Since the approval of Enbrel®, CD4-Fc fusion protein(for the treatment of rheumatoid arthritis) in 1998, Fc fusion therapies have evolved into a prominent class of therapeutics. Currently, 13 Fc fusion drugs are commercially available, while around 50 molecules are under development for various disease indications. Some of the Fc fusion therapeutics including Arcalyst® (recurrent pericarditis, March 2021), Reblozyl® (beta-thalassemia, September 2020) and Alprolix® (haemophilia B, May 2016) were approved recently. These molecules combine the beneficial pharmacological properties of biologically active ligands with the properties of the crystallizable fragment (Fc) domain of an immunoglobulin G (IgG). Among the fusion proteins, several fragment crystallizable (Fc)-fusion therapeutics have been successfully treating various diseases, including autoimmune and inflammatory, cancer, infectious, cardiovascular and type 2 diabetes mellitus.
Types of Fc Fusion Therapeutics
There are five types of Fc fusion therapeutics, namely receptor ECD-Fc, peptide-Fc, cytokine-Fc, enzyme-Fc and antibody-Fc.
Additional details, highlighting the characteristics of each therapeutics has been mentioned below:
Receptor ECD-Fc: The ECD of the human receptor are coupled to the Fc-portion of human IgG1. Some examples of Receptor ECD- based Fc fusion protein includes Enbrel1, ARCALYST2 and RC18.
Peptide-Fc: The biologically active peptides are coupled to an Fc-domain of IgG. The conjugation extends the half-life of the active peptide via FcRn-mediated recycling. Some examples include NPLATE, AMG 592 and CNTO 530.
Cytokine-Fc: The ligand binding domains of multiple receptors are coupled to the N-terminal ends of the human IgG1-Fc domain. Some examples of cytokine- based Fc fusion protein includes Lumitin1, ZALTRAP2 andRC18.
Enzyme-Fc: The enzymes such as Factor VIII, Factor IX are coupled to an IgG-Fc domain. This results in a significantly improved clinical candidate with reduced clearance of these factors, while retaining the correct biological activity.
Antibody-Fc: An antibody is fused with the Fc portion of a human IgG1.As a result the candidate offers better tumor tissue penetration, high affinity and stability, low immunogenicity, and comparable in vivo half-life.
The Evolving Landscape of Fusion Therapeutics
During our research, we identified 45 marketed drugs, 75 clinical stage drugs and 5 drug development programs for the treatment of various oncological and non-oncological indications.
Majority of the drug candidates are in clinical stage of development; primarily, these are Receptor ECD which are fused with the Fc region of the antibody. Fusion of IgG-Fc domain to a ligand, peptide or ECD of a receptor improves the therapeutic potential of active drugs, by recruiting effector function and increasing plasma half-life. A significant proportion of drug candidates are designed for subcutaneous administration; it facilitates rapid onset of therapeutic action that can be extended to a longer duration
There has been a continuous increase in the number of grants awarded for research efforts in this domain; NCI has emerged as the leading funding institute in terms of awarding grants. Majority of the grants were awarded for non-SBIR / STTR purposes; several of these grants have been raised for a period of less than five years. Around 210 grants were awarded in the last year; National Cancer Institute, Emory University and Brigham and Women’s Hospital emerged as the most popular recipient organizations
Over time, close to 10,000 patents related to fc-fusion therapies have been filed / granted, indicating the increased R&D activity in this field. In addition to industry players, various academic institutes have filed multiple patents related to fc-fusion therapies. We estimated the relative valuation of the patents based on parameters including patent age, citations and geographical reach.
Since the first description of Fc fusion in 1989, interest these therapeutics has intensified; this is evident from the volume of literature published since 2010. Over the years, there has been a gradual increase in the number of publications related to fc fusion therapeutics, including articles focused on understanding the new developments within this domain. Majority of the publications were focused on Fc fusion therapies being investigated for various oncological and blood disorders; such articles account for 70% of the total number of publications.
Fc fusion therapeutics are considered to be one of the most successful classes of IgG-based products, however attention is required in improving a few complexities associated with these therapies owing to the diversity in structure. Presently, only a few candidates are capable to enter the market. Hence, efforts are required to enhance the Fc-mediated effector functions and extend the half-life. Furthermore, the link between physicochemical improvements and possible clinical applications requires greater attention. In order to deal with the complexity associated with the structural diversity of Fc fusion therapeutics, better methods are required for the analytical characterization of these therapies.
For more details on this emerging domain, check out the following report: