At the turn of the 20^th century, physician Paul Ehrlich at the Institute of Experimental Therapy had a grand vision for the future of medicine. While researchers were beginning to understand how some diseases spread through tiny particles like viruses and bacteria, it remained unclear how to treat these microbe-based conditions. Based on his early research of the immune system, Ehrlich raised the possibility of a “magic bullet”: a new type of laser-focused treatment that killed only noxious microbes and spared healthy cells. 

Ehrlich’s 1909 discovery of Salvarsan as a treatment for syphilis became the first example of a magic bullet, and over a century later, medicine continues to search for precise treatments to ever more complicated conditions. Today, monoclonal antibodies are another manifestation of the magic bullet Ehrlich envisioned. These laboratory-made proteins can bind to substances in the body such as bacteria, viruses, or cancerous cells and efficiently treat dozens of conditions with minimal off-target effects. But many monoclonal antibody treatments share a certain flaw: the treatments may be magic bullets, but aiming the gun remains a challenge.

Roughly 70 percent of monoclonal antibody therapies are still delivered intravenously (IV), an administration route that’s inconvenient at best and ineffective at worst (1). Now, some researchers are reimagining how to deliver monoclonal antibodies with the hope of improving their efficacy and expanding the reach of these revolutionary therapies. 

The problem with antibodies

The first monoclonal antibody, Muromonab-CD3, was approved in 1986 to prevent kidney transplant rejection. Since then, the Food and Drug Administration (FDA) has approved more than 100 monoclonal antibody therapies to treat conditions including cancer, Alzheimer’s disease, autoimmune disorders, and infectious diseases. On the whole, these treatments have proven successful; the FDA approves up to a dozen new therapies every year, and the long half-life and favorable safety profile of monoclonal antibodies makes them particularly effective (2).

Compared to conventional drugs, antibodies are sprawling and unwieldy, preventing them from getting into the body easily. These Y-shaped molecules consist of multiple polypeptide chains that bind to specific targets and recruit a myriad of immune system players. This complex structure can result in a size 1000 times that of a single aspirin molecule (3). 

The IV delivery route presents multiple problems: First, because full-body infusion is by nature imprecise, it requires large volumes of antibody, increasing associated costs and systemic side effects. Second, in conditions affecting the central nervous system, such as Alzheimer’s disease or stroke, IV administration is particularly ineffective, with only 0.1 percent of an antibody solution able to cross the barriers that separate the brain and spinal cord from the general circulatory system (4). And finally, patients using these therapies need to visit clinics every few weeks, sitting for hours at a time for each infusion — a burden that may prevent some people from getting the care they need.

Helping hard-to-reach patients

This barrier to patient access is the reason that Andrew Barrett, chief scientific officer of Cessation Therapeutics, wants to design a preventive antibody for fentanyl overdose that can be injected subcutaneously rather than infused intravenously. 

US deaths from synthetic opioids exceeded 70,000 in 2021, with the majority of those deaths attributable to fentanyl (5). While naloxone (Narcan) has become a valuable tool to reverse opioid overdoses, Barrett envisioned a new prophylactic drug for high-risk populations, preventing both the psychoactive effects and dangerous respiratory depression associated with fentanyl.

“Despite the widespread availability of naloxone, we're still seeing an all-time high of fentanyl related overdose deaths,” said Barrett. “Our goal is to add another therapy to the armamentarium to attack these potential overdoses upstream.” 

Barrett recently published a study in Nature Communications  detailing new delivery methods for CSX-1004, an anti-fentanyl antibody currently being tested intravenously in a clinical trial (6). Barrett said that the company is pursuing subcutaneous injection — the most popular antibody delivery route after IV — because IV infusion simply isn’t realistic for their patient population. Opioid addicts at high risk for overdose may not have time to sit for long infusions or may quickly change their minds, and most harm reduction clinics don’t have the resources to support IV infusions. He wants to develop a treatment that people can complete in minutes, not hours.

“If someone were saying they want to make a change now and would accept a very, very quick subcutaneous injection, we think the access to that treatment would expand dramatically,” said Barett.

Barett’s published research showed that a subcutaneous injection of CSX-1004 protected both mice and nonhuman primates from fentanyl-induced respiratory depression for up to four weeks. Human formulations for subcutaneous injection are already underway, with plans to take the research into clinical trials as soon as possible. 

Straight to your head

Despite the widespread availability of naloxone, we’re still seeing an all-time high of fentanyl related overdose deaths. Our goal is to add another therapy to the armamentarium, to attack these potential overdoses upstream. 
– Andrew Barrett, Cessation Therapeutics

For researchers using antibodies to treat the central nervous system, IV infusion means losing 99 percent of antibodies at the blood-brain barrier and blood-cerebrospinal fluid barrier, which is one potential reason so many monoclonal antibody treatments for Alzheimer’s disease elicited lukewarm results, said Martin Schwab, a neuroscientist at the University of Zurich. “We would very much like to have a better way of application than intravenous,” he added.

Schwab spent decades studying Nogo-A, a molecule that blocks nerve growth after injuries like spinal cord damage and stroke. His team is developing a monoclonal antibody for Nogo-A that could aid recovery for these conditions. In a completed but still unpublished clinical trial of patients with spinal cord injuries, Schwab said that the team found success with an anti-Nogo-A antibody administered intrathecally, directly to the spinal cord. 

