title: Phase I study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies.
abstract: OBJECTIVE
  The novel bispecific ligand-directed toxin (BLT) DT2219 consists of a recombinant fusion between the catalytic and translocation enhancing domain of diphtheria toxin (DT) and bispecific single-chain variable fragments (scFV) of antibodies targeting human CD19 and CD22. We conducted a phase I dose-escalation study to assess the safety, maximum tolerated dose, and preliminary efficacy of DT2219 in patients with relapsed/refractory B-cell lymphoma or leukemia.
  
  
  METHODS
  DT2219 was administered intravenously over 2 hours every other day for 4 total doses. Dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in nine dose cohorts until a dose-limiting toxicity (DLT) was observed.
  
  
  RESULTS
  Twenty-five patients with mature or precursor B-cell lymphoid malignancies expressing CD19 and/or CD22 enrolled to the study. Patients received median 3 prior lines of chemotherapy and 8 failed hematopoietic transplantation. All patients received a single course of DT2219; one patient was retreated. The most common adverse events, including weight gain, low albumin, transaminitis, and fever were transient grade 1-2 and occurred in patients in higher dose cohorts (≥40 μg/kg/day). Two subjects experienced DLT at dose levels 40 and 60 μg/kg. Durable objective responses occurred in 2 patients; one was complete remission after 2 cycles. Correlative studies showed a surprisingly low incidence of neutralizing antibody (30%).
  
  
  CONCLUSIONS
  We have determined the safety of a novel immunotoxin DT2219 and established its biologically active dose between 40 and 80 μg/kg/day ×4. A phase II study exploring repetitive courses of DT2219 is planned.
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Veronika
authors.initials: V
authors.lastname: Bachanova
authors.affiliation: University of Texas Southwestern, Dallas, Texas.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Dixie
authors.initials: D
authors.lastname: Lewis
authors.affiliation: Department of Pathology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Grzywacz
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Celalettin
authors.initials: C
authors.lastname: Ustun
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Lazaryan
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Brian
authors.initials: B
authors.lastname: McClune
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Erica D
authors.initials: ED
authors.lastname: Warlick
authors.affiliation: MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
authors.affiliation: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
authors.affiliation: Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota. valle001@umn.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Vallera
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000009:adverse effects / Q000627:therapeutic use*; D018941:Antigens, CD19 / Q000378:metabolism*; D001402:B-Lymphocytes / Q000473:pathology; D004167:Diphtheria Toxin / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D054448:Precursor Cells, B-Lymphoid / Q000473:pathology; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000037:antagonists & inhibitors*
chemical_list: D000906:Antibodies; D018941:Antigens, CD19; C497867:CD22 protein, human; C502976:DT 2219 immunotoxin; D004167:Diphtheria Toxin; D000922:Immunotoxins; D051918:Sialic Acid Binding Ig-like Lectin 2