Advances in biotechnology have made it possible to engineer biologic therapies that harness the functional capabilities of many types of proteins,1 including enzymes, hormones, cytokines, and antibodies.2
Proteins by nature, however, are unstable molecules with fundamental properties that may limit their therapeutic utility.1 They are subject to destruction by proteolytic enzymes and rapid renal clearance, resulting in a short circulating half-life. They also are potentially immunogenic.3
One method that has proven successful in overcoming the inherent limitations of proteins as drug therapy is to covalently join the protein with polyethylene glycol (PEG), a nontoxic, nonimmunogenic polymer approved by the US Food and Drug Administration for use in foods, cosmetics, and pharmaceuticals.3
Conjugation with PEG, termed PEGylation, modifies the structure and function of the parent protein, resulting in a compound with improved therapeutic capabilities.1 In recent decades, the development of PEGylated protein therapies has led to important advances in the treatment of several disorders, including severe combined immunodeficiency disease (SCID), leukemia, chemotherapy-induced neutropenia, hepatitis C, and acromegaly.2
PEG has several beneficial properties that transfer to the compounds to which it is covalently bound.1,2 PEG is highly water soluble as well as flexible and stable in solution.1,2 It also tightly binds to water molecules, resulting in increased hydrodynamic volume.1,2
As a result of PEGylation, a therapeutic protein becomes highly hydrated and mobile in solution and much larger than the parent protein,3 with the following advantages:
Because PEGylation results in delayed elimination and therefore an extended drug half-life, it allows a reduced dosing frequency.1
There has been increasing interest in the use of antibodies and antibody fragments as the basis for new therapies to combat chronic disease.4
An important example is the development of agents aimed at downregulating the function of TNF-alpha. TNF-alpha is a key cytokine involved in mediating the chronic pathologic inflammation that contributes to joint destruction in rheumatoid arthritis.5
CIMZIA is the only PEGylated anti-TNF therapy. CIMZIA is composed of the Fab' antigen-binding domain of a humanized anti-TNF antibody, site-specifically bound to PEG so that it does not interfere with TNF binding.1,5 In studies, CIMZIA was shown to bind to and neutralize both membrane-bound and soluble human TNF-alpha in a dose-dependent manner.5
Because it lacks the Fc portion of the antibody, CIMZIA does not fix complement or induce antibody-dependent cell-mediated cytotoxicity in vitro.5 The clinical relevance of in vitro findings is unknown. CIMZIA also does not induce apoptosis or neutrophil degranulation.5
CIMZIA is administered by subcutaneous injection and is designed so it can be dosed on an every 4 weeks basis.5
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