A humanized HLA-DR antibody (hu1D10, apolizumab) in combination with granulocyte colony-stimulating factor (filgrastim) for the treatment of non-Hodgkin's lymphoma: A pilot study

Abstract

Apolizumab is a humanized monoclonal antibody against a polymorphic epitope on HLA DRbeta that demonstrated evidence for therapeutic activity in follicular lymphoma patients. In pre-clinical studies, we previously reported that granulocyte colony-stimulating factor (G-CSF) treatment significantly enhanced lymphoma cell killing by HLA class II antibodies, including apolizumab. These results suggested a combination trial of apolizumab and G-CSF (filgrastim). In this trial, we treated six patients with relapsed or refractory 1D10-positive non-Hodgkin's lymphoma with filgrastim and variable doses of apolizumab ranging from 0.15 to 1.5 mg/m2. The combination was clinically well tolerated, with only two patients experiencing grade III/IV hematological toxicity (thrombocytopenia and autoimmune hemolytic anemia). Another patient developed a pruritic skin rash, which was probably a treatment-related grade II skin toxicity. Interestingly, two patients with follicular lymphoma who received intensified apolizumab treatment on a three times weekly schedule experienced prolonged stabilization of their disease for 12 and more than 36 months. In conclusion, this small pilot study suggests that a combination of HLA class II antibodies and G-CSF is clinically feasible.

A Bispecific Antibody-IFNα2b Immunocytokine Targeting CD20 and HLA-DR Is Highly Toxic to Human Lymphoma and Multiple Myeloma Cells

“…Anti-HLA-DR MAbs efficiently induce apoptosis, which is mediated by direct signaling without the requirement of additional crosslinking, and are also potent inducers of ADCC and CDC (11,15,17). Where ADCC may enhance therapeutic potential, CDC is largely responsible for the pathogenesis of side effects associated with the MAb infusion (18).…”

Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers

“…Anti-HLA-DR mAbs, including hL243 IgG 1 , induce apoptosis, ADCC, and CDC. 9,11,36 Although ADCC may enhance therapeutic potential, CDC is largely responsible for the side effects associated with the mAb infusion 37 and may have limited the clinical use of another anti-HLA-DR mAb, Hu1D10. 38 The hL243␥4p variant (IMMU-114), which was engineered for improved clinical safety by using the constant region of the human IgG 4 isotype, maintains the ability to induce apoptosis but has diminished ADCC and CDC.…”

Therapy of B-cell malignancies by anti–HLA-DR humanized monoclonal antibody, IMMU-114, is mediated through hyperactivation of ERK and JNK MAP kinase signaling pathways

“…However, safety concerns have been raised regarding the clinical use of HLA-DR-directed antibodies because the antigen is expressed on normal as well as tumor cells. In addition, anti-HLA-DR mAbs are potent inducers of complement activation, 6 which plays a pivotal role in the pathogenesis of the side effects of mAb infusion. 7 The IgG4 IMMU-114 antibody was specifically generated to derive an agent that is able to kill tumor cells without CDC or ADCC.…”