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Most cytokines have short circulating half-lives. Is there a way to increase the duration of cytokine activity? Applications of cytokines with prolonged activity have very high potential to modulate immune response. With the creation of a group of new immunoglobulin-based cytokine fusion proteins, in which a cytokine sequence is fused to the hinge, CH2 and CH3 regions of an immunoglobulin, a solution has been found: These cytokine fusion proteins possess both the biological functions of the cytokine moiety and the prolonged circulating half-life determined by the Fc domain. Interested in the details? Read more. These long-living cytokine fusion proteins produced by Chimerigen are available at Biomol. All products are for research use only. They are preservative and carrier protein-free.
There are two types of cytokine Fc fusion proteins. Nonlytic cytokine-Fc act as long-lasting cytokine. Lytic cytokine-Fc not only binds to their receptors, they are also capable to mediate immune effector mechanisms (antibody-dependent cell mediated cytotoxicity and complementdependent cytotoxicity). Ig-based Fusion ProteinsImmunoglobulin Based Fusion Proteins are recombinant chimeric fusion proteins in which the targeting Fab or Fv domains of an immunoglobulin are replaced by a cytokine or the ectodomain of a cell surface receptor or adhesion molecule. These molecules thus can retain the Fc-related properties of longevity and the potential to direct immune cytolytic mechanisms, antibody-dependent cell mediated cytotoxicity (ADCC) and complementdependent cytotoxicity (CDC), against cellular targets bound by the amino terminal binding moiety. These fusion molecules also have the promise of being minimally to negligibly immunogenic since they can be made entirely from elements derived from the species to be treated. In addition, immunoligands may in many instances offer the potential to surpass target affinity and specificity of mAbs . Compared to the Kd of typical mAbs on the order of 1 nM, many cytokines, receptors and adhesion molecules bind their respective receptors or ligands with Kds of 1-100 pM. When the application calls for nonlytic chimeric fusion proteins, the amino acid residues necessary for FcR and /or C1q binding to the Fc fragment can be substituted to yield long-lived molecules essentially without ADCC or CDC potential. Most IgG based immunoligands retain only the hinge, CH2 and CH3 domains, i. e . the Fc fragment, from the immunoglobulin component. Mouse Cytokine Fusion Proteins with Long Circulation Half-lifeCytokines play important roles in regulating immune responses. The potential clinical application of cytokines to modulate immune responses is very high. Unfortunately, most cytokines have short circulating half-lives. For example, administration of IL-10 produces short-lived therapeutic effects, ca. 30 minutes in a murine septic shock model. Therefore, to facilitate study of cytokine effects in vivo, a variety of immunoglobulin-based cytokine fusion proteins have been created, IL-2/Fc, IL-4/Fc, and IL-10/Fc, in which a cytokine sequence had been genetically fused to the hinge, CH2 and CH3 regions of immunoglobulin. These cytokine fusion proteins possess both the biological functions of the cytokine moiety and a prolonged circulating half-life determined by the Fc domain. Since the Fc?2a murine isotype is able to bind effectively to cells expressing the high affinity Fc?R I receptor and possesses a complement (C1q) binding domain, it is able to facilitate antibody dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activity. With this in mind, the complement (C1q) and Fc?R I binding sites of the Fcg2a fragment have been mutated by site directed mutagenesis to produce a non-cytolytic form of cytokine fusions essentially without ADCC and CDC activities. Thus, the effects of cytokines can be assessed by administration of Ig-based cytokine fusion proteins that can be maintained at constant circulating levels without resorting to continuous administration in vivo. |
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