Toxicology and Efficacy Studies of Intrathecal VersaMab-101 for spinal cord injury treatment

鞘内注射 VersaMab-101 治疗脊髓损伤的毒理学和疗效研究

基本信息

批准号：
10697262
负责人：
Miao Sun
金额：
$ 238.06万
依托单位：
VERSAPEUTICS INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-18 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10697262
关键词：
Acute Adult Adverse effects Affect Affinity Age Agreement American Anatomy Animal Testing Antibodies Antibody Therapy Applications Grants Autopsy Axon Behavior Binding Blood Brain Bypass California Cardiovascular system Cell Line Chemicals Chronic Cicatrix Clinic Clinical Pathology Collaborations Communities Confusion Country Data Development Dose Embryo Engineering Epitopes FDA approved Funding Grant Growth Histopathology Human IgG4 Implantable Pump In Vitro Individual Infusion procedures Injections Injury Intravenous Bolus Laboratories Lead Legal patent Lesion Licensing Living Costs Long-Term Care Measures Medical Methods Mission Monoclonal Antibodies Mus National Institute of Neurological Disorders and Stroke Neuroglia Neurons Obstruction Osmosis Outcome Pain Threshold Pathway interactions Patients Penetration Pharmaceutical Preparations Pharmacology Phase Process Pump Quadriplegia Rattus Recommendation Recovery Recovery of Function Regimen Research Respiratory System Risk Rodent Safety Sampling Serum Severities Site Small Business Innovation Research Grant Solid Spinal Cord Spinal Cord Contusions Spinal cord injury Spinal cord injury patients Testing Therapeutic Therapeutic Monoclonal Antibodies Time Tissues Toxic effect Toxicokinetics Toxicology United States Universities Urine Variant Veterans Vial device Wnt proteins Work axon growth axon guidance axon injury axon regeneration axonal sprouting blood-brain barrier penetration cell bank cost cross reactivity drug candidate drug distribution efficacy study human tissue humanized antibody humanized monoclonal antibodies immunogenicity improved individual patient intravenous injection life time cost manufacture neural circuit nonhuman primate novel novel therapeutics pre-Investigational New Drug meeting preclinical study prevent professor receptor regenerative regenerative growth scale up stable cell line

项目摘要

PROJECT SUMMARY/ABSTRACT Spinal cord injury (SCI) is estimated to affect between 249,000 and 363,000 Americans, with about 17,730 new injuries occurring each year. There are around 42000 SCI patients that are veterans in the United States. Nearly half of all SCIs occur in patients between the ages of 16 and 36, which results in individuals living with SCI for decades. The lifetime costs of living with spinal cord injury can average up to $5.1M per patient for individuals with high tetraplegia. So far, there are no FDA approved drug therapeutics for SCI, which highlights a huge unmet medical need for those patients. Most spinal cord injuries are anatomically incomplete, which means by reestablishing neural circuits in the spinal cord, those patients would have functional recovery potential. To initiate the recovery process, injured axons from the remaining neurons above or near the injury level need to regenerative growth to bypass the lesion site, reconnect to the neurons below the injury level, and then reestablish the neural circuits. The major obstruction that prevents axon regrowth is the chemical and physical barriers that accumulated at the lesion site quickly after injury, which blocks the axonal regenerative growth. For instance, when axons regrowth to the lesion site, the Wnts protein reinduced there will interact with Ryk receptor that reinduced on the axons, and then stop axon regeneration. To remove this obstruction, the interactions between Ryk receptor and Wnts protein must be blocked. Advanced from the first-in-class research conducted in a world-famous research group in the University of California, San Diego (UCSD), we developed a novel humanized monoclonal antibody drug candidate, VersaMab-101, which could block the interaction between Wnt and the Ryk receptor. After injection into rats with spinal cord injury, this antibody promoted axons regenerative growth and bypass the lesion site by stopping the toxic interaction between Ryk and Wnts. The re-established neural circuits would then promote functional recovery in rats. This novel therapeutic will benefits the patients with acute spinal cord injury by promoting axon regeneration and improving their behavior recovery. This therapeutic will also benefit the whole community by reducing the cost of long-term care. According to FDA recommendations in our pre-IND meeting, we propose to conduct GLP-complaint toxicity study in rats in this grant application to evaluate the VersaMab-101 safety profiles. We will also investigate the minimal required efficacy dose for rats with spinal cord contusion injuries.

项目概要/摘要据估计，脊髓损伤 (SCI) 影响 249,000 至 363,000 名美国人，其中约 17,730 人每年都会发生新的伤害。美国约有 42000 名 SCI 患者是退伍军人。近一半的 SCI 发生在 16 岁至 36 岁之间的患者中，这导致患者生活在 SCI数十年。每位脊髓损伤患者的终生费用平均高达 510 万美元高位四肢瘫痪的人。迄今为止，尚无 FDA 批准的 SCI 药物治疗方法，这凸显了这些患者的巨大医疗需求未得到满足。大多数脊髓损伤在解剖学上是不完整的，这意味着通过重建脊髓中的神经回路，这些患者将具有功能恢复的潜力。到启动恢复过程，来自受伤水平以上或附近的剩余神经元的受伤轴突需要再生生长绕过病变部位，重新连接到损伤水平以下的神经元，然后重新建立神经回路。阻止轴突再生的主要障碍是化学和物理屏障损伤后迅速在病变部位积累，阻碍轴突再生生长。例如，当轴突重新生长到病变部位时，那里重新诱导的Wnts蛋白会与Ryk受体相互作用，重新诱导轴突，然后停止轴突再生。为了消除这种障碍，之间的相互作用必须阻断 Ryk 受体和 Wnts 蛋白。来自大学内世界著名研究小组进行的一流研究的先进成果加利福尼亚州圣地亚哥（UCSD），我们开发了一种新型人源化单克隆抗体候选药物， VersaMab-101，可以阻断 Wnt 和 Ryk 受体之间的相互作用。注射到大鼠体内后在脊髓损伤时，这种抗体促进轴突再生生长并通过停止来绕过病变部位 Ryk 和 Wnts 之间的毒性相互作用。重建的神经回路将促进功能大鼠的恢复。这种新型疗法将通过促进轴突使急性脊髓损伤患者受益再生并改善他们的行为恢复。这种疗法也将使整个社区受益降低长期护理费用。根据 FDA 在我们的 IND 前会议上的建议，我们建议在此拨款申请中对大鼠进行符合 GLP 的毒性研究，以评估 VersaMab-101 的安全性配置文件。我们还将研究脊髓挫伤损伤大鼠所需的最低有效剂量。