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(11) Application No (12) STANDARD PATENT (11) Application No. AU 2018247255 B2 (19) AUSTRALIAN PATENT OFFICE (54) Title SINGLE CHAIN FC FUSION PROTEINS (51) International Patent Classification(s) C07K 16/30 (2006.01) (21) Application No: 2018247255 (22) Date of Filing: 2018.10.10 (43) Publication Date: 2018.11.01 (43) Publication Journal Date: 2018.11.01 (44) Accepted Journal Date: 2019.12.05 (62) Divisional of: 2015364396 (71) Applicant(s) Alkermes, Inc. (72) Inventor(s) Moustakas, Demetri T.;Brodkin, Heather R.;McSweeney, Leslie A.;Alvaraz, Juan (74) Agent / Attorney Pizzeys Patent and Trade Mark Attorneys Pty Ltd, GPO Box 1374, BRISBANE, QLD, 4001, AU (56) Related Art US 2014/0234962 A1 US 2014/0056895 A1 US 20150071948A1 US 20100285014A1 ZHENG XX ET AL: "Administration of noncytolytic IL-10/Fc in murine models oflipopolysaccharide-induced septic shock and allogeneic islet transplantation", J.IMMUNOL., vol. 154, no. 10, 15May1995, pages 5590-5600, XP002637016 ZHENG XX ET AL: "Noncytolytic IL-10/Fc fusion protein prevents diabetes, blocksautoimmunity, and promotes suppressor phenomena in NOD mice", J. IMMUNOL.,vol. 158, no. 9, 1 May 1997, pages 4507-4513, XP000919084 ZHENG XX ET AL: "IL-2 receptor-targeted cytolytic IL-2/Fc fusion protein treatmentblocks diabetogenic autoimmunity in nonobese diabetic mice", J. IMMUNOL., vol. 163,no. 7, 1 October 1999, pages 4041-4048, XP002230805 ABSTRACT 2018 The present invention provides novel, single chain Fc fusion proteins having improved properties. The invention provides single chain fusions of soluble proteins fused to Oct the Fc region of an immunoglobulin via a novel linker comprising a constant region of an 10 immunoglobulin light chain linked to a CHI constant region of an immunoglobulin heavy chain. This novel linker confers favorable properties on the Fc fusion proteins of the invention such as improved bioactivity and increased half-life as compared to non-Fc fusion counterparts or as compared to prior art Fc fusion proteins. The novel Fc fusion protein scaffold as described herein may be designed to include soluble proteins of interest capable of binding or interacting with any target of interest. Preferably, the Fc fusion protein of the 2018247255 invention is a dimer. The dimer preferably forms via a disulfide bond between free cysteine residues in the hinge region of two monomeric Fc fusion proteins of the invention. WO 2016/100788 PCT/US2015/066610 2018 - 1- Oct Single Chain Fc Fusion Proteins 10 RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 62/094,242, filed on December 19, 2014. The entire teachings of the above application are incorporated 5 herein by reference. BACKGROUND OF THE INVENTION 2018247255 One strategy for increasing serum half-life of a therapeutic protein is to attach the protein to an Fc (fragment crystallizable) domain of an antibody. Many such fusion proteins 10 are capable of forming homodimers or heterodimers thereby forming antibody-like fusion protein molecules. However, many prior art approaches to Fc fusion protein engineering have limitations including, but not limited to, immunogenicity and poor pharmacokinetic properties. The present invention provides monomers and dimers of Fc fusion proteins 15 comprising novel linkers having single chain constant light (CL) and constant heavy (CHI) immunoglobulin domains. Such novel linkers are also referred to herein as scCLCHl linkers. Without limitation to a particular theory, the novel linkers of the invention reduce steric hindrance between the protein “payloads” on each of the single chain Fc fusion protein molecules when such molecules form dimers. Steric hindrance can result in losses in 20 bioactivity, inefficient dimerization or reduction in the half-life of the dimer molecule for example, due to reduced binding to the FcRn. Thus incorporation of the novel linkers of the invention may result in improvement in bioactivity, increased dimer formation, in increased half-life, and the ability to incorporate larger protein pay loads than those possible on prior Fc fusion proteins. Additionally, in some Fc proteins of the invention are able to form dimers 25 that provide a more native antibody structure around the Fc domain that may improve binding of the dimer molecules to the FcRn receptor and therefore increase the circulating half-life of the novel Fc fusion proteins of the invention as compared to prior art fusion proteins. WO 2016/100788 PCT/US2015/066610 -2- 2018 SUMMARY OF THE INVENTION Oct The present invention provides novel, single chain Fc fusion proteins having improved properties. The invention provides single chain fusions of soluble proteins fused to 10 the Fc region of an immunoglobulin via a novel linker comprising a constant region of an 5 