UPTAKE OF RECOMBINANT MYELOPEROXIDASE, FREE OR FUSED TO FC-GAMMA, BY MACROPHAGES ENHANCES KILLING ACTIVITY TOWARD MICROORGANISMS

A chimeric antibody-like molecule consisting of the human myeloperoxid ase (rMPO) fused to the second and third constant-sequence (C(H)2 and C(H)3) Fc domains of human immunoglobulin G-1 has been constructed and expressed in Chinese hamster ovary (CHO) cells, This fusion molecule was designed to combine the binding specificity of Fc with the antimic robial properties of rMPO, The rMPO-Fc fusion dimerized through the Fc fragment, while retaining the enzymatic activity of rMPO, The chimeri c molecule was glycosylated and most of the propeptide was eliminated, indicating a better processing of the polypeptide than for rMPO alone , Both rMPO and rMPO-Fc bound to and were internalized by macrophage-l ike U937 promonocytic cells, Unexpectedly, the chimera failed to bind to the Fc receptor but interacted with a higher affinity than rMPO wit h the same binding sites, The presence of the Fc fragment in the chime ra, in addition, did not extend the plasma half-life of the fusion pro tein, In vitro, rMPO-Fc exhibited a stronger killing effect than rMPO toward Candida albicans in the presence of either H2O2 alone or human macrophages. In vivo, rMPO-Fc similarly conferred a better protection than rMPO in a lethal model of murine cowdriosis, These properties cou ld be related to the Fc-induced dimerization of the fusion protein in CHO cells.