Immunogenicity and pharmacokinetic attributes of poly(ethylene glycol)-grafted immunoliposomes

• Published in: Biochimica et biophysica acta Vol. 1327; no. 2; pp. 181 - 192
• Main Authors: Harding, Jennifer A, Engbers, Charles M, Newman, Mary S, Goldstein, Neil I, Zalipsky, Samuel
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 25.07.1997
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - immunology; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; ErbB Receptors - immunology; Flow Cytometry; Humans; Immunogenicity; Immunoglobulin Fab Fragments - metabolism; Immunoliposomes; Liposomes - immunology; Liposomes - pharmacokinetics; Male; Mice; Pharmacokinetics; Phosphatidylethanolamines; Polyethylene glycol (PEG); Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured; HSPC, hydrogenated soy phosphatidyl choline; mPEG, methoxy-PEG; Antibodies; Immunoliposomes; AUC, area under curve; EGFR, epidermal growth factor receptor; Hz, hydrazide; MRT, mean residence time; TMB, 3,3′,5,5′-tetramethylbenzidine; Immunogenicity; Polyethylene glycol (PEG); NAM, N-acetylmethionine; PEG, poly(ethylene glycol); Pharmacokinetics; DSPE, distearoyl phosphatidylethanolamine
• ISSN: 0005-2736; 0006-3002; 1879-2642
• DOI: 10.1016/S0005-2736(97)00056-4

Immunoliposomes composed of hydrogenated soy phosphatidylcholine, cholesterol, methoxypoly(ethylene glycol)-distearoyl phosphatidylethanolamine (mPEG-DSPE), and hydrazide-PEG-DSPE (mole ratio, 57:38:3.3:1.7) linked to periodate-oxidized chimerized mouse IgG (C225, anti-human epidermal growth factor receptor) were prepared by an optimized aggregation-free procedure. The antigen-binding activity of the immunoliposomes was well preserved. When injected intravenously into naive rats, the immunoliposomes (∼18 IgG per 100 nm liposome) exhibited long circulation times (MRT=8.5 h, Cl=0.2 ml/h). Subsequent injections of the immunoliposomes into the same animals resulted in rapid clearance (MRT≤0.7 h, Cl≥7 ml/h), which was accompanied by a significant increase in anti-C225 specific titers. Upon repeated injection or coinjection with the parent liposomes free C225 consistently exhibited prolonged circulation without any increase in C225-specific antisera, but was cleared quickly when administered into animals that had been pretreated with the immunoliposomes. Screening of the immunoliposome induced antisera against human polyclonal IgG and C225-derived Fab′ fragment revealed that the immune response was specifically triggered by the constant human region of C225. These results demonstrate that the preparations of PEG-grafted immunoliposomes are more immunogenic than the free IgG component, which is of profound importance to the antibody-mediated liposomal drug delivery effort.