Growth plate-targeted IGF1 to treat Turner Syndrome

特纳综合征（TS）是一种罕见的疾病，发生率为1/2500活产女婴，由以下原因引起： X染色体的部分或完全单体性。TS患者中最常见的表型之一是 身材矮小，定义为低于年龄平均身高至少2个标准差，通常治疗 每天注射重组人生长激素（GH）作为标准治疗。而GH统计学 增加成人身高，TS患者通常无法达到其父母身高预测的中间值，甚至无法达到 成人身高在正常范围内。此外，TS患者的不良反应风险特别高 与长期GH治疗相关，包括高血糖症、颅内高压、 鼻咽淋巴组织、胰岛素抵抗和肢端肥大症改变。骑兵生物科学公司的目标是 通过开发由IGF 1组成的靶向治疗药物，解决安全性和有效性方面未满足的临床需求 (GH驱动骨生长的效应器）和基于抗基质蛋白-3（MATN 3）抗体的靶臂，所述靶臂驱动 定位于长骨的生长板。在临床前研究中，这种生长板IGF 1（GP-1）的原型被证实是一种新的生长板。 IGF 1）生物治疗剂，选择性定位于生长板，并增加生长板的大小，在小鼠模型的生长激素 缺陷我们的第一阶段提案的目标是将这种原型分子优化为具有PK- 有利于临床进步的PD有效性和可制造性特性。为了实现这一 我们将追求两个具体目标。在第一个目标中，我们将设计和表达下一代GP-IGF 1 具有修饰的融合蛋白，所述修饰（i）改善MATN 3结合以优化GP靶向，（ii）改变IGF 1的 对IGF 1 R的亲和力和/或与抑制IGF结合蛋白的活性相互作用的能力，和（iii）优化药物组合物。 共动力学（PK）。将测试所得分子在体外结合MATN 3和激活IGF 1 R的能力 和体内实验，这些实验都是我们在初步研究中开发的。将评估候选分子 用于小鼠中的PK和生物分布特性。在第二个目标中，我们将使用临床前模型来评估 下一代GP-IGF 1分子相对于重组GH和IGF 1的有效性和安全性。生长板高度 GH抑制小鼠的测量结果将用于下一代GP-IGF 1分子的初始功效测试 通过我们的药物优化计划产生。因为生长板的高度是软骨细胞 增殖和骨生长，这些实验将补充软骨的直接测量， 细胞增殖和骨形成。铅分子随后将被制成鼠模型用于长期实验 这将严格评估（i）它们加速长骨生长的程度和（ii）不良反应的可能性。 方面的影响.在第一阶段成功完成后，我们将确定一种经过测试的先导化合物 在小鼠中进行PK、生物分布、PD、功效和安全性。这将为第二阶段的应用奠定基础， 我们将进行IND使能研究，将我们的先导分子推进到适合于 人体测试

Turner syndrome (TS) is a rare disorder that occurs at a rate of 1 in 2500 live female births and is caused by partial or complete monosomy of the X chromosome. Among the most common phenotypes in TS patients is short stature, defined as at least 2 standard deviations below mean height for age, which is commonly treated with daily injections of recombinant human growth hormone (GH) as the standard of care. While GH statistically increases adult height, TS patients generally fail to reach their mid-parental height projection or even achieve adult heights within the normal range. Additionally, TS patients are at particularly high risk for adverse effects associated with prolonged GH treatment that include hyperglycemia, intracranial hypertension, growth of the nasopharyngeal lymphoid tissues, insulin resistance, and acromegalic changes. Cavalry Biosciences’ goal is to address the unmet clinical need in safety and efficacy by developing a targeted therapeutic consisting of IGF1 (GH effector that drives bone growth) and an anti-matrilin-3 (MATN3) antibody-based target arm that drives localization to growth plates of long bones. In preclinical studies, prototypes of such a Growth Plate IGF1 (GP- IGF1) biotherapeutics, selectively localized to and increased the size of growth plates in mouse models of GH deficiency. The objective of our Phase 1 proposal is to optimize this prototype molecule into a lead that has PK- PD-efficacy and manufacturability properties that are favorable for clinical advancement. To accomplish this objective, we will pursue two specific aims. In the first aim, we will design and express next-generation GP-IGF1 fusions proteins with modifications that (i) improve MATN3 binding to optimize GP targeting, (ii) alter IGF1’s affinity for IGF1R and/or ability to interact with activity inhibiting IGF-binding proteins, and (iii) optimize pharma- cokinetics (PK). The resulting molecules will be tested for their ability to bind MATN3 and activate IGF1R in vitro and in vivo using assays that we have developed in preliminary studies. Candidate molecules will be assessed for PK and biodistribution properties in mice. In the second aim, we will use preclinical models to evaluate the efficacy and safety of next-gen GP-IGF1 molecules relative to recombinant GH and IGF1. Growth plate height measurements in GH-inhibited mice will be used for initial efficacy testing of the next-gen GP-IGF1 molecules generated through our drug optimization program. Because growth plate height is a surrogate for chondrocyte proliferation and bone growth, these experiments will be complemented with direct measurements of chondro- cyte proliferation and bone formation. Lead molecules will then be murinized for use in longer-term experiments that will critically evaluate (i) the extent to which they accelerate long bone growth and (ii) the potential for adverse effects. At the successful completion of Phase 1, we will have identified a lead compound that has been tested in mice for PK, biodistribution, PD, efficacy, and safety. This will lay the foundation for a Phase 2 application, in which we will conduct the IND-enabling studies that advance our lead molecule to a drug candidate suitable for human testing.