Creation of an Anti-CD40 Superagonistic Monoclonal Antibody

描述：这一修订的SBIR应用的总体目标是生产和测试抗人CD40的单抗(MAb)，作为佐剂平台的一部分，具有“超级激动剂”活性。术语“超级激动剂”是由这些单抗所具有的特定免疫活性来定义的，这些活性与目前的CD40激动剂不同并且优于那些。目前，抗鼠CD40超激动剂存在，但它们的抗人(H)CD40对应物不存在。ImmuRx致力于开发“超级激动型”抗hCD40单抗，作为一个新颖的、专有的疫苗佐剂平台的一部分。这种佐剂将成为治疗性抗肿瘤免疫的组成部分。 这个专有的佐剂平台是基于CD40“超级激动剂”和TLR激动剂的组合使用，以有效和安全地放大细胞介导的免疫。这里的目标是生产和确定领先的CD40“超级激动剂”，以便继续开发成第二阶段计划。针对hCD40的“超级激动型”单抗将通过一种改进的噬菌体展示方法进行鉴定和生产。根据与鳄鱼生物科学公司的合同，人类H-L分子文库将从8株先前鉴定的激发型抗人CD40单抗中产生。在这8个单抗中，VH/VL文库将使用Find专有技术进行突变，允许生产数百万个新的变体，并对数千个进行测试。将进行另一轮亲和力/功能成熟。鳄鱼将为hCD40提供40-100个单抗，具有高水平的激动剂活性。这些将代表SBIR的单抗的起始库，从中将测试和选择领先的超级激动型单抗候选者。此外，ImmuRx还将采取传统的独立方法，生产鼠抗h CD40单抗。虽然“超级激动剂”将通过它们的体外活性来确定，但候选铅的活性及其与TLR激动剂的协同作用的最终验证将通过hCD40基因敲入小鼠的体内测试来确定。这些人源化的敲入小鼠将允许测试领先的CD40超级激动剂，以诱导更高的细胞介导性免疫，并评估基于抗体的治疗可能导致的毒性，然后再发展为亚人类灵长类动物。有大量的有效和安全的佐剂来免疫黑色素瘤。超级激动型抗CD40单抗代表了一个强大的新佐剂平台的一部分，这将使此类疫苗的开发成为可能。 公共卫生相关性：疫苗是人类已知的最成功的介入疗法。它们几乎将某些疾病从地球表面抹去。这项应用是为了生产一种药物，这种药物将增强疫苗的力量，以提高它们治疗转移性黑色素瘤的能力。

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.