Enhanced Engraftment of Stem Cells

描述(申请人提供)：增强干细胞植入。目前迫切需要提高清髓治疗后自体和异基因造血干细胞(HSC)的植入效率。尽管动员的外周血和脐带血(CB)扩大了供者细胞的可获得性，但导致发病率和死亡率的一个重要原因是未能获得完全和快速的造血重建。这通常是由于CD34+细胞数量较少；供体细胞归巢、保留和分化不足；和/或缺乏促进性细胞帮助(T细胞帮助植入和/或其他细胞群)。为了解决这些问题，我们开发了一种使用双特异性抗体(BiMab)进行细胞靶向的专利方法。一对抗体在化学上与靶细胞结合，以对抗在损伤部位发现的特定抗原。我们的初步数据显示，三种不同的BiMab增强了靶细胞在体内的保留。在第一阶段，我们将准备一套扩展的BiMabs，以展示它们改善受照小鼠的造血细胞恢复和植入的能力。显示出最大能力增强植入的BiMab将被选为第二阶段进一步开发临床候选的BiMab。干细胞增强植入造血干细胞(HSC)移植是一种常见的治疗方案，用于治疗血液系统恶性肿瘤和某些遗传和免疫疾病。HSC的高效输送、保留和分化仍然是骨髓移植成功的主要限制因素。识别骨髓特异性靶点和造血干细胞上抗原的双特异性抗体(BiMab)为极大地提高自体和同种异体干细胞治疗多种疾病的效率提供了新的手段。

DESCRIPTION (provided by applicant): Enhanced engraftment of stem cells. There is an urgent need for methods to improve the engraftment efficiency of autologous and allogeneic hematopoietic stem cells (HSC) after myeloablative therapy. Although mobilized peripheral blood and umbilical cord blood (CB) have expanded the availability of donor cells, a significant cause of morbidity and mortality is the failure to obtain complete and rapid hematopoietic reconstitution. This is most often due to the injection of low numbers of CD34+ cells; insufficient homing, retention and differentiation of donor cells; and/or lack of facilitator cell help (T cell help in engraftment and/or other cell populations). To address these problems, we have developed a proprietary approach to cell targeting using bispecific antibodies (BiMab). A pair of antibodies is chemically heteroconjugated to target cells to specific antigens found at sites of injury. Our preliminary data have shown that three different BiMabs enhance the retention of targeted cells in vivo. In Phase I we will prepare an expanded set of BiMabs to demonstrate their ability to improve hematopoietic cell recovery and engraftment of irradiated mice. The BiMab that shows the greatest capacity to enhance engraftment will be selected for further development of a clinical candidate in Phase II. Enhanced engraftment of stem cells Hematopoietic stem cell (HSC) transplantation is a common therapeutic option developed to treat hematologic malignancies and certain genetic and immunological disorders. Efficient delivery, retention and differentiation of HSC remain major limitations to the success of bone marrow engraftment. Bispecific antibodies (BiMab) recognizing a bone marrow-specific target and an antigen on hematopoietic stem cells provide a novel means to greatly improve the efficiency of autologous and allogeneic stem cell therapy for a broad spectrum of diseases.