A recombinant protein that increases engraftment of hematopoietic stem cells

一种增加造血干细胞植入的重组蛋白

• 批准号: 9048950
• 负责人: DARRICK Albert CARTER
• 金额: $ 20.86万
• 依托单位: PAI LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9048950
• 关键词: Affinity; Allogenic; Animal Model; Animals; Antibody Therapy; Area; Bone Marrow; CD34 gene; CD46 Antigen; Cell Count; Cell Survival; Cell surface; Cells; Clinical; Clinical Protocols; Clinical Trials; Combined Modality Therapy; Complement; Cyclic GMP; Data; Development; Disease; Dose; Dysmyelopoietic Syndromes; Engraftment; Enhancers; Fanconi' s Anemia; Future; Gene Expression; Genetic Engineering; Glioma; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hereditary Disease; Homing; Human; Inborn Errors of Metabolism; Lead; Lentivirus Vector; Ligation; Malignant - descriptor; Malignant Neoplasms; Mediating; Monoclonal Antibodies; Mus; Neuroblastoma; Non-Malignant; Outcome; Patients; Phase; Proteins; Protocols documentation; Public Health; Radiation; Recombinant Proteins; Recombinants; Relapse; Risk; Risk Factors; Signal Transduction; Solid Neoplasm; Stem cell transplant; Testing; Time; Translations; Transplant Recipients; Transplantation; Treatment Protocols; Viral Vector; chemotherapy; clinical application; combination cancer therapy; conditioning; gene therapy; graft failure; hematopoietic cell transplantation; humanized mouse; improved; in vivo; leukemia/lymphoma; meetings; mouse model; nonhuman primate; physical conditioning; preconditioning; public health relevance; research clinical testing; rituximab; success

 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.

 描述（由申请人提供）：造血干细胞（HSC）移植的一个问题是原发性或继发性移植失败的风险。例如，在接受首次清髓性异基因造血细胞移植的恶性血液病患者中，原发性移植物衰竭为5.5%。由于原发性移植物衰竭而再次移植后无复发的一年总生存率低至11%。原发性移植失败的风险因素是移植的HSC数量不足，以及由于待治疗患者的身体状况差而需要降低化疗和放疗的强度。在某些非恶性疾病如范可尼贫血中，HSC移植也需要降低强度调节。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++联合治疗的临床试验，该蛋白从细胞表面消耗补体抑制蛋白CD46，从而增强癌症的体内抗体治疗。出乎意料的是，我们已经发现这种蛋白质可能具有显著的离体用途：单独的Ad35 K ++，当加入到人CD34+细胞中时，显著增强了它们在骨髓消融动物中移植的能力。这对HSC移植具有重要意义。该项目将把这种HSC植入增强候选物推向人类临床试验。在需要植入的治疗中改善临床结果的公共卫生意义是显著的。将受益于本文提出的研究结果的具体领域包括：接受人HSC的人源化小鼠模型，HSC基因治疗和通过HSC移植治疗的疾病。其中包括恶性疾病（白血病、淋巴瘤、神经胶质瘤、神经母细胞瘤和其他实体瘤）、骨髓增生异常综合征、遗传性疾病和先天性代谢缺陷。该提案的具体目标包括：1.了解Ad35K++介导的移植增强机制2.为了优化该方法并以较低的HSC数量实现植入3.在更具挑战性的移植环境中测试植入增强剂。在第2阶段，我们将把研究结果扩展到非人灵长类动物，并开始翻译活动，导致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cGMP生产与利妥昔单抗联合治疗癌症的主要候选药物，因此本提案中的临床转化应该是直接的。该产品的商业潜力是明确的，如果我们的早期动物模型结果在人类中得到验证，对HSC移植患者有很大的益处。