A peripherally restricted MOR agonist for effective pain management with reduced risks

ABSTRACT Although opioids are effective in the treatment of moderate to severe pain, they are addictive and have dangerous side-effects, including respiratory depression, constipation, sedation, nausea and dizziness. Even when used in acute pain, up to 10% of patients become persistent users, and unused opioid tablets fuel misuse by the patient’s friends and family. Clearly, there is a need for new therapeutics that provide effective pain relief without these dangerous side-effects and risks of addiction and abuse. All opioid receptors belong to the family of G protein-coupled receptors (GPCRs) and are expressed throughout the central and peripheral nervous systems. The mu opioid receptor (MOR) is recognized as the dominant receptor for pain-relieving effects – Powerful analgesics such as morphine and codeine are agonists of the MOR. The major drawback of targeting the MOR for clinical analgesia is that it is also responsible for the undesirable central side effects. In fact, avoidance of central targeting using peripheral activators of MOR, showed efficacy in pain reduction with decreased side-effects. However, the potential for abuse and toxicity has limited therapeutic development. Abalone Bio proposes to develop a peripheral antibody agonist of MOR with reduced side effects utilizing its Functional Antibody Selection Technology (FAST) platform, which is a high-throughput, cell-based platform for directly identifying functional antibody candidates that modulate GPCR activity. Since antibodies do not readily cross the blood-brain barrier, these antibody agonists of MOR inherently would be peripheral activators of MOR. Moreover, the long half-life of antibodies would allow infrequent outpatient administration, limiting abuse potential. Furthermore, MOR agonists with G-protein signaling bias have the potential to retain analgesic effect, while reducing additional side-effects such as tolerance. For this reason, Abalone Bio will evaluate G-protein vs. β-arrestin bias for candidate antibodies and prioritize antibodies with bias toward G-protein signaling. Peripherally restricted and biased MOR antibody agonists are expected to deliver on the promise of previously failed attempts to eliminate the unwanted and dangerous side effects associated with MOR’s analgesic qualities. The specific aims for this Phase I project will be to identify agonist MOR antibodies utilizing Abalone Bio’s FAST platform (Aim 1). Stable cell lines that over-express human, mouse and cyno MOR will be created. Using these cell lines, we will validate two functional assays to characterize the MOR agonist antibodies (Aim 2). MOR agonist antibodies will be cloned, expressed and characterized for expression levels, stability, specificity, as well as function in the two in vitro assays developed above (Aim 3). Finally, we will assess the ability of the antibodies to reduce inflammatory nociception using an in vivo mouse model (Aim 4).