{"doi":"10.1101/2024.10.17.618959","title":"Targeted degradation of the HPV oncoprotein E6 reduces tumor burden in cervical cancer","abstract":"Abstract Human Papilloma Virus (HPV)-related cancers are a global health burden, yet there are no targeted therapies available for chronically infected patients. The HPV protein E6 is essential for HPV-mediated tumorigenesis and immune evasion, making it an attractive target for antiviral drug development. In this study, we developed an E6-targeting Proteolysis Targeting Chimera (PROTAC) that inhibits the growth of HPV(+) tumors. To develop E6 antagonists, we generated a panel of nanobodies targeting E6 proteins derived from the oncogenic HPV16 subtype. The highest affinity E6 nanobody, A5, was fused to Von Hippel Lindau protein (VHL) to generate a PROTAC that degrades E6 (PROTAC E6 ). Mutational rescue experiments validated specific degradation via the CRL2 VHL E3 ligase. Intralesional administration of the PROTAC E6 using a clinically viable DNA vaccine reduced tumor burden in an immunocompetent mouse model of HPV(+) cancer. The inhibitory effect of the PROTAC E6 was abrogated by CD4 + and CD8 + T-cell depletion, indicating that the antitumor function of the PROTAC E6 relies in part on a host immune response. Overall, these results suggest that the targeted degradation of E6 inhibits its oncogenic function and stimulates a robust immune response against HPV(+) tumors, opening new opportunities for virus-specific therapies in the treatment of HPV-related cancers.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":489154,"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":0.9528,"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":1334533,"name":"Angelo Nicolaci","orcid":null,"position":1,"is_corresponding":false},{"id":888244,"name":"Kim C. Tran","orcid":"0000-0003-1121-6029","position":2,"is_corresponding":false},{"id":1242288,"name":"Jameela Lokhandwala","orcid":"0000-0002-5146-3203","position":3,"is_corresponding":false},{"id":1229537,"name":"Nina Obertopp","orcid":"0009-0006-5100-1590","position":4,"is_corresponding":false},{"id":950948,"name":"Jenet K Matlack","orcid":"0009-0007-6864-0871","position":5,"is_corresponding":false},{"id":1257717,"name":"Robert E Miner","orcid":null,"position":6,"is_corresponding":false},{"id":391015,"name":"Michael N. Teng","orcid":"0000-0002-0722-3659","position":7,"is_corresponding":false},{"id":1334534,"name":"Shari Pilon-Thomas","orcid":null,"position":8,"is_corresponding":false},{"id":800894,"name":"Jennifer M. Binning","orcid":"0000-0001-5871-686X","position":9,"is_corresponding":false},{"id":933861,"name":"Tracess Smalley","orcid":"0000-0002-3295-7443","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:08:23.929823Z","pmid":"39464070","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":[]}