Antibody agonist for a G protein-coupled receptor as a treatment for pain in endometriosis

点击翻译按钮获取中文摘要

ABSTRACT Endometriosis is a chronic, painful and debilitating gynecological condition associated with vascularized, fibrotic, and innervated peritoneal lesions resembling endometrial glands, estimated to be present in ~50% of infertile women and ~80% of women with chronic pelvic pain. Endometriosis symptoms such as cyclic and non-cyclic pelvic pain and menstrual pain are thought to be associated with chronic peritoneal inflammation triggered by the ectopic endometrial tissue. Surgical lesion removal and estrogen inhibition therapies are invasive, ineffective long-term, or have severe and intolerable side effects. The most effective and lasting treatment for pain is complete hysterectomy, which still has ~85% response rate. Painkillers, including opioids, and nonsteroidal anti- inflammatory drugs are used off-label, but clinical studies do not support their effectiveness. Cannabinoid 2 receptors (CB2) are a promising target for endometriosis treatment. CB2 is most abundantly expressed in immune cells, nociceptive neurons, and peripheral structural cells, notably epithelial cells and myofibroblasts, including in uterine tissue. CB2 agonism (i.e., activation) reduces excess inflammation and fibrosis, but does not impair beneficial inflammatory responses, such as anti-pathogen or adaptive humoral B-cell responses. Beneficial for endometriosis, CB2 agonism is analgesic primarily in chronic pain conditions rather than in acute pain. Several companies have developed small molecule CB2 agonists that, unfortunately, are rapidly cleared, penetrate the blood-brain barrier and/or have off-target effects (notably cognitive ones) mediated by the CB1 receptor. Abalone Bio used its proprietary Functional Antibody Selection Technology (FAST) to isolate a selective CB2-activating nanobody (VHH), which we converted into a VHH-Fc fusion lead antibody, ABt140, for in vivo studies. ABt140 is expected to be a highly specific, long-lived, peripherally restricted CB2 receptor agonist antibody (Ab) therapy for endometriosis, as a means of reverting or attenuating peritoneal inflammation and fibrosis, and eliminating or reducing abdominal pain. Initial proof of concept has been achieved in mouse models of pain, inflammation and fibrosis, specifically a model of chemotherapy-induced neuropathy, a model of neuropathic pain that closely resembles human pain, a model of lung inflammatory disease and cytokine storm, and a model of liver fibrosis. This Phase 1 project, with its 3 complementary and non-overlapping aims, will advance our endometriosis program by, (1) validating in vitro our CB2 Ab agonist concept as an efficacious strategy for painful endometriosis, (2) demonstrating that our drug’s efficacy in mouse is due to mechanisms of action relevant to human endometriosis, and (3) improving the stability of our lead Ab to produce a commercially and clinically viable candidate. If successful, additional animal models in a larger animal will be implemented, further advancing Abalone’s antibody drug toward IND-enabling studies and first in human trials for painful endometriosis.