SBIR Phase I: Antibody Therapy that Targets Neoantigens in Acute Myeloid Leukemia via the Antibody Dependent Cell-mediated Cytotoxicity Mechanism of Natural Killer Cells

这个小型企业创新研究（SBIR）I期项目的更广泛的影响/商业潜力集中在提供个性化癌症治疗所需的癌症特异性抗体和过继性自然杀伤（NK）免疫细胞的独特组合上。 这项创新代表了一种平台技术，可以产生多种创新的癌症治疗方法，这可能会对生命科学创新产生积极影响，更重要的是，可以促进全球癌症人群的健康和福利。这种癌症免疫治疗的新方法预计是非常有效的，并且由于其作用机制的特异性，几乎没有毒性。鉴于全国癌症治疗的成本在2000亿美元范围内，这一点意义重大。该项目旨在提供癌症特异性抗体和过继性自然杀伤（NK）免疫细胞的独特组合，协同作用以实现高疗效，避免对健康细胞的毒性，并提供可扩展的，资源有效的和个性化的癌症治疗。该项目的重点是抗体靶向仅在患病的急性髓性白血病（AML）癌细胞中发现的新抗原，以开发复发/难治性疾病的有效治疗方法。通过首先免疫大鼠，使用专门的荧光激活细胞分选技术分离所得抗原特异性B细胞，测序和克隆抗体基因，并在生产细胞中表达抗体，产生并测试30-50种候选抗体。将检测候选抗体对新抗原靶标的特异性（酶联免疫吸附试验）和结合强度（表面等离子体共振），将列表缩减至约15种候选抗体。将通过评价抗体诱导NK细胞对AML细胞特异性杀伤来实现进一步筛选;读数将包括通过流式细胞术测量的AML靶细胞死亡和乳酸脱氢酶释放、NK细胞脱粒（指示杀伤活性）和细胞因子释放。最佳表现的3-5名候选人最终将被选中进行临床前测试。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智力价值和更广泛的影响审查标准进行评估。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project focuses on the unique combination of cancer-specific antibodies and adoptive Natural Killer (NK) immune cells needed to offer personalizable cancer therapies. This innovation represents a platform technology that can spawn multiple innovative cancer treatments, which could positively impact life sciences innovation and, more importantly, advance the health and welfare of the global cancer population. This novel approach to immunotherapy of cancer is expected to be highly efficacious and, due to the specificity of its mechanism of action, virtually devoid of toxicity. This is significant in light of the fact that the national cost of cancer care is in the $200 billion range.This project seeks to provide a unique combination of cancer-specific antibodies and adoptive Natural Killer (NK) immune cells that synergize to achieve high efficacy, avoid toxicity to healthy cells, and offer a scalable, resource-efficient and personalizable therapy for cancer. The project focus is antibody targeting of a neoantigen found exclusively in diseased Acute Myeloid Leukemia (AML) cancer cells, in order to develop an effective treatment for relapsed / refractory disease. The 30-50 candidate antibodies will be generated and tested by first immunizing rats, isolating the resulting antigen-specific B cells using a specialized fluorescence-activated cell sorting technique, sequencing and cloning the antibody genes, and expressing the antibodies in producer cells. Candidate antibodies will be tested for specificity (enzyme-linked immunosorbent assay) and binding strength (surface plasmon resonance) for the neoantigen target, whittling down the list to ~15 candidate antibodies. Further screening will be achieved by evaluating antibody induction of AML cell-specific killing by NK cells; readouts will include AML target cell death measured by flow cytometry and lactate dehydrogenase release, degranulation by NK cells (indicating killing activity), and cytokine release. The top-performing 3-5 candidates will eventually be selected for preclinical testing.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.