Modulation of gonadotropins activity by antibodies Elodie Kara, Laurence Dupuy, Céline Bouillon, Sophie Casteret, Marie-Christine Maurel To cite this version: Elodie Kara, Laurence Dupuy, Céline Bouillon, Sophie Casteret, Marie-Christine Maurel. Modulation of gonadotropins activity by antibodies. Frontiers in Endocrinology, Frontiers, 2019, 10, pp.1-12. 10.3389/fendo.2019.00015. hal-02625853 HAL Id: hal-02625853 https://hal.inrae.fr/hal-02625853 Submitted on 26 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License REVIEW published: 18 February 2019 doi: 10.3389/fendo.2019.00015 Modulation of Gonadotropins Activity by Antibodies Elodie Kara 1*, Laurence Dupuy 1, Céline Bouillon 1,2,3,4,5,6, Sophie Casteret 1 and Marie-Christine Maurel 1 1 Igyxos SA, Nouzilly, France, 2 Service de Médecine et Biologie de la Reproduction, CHRU de Tours, Tours, France, 3 Biologie Intégrative de l’Ovaire, INRA, UMR85, Physiologie de la Reproduction et des Comportements, Nouzilly, France, 4 CNRS, UMR7247, Nouzilly, France, 5 Université François Rabelais, Tours, France, 6 IFCE, Nouzilly, France Gonadotropins are essential for reproduction control in humans as well as in animals. They are widely used all over the world for ovarian stimulation in women, spermatogenesis stimulation in men, and ovulation induction and superovulation in animals. Despite the availability of many different preparations, all are made of the native hormones. Having different ligands with a wide activity range for a given receptor helps better understand its molecular and cellular signaling mechanisms as well as its physiological functions, and thus helps the development of more specific and adapted medicines. One way to control the gonadotropins’ activity could be the use of Edited by: modulating antibodies. Antibodies are powerful tools that were largely used to decipher Livio Casarini, Università Degli Studi di Modena e gonadotropins’ actions and they have shown their utility as therapeutics in several other Reggio Emilia, Italy indications such as cancer. In this review, we summarize the inhibitory and potentiating Reviewed by: antibodies to gonadotropins, and their potential therapeutic applications. Marco Bonomi, Istituto Auxologico Italiano (IRCCS), Keywords: potentiating antibodies, inhibitory antibodies, follicle-stimulating hormone, luteinizing hormone, Italy chorionic gonadotropin, signaling Luca De Toni, University of Padova, Italy *Correspondence: INTRODUCTION Elodie Kara [email protected] Gonadotropins, namely follicle-stimulating hormone (FSH), luteinizing hormone (LH), and chorionic gonadotropin (CG) are heterodimeric glycoproteins, constituted by an alpha- and a Specialty section: beta- subunit. The alpha subunit is common to all glycoprotein hormones, including thyroid This article was submitted to stimulating hormone (TSH) (1). FSH and LH/CG receptors are G-protein coupled receptors Reproduction, (GPCR), mainly expressed in granulosa cells in female ovaries and in Sertoli cells in male testis a section of the journal for FSH receptor (FSH-R) (2), and in granulosa and theca cells in female and Leydig cells in male Frontiers in Endocrinology for LH receptor (LH-R) (3). Received: 30 November 2018 Because of their role in reproduction, gonadotropins are routinely used in fertility treatments Accepted: 10 January 2019 in men and women for assisted reproductive technologies (ART) (4, 5). In women, it consists Published: 18 February 2019 on daily injections of FSH or a mixture of FSH/LH, for 8–12 days, to grow and mature follicles. Citation: The final maturation is then completed with an injection of human CG (hCG) 36h after the Kara E, Dupuy L, Bouillon C, last injection of FSH. In men, FSH and hCG injections 2–3 times a week for several months Casteret S and Maurel M-C (2019) Modulation of Gonadotropins Activity are used to treat hypogonadotropic hypogonadism and induce spermatogenesis (6–9). Currently, by Antibodies. the preparations used are either endogenous FSH extracted from post-menopausal women urine Front. Endocrinol. 