Use of milatuzumab in modulating graft vs. host disease

描述(申请人提供)：在Hu-SCID小鼠中用milatuzumab控制移植物抗宿主病(GVHD)，树突状细胞(DC)是移植物抗宿主病(GVHD)的主要始发者，GVHD是异基因造血干细胞移植(AllHSCT)的主要和威胁生命的并发症。DC耗竭已被证明是控制GVHD的有效方法。我们最近发现，人源化的抗CD74单抗Milatuzumab可以有效地清除人外周血单个核细胞中的髓样DC，并在不损害同种异体混合白细胞培养的CMV特异性CD8+T细胞的情况下，有效地抑制同种异体反应性T细胞的增殖，提示Milatuzumab可能成为预防和/或治疗GVHD的一种新型单抗。在这项拟议的研究中，我们将在人-PBL-SCID小鼠模型上评价这种新型单抗对GVHD的预防效果。我们还将研究Milatuzumab在控制GVHD的同时，是否对该模型中的第三方免疫功能有任何不利影响，包括抗病毒和移植物抗白血病功能，这将为临床使用这种单抗在异基因造血干细胞移植患者中提供关键的安全信息。我们相信，通过免疫医学公司和分子医学和免疫学中心的合作，这项STTR项目可能会导致开发一类新的单抗，通过耗尽表达CD74的髓系树突状细胞来更好地控制移植物抗宿主病。 公共卫生相关性：在Hu-SCID小鼠中，Milatuzumab控制移植物抗宿主病(GVHD)是异基因造血干细胞移植的主要威胁生命的并发症。Milatuzumab是一种人源化的抗CD74单抗，可以有效地清除人外周血单核细胞中的树突状细胞，提示其具有预防和/或治疗GVHD的潜力。我们将在人源化的小鼠模型上评估Milatuzumab对GVHD的预防效果，并在控制GVHD的同时，评估其是否对宿主抗病原体和白血病的免疫功能产生有害影响，包括抗病毒和移植物抗白血病功能。这项临床前研究可以为未来的临床研究提供有价值的信息。

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.