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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

基本信息

批准号：
9910117
负责人：
Andrea Grace Hohmann
金额：
$ 30万
依托单位：
ABALONE BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910117
关键词：
Absence of pain sensation Address Adenylate Cyclase Affinity Agonist Amino Acid Substitution Analgesics Animal Model Antibodies Binding Biological Biological Assay Biology Blood - brain barrier anatomy Brain CB2 knockout CNR1 gene CNR2 gene Cannabinoids Cell model Cells Chemotherapy-induced peripheral neuropathy Chronic Clinical Trials Constipation Country Data Dependence Development Directed Molecular Evolution Dose Escherichia coli Feasibility Studies Flow Cytometry Foundations Future G-Protein-Coupled Receptors Goals Half-Life Health Human Human Activities In Vitro Indiana Inflammation Knockout Mice Lead Life Limb structure Mammalian Cell Measures Methods Morphine Mus Opiate Addiction Opioid Outcome Paclitaxel Pain Pain management Patients Performance Peripheral Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phosphorylation Physical Dependence Prevention Measures Production Proteins Pruritus Small Business Innovation Research Grant Specificity Structure Technology Testing Therapeutic Therapeutic antibodies Time Tissues Ventilatory Depression Work abalone allodynia animal efficacy antibody libraries base cannabinoid receptor chemotherapy chronic neuropathic pain cross reactivity drug development drug discovery efficacy testing in vivo lead optimization medical specialties meetings morphine tolerance mouse model nanobodies non-opioid analgesic novel opiate tolerance opioid use disorder pain model pain reduction painful neuropathy preclinical efficacy prevent receptor internalization research and development side effect small molecule taxane

项目摘要

Summary: Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain Chronic, life-disrupting pain, such as allodynia from chemotherapy induced peripheral neuropathy (CIPN), is difficult to manage. In this Phase I SBIR, Abalone Bio proposes to develop a first-in-class specific CB2 agonist antibody that is BOTH an effective and safe analgesic against CIPN as well as a co-therapy to enable opioid-based pain management without developing tolerance. CIPN occurs in >30% of chemotherapy patients treated with taxanes, and in various degrees for other therapies. Taxane CIPN is an untreated chronic condition that involves various degrees of allodynia, for which there is no demonstrated relief by any drug. Opioids, while frequently prescribed, are not clinically proven to effectively treat CIPN. On the contrary, heavy usage can lead to tolerance to opioids, and in turn opioid use disorders (OUDs). Efforts to develop drugs aimed at novel pain targets, including the peripheral cannabinoid receptor CB2, have so far yielded lackluster performance in clinical trials. Small-molecule CB2 agonists have been shown to reduce allodynia and reduce opioid tolerance in an established mouse model of chronic chemotherapy-induced peripheral neuropathy (CIPN). But small-molecule CB2 agonists have drawbacks: they are rapidly cleared, undesirably stimulate brain CB2 receptors, and cross-react with CB1 receptors in the periphery and in the brain. Abalone’s CB2 agonist antibody will be BOTH highly specific and thus will not cross-react with CB1 receptors in the periphery avoid CB2 receptors, and will also avoid the stimulation of brain CB2 receptors by being naturally restricted to peripheral tissues by the blood-brain barrier. By using our proprietary FAST platform, we isolated three single-chain camelid VHH domain antibodies hits (a.k.a. “nanobodies”) consistent with agonist activity for human CB2. In this Phase I work, the first aim will be to identify in vitro at least 2 therapeutic-format VHH-Fcs with with Kd <2.5 nM for human CB2, Kd <25 nM for mouse CB2, and EC50 of AC inhibition or ERK activation <25 nM for human and mouse CB2. To do this, we’ll find suitable VHHs using FAST, convert them to FC fusions and produce protein for assays. We’ll measure hit function using mammalian cell-based assays and measure hit affinity (apparent KD) using flow cytometry on live cells. For antibody leads meeting criteria the second aim will be to assess in vivo effect on allodynia and opioid tolerance and identify at least 1 VHH-Fc that either or both reduces allodynia to ≥80% of baseline levels and extends morphine efficacy at day 3 of morphine treatment to ≥80% of day 1. We’ll use a broadly accepted C57BL/6J mouse model of CIPN and study their pharcokynetics, advancing all non-toxic leads to pharmacodynamic studies to determine dosing regime for subthreshold analgesia. Then we’ll measure prevention of opioid tolerance and CB2 specificity. The impact of this work could be very broad with our CB2 agonist antibody drug becoming a class-defining non-opioid analgesic and co-therapy that prevents the development of opioid tolerance.

概述：用于治疗化疗诱导的周围神经性疼痛的治疗性抗体慢性、扰乱生活的疼痛，如化疗引起的周围神经病变引起的异常性疼痛（CIPN），很难管理。在第一阶段SBIR中，鲍鱼生物建议开发一流的特异性CB2激动剂抗体是针对CIPN的有效且安全的镇痛剂，联合治疗，以实现基于阿片类药物的疼痛管理，而不会产生耐受性。CIPN发生在> 30% 紫杉烷类药物治疗的化疗患者，以及不同程度的其他治疗。紫杉烷CIPN 是一种未经治疗的慢性疾病，涉及不同程度的异常性疼痛，任何药物都能缓解症状。阿片类药物，虽然经常开处方，但临床上没有证明，有效治疗CIPN。相反，大量使用可导致对阿片类药物的耐受性，使用障碍（OUD）。努力开发针对新型疼痛靶点的药物，包括外周大麻素受体CB2迄今在临床试验中表现平平。小分子 CB2激动剂已显示在已建立的小鼠中减少异常性疼痛并减少阿片样物质耐受性慢性化疗诱导的周围神经病变（CIPN）模型。但是小分子CB2激动剂具有缺点：它们被迅速清除，不期望地刺激脑CB2受体，并且交叉反应周围和大脑中的CB1受体。鲍鱼的CB2激动剂抗体将是高度特异性，因此不会与周围的CB1受体交叉反应，避免CB2受体，也避免了刺激脑CB2受体被自然限制到外周组织，血脑屏障通过使用我们专有的FAST平台，我们分离了三个单链骆驼VHH 结构域抗体命中（也称为"纳米抗体"），这与对人CB2的激动剂活性一致。在这个阶段我的工作，第一个目标将是在体外鉴定至少2种治疗形式的VHH-Fc，其Kd <2.5 nM 对于人CB 2，对于小鼠CB 2，Kd <25 nM，对于人CB 2，AC抑制或ERK激活的EC50 <25 nM。人和小鼠CB2。为此，我们将使用FAST找到合适的VHH，将它们转化为FC融合物，产生用于测定的蛋白质。我们将使用基于哺乳动物细胞的分析来测量命中功能，在活细胞上使用流式细胞术测定命中亲和力（表观KD）。对于符合标准的抗体先导化合物，目的是评估对异常性疼痛和阿片耐受性的体内作用，并鉴定至少1种VHH-Fc，其中一种或两种都将异常性疼痛降低至基线水平的≥ 80%，并在治疗第3天延长吗啡疗效。吗啡治疗至第1天≥ 80%。我们将使用广泛接受的CIPN的C57BL/6J小鼠模型，研究他们的药动学，推进所有无毒导致药效学研究，以确定用于阈下镇痛的给药方案。然后，我们将测量阿片类药物耐受性和CB2的预防。的特异性这项工作的影响可能是非常广泛的，我们的CB2激动剂抗体药物成为类别定义的非阿片类镇痛药和共同治疗，防止阿片类药物耐受的发展。