Could monoclonal antibodies be a solution to chronic pain — and to the opioid crisis?

With the outbreak of the pandemic, monoclonal antibodies gained sudden importance when these lab-made proteins were found to reduce the risk of hospitalization from the new coronavirus in vulnerable and immunocompromised people. Now researchers are studying whether these types of proteins It may also be an effective treatment for a variety of chronic pain Conditions: Low back pain, pain from osteoarthritis, nerve pain (such as diabetic peripheral neuropathy), rheumatoid arthritis, and cancer pain.

Already, the FDA has approved four monoclonal antibodies (mAb) Prevention and treatment of chronic painful migraine attacks. last year, The US Food and Drug Administration has approved the use of this mAb (An injection of frunevetmab) for the treatment of osteoarthritis pain in cats. Similar drugs are in the works for people. Clinical trials of other mAbs for chronic pain are expected to begin later in 2023.

says Charles Argov, MD, professor of neurology and director of the Comprehensive Pain Center at Albany Medical Center in New York. “But we’re not there yet and I don’t think it will be tomorrow.”

Chronic pain is one of the most common conditions in the United States, 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 greatly affects physical and emotional health and the overall quality of life. With little potential for long-term relief, this is one reason many people turn to opioids, which carry a high risk of dependence or abuse. Opioid overdose deaths increased by approx 15 percent from 2020 to 2021 aloneaccording to Centers for Disease Control and Prevention. In a desperate effort to stem the opioid crisis, the National Institutes of Health launched in 2018 HEAL initiative (For short: Helping End Addiction Long-Term), which funds a broad range of research into opioid addiction prevention and the development of safer and more effective non-opioid pain therapies.

“In my lab, our idea was: Can we develop, improve and design antibodies that target the abnormal pain signals that cause chronic pain?” explains Vladimir Yarov-Yarovoy, a researcher specializing in computational and structural biology at the University of California, Davis. He and fellow researcher James Trimmer received a $1.5 million grant from the National Institutes of Health as part of the HEAL initiative. “In the case of chronic pain, pain signals in the peripheral nervous system are abnormal and must be silenced,” says Yarov Yarovoy. While the research is still in its infancy, Yarov-Yarovoy’s team is beginning preliminary trials on a prototype mAb targeting chronic pain and hopes to have it ready for clinical trials later this year.

Versatile technology

The reason mAbs can be used for so many different purposes is that they each have a very specific goal. During the pandemic, monoclonal antibodies have been used to block a protein on the COVID-19 virus that enabled it to bind to human cells. Similarly, the researchers believe they can design mAbs that can bind to receptors involved in pain transmission, thereby blocking the signals.

The Yarov-Yarovoy goal is to create monoclonal antibodies that target specific ion channels on the surface of neurons that receive Signals triggered by painful stimuli; Essentially stopping the transmission of chronic pain that occurs in a variety of medical conditions.

“In terms of chronic pain, we have to understand something because it’s so hard to treat and there aren’t a lot of great options,” says Ryan Marino, MD, a clinical toxicologist and addiction medicine specialist at Case Western Reserve University in Cleveland. . “Opiates lose potency with long-term use for many people, and there is a potential for developing dependence on them. Even if you take them as prescribed, you will have to take higher and higher doses for pain relief.”

Advantages of mAbs compared to opioids

Opioids carry the potential for misuse, addiction (a condition in which a person cannot control their drug use even when experiencing harmful consequences), or dependency (a condition in which a person tolerates the drug or needs a certain dose for prevention Withdrawal symptoms). These medications can also cause potentially life-threatening side effects such as respiratory distress. But this is not the case when mAbs are used for chronic pain.

“It may be because these large molecules don’t get to the parts of the brain that are associated with reward,” says John Markman, MD, a neurologist and director of the Translational Pain Research Program at the University of Rochester Medical Center in New York.

In addition, mAbs have “remarkable target selectivity and thus lower toxicity,” note the researchers at the magazine Clinical medicine.

What’s more, the effects of mAbs are longer-lasting than opioid drugs and non-steroidal anti-inflammatory drugs (NSAIDs). Once injected under the skin, experts say, it can circulate in the bloodstream for more than a month before finally breaking down and excreted in the urine. Thus, the expectation is that circulating antibodies can provide sustained pain relief for weeks, not just hours or days.

