Creation of an Anti-CD40 Superagonistic Monoclonal Antibody

抗 CD40 超激动单克隆抗体的创建

• 批准号: 7672854
• 负责人: HILLARY D. WHITE
• 金额: $ 32.99万
• 依托单位: IMMURX LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7672854
• 关键词: Adjuvant; Affinity; Agonist; Alligators; Antibodies; Antigens; Back; Binding; Biological Models; CD8B1 gene; Cancer Model; Cellular Immunity; Cellular Immunology; Clinical Trials; Commit; Contracts; Cooperative Research and Development Agreement; Data; Development; Directed Molecular Evolution; Disease; Dose-Limiting; Event; Face; Family; Frequencies; Genes; Goals; Hepatotoxicity; Human; Hybridomas; Immune response; Immunity; Immunization; Immunologics; Knock-in Mouse; Lead; Legal patent; Libraries; Ligands; Malignant Neoplasms; Measures; Metastatic Melanoma; Molecular; Molecular Bank; Monoclonal Antibodies; Mus; Mutate; National Institute of Allergy and Infectious Disease; Phage Display; Pharmaceutical Preparations; Phase; Primates; Prior Therapy; Safety; Scientist; Series; Small Business Innovation Research Grant; Small Business Technology Transfer Research; T memory cell; T-Lymphocyte; TLR4 gene; TNFRSF5 gene; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toll-like receptors; Toxic effect; Toxicology; Transgenic Mice; Translating; Tumor Immunity; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Vaccine Adjuvant; Vaccines; Variant; base; clinical efficacy; combinatorial; improved; in vitro activity; in vivo; meetings; melanoma; mouse model; nonhuman primate; novel; programs; public health relevance; receptor; safety testing; therapeutic development; tumor

Description: The overall goal of this revised SBIR application is to produce and test monoclonal antibodies (mab) to human CD40 that possess "super-agonistic" activity, as part of an adjuvant platform. The term "superagonist" is defined by specific immunological activities that these mabs possess, activities that are distinct from and superior to those of current CD40 agonists. At this time, anti-murine CD40 superagonists exist, however their anti-human (h) CD40 counterparts do not exist. ImmuRx is committed to the development of "super-agonistic" anti-hCD40 mabs as part of a novel, proprietary vaccine adjuvant platform. This adjuvant will be an integral component of therapeutic anti-tumor immunity. This proprietary adjuvant platform is based on the combined use of CD40 "superagonists" and TLR agonists to amplify cell-mediated immunity effectively and safely. The goal here is to produce and identify lead CD40 "superagonists" for continued development into a Phase II program. "Super-agonistic" mabs specific for hCD40 will be identified and produced through a modified Phage display approach. Under contract with Alligator BioSciences, a human H-L molecular library will be produced from 8 previously identified agonistic anti-human CD40 mabs. From these 8 mabs, the VH/VL library will be mutated using the FIND proprietary technology allowing millions of new variants to be produced and thousands to be tested. An additional round of affinity/functional maturation will be performed. Alligator will provide 40-100 mabs to hCD40 with high levels of agonistic activities. These will represent the starting library of mabs for the SBIR from which lead super-agonistic mab candidates will be tested and selected. In addition, ImmuRx will also take a conventional, independent approach and produce mouse anti-h CD40 mabs. While "super- agonists" will be identified by their in vitro activities, definitive verification of the activities of lead candidates and their ability to synergize with TLR agonistics will be determined by in vivo testing in hCD40 knock-in mice. These "humanized" knock-in mice will allow the testing of lead CD40 superagonists for inducing heightened cell-mediated immunity and the assessment of possible toxicity due to antibody-based therapy, prior to advancing into sub-human primates. There is a substantial need for potent and safe adjuvants to immunize against melanoma. Super-agonistic anti-CD40 mabs represent part of a powerful and new adjuvant platform that will allow the development of such vaccines. PUBLIC HEALTH RELEVANCE: Vaccines have been the most successful interventional therapy that mankind has known. They have all but wiped certain diseases from the face of the earth. This application is to produce a drug that will enhance the power of vaccines to improve their capacities to treat metastatic melanoma.

产品描述：这项修订后的SBIR申请的总体目标是生产和测试具有“超激动”活性的抗人CD 40单克隆抗体（mAb），作为佐剂平台的一部分。术语“超激动剂”由这些单克隆抗体所具有的特异性免疫活性定义，所述活性不同于并且上级于目前的CD 40激动剂的活性。此时，存在抗鼠CD 40超激动剂，但不存在其抗人（h）CD 40对应物。ImmuRx致力于开发“超级激动剂”抗hCD 40单克隆抗体，作为新型专有疫苗佐剂平台的一部分。该佐剂将是治疗性抗肿瘤免疫的组成部分。 这种专有的佐剂平台是基于CD 40“超激动剂”和TLR激动剂的组合使用，以有效和安全地增强细胞介导的免疫力。这里的目标是生产和鉴定领先的CD 40“超激动剂”，以继续发展到II期计划。将通过改良的噬菌体展示方法鉴定和产生对hCD 40特异的“超激动性”单克隆抗体。根据与Alligator BioSciences的合同，将从8种先前鉴定的激动性抗人CD 40单克隆抗体中产生人H-L分子文库。从这8个单克隆抗体中，将使用FIND专有技术对VH/VL文库进行突变，从而产生数百万种新变体并测试数千种变体。将进行另一轮亲和力/功能成熟。Alligator将为hCD 40提供40-100个具有高水平激动活性的单克隆抗体。这些将代表SBIR的起始mAb文库，将从该文库中检测和选择先导超级激动性mAb候选物。此外，ImmuRx还将采用传统的独立方法生产小鼠抗h CD 40单克隆抗体。虽然“超激动剂”将通过它们的体外活性来鉴定，但是先导候选物的活性及其与TLR激动剂协同作用的能力的确定性验证将通过在hCD 40敲入小鼠中的体内测试来确定。这些“人源化”基因敲入小鼠将允许在进入亚人灵长类动物之前测试用于诱导增强的细胞介导的免疫力的前导CD 40超激动剂，并评估由于基于抗体的治疗引起的可能毒性。对有效且安全的佐剂以免疫对抗黑素瘤存在实质性需求。超级激动性抗CD 40单克隆抗体代表了一个强大的和新的佐剂平台，将允许开发这样的疫苗的一部分。 公共卫生相关性：疫苗是人类已知的最成功的介入治疗。他们几乎把某些疾病从地球上消灭了。这项申请是为了生产一种药物，将提高疫苗的力量，以提高其治疗转移性黑色素瘤的能力。