Down-regulation resistant C3 convertase

#The present invention relates to novel modified proteins capable of forming C3 convertases resistant to down-regulation, DNA sequences encoding such proteins and the use of such proteins as therapeutic agents, particularly for use in depleting levels of complement pathway proteins or in targeting complement attack (C3b deposition) at specific sites.

#The complement system functions in the immune response of humans and other vertebrates, being of major importance in the effector functions such as phagocytosis, cytolysis and recruitment of cells that induce local inflammatory responses [15]. These properties are desirable for elimination of invading pathogens, such as bacteria, but undesirable when triggered to act against host tissues (e.g. in post-ischemic reperfusion injury [3]) or against foreign therapeutic material (e.g. hyperacute rejection of xenografts [7]). There have been attempts to abrogate these undesirable properties by exploiting derivatives of complement regulatory proteins whose normal function is to suppress complement activation [10, 18].

#The complement system comprises proteins both on the surface of cells, (receptors and regulators) as well as in the fluid-phase (blood plasma and other extracellular environments). The critical step for the generation of responses is the proteolytic conversion of C3 to the fragments C3b and C3a. C3a is an anaphylatoxin that, like C5a, attracts mast cells to the site of challenge, resulting in local release of histamine, vasodilation and other inflammatory effects. The nascent C3b has an ability to bind to surfaces around its site of generation. This C3b then focuses attack by the cytolytic complement components (C5-C9).

#The invention will now be described by way of the following examples, which should not be construed as in any way limiting the invention. The examples refer to the accompanying drawings in which:

#FIG. 1: shows the predicted protein sequence of human C3 as encoded in PC3; (using the standard one letter amino acid code)

#FIG. 2: shows the cDNA sequence in PC3; (using the standard one letter deoxynucleotide code for the sense strand, written 5′-3′).

#For ease of reference, the relationship between the claims on file which relate to particular proteins capable of acting as down-regulation resistant C3 convertases and the examples and tables provided hereafter is set out below:

#TABLE A Region of amino acid sequence (relative to human C3 convertase) believed to be important for down- Claims regulation resistance Example Table 5-8 1303/1320 1-6, 11 9-11 758-780/752-754 7 12 1427, 1431, 1433 8 I 13-15 992-1005 12, 13 II 16-19 1152-1155 14 II 20-29 1546-1663 15, 17 III 30-34 954-955 16

#The following standard methods and definitions are applicable to all the examples: