title: Delivery of saporin to human B-cell lymphoma using bispecific antibody: targeting via CD22 but not CD19, CD37, or immunoglobulin results in efficient killing.
abstract: A panel of bispecific F(ab')2 antibodies (BsAb) have been constructed for delivering the ribosome-inactivating protein saporin to human B cell lymphoma. Each derivative was prepared with specificity for saporin and CD19, CD22, CD37, or immunoglobulin. In vitro studies measuring inhibition of [3H]leucine uptake by cultured Daudi and Raji cells demonstrated that, despite all BsAb capturing saporin on the cell surface, BsAb targeting through CD22 were far more cytotoxic than those functioning via CD19, CD37, or surface immunoglobulin. This exceptional activity of the CD22-specific BsAb appears to derive from its ability to deliver and accumulate saporin inside the target cells. Further studies showed that four CD22-specific BsAb all performed with equal potency and were able to increase saporin toxicity (50% inhibitory concentration) up to 1000-fold, from 2 x 10(-7) M to 2 x 10(-10) M. Pairs of anti-CD22 BsAb which recognized different nonblocking epitopes on the saporin molecule were able to bind saporin more avidly to the target cell and, as a consequence, increased cytotoxicity by at least an additional 10-fold, resulting in 50% inhibitory concentration for protein synthesis of 2 x 10(-11) M. These results suggest that selected combinations of BsAb which bind cooperatively to a toxin and the cell surface may provide an efficient way of delivering toxins to unwanted cells in patients.
authors.affiliation: Lymphoma Research Unit, Tenovus Laboratory, General Hospital, Southampton, United Kingdom.
authors.forename: M A
authors.initials: MA
authors.lastname: Bonardi
authors.forename: R R
authors.initials: RR
authors.lastname: French
authors.forename: P
authors.initials: P
authors.lastname: Amlot
authors.forename: G
authors.initials: G
authors.lastname: Gromo
authors.forename: D
authors.initials: D
authors.lastname: Modena
authors.forename: M J
authors.initials: MJ
authors.lastname: Glennie
mesh_terms: D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D015703:Antigens, CD / Q000276:immunology*; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D000951:Antigens, Neoplasm; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000276:immunology; D015815:Cell Adhesion Molecules; D016923:Cell Death / Q000187:drug effects; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007128:Immunoglobulin Fragments; D007136:Immunoglobulins / Q000276:immunology*; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use*; D007457:Iodine Radioisotopes; D037102:Lectins; D007930:Leucine / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology*; D009699:N-Glycosyl Hydrolases; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010940:Plant Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D051918:Sialic Acid Binding Ig-like Lectin 2; D059470:Tetraspanins; D014316:Tritium; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D000951:Antigens, Neoplasm; C497867:CD22 protein, human; C059071:CD37 protein, human; D015815:Cell Adhesion Molecules; D006023:Glycoproteins; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D007136:Immunoglobulins; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D037102:Lectins; D009363:Neoplasm Proteins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D051918:Sialic Acid Binding Ig-like Lectin 2; D059470:Tetraspanins; D014316:Tritium; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D007930:Leucine