{"doi":"10.7554/elife.93908.1.sa0","title":"Reviewer #2 (Public Review): Targeted protein degradation systems to enhance Wnt signaling","abstract":"Molecules that facilitate targeted protein degradation (TPD) offer great promise as novel therapeutics. Human hepatic lectin, asialoglycoprotein receptor (ASGR) is selectively expressed on hepatocytes. We have previously engineered an anti-ASGR1 antibody-mutant RSPO2 (RSPO2RA) fusion protein (called SWEETSTM) to drive tissue-specific degradation of ZNRF3/RNF43 E3-ubiquitin ligases, leading to hepatocyte specific enhanced Wnt signaling, proliferation, and restored liver function in mouse models. Such an antibody-RSPO2RA fusion molecule is currently in human clinical trials. In the current study, we identified two new ASGR1 and ASGR1/2 specific antibodies, 8M24 and 8G8. High-resolution crystal structures of ASGR1:8M24 and ASGR2:8G8 complexes revealed that these antibodies bind to distinct epitopes on the opposite sides of ASGR, away from the substrate binding site. Both antibodies enhanced Wnt-activity when assembled as SWEETS molecules with RSPO2RA through specific effects sequestering E3 ligases. In addition, 8M24-RSPO2RA and 8G8-RSPO2RA efficiently downregulated ASGR1 through TPD mechanisms. These results demonstrate the possibility of combining different therapeutic effects and different degradation mechanisms in a single molecule.","journal":null,"year":2024,"id":494104,"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":0.9576,"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":1197080,"name":"Heekyung Jung","orcid":null,"position":1,"is_corresponding":false},{"id":1196736,"name":"Hui Chen","orcid":"0009-0003-4786-7453","position":2,"is_corresponding":false},{"id":1196737,"name":"Zhengjian Zhang","orcid":"0000-0002-2840-0837","position":3,"is_corresponding":false},{"id":1196738,"name":"Nicholas Suen","orcid":"0000-0002-6388-024X","position":4,"is_corresponding":false},{"id":1196739,"name":"Yiran Yang","orcid":"0000-0002-7759-1342","position":5,"is_corresponding":false},{"id":1196740,"name":"Zhong Huang","orcid":"0000-0003-0848-3281","position":6,"is_corresponding":false},{"id":521868,"name":"Tom Lopez","orcid":"0000-0002-8256-9668","position":7,"is_corresponding":false},{"id":1033484,"name":"Robert Benisch","orcid":"0000-0002-0612-7606","position":8,"is_corresponding":false},{"id":796878,"name":"Sung‐Jin Lee","orcid":"0000-0001-9348-8356","position":9,"is_corresponding":false},{"id":1197081,"name":"Jay Ye","orcid":null,"position":10,"is_corresponding":false},{"id":997476,"name":"Wen‐Chen Yeh","orcid":"0000-0002-8837-8301","position":11,"is_corresponding":false},{"id":644176,"name":"Yang Li","orcid":"0009-0003-4011-2816","position":12,"is_corresponding":false},{"id":1197079,"name":"Parthasarathy Sampathkumar","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:09:07.920649Z","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":[]}