Pharmacokinetics and tolerability of human mouse chimeric anti-CD22 monoclonal antibody in Chinese patients with CD22-positive non-Hodgkin lymphoma

Abstract

The safety and pharmacokinetics assessment of antibodies targeting CD22 (e.g., epratuzumab) have been established in western Caucasian populations, but there are no reports of the effects in Chinese populations. This dose-escalation study examines the safety, pharmacokinetics and biologic effects of multiple doses of anti-CD22 human-murine chimeric monoclonal antibody SM03 in 21 Chinese patients with CD22-positive non-Hodgkin lymphoma. Most of drug-related adverse events (AEs) were mild and reversible. Two patients experienced serious AEs (hemorrhage); one patient had grade 4 neutropenia; one patient had asymptomatic grade III prolongation of activated partial thromboplastin time (APTT). Major AEs included fever (71%), prolongation of APTT (42.8%), leukocytopenia (44.4%), alanine transaminase elevation (28.6%), elevated serum creatinine (23.8%) and injection site skin redness (14.3%). Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. Pharmacokinetic data revealed that mean maximum observed SM03 concentration and mean AUC from time zero to infinity increased in a dose-dependent manner up to 360 mg/m (2) SM03. Mean clearance was similar at doses ≤ 360 mg/m (2) and decreased significantly at dose 480 mg/m (2), supporting saturation of B-cell binding at 360 mg/m (2). Across all dose levels and histologies, one patient achieved partial response at 480 mg/m (2) dose; 14 patients had stable disease as best response and four patients progressed. Overall, SM03 was tolerated at doses ranging from 60-480 mg/m (2) and had potential efficacy in Chinese patients with follicular lymphoma.

Keywords: anti-CD22 monoclonal antibody; pharmacokinetics; tolerance.

Figure 1

Maximum percent change from baseline in SPD for each assessable treated patient with baseline and post-baseline SPD measurements (n = 20). *Patients with absolute value of maximum percentage change ≤1. Filled triangle, SPD value >100%; open circle, patients with progressive disease as best response; no post-baseline SPD measurement available.

Figure 2

Mean (SD) serum concentrations of total SM03 after 120, 240, 360, 480 mg/m² infusion of SM03 once-weekly for 4 consecutive weeks. Filled diamond, 120 mg/m²; filled square, 240 mg/m²; filled triangle, 360 mg/m²; X, 480 mg/m².

Figure 3

Dose-normalized area under the serum-concentration time curve (AUC AUC_0→∞, ng·ml⁻¹h) as function of SM03 doses ranging from 120 to 480 mg/m² (n = 19). Filled circle, individuals; open triangle, mean.

Figure 4

Post-treatment changes in peripheral B-cell counts (n = 21). B-cell levels as measured by CD19⁺ cell count decreased by 30–70% from baseline up to 42 d at dose 360 and 480 mg/m²/week.

Figure 5

(A) Total body clearance based on body surface area (CLpBSA) as function of SM03 doses ranging 120 to 480 mg/m² (n = 19). Filled circle, individuals; open triangle, mean. (B) Total body clearance based on body surface area as function of SM03 in female and male patients. Filled square, male; filled diamond, female.