title: Degradation of radioiodinated B cell monoclonal antibodies: inhibition via a FCgamma-receptor-II-mediated mechanism and by drugs.
abstract: Our aim is to treat patients with B cell malignancies with radioimmunotherapy using monoclonal antibodies (mAb) such as CD19, CD20 and CD22. In this study we investigated the rate of internalization and catabolism of these mAb. After 24 h at 37 degrees C, 20%-25% of initially cell-bound (125)I-CD19 mAb and (125)I-CD22 mAb was degraded in B cells, whereas almost no degredation occurred after binding of (125)I-CD20 mAb. For B cells expressing Fcgamma receptor II (FcgammaRII), isotype-dependent degradation was noted as the CD19 IgGl mAb showed an enhanced degradation rate compared to the switch variant IgG2a. The effect of various pharmaceutical agents that delay the internalization or subsequent degradation of mAb was evaluated. The degradation was inhibited most effectively by a combination of etoposide and vinblastine, resulting in accumulation of radioactivity in the target cell. Also the simultaneous application of CD20 or CD22 with (125)I-CD19 mAb or of CD20 with (125)I-CD22 mAb proved to be a potent inhibitor of the rapid degradation of these mAb, by inhibiting internalization via an FcgammaRII-mediated mechanism. Both methods of reducing the degradation of radioiodinated mAb are expected to prolong irradiation of malignant b cells and consequently result in an enhanced therapeutic effect in vivo.
authors.affiliation: Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, University of Amsterdam, The Netherlands.
authors.forename: S F
authors.initials: SF
authors.lastname: Vervoordeldonk
authors.forename: A Y
authors.initials: AY
authors.lastname: Balkenende
authors.forename: H
authors.initials: H
authors.lastname: van den Berg
authors.forename: A E
authors.initials: AE
authors.lastname: von dem Borne
authors.forename: C E
authors.initials: CE
authors.lastname: van der Schoot
authors.forename: E F
authors.initials: EF
authors.lastname: Van Leeuwen
authors.forename: I C
authors.initials: IC
authors.lastname: Slaper-Cortenbach
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D015703:Antigens, CD / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology*; D001692:Biological Transport / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000532:radiotherapy; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015815:Cell Adhesion Molecules; D002738:Chloroquine / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000378:metabolism; D000922:Immunotoxins / Q000378:metabolism / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D037102:Lectins; D015448:Leukemia, B-Cell / Q000532:radiotherapy; D051379:Mice; D008985:Monensin / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D016499:Radioimmunotherapy; D017452:Receptors, IgG / Q000187:drug effects* / Q000502:physiology*; D051918:Sialic Acid Binding Ig-like Lectin 2; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D000970:Antineoplastic Agents; C497867:CD22 protein, human; D002121:Calcium Channel Blockers; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D007132:Immunoglobulin Isotypes; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D037102:Lectins; D017452:Receptors, IgG; D051918:Sialic Acid Binding Ig-like Lectin 2; D014750:Vincristine; D014747:Vinblastine; D005047:Etoposide; D002738:Chloroquine; D008985:Monensin; D014700:Verapamil; D017239:Paclitaxel; D003078:Colchicine