1. Reduction of Minimal Residual Disease in Pediatric B-lineage Acute Lymphoblastic Leukemia by an Fc-optimized CD19 Antibody.
- Author
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Seidel UJ, Schlegel P, Grosse-Hovest L, Hofmann M, Aulwurm S, Pyz E, Schuster FR, Meisel R, Ebinger M, Feuchtinger T, Teltschik HM, Witte KE, Schwarze CP, Rammensee HG, Handgretinger R, Jung G, and Lang P
- Subjects
- Adolescent, Antibodies, Monoclonal pharmacology, Antibody-Dependent Cell Cytotoxicity, Cell Line, Tumor, Child, Child, Preschool, Combined Modality Therapy, Drug Monitoring, Drug Resistance, Neoplasm, Female, Gene Expression, Humans, Kaplan-Meier Estimate, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Retreatment, Treatment Outcome, Young Adult, Antibodies, Monoclonal therapeutic use, Antigens, CD19 immunology, Antigens, CD19 metabolism, Immunoglobulin Fc Fragments immunology, Neoplasm, Residual drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- 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.
- Published
- 2016
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