SBIR Phase I: Generation of directly active monoclonal antibodies to CD19 for the treatment of B-cell malignancies

该小型企业创新研究（SBIR）I期项目的更广泛影响/商业潜力涉及用于治疗B细胞癌症（白血病和淋巴瘤）的新型单克隆抗体（mAb）疗法。目前治疗这些癌症的药物会引起严重的副作用，患者绝大多数会复发。本文提出的试剂可能是第一种直接诱导这些疾病的有效治疗效果的mAb，并且被设计为比目前的疗法更具肿瘤特异性。因此，这些试剂提供了治愈的潜力，同时最大限度地减少了副作用的可能性。耐受性良好且有效的治疗剂是这些恶性肿瘤的已知未满足的需求。此外，这些直接活性mAb可以提供比最近批准的工程抗体更实惠的选择。对这些单克隆抗体的研究将阐明受体结构元件与其功能之间的关系。 这些单克隆抗体的成功将验证一个新的药物靶点发现平台，该平台将用于开发治疗其他癌症和自身免疫性疾病的抗体。这个小企业创新研究（SBIR）第一阶段项目应用了一个药物发现平台，专注于开发针对负责驱动致癌信号和恶性表型的膜受体的mAb。这些新的抗体可以通过中断细胞生长/存活途径诱导直接的生物学效应。控制涉及细胞存活和增殖的多种活化途径的关键参与者之一是CD 19，其在B细胞上普遍表达，并且其失调导致B细胞恶性肿瘤。尽管CD 19已被用作B细胞特异性药物靶标，但目前还没有直接影响该受体信号功能的疗法。这项工作有可能产生针对CD 19上两个选定表位的mAb。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

The broader impact /commercial potential of this Small Business Innovation Research (SBIR) Phase I project relates to novel monoclonal antibody (mAb) therapies for the treatment of B-cell cancers (leukemias and lymphomas). Current drugs for these cancers cause severe side effects, and patients overwhelmingly relapse. The reagents proposed here could be the first mAbs to directly induce potent therapeutic effect in these diseases and are designed to be more tumor-specific than current therapies. Thus, the reagents offer the potential of a cure while minimizing the likelihood of side effects. Well-tolerated and effective therapeutics are a known unmet need for these malignancies. Additionally, these directly active mAbs could provide more affordable options than the engineered antibodies that have recently been approved. Research on these mAbs will elucidate the relationship between structural elements of receptors and their function. The success of these mAbs will validate a novel drug-target discovery platform, which will be applied in developing antibodies to treat other cancers and autoimmune diseases. This Small Business Innovation Research (SBIR) Phase I project applies a drug discovery platform, focused on developing mAbs to membrane receptors responsible for driving oncogenic signaling and malignant phenotypes. These novel antibodies may induce direct biologic effects by interrupting cell-growth/survival pathways. One of the key players in controlling multiple activation pathways involved in cell survival and proliferation is CD19, which is ubiquitously expressed on B-cells and its dysregulation leads to B-cell malignancies. Though CD19 has been used as a B-cell-specific drug target, no therapies exist that directly impact the signaling function of this receptor. This work has the potential to generate mAbs to two selected epitopes on CD19. mAbs that are specific and directly active will be further developed for clinical use.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.