Date: 17th August 2021
There is a major unmet need for alternative, non-hormonal contraceptives for many women who wish to avoid hormonal contraceptives due to real or perceived side effects or for those that have medical contraindications. With a rapid expansion of the use of monoclonal antibodies to address disease, these synthetic versions of natural antibodies might provide the solution to eliminate unwanted species in the body, in this case, sperm. Now, researchers have engineered antibodies to target a unique surface antigen present on human sperm, limiting progressive sperm motility in the female reproductive tract, finding it a promising biologic for nonhormonal contraception.
Among ~ 1.9 billion women of reproductive age worldwide in 2019, an estimated 842 million are using contraceptive methods, and 270 million have an unmet need for contraception. Despite the availability of inexpensive and effective hormonal contraceptives in many countries, the unintended pregnancy rate is still approximately 45% of all pregnancies, creating an enormous emotional and cost burden on patients and the health care system.
However, an effective nonhormonal contraceptive mechanism does already exists in nature in the form of anti-sperm antibodies (ASAs) which can found in the female reproductive tract (FRT) of infertile women. These ASAs can trap vigorously motile sperm in mucus and prevent them from reaching the egg either by agglutinating sperm into clusters that are too large to penetrate mucus, or by trapping individual spermatozoa in mucus.
Now, researchers at the University of North Carolina at Chapel Hill, US, led by Samuel Lai have harnessed the power of ASAs, engineering a panel of sperm-binding IgG antibodies to contain 6-10 antigen-binding fragments (Fabs) isolated from a healthy immune-infertile woman. The resulting highly multivalent IgGs (HM-IgGs) were up to 16-fold more potent and faster at agglutinating sperm than the parent antibody (Ab), and translated into an effective (>99.9%) reduction of progressively motile sperm in the sheep vagina.
The team started by engineering different HM-IgG molecules with a Fab domain previously isolated from a healthy but immune-infertile woman. A natural IgG contains one Fc or constant region, and two identical Fabs which are the variable component. Here the scientists engineered IgGs with additional Fabs (6,8 and 10) linked to the baseline IgG using flexible linkers. All three of the HM-IgGs exhibited greater agglutination potency than IgG in in vitro assays, suggesting the increased number of Fabs were beneficial.
However, as the scientists wanted to develop this as an effective vaginal immunocontraceptive, speed of agglutination was also essential to prevent the sperm reaching the upper reproductive tract. Here, they showed the agglutination kinetics of all HM-IgGs were faster and more complete than the parent IgG at each Ab concentration and across all time points, suggesting multimerisation accelerated the agglutination kinetics. Furthermore, the HM-IgGs also preserved Fc-mucin cross-linking and blocking of individual sperm from penetrating bovine cervical mucus.
Finally, with no practical animal model to perform mating-based contraceptive efficacy studies, the team devised a sheep study that paralleled the human postcoital test (PCT) – assessing the reduction of progressively motile (PM) sperm in the female reproductive tract. Here, they found that the multivalent anti-sperm IgG constructs demonstrated stronger agglutination potency than the parent IgG in the sheep, they could also reduce PM sperm by 97 and >99% at a 10-fold lower concentration than the parental IgG. Together, these results suggest that these anti-sperm IgG can offer protection in vivo.
The team here have generated novel, ultrapotent, sperm-binding monoclonal antibodies as a new option for affordable, non-hormonal female contraception. Using the highly multivalent IgG platform, the engineered antibodies were at least 10- to 16-fold more potent at agglutinating sperm and reducing sperm permeation through mucus than the best known antibody.
Whilst, the researchers acknowledge the limitations of the study, such as preventing pregnancies rather than just sperm immobolisation and the lack of human trials, they believe that topical vaginal delivery will be hugely beneficial. It allows a low total dose of Ab, reducing side effects and confines the drug to the site of action. The mucus barrier of the vagina is continuously secreted and cleared, likely enabling a rapid return to fertility when required, and is a poor immunisation inductive site, with limited immune response, suggesting the application would not trigger local toxicities.
With this mind the parent IgG is currently being evaluated in a clinical trial via the human postcoital test in surgically sterilised women, which allows an early assessment of contraceptive promise without risk of pregnancy.
The team are now looking at methods of delivery for the new contraceptive, such as intravaginal ring that steadily releases the antibody across the fertility window, or a dissolvable film that can be inserted prior to sex. The molecule has been licensed by Mucommune, a startup spin out of the Lai Lab, which will be leading preclinical and clinical development efforts.
This is an interesting development for engineered antibody use, and we are starting to see a new generation of antibody therapies arising to treat a wide range of different diseases and conditions such as targeted antibody therapy to treat congenital myasthenia, new hybrid antibodies to fight COVID-19, or engineered antibody-cytokine protein fusion, called immunocytokines to treat aggressive cancer. These novel anti-sperm Abs offer an alternative and women-controlled method of contraceptive and will likely be a welcomed form of birth control for millions of women around the world in the near future.
For more information please see the press release from UNC Eshelman School of Pharmacy