Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain

用于治疗化疗引起的周围神经性疼痛的治疗性抗体

• 批准号: 10259561
• 负责人: Andrea Grace Hohmann
• 金额: $ 91.59万
• 依托单位: ABALONE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259561
• 关键词: Adverse reactions; Agonist; Animal Model; Animals; Anti Inflammatory Analgesics; Antibodies; Appearance; Astrocytes; Behavior; Binding; Biochemical; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Cell Count; Breast Cancer Patient; CNR1 gene; CNR2 gene; Cancer Patient; Cell Culture Techniques; Cells; Chemotherapy-induced peripheral neuropathy; Clinical; Clinical Trials; Cognitive; Color; Cyclic AMP; Data; Development; Dose; Drug or chemical Tissue Distribution; Engineering; Enzymes; Fc Receptor; Fiber; Freezing; Funding; Glial Fibrillary Acidic Protein; Goals; Half-Life; Health Care Costs; Histology; Immune; In Vitro; Inflammation; Inflammatory; Interleukin-10; Interleukin-6; Kidney; Lead; Liver; Measures; Mediating; Microglia; Modeling; Motor Skills; Mus; Neurologic; Neuronal Injury; Neurons; Neuropathy; Opioid; Organ; Organ Weight; Paclitaxel; Pain; Patients; Peripheral; Pharmaceutical Preparations; Phase; Prevention; Preventive; Quality of life; Reducing Agents; Risk; Rodent Model; Safety; Serum; Serum Markers; Shapes; Skin; Small Business Innovation Research Grant; Spinal Cord; Study models; Symptoms; TNF gene; Technology; Therapeutic; Therapeutic antibodies; Toxic effect; Travel; Variant; Weight; Yeasts; abalone; activating transcription factor 3; allodynia; cell growth; chemotherapeutic agent; chemotherapy; clinical candidate; cytokine; density; design; dimer; dosage; duloxetine; falls; first-in-human; immunogenicity; improved; in vivo; injured; macrophage; manufacturability; meetings; motor impairment; mouse model; nanobodies; nerve damage; off-label use; pain behavior; pain reduction; painful neuropathy; patient subsets; pharmacokinetics and pharmacodynamics; prevent; prophylactic; receptor; side effect; small molecule; taxane; tumor

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is an often long-lasting neurological condition that arises frequently in cancer patients who receive broadly used chemotherapies such as taxanes. CIPN causes abnormal pain and other symptoms that can limit chemotherapy dosage and significantly impact quality of life for years. There are no drugs that prevent CIPN or treat it well. Duloxetine is the only clinically proven efficacious pain- reducing agent, though it can cause significant side effects and its efficacy limited to a subset of patients. Opioids are used off-label, but also carry serious side effects. Thus, there is a critical unmet need for drugs that safely and effectively treat or prevent CIPN. Peripheral Cannabinoid 2 receptors (CB2) are a promising target for CIPN treatment. CB2 is constitutively expressed on inflammatory immune cells and induced in peripheral neurons in neuropathic conditions. Its activation has powerful neuroprotective, anti-inflammatory, and analgesic effects. Rodent models of CIPN show that small molecule CB2 agonists alleviate neuropathic pain behavior, and when administered prophylactically suppress CIPN both during dosing and for 100 days after. 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. Phase I SBIR results show that ABt140 rapidly and durably reversed allodynia in mice with CIPN. In this Phase II SBIR project, Abalone Bio will first improve ABt140’s immunogenicity and manufacturability by rational engineering, and then the FAST platform will be used to increase its potency to select durable agonists from millions of computationally- designed variants. We will select 1 lead and at least 2 alternates using in vitro and in vivo assays. Using the paclitaxel CIPN mouse model, we will assess the lead’s ability to prevent CIPN development, reduce in nerve damage and inflammation, show no impairment of motor skills, and not affect chemotherapy’s anti-tumor efficacy. Finally, we will determine the lead antibody’s half-life and tissue distribution in mice, and using blood markers and organs appearance and weight, we will assess its toxicity at high doses. Successful completion of these aims will de-risk the project sufficiently to advance Abalone’s antibody drug to IND-enabling studies and eventually first in human trials for painful CIPN. Abalone’s drug may also have broad utility for other neuropathic pains and inflammatory conditions.

抽象的 化疗引起的周围神经病变 (CIPN) 是一种通常长期持续的神经系统疾病， 经常发生在接受广泛使用的化疗（如紫杉烷类）的癌症患者中。 CIPN导致异常 疼痛和其他症状可能会限制化疗剂量并显着影响多年的生活质量。 没有药物可以预防 CIPN 或对其进行良好治疗。度洛西汀是唯一经临床证明有效的止痛药 还原剂，尽管它可能会引起显着的副作用，并且其功效仅限于一小部分患者。阿片类药物 是在标签外使用的，但也带有严重的副作用。因此，对安全药物的需求亟待满足 并有效治疗或预防CIPN。外周大麻素 2 受体 (CB2) 是 CIPN 有希望的靶点 治疗。 CB2 在炎症免疫细胞上组成型表达，并在周围神经元中诱导表达 神经病。它的激活具有强大的神经保护、抗炎和镇痛作用。 CIPN 啮齿动物模型表明，小分子 CB2 激动剂可减轻神经性疼痛行为，并且当 在给药期间和给药后 100 天内预防性地抑制 CIPN。多家公司已 开发了小分子 CB2 激动剂，不幸的是，它会被迅速清除，穿透血脑屏障 和/或具有由 CB1 受体介导的脱靶效应（尤其是认知效应）。鲍鱼生物利用其 专有的功能性抗体选择技术 (FAST)，用于分离选择性 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。第一阶段 SBIR 结果 表明 ABt140 可以快速、持久地逆转 CIPN 小鼠的异常性疼痛。在这个二期SBIR项目中， Abalone Bio将首先通过合理工程提高ABt140的免疫原性和可制造性，然后 FAST 平台将用于增强其从数百万计算中选择持久激动剂的效力 设计的变体。我们将使用体外和体内测定选择 1 个先导药物和至少 2 个替代药物。使用 紫杉醇 CIPN 小鼠模型，我们将评估导线预防 CIPN 发展、减少神经损伤的能力 损伤和炎症，不影响运动技能，不影响化疗的抗肿瘤作用 功效。最后，我们将确定先导抗体在小鼠体内的半衰期和组织分布，并使用血液 标记物和器官外观和重量，我们将评估其高剂量的毒性。顺利完成 这些目标将充分降低该项目的风险，以将鲍鱼的抗体药物推进 IND 启用研究，并且 最终首次在人体试验中进行痛苦的 CIPN。鲍鱼的药物也可能对其他神经病有广泛的用途 疼痛和炎症。