Enhanced killing of B lymphoma cells by granulocyte colony‐stimulating factor‐primed effector cells and Hu1D10 – a humanized human leucocyte antigen DR antibody

Abstract

Summary. 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 b-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 FccRI (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.

Within Peripheral Blood Mononuclear Cells, Antibody-Dependent Cellular Cytotoxicity of Rituximab-Opsonized Daudi cells Is Promoted by NK Cells and Inhibited by Monocytes due to Shaving

“…We isolated neutrophils from whole blood (49), and found that these cells do not promote killing of RTX-opsonized cells, in agreement with the reports of Stockmeyer et al (52,53), but they do remove Al488 RTX from RTX-opsonized Daudi cells. In separate experiments with neutrophils isolated from the blood of two different donors, we found that between 50 and 75% of the bound RTX was removed from Al488 RTX-opsonized Daudi cells.…”

Filgrastim enhances T-cell clearance by antithymocyte globulin exposure after unrelated cord blood transplantation

“…Previous studies support our finding that G-CSF enhances cytotoxicity of monoclonal antibodies by neutrophils, [22][23][24][25][26][27][28] which is partly explained by strong induction of the high-affinity IgG receptor (FcgRI; CD64). 28,29 For instance, G-CSF treatment was shown to enhance the antitumor effects of rituximab in CD20 1 models and of trastuzumab in HER21 models.…”

“…[22][23][24][25][26][27][28] We therefore hypothesized that Filgrastim (G-CSF) might affect IR through enhanced ATG-mediated cytotoxicity. G-CSF administration usually starts within the first week after CBT and lasts until neutrophil engraftment occurs (mostly within 3-4 weeks).…”

A Recombinant Bispecific Single-Chain Fragment Variable Specific for HLA Class II and FcαRI (CD89) Recruits Polymorphonuclear Neutrophils for Efficient Lysis of Malignant B Lymphoid Cells

“…HLA class II Abs, including Lym-1 and Hu1D10 (apolizumab) have been moved to the clinic and have been evaluated in phase I and II clinical trials in lymphoma patients, where they demonstrated therapeutic efficacy (5). Based on promising preclinical data, Hu1D10 was evaluated in a pilot study in combination with G-CSF for recruiting neutrophils as effector cells in relapsed lymphoma patients (6). Considerable safety concerns were initially raised, because HLA class II Abs showed to be potent in activating human complement and because HLA class II expression is not lymphoma-restricted (7).…”