{"doi":"10.1101/2024.11.13.623229","title":"Unbiased discovery of antibody therapies that stimulate macrophage-mediated destruction of B-cell lymphoma","abstract":"Macrophages are critical effectors of antibody therapies for lymphoma, but the best targets for this purpose remain unknown. Here, we sought to define a comprehensive repertoire of cell surface antigens that can be targeted to stimulate macrophage-mediated destruction of B-cell lymphoma. We developed a high-throughput assay to screen hundreds of antibodies for their ability to provoke macrophages to attack B-cell lymphoma cells. Across both mouse and human systems, we identified multiple unappreciated targets of opsonization as well as putative immune checkpoints. We used this information to engineer a compendium of 156 bispecific antibodies, and we identified dozens of bispecifics that dramatically stimulate macrophage-mediated cytotoxicity of lymphoma cells. Among these, a bispecific comprising a SIRPα decoy domain and a CD38-targeting arm (WTa2d1×CD38) exhibited maximal efficacy while minimizing the risk of hematologic toxicity. This bispecific stimulated robust anti-tumor responses in multiple xenograft models of aggressive B-cell lymphoma. Our approach can be directly applied to other cancers to rapidly discover bispecific antibodies that leverage anti-tumor responses by macrophages or other innate immune cells.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":489285,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1334638,"name":"Carlota Pagès-Geli","orcid":null,"position":1,"is_corresponding":false},{"id":1235753,"name":"Anna Meglan","orcid":null,"position":2,"is_corresponding":false},{"id":669450,"name":"José Velarde","orcid":"0000-0001-9001-1923","position":3,"is_corresponding":false},{"id":1235754,"name":"Jasmine Blandin","orcid":null,"position":4,"is_corresponding":false},{"id":991408,"name":"Kyle Vaccaro","orcid":null,"position":5,"is_corresponding":false},{"id":1334639,"name":"Thomas N Wienclaw","orcid":null,"position":6,"is_corresponding":false},{"id":1334640,"name":"Patricia Fernández-Guzmán","orcid":null,"position":7,"is_corresponding":false},{"id":844649,"name":"Cynthia K. Hahn","orcid":"0000-0001-8284-7261","position":8,"is_corresponding":false},{"id":1334190,"name":"Marta Crespo","orcid":"0000-0002-7732-7808","position":9,"is_corresponding":false},{"id":990874,"name":"Kipp Weiskopf","orcid":"0000-0002-9008-445X","position":10,"is_corresponding":false},{"id":1235307,"name":"Juliano Ribeiro","orcid":"0000-0002-4838-5494","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T02:08:23.929823Z","pmid":"39605364","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":[]}