title: Clinical experience with CD3 x CD19 bispecific antibodies in patients with B cell malignancies.
abstract: In extensive preclinical testing, a CD3 x CD19 bispecific antibody (BsAb) induced killing of malignant B cells by resting T cells even in an autologous situation. In a 14 day clonogenic assay using a CD19+ pre-B cell line (REH), BsAb required repeated administration together with IL-2 to achieve a 5 log kill by resting peripheral blood T cells. Intravenously administered BsAb in an intrapatient dose escalation study of 3 patients with B cell non-Hodgkin's lymphoma showed limited toxicity (WHO grade II fever and chills) due to tumor necrosis factor-alpha (TNF-alpha) release by T cells. Pharmacokinetics with 2.5 mg BsAb showed peak levels of 200-300 micrograms/ml and a t1/2 of 10.5 h. The next patient, with chronic lymphocytic leukemia (CLL), received 0.6 mg BsAb/m2 as an i.v. infusion preceded by 1 MU IL-2/m2 s.c. Improved T cell activation was noted, as indicated by an increase in IFN-gamma, IL-6, IL-8, and IL-10, in addition to high TNF-alpha increases. TNF-alpha increases were highest on the first day. Toxicity remained restricted to grade II fever and chills, observed every day after the infusion of BsAb. No clear clinical effects were seen in this chemotherapy-resistant CLL patient with a high tumor burden. If subsequent patients also show limited toxicity, treatment of patients with a lower tumor load seems to be warranted to evaluate the efficacy of CD3 x CD19 BsAb therapy.
authors.affiliation: Department of Hematology, University Hospital Utrecht, The Netherlands.
authors.forename: G C
authors.initials: GC
authors.lastname: De Gast
authors.forename: A A
authors.initials: AA
authors.lastname: Van Houten
authors.forename: I A
authors.initials: IA
authors.lastname: Haagen
authors.forename: S
authors.initials: S
authors.lastname: Klein
authors.forename: R A
authors.initials: RA
authors.lastname: De Weger
authors.forename: A
authors.initials: A
authors.lastname: Van Dijk
authors.forename: J
authors.initials: J
authors.lastname: Phillips
authors.forename: M
authors.initials: M
authors.lastname: Clark
authors.forename: B J
authors.initials: BJ
authors.lastname: Bast
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D018941:Antigens, CD19 / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D003131:Combined Modality Therapy; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016853:Muromonab-CD3 / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D014411:Neoplastic Stem Cells / Q000276:immunology*; D051381:Rats; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D007155:Immunologic Factors; D007376:Interleukin-2; D016853:Muromonab-CD3; D014409:Tumor Necrosis Factor-alpha