Fc fusion proteins

Sergejeva S, Ivanov S, Lotvall J, Linden A Interleukin-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation. Am J Respir Cell Mol Biol 2005 33 248-253. 96 Bush KA, Farmer KM, Walker JS, Kirkham BW Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgGl Fc fusion protein. Arthritis Rheum 2002 46 802-805. 

IL-13 KO mice failed to clear infection despite mounting equivalent type 2 cytokine responses to wild-type mice. Further evidence of a role for IL-13 in expulsion is shown in studies utilizing BALB/c IL-4 KO mice. While control mice cleared infection, treatment with A25 (a soluble IL-13 receptor alpha 2-human IgG-Fc fusion protein) prevented worm expulsion. (Data adapted from Bancroft et al., 1998 A.J. Bancroft, unpublished.)... 

Understanding the role of Fc and FcRN has allowed engineering of hybrid molecules that take advantage of Fc-dependent plasma half-life extension in designing fusion proteins intended for therapeutic use. An example is the construct of the TNF receptor-Fc fusion protein, which results in a significant increase in the half-life of the TNF receptor [20-22]. Enbrel, a recombinant TNF-a-receptor-Fc fusion protein, has provided effective treatment for rheumatoid arthritis patients. 

Murray, K.M., and S.L. Dahl, Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein (TNFR Fc) in rheumatoid arthritis. Ann Pharmacother, 1997. 31(11) 1335-8. 

Fc fusion protein, approved in 1998, has provided effective treatment for rheumatoid arthritis patients. 

TNF-alpha receptor-immune globlulin G1 Fc fusion protein,... 

Zheng, X.X., Steele, A.W., Hancock, W.W., Stevens, A.C., Nickerson, P.W., Roy-Chaudhury, P., Tian, Y. and Strom, T.B. (1997) A noncytolytic IL-10/Fc fusion protein prevents diabetes, blocks autoimmunity, and promotes suppressor phenomena in NOD mice. J. Immunol, 158,4507-4513. 

Key words Monoclonal antibodies, Fc-fusion proteins, FcRn, transgenic mice, pharmacokinetics, serum half-life. 

As of 2008, 25 therapeutic monoclonal antibodies (mAbs) mAbs had been approved for clinical use in the United States, and with over 400 antibodies being in preclinical and clinical development further increase of antibody therapies is assured (10, 11). As a general rule, the Fc fragment is a key component of therapeutic mAb design because it extends their pharmacokinetics. Inclusion of the Fc from IgG is also a key component of other bioactive proteins where prolongation of pharmacokinetics is desired, e.g., the tumor necrosis factor receptor (TNFR) fusion protein etan-ercept (Enbrel ) (12). Thus for both therapeutic antibodies and Fc-fusion proteins, the FcRn interaction is a generalized way to exploit FcRn protection to achieve the benefits of extended persistence in vivo. 

Conventional rodent model systems have proven problematic as they do not reliable model the pharmacokinetics of humanized mAb and Fc-fusion proteins. In contrast to the failure of mouse mAbs to be protected by human FcRn, humanized mAbs have an abnormally high affinity for mouse and rat FcRn, resulting in an artificially prolonged serum persistence (13, 16). This fact has greatly diminished the preclinical utility of standard mice for therapeutic mAb development and testing. The alternative cynamolo-gous monkey model has proven to be reliable, but it is hampered by considerable expense and ethical concerns that limit its routine use. 

The extracellular domain of cell membrane receptors can be produced recombi-nantly and used as a therapeutic product. The soluble receptor can be used to bind and neutralize the receptor s endogenous ligands (e.g., etanercept), or it can be used for stimulation of a co-receptor (e.g., abatacept). Soluble receptors are typically produced as IgG Fc fusion proteins to extend the half-life of the receptor in circulation. 

As with the anti-TNFa mAbs, neither an immunoadhesin containing type 1 TNF receptor sequences (TNF-RI-Fc fusion protein) (79) nor type II receptor sequences (TNF-RII-Fc fusion protein, etanercept) reduced mortality in patients with septic shock (80). Flowever, unlike the case of the mAh therapy, there appeared to be a significant, dose-dependent increase in mortality with the TNF-RII-Fc construct (doses tested were 0.15 mg/kg, 0.45 mg/kg and 1.5 mg/kg as a single infusion). The reasons for this result and the discrepancy with the mAh data are not clear. It may be related to the lymphotoxin-binding capacity of the TNF-R fusion protein, to the capacity of some mAbs to lyse membrane-associated TNFa-expressing monoytes, or to chance observation. 

Zeltser R, Valle L,Tanck C, Holyst MM, Ritchlin C, Gaspari AA. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept a recombinant tumor necrosis factor alpha receptor Fc fusion protein. Arch Dermatol 2001 137(7) 893-9. 

Dumont JA, Bitonti AJ, Clark D, Evans S, Pickford M, Newman SP. Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway. I Aerosol Med 2005 18(3) 294-303. 

Gustafsson E, Lindvall O, Kokaia Z (2003) Intraventricular infusion of TrkB-Fc fusion protein promotes ischemia-induced neurogenesis in adult rat dentate gyrus. Stroke 34 2710-2715. 

A cDNA encoding human IL-17 (hIL-17) has been cloned from a CD4 T-cell library. The predicted 155-amino acid sequence contains an N-terminal signal peptide and exhibits 72% amino acid identity with HVS13 and 63% with murine CTLA-8, High levels of hIL-17 were induced from primary peripheral blood CD4 T cells on stimulation. When expressed in CVl/EBNA cells, recombinant hIL-17 was secreted in both glycosylated and nonglycosylated forms. An hIL-17 Fc fusion protein and supernatants from cells transfected with hIL-17 induced IL-6 and IL-8 production and enhanced the surface expression of the ICAM-1 in human fibroblasts. ... 

A recombinant, soluble fusion protein that is a dimer of an extracellular portion of the human TNF receptor and the Fc portion of IgGl (TNFR Fc) binds and neutralizes TNFa and prevents death in animal models of bacteremia and endotoxemia. In patients with septic shock, treatment with the TNFR Fc fusion protein does not reduce mortality, and higher doses appear to be associated with increased mortality. 

Fisher CJ> Agosti JM Jr, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor receptor Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Medl996 334 1697-702. 

Kohno T,Tam LT, Stevens SR, Louie JS. Binding characteristics of tumor necrosis factor receptor-Fc fusion proteins vs anti-tumor necrosis factor mAbs. J Invest Dermatol Symp Proc 2007 12 5-8. 

Weinblatt M E, Kremer J M, Bankhurst A D, et al. (1999). A trial of etanercept, a recombinant tumor necrosis factor receptor Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. New Eng. J. Med. 340 253-259. 

Elanercept TNF receptor Fc fusion protein Rheumatoid arthritis Serious infeaion, malignancies, hepalotoxicity, hypasensitivity, infusion reactions... 

This 35-kDa protein was confirmed as the vCKBP by pierforming the same assays with two recombinant Ws, W RPVA35 and W Lister A35 from which the fully functional gene had been inactivated by insertion of the LacZ gene. Neither of these viruses produced a secreted protein that bound to I-chemokine. Furthermore, when the W Lister 35-kDa ORF was expressed with a G-terminal 6xHis-tag in the baculovirus system, or as an Fc fusion protein from stably transfected mammalian cells, binding of the recombinant products to... 

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