Boeckh M, Bowden R A, Storer B, Chao N J, Spielberger R, Tierney D K, Gallez-Hawkins G, Cunningham T, Blume K G, Levitt D, Zaia J A
Fred Hutchinson Cancer Research Center and University of Washington, Seattle 98109, USA.
Biol Blood Marrow Transplant. 2001;7(6):343-51. doi: 10.1016/s1083-8791(01)80005-7.
MSL-109 is a monoclonal antibody specific to the cytomegalovirus (CMV) glycoprotein H with high neutralizing capacity. In a prospective, randomized, double-blind study, allogeneic hematopoietic stem cell transplantation (HSCT) recipients with positive donor and/or recipient serology for CMV before transplantation received either 60 mg/kg MSL-109 (n = 59), 15 mg/kg MSL-109 (n = 60), or placebo (n = 60) intravenously every 2 weeks from day -1 until day 84 after transplantation. CMV pp65 antigenemia, CMV-DNA load in plasma, and viremia by culture were tested weekly. Primary end points were development of pp65 antigenemia at any level and/or viremia for which ganciclovir was given. There was no statistically significant difference in CMV pp65 antigenemia or viremia among patients in the 60-mg group (pp65 antigenemia, 47%; viremia, 15%), the 15-mg group (52%; 23%), and the placebo group (45%; 17%). There was also no difference in maximum levels of pp65 antigenemia, time to clearance of pp65 antigenemia after start of ganciclovir, CMV disease, invasive bacterial and fungal infections, time to neutrophil and platelet engraftment, acute graft-versus-host disease, days of hospitalization, and overall survival rate among the 3 groups. However, a subgroup analysis of CMV-seronegative recipients with a seropositive donor (D+/R-) showed a transiently improved survival rate by day 100 in MSL-109 recipients (mortality: 60-mg group, 1/13; 15-mg group, 1/12; placebo group, 6/10 [P = .02 for 60-mg versus placebo groups; P = .08 for 15-mg versus placebo groups]); by the end of follow-up, the difference was no longer statistically significant. The improved survival rate in D+/R- patients could not be attributed to a reduction in CMV disease; however, MSL-109 was associated with improved platelet engraftment and less grade III to IV acute graft-versus-host disease in this subgroup. In a subgroup analysis of CMV-seropositive recipients of MSL-109 (D+/R+ and D-/R+), overall mortality was increased compared to that of the placebo group (P = .12 for the 60-mg versus placebo groups, P = .05 for the 15-mg versus placebo groups, and P = .04 for the dose levels combined versus placebo). MSL-109 was well tolerated and no immune response to the drug was observed. Thus, MSL-109 was safe but did not reduce CMV infection in allogeneic HSCT recipients. The transient survival advantage seen early after transplantation in CMV D+/R- patients and the negative effect on survival in seropositive patients remain unexplained. Thus, there is no evidence that MSL-109 is beneficial in CMV-seropositive HSCT recipients.
MSL-109是一种针对巨细胞病毒（CMV）糖蛋白H的单克隆抗体，具有高中和能力。在一项前瞻性、随机、双盲研究中，移植前供体和/或受体血清学检测CMV呈阳性的异基因造血干细胞移植（HSCT）受者，从移植前第-1天至移植后第84天，每2周静脉注射60mg/kg MSL-109（n = 59）、15mg/kg MSL-109（n = 60）或安慰剂（n = 60）。每周检测CMV pp65抗原血症、血浆中CMV-DNA载量以及培养法检测病毒血症。主要终点是出现任何水平的pp65抗原血症和/或给予更昔洛韦治疗的病毒血症。60mg组（pp65抗原血症，47%；病毒血症，15%）、15mg组（52%；23%）和安慰剂组（45%；17%）患者的CMV pp65抗原血症或病毒血症无统计学显著差异。三组在pp65抗原血症的最高水平、开始使用更昔洛韦后pp65抗原血症清除时间、CMV疾病、侵袭性细菌和真菌感染、中性粒细胞和血小板植入时间、急性移植物抗宿主病、住院天数以及总生存率方面也无差异。然而，对供体血清学阳性（D+/R-）的CMV血清学阴性受者进行亚组分析显示，MSL-109受者在第100天时生存率有短暂改善（死亡率：60mg组，1/13；15mg组，1/12；安慰剂组，6/10 [60mg组与安慰剂组比较，P = 0.02；15mg组与安慰剂组比较，P = 0.08]）；到随访结束时，差异不再具有统计学意义。D+/R-患者生存率的提高不能归因于CMV疾病的减少；然而，在该亚组中，MSL-109与血小板植入改善以及III至IV级急性移植物抗宿主病减少有关。在MSL-109血清学阳性受者（D+/R+和D-/R+）的亚组分析中，与安慰剂组相比，总体死亡率增加（60mg组与安慰剂组比较，P = 0.12；15mg组与安慰剂组比较，P = 0.05；剂量水平合并与安慰剂组比较，P = 0.04）。MSL-109耐受性良好，未观察到对该药物的免疫反应。因此，MSL-109是安全的，但并未降低异基因HSCT受者的CMV感染。移植后早期在CMV D+/R-患者中观察到的短暂生存优势以及血清学阳性患者生存的负面影响仍无法解释。因此，没有证据表明MSL-109对CMV血清学阳性的HSCT受者有益。
