title: In vivo pharmacodynamic effects of Hu1D10 (remitogen), a humanized antibody reactive against a polymorphic determinant of HLA-DR expressed on B cells.
abstract: The humanized monoclonal antibody Hu1D10 (Remitogen, Protein Design Labs, Fremont, CA) recognizes a polymorphic determinant of human leukocyte antigen-DR expressed on the majority of B-cell lymphomas and on normal B cells of most individuals. Hu1D10 mediates complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and apoptosis of 1D10 antigen (Ag)-positive B cells in vitro. The 1D10 Ag is expressed on a variety of tissues but is restricted primarily to lymphocytes, macrophages, and mesenchymal dendritic cells. The safety and pharmacology of Hu1D10 were investigated in rhesus macaques. Animals were prescreened for 1D10 Ag expression on circulating B cells. Sixteen animals received either placebo (4 Ag+ animals), 1 mg/kg Hu1D10 (4 Ag+ animals), or 10 mg/kg Hu1D10 (4 Ag+ animals and 4 Ag- animals) daily via intravenous (i.v.) bolus-injection for 5 consecutive days, and 4 Ag+ animals received 10 mg/kg Hu1D10 via 90 min i.v. infusion x 5 days. Bolus-injection of Hu1D10 resulted in type 1 hypersensitivity reactions in the majority of Ag+ animals and one death due to anaphylaxis. Slow infusion of Hu1D10 was associated with only mild hypersensitivity reactions after the first dose but not subsequent doses. In animals treated with 10 mg/kg Hu1D10 via bolus-injection, the median terminal elimination half-life of Hu1D10 was 2.6 and 8.4 days in Ag+ and Ag- animals, respectively. Administration of Hu1D10 to Ag+ animals resulted in rapid and profound depletion of circulating B cells for 7-10 days following the last dose. No B-cell depletion was observed in Ag- animals, despite slower elimination of Hu1D10. These studies demonstrate that Hu1D10 reacts with antigen-presenting cells in rhesus macaques. It can be safely administered as a slow i.v. infusion but causes severe toxicity when given as a bolus. This study provides the foundation for testing Hu1D10 for the treatment of B-cell malignancies in humans.
authors.affiliation: Protein Design Labs, Inc., Fremont, CA 94555, USA.
authors.forename: Jia Dong
authors.initials: JD
authors.lastname: Shi
authors.forename: Chuck
authors.initials: C
authors.lastname: Bullock
authors.forename: William C
authors.initials: WC
authors.lastname: Hall
authors.forename: Valerie
authors.initials: V
authors.lastname: Wescott
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Levitt
authors.forename: Corine K
authors.initials: CK
authors.lastname: Klingbeil
mesh_terms: D000707:Anaphylaxis / Q000209:etiology; D000818:Animals; D000910:Antibodies, Heterophile / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004342:Drug Hypersensitivity / Q000209:etiology; D004354:Drug Screening Assays, Antitumor; D000939:Epitopes / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology*; D006207:Half-Life; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000209:etiology; D007262:Infusions, Intravenous; D007275:Injections, Intravenous / Q000009:adverse effects; D008212:Lymphocyte Depletion; D008221:Lymphoid Tissue / Q000276:immunology; D008223:Lymphoma / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D051379:Mice
chemical_list: D000910:Antibodies, Heterophile; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000939:Epitopes; D006684:HLA-DR Antigens; C448699:apolizumab