152. DEVELOPMENT OF A VAGINALLY APPLIED, NON-HORMONAL CONTRACEPTIVE: THE CONTRACEPTIVE EFFICACY AND IMPACT ON BONE TURNOVER OF PEGLA, A LONG-ACTING LIF ANTAGONIST

Abstract

The WHO has called for the urgent development of pharmacological, non-hormonal contraceptives. Leukaemia inhibitory factor (LIF) is obligatory for embryo implantation in mice and associated with infertility in women. Injection of a long-acting LIF antagonist (PEGLA) blocks uterine LIF, preventing implantation in mice, making PEGLA a promising non-hormonal contraceptive. LIF and LIFR null mice show decreased bone volume associated with increased osteoclast number and size, suggesting PEGLA may target bone. Vaginally administered PEGLA could be a ‘dual-role’ contraceptive: delivered in a microbicide which blocks the vaginal transmission of sexually transmitted infections. We aimed to establish the contraceptive efficacy of vaginally administered PEGLA and identify non-uterine targets of PEGLA in mice. PEGLA was administered to mated female mice by intraperitoneal (IP) injection or vaginally (n = 4/group) during the peri-implantation period to determine its effect on implantation and bone turnover. The tissue and blood accumulation of 125I-PEGLA or control was identified at various time-points following IP injection (≤120 h) or vaginal administration (≤24 h) (n = 3/group). PEGLA administered via vaginal gel blocked implantation (0.0+0.0 vs 8.5+0.5) at a lower dose (500 μg) than IP injection (1500 μg). PEGLA administered by IP injection resulted in fewer (4.0+0.3% vs 7.7+1.5%; P < 0.05) but larger (20.9+0.9 μm vs 18.1+0.5 μm; P < 0.05) osteoclasts and increased trabecular bone volume (6.8+0.9% vs 3.1+1.1%; P < 0.05) but vaginally administered PEGLA had no effect on bone (P > 0.05). 125 I-PEGLA accumulated more quickly (10 min vs 30 min) and was retained longer (96 h vs 24 h) in blood and tissue following IP injection compared to vaginal administration. This is the first study to show the contraceptive efficacy of a PEGylated compound following vaginal delivery. Local delivery of PEGLA decreased the required dose and eliminated the effect on bone, suggesting that local administration would minimise the non-target effects of PEGLA. Contraceptive trials are now required in non-human primates to progress PEGLA towards human clinical trials.