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 infertilewomen and ~80% of women with chronic pelvic pain. Endometriosis symptoms such as cyclic and non-cyclicpelvic pain and menstrual pain are thought to be associated with chronic peritoneal inflammation triggered bythe ectopic endometrial tissue. Surgical lesion removal and estrogen inhibition therapies are invasive, ineffectivelong-term, or have severe and intolerable side effects. The most effective and lasting treatment for pain iscomplete 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 2receptors (CB2) are a promising target for endometriosis treatment. CB2 is most abundantly expressed inimmune 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 notimpair 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 acutepain. 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 CB1receptor. Abalone Bio used its proprietary Functional Antibody Selection Technology (FAST) to isolate aselective CB2-activating nanobody (VHH), which we converted into a VHH-Fc fusion lead antibody, ABt140, forin vivo studies. ABt140 is expected to be a highly specific, long-lived, peripherally restricted CB2 receptor agonistantibody (Ab) therapy for endometriosis, as a means of reverting or attenuating peritoneal inflammation andfibrosis, and eliminating or reducing abdominal pain. Initial proof of concept has been achieved in mouse modelsof pain, inflammation and fibrosis, specifically a model of chemotherapy-induced neuropathy, a model ofneuropathic 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, willadvance our endometriosis program by, (1) validating in vitro our CB2 Ab agonist concept as an efficaciousstrategy for painful endometriosis, (2) demonstrating that our drug's efficacy in mouse is due to mechanisms ofaction relevant to human endometriosis, and (3) improving the stability of our lead Ab to produce a commerciallyand 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 painfulendometriosis.
Public Health Relevance Statement: NARRATIVE
Endometriosis is a painful, chronic and debilitating gynecological condition. Cannabinoid 2 receptors (CB2) are
a promising target for endometriosis treatment. Abalone Bio will test its highly specific, long-lived, peripherally
restricted CB2 receptor agonist antibody therapy for endometriosis, as a means of reverting or attenuating
peritoneal inflammation and fibrosis, and eliminating or reducing abdominal pain.
Project Terms: <α-Gs> | | | | |