Endocrine Abstracts

G Protein-Coupled Receptors (GPCRs) constitute the most abundant receptor family in the genome and also represent the primary class of therapeutic targets. Gonadotropins and their receptors play a central role in the control of both male and female reproduction. Gonadotropins (i.e. FSH, LH, hCG) are extensively used in assisted reproduction technologies (ART). However, no pharmacological tool allowing to tightly control gonadotropin receptors' activity through competitive antagonism or allosteric modulation is available in clinics. Therefore, some therapeutic needs remain unmet. Despite the tremendous success of antibodies as therapeutic agents, very few therapeutic antibodies targeting GPCRs have been approved to date. VHHs are small antibody fragments derived from the variable domain of heavy-chain antibodies (HcAbs) in camelids. Their small size (12 ~ 15 KDa) combined with their unique structural features (i.e., long CDR3, the ability to interact with concave surfaces, and access to cryptic epitopes that classical immunoglobulins cannot reach) make them intriguing tools for targeting GPCRs. In particular, VHHs have demonstrated their ability to modulate some GPCRs in an allosteric manner and have also proven to be valuable tools in structural biology for this receptor class. We have developed VHHs specific to gonadotropin receptors by phage display from immune and synthetic libraries. The selection and screening processes for identifying high-affinity/selectivity VHHs have been optimized to deal with high attrition rates and identify VHHs with specific pharmacological profiles. We have demonstrated novel biochemical and pharmacological properties of these VHHs that allow the modulation of fertility in mice without using exogenous hormones.