Bifunctional complement inhibitors

Abstract

The present invention relates to fusion proteins which interact with and regulate the activation and / or the activity of the complement system. Preferably the fusion protein comprises a pattern recognition molecule (PRM) or a fragment thereof and a complement control protein (CCP) or a fragment thereof.

Description

[0001] BIFUNCTIONAL COMPLEMENT INHIBITORS

[0002] FIELD OF THE INVENTION

[0003] The present disclosure presents fusion proteins that interacts with and regulates the activation and / or the activity of the complement system. These fusion proteins can be used to target and control the complement cascade and thus prevent or reduce overactivation of the complement system. More specifically the invention relates to fusion proteins comprising a pattern recognition molecule (PRM) or a fragment thereof and a complement control protein (CCP) or a fragment thereof.

[0004] Thus, the present disclosure provides a new approach for the treatment of diseases or disorders associated with the complement system and inflammation.

[0005] BACKGROUND

[0006] The complement system has been implicated in many diseases and conditions ranging from those related to inflammation, disorders with an autoimmune component, and, recently, neurodegenerative diseases and disorders of the nervous system such as Alzheimer’s.

[0007] Because of the complexity of the immune system and its part in these disorders, therapeutic treatment has proven difficult and in some cases, e.g. arthritis, the only options available for the patient are pain relief, generic anti-inflammatory medication and lifestyle changes.

[0008] Some inhibitors of the complement system are on the market, such as Eculizumab, which inhibits the cleavage of the terminal complement component 5 (C5) by the C5 convertase.

[0009] This late-stage inhibition of the complement system maintains the normal, disease-preventing functions mediated by the opsonin C3b and the anaphylatoxin C3a, while the properties of C5 that promote inflammation and cell destruction are impeded.

[0010] However, the inhibition at the C5 level still allows the cleavage of C3 and generation of the C3b opsonin and the pro-inflammatory C3a, which may result, among others, in cell activation and extravascular hemolysis.

[0011] Thus, there is an unmet need for the development of novel therapeutic agents and strategies for treatment of complement related inflammatory, autoimmune, and neurological diseases, disorders and conditions.

[0012] SUMMARY

[0013] This disclosure presents fusion proteins that regulate activation of the complement system. In one aspect, the present disclosure relates to a fusion protein comprising a pattern recognition molecule (PRM) or a fragment thereof and a complement control protein (CCP) or a fragment thereof.

[0014] In a different aspect, the present disclosure relates to a fusion protein having at least 70% identity to SEQ ID NO: 1 or SEQ ID NO: 2.

[0015] In another aspect, the present disclosure relates to a nucleic acid sequence encoding a fusion protein as defined herein or a nucleic acid construct encoding a fusion-protein as defined herein.

[0016] In a further aspect, the present disclosure relates to a host cell comprising a nucleic acid sequence or nucleic acid construct as defined herein.

[0017] In an additional aspect, the present disclosure relates to a method for producing a fusion protein as defined herein, the method comprising culturing the host cell comprising a nucleic acid sequence or nucleic acid construct encoding a fusion protein as described herein, and recovering the fusion protein.

[0018] In a different aspect, the present disclosure relates to compositions and / or pharmaceutical compositions contain a fusion protein as defined herein.

[0019] In yet another aspect, the present disclosure also relates to the use of a fusion protein as defined herein, a composition containing a fusion protein as defined herein, or a pharmaceutical composition comprising a fusion protein as defined herein as a medicament, in therapy and / or in prophylaxis.

[0020] DETAILED DESCRIPTION

[0021] Example 1 illustrates how complement activation regulatory function of fusion proteins can be evaluated.

[0022] Example 2 demonstrates that MBDAF is comprised of covalently bound MBL and DAF molecules.

[0023] Example 3 demonstrates that the fusion protein MBDAF maintains the lectin binding activity, demonstrating that addition of the regulatory molecule DAF in the N-terminus of the PRM MBL does not impair its binding activity.

[0024] As shown in examples 4-6, a fusion protein (MBDAF) comprising the Pattern Recognition Molecule (PRM) Mannose Binding Lectin (MBL) fused to a fragment of the Complement Control Protein (CCP) Decay Accelerating Factor (DAF) was demonstrated to effectively regulate activation of the complement system. The fusion protein achieved a reduction in Terminal Complement Complex (TCC) / Membrane Attack Complex (MAC) deposition that was comparable to that of eculizumab and a much greater reduction than what was achieved compared to the fusion partners (MBL and DAF) when they were tested either individually or together in solution (see e.g. examples 4-5 and figures 4-5).

[0025] The MBL-DAF fragment fusion protein (MBDAF) also showed a strong reduction of C3 deposition, demonstrating that the regulation of activation of the complement system occurs at an early stage in the complement system (See example 4).

[0026] Example 7 shows that the fusion protein MBDAF can effectively reduce complement activation with a potency much superior to MAPI and MAPI :CD55, illustrated as inhibition of C3 and TCC deposition.

[0027] As demonstrated by examples 8-10, fusion proteins combining different fragments of PRMs and CCPs can be engineered to regulate activation of the complement system.

[0028] Example 8 shows that different CCPs can be combined with MBL to generate fusion proteins capable of regulating complement cascades in distinct fashion, or regulating complement activation in serum from different species, enabling studies and tests in mouse models of disease. Example 9 shows that specific regions of the PRMs or the CCPs can be rationally removed to generate complement inhibitors with lower molecular weight that either maintain or improve on the activity of MBDAF. MBL fused to DAF domains 2-4 (MBDAFfrgmt) was more potent than MBDAF at reducing activation of the complement system, while a fusion protein containing a fragment of MBL (i.e. MBLfr9mt_DAFfr9mt) was as effective as the original MBDAF molecule. Moreover, a fusion protein without a linker (MBLfr9mt_DAFfr9mt_NL) showed a comparable activity to MBLfr9mt_DAFfr9mt, highlighting that a linker between CCP and PRM is not required to generate functional fusion proteins to regulate the complement system.

[0029] Example 10 shows that a fusion protein combining the PRM ficolin-3 and a fragment of the complement regulator DAF can bind to specific ficolin-3 ligands (i.e. acetylated-BSA) and reduce complement activation, illustrated as inhibition of C3 and TCC deposition.

[0030] These ground-breaking results demonstrate that Pattern Recognition Molecules (PRMs) can be used to guide Complement Control Proteins (CCPs) to their respective molecular targets, resulting in a more efficient regulation of complement system activation than the CCPs would be capable of on their own.

[0031] Accordingly, it is contemplated herein that fusion proteins comprising a Pattern Recognition Molecule or a fragment thereof fused to a Complement Control Protein or a fragment thereof are capable of providing a targeted regulation of activation of the complement system. Furthermore, selecting specific Pattern Recognition Molecules or fragments thereof and pairing them with specific CCPs or fragments thereof enables targeted regulation of specific complement activation pathways at specific stages.

[0032] This targeted approach allows for manufacturing fusion proteins that can be used for treating or alleviating or ameliorating symptoms of any disease, disorder or injury associated with specific complement activation pathways.

[0033] Thus, the fusion proteins disclosed herein provides both new therapeutic agents and a new approach to treatment of inflammatory and autoimmune diseases, that allows targeted, specific and effective regulation of activation of the complement system.

[0034] Without wishing to be bound by theory, it is presently thought that the ability of the Pattern Recognition Molecule to recognize both self and non-self molecular patterns and interact with the complement system proteins during activation of the complement system cascade, effectively allows the Pattern Recognition Molecule part of the fusion protein to colocalize with the complement system and thereby guide the fusion partner, a Complement Control Protein or a fragment thereof, into close proximity with the complement system proteins. This close proximity then allows the Complement Control Protein or fragment thereof to exert its control function and inactivate the complement system cascade proteins, thereby interrupting the complement cascade and leading to relief or cessation of the resulting inflammatory and / or immune response.

[0035] Fusion proteins

[0036] Fusion proteins are proteins created through the joining of genetic sequences encoding for partial or whole sequence of different proteins or protein fragments. Such joining of genetic sequences results in the transcription and translation of a single continuous genetic sequence, thereby resulting in chimeric proteins comprising the protein equivalents of each of the genetic sequences, which are fused to each other through peptide bonds as part of the translation process.

[0037] A fusion protein in the context of the present disclosure relates to a fusion-protein that comprises a Pattern Recognition Molecule or a fragment thereof and a Complement Control Protein or a fragment thereof.

[0038] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Collectins, Ficolins, Pentraxins and C1q or fragments thereof.

[0039] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Collectins, Ficolins and Pentraxins, or fragments thereof.

[0040] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Collectins, Ficolins and C1q, or fragments thereof. In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Collectins, Pentraxins and C1q, or fragments thereof.

[0041] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Ficolins, Pentraxins and C1q, or fragments thereof.

[0042] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Collectins and Ficolins, or fragments thereof.

[0043] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Collectins and Pentraxins, or fragments thereof.

[0044] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Collectins and C1q, or fragments thereof.

[0045] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Ficolins and Pentraxins, or fragments thereof.

