Bivalent binding by intermediate affinity of nimotuzumab: A contribution to explain antibody clinical profile

• Published in: Cancer biology & therapy Vol. 11; no. 4; pp. 373 - 382
• Main Authors: Garrido, Greta, Tikhomirov, Ilia A., Rabasa, Ailem, Yang, Eric, Gracia, Elías, Iznaga, Normando, Fernández, Luis E., Crombet, Tania, Kerbel, Robert S., Pérez, Rolando
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 15.02.2011
• Subjects: Animals; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antibody Affinity - immunology; Apoptosis - drug effects; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - genetics; Cetuximab; Cycle; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gene Expression Regulation, Neoplastic - genetics; Humans; Immunoglobulin Fab Fragments - metabolism; Immunoglobulin Fab Fragments - pharmacology; Immunoglobulin Fab Fragments - therapeutic use; Landes; Mice; Mice, SCID; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Organogenesis; Protein Binding; Proteins; Xenograft Model Antitumor Assays
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.11.4.14097

Nimotuzumab is an EGFR-targeting antibody that has demonstrated encouraging clinical results in the absence of severe side-effects observed with other approved anti-EGFR antibodies. We investigated whether different clinical behavior of nimotuzumab is related to its bivalent/monovalent binding profile. Binding properties of nimotuzumab and cetuximab, the most development of anti-EGFR antibodies, were studied in vitro using chip surfaces and cells with varying EGFR expression levels. Experimental observations demonstrated that in contrast to cetuximab, the intrinsic properties of nimotuzumab required bivalent binding for stable attachment to the cellular surface, leading to nimotuzumab selectively binding to cells that express moderate to high EGFR expression levels. At these conditions, both antibodies bound bivalently, and accumulated to similar degrees. When EGFR density is low, nimotuzumab monovalent interaction was transient, whereas cetuximab continued to interact strongly with the receptors. We compared the in vitro anti-tumor efficacy of nimotuzumab and cetuximab. Cetuximab decreased the cell viability and induced apoptosis for all the tested cell lines, effects which did not depend on EGFR expression level. In contrast, nimotuzumab also provoked significant anti-cellular effects, but its anti-tumor capacity decreased together with EGFR expression level. Cetuximab Fab fragment was able to impact tumor cell survival, whereas nimotuzumab fragment totally lost this effect. Tumor-xenograft experiments using cells with a high EGFR expression revealed similar tumor growth inhibiting effects for both antibodies. This study suggests an explanation for nimotuzumab clinical profile, whereby antitumor activity is obtained in absence of severe toxicities due to its properties of bivalent binding to EGFR. See commentary: Don't jump to rash conclusions