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
基本信息
- 批准号:10641465
- 负责人:
- 金额:$ 11.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Roland Bruno Walter其他文献
Roland Bruno Walter的其他文献
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{{ truncateString('Roland Bruno Walter', 18)}}的其他基金
Base-Edited Hematopoietic Stem and Progenitor Cells To Enable Safe Use Of Highly Potent CD33-Targeted Radioimmunotherapy
碱基编辑造血干细胞和祖细胞可安全使用高效 CD33 靶向放射免疫疗法
- 批准号:
10346735 - 财政年份:2022
- 资助金额:
$ 11.39万 - 项目类别:
Base-Edited Hematopoietic Stem and Progenitor Cells To Enable Safe Use Of Highly Potent CD33-Targeted Radioimmunotherapy
碱基编辑造血干细胞和祖细胞可安全使用高效 CD33 靶向放射免疫疗法
- 批准号:
10647646 - 财政年份:2022
- 资助金额:
$ 11.39万 - 项目类别:
CD117-Targeted Radioimmunotherapy with Astatine-211 for Acute Myeloid Leukemia and Myelodysplastic Syndrome
CD117 靶向放射免疫治疗砹 211 治疗急性髓系白血病和骨髓增生异常综合征
- 批准号:
10670383 - 财政年份:2022
- 资助金额:
$ 11.39万 - 项目类别:
Optimizing NK Cell-Engaging Bispecific Antibody Therapy Targeting CD33
优化靶向 CD33 的 NK 细胞双特异性抗体疗法
- 批准号:
10403976 - 财政年份:2021
- 资助金额:
$ 11.39万 - 项目类别:
Optimizing NK Cell-Engaging Bispecific Antibody Therapy Targeting CD33
优化靶向 CD33 的 NK 细胞双特异性抗体疗法
- 批准号:
10601351 - 财政年份:2021
- 资助金额:
$ 11.39万 - 项目类别:
Optimizing NK Cell-Engaging Bispecific Antibody Therapy Targeting CD33
优化靶向 CD33 的 NK 细胞双特异性抗体疗法
- 批准号:
10197394 - 财政年份:2021
- 资助金额:
$ 11.39万 - 项目类别:
Novel Approaches to CD33-Directed Radioimmunotherapy
CD33 定向放射免疫治疗的新方法
- 批准号:
10318979 - 财政年份:2019
- 资助金额:
$ 11.39万 - 项目类别:
Novel Approaches to CD33-Directed Radioimmunotherapy
CD33 定向放射免疫治疗的新方法
- 批准号:
10601434 - 财政年份:2019
- 资助金额:
$ 11.39万 - 项目类别:
CAR T-Cell Therapy Targeting the Membrane-Proximal C2-Set Domain of CD33 for Treatment of Acute Myeloid Leukemia and Other CD33-Expressing Hematopoietic Neoplasms
靶向 CD33 近膜 C2 组结构域的 CAR T 细胞疗法用于治疗急性髓系白血病和其他表达 CD33 的造血肿瘤
- 批准号:
10603015 - 财政年份:2019
- 资助金额:
$ 11.39万 - 项目类别:
Novel Approaches to CD33-Directed Radioimmunotherapy
CD33 定向放射免疫治疗的新方法
- 批准号:
10523534 - 财政年份:2019
- 资助金额:
$ 11.39万 - 项目类别:
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