Generation of a human IgM monoclonal antibody directed against HLA class II molecules: a potential agent in the treatment of haematological malignancies
- 84 Downloads
Major histocompatibility complex (MHC) class II molecules have been considered as a good target molecule for use in immunotherapy, because of the high expression in some lymphoma and leukaemia cells and, also, because of their restricted expression on human cells (monocytes, dendritic, B lymphocytes, thymic epithelial cells, and some cytokine-activated cells, such as T lymphocytes). We have obtained a human IgM monoclonal antibody directed against human leukocyte antigen (HLA) class II molecules, using transgenic mice carrying human Ig genes. The antibody BH1 (IgM/κ isotype) recognises HLA-class II on the surface of tumour cells from patients suffering from haematological malignancies, such as chronic and acute lymphocytic leukaemias, non-Hodgkin lymphomas and myeloid leukaemias. Interestingly, functional studies revealed that BH1 mAb recognises and kills very efficiently tumour cells from several leukaemia patients in the presence of human serum as a source of complement. These results suggest that this human IgM monoclonal antibody against HLA-class II could be considered as a potential agent in the treatment of several malignancies.
KeywordsHLA class II Human monoclonal antibodies Immunotherapy Leukaemia
We would like to thank Dr Marianne Brüggemann for supplying the transgenic mice used in this work; Angel Torreiro for assistance with maintenance of the mice; Charo de Pablo (Clínica Puerta de Hierro, Madrid) and Professor Alan Epstein (University of Southern California, USA) for providing antibodies Q2/70 and CHLym-1, respectively; and Darío Alves, Cristian Sánchez, Daniel Pérez, Elina Garet, Silvia Lorenzo and Marisa Abad for technical help. The contributions of B. D. and I. S. include the generation and characterisation of monoclonal antibodies, analysis of peripheral blood cells and complement lysis. S. M. performed most of the flow cytometry studies in different populations and supervised the complement lysis and analysis in leukaemia patients. F. G. and A. G. supervised the work undertaken by B. D., I. S. and S. M. in the Hospital and in the University, respectively. This study was supported by the Xunta de Galicia, the Instituto de Salud Carlos III (Red del FIS G03/136) and the Ministerio de Educación y Ciencia (Nanobiomed, Consolider-Ingenio2010).
Conflict of interest statement
The authors declare no competing financial interests.
- 4.Burgess T, Coxon A, Meyer S, Sun J, Rex K, Tsuruda T, Chen Q, Ho SY, Li L, Kaufman S, McDorman K, Cattley RC, Sun J, Elliott G, Zhang K, Feng X, Jia XC, Green L, Radinsky R, Kendall R (2006) Fully human monoclonal antibodies to hepatocyte growth factor with therapeutic potential against hepatocyte growth factor/c-Met-dependent human tumors. Cancer Res 66:1721–1729PubMedCrossRefGoogle Scholar
- 5.Carlo-Stella C, Di Nicola M, Turco MC, Cleris L, Lavazza C, Longoni P, Milanesi M, Magni M, Ammirante M, Leone A, Nagy Z, Gioffre WR, Formelli F, Gianni AM (2006) The anti-human leukocyte antigen-DR monoclonal antibody 1D09C3 activates the mitochondrial cell death pathway and exerts a potent antitumor activity in lymphoma-bearing nonobese diabetic/severe combined immunodeficient mice. Cancer Res 66:1799–1808PubMedCrossRefGoogle Scholar
- 6.Carlo-Stella C, Guidetti A, Di Nicola M, Longoni P, Cleris L, Lavazza C, Milanesi M, Milani R, Carrabba M, Farina L, Formelli F, Gianni AM, Corradini P (2006) CD52 antigen expressed by malignant plasma cells can be targeted by alemtuzumab in vivo in NOD/SCID mice. Exp Hematol 34:721–727PubMedCrossRefGoogle Scholar
- 7.Carlo-Stella C, Guidetti A, Di Nicola M, Lavazza C, Cleris L, Sia D, Longoni P, Milanesi M, Magni M, Nagy Z, Corradini P, Carbone A, Formelli F, Gianni AM (2007) IFN-gamma enhances the antimyeloma activity of the fully human anti-human leukocyte antigen-DR monoclonal antibody 1D09C3. Cancer Res.1 67(7):3269–3275CrossRefGoogle Scholar
- 22.Magadán S, Valladares M, Suárez E, Sanjuán I, Molina A, Ayling C, Davies SL, Zou X, Williams GT, Neuberger MS, Brüggemann M, Gambón F, Díaz-Espada F, González-Fernández A (2002) Production of antigen-specific human monoclonal antibodies: comparison of mice carrying IgH/kappa or IgH/kappa/lambda transloci. Biotechniques 33:680 See also 682,684PubMedGoogle Scholar
- 26.Nagy ZA, Hubner B, Lohning C, Rauchenberger R, Reiffert S, Thomassen-Wolf E, Zahn S, Leyer S, Schier EM, Zahradnik A, Brunner C, Lobenwein K, Rattel B, Stanglmaier M, Hallek M, Wing M, Anderson S, Dunn M, Kretzschmar T, Tesar M (2002) Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells. Nat Med 8:801–807PubMedGoogle Scholar
- 27.Flomenberg N, Knowles RW, Williams D, Horibe K, Rosenkrantz K, Dupont B (1985) T lymphocyte clones detecting novel supertypic HLA class II allospecificities, vol 22. Springer, Berlin, pp 270–300Google Scholar
- 28.Nicholson IC, Zou X, Popov AV, Cook GP, Corps EM, Humphries S, Ayling C, Goyenechea B, Xian J, Taussig MJ, Neuberger MS, Brüggemann M (1999) Antibody repertoires of four- and five-feature translocus mice carrying human immunoglobulin heavy chain and kappa and lambda light chain yeast artificial chromosomes. J Immunol 163:6898–6906PubMedGoogle Scholar
- 29.Ostendorf T, van Roeyen CR, Peterson JD, Kunter U, Eitner F, Hamad AJ, Chan G, Jia XC, Macaluso J, Gazit-Bornstein G, Keyt BA, Lichenstein HS, LaRochelle WJ, Floege J (2003) A fully human monoclonal antibody (CR002) identifies PDGF-D as a novel mediator of mesangioproliferative glomerulonephritis. J Am Soc Nephrol 14:2237–2247PubMedCrossRefGoogle Scholar
- 34.Suárez E, Magadán S, Sanjuán I, Valladares M, Molina A, Gambón F, Díaz-Espada F, González-Fernández A (2006) Rearrangement of only one human IGHV gene is sufficient to generate a wide repertoire of antigen specific antibody responses in transgenic mice. Mol Immunol 43:1827–1835PubMedCrossRefGoogle Scholar