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.

摘要 在多种人类疾病中，嗜酸性粒细胞和/或肥大细胞被认为是重要的致病因素。 作用有几种药物可用于治疗受影响的患者，但它们往往无效。因此，小说的必要性 改善这些疾病的结果的治疗方法是毫无疑问的。一个有希望的药物靶点 目的是唾液酸免疫球蛋白（IG）样凝集素8（Siglec-8;也称为SAF 2）。Siglec-8是独一无二的 在成熟过程后期在嗜酸性粒细胞、肥大细胞和（弱）嗜碱性粒细胞上表达， 在造血干细胞和其他血液和非血液细胞上显示。这个非常有限的表达 模式-连同观察到未缀合的Siglec-8抗体（mAb）引起细胞凋亡， 体外嗜酸性粒细胞-为开发用于患者应用的Siglec-8定向免疫疗法提供了动力。 虽然已经启动了人源化Siglec-8 mAb的早期临床试验，但目前尚不清楚Siglec-8如何最好地用于 有针对性的治疗。显示Siglec-8 mAb抑制肥大细胞功能但不诱导肥大细胞增殖的体外数据 细胞凋亡表明未缀合的mAb在一些Siglec-8阳性病症中可能具有不足的活性。 这让人想起Siglec-3（CD 33）的经验-目前靶向最广泛的Siglec家族 成员-其中未缀合的mAb在临床上大部分无效。更有效的治疗 成功的Siglec-8疗法可能需要多种形式，例如CD 3导向的双特异性抗体（BiAb）。 除了治疗方式，我们的数据表明，Siglec定向免疫治疗的疗效也受到影响 通过它所针对的域的位置。具体来说，在我们对Siglec-3的研究中，我们发现了膜近端 结合显著增强CD 3定向的BiAb的效应子功能。作为我们长期合作的第一步 我们的目标是开发和优化针对嗜酸性粒细胞和肥大细胞疾病的Siglec-8定向免疫疗法， 本文提出使用人源化（“Trianni”）小鼠来产生一组不同、完全人Siglec-8 mAb， 然后仔细比较不同治疗方式（mAb与BiAb）的疗效，并确定 近膜靶向作为增强Siglec-8靶向治疗剂的细胞毒性的手段的作用。我们 研究预计将提供关键的洞察力，以了解Siglec-8应如何靶向最大限度地发挥作用的原则。 治疗益处，同时，它们产生用于进一步临床开发的候选分子。 我们的工作可能会为嗜酸性粒细胞或肥大细胞疾病患者带来新的治疗选择， 结果仍然不能令人满意。