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（由应用提供）：造血干细胞（HSC）移植的问题是原发性或继发晶粒衰竭的风险。例如，在患有血液学恶性肿瘤的患者中，他们的第一次骨髓性同种造血细胞移植，一级谷物衰竭为5.5％。由于原发性谷物衰竭而没有缓解的原发性差异后，一年的总生存率低至11％。主要移植物失败的危险因素是移植的HSC数量不足，并且由于患者的身体状况不佳而导致的化学疗法和辐射调节强度的强度不足。在某些非恶性疾病（例如范科尼贫血）中，HSC移植也需要降低的强度调节。我们即将开始对利妥昔单抗的联合疗法和我们的重组，亲和力增强的蛋白AD35K ++的临床试验，从而耗尽了细胞表面补体抑制蛋白CD46，从而增强了癌症中体内抗体治疗的增强。出乎意料的是，我们发现该蛋白可能具有显着的外生体使用：仅将AD35K ++添加到人CD34+细胞中时，会大大增强其植入骨髓的动物的能力。这对HSC移植具有重要意义。该项目将把这种HSC植入增强候选者转移到人类的临床测试中。改善需要植入疗法的临床结果的公共卫生影响很大。从此处提出的研究结果中受益的特定领域包括：接受人类HSC，HSC基因治疗的人源化小鼠模型以及通过HSC移植治疗的疾病。其中包括恶性疾病（白血病，淋巴瘤，神经胶质瘤，神经母细胞瘤和其他固体瘤），骨髓增生综合症，遗传疾病和代谢的先天错误。该提案的具体目的包括：1。了解AD35K ++的机制 - 介导的植入增强2.优化方法并以较低的HSC数字3。在更挑战的移植设置中测试植入增强子。在第2阶段，我们将把发现扩展到非人类灵长类动物，并开始翻译活动，导致预先开会，以支持该离体增强子的临床试验。由于我们已经开始使用Rituximab组合癌症治疗的主要候选者制造CGMP，因此该提案中发现的临床翻译应该很简单。该产品的商业潜力很明显，如果我们的早期动物模型结果在人类中得到验证，则HSC移植患者有很大的好处。