The Human Contraceptive Antibody Targets A Semenogelin Galectin-3 N-Linked Glycan Complex on the Sperm Surface

The human contraception antibody (HCA) is an experimental topical contraceptive currently in Phase II clinical trials. It works by clumping and immobilizing sperm, preventing fertilization. Research has identified that the HCA's target is not the previously assumed N-linked polylactosamine glycan motif on CD52, as initially suggested.

Instead, the study suggests that HCA may bind to a complex involving semenogelin and galectin-3, which are found on the sperm surface. Semenogelins are glycosylated proteins that form gels and are cleaved into smaller fragments that adhere to sperm during semen liquefaction. These proteins were identified in the HCA purified sperm lysates, and their binding was found to be dependent on N-linked glycans.

The research also indicates that O-linked glycan modifications on the semenogelin proteins, containing LacNAc motifs, can bind to galectin-3, a protein also found in the HCA purified sperm lysates. When galectin-3 bound to the sperm surface was inhibited using competitive inhibitors, the HCA-mediated agglutination of sperm was reduced. This effect could be reversed by adding recombinant galectin-3/semenogelin-2 complexes to sperm cultures.

Overall, the findings point to the possibility that HCA's binding site involves a complex of semenogelin and galectin-3, anchored to the sperm surface via an N-linked glycan.