The new approach paves the way for a better understanding of prolactin in female-predominant conditions, including migraine and pain disorders. But targeting prolactin as a potential treatment approach in people faces significant challenges.
Women are at greater risk of experiencing many pain conditions, such as fibromyalgia and temporomandibular disorders, as well as migraine, which is approximately three times more frequent in women than in men. In recent years, research has pointed to the hormone prolactin as one potential mediator of these sex differences. Now, the development of new anti-prolactin antibodies sets the stage for a better understanding of prolactin’s contribution to migraine and other female-predominant disorders.
Researchers led by Pierre Rivière, from the biopharmaceutical company Peptide Logic, San Diego, US, have developed a humanized monoclonal antibody that effectively and selectively neutralizes prolactin. In a stress-related pain model, the antibody prevented pain behaviors in female mice expressing the human version of the hormone. However, it remains uncertain if an anti-prolactin antibody approach to treat migraine will be feasible in people.
“There’s been a fair amount of work that has been done in the last decade to try to better understand why migraine affects women more often than it does men. The authors show convincing efficacy and good pharmacokinetics for their prolactin antibody. This creates a really good opportunity to better understand prolactin in migraine,” said Ted Price, University of Texas at Dallas, US, who was not involved in the research.
Amynah Pradhan, Washington University School of Medicine in St. Louis, US, who was also not part of the study, said the research is important because it emphasizes the important role of sex as a biological variable in migraine.
“This is a really important movement, as in the past, preclinical studies were predominantly performed in males, and newer studies like this clearly show males and females regulate pain and migraine differently,” she told Migraine Science Collaborative via email.
The research appeared online on September 12, 2023, in the journal mAbs.
The link between prolactin and migraine
Prolactin is involved with lactation and breast development, and has broader roles in metabolism and the immune system. It has also emerged as a key factor in promoting headache in women.
“There are several papers, mostly from my colleague Greg Dussor, showing a very clear role of prolactin causing headache in women, and in certain populations like people who have hyperprolactinemia [higher than normal levels of prolactin]. It’s clearly a hormone that’s linked to the headache,” Price said.
A recent study from the Dussor lab found an important role for prolactin in a preclinical migraine model via its interactions with calcitonin gene-related peptide (CGRP), another peptide that is well known for its role in migraine, in meningeal nociceptors.
Together, “This [earlier] research identifies prolactin and its receptor as important therapeutic targets for migraine,” said Pradhan.
However, Price said it’s been difficult to modulate prolactin signaling in research studies – efforts have focused on the receptor for prolactin – which has hindered scientists’ abilities to probe its role in migraine more deeply.
“It’s been hard to make antagonists of the prolactin receptor. There are some peptide inhibitors that are okay, but they don’t have very good pharmacokinetics, so they’re tough to use for in vivo studies,” according to Price. Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of a drug by the body.
A selective antibody eases pain
In their paper, the authors (who did not respond to requests for an interview) pointed to the challenges of working with prolactin receptor antagonists. To overcome these hurdles, the researchers developed and characterized two new antibodies targeting human prolactin. The paper reports how the antibodies were developed, their pharmacokinetic properties, and also tested the efficacy of one of the antibodies in an animal model of pain in female mice.
Both antibodies had good affinity for human prolactin. And, they completely inhibited human prolactin signaling at the human prolactin receptor.
Importantly, the antibodies were selective for human prolactin, meaning that they did not neutralize other agonists that act at the prolactin receptor, but rather only prolactin itself.
The authors also showed that one of the antibodies reduced stress-related pain in female mice. Here, they generated a new strain of mice that express the human version of prolactin instead of the mouse version, with the goal of creating a more translationally relevant model.
The team used a restraint stress model, where the mice are placed in individual plastic restrainers, which inhibits the animals’ movement. As expected, this stress caused allodynia in the hindpaw of female mice. However, subcutaneous injection of the prolactin antibody completely blocked the allodynia.
Pradhan said this is good early evidence that the prolactin antibody is effective at blocking allodynia in mice, but more work is needed to understand the effects of the antibody in the context of migraine.
“Future studies would be to test this antibody in more migraine-specific/cephalic pain models, such as the priming or “two-hit” models, the nitroglycerin model of chronic migraine, as well as electrophysiological models such as cortical spreading depolarization,” said Pradhan.
Is prolactin a good therapeutic target?
One challenge for potential use of a prolactin antibody to treat migraine or pain in people is prolactin’s many roles in normal physiology.
“Antibody-based approaches are effective in migraine, for example those that target CGRP. However, time will tell whether prolactin antibodies will also be effective. But considering the high expression of prolactin receptor in the body, it would be important to understand what chronic blockage of prolactin will do to normal physiological functioning,” Pradhan said.
If targeting prolactin were to succeed, that would contribute to the needed growth of different ways to treat migraine, according to Pradhan.
“Migraine is very heterogeneous and likely mediated by many different mechanisms. Existing therapies are effective but there are still many patients who are partial or non-responders. The more mechanistically distinct migraine therapies we have, the better it will be for patients,” said Pradhan.
Price was more pessimistic about the chances of therapeutic success with prolactin antibodies and doubts whether prolactin will be the best target for migraine therapeutics.
“There’s a very clear association of prolactin with very important aspects of reproductive health. This raises the question of whether women would voluntarily take medications that interfere with prolactin signaling,” Price said.
But Price said he’d love to be proven wrong.
“If clinical testing of the antibody did show it to be efficacious in treating migraine, some people would choose to take it. It would be a breakthrough therapy.”
New tools for understanding prolactin’s role in migraine
Price said his concerns about the therapeutic viability of prolactin antibodies don’t reduce his enthusiasm for the paper.
“The reason I like this paper a lot is because it developed the tools we need to dive much deeper into the prolactin story. The exciting thing is we can understand what’s downstream of prolactin because I feel that’s where we’re likely to get better therapeutic ideas,” he said.
In particular, the mice expressing human prolactin will be a very useful tool for better understanding the role of prolactin in migraine, and for investigating other therapeutics with good translational value.
“For example, it’s still not well understood why prolactin signaling affects migraine in women more than men. As shown by the Dussor lab, it appears to involve a neuro-immune circuit, but the tools in this study can help us dissect further how CGRP and prolactin interact in more detail. We can look in the dura, in nociceptors, and other cell types like immune cells. This is going to be very important for getting deeper into the underlying mechanisms of migraine and to develop more precision-type therapeutics,” Price said.
Fred Schwaller, PhD, is a freelance science writer based in Germany. Follow him on Twitter @SchwallerFred
Discovery and characterization of prolactin neutralizing monoclonal antibodies for the treatment of female-prevalent pain disorders.
Maciuba et al.
MAbs. 2023 Jan-Dec;15(1):2254676.
Image credit: ID 120033256 © Stanislav Rykunov | Dreamstime.com
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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