title: Reduction of Minimal Residual Disease in Pediatric B-lineage Acute Lymphoblastic Leukemia by an Fc-optimized CD19 Antibody.
abstract: Prognosis of primary refractory and relapsed pediatric B-lineage acute lymphoblastic leukemia (ALL) is very poor. Relapse rates significantly correlate with persistent minimal residual disease (MRD). In MRD, favorable effector-target ratios prevail and thus this situation might be optimally suited for immunotherapy with antibodies recruiting immunological effector cells. We here report on the generation, preclinical characterization and first clinical application in B-lineage ALL of an Fc-optimized CD19 antibody. This third-generation antibody (4G7SDIE) mediated enhanced antibody-dependent cellular cytotoxicity (ADCC) against leukemic blasts with effector cells from healthy volunteers and B-lineage ALL patients. The antibody was produced in a university-owned production unit and was applied on a compassionate use basis to 14 pediatric patients with refractory and relapsed B-lineage ALL at the stage of MRD. In 10/14 patients, MRD was reduced by ≥ 1 log or below the patient-individual detection limit, and 5/14 patients have achieved ongoing complete molecular remission with a median leukemia-free survival of 428 days. Two additional patients died in complete molecular remission due to complications not related to antibody therapy. Besides profound in vivo B-cell depletion, side effects were negligible. A clinical phase 1/2 study to further assess the therapeutic activity of 4G7SDIE is in preparation.
authors.affiliation: Department of General Pediatrics, Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
authors.forename: Ursula Jördis Eva
authors.initials: UJ
authors.lastname: Seidel
authors.affiliation: Department of General Pediatrics, Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schlegel
authors.affiliation: SYNIMMUNE GmbH, Tübingen, Germany.|Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Grosse-Hovest
authors.affiliation: SYNIMMUNE GmbH, Tübingen, Germany.|Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hofmann
authors.affiliation: SYNIMMUNE GmbH, Tübingen, Germany.|Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Aulwurm
authors.affiliation: Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: Elwira
authors.initials: E
authors.lastname: Pyz
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Friedhelm R
authors.initials: FR
authors.lastname: Schuster
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Meisel
authors.affiliation: Department of General Pediatrics, Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebinger
authors.affiliation: Department of Pediatric Oncology/Hematology, Ludwig Maximilians University Munich, München, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Feuchtinger
authors.affiliation: Department of General Pediatrics, Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
authors.forename: Heiko-Manuel
authors.initials: HM
authors.lastname: Teltschik
authors.affiliation: Department of General Pediatrics, Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
authors.forename: Kai-Erik
authors.initials: KE
authors.lastname: Witte
authors.affiliation: Department of General Pediatrics, Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
authors.forename: Carl-Philipp
authors.initials: CP
authors.lastname: Schwarze
authors.affiliation: Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.affiliation: Department of General Pediatrics, Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
authors.forename: Gundram
authors.initials: G
authors.lastname: Jung
authors.affiliation: Department of General Pediatrics, Hematology/Oncology, University Children's Hospital Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
mesh_terms: D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D016903:Drug Monitoring; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D053208:Kaplan-Meier Estimate; D008297:Male; D018365:Neoplasm, Residual / Q000188:drug therapy*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019233:Retreatment; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D007141:Immunoglobulin Fc Fragments