Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain

摘要 化疗引起的周围神经病变(CIPN)是一种通常持续时间较长的神经系统疾病 通常在接受广泛使用的化疗药物如紫杉烷的癌症患者中。CIPN导致异常 疼痛和其他症状会限制化疗剂量，并显著影响多年来的生活质量。 目前还没有预防或治疗CIPN的药物。度洛西汀是临床上唯一被证明有效的止痛药- 还原剂，尽管它会引起显著的副作用，其疗效仅限于一小部分患者。阿片类药物 都是在标签外使用，但也会带来严重的副作用。因此，对安全的药物存在严重的未得到满足的需求 并有效治疗或预防CIPN。外周大麻素2受体(CB2)是CIPN很有前途的靶点 治疗。CB2在炎性免疫细胞上有结构性表达，并在外周神经元中诱导表达。 神经性疾病。其活性具有强大的神经保护、抗炎、镇痛作用。 CIPN的啮齿动物模型显示，小分子CB2激动剂可以减轻神经病理性疼痛行为，并且当 在给药期间和给药后100天内预防性给药均可抑制CIPN。有几家公司已经 开发的小分子CB2激动剂，不幸的是，它们被迅速清除，穿透血脑屏障 和/或具有由CB1受体介导的非靶点效应(特别是认知效应)。鲍鱼生物使用其 专有功能抗体选择技术(FAST)分离选择性CB2激活纳米抗体 (VHH)，我们将其转化为VHH-Fc融合前导抗体ABt140，用于体内研究。第一阶段SBIR结果 结果表明，ABt140可迅速、持久地逆转CIPN小鼠的痛觉异常。在这个SBIR二期项目中， 鲍鱼生物将首先通过合理的工程提高ABT140的S的免疫原性和可制造性，然后再 FAST平台将被用来提高其从数百万种计算-- 设计的变种。我们将使用体外和体内试验选择1个铅和至少2个替代。使用 建立紫杉醇CIPN小鼠模型，我们将评估其预防CIPN发展的能力，减少对神经的损伤 损伤和炎症，没有表现出运动技能的损害，也不影响化疗的抗肿瘤作用 功效。最后，我们将测定铅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的毒性。成功完成 这些目标将使该项目充分降低风险，使鲍龙的抗体药物进入能够促进IND的研究和 最终在疼痛的CIPN的人体试验中首次出现。鲍鱼的药物可能对其他神经性疾病也有广泛的用途 疼痛和炎症状况。

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.