A team of researchers affiliated with a host of institutions in the U.S. has found that an antibody they created was 99.9% effective at trapping human sperm. In their paper published in the journal Science Translational Medicine, the group describes how they developed their birth control antibodies as an alternative to hormonal forms of female contraception.
But, as the researchers note, all such options have drawbacks that lead to problems for women. In this new effort, the researchers sought a third alternative – one that involves using antibodies.
Prior research has shown that certain antibodies in the vaginas of some women can make them infertile. Last year, the researchers obtained some of these antibodies from female volunteers and subsequently removed the antigen-binding components.
More recently, the researchers added staggered amounts of the components to engineered IgG antibodies – 6, 8 and 10.
They then injected plasmids containing these antibodies into human embryonic cells resulting in the growth of new IgG cells with the engineered components. Next, the researchers tested the ability of their IgG cells to attract and bond with sperm cells in a petri dish and found they were up to 10 times better at trapping sperm cells than the original antibodies taken from the volunteer women.
That was followed by injections of human sperm. After two minutes, the researchers collected samples from the sheep vaginas and counted how many mobile sperm they were able to find. In so doing, they found reductions of 99.9% compared to control groups.
The researchers note that more work is required to determine if their technique could become a third contraceptive method for women in the future. They plan to next find out if their engineered antibodies will work the same in a human vagina.
Over the past 200 years the human population has grown from under 1 billion to over 7.7 billion individuals, and is on track to exceed 10 billion by the end of this century [[1], [2]]. Many population experts have voiced concern that this rapid rate of population growth exerts dangerous pressure on planetary resources and is unsustainable. Despite the availability of numerous effective birth control methods, over 40% of pregnancies worldwide are unintended. These pregnancies are significantly contributing to population growth, and unintended pregnancies can have pronounced adverse effects on maternal physical, mental, and economic wellbeing [[1]].
There is an urgent need for new contraception methods to address the problem of unintended pregnancies. The majority of effective female contraceptive methods require medical visits and/or procedures which can introduce economic and accessibility barriers. Among the most widely used reversible contraceptives, hormonal methods are frequently discontinued due to side effects, and barrier methods often fail due to inconsistent or improper use [3, 4, 5, 6].
New non-hormonal, woman-controlled methods that are safe, accessible, inexpensive, and discrete could provide an important contribution to the contraception field. Recent surveys indicate that women find two approaches highly desirable: on-demand contraception, and multipurpose prevention technology (MPT) products that provide dual protection against unintended pregnancy and sexually transmitted infections (STIs) [[7], [8]]. Such products could increase the popularity and use of contraceptive products.
Human monoclonal antibodies (mAbs), once used primarily as research and diagnostic tools, are now employed in a variety of clinical applications due to recent advances in cloning, genetic engineering, and improved mAb production platforms [[9]]. Over 100 mAbs have been approved for human therapeutic use, mostly in the fields of oncology, autoimmunity, and inflammatory disease [[10]]. A human anti-HIV mAb, VRC01, was recently tested in two large Phase 3 clinical trials for HIV prevention [[11]]. Most mAbs are administered systemically through intravenous or subcutaneous injection, but nonhuman primate studies and Phase 1 human clinical trials have also demonstrated the feasibility of topical intravaginal mAb administration to prevent the transmission of HIV-1 and other STIs [[9]].
Our group recently completed a Phase 1 clinical trial that assessed the safety and pharmacokinetics of a topical vaginal film containing human mAbs against HIV-1 and Herpes Simplex Viruses (HSV)-1 and 2 made in Nicotiana benthamiana, a species of tobacco plant. The Nicotiana platform is fast and versatile, and produces a very clean antibody product free from potential contamination with mammalian pathogens.
The trial demonstrated that mAbs made in Nicotiana were safe, and that effective concentrations of neutralizing antibodies could be detected in vaginal secretions for at least 24 h after film administration [[12]]. This study provides proof-of-concept that combinations of pathogen-specific mAbs administered intravaginally could safely protect women against a variety of STIs. The addition of mAbs against reproductive targets, such as sperm, could also confer contraceptive protection and constitute a unique non-hormonal MPT product.
Antisperm antibodies are often detected in the sera and genital secretions of infertility patients. Antibodies reactive with sperm surface antigens, most frequently detected in the clinical laboratory by immunobead assay, can affect a number of sperm functions. They appear to have a primary effect on endocervical mucus penetration by inducing sperm agglutination, complement-mediated sperm immobilization, or by trapping sperm through charge interactions between the antibody Fc region and mucus fibrils [13, 14, 15].
One such human antisperm mAb, H6-3C4, has shown promise as a contraceptive antibody. The mAb is directed against an N-linked carbohydrate epitope on a male reproductive tract (MRT)-specific glycoprotein, CD52g, which is expressed and secreted primarily by epithelial cells in the human cauda epididymis [[16]]. CD52g has a GPI anchor that mediates its insertion into the plasma membrane of sperm and other cells found in the lumen of the MRT.
The unique carbohydrate epitope differentiates MRT-CD52g from CD52 which is highly expressed on lymphocytes [[17]]. H6-3C4 was an IgM subclass antibody originally cloned from B-cells from a woman with infertility and a high titer of sperm-immobilizing antibodies [[18]].
Our research team used variable region sequences from H6-3C4 [[19]] to manufacture a human antisperm IgG1 mAb in Nicotiana benthamiana plants, a versatile, cost-effective platform that has been used to produce a variety of human mAbs and other proteins for clinical applications [20, 21, 22]. We have designated this antibody “Human Contraception Antibody (HCA)”. In this report, we describe the production of HCA, its specificity, and its performance in sperm function and safety assays.
reference link : https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00271-1/fulltext
More information: Bhawana Shrestha et al, Engineering sperm-binding IgG antibodies for the development of an effective nonhormonal female contraception, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abd5219
