Enhanced killing of B lymphoma cells by granulocyte colony-stimulating factor-primed effector cells and Hu1D10--a humanized human leucocyte antigen DR antibody.
Antibody-based approaches have become a novel treatment modality for lymphoma patients. Humanized 1D10 (Hu1D10; Remitogen) is among the antibodies that are currently under evaluation in phase II clinical trials in lymphoma patients. The 1D10 antibody is directed against a polymorphic epitope on the beta-chain of human leucocyte antigen (HLA) class II. We found expression of the 1D10 epitope on B cells and monocytes from approximately 50% of healthy donors. Analyses of 1D10 expression on malignant cells revealed that approximately half of the HLA class II-positive haematological malignancies expressed the 1D10 epitope. In whole blood antibody-dependent cellular cytotoxicity (ADCC) assays, Hu1D10 was more effective than rituxan in killing malignant ARH-77 B cells. Interestingly, Hu1D10-mediated lymphoma cell lysis was significantly enhanced when blood from granulocyte colony-stimulating factor (G-CSF)-treated patients was compared with blood from healthy controls. Analyses of the relevant effector cell populations revealed that FcgammaRI (CD64)-positive polymorphonuclear cells were critical for enhanced Hu1D10-mediated lymphoma killing during G-CSF therapy, while the same effector cell population induced only marginal lysis with rituxan. Furthermore, Hu1D10 was highly effective in inducing apoptosis in primary lymphoma cells from B chronic lymphocytic leukaemia patients. These preclinical results form the basis for a phase I/II clinical trial of Hu1D10 in combination with G-CSF.
Department of Medicine III, University of Erlangen - Nürnberg, Erlangen, Germany. Bernhard.Stockmeyer@med3.imed.uni-erlangen.de
Bernhard
B
Stockmeyer
Martin
M
Schiller
Roland
R
Repp
Hanns-Martin
HM
Lorenz
Joachim R
JR
Kalden
Martin
M
Gramatzki
Thomas
T
Valerius
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D017452:Receptors, IgG / Q000276:immunology; D000069283:Rituximab; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D017452:Receptors, IgG; D016179:Granulocyte Colony-Stimulating Factor; D000069283:Rituximab