A recombinant protein that increases engraftment of hematopoietic stem cells

 描述(由申请人提供)：造血干细胞(HSC)移植的一个问题是原发或继发移植失败的风险。例如，在首次接受清髓异基因造血细胞移植的恶性血液病患者中，原发移植物失败率为5.5%。由于初次移植失败而无复发的再次移植后一年的总存活率低至11%。原发移植失败的危险因素是移植的造血干细胞数量不足，以及由于接受治疗的患者的身体状况不佳而需要降低化疗和放射调理的强度。对于某些非恶性疾病，如Fanconi贫血的HSC移植，也需要降低强度的调理。我们即将启动利妥昔单抗和我们的重组亲和力增强蛋白Ad35K++的联合疗法的临床试验，该疗法可以清除细胞表面的补体抑制蛋白CD46，从而增强癌症的体内抗体治疗。出乎意料的是，我们发现这种蛋白可能在体外有重要的用途：Ad35K++单独加入到人CD34+细胞中时，显著增强了它们在骨髓切除动物体内的植入能力。这对HSC移植具有重要意义。该项目将使这种造血干细胞移植增强候选方案进入人体临床试验。在需要植入的治疗中，改善临床结果的公共卫生影响是显著的。将从这里提出的研究结果中受益的具体领域包括：接受人类HSC的人源化小鼠模型、HSC基因治疗以及通过HSC移植治疗的疾病。其中包括恶性疾病(白血病、淋巴瘤、胶质瘤、神经母细胞瘤和其他实体瘤)、骨髓增生异常综合征、遗传性疾病和先天代谢缺陷。该建议的具体目的包括：1.了解Ad35K+介导的植入增强机制2.优化方法并实现较低的HSC数植入3.在更具挑战性的移植环境中测试植入增强剂。在第二阶段，我们将把这些发现扩展到非人类灵长类动物，并开始翻译活动，导致召开IND前会议，以支持这种体外增强剂的临床试验。由于我们已经开始生产我们的联合癌症治疗的主要候选药物利妥昔单抗的cGMP，所以这项建议中的发现的临床翻译应该是直截了当的。这种产品的商业潜力是显而易见的，如果我们的早期动物模型结果在人类身上得到验证，那么对HSC移植患者有很大的好处。

 DESCRIPTION (provided by applicant): A problem with hematopoietic stem cell (HSC) transplantation is the risk of primary or secondary graft failure. As an example, in patients with hematologic malignancies who underwent their first myeloablative allogeneic hematopoietic cell transplantation, primary graft failure is 5.5%. One year overall survival after re-transplantation due to primary graft failure without relapse is as low as 11%. Risk factors for primary graft failue are insufficient numbers of transplanted HSCs and the necessity to reduce the intensity of chemotherapy and radiation conditioning due to the poor physical condition of patients to be treated. Reduced intensity conditioning is also required for HSC transplantation in certain non-malignant diseases such as Fanconi anemia. We are about to initiate clinical trials on a combination therapy of rituximab and our recombinant, affinity- enhanced protein, Ad35K++, that depletes the complement inhibitory protein CD46 from the cell surface and thereby enhances in vivo antibody therapy in cancers. Unexpectedly, we have found that this protein may have a significant ex vivo use: Ad35K++ alone, when added to human CD34+ cells, dramatically enhances their ability to engraft in myelo-ablated animals. This has important implications for HSC transplantation. This project will move this HSC engraftment enhancement candidate towards clinical testing in humans. The public health implications of improving clinical outcomes in therapies that require engraftment are significant. Specific areas that would benefit from the results of the studies proposed here include: humanized mouse models that receive human HSCs, HSC gene therapy, and diseases that are treated by HSC transplantation. Among these are malignant diseases (leukemia, lymphoma, gliomas, neuroblastomas, and other solid tumors), myelodysplastic syndromes, genetic diseases, and inborn errors of metabolism. The specific aims of the proposal include: 1. To understand the mechanism of Ad35K++-mediated engraftment enhancement 2. To optimize the approach and achieve engraftment with lower HSC numbers 3. To test the engraftment enhancer in more challenging transplantation settings. In phase 2 we will extend the findings to non-human primates and begin translational activities leading to a pre-IND meeting to support clinical trials on this ex vivo enhancer. Since we have already begun cGMP manufacture of our lead candidate for combination cancer therapy with rituximab, clinical translation of the findings in this proposal should be straightforward. The commercial potential for this product is clear and there is a great benefit to HSC transplant patients if our early animal model results are verified in humans.