Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma.
Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma.
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DOI：
10.1182/blood.v84.8.2457.bloodjournal8482457
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发表时间：
1994
期刊：
影响因子：
20.3
通讯作者：
D. Maloney;T. Liles;DK Czerwinski;C. Waldichuk;J. Rosenberg;A. Grillo‐López;R. Levy
中科院分区：
文献类型：
--
作者：
D. Maloney;T. Liles;DK Czerwinski;C. Waldichuk;J. Rosenberg;A. Grillo‐López;R. Levy
B细胞抗原CD 20在正常B细胞和几乎所有B细胞淋巴瘤中表达。这种非调节性抗原为抗体导向疗法提供了极好的靶点。已生产了一种嵌合抗CD 20抗体（IDEC-C2 B8）用于临床试验，该抗体由人IgG 1-κ恒定区和鼠单克隆抗CD 20抗体IDEC-2B 8的可变区组成。它通过补体和抗体依赖性细胞介导的裂解作用在体外裂解CD 20+细胞。临床前研究表明，嵌合抗体选择性地消耗猕猴血液和淋巴结中的B细胞。在该I期临床试验中，用静脉内施用的单剂量（10、50、100、250或500 mg/m2）抗体治疗15名复发性低度B细胞淋巴瘤患者（每个剂量水平3名）。与循环CD 20细胞数量相关的治疗相关症状和II级事件包括发热（5例患者）、恶心（2例）、寒战（2例）、体位性低血压（2例）、支气管痉挛（1例）和血小板减少症（1例）。在3个月的随访期间未观察到明显的毒性反应。血清C3、IgG和IgM水平、中性粒细胞和T细胞基本不变。在三个较高剂量水平下，游离抗体的药代动力学显示血清半衰期为4.4天（范围，1.6 - 10.5）。9名患者中有6名患者的水平持续超过10微克/毫升，持续时间超过14天。未检测到对输注抗体的可定量免疫应答。外周血中的CD 20 + B细胞在24 - 72小时内迅速特异性耗竭，并且在大多数患者中维持耗竭至少2 - 3个月。输注后两周的肿瘤活组织检查显示嵌合抗体与肿瘤细胞结合，B细胞百分比降低。15例患者中有6例发生肿瘤消退（2例部分缓解和4例轻微缓解）。该单次给药试验的结果已用于设计多次给药I/II期研究。
The B-cell antigen CD20 is expressed on normal B cells and by nearly all B-cell lymphomas. This nonmodulating antigen provides an excellent target for antibody-directed therapies. A chimeric anti-CD20 antibody (IDEC-C2B8), consisting of human IgG1-kappa constant regions and variable regions from the murine monoclonal anti-CD20 antibody IDEC-2B8, has been produced for clinical trials. It lyses CD20+ cells in vitro via complement and antibody-dependent cell-mediated lysis. Preclinical studies have shown that the chimeric antibody selectively depletes B cells in blood and lymph nodes in macaque monkeys. In this phase I clinical trial, 15 patients (3 per dose level) with relapsed low-grade B-cell lymphoma were treated with a single dose (10, 50, 100, 250, or 500 mg/m2) of antibody administered intravenously. Treatment-related symptoms correlated with the number of circulating CD20 cells and grade II events consisted of fever (5 patients); nausea (2), rigor (2), orthostatic hypotension (2), bronchospasm (1), and thrombocytopenia (1). No significant toxicities were observed during the 3 months of follow-up. Serum C3, IgG, and IgM levels, neutrophils, and T cells were largely unchanged. At the three higher dose levels, pharmacokinetics of the free antibody showed a serum half-life of 4.4 days (range, 1.6 to 10.5). Levels greater than 10 micrograms/mL persisted in 6 of 9 patients for more than 14 days. No quantifiable immune responses to the infused antibody have been detected. CD20+ B cells were rapidly and specifically depleted in the peripheral blood at 24 to 72 hours and remained depleted for at least 2 to 3 months in most patients. Two-week postinfusion tumor biopsies showed the chimeric antibody bound to tumor cells and a decrease in the percentage of B cells. Tumor regressions occurred in 6 of 15 patients (2 partial and 4 minor responses). The results of this single-dose trial have been used to design a multiple-dose phase I/II study.