Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy

doi:10.1073/pnas.0710110104

Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy

*Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia; and
^‡The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia

Contributed by Donald Metcalf, October 24, 2007 (received for review September 10, 2007)

Abstract

Blastocyst implantation is a critical stage in the establishment of pregnancy. Leukemia inhibitory factor (LIF) is essential for mouse blastocyst implantation and also plays a role in human pregnancy. We examined the effect of a potent LIF antagonist (LA) on mouse implantation. In mice, LIF expression peaks on day 3.5 of pregnancy (D3.5) (D0.5 = day of mating plug detection) in the uterine glandular epithelium. LA (7 mg/kg per day) administered from D2.5 to D4.5 via four hourly i.p. injections plus continuous administration via miniosmotic pump resulted in complete implantation failure. To improve its pharmacokinetic properties, we conjugated LA to polyethylene glycol (PEG), achieving a significant increase in serum levels. PEGylated LA (PEGLA) (37.5 mg/kg per day) administered via three i.p. injections between D2.5 and D3.5 also resulted in complete implantation failure. PEGLA immunolocalized to the uterine luminal epithelium at the time of blastocyst implantation. Both LA and PEGLA reduced phosphorylation of the downstream signaling molecule STAT3 in luminal epithelial cells on D3.5. The effects of PEGLA were found to be endometrial, with no embryo-lethal effects observed. These data demonstrate that administration of a PEGylated LIF antagonist is an effective method of targeting LIF signaling in the endometrium and a promising novel approach in the development of nonhormonal contraceptives for women.

Footnotes

^†To whom correspondence may be sent at the present address:
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
E-mail: white{at}wehi.edu.au
^¶To whom correspondence may be addressed at:
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
E-mail: metcalf{at}wehi.edu.au
Author contributions: C.A.W., L.A.S., N.A.N., L.R., and E.D. designed research; C.A.W., J.-G.Z., M.B., W.D.F., D.M., and E.D. performed research; C.A.W., J.-G.Z., D.M., and E.D. analyzed data; and C.A.W. and E.D. wrote the paper.
↵ ^§Present address: MedImmune, Inc., Gaithersburg, MD 20878.
Conflict of interest statement: The Walter and Eliza Hall Institute of Medical Research holds a patent for leukemia inhibitory factor.