[0046] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Ficolins and C1q, or fragments thereof.

[0047] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected from the group consisting of the Pentraxins and C1q, or fragments thereof.

[0048] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected as a Collectin or a fragment thereof.

[0049] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected as a Ficolin, or a fragment thereof.

[0050] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected as a Pentraxin or a fragment thereof.

[0051] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected as C1q or a fragment thereof.

[0052] Collectin

[0053] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a Collectin or fragment thereof selected from the group consisting of MBL, CL10, CL-11 , CL-12, SP- A and SP-D, or fragments thereof.

[0054] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a Collectin or fragment thereof selected from the group consisting of MBL, CL10, CL-11 and CL-12, or fragments thereof. In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a Collectin or fragment thereof selected from the group consisting of MBL and CL-11 , or fragments thereof.

[0055] In one or more preferred exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is MBL or a fragment thereof.

[0056] In one or more preferred exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is CL-11 or a fragment thereof.

[0057] Ficolin

[0058] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a Ficolin or fragment thereof selected from the group consisting of Ficolin-1 , Ficolin-2, and Ficolin-3, or fragments thereof.

[0059] In one or more preferred exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is Ficolin-3 or a fragment thereof. Data with ficolin-3 as the Pattern Recognition Molecule is provided in example 10.

[0060] C1q

[0061] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected as any one of the group consisting of C1q, C1qA, C1qB, C1qC and a C1q subunit consisting of CIqA, C1qB and C1qC, or fragments thereof.

[0062] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is C1 q or a fragment thereof.

[0063] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is selected as any one of the group consisting of CIqA, C1qB, C1qC, or fragments thereof.

[0064] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a C1 q subunit consisting of C1 qA, C1 qB and C1 qC, or fragments thereof.

[0065] Pentraxin

[0066] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a Pentraxin or fragment thereof selected from the group consisting of CRP, SAP, PTX3, GPR144, NPTXI, NPTXII and NPTXR, or fragments thereof.

[0067] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a Pentraxin or fragment thereof selected from the group consisting of CRP, SAP, PTX3 and GPR144, or fragments thereof. In one or more preferred exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a Pentraxin or fragment thereof selected from the group consisting of CRP, SAP and PTX3, or fragments thereof.

[0068] In one or more preferred exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is CRP or a fragment thereof.

[0069] In one or more preferred exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is SAP or a fragment thereof.

[0070] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a fragment of a Pattern Recognition Molecule that comprises at least the pattern recognition domain of the Pattern Recognition Molecule.

[0071] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a fragment of a Pattern Recognition Molecule that consists of the pattern recognition domain of the Pattern Recognition Molecule.

[0072] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a fragment of a Pattern Recognition Molecule that comprises at least the pattern recognition domain and the motif(s) responsible for interaction with the complement system of the Pattern Recognition Molecule.

[0073] In one or more exemplary embodiments, the Pattern Recognition Molecule or fragment thereof is a fragment of a Pattern Recognition Molecule that consists of at least the pattern recognition domain and the motif(s) responsible for interaction with the complement system of the Pattern Recognition Molecule.

[0074] Complement Control Protein

[0075] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is selected from the group consisting of Decay Accelerating Factor (DAF / CD55), Membrane Cofactor Protein (MCP / CD46), Protectin (CD59), Complement Receptor type 1 (CR1 / CD35 / Complement C3b / C4b receptor), Complement Regulator of the Immunoglobulin Superfamily (CRIg), Factor H (complement factor H, FH, CFH), C4-Binding Protein (C4bp), Complement Receptor 2 (CR2 / CD21), a DAF-CD59 fusion protein, a MCP-DAF fusion protein, a soluble DAF (sDAF), a soluble MCP (sMCP), a soluble CD59 (sCD59), soluble Complement Receptor type 1 (sCR1), a soluble Complement Receptor type 2 (sCR2), a soluble CRIg (sCRIg), a soluble DAF-CD59 fusion protein and a soluble MCP-DAF fusion protein (sMCP-DAF), or fragments thereof.

[0076] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is selected from the group consisting of Membrane Cofactor Protein (MCP / CD46), Decay Accelerating Factor (DAF / CD55), Protectin (CD59), Complement Receptor type 1 (CR1 / CD35 / Complement C3b / C4b receptor), or Complement Regulator of the Immunoglobulin Superfamily (CRIg), complement receptor 2 (CR2 / CD21), a soluble DAF (sDAF), a soluble MCP (sMCP), a soluble CD59 (sCD59), soluble Complement Receptor type 1 (sCR1), a soluble Complement Receptor type 2 (sCR2) and a soluble CRIg (sCRIg), or fragments thereof.

[0077] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is selected from the group consisting of Membrane Cofactor Protein (MCP / CD46), Decay Accelerating Factor (DAF / CD55), Protectin (CD59), Complement Receptor type 1 (CR1 / CD35 / Complement C3b / C4b receptor), or Complement Regulator of the Immunoglobulin Superfamily (CRIg)and complement receptor 2 (CR2 / CD21), or fragments thereof.

[0078] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a circulating CCP selected from the group consisting of Factor H and C4-Binding Protein (C4bp), or fragments thereof.

[0079] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is selected from the group consisting of the circulating CCPs, the membrane associated CCPs and the solubilized membrane associated CCPs.

[0080] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a membrane associated CCP or fragment thereof selected from the group consisting of Decay Accelerating Factor (DAF / CD55), Membrane Cofactor Protein (MCP / CD46), Protectin (CD59), Complement Receptor type 1 (CR1 / CD35 / Complement C3b / C4b receptor), Complement Regulator of the Immunoglobulin Superfamily (CRIg), Complement Receptor type 2 (CR2 / CD21 / Complement Receptor 2), or fragments thereof.

[0081] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a solubilized membrane associated CCP or fragment thereof selected from the group consisting of a soluble DAF (sDAF), a soluble MCP (sMCP), a soluble CD59 (sCD59), soluble Complement Receptor type 1 (sCR1), a soluble Complement Receptor type 2 (sCR2), a soluble CRIg (sCRIg), a soluble MCP-DAF fusion protein (sMCP-DAF) and a soluble DAF-CD59 fusion protein, or fragments thereof.

[0082] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a solubilized membrane associated CCP or fragment thereof selected from the group consisting of a soluble DAF (sDAF), a soluble MCP (sMCP), a soluble CD59 (sCD59), soluble Complement Receptor type 1 (sCR1), a soluble Complement Receptor type 2 (sCR2) and a soluble CRIg (sCRIg), or fragments thereof. In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a solubilized membrane associated CCP or fragment thereof selected from the group consisting of a soluble DAF (sDAF), a soluble MCP (sMCP), a soluble CD59 (sCD59), soluble Complement Receptor type 1 (sCR1) and a soluble Complement Receptor type 2 (sCR2), or fragments thereof.

[0083] In one or more presently preferred exemplary embodiments, the Complement Control Protein or fragment thereof is selected from the group consisting of DAF, Factor H, CD35 and CD46, or fragments thereof.

[0084] In one or more presently preferred exemplary embodiments, the Complement Control Protein or fragment thereof is selected from the group consisting of soluble DAF, Factor H, soluble CD35 and soluble CD46, or fragments thereof.

[0085] In one or more presently preferred exemplary embodiments, the Complement Control Protein or fragment thereof is selected from the group consisting of Factor H, CD35 and CD46, or fragments thereof.

[0086] In one or more presently preferred exemplary embodiments, the Complement Control Protein or fragment thereof is selected from the group consisting of Factor H, soluble CD35 and soluble CD46, or fragments thereof.

[0087] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is Decay Accelerating Factor (DAF / CD55) or a fragment thereof.

[0088] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is soluble DAF (sDAF) or a fragment thereof.

[0089] In one or more preferred exemplary embodiments, the Complement Control Protein or fragment thereof is Factor H or a fragment thereof.

[0090] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is Complement receptor type 1 (CD35) or a fragment thereof.

[0091] In one or more preferred exemplary embodiments, the Complement Control Protein or fragment thereof is soluble Complement receptor type 1 (CD35) or a fragment thereof.

[0092] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is MCP (CD46) or a fragment thereof.

[0093] In one or more preferred exemplary embodiments, the Complement Control Protein or fragment thereof is soluble MCP (CD46) or a fragment thereof.

[0094] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is Protectin (CD59) or a fragment thereof. In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is soluble Protectin (CD59) or a fragment thereof.

[0095] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is Complement Regulator of the Immunoglobulin Superfamily (CRIg) or a fragment thereof.

[0096] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is soluble Complement Regulator of the Immunoglobulin Superfamily (CRIg) or a fragment thereof.

[0097] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is Complement Receptor type 2 (CR2) or a fragment thereof.

[0098] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is soluble Complement Receptor type 2 (CR2) or a fragment thereof.

[0099] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is C4-Binding Protein (C4bp) or a fragment thereof.

[0100] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a fragment of a Complement Control Protein comprising the domain or motif responsible for the complement regulating activity of the Complement Control protein.

[0101] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a fragment of a Complement Control Protein comprising the domain or motif responsible for the complement regulating activity of the Complement Control protein.

