Human T cells resistant to complement lysis by bivalent antibody can be efficiently lysed by dimers of monovalent antibody

Abstract

We have previously shown that bivalent human ␥1 CD3 monoclonal antibody (mAb) is ineffective at mediating lysis of human T cells with human complement. In this paper we have used genetic engineering and sulfur chemistry to prepare 2 types of human ␥1 CD3 mAb dimer, with the aim of improving complement lysis activity. The IgG molecules forming the dimers were linked together at their Ctermini by stable bismaleimide thioether bridges. The first dimer was composed of 2 bivalent mAb molecules. This dimer proved incapable of lysing human T-cell blasts with human, rabbit, or guinea pig complement. The second dimer consisted of 2 molecules of a monovalent derivative (possessing a single Fab domain) of the bivalent mAb. This dimer was highly lytic with human complement, with a lytic titer 64-fold greater than that of the nondimerized monovalent mAb. The maximum level of lysis of human T-cell blasts achieved with this monovalent mAb dimer was equal to that obtained with the therapeutic antilymphocyte mAb alemtuzumab, but its lytic titer was 4-fold greater. The monovalent mAb dimer was also found to

Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density

“…Although the relation of ADCC and the redistribution into lipid rafts has been poorly defined, high density of IgG1 bound on CD20 multimer or localized CD20 in lipid rafts may induce ADCC even by high-fucose IgG1. The hypothesis that clustering IgG1 could enhance ADCC is supported by the reports of dimerized antibodies having potent ADCC (42,43).…”