TrkB agonist antibody ameliorates fertility deficits in aged and cyclophosphamide-induced premature ovarian failure model mice

• Published in: Nature communications Vol. 13; no. 1; pp. 914 - 17
• Main Authors: Qin, Xunsi, Zhao, Yue, Zhang, Tianyi, Yin, Chenghong, Qiao, Jie, Guo, Wei, Lu, Bai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 13/95; 14/19; 38/91; 631/136/7; 631/154/556; 631/443/7; 64/60; 692/699/2732/1577; 96/1; 96/106; Adult; Aging; Aging (artificial); Aging (natural); Aging - physiology; Agonists; Animal models; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - agonists; Brain-Derived Neurotrophic Factor - metabolism; Cell Line, Tumor; Chemical compounds; Cyclophosphamide; Cyclophosphamide - toxicity; Disease Models, Animal; Failure; Female; Fertility; Fertility - drug effects; Fertility Agents, Female - pharmacology; Fertility Agents, Female - therapeutic use; Follicles; Gametocytes; Granulosa cells; Humanities and Social Sciences; Humans; Infertility; Intravenous administration; Male; Maturation; Membrane Glycoproteins - agonists; Membrane Glycoproteins - metabolism; Mice; Middle Aged; multidisciplinary; Oocytes; Organ Culture Techniques; Ovaries; Ovary - drug effects; Ovary - pathology; Ovary - physiopathology; Pharmacology; Primary Ovarian Insufficiency - chemically induced; Primary Ovarian Insufficiency - drug therapy; Primary Ovarian Insufficiency - pathology; Primary Ovarian Insufficiency - physiopathology; Receptor, trkB - agonists; Receptor, trkB - metabolism; Receptors; Reproductive status; Science; Science (multidisciplinary); Signaling; TrkB receptors; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28611-2

Premature ovarian failure (POF) is a leading cause of women’s infertility without effective treatment. Here we show that intravenous injection of Ab4B19, an agonistic antibody for the BDNF receptor TrkB, penetrates into ovarian follicles, activates TrkB signaling, and promotes ovary development. In both natural aging and cyclophosphamide-induced POF models, treatment with Ab4B19 completely reverses the reduction of pre-antral and antral follicles, and normalizes gonadal hormone. Ab4B19 also attenuates gonadotoxicity and inhibits apoptosis in cyclophosphamide-induced POF ovaries. Further, treatment with Ab4B19, but not BDNF, restores the number and quality of oocytes and enhances fertility. In human, BDNF levels are high in granulosa cells and TrkB levels increase in oocytes as they mature. Moreover, BDNF expression is down-regulated in follicles of aged women, and Ab4B19 activates TrkB signaling in human ovary tissue ex vivo. These results identify TrkB as a potential target for POF with differentiated mechanisms, and confirms superiority of TrkB activating antibody over BDNF as therapeutic agents. Qin et al. report that an agonistic antibody targeting the BDNF receptor TrkB promotes follicle development and oocyte maturation, and reverse ovarian deficits and infertility in aged and cyclophosphamide-induced premature ovarian failure model mice.