Abstract
Background
Long-term prognosis remains poor for colorectal cancer (CRC) patients with advanced disease due to treatment resistance. The identification of novel targets is essential for the development of new therapeutic approaches. GPR56, an adhesion GPCR, is highly expressed in CRC tumours and correlates with poor survival. Here, we describe the generation and preclinical evaluation of a novel ADC consisting of an anti-GPR56 antibody (10C7) conjugated with the DNA-damaging payload duocarmycin.
Methods
RNA-seq dataset analysis was performed to determine GPR56 expression in CRC subtypes. The specificity of binding, epitope mapping, and internalisation of 10C7 was examined. 10C7 was conjugated to payload and ADC cytotoxicity was assessed against a panel of CRC cell lines and tumour organoids. Antitumour efficacy was evaluated in xenograft models of CRC cell lines and patient-derived tumours.
Results
High GPR56 was shown to be associated with the microsatellite stable (MSS) subtype that accounts for 80–85% of CRC. GPR56 ADC selectively induced cytotoxicity in CRC cells and tumour organoids at low nanomolar potency in a GPR56-dependent manner and showed significant antitumour efficacy against GPR56-expressing xenograft models.
Conclusions
This study provides the rationale for the future development of a GPR56-targeted ADC approach to potentially treat a large fraction of MSS CRC patients.
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Data availability
All data generated or analysed during this study are included in this article and its supplementary information files.
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Acknowledgements
We would like to thank Sheng Zhang and Wangsheng Yu for technical contributions, Betty Arceneaux and Dr. Karan Saluja with assistance in patient sample collection and processing, and Martha Thompson for assistance with regulatory approvals for research involving human subjects.
Funding
This work was supported by funding from the National Institutes of Health (NCI R01 CA226894) and Welch Foundation Endowment Fund Award (L-AU-0002-19940421) to KSC, funding from the Cancer Prevention and Research Institute of Texas (RP190542) to QJL and KSC, a fellowship of the Gulf Coast Consortia, on the Training Interdisciplinary Pharmacology Scientists Program (T32 GM139801) to JJ, and a Cancer Therapeutics Training Program Fellowship (RP210043) to LEF.
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Conceptualisation and design: KSC; methodology: KSC; investigation: KSC, LEF, JJ, TC, SS, ZL, QJL and JR; data curation: KSC, JJ, LEF, TC, ZL and SS; formal analysis: KSC, LEF, JJ, TC and SS; writing original draft: KSC and JJ; review and editing: KSC, JJ and QJL; resources: KSC, QJL and JR; funding acquisition: KSC and QJL; supervision: KSC.
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This study was performed in accordance with the Declaration of Helsinki. All studies involving human subjects and tissues were approved by the Institutional Review Board at UTHealth Houston (HSC-MS-20-0327 and HSC-MS-21-0074). Written informed consent was obtained from all participants. All animal experiments were approved by the Animal Welfare Committee (AWC-20-0144) at UTHealth Houston.
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Jacob, J., Francisco, L.E., Chatterjee, T. et al. An antibody–drug conjugate targeting GPR56 demonstrates efficacy in preclinical models of colorectal cancer. Br J Cancer 128, 1592–1602 (2023). https://doi.org/10.1038/s41416-023-02192-3
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DOI: https://doi.org/10.1038/s41416-023-02192-3