Hexavalent sperm-binding IgG antibody released from vaginal film for development of potent on-demand nonhormonal female contraception

Abstract

Nonhormonal products for on-demand contraception are a global health technology gap; this unmet need motivated us to pursue the use of sperm-binding monoclonal antibodies to enable effective on-demand contraception. Here, using the cGMP-compliant Nicotiana-expression system, we produced an ultrapotent sperm-binding IgG antibody possessing 6 Fab arms per molecule that bind a well-established contraceptive antigen target, CD52g. We term this hexavalent antibody “Fab-IgG-Fab” (FIF). The Nicotiana-produced FIF had at least 10-fold greater sperm-agglutination potency and kinetics than the parent IgG, while preserving Fc-mediated trapping of individual spermatozoa in mucus. We formulated the Nicotiana-produced FIF into a polyvinyl alcohol–based water-soluble contraceptive film and evaluated its potency in reducing progressively motile sperm in the sheep vagina. Two minutes after vaginal instillation of human semen, no progressively motile sperm were recovered from the vaginas of sheep receiving FIF Film. Our work supports the potential of multivalent contraceptive antibodies to provide safe, effective, on-demand nonhormonal contraception.

LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity

“…As part of clinical development, various engineered versions of HCA are being tested to determine whether they enhance antibody potency and reduce potential side effects. HCA variants have been engineered with increased valency to enhance agglutination potency [ 21 ]. A LALAPG HCA variant has also been developed and is being explored as a means to reduce the potential for undesirable Fc-mediated side effects such as inflammation and acquired immunity [ 22 , 23 ].…”

The urgent need for innovation in contraception

“…In addition to small molecule inhibitors, other approaches are being developed to retain sperm in the vagina such as sperm agglutination antibodies generated against male reproductive tract-specific molecules residing on the sperm surface. These provide opportunities for the development of innovative bioengineered female contraceptives [10,11]. Yet another class of innovative female non-hormonal methods under development utilizes pH modulation [12] or ionic spermiostatic agents (e.g., copper, zinc) that also affect sperm motility within the female reproductive tract [13][14][15].…”