Many women want non-hormonal birth control. A 22-year-old's findings were used to launch a company that could, within the decade, bring a new kind of contraceptive to the marketplace.
Unwanted pregnancy can now be added to the list of preventions that antibodies may be fighting in the near future. For decades, really since the 1980s, engineered monoclonal antibodies have been knocking out invading germs — preventing everything from cancer to COVID. Sperm, which have some of the same properties as germs, may be next.
Not only is there an unmet need on the market for alternatives to hormonal contraceptives, the genesis for the original research was personal for the then 22-year-old scientist who led it. Her findings were used to launch a company that could, within the decade, bring a new kind of contraceptive to the marketplace.
The genesis
It’s Suruchi Shrestha’s research — published in Science Translational Medicine in August 2021 and conducted as part of her dissertation while she was a graduate student at the University of North Carolina at Chapel Hill — that could change the future of contraception for many women worldwide. According to a Guttmacher Institute report, in the U.S. alone, there were 46 million sexually active women of reproductive age (15–49) who did not want to get pregnant in 2018. With the overturning of Roe v. Wade this year, Shrestha’s research could, indeed, be life changing for millions of American women and their families.
Now a scientist with NextVivo, Shrestha is not directly involved in the development of the contraceptive that is based on her research. But, back in 2016 when she was going through her own problems with hormonal contraceptives, she “was very personally invested” in her research project, Shrestha says. She was coping with a long list of negative effects from an implanted hormonal IUD. According to the Mayo Clinic, those can include severe pelvic pain, headaches, acute acne, breast tenderness, irregular bleeding and mood swings. After a year, she had the IUD removed, but it took another full year before all the side effects finally subsided; she also watched her sister suffer the “same tribulations” after trying a hormonal IUD, she says.
For contraceptive use either daily or monthly, Shrestha says, “You want the antibody to be very potent and also cheap.” That was her goal when she launched her study.
Shrestha unshelved antibody research that had been sitting idle for decades. It was in the late 80s that scientists in Japan first tried to develop anti-sperm antibodies for contraceptive use. But, 35 years ago, “Antibody production had not been streamlined as it is now, so antibodies were very expensive,” Shrestha explains. So, they shifted away from birth control, opting to focus on developing antibodies for vaccines.
Over the course of the last three decades, different teams of researchers have been working to make the antibody more effective, bringing the cost down, though it’s still expensive, according to Shrestha. For contraceptive use either daily or monthly, she says, “You want the antibody to be very potent and also cheap.” That was her goal when she launched her study.
The problem
The problem with contraceptives for women, Shrestha says, is that all but a few of them are hormone-based or have other negative side effects. In fact, some studies and reports show that millions of women risk unintended pregnancy because of medical contraindications with hormone-based contraceptives or to avoid the risks and side effects. While there are about a dozen contraceptive choices for women, there are two for men: the condom, considered 98% effective if used correctly, and vasectomy, 99% effective. Neither of these choices are hormone-based.
On the non-hormonal side for women, there is the diaphragm which is considered only 87 percent effective. It works better with the addition of spermicides — Nonoxynol-9, or N-9 — however, they are detergents; they not only kill the sperm, they also erode the vaginal epithelium. And, there’s the non-hormonal IUD which is 99% effective. However, the IUD needs to be inserted by a medical professional, and it has a number of negative side effects, including painful cramping at a higher frequency and extremely heavy or “abnormal” and unpredictable menstrual flows.
The hormonal version of the IUD, also considered 99% effective, is the one Shrestha used which caused her two years of pain. Of course, there’s the pill, which needs to be taken daily, and the birth control ring which is worn 24/7. Both cause side effects similar to the other hormonal contraceptives on the market. The ring is considered 93% effective mostly because of user error; the pill is considered 99% effective if taken correctly.
“That’s where we saw this opening or gap for women. We want a safe, non-hormonal contraceptive,” Shrestha says. Compounding the lack of good choices, is poor access to quality sex education and family planning information, according to the non-profit Urban Institute. A focus group survey suggested that the sex education women received “often lacked substance, leaving them feeling unprepared to make smart decisions about their sexual health and safety,” wrote the authors of the Urban Institute report. In fact, nearly half (45%, or 2.8 million) of the pregnancies that occur each year in the US are unintended, reports the Guttmacher Institute. Globally the numbers are similar. According to a new report by the United Nations, each year there are 121 million unintended pregnancies, worldwide.
The science
The early work on antibodies as a contraceptive had been inspired by women with infertility. It turns out that 9 to 12 percent of women who are treated for infertility have antibodies that develop naturally and work against sperm. Shrestha was encouraged that the antibodies were specific to the target — sperm — and therefore “very safe to use in women.” She aimed to make the antibodies more stable, more effective and less expensive so they could be more easily manufactured.
