Safe and effective anti CD154 antibodies for therapeutic intervention

用于治疗干预的安全有效的抗 CD154 抗体

• 批准号: 9271146
• 负责人: JAY L ROTHSTEIN
• 金额: $ 91.22万
• 依托单位: IMMUNEXT, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271146
• 关键词: Adverse event; Affinity; Antibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Award; Binding; Blocking Antibodies; Blood Platelets; Budgets; CD40 Ligand; Cell Line; Cellular Immunity; Chronic; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Complement; Cyclic GMP; Data; Development; Disabled Persons; Disease; Disease model; Disease remission; Drug Design; Drug Targeting; Drug toxicity; Drug usage; Engineering; Event; FDA approved; Failure; Fibronectins; Formulation; Funding; Grant; Half-Life; Human; Idiopathic Thrombocytopenic Purpura; Immune; Immune Tolerance; Immune system; Immunology; Immunomodulators; Immunotherapeutic agent; In Vitro; Inflammation; Inflammatory Bowel Diseases; Intervention; Knowledge; Laboratories; Lead; Length; Macaca mulatta; Modeling; Monoclonal Antibodies; Multiple Sclerosis; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; One-Step dentin bonding system; Organ Transplantation; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Preparation; Process; Production; Property; Proteins; Psoriasis; Reagent; Reproducibility; Resistance; Rheumatoid Arthritis; Risk; Roche brand of rituximab; Rodent; Role; Safety; Schedule; Site-Directed Mutagenesis; Small Business Innovation Research Grant; Systemic Lupus Erythematosus; TNF gene; TNFSF5 gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Therapeutic antibodies; Thrombosis; Toxic effect; Transplantation Tolerance; Treatment Efficacy; Validation; base; cell bank; clinical development; design; drug development; immune activation; immunogenicity; immunoregulation; in vivo; nonhuman primate; novel; novel therapeutics; pre-clinical; preclinical development; programs; safety study; sample fixation; success; therapeutic target; virtual

Abstract. CD154 (CD40L) is a key target for immunomodulation due to its central role in controlling the activation of the immune system. This well studied immune “switch” has been the focus of extensive drug development for over two decades. The validation of this drug target consists of reproducible and robust data using rodent and NHP models of chronic inflammation, autoimmune disease and organ transplant. In fact, this is one of the few undeveloped drug targets where antibodies have shown promising therapeutic efficacy in treating human autoimmune disease in several clinical trials. Therefore, the choice of CD154 as a drug target for commercial development is clear. The limitation on commercializing this clinical success was based on the thromboembolic toxicity of the drugs used in early trials and the limited knowledge on the cause of these adverse events (AEs). Consequent to these early trials the mechanism of toxicity was shown to be related to the FcR binding capacity of those former antibody drugs. Aggressive approaches to fix the AE's have proven successful in early human trials however these molecules show reduced potency in inhibiting the CD154 pathway likely owing to the use of non-conventional drug design. ImmuNext's engineering and development of a high affinity anti-CD154 antibody (INX021) shows that silencing the platelet Fc binding and ablating the complement fixation properties of the molecule eliminates the risk of thromoboembolic toxicity as demonstrated in vitro and an in vivo non-GLP NHP tox study. INX021 is a high affinity drug with a long half-life and likely low immunogenicity. Together, these features place INX021 as a best-in-class drug for several disease indications. Systemic lupus erythematosus is the first indication of choice. The mechanisms of action of CD154 also suggest that treating idiopathic thrombocytopena, IBD and TNF-resistant RA are plausible alternative indications to be considered following the completion of human safety studies. The Specific Aims of this proposal are: 1. Process Development, Formulation Development & Manufacture of GLP Tox Material. 2. Design of Phase 1A and 1B Clinical Trials and Supporting GLP Tox Study When these Aims are complete, ImmuNext can perform the IND-enabling GLP tox study that will enable partnering of this asset. Induction of tolerance - the `holy grail' of immunology - will be one step closer to commercial reality.

抽象的。CD 154（CD 40 L）是免疫调节的关键靶点，因为其在控制免疫应答中的核心作用。 激活免疫系统。这种研究充分的免疫“开关”一直是广泛的药物治疗的焦点。 发展了二十多年。该药物靶点的验证由可重复和稳健的数据组成 使用慢性炎症、自身免疫性疾病和器官移植的啮齿动物和NHP模型。其实这 是为数不多的未开发的药物靶点之一，其中抗体已显示出有希望的治疗效果， 治疗人类自身免疫性疾病的临床试验因此，选择CD 154作为药物靶点 商业发展是明确的。 将这种临床成功商业化的限制是基于其血栓栓塞毒性。 早期试验中使用的药物以及对这些不良事件（AE）原因的了解有限。随之 对于这些早期试验，毒性机制显示与这些细胞的FcR结合能力有关， 前抗体药物。在早期的人体试验中，修复AE的积极方法已被证明是成功的 然而，这些分子在抑制CD 154途径方面显示出降低的效力，这可能是由于使用了 非常规药物设计。ImmuNext的工程和高亲和力抗CD 154抗体的开发 （INX 021）显示沉默血小板Fc结合和消融血小板Fc结合的补体结合特性， 分子消除了血栓栓塞毒性的风险，如体外和体内非GLP NHP所证明的 毒性研究INX 021是一种高亲和力药物，半衰期长，免疫原性可能较低。所有这些 这些特性使INX 021成为多种疾病适应症的同类最佳药物。 系统性红斑狼疮是首选适应症。CD 154的作用机制也 提示治疗特发性类风湿关节炎、IBD和TNF抵抗性类风湿关节炎是合理选择， 完成人体安全性研究后考虑的适应症。 该提案的具体目标是： 1. GLP Tox材料的工艺开发、配方开发和生产。 2. 1A期和1B期临床试验设计和支持性GLP毒性研究 当这些目标完成后，ImmuNext可以进行IND使能GLP毒性研究， 这一资产的合作免疫学的“圣杯”--诱导耐受性将更接近于 商业现实。