# Engineering bispecific antibodies for non-hormonal contraception

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $520,731

## Abstract

Summary
Sperm must swim through mucus before ascending to the upper tract and fertilizing the egg. In addition, sperm
must be hyperactivated to penetrate the zona pellucida of the oocyte. Polymeric antibodies (Ab) such as IgM
that bind sperm surface antigens can agglutinate sperm into clusters too large to penetrate through the pores
of mucus. In addition, IgG can also be engineered to crosslink individual sperm to mucins, as well as inhibit
hyperactivation, consequently preventing sperm from reaching and fertilizing the egg. Topical passive
immunization based on vaginal delivery of anti-sperm Ab (ASA) was validated in animal models in the
1980s-1990s, and directly overcomes the variable intensity and uncertain reversibility of contraceptive
vaccines. However, this strategy was not practical due to the high costs of mAb production and challenges
with IgM formulation. Given the remarkable advances in bioprocessing that have greatly reduced the costs
of mAb manufacturing, and the possibility of sustained delivery of antibodies in the vagina via intravaginal
rings, we believe the time is now ripe to develop novel, ultra-potent ASA for non-hormonal contraception
based on topical passive immunization of the vagina against human sperm. In pilot studies, we have shown
that we can greatly increase the sperm-agglutination potency of ASA by >15-50-fold by engineering
multivalent, IgG-based construct comprised of six to ten Fab domains (i.e. 4 to 8 additional Fabs linked to the
parent IgG molecule). These novel constructs possess comparable stability to IgG in accelerated thermal
stability studies, and also similar production and purification yield as IgG. One of the constructs represent the
lead molecule under development in the Boston University Contraceptive Research Center, with two Phase I
clinical trials slated to begin in 2020. In this project, we seek to further improve the potencies by employing
cutting edge bispecific Ab engineering technology and affinity maturation via yeast and mamallian cell display
to engineer a library of ultra-potent bispecific multivalent ASA constructs. We will target both CD52g, a well
characterized and validated antigen target present on human sperm only, and EPPIN, a well established
contraceptive target that functions by inhibiting sperm hyperactivation. In Aim 1, we will utilize yeast display to
improve the affinity of Fab against CD52g and EPPIN, engineer a library of multivalent bispecific constructs
that bind both targets, and rigorously characterize these molecules. In Aim 2, we will perform a panel of
studies to assess their potential contraceptive efficacy, including sperm agglutination, trapping individual sperm
in mucus, and inhibition of sperm hyperactivation. To determine which construct will most effectively reduce
progressive sperm motility in human vagina, we will perform in vivo dose finding studies in Aim 3 with the two
most potent constructs from Aims 1 and 2 in a post-coital fertility test adapted to...

## Key facts

- **NIH application ID:** 10133708
- **Project number:** 5R01HD101562-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Samuel Lai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $520,731
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133708

## Citation

> US National Institutes of Health, RePORTER application 10133708, Engineering bispecific antibodies for non-hormonal contraception (5R01HD101562-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133708. Licensed CC0.

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