Attack on neoplastic cell membranes by therapeutic antibody

Mouse monoclonal antibody is not well fitted to destroying tumour cell targets. Complement and cellular effectors are inefficiently recruited, the cells can undergo antigenic modulation, antigen-negative mutants can arise, and the tumour-bearing subject can amount an immune response against the therapeutic antibody. This paper describes the preparation of two chimeric antibody derivatives designed to cirvumvent some of these problems. The first derivative is FabFc, prepared by linking Fab' gamma from monoclonal antibody to Fc gamma from human IgG. The bismaleimide linking agent forms a thioether bond with an SH group released by reduction of SS bonds in the hinge of each constituent. The second derivative is bisFabFc, formed by a bismaleimide in this case joining two FabFc molecules via a free SH in the Fc hinge of each. As regards antibody activity against target cells bisFabFc can be univalent (one active, one inactive Fab arm), bivalent, or bispecific (with each Fab arm directed against a different cell surface antigen). Its juxtaposed dual Fc regions are designed to promote cooperative binding of effectors. Some preliminary characterization in vitro has employed antibodies of anti-idiotypic specificity directed against guinea-pig L2C leukaemic B lymphocytes. The parent mouse IgG1 antibody failed to invoke complement cytotoxicity or antibody-dependent cellular cytotoxicity, while the chimeric derivatives yielded good killing in both systems. In complement lysis bivalent bicFabFc outperformed univalent, which in turn outperformed the FabFc monomer.