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.

抽象的 子宫内膜异位症是一种慢性、疼痛和使人衰弱的妇科疾病，与血管化、纤维化、 和类似于子宫内膜腺的受神经支配的腹膜病变，估计约 50% 的不孕患者存在 女性和约 80% 患有慢性盆腔疼痛的女性。子宫内膜异位症症状，如周期性和非周期性 盆腔疼痛和月经疼痛被认为与慢性腹膜炎症有关 异位子宫内膜组织。手术病灶切除和雌激素抑制疗法是侵入性的、无效的 长期或有严重且无法忍受的副作用。治疗疼痛最有效、最持久的方法是 完全子宫切除术，仍有约 85% 的缓解率。止痛药，包括阿片类药物和非甾体抗炎药 炎症药物在说明书外使用，但临床研究并不支持其有效性。大麻素2 受体（CB2）是子宫内膜异位症治疗的一个有前景的靶点。 CB2 最丰富地表达于 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， 包括子宫组织。 CB2 激动（即激活）可减少过度炎症和纤维化，但不会 损害有益的炎症反应，例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。几家公司开发了小分子 CB2 激动剂，不幸的是，它们很快就被清除了， 穿透血脑屏障和/或产生由 CB1 介导的脱靶效应（尤其是认知效应） 受体。 Abalone Bio 使用其专有的功能性抗体选择技术 (FAST) 分离出 选择性 CB2 激活纳米抗体 (VHH)，我们将其转化为 VHH-Fc 融合先导抗体 ABt140，用于 体内研究。 ABt140有望成为一种高度特异性、长效、外周限制性CB2受体激动剂 子宫内膜异位症的抗体（Ab）疗法，作为恢复或减轻腹膜炎症的一种手段 纤维化，消除或减轻腹痛。初步概念验证已在小鼠模型中实现 疼痛、炎症和纤维化的模型，特别是化疗引起的神经病变的模型， 与人类疼痛非常相似的神经性疼痛，肺部炎症性疾病和细胞因子风暴的模型， 以及肝纤维化模型。该第一阶段项目具有 3 个互补且互不重叠的目标，将 通过以下方式推进我们的子宫内膜异位症计划：(1) 在体外验证我们的 CB2 Ab 激动剂概念作为一种有效的药物 治疗痛苦的子宫内膜异位症的策略，（2）证明我们的药物对小鼠的功效是由于以下机制： 与人类子宫内膜异位症相关的行动，以及（3）提高我们的主要抗体的稳定性以生产商业化的抗体 和临床上可行的候选者。如果成功，将在更大的动物中建立更多的动物模型， 进一步推进 Abalone 的抗体药物走向 IND 研究，并首次在人体试验中用于治疗疼痛 子宫内膜异位症。