Unlike previous generations of mAbs, those being developed for chronic pain are designed for self-administration and home use; There is no need to inject in a medical facility as there is for COVID-19. “You don’t have to worry about people becoming dependent on them or that they will 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 tunneling proteins on neurons called voltage-gated sodium channels — Nav1.7, Nav1.8, and Nav1.9 — and block them from sending pain signals. (While there were at least nine voltage-gated sodium channels identified in the nervous systemThese three are closely related to pain.)

Yarov-Yarovoy explains that in chronic pain, sodium channels transmit signals that lead to an increase in pain. 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 use software to design complex virtual models of antibody proteins and analyze which ones fit into each of these three sodium channels. After identifying the most promising proteins, they will synthesize them in the lab and test them on nerve tissue.

New horizons for chronic pain

In recent years, the Food and Drug Administration has approved four monoclonal antibodies for the prevention and treatment of chronic migraine attacks: this A class of drugs that target proteins called gene-related peptides (CGRPs)., which are released during a migraine and cause blood vessels to dilate and stimulate inflammation, amplifying and perpetuating headache pain. CGRP monoclonal antibodies prevent these peptides from binding to their targets.

While this has been one of the biggest success stories to date when it comes to using mAbs for chronic pain, it’s not a great victory. Clinically, “we don’t see that most people are 100 percent comfortable using CGRPs for [chronic] Argov says. Indeed, A.J The study in Journal of Headache and Pain It was found that when people with chronic migraines used an anti-CGRP monoclonal antibody, approximately 61 percent saw the number of migraine days cut by at least half. In other words, the mAb helped, but it wasn’t a cure. However, these medications provide more relief for many people with chronic migraines than other treatments.

A monoclonal antibody called tanizumab (which targets a protein called nerve growth factor that is elevated in patients with various forms of pain) has been tested as a treatment for chronic low back pain at 191 sites in eight countries in North America, Europe and Asia. the Phase III study, published in the 2020 issue of the journal PainAnd It found that among people who received 10 milligrams of tanizumab every eight weeks for chronic low back pain, nearly half had at least a 50 percent decrease in pain and gained greater motor abilities at week 16.

“There is a critical, unmet need for safer and more effective therapies for chronic pain,” says Markman, one of the study’s co-authors. Such drugs, which can improve function associated with analgesia, are particularly attractive. That’s what we’re looking for – both of those things. There is only one other drug – SNRI [serotonin and norepinephrine reuptake inhibitor] Antidepressants – which have consistently reduced this type of lower back pain. “

Unfortunately, the tanizumab study also found that 2.6 percent of people who received a 10-milligram dose of the drug experienced accelerated osteoporosis. for this reason The drug has not been approved by the Food and Drug Administration. Eli Lilly and Pfizer have discontinued its clinical development.

The future of pain relief

Despite tanizumab’s setback, experts are optimistic that other mAbs can be developed to target different forms of chronic pain. The hope, Yarov Yarovoy says, is ultimately for mAbs to be created to treat nerve pain (such as peripheral neuropathy and diabetic neuropathy) and inflammatory pain (due to arthritis, chronic low back pain, and autoimmune diseases).

“It is unlikely with what we know that a single target will ever be found that will allow us to significantly reduce the experience of pain — by 50 to 100 percent — without side effects,” says Argov. The better we understand the molecules involved in pain transmission, “the more likely we will be able to find monoclonal antibodies that target specific types of chronic pain.”

In other words, there is not likely to be a one-size-fits-all monoclonal antibody for different types of chronic pain. Part of the challenge is that “when someone has pain, it’s a very complex chain of events,” explains Ezequiel Fink, a neurologist and pain specialist and medical director of pain management at Houston Methodist Hospital. “If you can pull one of the dominos off the chain, you can have success with pain management.”

With conditions like arthritis, nerve pain, and fibromyalgia, “there are different dominoes that line up to cause pain,” Fink adds. “If you can pick the right domino, mAbs are very good at hitting specific targets. The question is: where else do these molecules have an effect and what are the consequences? In terms of options for chronic pain, the juice should be worth squeezing.”

With the benefit of time and more research, experts hope to develop more effective and safer mAbs to target specific forms of chronic pain. For now, the enthusiasm is ahead of the science, but the approach still holds great promise. “The coolest thing about monoclonal antibodies is that you can design them for basically any target — if one target doesn’t work, there are lots of other things to look for,” says Marino. “Chronic pain is a really big problem. This is definitely something we should all support.”