title: Antitumour effects of single or combined monoclonal antibodies directed against membrane antigens expressed by human B cells leukaemia.
abstract: BACKGROUND
  The 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Altogether these data suggest that the combined use of two mAbs, such as anti-HLA-DR and anti-CD5, may significantly enhance their therapeutic potential.
authors.affiliation: EA2216 and IFR148, University Medical School, Université Européenne de Bretagne, F-9238 Brest, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Loisel
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: André
authors.forename: Josee
authors.initials: J
authors.lastname: Golay
authors.forename: Franz
authors.initials: F
authors.lastname: Buchegger
authors.forename: Jean
authors.initials: J
authors.lastname: Kadouche
authors.forename: Martine
authors.initials: M
authors.lastname: Cérutti
authors.forename: Luca
authors.initials: L
authors.lastname: Bologna
authors.forename: Marek
authors.initials: M
authors.lastname: Kosinski
authors.forename: David
authors.initials: D
authors.lastname: Viertl
authors.forename: Angelika Bischof
authors.initials: AB
authors.lastname: Delaloye
authors.forename: Christian
authors.initials: C
authors.lastname: Berthou
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Mach
authors.forename: Laurence
authors.initials: L
authors.lastname: Boumsell
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007457:Iodine Radioisotopes; D015448:Leukemia, B-Cell / Q000503:physiopathology; D008223:Lymphoma / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D011485:Protein Binding; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes