Abstract
IntroductionMUC1 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.MethodsPatients 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.ResultsTwenty-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.ConclusionsRepeated 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.Trial registrationClinicalTrials.gov Identifier: NCT00096057.
Highlights
MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction
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 antibody-dependent cellular cytotoxicity (ADCC) activity observed in vitro
Summary
MUC1 is a cell-surface glycoprotein that establishes a molecular barrier at the epithelial surface and engages in morphogenetic signal transduction. 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 is a potent inducer of antibody-dependent cellular cytotoxicity (ADCC), against MUC1-expressing tumor cells. MUC1 is overexpressed in more than 90% of breast cancers and the majority of epithelial tumors and has prognostic value in a number of malignancies, including breast cancer [2]. The MUC1 N-terminal subunit contains a variable number of 20-amino-acid tandem repeats that are modified by Olinked glycans. The MUC1 C-terminal subunit comprises a 58amino-acid extracellular domain, a 28-amino-acid transmembrane domain, and a 72-amino-acid cytoplasmic tail. This Cterminal domain accumulates in the cytosol of transformed cells and is delivered to the nucleus and mitochondria [4]. The MUC1 cytoplasmic domain associates with β-catenin and with the p53 tumor suppressor and is subject to phosphorylation by the epidermal growth factor receptor, c-Src, and glycogen synthase kinase-3β, suggesting a role for MUC1 in the erbB receptor kinase and Wnt signaling pathways [5]
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