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.

摘要：用于治疗化疗引起的周围神经性疼痛的治疗性抗体慢性、破坏生活的疼痛，例如化疗引起的周围神经病变引起的异常性疼痛（CIPN），在这一阶段的 SBIR 中，Abalone Bio 建议开发一流的药物。特异性 CB2 激动剂抗体，既是一种有效且安全的 CIPN 镇痛剂，又是一种联合治疗以实现基于阿片类药物的疼痛管理而不产生 CIPN 耐受性的比例超过 30%。接受紫杉烷治疗的化疗患者以及不同程度接受其他治疗的紫杉烷 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，目前尚无治疗方法任何药物虽然经常被证明可以缓解阿片类药物的症状，但尚未得到临床证明。有效治疗 CIPN 相反，大量使用会导致对阿片类药物的耐受，进而导致对阿片类药物的耐受。努力开发针对新疼痛目标（包括外周疼痛）的药物。大麻素受体 CB2 迄今为止在临床试验中表现平平。 CB2 激动剂已被证明可以减轻小鼠的异常性疼痛并降低阿片类药物耐受性慢性化疗引起的周围神经病变（CIPN）模型，但小分子CB2激动剂。也有缺点：它们会被快速清除，刺激大脑 CB2 受体，并且会发生交叉反应鲍鱼的 CB2 激动剂抗体将同时存在于外周和大脑中。特异性，因此不会与周围的 CB1 受体发生交叉反应，避免 CB2 受体，并且会还可以通过自然限制到周围组织来避免刺激大脑 CB2 受体通过使用我们专有的 FAST 平台，我们分离出三种单链骆驼科动物 VHH。在此阶段，域抗体命中（又名“纳米抗体”）与人 CB2 的激动剂活性一致。我工作的首要目标是在体外鉴定至少 2 种 Kd <2.5 nM 的治疗型 VHH-Fc 对于人 CB2，对于小鼠 CB2，Kd <25 nM，对于 AC 抑制或 ERK 激活的 EC50 <25 nM 为此，我们将使用 FAST 找到合适的 VHH，将它们转换为 FC 融合并我们将使用基于哺乳动物细胞的分析方法来生产蛋白质并测量命中功能。对于符合第二个标准的抗体先导，使用流式细胞术对活细胞进行亲和命中（表观 KD）。目的是评估对异常性疼痛和阿片类药物耐受性的体内影响，并确定至少 1 个 VHH-Fc 任一或两者都可将异常性疼痛降低至基线水平 ≥80%，并延长吗啡在治疗第 3 天的疗效吗啡治疗至第 1 天≥80%。我们将使用广泛接受的 CIPN C57BL/6J 小鼠模型，研究它们的药代动力学，将所有无毒线索推进药效学研究以确定然后我们将测量阿片类药物耐受性和 CB2 的预防剂量。随着我们的 CB2 激动剂抗体药物成为一种特异性，这项工作的影响可能非常广泛。类定义的非阿片类镇痛药和联合治疗，可防止阿片类药物耐受的发展。