Chimeric Fusion Proteins Used for Therapy: Indications, Mechanisms, and Safety

Abstract

Chimeric fusion proteins, produced by genetic engineering, are currently made up of effector peptides, for example, a ligand-binding portion of a cytokine or growth factor, extracellular domains of lymphocyte antigens, or a toxin linked to a suitable fusion partner. This review covers eight fusion proteins that have received regulatory approval for human therapy: etanercept, belatacept, abatacept, alefacept, rilonacept, romiplostim, aflibercept, and denileukin-diftitox. Important requirements for an effective fusion protein are effective targeting and binding, cytotoxicity, and a stable molecule with an extended half-life. The Fc region of human IgG1 is generally chosen as the fusion partner for the effector molecule(s) because it extends the fusion protein half-life by recycling via the salvage neonatal FcRn receptor and protects the molecule from lysosomal degradation. Each of the fusion proteins has IgG1 Fc as a fusion partner except denileukin-diftitox, which employs a modified diphtheria toxin effector peptide linked to interleukin-2. For six of the Fc fusion proteins, the effector peptide(s) is linked to the N-terminus of the Fc piece but for the thrombopoietin-mimetic romiplostim, linkage is through the C-terminus. Although some clear type I and IV hypersensitivities are known to be induced by fusion protein therapy, the pathomechanisms underlying many adverse hematologic, respiratory, renal, and cutaneous events have generally not been investigated. Assessment of immunogenicity risk is important because a number of immune-based, or influenced, adverse reactions such as anaphylaxis, cutaneous manifestations, infusion, and injection-site reactions, and cytokine release syndrome can occur. Features of many reactions, some autoimmune in nature, suggest type II, III, or IV hypersensitivities. Clinical findings with the anti-arthritis anti-psoriasis biologic etanercept provide the largest body of current knowledge of fusion protein-induced adverse events. For most fusion proteins, little information is available on appropriate diagnostic and desensitization procedures for hypersensitivity and other adverse responses, although skin test concentrations and some successful desensitization protocols have been published for etanercept.

Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells

“…Importantly, these proteins do not induce immunogenicity-related adverse events and ADA production in a total of 531 human volunteers in phase I/IIa clinical trials (EPO-Fc: NCT02291991/NCT02044653, G-CSF-Fc: NCT01951027/ EudraCT 2015-002693-20, and hGH-Fc: EudraCT 2013-002771-18/EudraCT 2014-002698-13 and EudraCT 2015-001939-21). Furthermore, the commercialized Fc-fused proteins, including abatacept (CTLA4-IgG1) and etanercept (TNFR-IgG1), induce ADA in humans, but these antibodies do not affect the drug efficacy (50). Taken together, although it will be necessary to address the immunogenicity issues of IL7-Fc in future study, we speculate that the application of IL7-Fc in humans may be safe and does not cause immunogenicityrelated problems.…”

“…4B and C). To further determine the role of CD8 T cells in combinatory antitumor therapeutic efficacy, vaccine plus IL7-Fc adjuvant-treated Tet E7 [49][50][51][52][53][54][55][56][57] Tet L1 [165][166][167][168][169][170][171][172][173] Tet E7…”

A New Approach to Drug Therapy: Fc-Fusion Technology

“…In fact, more than 180 therapeutic proteins and peptides have been approved by the FDA [9]. However, many of these peptides and proteins have less than ideal pharmacokinetic properties, either because they are eliminated by kidney filtration due to their small size and/or due to proteolytic metabolism, thus imposing constant infusions or frequent subcutaneous administration to keep their circulating concentrations within the effective range, which is clinically undesirable [9][10][11][12][13][14][15][16].…”

“…We will describe three selected IgGFc fusion proteins in more detail below. For more information on other clinically used Fc-fusion therapeutics not described below, see reviews [9][10][11][12][13][14][15][16]. Etanercept (Enbrel ® ) was approved by the FDA in 1998 as a biweekly or weekly subcutaneous injection for the treatment of various forms of arthritis including rheumatoid arthritis, psoriatic arthritis and juvenile idiopathic arthritis, as well as, plaque psoriasis and ankylosing spondylitis.…”

Current drug design to target the Semaphorin/Neuropilin/Plexin complexes

“…If therapeutic peptides such as insulin have undoubtedly shown their efficacy and safety, 68 the classical challenges of peptide and protein immunogenicity 69 or delivery 70 slows down the emergence of new drugs in comparison to the development of small molecule inhibitors (Fig. 2).…”