Reduction of Minimal Residual Disease in Pediatric B-lineage Acute Lymphoblastic Leukemia by an Fc-optimized CD19 Antibody

Mol Ther. 2016 Sep;24(9):1634-43. doi: 10.1038/mt.2016.141. Epub 2016 Jul 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibody-Dependent Cell Cytotoxicity
  • Antigens, CD19* / immunology
  • Antigens, CD19* / metabolism
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Combined Modality Therapy
  • Drug Monitoring
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression
  • Humans
  • Immunoglobulin Fc Fragments* / immunology
  • Kaplan-Meier Estimate
  • Male
  • Neoplasm, Residual / drug therapy*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / diagnosis*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Retreatment
  • Treatment Outcome
  • Young Adult

Substances

  • Antibodies, Monoclonal
  • Antigens, CD19
  • Immunoglobulin Fc Fragments