Phase I study of intravenously applied bispecific antibody in renal cell cancer patients receiving subcutaneous interleukin 2.
Phase I study of intravenously applied bispecific antibody in renal cell cancer patients receiving subcutaneous interleukin 2.
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DOI：
10.1038/bjc.1994.366
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发表时间：
1994-10
影响因子：
8.8
通讯作者：
Mulder, N. H.
中科院分区：
文献类型：
--
作者：
Kroesen, B. J.;Buter, J.;Sleijfer, D. Th.;Janssen, R. A. J.;Van Der Graaf, W. T. A.;The, T. H.;De Leij, L.;Mulder, N. H.
在一项I期试验中，研究了静脉（i.v）双特异性单克隆抗体BIS-1和皮下（s.c）白介素2 （IL-2）联合治疗肾细胞癌患者的毒性和免疫调节作用。BIS-1结合了对T淋巴细胞上CD3的特异性和对40 kDa的胰腺癌相关抗原EGP-2的特异性。患者在给予标准sc IL-2治疗的同时，静脉注射BIS-1 F(ab')2片段，剂量分别为1、3和5微克/公斤体重。对于每个剂量，4名患者在IL-2治疗的第二和第四周接受2小时BIS-1输注治疗。在3和5微克kg-1剂量水平下，2/4和5/5患者分别观察到急性BIS-1 F(ab')2相关毒性，表现为寒战、周围血管收缩和暂时性呼吸困难。BIS-1 F(ab')2的最大耐受剂量（MTD）为5微克kg-1。MTD检测到肿瘤坏死因子α (tnf - α)和干扰素γ (ifn - γ)血浆水平升高。流式细胞分析显示BIS-1 F(ab')2与循环T淋巴细胞的结合呈剂量依赖性。在体外实验中，用3和5微克kg-1 BIS-1处理后分离的外周血单核细胞（PBMCs）显示出对EGP-2+肿瘤细胞的特异性细胞溶解能力增加。通过向实验中添加过量的BIS-1来评估pbmc的最大杀伤能力，在以5微克kg-1 BIS-1 F(ab')2输注BIS-1后显示下降。观察到外周血循环单核细胞的BIS-1 F(ab')2剂量依赖性消失。在循环CD3+ CD8+淋巴细胞群内。LFA-1 α -bright和HLA-DR+ t细胞数量优先下降。结果表明，i.v. BIS-1 F(ab')2与s.c.l -2联合使用时，其MTD为5微克kg-1。治疗赋予T淋巴细胞特异性抗egp -2导向的细胞毒潜能。
In a phase I trial the toxicity and immunomodulatory effects of combined treatment with intravenous (i.v.) bispecific monoclonal antibody BIS-1 and subcutaneous (s.c.) interleukin 2 (IL-2) was studied in renal cell cancer patients. BIS-1 combines a specificity against CD3 on T lymphocytes with a specificity against a 40 kDa pancarcinoma-associated antigen, EGP-2. Patients received BIS-1 F(ab')2 fragments intravenously at doses of 1, 3 and 5 micrograms kg-1 body weight during a concomitantly given standard s.c. IL-2 treatment. For each dose, four patients were treated with a 2 h BIS-1 infusion in the second and fourth week of IL-2 therapy. Acute BIS-1 F(ab')2-related toxicity with symptoms of chills, peripheral vasoconstriction and temporary dyspnoea was observed in 2/4 and 5/5 patients at the 3 and 5 micrograms kg-1 dose level respectively. The maximum tolerated dose (MTD) of BIS-1 F(ab')2 was 5 micrograms kg-1. Elevated plasma levels of tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) were detected at the MTD. Flow cytometric analysis showed a dose-dependent binding of BIS-1 F(ab')2 to circulating T lymphocytes. Peripheral blood mononuclear cells (PBMCs), isolated after treatment with 3 and 5 micrograms kg-1 BIS-1, showed increased specific cytolytic capacity against EGP-2+ tumour cells as tested in an ex vivo performed assay. Maximal killing capacity of the PBMCs, as assessed by adding excess BIS-1 to the assay, was shown to be decreased after BIS-1 infusion at 5 micrograms kg-1 BIS-1 F(ab')2. A BIS-1 F(ab')2 dose-dependent disappearance of circulating mononuclear cells from the peripheral blood was observed. Within the circulating CD3+ CD8+ lymphocyte population. LFA-1 alpha-bright and HLA-DR+ T-cell numbers decreased preferentially. It is concluded that i.v. BIS-1 F(ab')2, when combined with s.c. IL-2, has a MTD of 5 micrograms kg-1. The treatment endows the T lymphocytes with a specific anti-EGP-2-directed cytotoxic potential.
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影响因子：
8.4
作者：
BUTER, J;JANSSEN, RAJ;MULDER, NH
通讯作者：
MULDER, NH
影响因子：
6.4
作者：
RIVOLTINI, L;CATTORETTI, G;PARMIANI, G
通讯作者：
PARMIANI, G
影响因子：
6.4
作者：
BRAAKMAN, E;GOEDEGEBUURE, PS;BOLHUIS, RLH
通讯作者：
BOLHUIS, RLH
影响因子：
5.8
作者：
JANSSEN, RAJ;BUTER, J;DELEIJ, L
通讯作者：
DELEIJ, L
影响因子：
6.4
作者：
FERRINI, S;PRIGIONE, I;MORETTA, L
通讯作者：
MORETTA, L