Evaluation of ricin A chain-containing immunotoxins directed against different epitopes on the delta-chain of cell surface-associated IgD on murine B cells.
Over the past decade, immunotoxins (IT) composed of mAb covalently coupled to toxins or their subunits have been developed for the treatment of malignancies and autoimmune diseases. Despite specific binding to target cells, not every mAb makes a therapeutically potent ricin A chain-containing IT (IT-A). A number of variables influence the potency of a mAb as an IT-A, including the affinity of the mAb, the nature and density of the cell surface Ag, and the type of target cell used. The present report investigates the influence of the epitope specificity of a mAb on the effectiveness of that mAb as an IT-A. Seven mAb directed against different regions of the mouse delta H chain of surface IgD, were conjugated to deglycosylated ricin A chain, and tested for their ability to kill murine B cells. The panel of IT-A had similar A chain activities and similar binding avidities. However, the mAb directed against epitopes in the Fc portion of surface IgD made more effective IT-A than those directed against epitopes in the Fd region. Overall, the anti-Fc-A were approximately 60- to 150-fold more toxic than the anti-Fd-A. Taken together with previous studies, these findings suggest that the epitope on a target Ag recognized by a given mAb is an important variable in determining the potency of a mAb as an IT-A.
May
R D
RD
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas 75235.
Finkelman
F D
FD
Wheeler
H T
HT
Uhr
J W
JW
Vitetta
E S
ES
D000911:Antibodies, Monoclonal / Q000276:immunology; D000915:Antibody Affinity; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000276:immunology*; D001667:Binding, Competitive; D003602:Cytotoxicity, Immunologic; D000939:Epitopes; D005434:Flow Cytometry; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000276:immunology; D007138:Immunoglobulin delta-Chains / Q000276:immunology*; D000922:Immunotoxins / Q000633:toxicity*; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000276:immunology / Q000648:ultrastructure; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000648:ultrastructure; D012276:Ricin / Q000008:administration & dosage*
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007141:Immunoglobulin Fc Fragments; D007128:Immunoglobulin Fragments; D007143:Immunoglobulin Heavy Chains; D007132:Immunoglobulin Isotypes; D007138:Immunoglobulin delta-Chains; D000922:Immunotoxins; D008565:Membrane Proteins; D011947:Receptors, Antigen, B-Cell; D012276:Ricin