Scientists are testing an innovative antibody designed to target cell adhesion molecule 1 and reduce pain-related nerve signaling.
Cell surface proteins are vital components that enable cells to communicate effectively and detect changes in their surroundings. By responding to external cues, these proteins can regulate various internal cellular processes, rendering them attractive candidates for therapeutic applications aimed at treating a range of diseases.
Cell Adhesion Molecule 1 (CADM1) is a widely expressed protein, found in a variety of cell types such as neurons, respiratory and endometrial epithelial cells, and mast cells. A significant breakthrough has been made with the discovery of the 3E1 antibody, which selectively targets the extracellular domain of CADM1, holding great promise for delivering targeted therapies to CADM1-expressing cells.
Notably, CADM1 is highly expressed in peripheral nerves and is distributed throughout the neurites, prompting the question of whether anti-CADM1 antibodies can influence nerve function and biological activity.
Investigating the Consequences of Anti-CADM1 Antibody Binding:
Researchers Professor Akihiko Ito and Dr. Fuka Takeuchi from Kindai University Faculty of Medicine's Department of Pathology in Japan undertook a study to address this crucial question. Their investigation into the effects of anti-CADM1 antibodies on neuronal activity has yielded valuable insights, now published in the journal Life Sciences.
Researchers injected the anti-CADM1 antibody 3E1 under the skin of mice to examine its distribution on nerve fibers. Using immunohistochemical and immunofluorescence techniques, they found that the 3E1 antibody selectively bound to peripheral nerves located in the dermal layer.
We speculated that the accumulation of 3E1 might reduce neuronal sensitivity, potentially producing an analgesic effect, by altering CADM1 expression on nerve fibers. CADM1's role in recruiting neuronal receptors to the plasma membrane supported this hypothesis. However, surprisingly, our research revealed a significant knowledge gap, as no previous studies have explored the development of drugs targeting CADM1 inhibition in nerves.Akihiko Ito, Professor, Faculty of Medicine's Department of Pathology, Kindai University, Japan
According to Professor Ito, the study's lead author, "We speculated that the accumulation of 3E1 might reduce neuronal sensitivity, potentially producing an analgesic effect, by altering CADM1 expression on nerve fibers. CADM1's role in recruiting neuronal receptors to the plasma membrane supported this hypothesis. However, surprisingly, our research revealed a significant knowledge gap, as no previous studies have explored the development of drugs targeting CADM1 inhibition in nerves."
The analgesic effects of 3E1 were evaluated using a formalin-induced pain test and behavioral analysis via video recordings at 6, 12, and 24 hours after injection. The results demonstrated that mice administered 3E1 displayed reduced pain-related behaviors compared to controls, with the analgesic effects sustained for up to 24 hours. This prolonged duration of pain relief surpasses that of levobupivacaine, a local anesthetic with a typical duration of 5-8 hours.
To further elucidate the effects of 3E1 on neuronal stimulation, researchers conducted experiments using primary cultures of mouse dorsal root ganglion cells. Through live cell imaging, they observed that 3E1 selectively targeted the neurites. Moreover, protein analysis showed that 3E1 bound to CADM1, leading to a decrease in CADM1 expression. Additionally, the team employed a femtosecond laser pulse to induce mechanical stimulation, visualizing neuronal activity through calcium fluorescence (Fluo-8). Notably, the results revealed that neural transmission was significantly impaired in cells treated with 3E1.
A significant finding in this study was the absence of paralysis or behavioral abnormalities in the mice treated with 3E1, suggesting a selective action on sensory nerves while sparing motor nerves.
Breaking the Pain Barrier: The 3E1 Safer Alternative
The emergence of 3E1 marks a significant breakthrough in pain management, particularly in the context of osteoarthritis and chronic pain. Despite a decade of research, efforts to develop effective antibody treatments have been hindered by limited success. Antibodies targeting nerve growth factor (NGF), such as tanezumab, fasinumab, and fulranumab, showed initial promise but were ultimately plagued by severe side effects, including ischemia and tissue necrosis. In contrast, 3E1 offers a novel, safer, and more effective pain-relieving strategy, with fewer drawbacks and greater therapeutic potential.
The distinctive ability of antibody 3E1 to cluster CADM1 on the cell surface is a key factor in its effectiveness. Remarkably, just one dose of 3E1 can deliver lasting pain relief, often for 24 hours or longer, all without causing debilitating motor paralysis or toxic side effects.
Building on the importance of their discovery, Professor Ito expressed his excitement, noting that the identification of an antibody that accumulates in nerves and produces pain relief after injection has the potential to launch a new area of research focused on "antibody anesthetics."
According to Professor Ito, this study stands out because it highlights adhesion molecules as promising new targets, and efforts to adapt 3E1 for human use are anticipated to yield long-lasting pain relievers.
Reference:
1) “Relief of pain in mice by an antibody with high affinity for cell adhesion molecule 1 on nerves” by Fuka Takeuchi, Man Hagiyama, Azusa Yoneshige, Akihiro Wada, Takao Inoue, Yoichiroh Hosokawa and Akihiko Ito, 22 August 2024, Life Sciences.
DOI: 10.1016/j.lfs.2024.122997
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