P-081 A first in class potentiating therapeutic antibody as a new male fertility treatment
Authors: Maurel M  C , Dupuy L , Decourtye J , Casteret S , Kara E 
Published: July 2024

Abstract

Study question
Can we improve spermatogenesis in male by increasing FSH activity with a potentiating antibody?

Summary answer
IGYXOS developed a first in class potentiating therapeutic antibody that is able to stimulate spermatogenesis better than gonadotropins only as demonstrated in animal models.

What is known already
Idiopathic male infertility, including oligozoospermia, oligoasthenoteratospermia (OATS) and azoospermia, accounts for at least 75% of infertile men population, and no treatment is available at the moment for them. IGYXOS developed a monoclonal antibody directed against human FSH. IGX12 is a humanized IgG4 and it is able to potentiate FSH activity in vitro and in vivo in several animal models.

Study design, size, duration
IGX12 was tested in azoospermic rat and mouse models. The first model was created by treating Wistar Han rats with a GnRH antagonist. Gonadotropin treatment started after full inhibition of spermatogenesis. Four rats per group were treated with FSH+hCG regimen alone or in combination with IGX12. The second model was hpg mice that are congenitally hypogonadal because of their inability to synthetize GnRH. Seven mice per group were treated with FSH only or FSH+IGX12.

Participants/materials, setting, methods
IGX12 was tested in vitro on HEK293 cells and in vivo in Steelman and Pohley bioassay. The potentiating effect was investigated in azoospermic rats, that were treated for 8 weeks with FSH+hCG or FSH+hCG+IGX12. Hpg mice were treated with Gonal-f or Gonal-f+IGX12 for 7 weeks, followed by a treatment with Menopur or Menopur+IGX12 for a further 7 weeks. At the end of treatment, sperm counts in the testes and in the epididymides were assessed.

Main results and the role of chance
In vitro on HEK 293 cells expressing the human FSH receptor, IGX12 combined to FSH improved 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. Ovaries weight of immature female rats was increased significantly in the group treated with hCG/FSH+IGX12 compared to hCG/FSH only. To further analyze the potential benefit of IGX12 on male fertility, its effect was investigated in azoospermic rodent models. In rats with acquired azoospermia, treatment with FSH+hCG reached ∼50% of spermatogenesis of wild-type (WT) animals. Doubling the dose of gonadotropins did not improve their effect, whereas the addition of IGX12 on top of FSH+hCG treatment during one spermatogenesis cycle only (8 weeks) significantly improved sperm count in the testes and in the epididymides, reaching the level of WT animals. In hpg mice with congenital azoospermia, sperm count in the testis was 3.6 times higher and the sperm count in the epididymides was 6 times higher in the group treated with IGX12+FSH compared with FSH only (p &lt; 0.05). In conclusion, IGX12 combined to a standard treatment stimulated spermatogenesis better than standard gonadotropin treatment.

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 treat male patients with idiopathic infertility, especially with oligozoospermia.

Trial registration number
not applicable