[0102] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a fragment of a Complement Control Protein consisting of at least two SCR domains of the complement control protein.

[0103] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a fragment of a Complement Control Protein consisting of at least three SCR domains of the complement control protein.

[0104] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a fragment of a Complement Control Protein consisting of at least four SCR domains of the complement control protein.

[0105] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a DAF fragment.

[0106] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a soluble DAF fragment. In one or more preferred exemplary embodiments, the Complement Control Protein or fragment thereof is a DAF fragment comprising the sequence of SCR domains 1-4 of DAF, such as SEQ ID NO: 41.

[0107] In a more preferred exemplary embodiment, the Complement Control Protein or fragment thereof is a DAF fragment consisting of the sequence of SCR domains 2-4 of DAF, such as SEQ ID NO: 42. In figure 13 it is shown that a construct comprising DAF SCR domains 2-4 is even better than the construct comprising SCR domains 1-4 of DAF.

[0108] In one or more exemplary embodiments, the Complement Control Protein or fragment thereof is a DAF fragment according to SEQ ID NO: 31 or a functional homologue thereof having at least 70% identity to SEQ ID NO: 31 , such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 31.

[0109] In one or more exemplary embodiments, the fusion protein comprises a PRM or fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 3- 21 , a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 3-21 , or fragments thereof, and a CCP or a fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 22-31 , a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 22-31 , or fragments thereof.

[0110] In one or more exemplary embodiments, the fusion protein comprises a PRM or fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 3- 21 , a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 3-21 , or fragments thereof, and a CCP or a fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 22, 23, 25 and 27, a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 22, 23, 25 and 27, or fragments thereof.

[0111] In one or more exemplary embodiments, the fusion protein comprises a PRM or fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 3, 5 and 11 -16, a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 3, 5 and 11-16, or fragments thereof, and a CCP or a fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 22-31 , a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 22-31 , or fragments thereof. In one or more exemplary embodiments, the fusion protein comprises a PRM or fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 3, 5, 11 , 15 and 16, a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 3, 5, 11 , 15 and 16, or fragments thereof, and a CCP or a fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 22-31 , a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 22-31 , or fragments thereof.

[0112] In one or more exemplary embodiments, the fusion protein comprises a PRM or fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 3, 5 and 11 -16, a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 3, 5 and 11-16, or fragments thereof, and a CCP or a fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 22, 23, 25 and 27, a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 22, 23, 25 and 27, or fragments thereof.

[0113] In one or more exemplary embodiments, the fusion protein comprises a PRM or fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 3, 5, 11 , 15 and 16, a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 3, 5, 11 , 15 and 16, or fragments thereof, and a CCP or a fragment thereof selected from the group consisting of a protein sequence according to any one of SEQ ID NOs: 22, 23, 25 and 27, a functional homologue thereof having at least 70% sequence identity such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NOs: 22, 23, 25 and 27, or fragments thereof.

[0114] A fusion protein according to the present disclosure can comprise any combination of a PRM or a fragment thereof and a CCP or a fragment thereof as defined herein.

[0115] Additionally, any of the fusion proteins defined herein, may further comprise a linker.

[0116] Linkers

[0117] In the context of the present disclosure, a linker is a series of one or more amino acids that is located between the amino acid sequences of different proteins or protein fragments that are to be fused together. In this way, the linker connects the different proteins or protein fragments to each other through peptide bonds. To create a fusion protein including a linker, the genetic sequence encoding the different proteins or protein fragments to be fused together, must also include a genetic sequence encoding the linker that is inserted between the sequences encoding the different proteins or protein fragments. Once the genetic sequence is introduced into a suitable host cell, the fusion protein is then produced including the linker, as part of the transcription and translation processes in the host cell.

[0118] Thus, in one or more exemplary embodiments a fusion protein as disclosed herein contains a linker that connects the constituent parts of the fusion protein to each other.

[0119] In one or more exemplary embodiments of the present disclosure, a fusion protein as disclosed herein, comprises a linker connecting a Pattern Recognition Molecule (PRM) or a fragment thereof to a Complement Control Protein (CCP) or a fragment thereof.

[0120] Suitable linkers for use in the fusion proteins as defined herein, are linkers that allow for some freedom of movement of the Complement Control Protein or fragment thereof relative to the Pattern Recognition Molecule or fragment thereof and which do not interfere with the folding of either the Pattern Recognition Molecule or fragment thereof or the Complement Control Protein or fragment thereof.

[0121] These suitable linkers include flexible linkers, hydrophilic linkers and / or linkers which do not generate a secondary structure.

[0122] One example of a commonly used linker is the poly-glycine linker, which consists of a series of glycine residues.

[0123] The poly-glycine linker allows for sufficient freedom of movement for the protein constituent parts, by providing a region that can curl and form an adaptable shape depending on the environment the fusion protein is currently in.

[0124] Other suitable linkers include the glycine-serine linkers, which consist of glycine and serine residues that also allow for freedom of movement of the protein constituent parts.

[0125] The glycine-serine linker is for example selected as a one of a (G4S1)n-linker, a (GsS^n-linker, a (G2S1)n-linker or (G^ n-linker, wherein n is a number selected from the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10 and n designates the number of times the glycine-serine motif is repeated in the linker.

[0126] Many linkers that allow for flexibility of the fusion protein constituent parts and methods for introducing these into fusion proteins, are well known in the prior art and it would be simple for the skilled person to adapt the use of these linkers according to circumstances, when designing a fusion protein.

[0127] Thus, in one or more exemplary embodiments, the linker is a flexible linker.

[0128] In one or more exemplary embodiments, the linker is a hydrophilic linker.

[0129] In one or more exemplary embodiments, the linker does not form a secondary structure. In one or more exemplary embodiments, the linker is flexible, hydrophilic and does not form a secondary structure.

[0130] In one or more exemplary embodiments, the linker consists of only glycine residues.

[0131] In one or more exemplary embodiments, the linker consists of at least 1 , such as at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or at least 16 glycine residues.

[0132] In one or more exemplary embodiments, the linker consists of at least 4, such as at least 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 or at least 16 glycine residues.

[0133] In one or more exemplary embodiments, the linker is a (G4S1)n-linker, wherein n is as one of the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10, and n designates the number of times the glycine-serine motif is repeated in the linker.

[0134] In one or more exemplary embodiments, the linker is a (GsS^n-linker, wherein n is as one of the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10, and n designates the number of times the glycine-serine motif is repeated in the linker.

[0135] In one or more exemplary embodiments, the linker is a (G2S1)n-linker, wherein n is as one of the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10, and n designates the number of times the glycine-serine motif is repeated in the linker.

[0136] In one or more exemplary embodiments, the linker is a (G^ n-linker, wherein n is as one of the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10, and n designates the number of times the glycine-serine motif is repeated in the linker.

[0137] In one or more exemplary embodiments, the linker is selected as one from the group consisting of GGGGS (SEQ ID NO: 34), GGGGSGGGGS (SEQ ID NO: 35) and GGGGSGGGGSGGGGS (SEQ ID NO: 36).

[0138] In one or more exemplary embodiments closure, the linker is selected as GGGGSGGGGSGGGGS (SEQ ID NO: 36).

[0139] In one or more exemplary embodiments, the fusion protein is MBDAF.

[0140] MBDAF is a fusion protein comprising an N-terminal soluble DAF fragment consisting of SCR domains 1-4 of the DAF protein, that is connected to MBL through a GGGGSGGGGSGGGGS (SEQ ID NO: 36) linker (see also figure 7). The N-terminal signal peptide of MBL is removed in the MBL sequence incorporated into the fusion protein MBDAF.

[0141] The sequence of MBDAF is disclosed in SEQ ID NO: 1 .

[0142] Accordingly, in one or more exemplary embodiments, the fusion protein as defined herein is a fusion protein according to SEQ ID NO: 1 or a functional homologue thereof having at least 70% identity to SEQ ID NO: 1 , such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1.

[0143] The MBDAF fusion protein can also further comprise the addition of an N-terminal HSA secretion signal peptide sequence. The sequence of MBDAF with an added N-terminal HSA secretion signal peptide is disclosed in SEQ ID NO: 2.

[0144] Therefore, in one or more exemplary embodiments, the fusion protein as defined herein is a fusion protein according to SEQ ID NO: 2 or a functional homologue thereof having at least 70% identity to SEQ ID NO: 2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 2. An overview of examples of fusion proteins as defined within the present disclosure and their protein sequences can be found in Table 1 .

[0145] Table 1 : Examples of fusion proteins of the present disclosure and their protein sequences.

[0146] In a preferred embodiment a) the fusion protein is encoded by SEQ ID NOs: 1 , 2, 45, 46, 47, 48, or 49, or b) the fusion protein is a functional homologue thereof having at least 70% identity to a fusion protein according to a), such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to a fusion protein according to a). All of these fusion proteins have been tested in the example section.

[0147] In one or more exemplary embodiments, the fusion protein comprises DAF and C1q or a fragment thereof.

[0148] C1q is a protein complex formed by the combination of three peptide chains named C1qA, C1qB, C1qC). Thus, the present disclosure relates to the regulator (DAF) fused to all 3 chains (DAFC1qA+DAFC1qB+DAFC1qC) or fused to a single chain of the trimer (DAFC1qA+C1qB+C1qC or C1 qA+DAFC1 qB+C1 qC or C1 qA+C1 qB+DAFC1 qC) and all possible pair combinations (DAFC1qA+DAFC1qB+C1qC or DAFC1qA+C1qB+DAFC1qC or (C1qA+DAFC1qB+DAFC1qC).

[0149] In one or more exemplary embodiments, the fusion protein as defined herein comprises a soluble DAF and C1q or a fragment thereof.

[0150] In one or more exemplary embodiments, the fusion protein as defined herein comprises SCR domains 1-4 of DAF and C1q or a fragment thereof.

[0151] In another preferred embodiment, the fusion protein as defined herein comprises SCR domains 2-4 of DAF and C1q or a fragment thereof, preferably DAF2-4 is used since it seems to be better as outlined in the example section. Hence preferably DAF2-4 is used.

[0152] Thus, in one or more exemplary embodiments, the present disclosure relates to a soluble DAF or the SCR domains 1 -4 or 2-4 of DAF fused to all 3 chains of C1 q (as described for DAF above) or fused to a single chain of the trimer of C1q (as described for DAF above) and all possible pair combinations (as described for DAF above).

[0153] In one or more exemplary embodiments, the fusion protein as defined herein comprises DAF and Ficolin-3 or a fragment thereof.

[0154] In one or more exemplary embodiments, the fusion protein as defined herein comprises soluble DAF and Ficolin-3 or a fragment thereof.

[0155] In one or more exemplary embodiments, the fusion protein as defined herein comprises SCR domains 1-4 or 2-4 of DAF and Ficolin-3 or a fragment thereof.

[0156] In one or more exemplary embodiments, the fusion protein comprises MBL or a fragment thereof and SCR domains 2-4 of DAF.

[0157] In one or more exemplary embodiments, the fusion protein comprises a MBL fragment and SCR domains 2-4 of DAF.

[0158] In one or more exemplary embodiments, the fusion protein comprises MBL or a fragment thereof and SCR domains 2-4 of DAF, wherein the lysine residue (K) in the sequence motif PGKLGP (SEQ ID NO: 37) in the MBL protein sequence or fragment thereof is replaced by another amino acid. The lysine residue mentioned above also corresponds to the lysine residue at position 321 of SEQ ID NO: 1 , the lysine residue at position 339 of SEQ ID NO: 2 and the lysine residue at position 75 of SEQ ID NO: 3.

[0159] In one or more exemplary embodiments, the fusion protein comprises MBL or a fragment thereof and SCR domains 1-5 of Factor H.

[0160] Complement system

[0161] The complement system, also known as the complement cascade, is a part of the innate immune system, which when stimulated leads to inflammation, phagocyte recruitment and activation of the membrane-attack-complex (MAC). The complement system consists of proteins that circulate in the blood as inactive precursors, that when activated / stimulated cause protease cleavage of specific proteins leading to cytokine release, which initiates an amplifying cascade of further protein cleavage. The complement system comprises three activation pathways, the classical, the lectin and the alternative pathway, which are briefly described below.

[0162] Classical pathway

[0163] The classical pathway of the complement system can either be activated directly by the binding of the pattern recognition molecule (PRM) C1q to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) or alternatively initiated indirectly through interactions with immunoglobulins or other molecules such as for example C-reactive protein (CRP), Serum amyloid P (SAP), and Pentraxin 3 (PTX3).

[0164] C1q is found in complex (C1 complex) with the two serine proteases C1 r and C1s and upon C1q binding, the C1 complex is activated resulting in cleavage of C4 and C2 by C1s and the formation of a C3 convertase (C4b2a).

[0165] Lectin pathway

[0166] The lectin pathway is initiated by the binding of one of the pattern recognition molecules (PRMs) mannose binding lectin (MBL), Collectin 10 (CL-10 / CL-L1), Collectin 11 (CL-11 / CL-K1), Ficolin 1 (M-Ficolin), Ficolin 2 (L-ficolin), or Ficolin 3 (H-ficolin / Hakata antigen) to PAMPs or DAMPs. The lectin pathway PRMs are found in complex with the mannan-binding lectin serine proteases (MASPs) and activation of this complex also results in the cleavage of C4 and C2 and the formation of a C3 convertase (C4b2a). Alternative pathway

[0167] The alternative pathway is activated by spontaneous hydrolysis of C3, which allows factor B (FB) to bind to C3. FB is then cleaved by factor D (FD) resulting in formation of the alternative C3 convertase (C3bBb). The alternative C3 convertase is stabilized by the plasma protein properdin.

[0168] Complement convertase activity

[0169] Following activation of complement system through the classical, lectin and alternative pathway, the C3 convertases (C4b2a and C3bBb) cleave C3 into the opsonin C3b and the anaphylatoxin C3a.

[0170] C3b can then either be recruited to form further C3 convertases leading to a positive feedback loop, be recruited by either of the C3 convertases (C3bBb and C4b2a) to form the C5 convertases (C3Bb3B and C4b2a3b), or participate in opsonization by tagging of pathogens, antibody-antigen complexes, and apoptotic cells for phagocytosis.

[0171] When the C5 convertases are formed they cleave C5 into the anaphylatoxins C5a and C5b, ultimately leading to formation of the membrane attack complex (C5b-9 / MAC).

[0172] Pattern Recognition Molecules (PRMs)

[0173] Within the present context, the term Pattern Recognition Molecule (PRM) is used to represent nonantibody proteins that recognize carbohydrates (e.g. polysaccharides and oligosaccharides), acetylated ligands, lipids and / or nuclear antigens, and which play a role in the activation of the complement system.

[0174] The PRMs are sometimes also referred to as soluble pathogen recognition receptors.

[0175] PRMs are involved with the immune and inflammatory responses, including, e.g., recruitment of leukocytes, opsonic activity, removal of apoptotic cells and inhibition of viral entry.

[0176] PRMs recognize both self and non-self and are involved in the processes of the immune system that distinguish self from non-self. PRMs are ideal to guide complement system proteins. The ability of PRMs to both recognize self and non-self antigens, enables PRM-CCP fusion proteins to effectively target and regulate complement activation caused by autoimmune disorders, injury, organ transplantation, and other inflammatory conditions.

[0177] Additionally, because different PRMs play a specific role in the initiation of different activation pathways of the complement system, PRM-CCP fusion proteins can be designed to regulate complement activation caused by activation of a specific complement pathway, through selection of a specific PRM. Thus, because CCPs regulate complement system via distinct mechanisms, the choice of combining specific PRMs with specific CCPs in fusion proteins allows engineering of fusion proteins with specificity to regulate different complement pathways, specificity to target specific components of the complement system and / or specificity to regulate complement activation in different pathologies.

[0178] In one or more exemplary embodiments, the PRMs are selected from the group consisting of the Collectins, the Ficolins, the Pentraxins and C1q.

[0179] Thus, in one or more exemplary embodiments, the Collectins and Ficolins can be used to directly target complement activation through the lectin pathway, whereas C1q can be used to directly target the classical pathway.

[0180] The Pentraxins interact with both the PRMs of the classical pathway (at least C1q) and the lectin pathway (at least MBL, Ficolin-2 and CL-11) and the circulating CCPs such as for example FH and C4BP.

[0181] Accordingly, in one or more exemplary embodiments, the Pentraxins can be used to target complement activation through the classical, the alternative and the lectin complement activation pathways.

[0182] In one or more exemplary embodiments, the Pentraxins can be used to target complement activation through the classical complement activation pathway, the lectin complement activation pathway and / or both the lectin and the classical complement activation pathways.

[0183] Any of these Pattern Recognition Molecules or fragments thereof can be used in a fusion protein as defined herein.

[0184] The Collectins, Ficolins, Pentraxins, C1q and fragments thereof are described in more detail below.

[0185] Collectins

[0186] In the present context, the Collectins are a group of non-antibody proteins that bind to carbohydrate ligands. They are involved in the activities of the innate immune system and play a part in the activation of the complement system, opsonization and agglutination.

[0187] MBL, CL-11 and complexes of CL-10 / CL-11 are known to be involved in activation of the lectin pathway together with the MASPs and it suspected that CL-11 may also be involved in activation of the alternative pathway through recruitment of MASP-3.

[0188] Because the Collectins are involved in the complement activation pathways, Collectin-Complement Control Protein fusion proteins can directly regulate at least the activation of the lectin pathway of the complement system and / or indirectly regulate the general complement system. The human Collectins include mannose-binding lectin (MBL / mannan-binding lectin), Collectin 10 (CL10 / CL-L1), Collectin 11 (CL-11 / CL-K1), Collectin 12 (CL12 / CL-P1), SP-A (surfactant protein A), SP-D (surfactant protein D).

[0189] The Collectins form trimers, and these trimers further oligomerize into an arrangement that resembles flowers arranged in a bouquet (See figure 8). These trimers are usually homotrimers made up of three identical polypeptides (e.g. three MBL proteins or three CL-11 proteins) although heterotrimers have also been observed for at least SP-A, CL-10 and CL-11 .

[0190] The subunit of each collectin is composed of (i) a short N-terminal (7-28 amino acid residues) cysteine-rich domain that is involved in multimerization (by disulphide bridging); (ii) a collagen-like domain composed of Gly-X-Y triplets repeats, where X and Y represent any amino acids although the X and Y positions of the triplet repeats are most frequently taken up by proline and / or hydroxyproline; (iii) a short neck region which can form coiled-coil helices, and (iv) the C-terminal globular C-type lectin domain, also called the CRD (carbohydrate recognition domain).

[0191] For example the Collectin MBL contains four domains: a 21 -amino acid (aa) N-terminal cysteine- rich region; (ii) a 59-aa collagen-like domain consisting of 20 tandem repeats of Glycine-Xaa- Yaa (except repeat 8, which consists of only Glycine-Glutamine) that account for a linear stalk-like part of the molecule; (iii) a 30-aa neck region; and (iv) a 118-aa C-terminal carbohydrate recognition domain (CRD).

[0192] The neck regions of the Collectin subunits self-assemble into triple alpha-helical hydrophobic coiled-coil structures, that forms trimeric subunits. The neck regions, collagen-like domains and the cysteine rich regions of these trimeric subunits form a stem like structure, while the carbohydrate recognition domains (CRD) are arranged in a pattern that resembles the arrangement of flowers in a bouquet (see e.g. figure 8). These trimeric subunits then further associate with other trimeric subunits to form Collectin oligomers.

[0193] The triple alpha-helical hydrophobic coiled-coil structure is crucial to formation of the Collectin oligomerization and the N-terminal cysteine-rich regions are also involved in oligomerization of the Collectins by formation of intra- and interchain disulfide bonds.

[0194] However, it is the carbohydrate recognition domain (CRD) that mediates binding to ligands (which would otherwise activate complement by binding to native PRMs), thereby enabling Collectin-CCP fusion proteins to target and concentrate in tissues where these ligands are present and / or expressed. Binding to these complement activating-ligands in turn enables the Collectins-CCP fusion proteins to exert the CCP control function leading to specific / targeted regulation of complement activation by these fusion proteins disclosed herein. The fusion proteins of the present disclosure can comprise any of the Collectins or fragments thereof as defined herein.

[0195] Thus, in one or more exemplary embodiments, a Collectin as defined herein is selected from the group consisting of MBL, CL10, CL-11 , CL-12, SP-A, and SP-D, or fragments thereof.

[0196] In one or more exemplary embodiments, a Collectin as defined herein is selected from the group consisting of MBL, CL10, CL-11 , and CL-12 or fragments thereof.

[0197] In one or more exemplary embodiments, a Collectin as defined herein is selected from the group consisting of MBL and CL-11 or fragments thereof.

[0198] In one or more exemplary embodiments, the Collectin is selected as CL10, or a fragment thereof.

[0199] In one or more exemplary embodiments, the Collectin is selected as CL-12, or a fragment thereof.

[0200] In one or more exemplary embodiments, the Collectin is selected as SP-A, or a fragment thereof.

[0201] In one or more exemplary embodiments, the Collectin is selected as SP-D, or a fragment thereof.

[0202] In one or more preferred exemplary embodiments, the Collectin is selected as MBL, or a fragment thereof.

[0203] In one or more preferred exemplary embodiments, the Collectin is selected as CL-11 or a fragment thereof.

[0204] There are several sequences known to encode Collectins in the prior art and all of those are suitable for use herein. The retrieval of such sequences, e.g. from online databases, is merely a routine task for the skilled person. Table 2 contains examples of protein sequences encoding Collectins and their corresponding accession numbers.

[0205] Table 2: Examples of protein sequences and accession numbers that encode Collectins

[0206] In one or more exemplary embodiments, a Collectin as defined herein is selected from the group consisting of SEQ ID NOs 3-8, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 3-8, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 3-8, or fragments thereof.

[0207] In one or more exemplary embodiments, a Collectin as defined herein is selected from the group consisting of SEQ ID NOs 3-6, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 3-6, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 3-6, or fragments thereof.

[0208] In one or more exemplary embodiments, a Collectin as defined herein is selected from the group consisting of SEQ ID NOs 3 and 5, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 3 and 5, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 3 and 5, or fragments thereof.

[0209] In one or more exemplary embodiments, the Collectin is selected as SEQ ID NO: 4 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 4, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 4, or a fragment thereof.

[0210] In one or more exemplary embodiments, the Collectin is selected as SEQ ID NO: 6, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 6, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 6, or a fragment thereof.

[0211] In one or more exemplary embodiments, the Collectin is selected as SEQ ID NO: 7, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 7, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 7, or a fragment thereof.

[0212] In one or more exemplary embodiments, the Collectin is selected as SEQ ID NO: 8, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 8, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 8, or a fragment thereof.

[0213] In one or more exemplary embodiments, the Collectin is selected as SEQ ID NO: 3, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 3, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 3, or a fragment thereof.

[0214] In one or more exemplary embodiments, the Collectin is selected as SEQ ID NO: 5, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 5, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 5, or a fragment thereof.

[0215] Ficolins

[0216] In the present context, the Ficolins are a group of Pattern Recognition Molecules, that bind a spectrum of ligands and microorganisms, with a particular affinity for acetylated ligands and carbohydrates. They are involved in initiation of the lectin pathway in the complement system together with the MASPs (mannan-binding lectin-associated serine proteases). Because the Ficolin’s are involved in initiation of the lectin pathway, Ficolin-Complement Control Protein fusion proteins can be used to directly regulate activation of the lectin pathway of the complement system and / or indirectly regulate the general complement system.

[0217] The human Ficolins consist of Ficolin-1 (M-Ficolin), Ficolin-2 (L-Ficolin), and Ficolin-3 (H-ficolin).

[0218] The Ficolin proteins all consist of four domains: (i) an N-terminal region containing two cysteine residues; (ii) a collagen-like domain with varying repeats of Gly-Xaa-Yaa triplets; (iii) a linker region; and (iv) a C-terminal fibrinogen-like (FBG) domain.

[0219] Three polypeptides (i.e. for example 3x Ficolin-1) assemble into trimer subunits through the collagen-like domain. These trimers are held together by interchain disulfide bonds in the N- terminus of the proteins and non-covalent interactions between the collagen-like domains. These trimers can further assemble into oligomers that resemble bouquet-like structures similar to those of MBL and the collectins.

[0220] The C-terminal fibrinogen-like domain is the part of the Ficolin proteins that is responsible fortheir ability to recognize and bind a variety of ligands, such as microorganisms and acetylated carbohydrates. Following Ficolin binding to a ligand, e.g. a microorganism or a damaged cell, the complement system is activated by associated MASPs that activate C2 and C4. Because of the association between the MASPs and the Ficolins, the Ficolin-CCP fusion proteins can be used effectively to guide the CCPs or fragments thereof and enable the CCPs or fragments thereof to exert their complement regulating activity.

[0221] Any one of the Ficolins or fragments thereof can be used in the fusion proteins as defined herein.

[0222] In one or more exemplary embodiments, a Ficolin as defined herein is selected from the group consisting of Ficolin-1 , Ficolin-2 and Ficolin-3, or fragments thereof.

[0223] In one or more preferred exemplary embodiments, a Ficolin as defined herein is selected as Ficolin-3, or a fragment thereof. In example 10 it is shown that FCN-3:DAF is an effective regulator of complement activation, confirming that different PRIVIs can be used to target the fusion proteins to different ligands or surfaces.

[0224] There are several sequences known to encode Ficolins in the prior art and all of those are suitable for use herein. The retrieval of such sequences, e.g. from online databases, is merely a routine task for the skilled person. Table 3 contains examples of protein sequences encoding Ficolins and their corresponding accession numbers.

[0225] Table 3: Examples of protein sequences and accession numbers that encode Ficolins | Ficolin-3 | NP 003656.2 | SEQ ID NO: 11 |

[0226] In one or more exemplary embodiments, a Ficolin as defined herein is selected from the group consisting of SEQ ID NOs 9-11 , a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 9-11 , such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 9-11 , or fragments thereof.

[0227] In one or more exemplary embodiments, the Ficolin is selected as SEQ ID NO: 9 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 9, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 9, or a fragment thereof.

[0228] In one or more exemplary embodiments, the Ficolin is selected as SEQ ID NO: 10 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 10, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 10, or a fragment thereof.

[0229] In one or more exemplary embodiments, the Ficolin is selected as SEQ ID NO: 11 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 11 , such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 11 , or a fragment thereof. Again, example 10 shows data with ficolin-3.

[0230] C1q

[0231] C1q, also known as complement component 1q, is a protein complex comprising 18 proteins and it forms part of the C1 complex in the classical activation pathway of the complement system. C1q recognizes both self and non-self and binds a large variety of molecules including damage- associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs) and antibody-antigen complexes. C1q is therefore considered to be the pattern recognizing part of the C1 complex and plays an important part of the initiation of the classical activation pathway of the complement system.

