title: CD8 T cell activation after intravenous administration of CD3 x CD19 bispecific antibody in patients with non-Hodgkin lymphoma.
abstract: A bispecific antibody directed to T and B cells (CD3 x CD19 bsAb) was daily infused intravenously in escalating doses from 10 micrograms up to 5 mg in three patients with chemotherapy-resistant non-Hodgkin lymphoma; in this way we aimed to activate T cells to kill the malignant B cells. Only limited toxicity was observed, consisting of moderate fever preceded by chills or shivers and mild thrombocytopenia. No human anti-(mouse Ig) antibodies were found. Pharmacokinetics showed a t1/2 of 10.5 h with peak levels of 200-300 ng/ml after infusion of 2.5 mg bsAb. bsAb in serum was functionally active in vitro. After bsAb infusion a rise in serum tumour necrosis factor alpha was observed, accompanied by an increase in soluble CD8 and to some extent in soluble interleukin-2 receptor (IL-2R), but not in interferon gamma. IL-4 or soluble CD4. No evidence was found for monocyte activation (no increases in IL-6, IL-8 or IL-1 beta in serum). No gross changes in histology or number of IL-2R+, CD4+ or CD8+ cells were found in the lymph nodes after therapy, but one patient showed activated CD8+ T cells within the tumour nodules. In conclusion, after intravenously administered CD3 x CD19 bsAb only moderate toxicity was found, probably due to CD8+ T cell activation and cytokine release, without CD4+ T cell activation.
authors.affiliation: Department of Immunology, University Hospital Utrecht, The Netherlands.
authors.forename: G C
authors.initials: GC
authors.lastname: de Gast
authors.forename: I A
authors.initials: IA
authors.lastname: Haagen
authors.forename: A A
authors.initials: AA
authors.lastname: van Houten
authors.forename: S C
authors.initials: SC
authors.lastname: Klein
authors.forename: A J
authors.initials: AJ
authors.lastname: Duits
authors.forename: R A
authors.initials: RA
authors.lastname: de Weger
authors.forename: T M
authors.initials: TM
authors.lastname: Vroom
authors.forename: M R
authors.initials: MR
authors.lastname: Clark
authors.forename: J
authors.initials: J
authors.lastname: Phillips
authors.forename: A J
authors.initials: AJ
authors.lastname: van Dijk
mesh_terms: D000328:Adult; D018033:Antibodies, Bispecific / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007262:Infusions, Intravenous; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged
chemical_list: D018033:Antibodies, Bispecific; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D017252:CD3 Complex