Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain

摘要 化疗引起的周围神经病变（CIPN）是一种长期的神经系统疾病， 通常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。 没有药物可以预防或治疗CIPN。度洛沙汀是唯一一种临床证明有效的止痛药- 还原剂，虽然它可能会导致显着的副作用，其疗效仅限于一个子集的患者。阿片 都是超说明书使用，但也会带来严重的副作用。因此，对安全地使用药物的需求尚未得到满足。 并有效治疗或预防CIPN。外周大麻素2受体（CB 2）是CIPN的有希望的靶点 治疗CB 2在炎性免疫细胞上组成性表达，并在外周神经元中诱导表达。 神经性疾病它的激活具有强大的神经保护，抗炎和镇痛作用。 CIPN的啮齿类动物模型显示小分子CB 2激动剂减轻神经性疼痛行为，并且当 在给药期间和给药后100天内，给药均抑制CIPN。几家公司已经 开发了小分子CB 2激动剂，不幸的是，它很快被清除，穿透血脑屏障， 和/或具有由CB 1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。第一阶段SBIR结果 表明ABt 140快速且持久地逆转了CIPN小鼠异常性疼痛。在第二阶段SBIR项目中， Abalone Bio将首先通过合理的工程改造提高ABt 140的免疫原性和可制造性，然后 FAST平台将用于提高其效力，从数百万计算中选择持久的激动剂， 设计变种我们将使用体外和体内试验选择1种电极导线和至少2种替代电极导线。使用 紫杉醇CIPN小鼠模型，我们将评估铅的能力，以防止CIPN的发展，减少在神经 损伤和炎症，显示运动技能无损害，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，我们将评估其在高剂量下的毒性。成功完成 这些目标将充分降低该项目的风险，以推动鲍鱼的抗体药物进入IND研究， 最终首次用于疼痛性CIPN的人体试验。鲍鱼的药物也可能有广泛的效用，其他神经病变 疼痛和炎症。

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.