FSH-blocking therapeutic for osteoporosis
Sakshi Gera, Tan‐Chun Kuo, Anisa Gumerova, Funda Korkmaz, Damini Sant, Victoria DeMambro, Karthyayani Sudha, Ashley Padilla, Geoffrey Prévot, Jazz Munitz, Abraham J. P. Teunissen, Mandy MT van Leent, Tomas Post, Jessica Fernandes, Jessica Netto, Farhath Sultana, Eleanor Shelly, Satish Rojekar, Pushkar Kumar, Liam Cullen, Jiya Chatterjee, Anusha Pallapati, Sari Miyashita, Hasni Kannangara, Megha Bhongade, Puja Sengupta, Kseniia Ievleva, Valeriia Muradova, Rogerio Batista, Cemre Robinson, Anne Macdonald, Susan Hutchison, Mansi Saxena, Marcia Meseck, John Caminis, Jameel Iqbal, Maria I. New, Vitaly Ryu, Se‐Min Kim, Jay Cao, Neeha Zaidi, Zahi A. Fayad, Daria Lizneva, Clifford J. Rosen, Tony Yuen, Mone Zaidi
Abstract
Pharmacological and genetic studies over the past decade have established the follicle-stimulating hormone (FSH) as an actionable target for diseases affecting millions, namely osteoporosis, obesity, and Alzheimer’s disease. Blocking FSH action prevents bone loss, fat gain, and neurodegeneration 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 Good Laboratory Practice (GLP)-compliant platform, we now report the efficacy of MS-Hu6 in preventing and treating osteoporosis in mice and parameters of acute safety in monkeys. Biodistribution studies using 89 Zr-labeled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. The MS-Hu6 displayed a β phase t ½ of 7.5 days (180 hr) in humanized Tg32 mice. We tested 217 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. The MS-Hu6 showed the same level of “humanness” as human IgG1 in silico and was non-immunogenic in ELISpot assays for IL-2 and IFN-γ 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.