{"doi":"10.1101/2022.08.11.503187","title":"An antibody-drug conjugate targeting GPR56 demonstrates efficacy in preclinical models of colorectal cancer","abstract":"Abstract Antibody-drug conjugates (ADCs) have become an increasingly successful class of anticancer therapy, particularly within the past few years. Though ADCs are in clinical trials for colorectal cancer (CRC), a candidate has yet to be approved. CRC continues to be a leading cause of cancer-related death, emphasizing the need to identify novel target antigens for ADC development. GPR56, a member of the 7TM receptor family, is upregulated in colorectal tumors compared to normal tissues and located on the surface of CRC cells, making it a promising ADC target. Furthermore, high GPR56 expression occurs in tumors that are microsatellite stable, negative for the CpG methylator phenotype, and show chromosomal instability. We previously reported the generation of a high affinity GPR56-specific monoclonal antibody, 10C7, and we have now mapped the epitope to the C-terminal end of the extracellular domain, proximal to the GPCR proteolysis site. Here, we describe the development of a duocarmycin-conjugated 10C7 ADC. 10C7 co-internalized with GPR56 and trafficked to the lysosomes of CRC cells, which is critical for efficient ADC payload release. Evaluation of the ADC in a panel of CRC cell lines and tumor organoids with different levels of GPR56 expression showed the ADC selectively induced cytotoxicity at low nanomolar concentrations in a GPR56-dependent manner. A nontargeting control ADC showed minimal to no activity. Furthermore, GPR56 ADC exhibited significant antitumor efficacy against GPR56-expressing patient-derived xenograft models of CRC. This study provides rationale for the development of a GPR56-targeted ADC approach to potentially treat a large fraction of CRC patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":297403,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":503164,"name":"Liezl E. Francisco","orcid":"0000-0002-3680-3767","position":1,"is_corresponding":false},{"id":570588,"name":"Treena Chatterjee","orcid":null,"position":2,"is_corresponding":false},{"id":701949,"name":"Zhengdong Liang","orcid":"0000-0003-4861-3941","position":3,"is_corresponding":false},{"id":985415,"name":"Shraddha Subramanian","orcid":"0000-0002-7351-5924","position":4,"is_corresponding":false},{"id":330790,"name":"Qingyun J. Liu","orcid":"0000-0001-7683-5088","position":5,"is_corresponding":false},{"id":985990,"name":"Julie H. Rowe","orcid":null,"position":6,"is_corresponding":false},{"id":330789,"name":"Kendra S. Carmon","orcid":"0000-0002-3244-6096","position":7,"is_corresponding":false},{"id":491803,"name":"Joan Jacob","orcid":"0000-0002-9756-8449","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T00:31:26.161109Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}