Developing a prenatal biologic therapy to mitigate ASD risk from maternal autoantibodies to Caspr2

项目总结 自闭症谱系障碍(ASD)描述了一组不同程度的神经发育异常 据估计，这种严重程度影响了超过1%的美国人，其中大部分是男性。ASD可能会带来负面影响 影响一个人沟通和驾驭社会互动的能力。在其最严重的形式中，ASD也可以 导致自我毁灭、重复的行为，需要将患者送进精神病院 安全。ASD的患病率在近几十年里有所增长；对这种趋势的一种解释是 被认可的环境因素增加了这种疾病的潜在发病率。 在子宫早期接触循环中的母体抗体(Ab)已越来越多地被认为是主要的 儿童患自闭症的危险因素。这个模型假设母体抗体与母体上的蛋白质结合 会影响胎儿大脑的表面，并干扰正常发育。它得到了对小鼠的研究和 猴子透露，从患有自闭症儿童的母亲身上提纯的血清，当在危急情况下注射时 在妊娠期，会在后代中引发大脑解剖和ASD样行为表型的变化。 事实上，10%的自闭症病例可能是因为胎儿接触了母体脑部反应性抗体。还没有 这种致病模式有两个显著后果：1)母体抗体代表可检测到的生物标志物 可以指示ASD的风险，以及2)ASD的风险可以通过治疗母亲的“诱饵抗原”来减轻 中和有害抗体。Spark2Flame(S2F)寻求在这两个领域开发临床产品。 在第一阶段的工作中，S2F在小鼠身上表明，出生前接触到结合 跨膜蛋白Caspr2干扰男性大脑发育并导致行为表型 后代。这种效应，概括了ASD在人类中表现出的性别偏见，在几个方面得到了证实 不同的老鼠模型。因此，这些结果强烈建议将Caspr2反应性抗体作为 “诱饵抗原”疗法。 在这个第二阶段的SBIR中，S2F将测试一组基于Caspr2细胞外的治疗性生物制剂 将结构域与Ig G Fc结构域融合，以增加稳定性。在目标1中，候选人的特征将是稳定性和 有能力中和Caspr2反应性抗体，小组将缩小到两个领先候选者(线索)。 AIMS 2和AIMS 3分别在成年和胎鼠身上进行初步毒理学研究。在目标4中，S2F 探索铅对具有人源化免疫系统的小鼠的免疫毒性。Aim 5测试了 脑组织分析阻断多克隆母体Caspr2免疫致病效应的先导 子代的形态和行为表型。这一二期项目的圆满完成将 为Leads的持续临床前开发奠定坚实的基础，这最终可能导致 一流的治疗方法，以减少由一类病理性母体抗体引起的ASD风险。

PROJECT SUMMARY Autism Spectrum Disorder (ASD) describes a collection of neurodevelopmental abnormalities of varying severity that have been estimated to impact more than 1% of Americans, mostly males. ASD can negatively impact one’s ability to communicate and navigate social interactions. In its most severe forms, ASD also can lead to self-destructive, repetitive behaviors that require afflicted persons be institutionalized for their own safety. The prevalence of ASD has grown in recent decades; one explanation for this trend is that poorly appreciated environmental factors have raised the underlying incidence of the disorder. Early in utero exposure to circulating maternal antibodies (Ab) has been implicated increasingly as a major risk factor for children to develop ASD. This model posits that maternal antibodies bind to proteins on the surface of the fetal brain and interfere with normal development. It is supported by studies in mice and monkeys that have revealed that sera purified from mothers with ASD children, when injected before a critical point in gestation, can trigger changes in brain anatomy and ASD-like behavioral phenotypes in offspring. Indeed, > 10% of ASD cases may be explained by fetal exposure to maternal brain-reactive antibodies. Yet this mode of pathogenesis has two salient consequences: 1) maternal Ab represent detectable biomarkers that can indicate ASD risk, and 2) ASD risk could be mitigated by treating mothers with a “decoy antigen” to neutralize deleterious antibodies. Spark2Flame (S2F) seeks to develop clinical products in both of these areas. During Phase I work, S2F showed in mice that prenatal exposure to antibodies that bind the transmembrane protein Caspr2 disrupts brain development and causes behavioral phenotypes in male offspring. This effect, which recapitulates the sex-bias ASD shows in humans, was corroborated in several distinct mouse models. Thus, these results strongly recommend Caspr2-reactive antibodies as targets for a “decoy antigen” therapy. In this Phase II SBIR, S2F will test a panel of therapeutic biologics based on the Caspr2 extracellular domain fused to IgG Fc domain to increase stability. In Aim 1, candidates will be characterized stability and for ability to neutralize Caspr2-reactive antibodies, and the panel will be narrowed to two lead candidates (leads). Aims 2 and 3 conduct preliminary toxicology studies in adult and fetal mice, respectively. In Aim 4, S2F explores the immunotoxicity of leads in mice with humanized immune systems. Aim 5 tests the efficacy of leads for blocking the pathogenic effects of polyclonal maternal Caspr2 immunity by assaying the brain morphology and behavioral phenotypes of offspring. Successful completion of this Phase II project will establish a strong foundation for continued pre-clinical development of leads, which ultimately may result in a first-in-class therapy to mitigate ASD risk caused by a class of pathologic maternal antibodies.