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

As the pandemic raged, monoclonal antibodies suddenly gained notoriety when these lab-made proteins were found to reduce the risk of COVID hospitalization in vulnerable and immunocompromised people. Now researchers are investigating whether these kinds of proteins could also be an effective treatment for a variety of chronic pain conditions: low back pain, osteoarthritis pain, neuropathic pain (such as diabetic peripheral neuropathy), rheumatoid arthritis and cancer pain.

The Food and Drug Administration has already approved four monoclonal antibodies (mAb) to prevent and treat painful chronic migraine attacks. Last year, the FDA approved the use of a mAb (an injection of frunevetmab) to treat osteoarthritic pain in cats; similar drugs are in the works for humans. 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 target different forms of chronic pain,” said Charles Argoff, a 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’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, this is one of the reasons many people turn to opioids, which carry a high risk of dependence or abuse. According to the Centers for Disease Control and Prevention, opioid overdose deaths have increased by nearly 15 percent from 2020 to 2021 alone. In an aggressive effort to halt the opioid crisis, in 2018 the National Institutes of Health launched the HEAL (short for: Helping to End Addiction Long-term) initiative, which funds a broad range 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 that target abnormal pain signals that are at the root of 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 NIH grant 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,” says Yarov-Yarovoy. While research is still in its early stages, the Yarov-Yarovoy team is starting preliminary experiments with a mAb prototype targeting chronic pain and hoping to be ready for clinical trials later this year.

A versatile technology

The reason why mAbs can be used for many different purposes is that they all have a very specific purpose. During the pandemic, monoclonal antibodies were used to block the protein on the COVID-19 virus that allowed it to attach to human cells. Similarly, researchers believe they can design mAbs that can bind to receptors involved in pain transmission, blocking the signals.

Yarov-Yarovoy’s goal is to make monoclonal antibodies that target specific ion channels on the surface of nerve cells that receive signals triggered by painful stimuli; essentially shutting down the transmission of chronic pain that occurs with various medical conditions.

“In terms of chronic pain, we have to figure something out because it’s hard to treat and there aren’t many good options,” says Ryan Marino, a medical toxicologist and addiction medicine specialist at Case Western Reserve University in Cleveland. . “Opioids lose their effectiveness for many people with prolonged use and there is a potential for dependence. Even if you take them as directed, you will have to take higher and higher doses to get pain relief.”

The advantages of mAbs over opioids

Opioids can lead to abuse, addiction (a state in which a person cannot control their use of the drug even if they experience harmful effects), or dependence (a state in which a person builds a tolerance to the drug or a drug need). certain dose to avoid withdrawal symptoms). These medications can also cause potentially life-threatening side effects, such as difficulty breathing. But that’s not the case when using mAbs for chronic pain.

“That may be because these large molecules don’t reach the parts of the brain 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 “excellent target selectivity and thus less toxicity,” as researchers noted in the journal Clinical medicine.

In addition, the effects of mAbs last longer than those of opioids and non-steroidal anti-inflammatory drugs (NSAIDs). Once injected under the skin, mAbs can circulate in the bloodstream for more than a month before finally being broken down and excreted in the urine, experts say. Consequently, the circulating antibodies are expected to provide long-lasting pain relief for weeks, not just hours or days.

Unlike previous generations of mAbs, those in development for chronic pain are designed for self-administration and home use; no drip is needed in a medical facility as with COVID-19. And “you don’t have to worry about people becoming dependent on them or losing their effectiveness,” adds Marino.

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. (Although at least nine voltage-gated sodium channels have been identified in the nervous system, these three are closely associated with pain.)

In chronic pain, these sodium channels transmit signals that lead to more pain, Yarov-Yarovoy explains. He thinks that by making antibodies that fit into each of these sodium channels, like a pin in a hole, these mAb proteins will block the transmission of pain signals without interfering with other messages sent by the same nerve cells.

The researchers use software programs to design complex virtual models of antibody proteins and analyze which ones best match each of these three sodium channels. After identifying promising proteins, they will make them in the lab and test them on neural tissue.

New perspectives on chronic pain

In recent years, the FDA has 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 dilate and cause inflammation, amplifying and perpetuating headache pain. The CGRP monoclonal antibodies block the binding of these peptides 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 an overwhelming win. Clinically, “we don’t see most people having 100 percent relief with CGRPs for [chronic] migraines,” says Argoff. In fact, a study in The diary of headaches and pain found that when people with chronic migraines took anti-CGRP monoclonal antibodies, about 61 percent of them saw the number of migraine days reduced by at least half. In other words, the mAb helped, but it was not a cure. Still, these drugs provide many people with chronic migraines with more relief than they’ve achieved with other treatments.

A monoclonal antibody called tanezumab (which targets a protein called nerve growth factor that is elevated in patients with various types of pain) was being tested as a treatment for chronic low back pain at 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 of the people who received 10 milligrams of tanezumab every eight weeks for their chronic low back pain, nearly half had reduced their pain levels by at least 50 percent and increased their ability to exercise after 16 weeks.

“There is a critical unmet need for safer, more effective therapies to treat chronic pain,” said Markman, one of the study’s co-authors. “Drugs like these that can improve function related to pain relief are particularly attractive. That’s what we’re looking for – both things. There’s only one other drug: an SNRI [serotonin and norepinephrine reuptake inhibitor] antidepressant – which has consistently reduced this type of lower back pain.

Unfortunately, the tanezumab study also found that 2.6 percent of people who received the 10-milligram dose of the drug experienced an acceleration of osteoarthritis. Therefore, the drug was not approved by the FDA. Eli Lilly and Pfizer pulled the plug on clinical development.

The future of pain management

Despite the tanezumab setback, experts are optimistic that other mAbs can be developed to target various forms of chronic pain. Ultimately, 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), says Yarov-Yarovoy.

“It’s unlikely from what we know that a single target will be found that will allow us to dramatically dampen the pain experience — by 50 to 100 percent — without side effects,” says Argoff. The better we understand the molecules involved in pain transmission, “the more likely we are to find monoclonal antibodies that target specific types of chronic pain.”

In other words, there probably isn’t a one-size-fits-all monoclonal antibody for different types of chronic pain. Part of the challenge is that “when someone 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 get one of the dominoes out of the chain, you can have success in managing pain.”

With arthritic conditions, neuropathic pain, and fibromyalgia, “there are several dominoes that cause pain,” adds Fink. “If you can pick the right dominoes, mAbs are very good at hitting specific targets. The question is: where else do these molecules have an influence 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. At the moment, the enthusiasm is ahead of the science, but the approach remains promising. “The coolest thing about monoclonal antibodies is that you can design them for pretty much any target — if one target doesn’t work, there are plenty of others to look for,” says Marino. “Chronic pain is a very big problem. This is definitely something we should all get behind and support.”

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