Soluble Complement Receptor 1 Therapeutics (original) (raw)
Related papers
Journal of Clinical Investigation, 2003
In a strategy to specifically target complement inhibitors to sites of complement activation and disease, recombinant fusion proteins consisting of a complement inhibitor linked to a C3 binding region of complement receptor (CR) 2 were prepared and characterized. Natural ligands for CR2 are C3 breakdown products deposited at sites of complement activation. Fusion proteins were prepared consisting of a human CR2 fragment linked to either the N terminus or C terminus of soluble forms of the membrane complement inhibitors decay accelerating factor (DAF) or CD59. The targeted complement inhibitors bound to C3-opsonized cells, and all were significantly more effective (up to 20-fold) than corresponding untargeted inhibitors at protecting target cells from complement. CR2 fusion proteins also inhibited CR3-dependent adhesion of U937 cells to C3 opsonized erythrocytes, indicating a second potential anti-inflammatory mechanism of CR2 fusion proteins, since CR3 is involved in endothelial adhesion and diapedesis of leukocytes at inflammatory sites. Finally, the in vivo validity of the targeting strategy was confirmed by the demonstration that CR2-DAF, but not soluble DAF, targets to the kidney in mouse models of lupus nephritis that are associated with renal complement deposition.
Progress and Trends in Complement Therapeutics
Advances in experimental medicine and biology, 2013
The past few years have proven to be a highly successful and exciting period for the field of complement-directed drug discovery and development. Driven by promising experiences with the first marketed complement drugs, increased knowledge about the involvement of complement in health and disease, and improvements in structural and analytical techniques as well as animal models of disease, the field has seen a surge in creative approaches to therapeutically intervene at various stages of the cascade. An impressive panel of compounds that show promise in clinical trials is meanwhile being lined up in the pipelines of both small biotechnology and big pharmaceutical companies. Yet with this new focus on complement-targeted therapeutics, important questions concerning target selection, point and length of intervention, safety, and drug delivery emerge. In view of the diversity of the clinical disorders involving abnormal complement activity or regulation, which include both acute and ch...
Complement-targeted therapeutics
Nature Biotechnology, 2007
The complement system is a central component of innate immunity and bridges the innate to the adaptive immune response. However, it can also turn its destructive capabilities against host cells and is involved in numerous diseases and pathological conditions. Modulation of the complement system has been recognized as a promising strategy in drug discovery, and a large number of therapeutic modalities have been developed. However, successful marketing of complement-targeted drugs has proved to be more difficult than initially expected, and many strategies have been discontinued. The US Food and Drug Administration's approval of the first complement-specific drug, an antibody against complement component C5 (eculizumab; Soliris), in March 2007, was a long-awaited breakthrough in the field. Approval of eculizumab validates the complement system as therapeutic target and might facilitate clinical development of other promising drug candidates.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1993
Human CR1 is a membrane-bound protein which plays an important role in the control of the human complement system. In addition to its involvment in the processing and clearance of immune complexes with C3b or C4b on their surfac e, CR1 acts as a cofactor for the proteolysis of C3b and C4b by Factor I. sCR1 is a recombinant, soluble form of CRI which retains the cofactor activities of CR1, and is of potential therapeutic value for the suppression of complement-mediated tissue damage in vivo. An assay has been established using microtitre plates to explore the binding of sCRI to the two isotypes of C4, C4A and C4B, and to C4 fragments. Specific binding of lzSI-sCR1 to C4b and ammonia-treated C4 has been demonstrated. The binding of 125I-sCR1 to ammonia-treated C4 is dependent on pH and ionic strength, decreasing with an increase in pH and with an increase in ionic strength. At physiological ionic strength, up to twice as much 1eSI-sCR1 bound to ammonia-treated C4A as bound to ammonia-treated C4B. This preference of sCR1 for binding to the C4A isotype has implications for the clinical association of immune complex disease with C4A null alleles.
Biochemical Journal, 1998
The complement C3b/C4b receptor (CR1) is an integral protein, anchored in the plasma membrane through a hydrophobic domain of 25 amino acids, but is also found in the plasma in soluble form (sCR1). A recombinant, soluble form of CR1 has been demonstrated to reduce complement-dependent tissue injury in animal models of ischaemia/reperfusion. In view of the important pathophysiological relevance of sCR1, we have investigated the mechanisms governing CR1 release by using various mutated and chimaeric receptors transiently expressed in COS cells. Pulse-chase experiments revealed that (1) sCR1 is produced by a proteolytic process, (2) the cleavage site lies within the C-terminus of CR1 transmembrane domain, (3) the proteolytic process involves a fully glycosylated CR1 form and (4) this process takes place in late secretory vesicles or at the plasma membrane.
