A chimeric antibody with dual Fc regions (bisFabFc) prepared by manipulations at the IgG hinge.
A new chimeric antibody for therapeutic use in human cancer is described. First the derivative FabFc was prepared by linking Fab' gamma from monoclonal antibody to Fc gamma from human normal IgG1. The bismaleimide linking agent forms a thioether bond with an SH group released by reduction of SS bonds in the hinge of each constituent. It follows that one of the original two SS bonds in the Fc hinge still has both its S atoms free, and this bond is reformed by thiol-disulphide interchange. The lone free SH in the Fc hinge can now be used to join two FabFc molecules through a similar bismaleimide linker to yield bisFabFc. As regards antibody activity against target cells, bisFabFc can be univalent, bivalent, or bispecific. Its juxtaposed dual Fc regions are designed to promote cooperative binding of effectors, and bisFabFc is indeed notably more powerful than its parent FabFc molecules in promoting complement lysis and antibody-dependent cellular cytotoxicity. However it is not possible at present to distinguish the separate contributions of Fc architecture, antibody affinity and other factors towards this improvement. In the present state of development a variety of FabFc against a given neoplasm may be prepared in high yield from mouse IgG1 and IgG2a antibodies, and when convenient dimerized to bisFabFc in any combination of specificities.
Stevenson
G T
GT
Lymphoma Research Unit, Tenovus Laboratory, General Hospital, Southampton, UK.
Pindar
A
A
Slade
C J
CJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D003432:Cross-Linking Reagents / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000032:analysis / Q000276:immunology / Q000302:isolation & purification; D007141:Immunoglobulin Fc Fragments / Q000032:analysis / Q000276:immunology / Q000302:isolation & purification; D007074:Immunoglobulin G / Q000276:immunology / Q000302:isolation & purification; D007130:Immunoglobulin Idiotypes / Q000276:immunology; D007167:Immunotherapy; D051379:Mice
D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007130:Immunoglobulin Idiotypes