Anti-EGFR biparatopic-SEED antibody has enhanced combination-activity in a single molecule.

Autor: Kelton C; EMD Serono Research Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA., Wesolowski JS, Soloviev M, Schweickhardt R, Fischer D, Kurosawa E, McKenna SD, Gross AW
Jazyk: angličtina
Zdroj: Archives of biochemistry and biophysics [Arch Biochem Biophys] 2012 Oct 15; Vol. 526 (2), pp. 219-25. Date of Electronic Publication: 2012 Mar 10.
DOI: 10.1016/j.abb.2012.03.005
Abstrakt: Certain combinations of non-competitive anti-EGFR antibodies have been reported to produce new effects on cells compared to either antibody used separately. New and enhanced combination-activity includes increased inhibition of signaling, increased receptor internalization and degradation, reduced proliferation of tumor cell lines and induction of complement-dependent cytotoxicity (CDC) effector function. To test requirements and mechanisms to elicit enhanced combination-activity with different EGFR binding domains, we created an anti-EGFR biparatopic antibody. A biparatopic antibody interacts through two different antigen-binding sites to a single antigen. A heterodimeric antibody with one binding domain derived from the C225 antibody and one binding domain derived from the humanized 425 (hu425) antibody was built on the strand-exchange engineered domain (SEED) scaffold. This anti-EGFR biparatopic-SEED antibody was compared to parental antibodies used alone and in combination, and to the corresponding monovalent anti-EGFR-SEED antibodies used alone or in combination. We found that the anti-EGFR biparatopic-SEED had enhanced activity, similar to the combination of the two parental antibodies. Combinations of monovalent anti-EGFR-SEED antibodies did not produce enhanced effectiveness in cellular assays. Our results show that the anti-EGFR biparatopic antibody created using the SEED scaffold has enhanced combination-activity in a single molecule. Furthermore, these data suggest that the potential to cross-link the two different epitopes is an important requirement in the mechanism of enhanced combination-activity.
(Copyright © 2012 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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