Still, Schwab admitted that intrathecal delivery can cause uncomfortable headaches, and it requires specialized personnel and equipment. That’s why he’s also testing an intranasal route for his anti-Nogo-A antibody, using a nasal spray that puffs antibodies straight into the sensory neurons of the nose. In a study published in Proceedings of the National Academy of Sciences exploring the technique, he reported that over two-thirds of rats treated with an intranasal antibody after stroke regained mobility in their forelimbs, whereas only roughly one-third of the control group recovered (7). 

While these initial results are promising, Schwab said a major hurdle for this method is that researchers still don’t understand exactly how it works. They believe that antibodies may cross through the sensory cells of the nose and into the brain through a process called transcytosis, but those mechanisms remain unclear. Schwab said that until he and other researchers understand the process better, he’s not ready to take a gamble on a costly and time-intensive clinical trial. 

Still, he believes that more direct, patient-friendly delivery methods are the future of antibody treatment for neurological disorders. If not intranasal application, Schwab thinks that other experimental approaches like Roche’s Brainshuttle could soon make monoclonal antibody delivery to the central nervous system much more efficient.

“I would be ready to replace intrathecal application as soon as a really good method comes along,” said Schwab. “My gut feeling at the moment is that one of these two techniques is going to make it.”

Antibody recipes

A few researchers have an entirely different vision for delivering monoclonal antibodies. Rather than manufacturing these antibodies in a lab and delivering them into the body pre-assembled, some are developing platforms for synthesizing antibodies in the body itself.

Kar Muthumani, chief scientific officer of the biopharmaceutical company GeneOne Life Science, believes that DNA- or RNA-based antibody synthesis could be particularly advantageous in the fight against infectious diseases. When Muthumani witnessed the outbreak of Chikungunya virus in India beginning in 2004, he realized that even if a vaccine was developed, it couldn’t work quickly enough to protect people who had already been exposed. Muthumani understood that to curb these sorts of outbreaks, health officials needed a treatment that imparted immunity within days and could be administered in a low-resource setting. 

Muthumani and colleagues are working on a synthetic nucleic acid-based delivery platform for monoclonal antibodies. Using an intramuscular injection of DNA, mRNA, or a viral vector, the platform gives the body the genetic instructions for creating a monoclonal antibody. The muscles then become a living “antibody factory,” eventually circulating the therapeutic antibodies throughout the bloodstream.

This platform is basically a way of producing monoclonal antibodies by your body itself.
- Kar Muthumani, GeneOne Life Science

“This platform is basically a way of producing monoclonal antibodies by your body itself,” explained Muthumani. He tested a DNA-based delivery system for monoclonal antibodies against Zika virus in a mouse model and found that those antibodies protected against the virus within days (8). He also found success using a similar DNA delivery technique to treat HER2+ breast cancer in mice (9). 

Muthumani is particularly interested in DNA-based techniques for monoclonal antibody synthesis as they don’t require cold chain storage, making them most accessible for managing infectious diseases in low-resource settings. The company is developing the platform in tandem with a handheld intramuscular injector device called GeneDerm that allows for easy delivery of the genetic material (10). Muthumani said that the team still needs to translate the work into larger animal models and humans, but he’s optimistic about what a genetic delivery platform represents for the future of monoclonal antibodies.

In a 2018 study, researchers found that the average price for a year of monoclonal antibody treatment was $96,731 (11). While high prices stem from myriad factors, the World Health Organization (WHO) reported that immense manufacturing costs are a major driver of the price for monoclonal antibodies, and high prices prevent these life-saving drugs from being fully utilized in developing countries (12). While the research is still in its early stages, genetic delivery platforms for monoclonal antibodies could usher in a future where antibody drugs are cheaper and more accessible.

This evolving field holds the potential to fulfill Ehrlich's vision by making monoclonal antibodies not only precise but also more broadly available. As these technologies advance, the way doctors and researchers administer antibody treatments could shift dramatically, opening the door to more accessible care and broadening the effect of these critical therapies.

References

1. Pitiot, A. et al. Alternative Routes of Administration for Therapeutic Antibodies—State of the Art. Antibodies  11, 56 (2022).
2. Antibody Society. Antibody therapeutics approved or in regulatory review in the EU or US. (2024). 
3. Australian Institute for Bioengineering and Nanotechnology. What are biologics? The University of Queensland (2019).
4. St-Amour, I. et al. Brain Bioavailability of Human Intravenous Immunoglobulin and its Transport through the Murine Blood–Brain Barrier. Journal of Cerebral Blood Flow & Metabolism  33, 1983-1992 (2013).
5. National Institute on Drug Abuse. Drug Overdose Death Rates. National Institutes of Health (2021).
6. Bremer, P.T. et al. Investigation of monoclonal antibody CSX-1004 for fentanyl overdose. Nat Commun  14, 7700 (2023).
7. Correa, D. et al. Intranasal delivery of full-length anti-Nogo-A antibody: A potential alternative route for therapeutic antibodies to central nervous system targets. PNAS  120, e2200057120 (2023).
8. Choi, H. et al. Synthetic nucleic acid antibody prophylaxis confers rapid and durable protective immunity against Zika virus challenge. Hum Vaccin Immunother  16, 907–918 (2020).
9. Perales-Puchalt, A. et al. DNA-encoded bispecific T cell engagers and antibodies present long-term antitumor activity. JCI Insight  4, e126086 (2019). 
10. Lallow, E.O. et al.  Novel suction-based in vivo cutaneous DNA transfection platform. Sci Adv  7, eabj0611 (2021).
11. Hernandez, I. et al. Pricing of monoclonal antibody therapies: higher if used for cancer? Am J Manag Care  24, 109-112 (2018).
12. World Health Organization. Call for consultant on monoclonal antibodies for infectious diseases. (2021).