{"doi":"10.1101/2022.02.28.482279","title":"A Single Multipurpose FSH–Blocking Therapeutic for Osteoporosis and Obesity","abstract":"ABSTRACT Pharmacological and genetic studies over the past decade have established FSH as an actionable target for diseases affecting millions, notably osteoporosis, obesity and Alzheimer’s disease (AD). Blocking FSH action prevents bone loss, fat gain and AD–like features in mice. We recently developed a first–in–class, humanized, epitope–specific FSH blocking antibody, MS-Hu6, with a K D of 7.52 nM. Using a GLP–compliant platform, we now report the efficacy of MS-Hu6 in preventing obesity and osteoporosis in mice, and parameters of acute safety in monkeys. Biodistribution studies using 89 Zr–labelled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone, bone marrow and fat depots. MS-Hu6 displayed a β phase t ½ of 13 days (316 hours) in humanized Tg32 mice, and bound endogenous FSH. We tested 215 variations of excipients using the protein thermal shift assay to generate a final formulation that rendered MS-Hu6 stable in solution upon freeze–thaw and at different temperatures, with minimal aggregation, and without self–, cross–, or hydrophobic interactions or appreciable binding to relevant human antigens. MS-Hu6 showed the same level of “humanness” as human IgG1 in silico , and was non–immunogenic in ELISPOT assays for IL-2 and IFNγ in human peripheral blood mononuclear cell cultures. We conclude that MS-Hu6 is efficacious, durable and manufacturable, and is therefore poised for future human testing as a multipurpose therapeutic.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":306191,"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":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":992468,"name":"Tan‐Chun Kuo","orcid":"0000-0001-5301-755X","position":1,"is_corresponding":false},{"id":537764,"name":"Funda Korkmaz","orcid":"0000-0002-9174-8369","position":2,"is_corresponding":false},{"id":1000650,"name":"Damini Sant","orcid":null,"position":3,"is_corresponding":false},{"id":292699,"name":"Victoria DeMambro","orcid":"0000-0002-4557-461X","position":4,"is_corresponding":false},{"id":538287,"name":"Anisa Gumerova","orcid":null,"position":5,"is_corresponding":false},{"id":1000651,"name":"Kathayani Sudha","orcid":null,"position":6,"is_corresponding":false},{"id":992469,"name":"Ashley Padilla","orcid":"0000-0003-4877-5465","position":7,"is_corresponding":false},{"id":245635,"name":"Geoffrey Prévot","orcid":"0000-0002-5191-9784","position":8,"is_corresponding":false},{"id":245634,"name":"Jazz Munitz","orcid":"0000-0002-9173-2666","position":9,"is_corresponding":false},{"id":245628,"name":"Abraham J. 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