Methods of treating a disease with anti-C5 alpha antibodies

#The content of the electronically submitted sequence listing (Name: sequencelisting_ascii_v2.txt, Size: 28,505 bytes; and Date of Creation: Sep. 22, 2011) filed herewith the application is incorporated by reference in its entirety.

#Activation of the complement system (C system) represents an important mechanism in the immune defence. At the same time it represents a double-edged weapon because on the one hand guarantees protection of the host but on the other is capable of damaging tissues where complement is activated by several pathological circumstances. The increased susceptibility to bacterial infections and autoimmune disorders observed in patients with inherited deficiencies of the C system clearly demonstrates the particular importance of this system in host protection against infectious agents and in the clearance of immunocomplexes.

#These protective functions result from complement activation in cascade fashion that generates biologically active products. Some of those, such as C1q, C3b and C3bi, opsonize the infectious agents enabling their disposal. Instead others, such as C5a and C5b67, have the function to recruit phagocytic cells at the site of inflammation or lyse sensitive targets as in the case of the membrane attack complex (MAC). Unfortunately, these molecules, once they are produced, are not able to discriminate between endogenous and exogenous targets, and would provoke serious damage to tissues and cells if those were not protected by potent membrane or extracellular inhibitors acting at various levels in the complement activation cascade. However, the action of inhibitors is overwhelmed in presence of a massive activation of the C system, in serious infectious diseases or autoimmune disorders, and the activated complement causes tissue and cell destruction.

#FIG. 1. Assessment of the ability of anti-C5 clones scFv Ts-a12 and Ts-a12/22 to inhibit formation of C5a fragment by means of an ELISA assay (panel A) and an haemolytic assay (panel B).

#Panel A) The ELISA assay measures the amount of C5a fragment released in the supernatant after enzymatic cleavage of C5, using antibodies anti-C5 as described in example 6. Incubation of C5 with antibodies Ts-a12 and Ts-a12/22 of the invention inhibits formation of the C5a fragment. Sheep erythrocytes sensitised with antibodies and coated until the C3b (EAC1-3b) complement step were added to the mixture of TS-A12 or TS-A12/22 and C5, and the mixture was further incubated for 30 minutes at 37° C. (panel B). As shown in FIGS. 1A and B, TS-A12 and TS-A12/22 antibodies inhibit C5 cleavage by C5 convertase and therefore inhibit formation of C5a (Panel A) and of TCC (Panel B).

#Symbols: -▴-: Ts-A12/22; -▪-: unrelated scFv; -⋄-: TS-A12.

#The main object of the present invention relates to an antibody of human origin which has specificity for the C5 component of the complement system and is characterised by the fact of inhibiting the cleavage of C5 alpha chain, also termed activated C5, into C5a and C5b fragments. This cleavage occurs as result of complement activation occurring by known mechanisms.

#Following Complement activation, a C5 convertase is produced which cleaves the alpha chain of factor C5 generating a fragment of approximately 70 amino acids (aa), known as C5a, and a C-terminal fragment of 925 aa, C5b. The products resulting from C5 activation, C5a and C5b, are biologically active. In particular, C5a has chemotactic activity toward polymorphonuclear leukocytes and monocytes, whereas the C5b fragment contributes to formation of the terminal complement complex (TCC).

#The antibody is preferably recombinant.