[0232] The 18 proteins that make up C1q are of three different proteins which are commonly referred to as A-chains (C1qA), B-chains (C1qB) and C-chains (C1qC). The 18 proteins of C1q are arranged in 6 subunits, each subunit consisting of a trimer of a C1qA, a C1qB and a C1qC chain.

[0233] Each of the C1qA, C1qB and a C1qC chains contain a small globular N-terminal domain, a collagen-like Gly-Pro-rich central region, and a conserved C-terminal region. The N-terminal globular domains of the three chains of a single subunit form a globular head and it is this globular head that is thought to be responsible for the pattern recognition activity of C1 q. Disulfide bridges between the C1 qC chains are thought to help the 6 trimeric subunits associate and together form the C1q complex. In one or more exemplary embodiments, C1q is selected as any one of the group consisting of C1q, C1qA, C1qB, C1qC and a C1q subunit consisting of C1qA, C1qB and C1qC, or fragments thereof.

[0234] In one or more exemplary embodiments, C1q is selected as any one of the group consisting of C1q and a C1q subunit consisting of C1qA, C1qB and C1qC, or fragments thereof.

[0235] In one or more exemplary embodiments, C1q is selected as any one of the group consisting of C1q, C1qA, ClqB and C1qC, or fragments thereof.

[0236] In one or more exemplary embodiments, C1q is selected as any one of the group consisting of C1qA, C1qB, C1qC and a C1q subunit consisting of C1qA, C1qB and C1qC, or fragments thereof.

[0237] In one or more exemplary embodiments, C1q is selected as any one of C1q, a C1q subunit consisting of C1qA, C1qB and C1qC, C1qA, a C1qB peptide chain and a C1qC peptide chain, or fragments thereof.

[0238] There are several sequences known to encode the proteins that make up C1q in the prior art and all of those are suitable for use herein. The retrieval of such sequences, e.g. from online databases, is merely a routine task for the skilled person. Table 4 contains examples of protein sequences encoding C1q proteins and their corresponding accession numbers.

[0239] Table 4: Examples of protein sequences and accession numbers that encode proteins that make up C1q.

[0240] In one or more exemplary embodiments, C1q consists of six identical copies of each one of SEQ NOs 12-14, six identical functional homologues of each one of SEQ ID NOs: 12-14 having at least 70% sequence identity to each one of SEQ ID NOs: 12-14, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to each one of SEQ ID NOs: 12-14, or fragments thereof.

[0241] In one or more exemplary embodiments, a C1q subunit is selected as any one the group consisting of one of each of SEQ NOs 12-14 and a functional homologue of one of each of SEQ ID NOs: 12- 14 having at least 70% sequence identity to each one of SEQ ID NOs: 12-14, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to each one of SEQ ID NOs: 12-14, or fragments thereof.

[0242] In one or more exemplary embodiments, C1q is selected as any of the group consisting of SEQ ID NOs 12-14, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 12-14, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 12-14, or fragments thereof.

[0243] In one or more exemplary embodiments, C1q is selected as SEQ ID NO: 12 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 12, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 12, or a fragment thereof.

[0244] In one or more exemplary embodiments, C1q is selected as SEQ ID NO: 13 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 13, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 13, or a fragment thereof.

[0245] In one or more exemplary embodiments, C1q is selected as SEQ ID NO: 14 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 14, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 14, or a fragment thereof.

[0246] Pentraxins

[0247] The Pentraxins are a conserved family of proteins that are characterized by containing a pentraxin protein domain. The Pentraxins are involved in the innate immune response and modulation of inflammation. They bind to microorganisms and facilitate their phagocytosis via direct interaction with Fc gamma receptors and by the activation of the complement system. The pentraxins also interact with different cell components, such as DNA and nuclear antigens, and regulate the inflammatory response.

[0248] The human pentraxins are CRP (C-reactive protein), SAP (serum amyloid P), PTX3 (Pentraxin 3 / Pentraxin related protein 3), GPR144, NPTXI, NPTXII, and NPTXR.

[0249] The short pentraxins (e.g. CRP and SAP) have a pentameric radial symmetry and consist of 5 or 10 identical subunits. CRP recognizes small nuclear ribonucleoproteins, whereas SAP is a major recognition molecule for DNA.

[0250] In one or more exemplary embodiments, a Pentraxin as defined herein is selected from the group consisting of CRP, SAP, PTX3, GPR144, NPTXI, NPTXII and NPTXR, or fragments thereof.

[0251] In one or more preferred exemplary embodiments, a Pentraxin as defined herein is selected from the group consisting of CRP, SAP and PTX3, or fragments thereof.

[0252] In one or more preferred exemplary embodiments, a Pentraxin as defined herein is selected as CRP or a fragment thereof.

[0253] In one or more preferred exemplary embodiments, a Pentraxin as defined herein is selected as SAP or a fragment thereof. In one or more exemplary embodiments, a Pentraxin as defined herein is selected as PTX3 or a fragment thereof.

[0254] There are several sequences known to encode Pentraxins in the prior art and all of those are suitable for use herein. The Retrieval of such sequences, e.g. from online databases, is merely a routine task for the skilled person. Table 5 contains examples of protein sequences encoding Pentraxins and their corresponding accession numbers.

[0255] Table 5: Examples of protein sequences and accession numbers that encode Pentraxins.

[0256] In one or more exemplary embodiments, a Pentraxin as defined herein is selected from the group consisting of SEQ ID NOs 15-21 , a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 15-21 , such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 15-21 , or fragments thereof.

[0257] In one or more exemplary embodiments, a Pentraxin as defined herein is selected from the group consisting of SEQ ID NOs 15-17, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 15-17, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 15-17, or fragments thereof.

[0258] In one or more exemplary embodiments, the Pentraxin is selected as SEQ ID NO: 15 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 15, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 15, or a fragment thereof.

[0259] In one or more exemplary embodiments, the Pentraxin is selected as SEQ ID NO: 16 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 16, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 16, or a fragment thereof.

[0260] In one or more exemplary embodiments, the Pentraxin is selected as SEQ ID NO: 17 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 17, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 17, or a fragment thereof. In one or more exemplary embodiments, the Pentraxin is selected as SEQ ID NO: 18 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 18, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 18, or a fragment thereof.

[0261] In one or more exemplary embodiments, the Pentraxin is selected as SEQ ID NO: 19 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 19, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 19, or a fragment thereof.

[0262] In one or more exemplary embodiments, the Pentraxin is selected as SEQ ID NO: 20 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 20, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 20, or a fragment thereof.

[0263] In one or more exemplary embodiments, the Pentraxin is selected as SEQ ID NO: 21 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 21 , such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 21 , or a fragment thereof.

[0264] PRM fragments

[0265] In the present context, the term Pattern Recognition Molecule fragment is used to represent an amino acid sequence consisting of one or more sections of a Pattern recognition molecule (PRM) amino acid sequence.

[0266] In one or more exemplary embodiments, a Pattern Recognition Molecule fragment consists of one or more sections of a pattern recognition molecule (PRM) amino acid sequence corresponding to at least 30%, such as at least 35%, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or at least 98% of the pattern recognition molecule (PRM) amino acid sequence.

[0267] In one or more exemplary embodiments, the Pattern Recognition Molecule (PRM) fragment comprises at least the pattern recognition domain of the Pattern Recognition Molecule.

[0268] In one or more exemplary embodiments, the Pattern Recognition Molecule fragment consists of the pattern recognition domain of the Pattern Recognition Molecule.

[0269] In one or more exemplary embodiments, the Pattern Recognition Molecule fragment comprises at least the motif(s) responsible for interaction with the complement system of the Pattern Recognition Molecule. In one or more exemplary embodiments, the Pattern Recognition Molecule fragment consists of at least the motif(s) responsible for interaction with the complement system of the Pattern Recognition Molecule.

[0270] In one or more exemplary embodiments, the Pattern Recognition Molecule fragment consists of at least the motif(s) responsible for interaction with the proteases (e.g. the MASPs, Ci r and C1s) of the complement system.

[0271] The motif(s) responsible for interaction with the proteases of the complement system is thought to be a protein having the sequence P^KXGP (SEQ ID NO: 33) for the Collectins and Ficolins and the sequence P^KXGY (SEQ ID NO: 32) for C1q, wherein P1is 4-hydroxyproline and X is an amino acid with a hydrophobic side chain selected from the group consisting of F, L, I, Y, W, V, M and P.

[0272] In one or more exemplary embodiments, the Pattern Recognition Molecule fragment comprises a motif having the protein sequence of P^KXGP, wherein P1is 4-hydroxyproline and X is a hydrophobic residue selected from the group consisting of F, L, I, Y, W, V, M and P.

[0273] In one or more exemplary embodiments, the Pattern Recognition Molecule fragment consists of a motif having the protein sequence P^KXGP, wherein P1is 4-hydroxyproline and X is a hydrophobic residue selected from the group consisting of F, L, I, Y, W, V, M and P.

