This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kitamura, K. Articles by Hakomori, S.-i. Search for Related Content PubMed PubMed Citation Articles by Kitamura, K. Articles by Hakomori, S.-i.

Chemical Engineering of the Monoclonal Antibody A7 by Polyethylene Glycol for Targeting Cancer Chemotherapy¹

First Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamikyo-ku, Kyoto, 602 Japan, and The Biomembrane Institute, Seattle, Washington 98104

The murine monoclonal antibody A7 (Mab A7) against human colon cancer was chemically modified with methoxypolyethylene glycol (PEG) (M_r 5000). A high substitution of PEG molecules on Mab A7 produced a progressive reduction in antibody-binding activity. The pharmacokinetic and immunological properties of PEG-modified monoclonal antibody A7 (Mab A7) and the PEG-modified F(ab')₂ fragment, which retained their antibody-binding activity, were assessed and compared with the parent Mab A7 and the parent F(ab')₂ fragment. Blood clearance of PEG-modified antibodies appeared to be diminished by PEG modification and was fitted by a two-compartment model. Low PEG-substituted Mab A7 showed less organ uptake in the liver and spleen and similar uptake in the lung and kidney, compared with the parent Mab A7. PEG-F(ab')₂ showed less uptake in the liver and kidney. Both preparations exhibited less tissue:blood ratios in all resected organs as compared with parent antibodies. Tumor localization was enhanced by PEG modification for the F(ab')₂ fragment, but not by PEG modification for the whole Mab A7. Multiple i.v. administration of PEG-modified antibody to rabbit did not appear to elicit a measurable immune response to the antibody portion of the conjugate. In conclusion, PEG-modified antibodies are promising reagents as drug carriers to the target tumor.

¹ This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture and from the Ministry of Health and Welfare, Japan.

² To whom requests for reprints should be addressed.

Received 2/19/91. Accepted 6/ 5/91.

This article has been cited by other articles:

				D. P. Humphreys, S. P. Heywood, A. Henry, L. Ait-Lhadj, P. Antoniw, R. Palframan, K. J. Greenslade, B. Carrington, D. G. Reeks, L. C. Bowering, et al. Alternative antibody Fab' fragment PEGylation strategies: combination of strong reducing agents, disruption of the interchain disulphide bond and disulphide engineering Protein Eng. Des. Sel., May 1, 2007; 20(5): 227 - 234. [Abstract] [Full Text] [PDF]

				P. Alvarez, C. A. Buscaglia, and O. Campetella Improving Protein Pharmacokinetics by Genetic Fusion to Simple Amino Acid Sequences J. Biol. Chem., January 30, 2004; 279(5): 3375 - 3381. [Abstract] [Full Text] [PDF]

				S. J. DeNardo, Z. Yao, K. S. Lam, A. Song, P. A. Burke, G. R. Mirick, K. R. Lamborn, R. T. O'Donnell, and G. L. DeNardo Effect of Molecular Size of Pegylated Peptide on the Pharmacokinetics and Tumor Targeting in Lymphoma-Bearing Mice Clin. Cancer Res., September 1, 2003; 9(10): 3854S - 3864. [Abstract] [Full Text] [PDF]

				B. Vanhove, G. Laflamme, F. Coulon, M. Mougin, P. Vusio, F. Haspot, J. Tiollier, and J.-P. Soulillou Selective blockade of CD28 and not CTLA-4 with a single-chain Fv-{alpha}1-antitrypsin fusion antibody Blood, July 15, 2003; 102(2): 564 - 570. [Abstract] [Full Text] [PDF]

				A. Pendri, C. W. Gilbert, S. Soundararajan, D. Bolikal, R. G. L. Shorr, and R. B. Greenwald PEG Modified Anticancer Drugs: Synthesis and Biological Activity Journal of Bioactive and Compatible Polymers, April 1, 1996; 11(2): 122 - 134. [Abstract]