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An antibody inhibitor of the LMO2-protein complex blocks its normal and tumorigenic functions


The LIM-domain protein LMO2 is a T-cell oncogenic protein first recognized by gene activation through chromosomal translocations, but it is also responsible for leukaemias arising as secondary, adverse effects in an X-SCID gene therapy trial. There are no specific reagents currently available to analyse the LMO2 multiprotein complex or to combat LMO2-dependent leukaemias. Accordingly, we have isolated an anti-LMO2 single chain Fv antibody fragment to determine if intracellular interference with LMO2-protein complexes can avert LMO2-dependent functions in normal and cancer settings. The anti-LMO2 single chain Fv, obtained using Intracellular Antibody Capture (IAC) technology, is specific for LMO2 among the LIM-only protein family and binds LMO2 through the third and fourth LIM fingers. Using vector-mediated expression of anti-LMO2 scFv, we show inhibition of Lmo2-dependent erythropoiesis but not endothelial development. We also demonstrate inhibition of Lmo2-dependent leukaemia in a mouse T-cell tumourigenesis transplantation assay with retroviral-mediated expression of anti-LMO2 scFv. Our studies establish that interference with the LMO2 multiprotein complex inhibits both normal and tumourigenic roles. The antibody fragment is a tool for dissecting LMO2 function in haematopoiesis and leukaemia and is a lead for development of therapeutics against LMO2-dependent T-ALL.

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This work was supported by the Medical Research Council. CHN was supported by a fellowship from the Lady Tata Memorial Trust. We would like to thank Dr T Kitamura (University of Tokyo) for PlatE packaging cells and Dr D Baltimore (California Institute of Technology) for pMIG vector.

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Correspondence to T H Rabbitts.

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Nam, CH., Lobato, M., Appert, A. et al. An antibody inhibitor of the LMO2-protein complex blocks its normal and tumorigenic functions. Oncogene 27, 4962–4968 (2008).

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