P-654 A first in class potentiating therapeutic antibody as a new treatment for female fertility

Abstract

Abstract Study question Can we improve controlled ovarian stimulation (COS) outcome in female by increasing FSH activity with a potentiating antibody? Summary answer IGYXOS developed a first in class potentiating antibody that improves COS treatments’ outcome by increasing FSH efficacy in vivo as demonstrated in non-human primates (NHP). What is known already For a COS in IVF cycles, FSH-containing preparations are injected to patients in order to obtain mature and fertilizable oocytes. However, the efficacy of these treatments is still limited and several attempts are needed before reaching a pregnancy and a live birth. One of the parameters that could be improved to avoid several attempts is the number of mature and thus fertilizable oocytes. It was previously demonstrated that breeding animals treated with gonadotropins could develop anti-gonadotropin antibodies that enhance their bioactivity instead of inhibiting it. These females had a high kidding rate and were hyperprolific. Study design, size, duration IGYXOS developed a monoclonal antibody (mAb) IGX12, a humanized IgG4, directed against human FSH. IGX12 was selected based on its ability to increase FSH activity in vitro and in vivo in rat., It was tested in mature cynomolgus female monkeysthat were treated as women undergoing ovarian stimulation for IVF with FSH alone or in combination with IGX12. Participants/materials, setting, methods IGX12 was tested in vitro on HEK 293 cells expressing the human FSH receptor. In vivo, the mAb was tested according to the Steelman and Pohley protocol. The potentiating effect was further investigated in NHP treated with mAb combined to a standard FSH treatment, under an agonist protocol. After hCG injection, oocytes were retrieved and their quality was analyzed. Blood was collected for hormonal assessments. Main results and the role of chance In vitro on HEK 293 cells expressing the human FSH receptor, IGX12 combined to FSH improves both the potency (EC50) and the efficacy (Emax) of FSH by increasing the cyclic AMP production at all tested FSH concentrations. The potentiating activity was confirmed in vivo in the Steelman and Pohley bioassay. Immature female rats received hCG+FSH alone or combined to mAb, twice a day, during 3 days. The animals were sacrificed the fourth day of treatment and the weight of the ovaries was compared. Ovaries weight was increased significantly in the group treated with hCG/FSH+IGX12 compared to hCG/FSH only. To further analyze the potential benefit of a IGX12 on human fertility, its effect was investigated in mature cynomolgus monkeys. IGX12 combined to a standard FSH treatment stimulated the follicular growth better than FSH only, and tripled the number of collected mature oocytes. Improved follicular growth correlated well with increased estradiol secretion during follicular phase and progesterone secretion during luteal phase. Limitations, reasons for caution After several proofs of concept and regulatory safety and toxicology evaluation in different animal models, IGX12 safety and tolerability is now assessed in a randomized, double blinded clinical phase I study on healthy men and women volunteers. Wider implications of the findings This first in class potentiating antibody IGX12 represents an innovative and promising new therapy to better stimulate patients with limited response to classical FSH treatments in order to improve the outcome of COS, and for normo-responders to avoid repetition of treatments. Trial registration number not applicable