[0274] In one or more exemplary embodiments, the Pattern Recognition Molecule fragment comprises a motif having the protein sequence P^KXGY, wherein P1is 4-hydroxyproline and X is an amino acid with a hydrophobic side chain selected from the group consisting of F, L, I, Y, W, V, M and P.

[0275] In one or more exemplary embodiments, the Pattern Recognition Molecule fragment consists of a motif having the protein sequence P^KXGY, wherein P1is 4-hydroxyproline and X is an amino acid with a hydrophobic side chain selected from the group consisting of F, L, I, Y, W, V, M and P.

[0276] In one or more exemplary embodiments, the Pattern Recognition Molecule fragment comprises the MBL motif having the protein sequence of PGKLGP (SEQ ID NO: 37).

[0277] In one or more exemplary embodiments, the Pattern Recognition Molecule fragment consists of the MBL motif having the protein sequence of PGKLGP (SEQ ID NO: 37).

[0278] Table 6 contains examples of sequence motifs that are thought to be responsible PRM interaction with the complement system.

[0279] Table 6: Examples of sequence motifs responsible for PRM interaction with the complement system

[0280] In one or more exemplary embodiments, the Pattern Recognition Molecule fragment comprises at least the pattern recognition domain and the motif(s) responsible for interaction with the complement system of the Pattern Recognition Molecule.

[0281] In one or more exemplary embodiments, the pattern recognition molecule consists of the pattern recognition domain and the motif(s) responsible for interaction with the complement system of the Pattern Recognition Molecule.

[0282] Collectin fragments

[0283] The carbohydrate recognition domain (CRD) is the structural part of the Collectins, which allows them to recognize molecular patterns.

[0284] In one or more exemplary embodiments, a Collectin fragment as defined herein, is a fragment that comprises the carbohydrate recognition domain of a Collectin.

[0285] In one or more exemplary embodiments, a Collectin fragment, is a fragment that consists of the carbohydrate recognition domain of a Collectin.

[0286] In one or more exemplary embodiments, a Collectin fragment can also be a Collectin, where the cysteine rich region, the collagen-like domain, or the neck region has been deleted.

[0287] In one or more exemplary embodiments, a Collectin fragment can also be a Collectin, where the collagen-like domain has been partially deleted. See Example 9 and Figure 13.

[0288] In one or more exemplary embodiments, a Collectin fragment is a collectin where the collagen-like domain has been deleted as defined in SEQ ID NO: 44.

[0289] In one or more exemplary embodiments, a Collectin fragment can also be a Collectin, wherein the N-terminal signal peptide has been deleted.

[0290] In one or more exemplary embodiments, a Collectin fragment as defined herein is a fragment comprising the carbohydrate recognition domain of a Collectin selected from the group consisting of MBL, CL10, CL-11 , CL-12, SP-A, SP-D.

[0291] In one or more exemplary embodiments, a Collectin fragment is a fragment comprising the carbohydrate recognition domain of any Collectin selected from the group consisting of MBL, CL10, CL-11 , and CL-12.

[0292] In one or more exemplary embodiments, a Collectin fragment is selected as a fragment comprising the carbohydrate recognition domain of MBL. In one or more exemplary embodiments, a Collectin fragment is selected as a fragment comprising the carbohydrate recognition domain of CL-11.

[0293] In one or more exemplary embodiments, a Collectin fragment is a fragment comprising the motif(s) responsible for interaction with the proteases of the complement system of a Collectin.

[0294] In one or more exemplary embodiments, a Collectin fragment is a fragment comprising the motif(s) responsible for interaction with the proteases as defined in SEQ ID NO: 33.

[0295] The structure of the Collectins is well known in the prior art and it would be a simple matter for the skilled person to make fragments of Collectins according to the instructions given herein.

[0296] Ficolin fragments

[0297] The fibrinogen-like domain is the structural part of the Ficolins which allows them to recognize molecular patterns.

[0298] In one or more exemplary embodiments, a Ficolin fragment as defined herein is a fragment comprising the fibrinogen-like domain of a Ficolin selected from the group consisting of Ficolin-1 , Ficolin-2, and Ficolin-3.

[0299] In one or more exemplary embodiments, a Ficolin fragment is selected as a fragment comprising the fibrinogen-like domain of Ficolin-3.

[0300] In one or more exemplary embodiments, a Ficolin fragment can also be a Ficolin, where the N- terminal region, the collagen-like domain, or the linker region has been deleted.

[0301] In one or more exemplary embodiments, a Ficolin fragment can also be a Ficolin, where the collagen-like domain has been partially deleted.

[0302] In one or more exemplary embodiments, a Ficolin fragment can also be a Ficolin, wherein the N- terminal region has been deleted.

[0303] In one or more exemplary embodiments, a Ficolin fragment is a fragment comprising the motif(s) responsible for interaction with the proteases of the complement system of a Ficolin.

[0304] In one or more exemplary embodiments, a Ficolin fragment is a fragment comprising the motif(s) responsible for interaction with the proteases as defined in SEQ ID NO: 33.

[0305] The structure of the Ficolins is well known in the prior art and it would be a simple matter for the skilled person to make fragments of Ficolins according to the instructions given herein.

[0306] C1q fragments

[0307] The small globular N-terminal domain of the C1qA, C1qB and C1qC proteins that make up C1q is thought to be the structural part of these proteins that allows them to recognize molecular patterns. In one or more exemplary embodiments, a C1q fragment suitable for use in the fusion proteins as defined herein is a fragment that comprises the small globular domain of any one of C1 qA, C1 qB and C1 qC.

[0308] In one or more exemplary embodiments, a C1q fragment suitable for use in the fusion proteins as defined herein is a fragment that comprises the small globular domain of each one of C1qA, C1qB and C1 qC.

[0309] In one or more exemplary embodiments, a C1q fragment suitable for use in the fusion proteins as defined herein is a fragment that comprises the small globular domain of C1qA.

[0310] In one or more exemplary embodiments, a C1q fragment suitable for use in the fusion proteins as defined herein is a fragment that comprises the small globular domain of C1qB.

[0311] In one or more exemplary embodiments, a C1q fragment suitable for use in the fusion proteins as defined herein is a fragment that comprises the small globular domain of C1qC.

[0312] In one or more exemplary embodiments, a C1q fragment is a fragment comprising the motif(s) responsible for interaction with the proteases of the complement system of C1q.

[0313] In one or more exemplary embodiments, a C1q fragment is a fragment comprising the motif(s) responsible for interaction with the proteases as defined in SEQ ID NO: 32.

[0314] The structure of the C1q is well known in the prior art and it would be a simple matter for the skilled person to make fragments of C1q according to the instructions given herein.

[0315] Pentraxin fragments

[0316] In one or more exemplary embodiments, a pentraxin fragment is a fragment of a Pentraxin comprising the sequence motif(s) responsible for interaction with the complement system proteins.

[0317] In one or more exemplary embodiments, a pentraxin fragment is a fragment of a Pentraxin consisting of the sequence motif(s) responsible for interaction with the complement system proteins.

[0318] In one or more exemplary embodiments, a pentraxin fragment is a fragment of a Pentraxin comprising the sequence motif(s) responsible for recruitment of other PRMs.

[0319] In one or more exemplary embodiments, a pentraxin fragment is a fragment of a Pentraxin consisting of the sequence motif(s) responsible for recruitment of other PRMs.

[0320] Complement Control Proteins (CCPs)

[0321] In the present context, the term Complement Control Proteins (CCPs) is used to represent a family of protein regulators of complement activation that is characterized by containing Short Consensus Repeat domains. These Short Consensus Repeat domains are also known as SCR domains and sometimes referred to as Sushi domains and Complement Control Protein (CCP) domains.

[0322] CCPs regulate activation of the complement system by either preventing activation or inactivating the complement system and they often act on the convertases of the complement system.

[0323] The regulation of complement activation performed by the CCPs is a key part of the process that help distinguish target cells as self or non-self.

[0324] CCPs act in several ways including decay accelerating activity (convertase destabilisation), cofactor mediated cleavage (convertase inactivation), C1 complex inactivation, membrane attack complex (MAC) inhibition (e.g., inhibition of C9 association with C5b, C6, C7 and C8, thus preventing MAC formation).

[0325] For example, the CCPs regulate activation of the complement system by promoting C3b and C4b degradation by Fl (CD35, CD46, FH and C4BP), accelerating convertase dissociation (DAF, CD35, FH, and C4BP) or blocking MAC / TCC formation (CD59).

[0326] Some CCPs are membrane associated and are therefore either present on the cell surface, attached to or embedded in the membrane of host cells, where they protect the host cells by inactivating or preventing activation of the complement system.

[0327] Other CCPs circulate with the circulatory system, where they recognize and associate with molecules present either on the cell surface, or embedded in / attached to the membrane of host cells, or directly associate with complement components, and thereby inactivate or prevent activation of the complement system.

[0328] Circulating CCPs

[0329] In the present context, a circulating CPP is a CCP that circulates in the host organism through the circulatory system. The circulating CCPs are present for example in the plasma or extracellular fluid of the host organism and are not attached to or embedded in a membrane.

