Optimization of Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders

针对嗜酸性粒细胞和肥大细胞疾病的 Siglec-8 定向免疫疗法的优化

• 批准号: 10641465
• 负责人: Roland Bruno Walter
• 金额: $ 11.39万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10641465
• 关键词: Optimization; Siglec; Directed; Immunotherapy; Eosinophilic

ABSTRACT In a wide variety of human diseases, eosinophils and/or mast cells are thought to play an important pathogenetic role. Several drugs are available to treat affected patients, but they are often ineffective. Thus, the need for novel therapeutics to improve outcomes for these disorders is unquestioned. One promising drug target for this purpose is sialic acid immunoglobulin (Ig)-like lectin 8 (Siglec-8; also known as SAF2). Siglec-8 is uniquely expressed on eosinophils, mast cells and (weakly) basophils late during the maturation process and is not displayed on hematopoietic stem cells and other blood and non-blood cells. This very restricted expression pattern – together with the observation that unconjugated Siglec-8 antibodies (mAbs) cause apoptosis of eosinophils in vitro – provides the impetus to develop Siglec-8-directed immunotherapy for patient application. While early clinical trials with a humanized Siglec-8 mAb have been initiated, it is unknown how Siglec-8 is best targeted therapeutically. In vitro data showing Siglec-8 mAbs inhibit mast cell function but do not induce mast cell apoptosis suggest that unconjugated mAbs may have insufficient activity in some Siglec-8-positive disorders. This is reminiscent of the experience with Siglec-3 (CD33) – the currently most widely targeted Siglec family member – where unconjugated mAbs have been largely ineffective in the clinic. More potent treatment modalities, e.g. CD3-directed bispecific antibodies (BiAbs), may be required for successful Siglec-8 therapy. Besides treatment modality, our data suggest that the efficacy of Siglec-directed immunotherapy is also affected by the location of the domain it targets. Specifically, in our studies with Siglec-3, we found membrane-proximal binding substantially enhances effector functions of CD3-directed BiAbs. As a first step toward our long-term goal of developing and optimizing Siglec-8-directed immunotherapy for eosinophilic and mast cell disorders, we here propose to use humanized (“Trianni”) mice to generate a panel of diverse, fully human Siglec-8 mAbs and then to carefully compare the efficacy of different treatment modalities (mAbs vs. BiAbs) and to determine the role of membrane-proximal targeting as means to enhance the cytotoxicity of Siglec-8-targeted therapeutics. Our studies are expected to provide critical insight into the principles of how Siglec-8 should be targeted for maximal therapeutic benefit while, at the same time, they generate candidate molecules for further clinical development. Our work may lead to a new treatment option for patients with eosinophilic or mast cell disorders for whom outcomes continue to be unsatisfactory.

抽象的 在各种各样的人类疾病中，嗜酸性粒细胞和/或肥大细胞被认为起着重要的致病性 角色。有几种药物可用于治疗受影响的患者，但通常无效。那，需要小说 毫无疑问，可以改善这些疾病的预后。一个应许的药物目标 目的是唾液酸免疫球蛋白（Ig）类似于讲座8（Siglec-8；也称为SAF2）。 Siglec-8是独特的 在成熟过程后期以嗜酸性粒细胞，肥大细胞和（弱）嗜碱性粒细胞表示，不是 显示在造血干细胞以及其他血液和非血细胞上。这个非常有限的表达 模式 - 以及观察到未结合的Siglec-8抗体（mAb）引起凋亡的凋亡 体外嗜酸性粒细胞 - 提供了开发SIGLEC-8定向免疫疗法的动力。 尽管已经开始使用人源化SIGLEC-8 MAB进行的早期临床试验，但尚不清楚Siglec-8是最好的 针对治疗的目标。体外数据显示SIGLEC-8 MAB抑制肥大细胞功能，但不会诱导桅杆 细胞凋亡表明，未结合的mAB可能在某些SIGLEC-8阳性疾病中具有不足的活性。 这让人想起Siglec-3（CD33）的经验 - 目前最广泛的SIGLEC家族 成员 - 在诊所中，未结合的mAb在很大程度上无效。更多潜在的治疗 模式，例如成功的SIGLEC-8治疗可能需要CD3定向的双特异性抗体（BIAB）。 除了治疗方式外，我们的数据表明，SIGLEC指导的免疫疗法的效率也受到影响 根据域的位置，它针对的。具体而言，在我们对Siglec-3的研究中，我们发现了膜膜 结合大大增强了CD3定向BIAB的效应子功能。作为我们长期的第一步 为嗜酸性和肥大细胞疾病开发和优化SIGLEC-8定向的免疫疗法，我们 这里建议使用人源化（“ Trianni”）小鼠生成一组潜水员，完全人类Siglec-8 mabs和 然后仔细比较不同治疗方式的效率（mabs vs. biabs），并确定 膜透明靶向作为增强SIGLEC-8靶向治疗的细胞毒性的手段的作用。我们的 期望研究将对SIGLEC-8的原理提供批判性见解，以最大程度的目标 治疗益处，同时，它们产生候选分子以进一步临床发育。 我们的工作可能会为患有嗜酸性或肥大细胞疾病的患者提供新的治疗选择 结果仍然不令人满意。