Since antibodies tend to stick to things that you tell them to stick to, the idea was, basically, to engineer antibodies to stick to sperm so they would stop swimming. Shrestha and her colleagues took the binding arm of an antibody that they’d isolated from an infertile woman. Then, targeting a unique surface antigen present on human sperm, they engineered a panel of antibodies with as many as six to 10 binding arms — “almost like tongs with prongs on the tongs, that bind the sperm,” explains Shrestha. “We decided to add those grabbers on top of it, behind it. So it went from having two prongs to almost 10. And the whole goal was to have so many arms binding the sperm that it clumps it” into a “dollop,” explains Shrestha, who earned a patent on her research.
Suruchi Shrestha works in the lab with a colleague. In 2016, her research on antibodies for birth control was inspired by her own experience with side effects from an implanted hormonal IUD.
UNC - Chapel Hill
The sperm stays right where it met the antibody, never reaching the egg for fertilization. Eventually, and naturally, “Our vaginal system will just flush it out,” Shrestha explains.
“She showed in her early studies that [she] definitely got the sperm immotile, so they didn't move. And that was a really promising start,” says Jasmine Edelstein, a scientist with an expertise in antibody engineering who was not involved in this research. Shrestha’s team at UNC reproduced the effect in the sheep, notes Edelstein, who works at the startup Be Biopharma. In fact, Shrestha’s anti-sperm antibodies that caused the sperm to agglutinate, or clump together, were 99.9% effective when delivered topically to the sheep’s reproductive tracts.
The future
Going forward, Shrestha thinks the ideal approach would be delivering the antibodies through a vaginal ring. “We want to use it at the source of the spark,” Shrestha says, as opposed to less direct methods, such as taking a pill. The ring would dissolve after one month, she explains, “and then you get another one.”
Engineered to have a long shelf life, the anti-sperm antibody ring could be purchased without a prescription, and women could insert it themselves, without a doctor. “That's our hope, so that it is accessible,” Shrestha says. “Anybody can just go and grab it and not worry about pregnancy or unintended pregnancy.”
Her patented research has been licensed by several biotech companies for clinical trials. A number of Shrestha’s co-authors, including her lab advisor, Sam Lai, have launched a company, Mucommune, to continue developing the contraceptives based on these antibodies.
And, results from a small clinical trial run by researchers at Boston University Chobanian & Avedisian School of Medicine show that a dissolvable vaginal film with antibodies was safe when tested on healthy women of reproductive age. That same group of researchers earlier this year received a $7.2 million grant from the National Institute of Health for further research on monoclonal antibody-based contraceptives, which have also been shown to block transmission of viruses, like HIV.
“As the costs come down, this becomes a more realistic option potentially for women,” says Edelstein. “The impact could be tremendous.”
Biochemist Longxing Cao is working with colleagues at the University of Washington on promising research to disable infectious coronavirus in a person's nose.
This may sounds like science fiction, but several research groups are already working on such trickster coronavirus drugs, with some candidates close to clinical trials and possibly even becoming available late this year. The teams began working on them when the pandemic arrived, and continued in lockdown.
When the pandemic first hit and the state of California issued a lockdown order on March 16, postdoctoral researchers Anum and Jeff Glasgow found themselves stuck at home with nothing to do. The two scientists who study bioengineering felt that they were well equipped to research molecular ways of disabling coronavirus's cell-penetrating spike protein, but they could no longer come to their labs at the University of California San Francisco.
"We were upset that no one put us in the game," says Anum Glasgow. "We have a lot of experience between us doing these types of projects so we wanted to contribute." But they still had computers so they began modeling the potential virus-disabling proteins in silico using Robetta, special software for designing and modeling protein structures, developed and maintained by University of Washington biochemist David Baker and his lab.
"We saw some imperfections in that lock and key and we created something better. We made a 10 times tighter adhesive."
The SARS-CoV-2 virus that causes Covid-19 uses its surface spike protein to bind on to a specific receptor on human cells called ACE2. Unfortunately for humans, the spike protein's molecular shape fits the ACE2 receptor like a well-cut key, making it very successful at breaking into our cells. But if one could design a molecular ACE2-mimic to "trick" the virus into latching onto it instead, the virus would no longer be able to enter cells. Scientists call such mimics receptor traps or inhibitors, or blockers. "It would block the adhesive part of the virus that binds to human cells," explains Jim Wells, professor of pharmaceutical chemistry at UCSF, whose lab took part in designing the ACE2-receptor mimic, working with the Glasgows and other colleagues.
