Effect of Target Dynamics on Pharmacokinetics of a Novel Therapeutic Antibody against the Epidermal Growth Factor Receptor: Implications for the Mechanisms of Action

Abstract

The epidermal growth factor receptor (EGFR) is overexpressed on many solid tumors and represents an attractive target for antibody therapy. Here, we describe the effect of receptormediated antibody internalization on the pharmacokinetics and dose-effect relationship of a therapeutic monoclonal antibody (mAb) against EGFR (2F8). This mAb was previously found therapeutically active in mouse tumor models by two dose-dependent mechanisms of action: blockade of ligand binding and induction of antibody-dependent cell-mediated cytotoxicity. In vitro studies showed 2F8 to be rapidly internalized by EGFR-overexpressing cells. In vivo, accelerated 2F8 clearance was observed in cynomolgus monkeys at low doses but not at high doses. This enhanced clearance seemed to be receptor dependent and was included in a pharmacokinetic model designed to explain its nonlinearity. Receptormediated clearance was also found to affect in situ antibody concentrations in tumor tissue. Ex vivo analyses of xenograft tumors of 2F8-treated nude mice revealed that relatively high antibody plasma concentrations were required for maximum EGFR saturation in high-EGFR-expressing human A431 tumors, in contrast to lower-EGFR-expressing human xenograft tumors. In summary, receptor-mediated antibody internalization and degradation provides a saturable route of clearance that significantly affects pharmacokinetics, particularly at low antibody doses. EGFR saturation in normal tissues does not predict saturation in tumor tissue as local antibody concentrations in EGFR-overexpressing tumors may be more rapidly reduced by antibody internalization. Consequently, antibody saturation of the receptor may be affected, thereby affecting the local mechanism of action. (Cancer Res 2006; 66(15): 7630-8)

A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity

“…M60-A02 and EI-04 both bind to cynomolgus and rodent EGFRs with similar activity to human EGFR (data not shown), and both show non-linear PK profiles in mice due to target-mediated disposition, as reported for other anti-EGFR mAbs in human and cynomolgus. 49,50 Antibody serum concentration analysis using EGFR-specific and EGFR/IGF-1R bispecific binding assays gave similar results, indicating that the EI-04 bispecific antibody was intact in vivo throughout the course of the study. C06 does not bind to rodent IGF-1R and the half-life of C06 was previously reported to be ~10 days in mice.…”

Human IgG2 Antibodies against Epidermal Growth Factor Receptor Effectively Trigger Antibody-Dependent Cellular Cytotoxicity but, in Contrast to IgG1, Only by Cells of Myeloid Lineage

“…Using doses of 1 mg/mouse i.p. in this model, peak serum levels were predicted to remain ,0.5 mg/ml shortly after injection, declining thereafter by monoexponential decay (40). Under these conditions, Ab levels in vivo were presumably too low to achieve effective EGF-R blockade ( Fig.…”

Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors

“…From this panel of 42 Abs, daratumumab was selected on basis of its unique ability to induce CDC of Daudi cells. In all experiments, anti-KLH, a human IgG1 Ab directed at KLH, was used as negative control (25).…”