{"doi":"10.1101/2020.01.19.911941","title":"Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer","abstract":"Abstract Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have improved for a number of solid tumors. Unfortunately, ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB) with reported low patient response rates. Using IHC staining, we find that PD-L2 is highly expressed in ovarian cancers and other malignancies with sub-optimal response to ICB, and is expressed at low levels in cancers responsive to ICB. Based on this observation, we hypothesized that the elevated expression of PD-L2 produced by both tumor and surrounding stromal cells contributes to immune-suppression. Since PD-L2 has been reported to have a 6- to10-fold higher native binding affinity to PD-1 compared with PD-L1, we hypothesized that high levels of PD-L2 can lead to insufficient blockade of the PD-1 signaling pathway. To overcome the immune repressive activity of PD-L2, we engineered a soluble PD-1 decoy molecule (sPD-1 mutant) that binds and neutralizes both PD-L1 and PD-L2 with a 10,000- and 200- fold improvement in binding affinity, respectively, when compared to wild-type binding to these same molecules. Such enhancement in binding affinity is facilitated by amino acid mutations both within and outside of the binding interface. Furthermore, this high affinity sPD-1 mutant molecule demonstrates superior in vivo efficacy in multiple cancer models including ovarian cancer where PD-L2 is highly expressed on the cell surface. One Sentence Summary Dual Inhibition of PD-L1 and PD-L2 using an affinity enhanced sPD-1 decoy molecule delivers superior antitumor activity when compared with αPD-1 and αPD-L1 antibodies in ovarian cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124538,"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":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":569186,"name":"Kaushik N. Thakkar","orcid":"0000-0002-4900-3371","position":1,"is_corresponding":false},{"id":569187,"name":"Jin Qian","orcid":"0000-0002-9684-1685","position":2,"is_corresponding":false},{"id":381575,"name":"Mihalis S. Kariolis","orcid":"0000-0003-2067-4013","position":3,"is_corresponding":false},{"id":569653,"name":"Huang Wei","orcid":null,"position":4,"is_corresponding":false},{"id":569188,"name":"Saravanan Nandagopal","orcid":"0000-0002-1787-3356","position":5,"is_corresponding":false},{"id":569654,"name":"Teddy Yang","orcid":null,"position":6,"is_corresponding":false},{"id":569189,"name":"Anh N. Diep","orcid":"0000-0001-6202-6394","position":7,"is_corresponding":false},{"id":569190,"name":"Gerald Maxwell Cherf","orcid":"0000-0003-4400-2414","position":8,"is_corresponding":false},{"id":569191,"name":"Yu Xu","orcid":"0000-0001-9332-9013","position":9,"is_corresponding":false},{"id":569192,"name":"Eui Jung Moon","orcid":"0000-0001-7916-7978","position":10,"is_corresponding":false},{"id":569193,"name":"Yiren Xiao","orcid":"0000-0003-3804-3383","position":11,"is_corresponding":false},{"id":569194,"name":"Haizea Alemany","orcid":"0000-0002-2021-9099","position":12,"is_corresponding":false},{"id":569655,"name":"Tianer Li","orcid":null,"position":13,"is_corresponding":false},{"id":569195,"name":"Wenhua Yu","orcid":"0000-0002-4733-8610","position":14,"is_corresponding":false},{"id":569196,"name":"Bo Wei","orcid":"0000-0001-7386-2689","position":15,"is_corresponding":false},{"id":381577,"name":"Erinn B. Rankin","orcid":"0000-0002-2045-2296","position":16,"is_corresponding":false},{"id":232230,"name":"Amato J. Giaccia","orcid":"0000-0002-1940-2750","position":17,"is_corresponding":false},{"id":309394,"name":"Yu Rebecca Miao","orcid":"0000-0002-5848-9924","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-18T23:15:07.789881Z","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":[]}