{"doi":"10.1093/jimmun/vkaf283.027","title":"A multi-faceted discovery strategy identifies functional Dickkopf-1 antibodies binding to cysteine-rich domain 1 of hDKK1 for cancer immunotherapy via Wnt non-canonical pathway 2061","abstract":"Abstract Description Wnt signaling plays an important role in embryonic development and tumorigenesis. These biological effects can be exerted by activation of Wnt canonical or pathway or non-canonical pathway, and regulation of a set of downstream genes. DKK1 is a potent inhibitor of Wnt signaling via competing with Wnt binding to the LRP5/6 co-receptors. DKK1 is tumorigenic in multiple cancer types and immunosuppressive via MDSCs and NK cells. DKK1 has become a promising target for cancer immunotherapy. In this study, we created phage display libraries and machine learning models for optimal discovery. We discovered anti-DKK1 antibodies blocking the binding of DKK1 to the co-receptors. Binding of the antibodies to different cysteine-rich domains (CRDs) of hDKK1 leads to different activation effects. The in vitro functional assays showed the interaction of Wnt canonical pathway was restored in the presence of anti-DKK1 antibodies binding to DKK1 C-terminal CRD2, resulting in upregulating Wnt canonical TCF/LEF signaling and reactivating osteoblast differentiation. Moreover, anti-DKK1 antibodies binding to DKK1 N-terminal CRD1 induced Wnt non-canonical JNK phosphorylation, immune cell activation and led to tumor cell cytotoxicity. In vivo studies indicated that anti-DKK1 antibody leads are potent in tumor regression and may have promising efficacy as a cancer immunotherapy via activating Wnt non-canonical pathway. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)","journal":"The Journal of Immunology","year":2025,"id":582451,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1494126,"name":"Sean M. Peterson","orcid":"0000-0003-4873-0283","position":1,"is_corresponding":false},{"id":1305251,"name":"Marisa Yang","orcid":"0000-0002-9898-2094","position":2,"is_corresponding":false},{"id":1494517,"name":"Ana G Lujan Hernandez","orcid":null,"position":3,"is_corresponding":false},{"id":618444,"name":"Tom Z. Yuan","orcid":"0000-0003-4585-8943","position":4,"is_corresponding":false},{"id":173182,"name":"Zhen Han","orcid":null,"position":5,"is_corresponding":false},{"id":1494127,"name":"Vishwas Prabhu","orcid":"0000-0002-0649-6022","position":6,"is_corresponding":false},{"id":654692,"name":"Kara Y. Chan","orcid":"0000-0003-4477-9151","position":7,"is_corresponding":false},{"id":1494518,"name":"Cameron F. Hu","orcid":null,"position":8,"is_corresponding":false},{"id":1494519,"name":"Mouna Villalta","orcid":null,"position":9,"is_corresponding":false},{"id":1494520,"name":"Tammy Htoy","orcid":null,"position":10,"is_corresponding":false},{"id":1494521,"name":"Paul Van Dyke","orcid":null,"position":11,"is_corresponding":false},{"id":1305584,"name":"Carson Holliday","orcid":null,"position":12,"is_corresponding":false},{"id":1305583,"name":"Hector Franco","orcid":null,"position":13,"is_corresponding":false},{"id":1494522,"name":"Hansika Wadhwa","orcid":null,"position":14,"is_corresponding":false},{"id":1305254,"name":"Hoa Giang","orcid":"0000-0001-6549-8012","position":15,"is_corresponding":false},{"id":1494128,"name":"Ryan Stafford","orcid":"0000-0002-3584-9966","position":16,"is_corresponding":false},{"id":1354821,"name":"Fumiko Axelrod","orcid":null,"position":17,"is_corresponding":false},{"id":618439,"name":"Aaron K. Sato","orcid":"0000-0003-1922-9780","position":18,"is_corresponding":false},{"id":1494516,"name":"Linya Wang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:58:55.657290Z","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":[]}