10:15. (human menopausal gonadotropins, hMG), highly purified urinary FSH, or recombinant FSH. doi: 10.3389/fendo.2019.00015 The first recombinant versions of FSH (follitropin alpha and beta, corifollitropin) and all their Frontiers in Endocrinology | www.frontiersin.org 1 February 2019 | Volume 10 | Article 15 Kara et al. Anti-gonadotropin Antibodies biosimilars were produced in Chinese hamster ovary (CHO) STRUCTURE AND FUNCTION OF cells. The follitropin delta approved in Europe in 2015 GONADOTROPINS TM (Rekovelle ) and follitropin epsilon still under development are produced in human cell lines: PER.C6 for follitropin delta Alpha- and beta-subunits of gonadotropins are non-covalently (10) and GlycoExpress for follitropin epsilon (11). For LH linked. The alpha-subunit is common to all glycoprotein and hCG, recombinant versions produced in CHO cells are hormones in a given species, and presents two major sites of N- also available. In animals, equine CG (eCG), formerly named glycosylation (1). The specificity of each hormone is conferred pregnant-mare serum gonadotropin (PMSG), is widely used by the beta-subunit, that contains 2 N-glycosylation sites. hCG, to induce ovulation in small ruminants (12). Porcine pituitary eLH and eCG present a longer beta-subunit with an additional extracts are used for current superovulation treatments in cattle carboxy-terminal peptide (CTP) that is ∼30 amino-acids long (13), whereas ovulation in swine herds is induced with a mixture and contains multiple O-glycosylation sites. of hCG and eCG (14). eCG originates from uterine endometrial cups and is extracted Despite all the preparations that are on the market, the from pregnant mare serum (39, 40). eLH and eCG beta-subunits only ligands available for gonadotropin receptors as therapeutics are encoded by a single gene (41) but they differ in glycosylation. are native hormones. New biased ligands or ligands with They both exhibit N-glycans on alpha- and beta-subunits, and different potencies and efficacies on gonadotropin receptors O-glycans on the carboxy-terminal peptide (CTP) constituted can help better understand receptor signaling, decipher the of the last 29 amino-acids of the beta-subunit (beta 121–149) implication of the different signaling pathways in physiological (42). With a carbohydrate content higher than 40% (43) and and pathophysiological mechanisms, and finally bring to N-glycan chains terminated by sialic acids, eCG is the most the market new molecules to improve ART treatments. In heavily glycosylated glycoprotein hormone and has a longer 2015 in USA, 182,111 ART procedures were performed in vivo half-life than other gonadotropins (∼60h) (44, 45). leading to 59,334 live-birth deliveries (15). Among other eCG binds to LH receptors in equine, but exerts FSH and strategies like small molecule ligands, one way to modulate the LH actions in non-equine species by stimulating FSH and gonadotropins’ activity could be the use of antibodies, targeting LH receptors respectively (46–51). Its dual FSH/LH activity either directly the receptor itself, or its ligand to modulate and its longer half-life were the reasons why eCG was widely hormone’s activity. used since decades to induce ovulation in breeding animals, Antibodies are useful tools that help to better understand especially in goats and ewes for out-of-season breeding to allow gonadotropins’ structure by epitope mapping (16–18) and artificial insemination. their function by neutralizing the effect of endogenous hCG is mainly produced during pregnancy, by gonadotropins (19–22). They also allow their quantification syncytiotrophoblast cells and a hyperglycosylated isoform by the development of radioimmunoassays (RIA) and enzyme- is produced by cytotrophoblast cells. These two isoforms are linked immunosorbent assays (ELISA) (23–27). Finally, implicated in implantation and early embryo development. antibodies permitted the development of specific purification Regular hCG for example promotes progesterone secretion by methods for gonadotropins, making them safer to use as corpus lutea, angiogenesis of uterine vasculature, or growth, and therapeutic agents (28–30). differentiation of fetal organs, whereas hyperglycosylated hCG The effect of antibodies, if any, is expected to be inhibitory stimulates implantation by invasion of cytotrophoblast cells or on antigen activity by impairing its interaction with its receptor. stimulates growth of placenta (52). However, hCG can also be Surprisingly, some of them were described as being able to produced in non-pregnant women: it is produced at low levels increase the activity of their antigenic protein. Potentiating by gonadotrope cells of the anterior pituitary, and seems to have polyclonal antibodies directed against epidermal growth factor an LH-like activity during menstrual cycle. Free beta-subunit (EGF) and insulin were first described by Shechter et al. of hCG is produced by multiple non-trophoblastic