Antitumour effects of single or combined monoclonal antibodies directed against membrane antigens expressed by human B cells leukaemia

Abstract

BackgroundThe increasing availability of different monoclonal antibodies (mAbs) opens the way to more specific biologic therapy of cancer patients. However, despite the significant success of therapy in breast and ovarian carcinomas with anti-HER2 mAbs as well as in non-Hodkin B cell lymphomas with anti-CD20 mAbs, certain B cell malignancies such as B chronic lymphocytic leukaemia (B-CLL) respond poorly to anti-CD20 mAb, due to the low surface expression of this molecule. Thus, new mAbs adapted to each types of tumour will help to develop personalised mAb treatment. To this aim, we analyse the biological and therapeutic properties of three mAbs directed against the CD5, CD71 or HLA-DR molecules highly expressed on B-CLL cells.ResultsThe three mAbs, after purification and radiolabelling demonstrated high and specific binding capacity to various human leukaemia target cells. Further in vitro analysis showed that mAb anti-CD5 induced neither growth inhibition nor apoptosis, mAb anti-CD71 induced proliferation inhibition with no early sign of cell death and mAb anti-HLA-DR induced specific cell aggregation, but without evidence of apoptosis. All three mAbs induced various degrees of ADCC by NK cells, as well as phagocytosis by macrophages. Only the anti-HLA-DR mAb induced complement mediated lysis. Coincubation of different pairs of mAbs did not significantly modify the in vitro results. In contrast with these discrete and heterogeneous in vitro effects, in vivo the three mAbs demonstrated marked anti-tumour efficacy and prolongation of mice survival in two models of SCID mice, grafted either intraperitoneally or intravenously with the CD5 transfected JOK1-5.3 cells. This cell line was derived from a human hairy cell leukaemia, a type of malignancy known to have very similar biological properties as the B-CLL, whose cells constitutively express CD5. Interestingly, the combined injection of anti-CD5 with anti-HLA-DR or with anti-CD71 led to longer mouse survival, as compared to single mAb injection, up to complete inhibition of tumour growth in 100% mice treated with both anti-HLA-DR and anti-CD5.ConclusionsAltogether these data suggest that the combined use of two mAbs, such as anti-HLA-DR and anti-CD5, may significantly enhance their therapeutic potential.

Design and Validation of a Novel Generic Platform for the Production of Tetravalent IgG1-like Bispecific Antibodies

“…The JOK1 5.3 cell line (JOK1 Hairy Cell Leukemia cell lines stably transduced with human CD5 cDNA) has been described previously (40). JOK1 5.3, REH acute leukemia, MOLT4, and JURKAT T cell leukemias and K562 erythroleukemia cell lines were grown in RPMI 1640 medium supplemented with 2 mM glutamine, 10% FBS (all from Euroclone, Milano, Italy) and 110 mM gentamicin (PHT Pharma, Milan, Italy).…”

Targeted drug delivery and cross-linking induced apoptosis with anti-CD37 based dual-ligand immunoliposomes in B chronic lymphocytic leukemia cells

“…Previous studies have revealed that the activity of therapeutic Abs can be enhanced by creating multivalent constructs such as ILs [33, 35]. Combination of multiple monoclonal antibodies has shown synergistic therapeutic effects in B cells leukemia [40, 41]. Therefore, the dual mAbs on the same ILs may potentially enhance the cross-linking induced apoptosis of CLL B cells.…”

Cytometric evaluation of transferrin receptor 1 (CD71) in childhood acute lymphoblastic leukemia

“…Yeh et al found increased transferrin binding in peripheral blood mononuclear cells from patients with leukemia, lymphoma and myeloma [29]. In B-cell chronic lymphocytic leukemia, CD71 expression is heterogenous, with some cases showing high expression [30][31][32]. Both B and T lineage non-Hodgkin's lymphomas have been reported to express CD71, with the expression level correlating with the lymphoma grading, though not with patient survival [18,33].…”