COMPLEMENT RECEPTOR IS AN INHIBITOR OF THE COMPLEMENT CASCADE
1981
Human erythrocytes interact with particles or soluble immune complexes bearing C3b, the major fragment of the third component of complement. This phenomenon is known as immune adherence (1). B lymphocytes (2), neutrophils, macrophages, monocytes (3-5), and epithelial cells of the kidney glomerulus (6) also have membrane receptors for C3b. The C3b receptors function in phagocytosis, facilitating the attachment of the particle to the phagocytes, and, in synergy with the Fc receptors for IgG, promote ingestion of sensitized particles (7, 8). Recently, a glycoprotein of 205,000 mol wt has been isolated from the membrane of human erythrocytes and identified as the C3b receptor (CR1) (9, 10). This protein was characterized as an inhibitor of the alternative pathway C3 convertase (C3b,Bb) and as a cofactor for the cleavage of the a' chain of C3b in the fluid phase by a serum enzyme, C3b/C4b inactivator.
American Journal of Medical Sciences and Medicine, 2014
The multiple interconnections among complement proteins, immune cells, and mediators provide an excellent mechanism to protect the organism against infections and support the repair of damaged tissues. However, disturbances in this "defense machinery" contribute to the pathogenesis of various diseases. The role of complement in various inflammatory disorders is multifaceted; for example, the activation of complement can significantly contribute to inflammation-mediated tissue damage, whereas inherited or acquired complement deficiencies highly favor the development of autoimmunity. Complement as an essential component of the immune system is of substantial relevance for the destruction of invading microorganisms and for maintaining tissue homeostasis including the protection against autoimmune diseases. The involvement of complement in the pathogenesis of a great number of partly life threatening diseases defines the importance to develop inhibitors which specifically interfere with its deleterious action. Endogenous soluble complement-inhibitors, antibodies or low molecular weight antagonists, either blocking key proteins of the cascade reaction or neutralizing the action of the complementderived anaphylatoxins have successfully been tested in various animal models over the past years.
PLOS ONE, 2015
The complement system has been increasingly recognized to play a pivotal role in a variety of inflammatory and autoimmune diseases. Consequently, therapeutic modulators of the classical, lectin and alternative pathways of the complement system are currently in preclinical and clinical development. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement and is referred to as Peptide Inhibitor of Complement C1 (PIC1). In this study, we determined that the lead PIC1 variant demonstrates a salt-dependent binding to C1q, the initiator molecule of the classical pathway. Additionally, this peptide bound to the lectin pathway initiator molecule MBL as well as the ficolins H, M and L, suggesting a common mechanism of PIC1 inhibitory activity occurs via binding to the collagen-like tails of these collectin molecules. We further analyzed the effect of arginine and glutamic acid residue substitution on the complement inhibitory activity of our lead derivative in a hemolytic assay and found that the original sequence demonstrated superior inhibitory activity. To improve upon the solubility of the lead derivative, a pegylated, water soluble variant was developed, structurally characterized and demonstrated to inhibit complement activation in mouse plasma, as well as rat, non-human primate and human serum in vitro. After intravenous injection in rats, the pegylated derivative inhibited complement activation in the blood by 90% after 30 seconds, demonstrating extremely rapid function. Additionally, no adverse toxicological effects were observed in limited testing. Together these results show that PIC1 rapidly inhibits classical complement activation in vitro and in vivo and is functional for a variety of animal species, suggesting its utility in animal models of classical complement-mediated diseases.
Complement in Immune and Inflammatory Disorders: Therapeutic Interventions
The Journal of Immunology, 2013
With the awareness that immune-inflammatory crosstalk is at the heart of many disorders, the desire for novel immunomodulatory strategies in the therapy of such diseases has grown dramatically. As a prime initiator and important modulator of immunological and inflammatory processes, the complement system has emerged as an attractive target for early and upstream intervention in inflammatory diseases and has moved into the spotlight of drug discovery. While prevalent conditions such as age-related macular degeneration have attracted the most attention, the diverse array of complement-mediated pathologies, with distinct underlying mechanisms, demands a multifaceted arsenal of therapeutic strategies. Fortunately, efforts in recent years have not only introduced the first complement inhibitors to the clinic but also filled the pipelines with promising candidates. With a focus on immunomodulatory strategies, this review discusses complement-directed therapeutic concepts and highlights promising candidate molecules. Many concepts of modern drug discovery have deep roots in immunology research, with Paul Ehrlich's notions of the "magic bullet" and his "side-chain theory" being among the most prominent examples (1). The connection between these two disciplines has even intensified in recent years in view of biological drugs such as mAb's. Therapeutic immune modulation is increasingly recognized as a promising strategy for tackling inflammatory diseases, yet is in need of more selective modulators that help restore the immune balance and resolve inflammation (2). Fueled by the discovery of new functional roles, immune crosstalk mechanisms, and a growing number of disease associations (see accompanying review (3)), complement has emerged as focal point of interest in immunomodulatory and anti-inflammatory strategies (4). The variety of intervention points and high number of extracellular targets within the complement cascade (Fig. 1), the availability of potent natural inhibitor templates, and a spike in structure-function insight have all contributed to rapid advances in the field of complement-related drug discovery. While only two drugs with connection to complement are currently available in the clinic, ongoing research efforts have produced a plethora of innovative and diverse drug candidates that demonstrate great promise in many clinical conditions. In the following sections, we provide an overview of current therapeutic strategies and highlight drug candidates that are in preclinical or clinical development.