Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Fusion protein or fusion polypeptide
Reexamination Certificate
2000-09-01
2003-04-22
Saidha, Tekchand (Department: 1652)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Fusion protein or fusion polypeptide
C435S069100, C435S069700, C536S023720
Reexamination Certificate
active
06551595
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is inhibition of complement activation.
BACKGROUND OF THE INVENTION
The complement system plays a fundamental role in both the innate and acquired immune responses. As such, it also participates in the majority of diseases characterized by acute and/or chronic inflammation. For example, a critical role of the complement system has been demonstrated in rheumatoid arthritis, post-myocardial infarction reperfusion injury, post-bowel ischemia reperfusion injury, and systemic lupus erythematosus. These specific disorders are simply representative of most inflammatory states in which similar or identical molecular pathways result in complement activation and concomitant tissue injury.
Hyperacute rejection of xenografts has also been shown to result from activation of the human complement system. The utilization of organs obtained from nonhuman donors is an appealing solution to the increasing shortage of organs available for clinical transplantation. Although xenotransplantation using organs obtained from primate donors has been performed with limited clinical success, the use of distantly related species, such as pigs or sheep, avoids ethical dilemmas, potential virus transmission, and limited availability associated with the use of primates as xenograft donors. However, the use of organs from distantly related species for xenotransplantation is impractical due to hyperacute rejection (hyperacute rejection), a process that leads to irreversible xenograft damage and organ loss within minutes to hours. In xenotransplantation of vascularized tissues, hyperacute rejection is thought to be mediated by the binding of naturally occurring recipient antibodies to the endothelium of the xenograft.
The fundamental molecular basis for hyperacute rejection is thought to be activation of the classical pathway of the human complement system by human antibodies directed to immunologically foreign epitopes present on donor endothelial cells. In pig to primate xenotransplantation, it has been demonstrated that primate antibodies are primarily directed to a post-translational modification of pig membrane proteins, which modification does not occur in human cells. Specifically, foreign epitopes are generated by oligosaccharide moieties containing galactose (&agr;1-3) galactose, the result of a swine enzyme that is not present in human cells. In some combinations of discordant species, activation of the alternative pathway of complement also participates in hyperacute rejection. Activation of either the classical pathway or the alternative pathway of complement leads to endothelial cell activation, thrombosis, intravascular coagulation, edema, and eventual loss of function and rejection of the transplanted organ.
The fundamental role of the complement system during hyperacute rejection has led to investigations of the potential to prevent hyperacute rejection through the use of recombinant inhibitors of the human complement system. Initial studies focused upon the use of naturally occurring endogenous human complement regulatory proteins.
Human cells and tissues are protected from inadvertent complement-mediated injury by a diverse and apparently redundant family of regulatory molecules, most of which belong to the regulators of complement activation (RCA) family. One primary function of these molecules is to inhibit formation and accumulation of C3b, which is a product of C3 cleavage by either the classical (C4b2a) or the alternative (C3bBb) pathway convertase. In general, RCA proteins can be viewed as either function-specific or pathway-specific. For example, proteins such as decay accelerating factor (DAF; CD55) and membrane cofactor protein (MCP; CD46) are capable of regulating both the alternative and classical pathways, yet each has a limited functional role by performing either decay or cofactor function, respectively. DAF acts to dissociate the components within each of the bimolecular enzymes, whereas MCP acts as a cofactor for the serine protease factor I that cleaves C3b to form C3bi which is incapable of further participation in the complement cascade. In contrast, Factor H and C4b binding protein function specifically within the alternative pathway and classical pathway, respectively, yet each protein provides both MCP- and DAF-like control in this regard. Complement receptor type 1 (CR1) is the most versatile human complement inhibitor; it serves to regulate both the alternative pathway and classical pathway having decay and cofactor activities, and also provides a clearance function. for C3- or C4-bearing complexes which, following inactivation, it retains and transports to the reticuloendothelial system for degradation.
The functional domains of CRI, DAF, MCP, and all other RCA family members consist of repeating modules termed short consensus repeats (SCRs). Each SCR contains approximately 60 amino acids that form hypervariable domains as well as highly conserved regions. Electron microscopic studies of CRI and other family members have demonstrated that the multiple SCRs within an individual protein are tandemly arranged end to end, with each SCR representing a discrete structural unit. Each RCA family member is composed of multiple SCRs ranging from 4 SCRS in the case of DAF and MCP, to 30 SCRs in the case of the most common allotype of CR1. Amino acid homology between any two SCRs within the family ranges from 10% to 99%. These structural features of SCRs translate into the functionally conserved capacity among family members to bind C3b as well as the functionally diverse consequences of this interaction as described above.
It has been demonstrated that transgenic expression of human endogenous complement regulatory proteins (e.g. DAF, CD59) on xenografts may diminish or prevent hyperacute rejection. The human proteins that were initially chosen for these studies were presumably selected because they were among the first complement regulatory proteins to be discovered, rather than for any particular function or combinations of functions. As described above, RCA proteins are classified in three ways. A given RCA protein is described in terms of its ligands, its capacity to provide cofactor and/or decay accelerating activity, and its capacity to inhibit the alternative pathway, the classical pathway or both (Table 1). All of the RCA proteins described in Table 1 demonstrate some degree of functional versatility by inhibiting complement activation at more than one point in the cascade. Similarly, CR1 is considered the most versatile inhibitor.
TABLE 1
Functional Categorization of Human Complement Regulatory Proteins
Inhibitor
Ligand(s)
Function
Pathway
DAF
C3b?
D
AP, CP
MCP
C3b
C
AP, CP
CR1
C3b, iC3b, C4b
D, C, IC
AP, CP
H
C3b
D, C
AP
C4bp
C4b
D, C
CP
D = Decay Acceleration;
C = Factor I Cofactor;
AP = Alternative Pathway;
CP = Classical Pathway;
IC = Immune Complex Clearance
Recombinant versions of regulators of complement activation have been reported. Hebel et al. (WO 91/16437, Oct. 31, 1991) describe soluble peptide analogs containing binding sites for complement. Kotwal et al. (1990, Science 250:827-830) describe a gene encoding the anti-complement protein, vaccinia virus complement control protein (VCP) (U.S. Pat. No. 5,187,268, Feb. 16, 1993), a 35 kD protein that is secreted by cells infected with vaccinia. Structurally, VCP consists entirely of four SCRs which bear 35% and 31% amino acid identity to MCP and DAF, respectively. Several studies over the past few years have demonstrated that VCP is capable of inhibiting the classical and alternative pathways through both decay and cofactor activities.
Historically, vaccinia virus was used as a vaccine to protect against infection by variola virus, the etiologic agent of smallpox. The amino acid sequence homology between most of the proteins in the two viruses is approximately 95%.
The virus that causes smallpox has been completely eradicated in that the last confirmed case of naturally occurring smallpox was reported in Somalia in Oct
Ahearn Joseph M.
Rosengard Ariella M.
Saidha Tekchand
The Trustees of the University of Pennsylvania
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