Blood, 1 December 2002, Vol. 100, No. 12, pp. 4067-4073
IMMUNOBIOLOGY
Human T cells resistant to complement lysis by bivalent
antibody can be efficiently lysed by dimers of monovalent
antibody
Soren U. Nielsen and
Edward G. Routledge
From the Department of Microbiology and Immunology,
University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne,
England.
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 C-termini 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 be lytic in the presence of rabbit and guinea pig complement. Dimerization of monovalent antibodies may provide a general strategy for improving the cytolytic activity of other mAbs that are normally unable to induce lysis with complement. The monovalent CD3 mAb dimer
may have potential for development as an agent for immunotherapy of
T-cell leukemia.
