{"doi":"10.20517/cdr.2025.151","title":"Identification of antibody-drug conjugate payloads that are substrates of ATP-binding cassette drug efflux transporters","abstract":"<jats:p>Aim: Antibody-drug conjugates (ADCs) feature an antibody recognizing a specific protein joined to a potent toxic payload. Numerous ADCs have received U.S. Food and Drug Administration (FDA) approval; however, clinical resistance arises. Resistance mechanisms include decreased expression or mutation of the antibody target, impaired payload release, or increased expression of adenosine triphosphate (ATP)-binding cassette (ABC) efflux transporters associated with multidrug resistance. We therefore sought to characterize the interactions of ABC multidrug transporters with ADC payloads.</jats:p>\n                  <jats:p>Methods: We performed a high-throughput screen with 27 common ADC payloads using cell lines expressing ABC transporters P-glycoprotein [P-gp, encoded by ABC subfamily B member 1 (ABCB1)] or ABC subfamily B member G2 (ABCG2, encoded by ABCG2). Confirmatory assays were also performed using cells transfected to express P-gp, ABCG2, or multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1).</jats:p>\n                  <jats:p>Results: Several commonly used ADC payloads were substrates of P-gp, including calicheamicin γ1, monomethyl auristatin E, mertansine (DM1), and ravtansine (DM4). All the pyrrolobenzodiazepines tested - SJG136, SGD-1882, SG2057, and SG3199 - were substrates of P-gp, ABCG2, and MRP1. The modified anthracyclines nemorubicin and its metabolite PNU-159682 were poorly transported by both ABCB1 and ABCG2 and displayed nanomolar to picomolar toxicity. Further, we found that the efficacy of the FDA-approved ADC mirvetuximab soravtansine, with DM4 as the toxic payload, was decreased in cell lines expressing P-gp. In contrast, Duocarmycin DM and PNU-159682 were exquisitely toxic to a panel of 99 cancer cell lines of varying origins.</jats:p>\n                  <jats:p>Conclusion: Several commonly used ADC payloads can be transported by ABC transporters, potentially leading to transporter-mediated drug resistance in patients. Future ADCs should be developed using payloads that are not ABC transporter substrates.</jats:p>","journal":"Cancer Drug Resistance","year":2026,"id":673422,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":550315,"name":"Hui Guo","orcid":"0000-0002-4288-8058","position":1,"is_corresponding":false},{"id":479645,"name":"Lu Chen","orcid":"0000-0002-8097-2699","position":2,"is_corresponding":false},{"id":1460535,"name":"Min Shen","orcid":"0000-0003-1125-5001","position":3,"is_corresponding":false},{"id":1759454,"name":"Omotola Gbadegesin","orcid":null,"position":4,"is_corresponding":false},{"id":378982,"name":"Robert W. Robey","orcid":"0000-0002-0857-3650","position":5,"is_corresponding":false},{"id":378983,"name":"Michael M. Gottesman","orcid":"0000-0001-8908-2097","position":6,"is_corresponding":false},{"id":255126,"name":"Matthew D. Hall","orcid":"0000-0002-5073-442X","position":7,"is_corresponding":false},{"id":431728,"name":"Jacob S. Roth","orcid":"0000-0003-0521-8677","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Identification of antibody-drug conjugate payloads that are substrates of ATP-binding cassette drug efflux transporters","abstract":"<jats:p>Aim: Antibody-drug conjugates (ADCs) feature an antibody recognizing a specific protein joined to a potent toxic payload. Numerous ADCs have received U.S. Food and Drug Administration (FDA) approval; however, clinical resistance arises. Resistance mechanisms include decreased expression or mutation of the antibody target, impaired payload release, or increased expression of adenosine triphosphate (ATP)-binding cassette (ABC) efflux transporters associated with multidrug resistance. We therefore sought to characterize the interactions of ABC multidrug transporters with ADC payloads.</jats:p>\n                  <jats:p>Methods: We performed a high-throughput screen with 27 common ADC payloads using cell lines expressing ABC transporters P-glycoprotein [P-gp, encoded by ABC subfamily B member 1 (ABCB1)] or ABC subfamily B member G2 (ABCG2, encoded by ABCG2). Confirmatory assays were also performed using cells transfected to express P-gp, ABCG2, or multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1).</jats:p>\n                  <jats:p>Results: Several commonly used ADC payloads were substrates of P-gp, including calicheamicin γ1, monomethyl auristatin E, mertansine (DM1), and ravtansine (DM4). All the pyrrolobenzodiazepines tested - SJG136, SGD-1882, SG2057, and SG3199 - were substrates of P-gp, ABCG2, and MRP1. The modified anthracyclines nemorubicin and its metabolite PNU-159682 were poorly transported by both ABCB1 and ABCG2 and displayed nanomolar to picomolar toxicity. Further, we found that the efficacy of the FDA-approved ADC mirvetuximab soravtansine, with DM4 as the toxic payload, was decreased in cell lines expressing P-gp. In contrast, Duocarmycin DM and PNU-159682 were exquisitely toxic to a panel of 99 cancer cell lines of varying origins.</jats:p>\n                  <jats:p>Conclusion: Several commonly used ADC payloads can be transported by ABC transporters, potentially leading to transporter-mediated drug resistance in patients. Future ADCs should be developed using payloads that are not ABC transporter substrates.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41668804","pmcid":"PMC12883344","openalex_id":null,"authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.20517/cdr.2025.151","host_type":"publisher"},{"url":"https://www.oaepublish.com/articles/cdr.2025.151","host_type":"publisher"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12883344","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12883344/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12883344","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12883344?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":[],"mesh_terms":[],"keywords":["Drug resistance","P-glycoprotein","ABC transporter","ABCG2","Antibody-drug Conjugate"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-16T13:23:26.811285Z","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":[]}