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

G 蛋白偶联受体抗体激动剂用于治疗子宫内膜异位症疼痛

• 批准号: 10482595
• 负责人: Stacy L McAllister
• 金额: $ 29.29万
• 依托单位: ABALONE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482595
• 关键词: Abdominal Pain; Acute Pain; Agonist; Analgesics; Animal Model; Animals; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Antibody Therapy; Attenuated; Autologous; B-Lymphocytes; Behavior; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Bronchioles; CNR1 gene; CNR2 gene; Cell Culture Techniques; Cell Line; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Cognitive; Development; Dysmenorrhea; Effectiveness; Endometrial; Epithelial Cells; Estrogens; Excision; Fc Receptor; Fibrosis; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Generations; Gland; Goals; Human; IL8 gene; Immune; Immunity; In Vitro; Infertility; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-6; Lead; Lesion; Libraries; Liver Fibrosis; Measures; Mediating; Medical Genetics; Messenger RNA; Modeling; Mus; Myofibroblast; Neuropathy; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opioid; Pain; Pain management; Patients; Pelvic Pain; Periodicity; Peripheral; Peritoneal; Phage Display; Pharmaceutical Preparations; Phase; Proteins; Rattus; Rodent Model; Symptoms; System; TNF gene; Technology; Testing; Tissues; Total Hysterectomy; Toxic effect; Uterus; Variant; Viscosity; Woman; abalone; allodynia; antagonist; chemotherapy induced neuropathy; chronic painful condition; chronic pelvic pain; clinical candidate; cytokine; cytokine release syndrome; dimer; drug efficacy; endogenous cannabinoid system; endometriosis; experimental study; first-in-human; genetic association; improved; in vivo; inflammatory lung disease; macrophage; manufacturability; mouse model; mutant; nanobodies; off-label use; pain model; pain relief; painful neuropathy; pathogen; programs; receptor; response; side effect; small molecule

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.

摘要 子宫内膜异位症是一种慢性、疼痛和使人衰弱的妇科疾病， 和类似于子宫内膜腺体的神经支配的腹膜病变，估计存在于约50%的不孕症患者中， 约80%的女性患有慢性盆腔疼痛。子宫内膜异位症的症状如周期性和非周期性 盆腔痛和月经痛被认为与慢性腹膜炎有关， 异位子宫内膜组织手术切除病灶和雌激素抑制疗法是侵入性的，无效的 长期的，或有严重的和无法忍受的副作用。最有效和持久的治疗疼痛是 全子宫切除术，仍然有~85%的反应率。止痛药，包括阿片类药物和非甾体抗- 炎性药物被用于标签外，但临床研究并不支持其有效性。大麻素2 受体（CB 2）是子宫内膜异位症治疗的有希望的靶点。CB 2在以下组织中表达最丰富： 免疫细胞、伤害感受神经元和外周结构细胞，特别是上皮细胞和肌成纤维细胞， 包括子宫组织。CB 2激动作用（即，激活）减少过度炎症和纤维化，但不 削弱有益炎症反应，如抗病原体或适应性体液B细胞反应。 对于子宫内膜异位症有益的是，CB 2激动主要在慢性疼痛状况中而不是在急性疼痛状况中是镇痛的。 痛苦几家公司已经开发了小分子CB 2激动剂，不幸的是，这些激动剂被迅速清除， 穿透血脑屏障和/或具有由CB 1介导的脱靶效应（特别是认知效应） 受体的Abalone Bio使用其专有的功能性抗体选择技术（FAST）分离出一种 选择性CB 2激活纳米抗体（VHH），我们将其转化为VHH-Fc融合先导抗体ABt 140，用于 体内研究。ABt 140有望成为一种高特异性、长寿命、外周限制性CB 2受体激动剂 子宫内膜异位症的抗体（Ab）治疗，作为恢复或减弱腹膜炎症的手段， 纤维化和消除或减轻腹痛。在小鼠模型中实现了初步的概念验证 疼痛，炎症和纤维化的模型，特别是化疗诱导的神经病变的模型， 神经性疼痛与人类疼痛非常相似，是肺部炎症疾病和细胞因子风暴的模型， 和肝纤维化模型。该项目的第一阶段，其3个互补和不重叠的目标，将 推进我们的子宫内膜异位症计划，（1）在体外验证我们的CB 2 Ab激动剂概念作为一种有效的 疼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中的疗效是由于 与人类子宫内膜异位症相关的作用，以及（3）提高我们的先导抗体的稳定性，以生产商业上 临床上可行的候选人。如果成功，将在更大的动物中实施额外的动物模型， 进一步推进Abalone的抗体药物的IND研究，并首次在人体试验中用于疼痛 子宫内膜异位症