title: Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma.
abstract: The B-cell antigen CD20 is expressed on normal B cells and by nearly all B-cell lymphomas. This nonmodulating antigen provides an excellent target for antibody-directed therapies. A chimeric anti-CD20 antibody (IDEC-C2B8), consisting of human IgG1-kappa constant regions and variable regions from the murine monoclonal anti-CD20 antibody IDEC-2B8, has been produced for clinical trials. It lyses CD20+ cells in vitro via complement and antibody-dependent cell-mediated lysis. Preclinical studies have shown that the chimeric antibody selectively depletes B cells in blood and lymph nodes in macaque monkeys. In this phase I clinical trial, 15 patients (3 per dose level) with relapsed low-grade B-cell lymphoma were treated with a single dose (10, 50, 100, 250, or 500 mg/m2) of antibody administered intravenously. Treatment-related symptoms correlated with the number of circulating CD20 cells and grade II events consisted of fever (5 patients); nausea (2), rigor (2), orthostatic hypotension (2), bronchospasm (1), and thrombocytopenia (1). No significant toxicities were observed during the 3 months of follow-up. Serum C3, IgG, and IgM levels, neutrophils, and T cells were largely unchanged. At the three higher dose levels, pharmacokinetics of the free antibody showed a serum half-life of 4.4 days (range, 1.6 to 10.5). Levels greater than 10 micrograms/mL persisted in 6 of 9 patients for more than 14 days. No quantifiable immune responses to the infused antibody have been detected. CD20+ B cells were rapidly and specifically depleted in the peripheral blood at 24 to 72 hours and remained depleted for at least 2 to 3 months in most patients. Two-week postinfusion tumor biopsies showed the chimeric antibody bound to tumor cells and a decrease in the percentage of B cells. Tumor regressions occurred in 6 of 15 patients (2 partial and 4 minor responses). The results of this single-dose trial have been used to design a multiple-dose phase I/II study.
authors.affiliation: Department of Medicine, Stanford University Medical Center, CA.
authors.forename: D G
authors.initials: DG
authors.lastname: Maloney
authors.forename: T M
authors.initials: TM
authors.lastname: Liles
authors.forename: D K
authors.initials: DK
authors.lastname: Czerwinski
authors.forename: C
authors.initials: C
authors.lastname: Waldichuk
authors.forename: J
authors.initials: J
authors.lastname: Rosenberg
authors.forename: A
authors.initials: A
authors.lastname: Grillo-Lopez
authors.forename: R
authors.initials: R
authors.lastname: Levy
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D018951:Antigens, CD20; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D003165:Complement System Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D016219:Immunotherapy, Adoptive / Q000009:adverse effects; D008198:Lymph Nodes / Q000473:pathology; D018655:Lymphocyte Count; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010976:Platelet Count
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018951:Antigens, CD20; D000944:Antigens, Differentiation, B-Lymphocyte; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D003165:Complement System Proteins