Zhong R K, Donnenberg A D, Shultz L D, Swerdlow S H, Lee E, Rubin J, Kozii R, Chen J, Griffin D L, Wilson J, Ball E D
Department of Medicine, Pittsburgh Cancer Institute, University of Pittsburgh, PA 15213, USA.
Leuk Res. 1996 Jul;20(7):581-9. doi: 10.1016/0145-2126(96)00004-5.
The therapeutic potential of the IgM complement-fixing murine monoclonal antibody (mAb) PM-81 (anti-CD15) against acute myeloid leukemia (AML) was assessed in a SCID/hu leukemia model. Intraperitoneal (i.p.) injection of NB4 leukemia cells resulted in aggressive growth of leukemia cells in the peritoneal cavity of irradiated SCID/CB-17 mice. Flow cytometric analysis of human CD15, 33 and 45 expression, as well as cytologic examination, revealed that leukemia cells disseminated into the peripheral blood and multiple tissues of the mice. The approximately linear relationship between the injected leukemia cells and the subsequent leukemia cell proliferation provided a reliable model for monitoring the therapeutic effects of immunotherapy. Intraperitoneal injection of the mAb PM-81 markedly suppressed leukemia cell growth in this SCID/leukemia model. Most of the untreated mice died within 35-50 days of leukemia cell inoculation. Four weeks after inoculation of NB4 cells, five of nine mAb PM-81 treated mice had no solid tumor growth and six of nine had no detectable peritoneal exudate leukemia cells as determined by flow cytometry. In contrast, 100% of the mice in the untreated or control mAb groups were found to have both solid and peritoneal leukemia growth. In further experiments designed to evaluate the effects of therapy on survival, 50% (4/8) of PM-81 treated mice survived to 150 days, and had no detectable solid or suspension leukemia cells detectable at necropsy. In contrast, the median survival of untreated or negative control antibody-treated mice was 40 days (comparison to PM-81 treated; p = 0.006 and p = 0.03, respectively). The mechanism of leukemia cell suppression is not likely due to complement fixation since we could not demonstrate in vitro any cytotoxicity mediated by SCID mouse plasma. Further study is required to understand the mechanism of the antileukemia effect of PM-81 in this model.
在SCID/hu白血病模型中评估了IgM补体结合型鼠单克隆抗体（mAb）PM-81（抗CD15）对急性髓系白血病（AML）的治疗潜力。腹腔内（i.p.）注射NB4白血病细胞导致照射后的SCID/CB-17小鼠腹腔内白血病细胞的侵袭性生长。对人CD15、33和45表达的流式细胞术分析以及细胞学检查显示，白血病细胞扩散到小鼠的外周血和多个组织中。注射的白血病细胞与随后的白血病细胞增殖之间的近似线性关系为监测免疫治疗的疗效提供了可靠的模型。在这个SCID/白血病模型中，腹腔内注射mAb PM-81显著抑制了白血病细胞的生长。大多数未治疗的小鼠在接种白血病细胞后35 - 50天内死亡。接种NB4细胞四周后，通过流式细胞术测定，9只接受mAb PM-81治疗的小鼠中有5只没有实体瘤生长，9只中有6只没有可检测到的腹腔渗出液白血病细胞。相比之下，未治疗组或对照单克隆抗体组的小鼠100%都有实体和腹腔白血病生长。在进一步评估治疗对生存影响的实验中，50%（4/8）接受PM-81治疗的小鼠存活至150天，尸检时未检测到实体或悬浮白血病细胞。相比之下，未治疗或阴性对照抗体治疗的小鼠的中位生存期为40天（与PM-81治疗组相比；p分别为0.006和0.03）。白血病细胞抑制机制不太可能是由于补体固定，因为我们在体外未能证明SCID小鼠血浆介导的任何细胞毒性。需要进一步研究以了解该模型中PM-81抗白血病作用的机制。
