Safe and effective anti CD154 antibodies for therapeutic intervention

抽象的。CD154(CD40L)是免疫调节的关键靶点，因为它在控制 激活免疫系统。这种经过充分研究的免疫“开关”一直是广泛药物研究的焦点。 二十多年来的发展。该药物靶点的验证由可重复性和健壮的数据组成 使用啮齿动物和NHP慢性炎症、自身免疫性疾病和器官移植模型。事实上，这一点 是为数不多的未开发的药物靶点之一，抗体在 在几个临床试验中治疗人类自身免疫性疾病。因此，CD154作为药物靶点的选择 对于商业发展来说，这是显而易见的。 限制将这一临床成功商业化的基础是 早期试验中使用的药物以及对这些不良事件(AE)原因的有限了解。后果性 在这些早期试验中，毒性机制被证明与FCR结合能力有关 以前的抗体药物。在早期的人体试验中，积极的方法修复AE被证明是成功的 然而，这些分子显示出抑制CD154途径的效力降低，这可能是由于使用了 非常规药物设计。高亲和力抗CD154抗体的构建及免疫原核表达 (INX021)表明，沉默血小板Fc结合和消融补体结合特性 分子消除血栓栓塞性毒性的风险，如体外和体内证明的非GLP NHP 毒理研究。INX021是一种高亲和力药物，半衰期较长，免疫原性可能较低。加在一起，这些 INX021是几种疾病适应症的最佳药物。 系统性红斑狼疮是首选的适应症。CD154的作用机制也 提示治疗特发性血小板减少、炎症性肠病和肿瘤坏死因子抵抗的类风湿关节炎是可行的选择 人体安全研究完成后应考虑的适应症。 这项建议的具体目标是： 1.GLP Tox材料的工艺开发、配方开发和制造。 2.A期和1B期临床试验设计及GLP毒素支持研究 当这些目标完成后，ImmuNext可以进行启用IND的GLP TOX研究，这将使 合伙经营这项资产。诱导免疫耐受--免疫学的“圣杯”--将更接近 商业现实。

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.