Use of milatuzumab in modulating graft vs. host disease

米拉妥珠单抗在调节移植物抗宿主病中的用途

• 批准号: 8061187
• 负责人: Chien Hsing K. Chang
• 金额: $ 19.11万
• 依托单位: IMMUNOMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-15 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061187
• 关键词: Acute Graft Versus Host Disease; Allogenic; Animals; Blood; CD8B1 gene; Cells; Clinical; Clinical Trials; Collaborations; Complication; Cytolysis; Cytomegalovirus; Dendritic Cells; Development; Disease; Disease model; Dose; Engraftment; Failure; Frequencies; Future; HLA A*0201 antigen; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Housing; Human; Immune response; Immunity; In Vitro; Infection; Infiltration; Lead; Leukemic Cell; Leukocytes; Life; Liver; Lung; Lymphocyte; Measures; Methods; Modeling; Molecular Immunology; Molecular Medicine; Monoclonal Antibodies; Mononuclear; Myelogenous; Patients; Peripheral; Peripheral Blood Lymphocyte; Peripheral Blood Mononuclear Cell; Phase; Play; Preparation; Prevention; Preventive; Relapse; Reporting; Residual state; Role; SCID Mice; SCID-hu Mice; Safety; Severity of illness; Small Business Technology Transfer Research; Staining method; Stains; Stem cell transplant; Steroids; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Transplantation; Viral; conditioning; cytokine; dosage; graft vs host disease; immune function; in vivo; leukemia; mortality; mouse model; novel; pathogen; pre-clinical; preclinical study; prevent; prophylactic; research study; sound

DESCRIPTION (provided by applicant): Control of GVHD by milatuzumab in hu-SCID mice Dendritic cells (DCs) are the primary initiator of graft-versus-host disease (GVHD), a major and life- threatening complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Depletion of DCs has been demonstrated to be an effective approach for control of GVHD. We recently found that milatuzumab, a humanized anti-CD74 monoclonal antibody, can efficiently deplete myeloid DCs from human peripheral blood mononuclear cells, and potently suppress the proliferation of alloreactive T cells without impairing CMV-specific CD8+ T cells in allogeneic mixed leukocyte cultures, suggesting that milatuzumab may be developed as a novel mAb for prophylactic and/or therapeutic control of GVHD. In this proposed study, we will evaluate the efficacy of this novel mAb for its prophylactic efficacy against GVHD in a human-PBL-SCID mouse model. We will also investigate whether milatuzumab, while controlling GVHD, has any detrimental effect on the "third-party" immunity in this model, including anti-viral and graft-versus-leukemic functions, which will provide key safety information for clinical use of this mAb in patients undergoing allo-hematopoietic stem cell transplant. We believe that this STTR project, through the collaboration between Immunomedics, Inc., and the Center for Molecular Medicine and Immunology, could lead to the development of a novel class of monoclonal antibodies for better control of GVHD through depletion of CD74-expressing myeloid DCs. PUBLIC HEALTH RELEVANCE: Control of GVHD by milatuzumab in hu-SCID mice Graft-versus-host disease (GVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. Milatuzumab, a humanized anti-CD74 monoclonal antibody, can efficiently deplete dendritic cells from human peripheral mononuclear cells, suggesting its potential to prevent and/or treat GVHD. We will evaluate the preventive efficacy of milatuzumab on GVHD in a "humanized" mouse model, and while controlling GVHD, if it has any harmful effect on the host immunity against pathogens and leukemia, including anti-viral and graft-versus-leukemic functions. This preclinical study could provide valuable information to justify future clinical investigations.

描述（由申请人提供）：在hu-SCID小鼠中通过米拉珠单抗控制GVHD树突细胞（DC）是移植物抗宿主病（GVHD）的主要引发者，GVHD是同种异体造血干细胞移植（alloHSCT）的主要和危及生命的并发症。已经证明消耗DC是控制GVHD的有效方法。我们最近发现，人源化抗CD 74单克隆抗体milatuzumab可以有效地从人外周血单核细胞中去除髓样DC，并有效地抑制同种异体反应性T细胞的增殖，而不损害同种异体混合白细胞培养物中CMV特异性CD 8 + T细胞，这表明milatuzumab可能被开发为用于预防和/或治疗GVHD的新型mAb。在这项拟议的研究中，我们将评估这种新型mAb在人-PBL-SCID小鼠模型中对GVHD的预防功效。我们还将研究米拉珠单抗在控制GVHD的同时，是否对该模型中的“第三方”免疫有任何不利影响，包括抗病毒和移植物抗白血病功能，这将为该mAb在接受同种异体造血干细胞移植的患者中的临床使用提供关键安全性信息。我们相信这个STTR项目，通过免疫医学公司，以及分子医学和免疫学中心的研究，可能导致开发一类新的单克隆抗体，通过耗尽表达CD 74的髓样DC来更好地控制GVHD。 公共卫生关系：在hu-SCID小鼠中通过米拉珠单抗控制GVHD移植物抗宿主病（GVHD）是异基因造血干细胞移植的主要危及生命的并发症。Milatuzumab是一种人源化抗CD 74单克隆抗体，可以有效地从人外周血单核细胞中清除树突状细胞，表明其具有预防和/或治疗GVHD的潜力。我们将在“人源化”小鼠模型中评价米拉珠单抗对GVHD的预防疗效，以及在控制GVHD时，其是否对宿主对病原体和白血病的免疫力（包括抗病毒和移植物抗白血病功能）有任何有害影响。这项临床前研究可以提供有价值的信息，以证明未来的临床研究。