As the pandemic raged, monoclonal antibodies gained sudden prominence when these laboratory-made proteins were found to reduce the risk of hospitalization from COVID in vulnerable and immunocompromised people. Now researchers are investigating whether these types of proteins might also be an effective treatment for a variety of chronic pain conditions: low back pain, pain from osteoarthritis, neuropathic pain (such as diabetic peripheral neuropathy), rheumatoid arthritis, and cancer pain.
Already, the Food and Drug Administration has approved four monoclonal antibodies (mAb) to prevent and treat painful chronic migraine attacks. Last year, the FDA approved use of an mAb (an injection of frunevetmab) to treat osteoarthritic pain in cats; similar drugs are in the works for people. And clinical trials for other mAbs for chronic pain are expected to begin later in 2023.
“The hope is that as we learn more about specific pain mechanisms, we can develop monoclonal antibodies that would target different forms of chronic pain,” says Charles Argoff, a professor of neurology and director of the Comprehensive Pain Center at the Albany Medical Center in New York. “But we’re not there yet and I don’t think it’s going to happen tomorrow.”
Chronic pain is one of the most common conditions in the U.S., affecting 50.2 million people—or 20.5 percent of the adult population—according to a study published last year in the journal Pain. Chronic pain takes a significant toll on physical and emotional health, and overall quality of life. With little prospect of long-term relief, it is one reason many people turn to opioids, which carry a high risk for dependence or abuse. Overdose deaths from opioids increased by nearly 15 percent from 2020 to 2021 alone, according to the Centers for Disease Control and Prevention. In an aggressive effort to stem the opioid crisis, the National Institutes of Health in 2018 launched the HEAL Initiative (short for: Helping to End Addiction Long-term), which funds a wide array of research into preventing opioid addiction and developing safer, effective non-opioid pain treatments.
“In my lab, our idea was: Can we develop, optimize and design antibodies targeting abnormal pain signals that are the cause of chronic pain?” explains Vladimir Yarov-Yarovoy, a researcher who specializes in computational and structural biology at University of California, Davis. He and fellow researcher James Trimmer received an NIH grant of $1.5 million as part of the HEAL initiative. “In the case of chronic pain, those pain signals in the peripheral nervous system are abnormal and need to be silenced,” Yarov-Yarovoy says. While the research is still in the early stages, Yarov-Yarovoy’s team is beginning preliminary experiments with a mAb prototype targeting chronic pain and hoping they will be ready for clinical trials in the next few years.
A versatile technology
The reason mAbs can be used for many different purposes is that each one has a highly specific target. During the pandemic, monoclonal antibodies were used to block the protein on the COVID-19 virus that enabled it to attach to human cells. Similarly, researchers believe they can design mAbs that can bind to receptors involved in pain transmission, thus blocking the signals.
Yarov-Yarovoy’s goal is to create monoclonal antibodies that target specific ion channels on the surface of nerve cells that receive signals caused by painful stimuli; essentially shutting off the transmission of chronic pain that occurs in a variety of medical conditions.
“In terms of chronic pain, we’ve got to figure something out because it’s difficult to treat and there aren’t a lot of great options,” says Ryan Marino, a medical toxicologist and addiction medicine specialist at Case Western Reserve University in Cleveland. “Opioids lose their effectiveness with long-term use for a lot of people, and there’s a potential for dependency to develop. Even if you’re taking them as prescribed, you will have to take higher and higher doses to get pain relief.”
The advantages of mAbs compared to opioids
Opioids carry a potential for abuse, addiction (a state in which a person can’t control their use of the drug even when experiencing harmful consequences), or dependency (a condition in which a person builds up a tolerance to the drug or needs a certain dose to prevent withdrawal symptoms). These drugs can also cause potentially life-threatening side effects such as respiratory distress. But that isn’t the case when using mAbs for chronic pain.
“That may be because these large molecules are not reaching the parts of the brain that are associated with reward,” says John Markman, a neurologist and director of the Translational Pain Research Program at the University of Rochester Medical Center in New York.
In addition, mAbs have “exquisite target selectivity and hence less toxicity,” as researchers noted in the journal Clinical Medicine.
What’s more, the effects of mAbs last longer than opioids and non-steroidal anti-inflammatory drugs (NSAIDs). Once they are injected under the skin, mAbs can circulate in the bloodstream for more than a month before they are eventually broken down and excreted in urine, experts say. Consequently, the expectation is that the circulating antibodies could provide sustained pain relief for weeks, not just hours or days.
Unlike previous generations of mAbs, the ones in development for chronic pain are designed for self-administration and home use; there’s no need for an infusion at a medical facility as there is for COVID-19. And “you don’t have to worry about people becoming dependent on them or that they’ll lose their effectiveness,” Marino adds.
