Structure-Activity Relationship of CM101 Tumor antiangiogenic agent with its lect

CM101肿瘤抗血管生成剂及其选择的构效关系

• 批准号: 8393539
• 负责人: Betty ChouRong Zhu
• 金额: $ 15万
• 依托单位: TUMOREND, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393539
• 关键词: Angiogenesis Inhibitors; Animals; Applications Grants; Avastin; Binding; Biochemical; Biological; Biological Assay; Blood capillaries; Businesses; Cell surface; Cells; Chemicals; Clinical Trials; Complement; Complement Activation; Development; Endothelial Cells; Endothelium; Exhibits; Failure; Fee-for-Service Plans; Future; Human; Immune; Incentives; Inflammatory; Inflammatory Response; Intellectual Property; Laboratories; Lectin; Lectin Receptors; Methodology; Molecular Structure; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Polysaccharides; Publishing; Recruitment Activity; Safety; Small Business Innovation Research Grant; Streptococcus Group B; Structure; Structure-Activity Relationship; Sum; Technology; Testing; Therapeutic; Toxin; Tumor Angiogenesis; Universities; Update; angiogenesis; base; cancer therapy; capillary; chemical substitution; cytokine; granulocyte; neoplastic cell; neovasculature; pharmacophore; receptor; tumor

DESCRIPTION (provided by applicant): CM101 is a polysaccharide tumor angiogenesis-targeting, complement activating, immune stimulating biological produced fermentatively from Group B Streptococcus. CM101 binds a capillary endothelium receptor, HP59, causing inflammatory cytokine cascades, recruiting CD69+ granulocytes to destroy neovasculature and surrounding tumor. This SBIR proposal is to determine Structure-Activity-Relationship (SAR) for CM101 to identify angiogenesis-specific HP59-targeting mechanisms and establish minimal active molecular structure (pharmacophore). CM101 is not an angiogenesis inhibitor like Avastin and related biologicals and drugs, but has a completely different mechanism of action, stimulating immune attack on HP59+ tumor neovasculature. CM101 is a promising active pharmaceutical ingredient (API) biological for cancer therapy in results from animal studies and a human Phase I safety trial published in 1997. More recent intellectual property for CM101 purification and the HP59 receptor now protects products through 2026-2028. CM101 development was interrupted by previous business failures, despite the promising technology. By establishing the pharmacophore, pinpointing biochemical binding interaction with the tumor capillary endothelium lectin receptor HP59 (See Wikipedia), we will discover mechanism of action details, new composition of matter intellectual property, and potential for development of small drug pipelines, to stimulate investors and major pharmaceutical companies' incentive to support planned Phase I/II clinical trials. In sum, CM101, the Group B Streptococcal Toxin (GBS-Toxin) is a 270Kda polysaccharide exhibits targeted binding to HP59, a specific tumor cell endothelial cell surface lectin, therefore a highly specific tumor vasculature targeting biological therapeutic, needing SAR for development. PUBLIC HEALTH RELEVANCE: This SBIR grant proposal seeks to determine the Structure-Activity-Relationship for CM101, a tumor neovasculature targeting Group B Streptococcal toxin that binds the lectin tumor angiogenesis marker HP59. HP59 binding by CM101 results in complement activation and subsequent inflammatory response against the tumor, which has been published in animal and human Phase I trials. We intend to molecularly identify the HP59 targeting mechanism, to define mechanism of action, to establish updated intellectual property, and provide potential drug pipelines by identification of a minimum pharmacophore for HP59 binding and for complement activation.

描述(申请人提供)：cm101是由B群链球菌发酵产生的一种多糖类肿瘤，具有靶向血管生成、激活补体、刺激免疫的作用。Cm101与毛细血管内皮细胞受体HP59结合，引起炎性细胞因子级联反应，募集CD69+粒细胞破坏新生血管和周围肿瘤。这个SBIR建议是为了确定cm101的结构-活性-关系(SAR)，以确定血管生成特异性的HP59靶向机制，并建立最小的活性分子结构(药效团)。Cm101不是像阿瓦斯丁及相关生物制品和药物那样的血管生成抑制剂，但具有完全不同的作用机制，刺激对HP59+肿瘤新生血管的免疫攻击。根据1997年发表的动物研究和人类I期安全性试验的结果，cm101是一种很有前途的癌症治疗活性药物成分(API)生物制剂。最近对cm101纯化和HP59受体的知识产权现在保护产品到2026-2028年。尽管技术前景看好，但cm101的开发因之前的商业失败而中断。通过建立药效团，确定与肿瘤毛细血管内皮凝集素受体HP59(见维基百科)的生化结合相互作用，我们将发现作用细节的机制、新的物质知识产权组成和开发小型药物管道的潜力，以刺激投资者和主要制药公司支持计划中的I/II期临床试验的动机。综上所述，cm101是B组链球菌毒素(GBS-Toxin)，是一种270Kda的多糖靶向结合HP59的肿瘤细胞内皮细胞表面凝集素，因此是一种高度特异的肿瘤血管生物靶向系统 治疗，需要SAR才能发展。 公共卫生相关性：这项SBIR赠款提案旨在确定cm101的结构-活性-关系。cm101是一种针对B组链球菌毒素的肿瘤新生血管，与凝集素肿瘤血管生成标记物HP59结合。Cm101与HP59的结合导致补体激活和随后的针对肿瘤的炎症反应，这已在动物和人类I期试验中发表。我们打算从分子上确定HP59的靶向机制，定义作用机制，建立最新的知识产权，并通过确定HP59结合和补体激活的最低药效基团来提供潜在的药物管道。