immunoglobulin light chain (CL) linked to a CHI constant region of an immunoglobulin heavy chain (scCLCHl or scCHICL linkers). This novel linker confers favorable properties on the Fc fusion proteins of the invention such as improved bioactivity and increased half-life as compared to non-Fc fusion counterparts or as compared to prior art Fc fusion proteins. The novel Fc fusion proteins as described herein may be designed to include soluble proteins of 2018247255 10 interest capable of binding or interacting with any target of interest with high specificity and affinity. Preferably, an Fc fusion protein of the invention is a dimer. The dimers may be formed via covalent (e.g. disulfide linkages) or non-covalent interactions between single chain fusion proteins of the invention resulting in a homodimeric or heterodimeric protein 15 complex retaining the advantageous properties of an antibody molecule for use as a therapeutic molecule. In another aspect, the invention provides nucleic acids encoding the Fc fusion proteins provided herein. Also provided are vectors, including expression vectors, comprise a nucleic acid encoding any of the Fc fusion proteins described herein. Also provided are host cells 20 containing such expression vectors and methods for producing the Fc fusion proteins described herein in the host cells. BRIEF DESCRIPTION OF THE DRAWINGS The foregoing and other objects, features and advantages of the invention will be 25 apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. FIG. 1A is a diagram of an Fc fusion protein homodimer comprising X fused to the Fc 30 region of an IgGl antibody via the novel scCLCHl linker in accordance with the invention. WO 2016/100788 PCT/US2015/066610 - 3 - 2018 FIG. IB is a diagram of an Fc fusion protein heterodimer of two polypeptide chains, Oct where the first comprises X fused to the Fc region of an IgGl antibody via the novel scCLCHl linker, and the second comprises Y, where Y is different from X, fused to the Fc 10 region of an IgGl antibody via the novel scCLCHl linker in accordance with the invention. 5 FIG. 1C is a diagram of an Fc fusion protein homodimer comprising X fused to the Fc region of an IgGl antibody via the novel scCHICL linker in accordance with the invention. FIG. ID is a diagram of an Fc fusion protein heterodimer of two polypeptide chains, where the first comprises X fused to the Fc region of an IgGl antibody via the novel scCHICL linker, and the second comprises Y, where Y is different from X, fused to the Fc 2018247255 10 region of an IgGl antibody via the novel scCHICL linker in accordance with the invention. FIG. 2 is an SDS-PAGE showing expression of an Fc fusion protein comprising Factor IX fused to the Fc region of an IgGl antibody via the novel scCLCHl linker in accordance with the invention. FIG. 3 is graph showing the clotting activity of an Fc fusion protein comprising 15 Factor IX fused to the Fc region of an IgGl antibody via the novel scCLCHl linker in accordance with the invention. FIG. 4 is a graph showing the in vivo half-life in rats when intravenously administered an Fc fusion protein comprising Factor IX fused to the Fc region of an IgGl antibody via the novel scCLCHl linker. 20 FIG. 5A is an SDS-PAGE showing expression of an Fc fusion protein comprising TNFR2 fused to the Fc region of an IgGl antibody via the novel scCLCHl linker under reducing conditions. FIG. 5B is an SDS-PAGE showing expression of an Fc fusion protein comprising TNFR2 fused to the Fc region of an IgGl antibody via the novel scCLCHl linker under non- 25 reducing conditions. FIG. 6 is a graph showing the inhibition of the activation of a reporter gene by the TNFR2 fusion protein of the invention as compared to a standard TNF direct fusion protein. FIG. 7 is a graph showing the in vivo half-life in rats when intravenously administered an Fc fusion protein comprising TNFR2 fused to the Fc region of an IgGl antibody via the 30 novel scCLCHl linker as compared to a standard TNF direct fusion protein. WO 2016/100788 PCT/US2015/066610 -4- 2018 FIG. 8A is an SDS-PAGE showing expression of an Fc fusion protein comprising Oct ILIRa fused to the Fc region of an IgGl antibody via the novel scCLCHl linker under reducing conditions. 10 FIG. 8B is an SDS-PAGE showing expression of an Fc fusion protein comprising 5 ILIRa fused to the Fc region of an IgGl antibody via the novel scCLCHl linker under non­ reducing conditions. FIG. 9 is a graph showing the inhibition of the activation of a reporter gene by the ILIRa fusion protein of the invention. FIG. 10 is a graph showing the in vivo half-life in rats when intravenously 2018247255 10 administered an Fc fusion protein comprising ILIRa fused to the Fc region of an IgGl antibody via the novel scCLCHl linker.
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