Development of an Anti-PSGL-1 Antibody to Treat Crohn's Disease

开发治疗克罗恩病的抗 PSGL-1 抗体

基本信息

批准号：
8307272
负责人：
SCOTT A ROLLINS
金额：
$ 31.04万
依托单位：
SELEXYS PHARMACEUTICALS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-10 至 2017-03-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307272
关键词：
Acute Address Adhesions Adverse effects Affect Affinity Animal Model Antibodies Binding Biological Assay Biological Response Modifier Therapy C-reactive protein Cell Adhesion Molecules Cell Line Cells Chemotaxis Chronic Cities Clinical Clinical Research Clinical Trials Complement Contracts Crohn&apos s disease Data Development Disease Disease remission Dose Drug Kinetics Endothelial Cells Engineering Gastrointestinal tract structure Goals Grant Half-Life Human Human Volunteers IgG2 Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Intestines Leukocyte Rolling Leukocytes Macaca Macaca fascicularis Mediating Medical Mucins Oklahoma P-selectin ligand protein Patients Persons Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Phase II Clinical Trials Pilot Projects Prevention Primates Property Quality of life Regimen Safety Selectins Site Specificity Testing Therapeutic Therapeutic Effect Therapeutic Monoclonal Antibodies Therapeutic antibodies Tissues Toxic effect Toxicokinetics Toxicology Work base chemokine cross reactivity design effective therapy efficacy trial healthy volunteer human monoclonal antibodies humanized antibody immunogenic immunogenicity improved indexing inflammatory marker inhibitor/antagonist innovation intravenous administration novel phase 1 study preclinical study prevent programs public health relevance randomized placebo controlled trial safety study volunteer

项目摘要

DESCRIPTION (provided by applicant): The primary objective of this proposal is to develop and commercialize a safe and more effective therapy for the treatment of Crohn's Disease, an inflammatory bowel disease. Crohn's Disease is a chronic inflammatory disorder of the gastrointestinal tract that affects some 500,000 patients in the US. Selexys Pharmaceuticals is developing a fully human anti-PSGL-1 antibody drug directed against P-selectin glycoprotein ligand-1 (PSGL-1), a dimeric mucin on circulating leukocytes that binds selectins and chemokines, for the treatment of Crohn's Disease. PSGL-1 mediates the first step in the recruitment of leukocytes to sites of inflammation by binding to selectins, cell adhesion molecules that are upregulated in Crohn's Disease patients. PSGL-1 also binds chemokines that amplify the inflammatory response through chemotaxis of inflammatory cells to endothelial cells that line the gut. In preclinical studies in animal models of Crohn's Disease, anti-PSGL-1 antibodies have been shown to block recruitment of leukocytes resulting in a profound therapeutic effect. Thus anti-PSGL-1 antibodies represent a novel new potential therapeutic approach in the treatment of Crohn's Disease. In Phase 1 of this Fast Track Proposal, Selexys is proposing to conduct primate safety and toxicity studies in cynomolgus monkey with a human anti-PSGL-1 IgG2 antibody that has been engineered to lack effector function and complement binding. Pharmacokinetic (PK), pharmacodynamic (PD) and immunogenicity bioassays in support of this proposal are currently being developed by Selexys. Manufacture of drug substance to support the proposed preclinical studies and clinical trials is underway at Cytovance Biologics in Oklahoma City. Selexys is proposing to conduct a PK pilot dose ranging study in cynomolgus monkey (Macaca fascicularis) to assess safety and PK of the anti-PSGL-1 antibody. The pilot study will guide dosing plans to conduct an IND enabling 4-week IV repeat dose toxicity study in cynomolgus monkey. In Phase 2 of this application Selexys proposes to conduct a Phase I safety study in healthy volunteers leading to a Phase IIa safety and efficacy trial in Crohn's Disease patients. The primary goal of the proposed study is to characterize the antibody prior to commencing a Phase IIb six months chronic dosing trial. The overarching goal of the program is to develop and commercialize a humanized antibody to PSGL- 1 to treat Crohn's Disease patients. In doing so Selexys will address an inflammatory bowel disease with major unmet medical needs with a therapy that may be safer than current approved biologic therapies and that has the potential to sustain remission and/or ameliorate the devastating effects of this disease. PUBLIC HEALTH RELEVANCE: This proposal supports development of a fully human antibody to PSGL-1 to treat Crohn's Disease patients. Crohn's Disease is an inflammatory bowel disease that affects 500,000 persons in the U.S. The drug being developed addresses a major unmet medical need for a therapy that can maintain remission and/or ameliorate the devastating effects of this disease.

描述（由申请人提供）：该提案的主要目标是开发一种安全且更有效的疗法并将其商业化，用于治疗克罗恩病（一种炎症性肠病）。克罗恩病是一种胃肠道慢性炎症性疾病，影响美国约 500,000 名患者。 Selexys Pharmaceuticals 正在开发一种针对 P-选择素糖蛋白配体-1 (PSGL-1) 的全人抗 PSGL-1 抗体药物，PSGL-1 是循环白细胞上的一种二聚体粘蛋白，可结合选择素和趋化因子，用于治疗克罗恩病。 PSGL-1 通过与选择素（克罗恩病患者中表达上调的细胞粘附分子）结合，介导白细胞募集到炎症部位的第一步。 PSGL-1 还结合趋化因子，通过炎症细胞向肠道内皮细胞的趋化作用来放大炎症反应。在克罗恩病动物模型的临床前研究中，抗 PSGL-1 抗体已被证明可以阻止白细胞的募集，从而产生深远的治疗效果。因此，抗PSGL-1抗体代表了治疗克罗恩病的一种新的潜在治疗方法。在该快速通道提案的第一阶段中，Selexys 提议使用人类抗 PSGL-1 IgG2 抗体在食蟹猴中进行灵长类动物安全性和毒性研究，该抗体已被设计为缺乏效应子功能和补体结合。 Selexys 目前正在开发支持该提案的药代动力学 (PK)、药效学 (PD) 和免疫原性生物测定法。俄克拉荷马城的 Cytovance Biologics 正在进行药物生产，以支持拟议的临床前研究和临床试验。 Selexys 提议在食蟹猴 (Macaca fascicularis) 中进行 PK 试验剂量范围研究，以评估抗 PSGL-1 抗体的安全性和 PK。该试点研究将指导剂量计划，以进行 IND，在食蟹猴中进行为期 4 周的 IV 重复剂量毒性研究。在本申请的第 2 阶段中，Selexys 提议在健康志愿者中进行 I 期安全性研究，从而在克罗恩病患者中进行 IIa 期安全性和有效性试验。拟议研究的主要目标是在开始为期六个月的 IIb 期长期给药试验之前表征抗体。该计划的总体目标是开发和商业化 PSGL-1 人源化抗体，以治疗克罗恩病患者。在此过程中，Selexys 将通过一种可能比目前批准的生物疗法更安全的疗法来解决主要未满足医疗需求的炎症性肠病，并且有可能维持缓解和/或减轻这种疾病的破坏性影响。公共健康相关性：该提案支持开发 PSGL-1 的全人源抗体来治疗克罗恩病患者。克罗恩病是一种炎症性肠病，在美国影响着 500,000 人。正在开发的药物解决了对可维持缓解和/或减轻这种疾病的破坏性影响的治疗的主要未满足的医疗需求。