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

摘要 子宫内膜异位症是一种慢性、疼痛和衰弱的妇科疾病，与血管化、纤维化、 和类似子宫内膜腺的神经性腹膜病变，估计约50%的不孕症患者 女性和约80%患有慢性盆腔疼痛的女性。子宫内膜异位症的周期性和非周期性症状 盆腔疼痛和经期疼痛被认为与慢性腹膜炎症有关，由 异位子宫内膜组织。外科手术切除病变和雌激素抑制治疗是侵入性的，无效的。 长期的，或有严重的和无法忍受的副作用。对疼痛最有效、最持久的治疗方法是 全子宫切除术，仍有85%的有效率。止痛药，包括阿片类药物和非类固醇抗痛药 炎症药物是在标签外使用的，但临床研究并不支持它们的有效性。大麻素2 受体(CB2)是治疗子宫内膜异位症的一个有前景的靶点。CB2最丰富的表达形式是 免疫细胞、伤害性神经元和外周结构细胞，特别是上皮细胞和肌成纤维细胞， 包括在子宫组织中。CB2激动剂(即激活)可减少过度炎症和纤维化，但不能 损害有益的炎症反应，如抗病原体或适应性体液B细胞反应。 CB2激动剂对子宫内膜异位症有益，主要用于慢性疼痛而不是急性疼痛。 疼痛。几家公司已经开发出小分子CB2激动剂，不幸的是，它们很快就被清除了， 穿透血脑屏障和/或具有CB1介导的非靶点效应(特别是认知效应) 受体。鲍鱼生物利用其专有的功能性抗体选择技术(FAST)分离出一种 选择性CB2激活纳米体(VHH)，我们将其转化为VHH-Fc融合前导抗体ABt140，用于 活体研究。ABt140有望成为一种高度特异、长寿、外周受限的CB2受体激动剂。 抗体治疗子宫内膜异位症，作为一种逆转或减轻腹膜炎症和 纤维化，消除或减轻腹痛。概念的初步验证已经在小鼠模型中实现 疼痛、炎症和纤维化，特别是化疗引起的神经病变模型， 神经性疼痛，与人类疼痛非常相似，是肺部炎症性疾病和细胞因子风暴的模型， 和肝纤维化的模型。这个第一阶段项目有三个相辅相成和互不重叠的目标，将 推进我们的子宫内膜异位症计划，(1)在体外验证我们的CB2抗体激动剂概念是有效的 痛性子宫内膜异位症的治疗策略，(2)证明我们的药物在小鼠身上的疗效是由于 与人类子宫内膜异位症相关的作用，以及(3)提高我们的铅抗体的稳定性，以生产商业化的 临床上可行的候选人。如果成功，将在更大的动物身上实施更多的动物模型， 进一步推进鲍鱼抗体药物用于IND的研究，并首次用于疼痛的人体试验 子宫内膜异位症。

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.