FSH-blocking therapeutic for osteoporosis.
FSH-blocking therapeutic for osteoporosis.
复制标题
DOI：
10.7554/elife.78022
复制
发表时间：
2022-09-20
期刊：
影响因子：
7.7
通讯作者：
Zaidi M
中科院分区：
文献类型：
--
作者：
Gera S;Kuo TC;Gumerova AA;Korkmaz F;Sant D;DeMambro V;Sudha K;Padilla A;Prevot G;Munitz J;Teunissen A;van Leent MMT;Post TGJM;Fernandes JC;Netto J;Sultana F;Shelly E;Rojekar S;Kumar P;Cullen L;Chatterjee J;Pallapati A;Miyashita S;Kannangara H;Bhongade M;Sengupta P;Ievleva K;Muradova V;Batista R;Robinson C;Macdonald A;Hutchison S;Saxena M;Meseck M;Caminis J;Iqbal J;New MI;Ryu V;Kim SM;Cao JJ;Zaidi N;Fayad ZA;Lizneva D;Rosen CJ;Yuen T;Zaidi M
过去十年的药理学和遗传学研究已经确定促卵泡激素（FSH）是影响数百万人的疾病，即骨质疏松症、肥胖症和阿尔茨海默病的可行靶点。阻断FSH的作用可以防止小鼠骨质流失、脂肪增加和神经变性。我们最近开发了一种一流的人源化表位特异性fsh阻断抗体MS-Hu6， KD为7.52 nM。利用良好实验室规范（GLP）合规平台，我们现在报告MS-Hu6在小鼠预防和治疗骨质疏松症的功效以及猴子急性安全性参数。使用89zr标记的、生物素化的或未结合的MS-Hu6在小鼠和猴子中的生物分布研究表明，MS-Hu6定位于骨骼和骨髓。MS-Hu6在人源化Tg32小鼠体内的β期为7.5天（180小时）。我们使用蛋白质热移测定法测试了217种辅料的变化，以产生最终配方，使MS-Hu6在冻融和不同温度下在溶液中稳定，具有最小的聚集，没有自、交叉或疏水相互作用，也没有与相关人类抗原的明显结合。MS-Hu6显示出与人IgG1相同水平的“人源性”，并且在人外周血单核细胞培养物中IL-2和IFN-γ的ELISpot检测中无免疫原性。我们的结论是MS-Hu6是有效的，耐用的，可制造的，因此为未来的人体测试做好了准备。
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 KD 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 89Zr-labeled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. The MS-Hu6 displayed a β phase t½ 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.