Inhibition of tumor growth by poly(ethylene glycol) derivatives of anti-ErbB2 antibodies

• Published in: Cancer Immunology, Immunotherapy Vol. 49; no. 4-5; pp. 226 - 234
• Main Authors: HURWITZ, E, KLAPPER, L. N, WILCHEK, M, YARDEN, Y, SELA, M
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.07.2000; Springer-Verlag
• Subjects: Animals; Antibodies, Monoclonal - drug effects; Antibodies, Monoclonal - immunology; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Cell Division - drug effects; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Dose-Response Relationship, Immunologic; ErbB-2 protein; Female; Humans; Immunoglobulin Fab Fragments - immunology; Immunotherapy; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Original; Paclitaxel - therapeutic use; Pharmacology. Drug treatments; polyethylene glycol; Polyethylene Glycols - pharmacology; Protein Binding; Receptor, ErbB-2 - immunology; Time Factors; Tumor Cells, Cultured; Antineoplastic agent; Cell proliferation; Animal model; Monoclonal antibody; Ethylene oxide polymer; Binding capacity; Immunotherapy; Taxane derivatives; Established cell line; Paclitaxel; Fab'-Fragment; Inhibition; Treatment efficiency; Rodentia; Malignant tumor; In vitro; Biological activity; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Combined treatment; Conjugated compound
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s002620000112

Poly(ethylene glycol) (PEG) modification of substances with antitumor activity was shown to enhance penetration into growing solid tumors and extend antitumor effects. Accordingly, PEG was introduced as a modifier to two types of monoclonal antibodies (N12 and L26) specific to the ErbB2 (HER2) oncoprotein. These antibodies suppress the growth of tumors overexpressing ErbB2 (e.g. N87 human tumor) and the effect of PEG on their antitumor activity was evaluated. Methoxy-PEG-maleimide conjugated to sulfhydryl groups at the hinge region of the antibodies impaired their antibody binding to N87 tumor cells and did not enhance the antitumor inhibitory activity in tumor-bearing mice. A branched N-hydroxysuccinimide-activated PEG (PEG2), conjugated through amino groups of the protein, was used for binding to the whole antibody (Ab) or to its monomeric Fab' fragment. When tested against N87 cells in vitro, the binding activity and antitumor cytotoxic effects of Ab-PEG2 were mostly preserved. PEG2 modification did not seem to alter the tumor-inhibitory activity of the antibodies in vivo and the same pattern of tumor development was observed during the first few weeks following administration. However, the stimulating effects of PEG were observed at later stages of tumor growth since tumor development was either slowed down or completely arrested. Furthermore, a second tumor implanted into the same mice during this later stage was significantly or completely inhibited, as compared to results in mice injected with the unmodified antibody. The Fab'-PEG2 monomeric derivative was also shown to be effective in inhibiting the growth of a second tumor. The extended and prolonged enhancing effect of PEG on the antitumor activity of antibodies or Fab' fragments directed against ErbB2 may be of importance in the treatment of ErbB2-overexpressing neoplasms.