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.
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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.”
Dr. Robert Montgomery, almost one year post-transplant, at a vineyard in Casablanca, Chile, August 2019.
(Courtesy Montgomery)
Having spent my working life as a transplant surgeon, it is the ultimate irony that I have now become a heart transplant patient. I knew this was a possibility since 1987, when I was 27 years old and I received a phone call from my sister-in-law telling me that my 35-year-old brother, Rich, had just died suddenly while water skiing.
Living from one heartbeat to the next I knew I had to get it right and nail my life—and in that regard my disease was a blessing.
After his autopsy, dots were connected and it was clear that the mysterious heart disease my father had died from when I was 15 years old was genetic. I was evaluated and it was clear that I too had inherited cardiomyopathy, a progressive weakening condition of the heart muscle that often leads to dangerous rhythm disturbances and sudden death. My doctors urged me to have a newly developed device called an implantable cardioverter-defibrillator (ICD) surgically placed in my abdomen and chest to monitor and shock my heart back into normal rhythm should I have a sudden cardiac arrest.
They also told me I was the first surgeon in the world to undergo an ICD implant and that having one of these devices would not be compatible with the life of a surgeon and I should change careers to something less rigorous. With the support of a mentor and armed with what the British refer to as my "bloody-mindedness," I refused to give up this dream of becoming a transplant surgeon. I completed my surgical training and embarked on my career.
What followed were periods of stability punctuated by near-death experiences. I had a family, was productive in my work, and got on with life, knowing that this was a fragile situation that could turn on its head in a moment. In a way, it made my decisions about how to spend my time and focus my efforts more deliberate and purposeful. Living from one heartbeat to the next I knew I had to get it right and nail my life—and in that regard my disease was a blessing.
In 2017 while pursuing my passion for the outdoors in a remote part of Patagonia, I collapsed from bacterial pneumonia and sepsis. Unknowingly, I had brought in my lungs one of those super-bugs that you read about from the hospital where I worked. Several days into the trip, the bacteria entered my blood stream and brought me as close to death as a human can get.
I lay for nearly 3 weeks in a coma on a stretcher in a tiny hospital in Argentina, septic and in cardiogenic shock before stabilizing enough to be evaced to NYU Langone Hospital, where I was on staff. I awoke helpless, unable to walk, talk, or swallow food or drink. It was a long shot but I managed to recover completely from this episode; after 3 months, I returned to work and the operating room. My heart rebounded, but never back to where it had been.
Then, on the eve of my mother's funeral, I arrested while watching a Broadway show, and this time my ICD failed to revive me. There was prolonged CPR that broke my ribs and spine and a final shock that recaptured my heart. It was literally a show stopper and I awoke to a standing ovation from the New York theatre audience who were stunned by my modern recreation of the biblical story of Lazarus, or for the more hip among them, my real-life rendition of the resurrection of Jon Snow at the end of season 5 of Game of Thrones.
Against the advice of my doctors, I attended my mom's funeral and again tried to regain some sense of normalcy. We discussed a transplant at this point but, believe it or not, there is such a scarcity of organs I was not yet "sick enough" to get enough priority to receive a heart. I had more surgery to supercharge my ICD so it would be more likely to save my life the next time -- and there would be a next time, I knew.
As a transplant surgeon, I have been involved in some important innovations to expand the number of organs available for transplantation.
Months later in Matera, Italy, where I was attending a medical meeting, I developed what is referred to as ventricular tachycardia storm. I had 4 cardiac arrests over a 3-hour period. With the first one, I fell on to a stone floor and split my forehead open. When I arrived at the small hospital it seemed like Patagonia all over again. One of the first people I met was a Catholic priest who gave me the Last Rights.
I knew now was the moment and so with the help of one of my colleagues who was at the meeting with me and the compassion of the Italian doctors who supplied my friend with resuscitation medications and left my IV in place, I signed out of the hospital against medical advice and boarded a commercial flight back to New York. I was admitted to the NYU intensive care unit and received a heart transplant 3 weeks later.
Now, what I haven't said is that as a transplant surgeon, I have been involved in some important innovations to expand the number of organs available for transplantation. I came to NYU in 2016 to start a new Transplant Institute which included inaugurating a heart transplant program. We hired heart transplant surgeons, cardiologists, and put together a team that unbeknownst to me at the time, would save my life a year later.
It gets even more interesting. One of the innovations that I had been involved in from its inception in the 1990s was using organs from donors at risk for transmitting viruses like HIV and Hepatitis C (Hep C). We popularized new ways to detect these viruses in donors and ensure that the risk was minimized as much as possible so patients in need of a life-saving transplant could utilize these organs.
When the opioid crisis hit hard about four years ago, there were suddenly a lot of potential donors who were IV drug users and 25 percent of them were known to be infected with Hep C (which is spread by needles). In 2018, 49,000 people died in the U.S. from drug overdoses. There were many more donors with Hep C than potential recipients who had previously been exposed to Hep C, and so more than half of these otherwise perfectly good organs were being discarded. At the same time, a new class of drugs was being tested that could cure Hep C.
I was at Johns Hopkins at the time and our team developed a protocol for using these Hep C positive organs for Hep C negative recipients who were willing to take them, even knowing that they were likely to become infected with the virus. We would then treat them after the transplant with this new class of drugs and in all likelihood, cure them. I brought this protocol with me to NYU.
When my own time came, I accepted a Hep C heart from a donor who overdosed on heroin. I became infected with Hep C and it was then eliminated from my body with 2 months of anti-viral therapy. All along this unlikely journey, I was seemingly making decisions that would converge upon that moment in time when I would arise to catch the heart that was meant for me.
Dr. Montgomery with his wife Denyce Graves, September 2019.
(Courtesy Montgomery)
Today, I am almost exactly one year post-transplant, back to work, operating, traveling, enjoying the outdoors, and giving lectures. My heart disease is gone; gone when my heart was removed. Gone also is my ICD. I am no longer at risk for a sudden cardiac death. I traded all that for the life of a transplant patient, which has its own set of challenges, but I clearly traded up. It is cliché, I know, but I enjoy every moment of every day. It is a miracle I am still here.