Using artificial intelligence to design mAbs
To treat chronic pain, the UC Davis team is currently developing mAbs that target three specific tunnel-shaped proteins on the nerve cells called voltage-gated sodium channels—Nav1.7, Nav1.8, and Nav1.9—and prevent them from transmitting pain signals. (While at least nine voltage-gated sodium channels have been identified in the nervous system, these three are closely associated with pain.)
With chronic pain, these sodium channels transmit signals that lead to increased pain, explains Yarov-Yarovoy. He thinks that by creating antibodies that fit into each of these sodium channels, like a peg in a hole, these mAb proteins will block the transmission of pain signals without interfering with other messages sent through the same nerve cells.
The researchers are using software programs to design complex virtual models of antibody proteins and analyze which ones will best fit each of these three sodium channels. After identifying promising proteins, they will manufacture them in the lab and test them on neural tissue.
New perspectives on chronic pain
In recent years, the FDA approved four monoclonal antibodies to prevent and treat chronic migraine attacks: This class of drugs targets proteins called calcitonin gene-related peptides (CGRPs), which are released during a migraine and cause blood vessels to expand and trigger inflammation, thereby amplifying and perpetuating headache pain. The CGRP monoclonal antibodies block these peptides from binding to their targets.
While this has been one of the biggest success stories so far when it comes to the use of mAbs for chronic pain, it’s not a slam-dunk victory. Clinically, “we don’t see most people having 100 percent relief with CGRPs for [chronic] migraine,” says Argoff. In fact, a study in The Journal of Headache and Pain found that when people with chronic migraine used anti-CGRP monoclonal antibodies, approximately 61 percent of them saw the number of migraine days reduced by at least half. In other words, the mAb helped, but it wasn’t a cure. Even so, these drugs are providing many people with chronic migraine with greater relief than they have gained with other treatments.
A monoclonal antibody called tanezumab (which targets a protein called nerve growth factor that is elevated in patients with various forms of pain) was tested as a treatment for chronic low back pain in 191 sites in eight countries in North America, Europe, and Asia. The phase 3 study, published in a 2020 issue of the journal Pain, found that among people who received 10 milligrams of tanezumab every eight weeks for their chronic low back pain almost half had at least a 50 percent reduction in their pain level and gained greater movement abilities at 16 weeks.
“There’s a critical unmet need for safer, more effective therapies to treat chronic pain,” says Markman, one of the study’s coauthors. “Drugs like this that can improve function related to pain relief are particularly attractive. That’s what we’re looking for—both of those things. There’s only one other drug—an SNRI [serotonin and norepinephrine reuptake inhibitor] antidepressant—that has consistently reduced this type of low back pain.”
Unfortunately, the tanezumab study also found that 2.6 percent of the people who received the 10 milligram dose of the drug experienced an acceleration of osteoarthritis. That’s why the drug wasn’t approved by the FDA. Eli Lilly and Pfizer pulled the plug on its clinical development.
The future of pain relief
Despite the tanezumab setback, experts are optimistic that other mAbs can be developed to target various forms of chronic pain. Eventually, the hope is that mAbs can be created to treat neuropathic pain (such as peripheral neuropathy and diabetic neuropathy) and inflammatory pain (due to arthritis, chronic low back pain, and autoimmune diseases), Yarov-Yarovoy says.
“It’s unlikely with what we know that a single target will be found that will allow us to dampen the pain experience dramatically—by 50 to 100 percent—without side effects,” Argoff says. The better we understand the molecules involved in pain transmission, “the more likely it is that we’ll be able to find monoclonal antibodies that target specific types of chronic pain.”
In other words, there isn’t likely to be a one-size-fits-all monoclonal antibody for different types of chronic pain. Part of the challenge is that “when somebody experiences pain, it’s a very complicated cascade of events,” explains Ezekiel Fink, a neurologist and pain specialist and medical director of pain management at Houston Methodist Hospital. “If you can take one of the dominos out of the chain, you can have success in managing pain.”
With arthritic conditions, neuropathic pain, and fibromyalgia, “there are different dominos that line up to cause pain,” Fink adds. “If you can pick out the right domino, mAbs are very good at hitting specific targets. The question is: Where else are these molecules having an impact and what are the consequences? In terms of options for chronic pain, the juice has to be worth the squeeze.”
With the benefit of time and further research, experts hope that more effective, safer mAbs will be developed to target specific forms of chronic pain. Right now, the enthusiasm is ahead of the science, but the approach continues to hold considerable promise. “The coolest thing about monoclonal antibodies is you can design them for essentially any target—if one target doesn’t work, there are plenty of others to look for,” Marino says. “Chronic pain is a really big issue. This is definitely something we should all get behind and support.”