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

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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.

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Acknowledgments

The author thanks Dr. Nghia H. Pham for his help in the preparation of Figs. 1, 6, and 7 and Drs. Aparecida Tiemi Nagao-Dias and Fatima E Abourazzak for generously providing the photographs for Figs. 4a and b and 5, respectively.

Since this review entered the production stage, four more fusion proteins, albiglutide (fused to albumin) and dulaglutide (an Fc fusion), both for glycemic control, and Fc fusion proteins of coagulation factors VIII and IX have been approved by the FDA.

Conflict of interest

No sources of funding were used to assist in the preparation of this study. Brian A. Baldo has no conflicts of interest that are directly relevant to the content of this study.

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    Brian A. Baldo

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Correspondence to Brian A. Baldo.

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B.A. Baldo (retired) was formerly with Molecular Immunology Unit, Royal North Shore Hospital of Sydney, Kolling Institute of Medical Research and Department of Medicine, University of Sydney, Sydney, Australia

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Baldo, B.A. Chimeric Fusion Proteins Used for Therapy: Indications, Mechanisms, and Safety. Drug Saf 38, 455–479 (2015). https://doi.org/10.1007/s40264-015-0285-9

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