The idea of disabling infectious or inflammatory agents by tricking them into binding to the targets' molecular look-alikes is something scientists have tried with other diseases. The anti-inflammatory drugs commonly used to treat autoimmune conditions, including rheumatoid arthritis, Crohn's disease and ulcerative colitis, rely on conceptually similar molecular mechanisms. Called TNF blockers, these drugs block the activity of the inflammatory cytokines, molecules that promote inflammation. "One of the biggest selling drugs in the world is a receptor trap," says Jeff Glasgow. "It acts as a receptor decoy. There's a TNF receptor that traps the cytokine."
In the recent past, scientists also pondered a similar look-alike approach to treating urinary tract infections, which are often caused by a pathogenic strain of Escherichia coli. An E. coli bacterium resembles a squid with protruding filaments equipped with proteins that can change their shape to form hooks, used to hang onto specific sugar molecules called ligands, which are present on the surface of the epithelial cells lining the urinary tract.
A recent study found that a sugar-like compound that's structurally similar to that ligand can play a similar trick on the E. Coli. When administered in in sufficient amounts, the compound hooks the bacteria on, which is then excreted out of the body with urine. The "trickster" method had been also tried against the HIV virus, but it wasn't very effective because HIV has a high mutation rate and multiple ways of entering human cells.
But the coronavirus spike protein's shape is more stable. And while it has a strong affinity for the ACE2 receptors, its natural binding to these receptors isn't perfect, which allowed the UCSF researchers to design a mimic with a better grip. "We saw some imperfections in that lock and key and we created something better," says Wells. "We made a 10 times tighter adhesive." The team demonstrated that their traps neutralized SARS-CoV-2 in lab experiments and published their study in the Proceedings of the National Academy of Sciences.
Baker, who is the director of the Institute for Protein Design at the University of Washington, was also devising ACE2 look-alikes with his team. Only unlike the UCSF team, they didn't perfect the virus-receptor lock and key combo, but instead designed their mimics from scratch. Using Robetta, they digitally modeled over two million proteins, zeroed-in on over 100,000 potential candidates and identified a handful with a strong promise of blocking SARS-CoV-2, testing them against the virus in human cells. Their design of the miniprotein inhibitors was published in the journal Science.
Biochemist David Baker, pictured in his lab at the University of Washington.
UW
The concept of the ACE2 receptor mimics is somewhat similar to the antibody plasma, but better, the teams explain. Antibodies don't always coat all of the virus's spike proteins and sometimes don't bind perfectly. By contrast, the ACE2 mimics directly compete with the virus's entry mechanism. ACE2 mimics are also easier and cheaper to make, researchers say.
Antibodies, which are long protein chains, must be grown inside mammalian cells, which is a slow and costly process. As drugs, antibody cocktails must be kept refrigerated. On the contrary, proteins that mimic ACE2 receptors are smaller and can be produced by bacteria easily and inexpensively. Designed to specs, these proteins don't need refrigeration and are easy to store. "We designed them to be very stable," says Baker. "Our computation design tries to come up with the stable proteins that have the desired functions."
That stability may allow the team to create an inhaler drug rather than an intravenous one, which would be another advantage over the antibody plasma, given via an IV. The team envisions people spraying the miniprotein solution into their nose, creating a protecting coating that would disable the inhaled virus. "The infection starts from your respiratory system, from your nose," explains Longxing Cao, the study's co-author—so a nasal spray would be a natural way to administer it. "So that you can have it like a layer, similar to a mask."
As the virus evolves, new variants are arising. But the teams think that their ACE2 protein mimics should work on the new variants too for several reasons. "Since the new SARS-CoV-2 variants still use ACE2 for their cell entry, they will likely still be susceptible to ACE2-based traps," Glasgow says.
Cao explains that their approach should work too because most of the mutations happen outside the ACE2 binding region. Plus, they are building multiple binders that can bind to an array of the coronavirus variants. "Our binder can still bind with most of the variants and we are trying to make one protein that could inhibit all the future escape variants," he says.
Baker and Cao hope that their miniproteins may be available to patients later this year. But besides getting the medicine out to patients, this approach will allow researchers to test the computer-modeled mimics end-to-end with an unprecedented speed. That would give humans a leg up in future pandemics or zoonotic disease outbreaks, which remain an increasingly pressing threat due to human activity and climate change.
"That's what we are focused on right now—understanding what we have learned from this pandemic to improve our design methods," says Baker. "So that we should be able to obtain binders like these very quickly when a new pandemic threat is identified."
