X. Kwah¹, Tahleesa J. Cuda¹, Cameron E. Snell^1,2, Brian W. Tse³, Kamil A. Sokolowski³, Lesley A. Pearce⁴, Timothy E. Adams⁴, Stephen E. Rose⁵, Simon Puttick⁵, Marina Pajic⁶, Mark N. Adams⁷, Yaowu He¹, John D. Hooper^1✉, Thomas Kryza^1✉

1. Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, QLD, Australia.
2. Mater Health Services, South Brisbane, QLD, Australia.
3. Preclinical Imaging Facility, Translational Research Institute, Woolloongabba, QLD, Australia.
4. Commonwealth Scientific and Industrial Research Organisation Manufacturing, Parkville, VIC, Australia.
5. Commonwealth Scientific and Industrial Research Organisation, Herston, QLD, Australia.
6. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.
7. School of Biomedical Sciences, Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD, Australia.
*Authors with equal contributions.

✉ Corresponding authors: E-mail: thomas.kryzauq.edu.au; john.hooperuq.edu.au.

Abstract

Rationale: An antibody-drug conjugate (ADC) is a targeted therapy consisting of a cytotoxic payload that is linked to an antibody which targets a protein enriched on malignant cells. Multiple ADCs are currently used clinically as anti-cancer agents significantly improving patient survival. Herein, we evaluated the rationale of targeting the cell surface oncoreceptor CUB domain-containing protein 1 (CDCP1) using ADCs and assessed the efficacy of CDCP1-directed ADCs against a range of malignant tumors.

Methods: CDCP1 mRNA expression was evaluated using large transcriptomic datasets of normal/tumor samples for 23 types of cancer and 15 other normal organs, and CDCP1 protein expression was examined in 34 normal tissues, >300 samples from six types of cancer, and in 49 cancer cell lines. A recombinant human/mouse chimeric anti-CDCP1 antibody (ch10D7) was labelled with ⁸⁹Zirconium or monomethyl auristatin E (MMAE) and tested in multiple pre-clinical cancer models including 36 cancer cell lines and three mouse xenograft models.

Results: Analysis of CDCP1 expression indicates elevated CDCP1 expression in the majority of the cancers and restricted expression in normal human tissues. Antibody ch10D7 demonstrates a high affinity and specificity for CDCP1 inducing cell signalling via Src accompanied by rapid internalization of ch10D7/CDCP1 complexes in cancer cells. ⁸⁹Zirconium-labelled ch10D7 accumulates in CDCP1 expressing cells enabling detection of pancreatic cancer xenografts in mice by PET imaging. Cytotoxicity of MMAE-labelled ch10D7 against kidney, colorectal, lung, ovarian, pancreatic and prostate cancer cells in vitro, correlates with the level of CDCP1 on the plasma membrane. ch10D7-MMAE displays robust anti-tumor effects against mouse xenograft models of pancreatic, colorectal and ovarian cancer.

Conclusion: CDCP1 directed imaging agents will be useful for selecting cancer patients for personalized treatment with cytotoxin-loaded CDCP1 targeting agents including antibody-drug conjugates.

Keywords: CDCP1, cancer, theranostics, antibody-drug conjugate, receptor

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