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Immunomodulatory activity of a methionine aminopeptidase‐2 inhibitor on B cell differentiation

Methionine aminopeptidase‐2 (MetAP‐2) inhibitors have potent anti‐angiogenesis activity and are being developed for the treatment of solid tumours. The recently observed specific expression of MetAP‐2 in germinal centre B cells suggests that it has a role in regulating B cell function. We have demonstrated a potent MetAP‐2‐dependent inhibitory effect on the antibody secretion from B cell receptor and CD40 co‐stimulated primary human B cells in the presence of interleukin‐21. The effect of MetAP‐2 inhibition on antibody secretion was due to a block in differentiation of B cells into plasma cells. Immunohistochemical analysis of germinal centres from human, mouse and marmoset spleen showed a similar expression pattern of MetAP‐2 in the marmoset and man, whereas mouse spleen showed no detectable expression. In a marmoset, T dependent immunization model, the MetAP‐2 inhibitor suppressed an antigen‐specific antibody response. Furthermore, histological analysis showed loss of B cells in the spleen and disrupted germinal centre formation. These results provide experimental evidence to support a novel role for MetAP‐2 in immunomodulation. These effects of MetAP‐2 are mediated by disruption of the germinal centre reaction and a block in the differentiation of B cells into plasma cells.