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，痛苦和衰弱的妇科疾病，与血管化，纤维化， 并且神经支配的腹膜病变类似于子宫内膜腺，估计存在于〜50％的不育中 妇女和约80％的慢性骨盆疼痛的妇女。子宫内膜异位症症状，例如环状和非周期性 骨盆疼痛和月经疼痛被认为与慢性腹膜感染有关 异位子宫内膜组织。外科病变去除和雌激素抑制疗法是侵入性，无效的 长期或具有严重且可实现的副作用。疼痛最有效，最持久的治疗方法是 完整的子宫切除术，其反应率仍然约为85％。止痛药，包括阿片类药物和非甾体类抗 炎性药物是在标签外使用的，但临床研究不支持其有效性。大麻素2 受体（CB2）是子宫内膜异位症治疗的前景靶标。 CB2最彻底地表达 免疫细胞，伤害性神经元和周围结构细胞，尤其是上皮细胞和成肌纤维细胞， 包括子宫组织。 CB2激动剂（即激活）减少了过量的感染和纤维化，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。 在慢性疼痛条件下，CB2激动剂对子宫内膜异位症有益，而不是急性 疼痛。不幸的是，几家公司开发了小分子CB2激动剂，这些激动剂已迅速清除， 穿透血脑屏障和/或具有CB1介导的靶点效应（尤其是认知效果） 接收者。鲍鱼生物使用其专有功能抗体选择技术（快速）来隔离 选择性CB2激活纳米病（VHH），我们将其转换为VHH-FC融合铅抗体ABT140，用于 体内研究。预计ABT140将是高度特异性，长寿，外周受限制的CB2受体激动剂 用于子宫内膜异位症的抗体（AB）疗法，作为恢复或衰减腹膜注射和 纤维化，消除或减轻腹痛。在鼠标模型中已经实现了概念的初始证明 疼痛，感染和纤维化，特别是化学疗法诱导的神经病的模型，一种模型 神经性疼痛与人类疼痛非常相似，这是一种肺部感染疾病和细胞因子风暴的模型， 和肝纤维化模型。这个阶段1项目具有3个完整和不重叠的目标，将 通过，（1）在体外验证我们的CB2 AB激动剂概念为有效的子宫内膜异位症计划 （2）证明我们的药物在小鼠中的效率是由于机制造成的（2） 与人子宫内膜异位有关 和临床上可行的候选人。如果成功，将实施大型动物中的其他动物模型， 进一步推进鲍鱼的抗体药物，用于辅助研究，首先是人类试验的痛苦试验 子宫内膜异位症。