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

• 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
• 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

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.

项目摘要/摘要 据估计，脊髓损伤（SCI）会影响249,000至363,000美国人，约有17,730 新伤害每年发生。在美国，大约有42000名SCI患者是退伍军人。 在16至36岁之间的患者中，所有SCI的几乎一半发生，这导致患者患有患者 SCI数十年。脊髓损伤生活的终生费用平均每位患者最高可达510万美元 四翼型高的人。到目前为止，还没有FDA批准的SCI药物治疗剂，它突出显示 这些患者的巨大未满足医疗需求。大多数脊髓损伤在解剖学上是不完整的，这意味着 通过重新建立脊髓中的神经回路，这些患者将具有功能恢复潜力。到 启动恢复过程，从上方或接近受伤水平的其余神经元受伤的轴突需要 再生生长以绕过病变部位，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阻塞是化学和物理障碍 受伤后迅速在病变部位积聚，这阻塞了轴突再生生长。例如， 当轴突再生长到病变部位时，在其中诱导的Wnts蛋白将与RYK受体相互作用 在轴突上降低，然后停止轴突再生。为了消除这种障碍， RYK受体和WNT蛋白必须被阻断。 从大学举世闻名的研究小组中进行的第一类研究。 加利福尼亚州圣地亚哥（UCSD），我们开发了一种新型的人源性单克隆抗体候选药物， Versamab-101，可以阻止Wnt和RYK受体之间的相互作用。注入大鼠后 由于脊髓损伤，该抗体通过停止促进轴突再生生长并绕过病变部位 RYK和WNT之间的有毒相互作用。重建的神经回路将促进功能 大鼠的恢复。 这种新颖的治疗方法将通过促进轴突使急性脊髓损伤的患者受益 再生并改善其行为恢复。这种治疗方法还将受益于整个社区 降低长期护理的成本。根据FDA在我们的预定会议上的建议，我们建议 在此赠款申请中，在大鼠中进行GLP-COMPART毒性研究，以评估Versamab-101安全性 概况。我们还将研究患有脊髓挫伤损伤的大鼠所需的最小疗效剂量。