Development of ADAM10 Prodomain as a Therapeutic Agent

ADAM10 Prodomain 作为治疗剂的开发

• 批准号: 7674433
• 负责人: PETER J DEMPSEY
• 金额: $ 10.74万
• 依托单位: BIOZYME, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674433
• 关键词: Adverse effects; Applications Grants; Biological Assay; Biology; Cancer cell line; Cause of Death; Cell Adhesion Molecules; Cell Proliferation; Cell Surface Receptors; Cells; Cessation of life; Chimeric Proteins; Chinese Hamster Ovary Cell; Development; Disease; Disintegrin Domain; Disintegrins; Drug Kinetics; ERBB2 gene; Event; Extracellular Domain; Family member; Fc domain; Goals; Grant; Half-Life; Human; Immunoglobulin G; Immunoglobulins; In Vitro; Inhibition of Cell Proliferation; Ligands; Malignant Neoplasms; Matrix Metalloproteinases; Metalloproteases; Modeling; Peptide Hydrolases; Pharmacodynamics; Physiology; Plasma; Production; Proteins; Recombinant Fusion Proteins; Recombinants; Research; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Small Business Technology Transfer Research; Specificity; Therapeutic; Therapeutic Agents; Treatment Efficacy; United States; base; betacellulin; cancer therapy; chemotherapeutic agent; design and construction; improved; in vivo; inhibitor/antagonist; large scale production; metaplastic cell transformation; novel; novel strategies; public health relevance; technology development; therapeutic protein; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Recent cancer therapies have focused on using biologics to target specific signal transduction pathways implicated in the tumor development or progression. For example, recombinant fusion proteins consisting of the extracellular domain of the immunoregluatory proteins and the constant (Fc) domain of immunoglobulin (IgG) represent a growing class of protein therapeutics with improved plasma half-lives and with the potential for avoiding many of the side effects associated with traditional chemotherapeutic agents. Disintegrin- metalloproteases such as ADAM10 (Kuzbanian) are sheddases involved in the ectodomain cleavage of a variety of cell surface receptors, ligands, adhesion molecules and other signaling molecules. Many ADAM substrates are involved in signaling events that are dysregulated in cancers and/or during tumor progression. Indeed, several recent studies have highlighted the potential of targeting ADAM family members as a new approach for anti-tumor therapies. We have recently demonstrated that bacterially-expressed recombinant ADAM10 prodomain is a potent and specific inhibitor of ADAM10 catalytic activity. Importantly, the recombinant ADAM10 prodomain was capable of inhibiting substrate shedding (e.g. betacellulin (BTC) and HER2) in cell- based assays and could inhibit cell proliferation of human cancer cell lines in vitro. The long-term objective of our research is to understand the biology of ADAM proteases in normal physiology and disease states. The goal of this specific STTR grant proposal is to employ recombinant Fc fusion technology for the development and characterization of an ADAM10 prodomain-Fc fusion protein as a cancer therapeutic agent. PUBLIC HEALTH RELEVANCE: Cancer is the second leading cause of death in the United States with over 500,000 cancer deaths each year. The disintegrin-metalloprotease ADAM10 is required for the activation of several critical signaling pathways (e.g. HER2 signaling) involved in cellular transformation and tumor progression. This grant proposes to develop the ADAM10 prodomain-Fc fusion protein as a novel cancer therapeutic.

描述（由申请人提供）：最近的癌症治疗集中于使用生物制剂靶向与肿瘤发生或进展有关的特定信号转导途径。例如，由免疫调节蛋白的细胞外结构域和免疫球蛋白（IgG）的恒定（Fc）结构域组成的重组融合蛋白代表了一类不断增长的蛋白质治疗剂，其具有改善的血浆半衰期并且具有避免与传统化疗剂相关的许多副作用的潜力。去整合素-金属蛋白酶如ADAM 10（Kuzbanian）是参与多种细胞表面受体、配体、粘附分子和其它信号传导分子的胞外域切割的脱落酶。许多ADAM底物参与在癌症中和/或在肿瘤进展期间失调的信号传导事件。事实上，最近的几项研究强调了靶向ADAM家族成员作为抗肿瘤治疗新方法的潜力。我们最近已经证明，细菌表达的重组ADAM 10前结构域是一种有效的和特异性的ADAM 10催化活性的抑制剂。重要的是，重组ADAM 10前结构域能够在基于细胞的测定中抑制底物脱落（例如β细胞素（BTC）和HER 2），并且可以在体外抑制人类癌细胞系的细胞增殖。我们研究的长期目标是了解ADAM蛋白酶在正常生理和疾病状态下的生物学。该特定STTR资助提案的目标是采用重组Fc融合技术开发和表征作为癌症治疗剂的ADAM 10前结构域-Fc融合蛋白。癌症是美国第二大死亡原因，每年有超过50万人死于癌症。去整合素-金属蛋白酶ADAM 10是激活参与细胞转化和肿瘤进展的几种关键信号传导途径（例如HER 2信号传导）所必需的。该资助计划开发ADAM 10前结构域-Fc融合蛋白作为新型癌症治疗药物。