Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.
Phase I dose escalation pharmacokinetic assessment of intravenous humanized anti-MUC1 antibody AS1402 in patients with advanced breast cancer.
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DOI：
10.1186/bcr2409
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Courtenay Luck N
中科院分区：
文献类型：
--
作者：
Pegram MD;Borges VF;Ibrahim N;Fuloria J;Shapiro C;Perez S;Wang K;Schaedli Stark F;Courtenay Luck N
MUC 1是一种细胞表面糖蛋白，在上皮表面建立分子屏障并参与形态发生信号转导。MUC 1糖基化的改变伴随癌症的发展，并影响细胞生长、分化、转化、粘附、侵袭和免疫监视。形成MUC 1核心蛋白的20个氨基酸串联重复序列在大多数上皮肿瘤中过表达并异常糖基化。AS 1402（以前称为R1550）是一种人源化IgG 1 k单克隆抗体，可与该串联重复序列内的PDTR序列结合，而该序列在正常细胞中未暴露。AS 1402是一种有效的抗体依赖性细胞毒性（ADCC）诱导剂，特异性针对MUC 1表达肿瘤细胞。本研究的目的是确定AS 1402单药治疗在蒽环类和紫杉烷类药物治疗后进展的局部晚期或转移性MUC 1阳性乳腺癌患者中的安全性、耐受性和药代动力学（PK）特征。患者在1至3小时内接受AS 1402静脉（i. v.）以1至16 mg/kg的剂量输注，每1至3周重复给药一次（基于患者个体化PK评估），直至疾病进展。静脉给药后多次测量血清AS 1402水平。测量人抗人抗体（HAHA）应答，以确定AS 1402的免疫原性。测定非房室药代动力学参数，并用于评估研究剂量范围内的剂量依赖性。26名患者接受了治疗。AS 1402通常耐受性良好。报告了2例3/4级药物相关不良事件，均为3 mg/kg剂量。在扩展或后续给药队列中均未观察到。未检测到抗人抗体。在评估的1- 16 mg/kg剂量范围内，AS 1402的血浆浓度似乎与剂量成比例，平均终末半衰期为115.4 ± 37.1小时。AS 1402重复iv给药耐受性良好，最大耐受剂量（MTD）超过16 mg/kg，这是本研究的最高给药剂量。AS 1402的半衰期和暴露量使得每周一次给药可达到与体外观察到的最大ADCC活性相对应的血浆浓度。正在进行一项II期研究，以评价AS 1402在晚期乳腺癌患者中的临床活性。ClinicalTrials.gov标识符：NCT 00096057。
MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. Alterations in MUC1 glycosylation accompany the development of cancer and influence cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance. A 20-amino-acid tandem repeat that forms the core protein of MUC1 is overexpressed and aberrantly glycosylated in the majority of epithelial tumors. AS1402 (formerly R1550) is a humanized IgG1k monoclonal antibody that binds to PDTR sequences within this tandem repeat that are not exposed in normal cells. AS1402 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), specifically against MUC1-expressing tumor cells. The objective of this study was to determine the safety, tolerability, and pharmacokinetic (PK) characteristics of AS1402 monotherapy in patients with locally advanced or metastatic MUC1-positive breast cancer that had progressed after anthracyclines- and taxane-based therapy. Patients received AS1402 over a 1- to 3-hour intravenous (i.v.) infusion at doses between 1 and 16 mg/kg, with repeated dosing every 1 to 3 weeks (based on patient-individualized PK assessment) until disease progression. Serum AS1402 levels were measured at multiple times after i.v. administration. Human anti-human antibody (HAHA) responses were measured to determine the immunogenicity of AS1402. Noncompartmental pharmacokinetic parameters were determined and were used to assess dose dependency across the dose range studied. Twenty-six patients were treated. AS1402 was generally well tolerated. Two grade 3/4 drug-related adverse events were reported, both at the 3-mg/kg dose. Neither was observed in expanded or subsequent dosing cohorts. No anti-human antibodies were detected. Plasma concentrations of AS1402 appeared to be proportional to dose within the 1- to 16-mg/kg dose range assessed, with a mean terminal half-life of 115.4 ± 37.1 hours. Repeated iv administration of AS1402 was well tolerated, with a maximum tolerated dose (MTD) exceeding 16 mg/kg, the highest dose administered in this study. The half-life and exposure of AS1402 were such that weekly dosing could achieve plasma concentrations corresponding to the maximal ADCC activity observed in vitro. A phase II study is ongoing to evaluate the clinical activity of AS1402 in patients with advanced breast cancer. ClinicalTrials.gov Identifier: NCT00096057.
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