[0330] In one or more presently preferred exemplary embodiments, the circulating CCPs can be any one of Factor H and C4-Binding Protein (C4bp).

[0331] Membrane associated CCPs

[0332] In the present context, a membrane associated CCP is a CCP that comprises one or more transmembrane domains or membrane anchors and is found either embedded in or anchored on the plasma membrane of a host cell.

[0333] In one or more exemplary embodiments, the membrane associated CCPs of the present disclosure includes Decay Accelerating Factor (DAF / CD55), Membrane Cofactor Protein (MCP / CD46), Protectin (CD59), Complement Receptor type 1 (CR1 / CD35 / Complement C3b / C4b receptor), Complement Regulator of the Immunoglobulin Superfamily (CRIg) and Complement Receptor 2 (CR2 / CD21).

[0334] Solubilized membrane associated CCPs

[0335] In the present context a solubilized membrane associated CCP is a CCP where the transmembrane domains and / or membrane anchor has been deleted from the CCP.

[0336] In some cases where the membrane anchor is added to a CCP through posttranscriptional modification (e.g. the addition of a GPI-anchor to DAF), the membrane anchor can be deleted by removal of the responsible signal peptide and / or the removal of the hydrophobic C-terminal sequence that is replaced by the GPI-anchor.

[0337] In some cases, the solubilized CCPs may also have their intracellular domains removed.

[0338] Many methods for providing solubilized versions of membrane-associated, membrane-bound or membrane-anchored proteins are known in the prior art and application of such methods to membrane associated Complement Control Proteins would involve only routine work for the skilled person.

[0339] In one or more exemplary embodiments, solubilized CCP fragments includes soluble DAF (sDAF), soluble MCP (sMCP), soluble CD59 (sCD59), soluble CR1 (sCR1), soluble Complement Receptor 2 (CR2 / CD21) fragment and soluble CRIg (sCRIg).

[0340] Other CCP constructs:

[0341] Other CCP constructs: DAF-CD59 fusion, MCP-DAF fusion, soluble fragment of MCP fused to DAF.

[0342] Any of the CCPs disclosed herein or fragments thereof are suitable for use in the fusion proteins of the present disclosure.

[0343] There are several sequences known to encode the Complement Control Proteins in the prior art and all of those are suitable for use herein. The retrieval of such sequences, e.g. from online databases, is merely a routine task for the skilled person. Table 7 contains examples of protein sequences encoding Complement Control Proteins and their corresponding accession numbers.

[0344] Table 7: Examples of protein sequences encoding Complement Control Proteins and their corresponding accession numbers.

[0345] In an embodiment, a CCP as defined herein is selected from the group listed in Table 7, such as being selected from SEQ ID NO:s 22-29, 38-40 and 50, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 22-29, 38-40 and 50, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 22-29, 38- 40 and 50, or fragments thereof.

[0346] In one or more exemplary embodiments, a CCP as defined herein is selected from the group consisting of SEQ ID NOs: 22-29, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 22-29, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 22-29, or fragments thereof.

[0347] In one or more exemplary embodiments, a CCP as defined herein is selected from the group consisting of SEQ ID NOs: 22-28, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 22-28, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 22-28, or fragments thereof.

[0348] In one or more exemplary embodiments, a CCP as defined herein is selected from the group consisting of SEQ ID Nos: 22-27, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 22-27, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 22-27, or fragments thereof.

[0349] In one or more exemplary embodiments, a CCP as defined herein is selected from the group consisting of SEQ ID NOs: 22-26 and 29, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 22-26, and 29 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 22-26, and 29, or fragments thereof. In one or more exemplary embodiments, a CCP as defined herein is selected from the group consisting of SEQ ID NOs: 27-28, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 27-28 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 27-28, or fragments thereof.

[0350] In one or more exemplary embodiments, a CCP as defined herein is selected from the group consisting of SEQ ID NOs: 22-27 and 29, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 22-27, and 29 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 22-27, and 29, or fragments thereof.

[0351] In one or more exemplary embodiments, a CCP as defined herein is selected from the group consisting of SEQ ID NOs: 22-25 and 27-29, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 22-25 and 27-29 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 22-25 and 27-29, or fragments thereof.

[0352] In one or more exemplary embodiments, a CCP as defined herein is selected from the group consisting of SEQ ID NOs: 22-24 and 27-29, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 22-24 and 27-29 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 22-24 and 27-29, or fragments thereof.

[0353] In one or more exemplary embodiments, a CCP as defined herein is selected from the group consisting of SEQ ID NOs: 22-23, 25 and 27, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 22-23, 25 and 27 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 22-23, 25 and 27, or fragments thereof.

[0354] In one or more exemplary embodiments, a CCP as defined herein is selected from the group consisting of SEQ ID NOs: 23, 25 and 27, a functional homologue thereof having at least 70% sequence identity to any one of SEQ ID NOs: 23, 25 and 27 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 23, 25 and 27, or fragments thereof.

[0355] In one or more exemplary embodiments, a CCP as defined herein is selected as SEQ ID NO: 24, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 24 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NOs: 24, or a fragment thereof. In one or more exemplary embodiments, a CCP as defined herein is selected as SEQ ID NO: 26, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 26 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 26, or a fragment thereof.

[0356] In one or more exemplary embodiments, a CCP as defined herein is selected as SEQ ID NO: 28, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 28 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 28, or a fragment thereof.

[0357] In one or more exemplary embodiments, a CCP as defined herein is selected as SEQ ID NO: 29, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 29 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 29, or a fragment thereof.

[0358] In one or more exemplary embodiments, a CCP as defined herein is selected as SEQ ID NO: 22, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 22 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 22, or a fragment thereof.

[0359] In one or more exemplary embodiments, a CCP as defined herein is selected as SEQ ID NO: 23, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 23 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 23, or a fragment thereof.

[0360] In one or more exemplary embodiments, a CCP as defined herein is selected as SEQ ID NO: 25, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 25 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 25, or a fragment thereof.

[0361] In one or more exemplary embodiments, a CCP as defined herein is selected as SEQ ID NO: 27, a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 27 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 27, or a fragment thereof.

[0362] SCR domain

[0363] The short consensus repeat (SCR) domain, also known as a sushi domain or complement control protein module, is an evolutionarily conserved domain with a common structure and function. These domains are known to be involved in many recognition processes including for example the binding of many complement factors to fragments C3b and C4b. The SCR domain is characterized by a consensus sequence spanning about 60 residues containing four invariant cysteine residues forming two disulfide-bridges, a highly conserved tryptophan, and conserved glycine, proline, and hydrophobic residues.

[0364] The SCR domain folds into a small and compact hydrophobic core enveloped by six p-strands and stabilised by two disulfide-bridges. The relative structural orientation of the p-2 and p-4 strands is shared by all the sushi structures, whereas the topology of the other strands relative to this central conserved core is variable.

[0365] These domains are well known and several SCR domain structures have been disclosed, see e.g. one such structure of an SCR domain of Factor H under reference 1 hcc in the EMBL EBI (https: / / www.ebi.ac.uk / ebisearch / about) databases.

[0366] CCP fragments

[0367] In the present context, the term Complement Control Protein fragment is used to represent an amino acid sequence consisting of one or more sections of a Complement Control Protein amino acid sequence.

[0368] In one or more exemplary embodiments, a Complement Control Protein fragment consists of one or more sections of a complement control protein amino acid sequence corresponding to at least 30%, such as at least 35%, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or at least 98% of the Complement Control Protein amino acid sequence.

[0369] In one or more exemplary embodiments, a Complement Control Protein fragment comprises the domain(s) of a Complement Control Protein that is responsible for regulation, control and / or interaction with the complement system.

[0370] In one or more exemplary embodiments, a Complement Control Protein fragment comprises the domain(s) of a Complement Control Protein that is responsible for regulation, control and / or interaction with the complement system.

[0371] In one or more exemplary embodiments, a Complement Control Protein fragment comprises the SCR domain(s) of a Complement Control Protein that is responsible for regulation, control and / or interaction with the complement system.

[0372] In one or more exemplary embodiments, a Complement Control Protein fragment comprises the domain(s) of a Complement Control Protein that is responsible for regulating activity and / or activation of the complement system.

[0373] In one or more exemplary embodiments, a Complement Control Protein fragment comprises one or more SCR domains of a Complement Control Protein. In one or more exemplary embodiments, a Complement Control Protein fragment consists of one or more SCR domains of a Complement Control Protein.

[0374] In one or more exemplary embodiments, a Complement Control Protein fragment comprises four SCR domains of a Complement Control Protein.

[0375] In one or more exemplary embodiments, a Complement Control Protein fragment consists of four SCR domains of a Complement Control Protein.

[0376] In one or more exemplary embodiments, the Complement Control Protein fragment consists of SCR domains 1-4 of decay accelerating factor (DAF).

[0377] In one or more exemplary embodiments, the protein sequence of SCR domains 1-4 of DAF is defined by SEQ ID NO: 31.

[0378] In one or more exemplary embodiments, the Complement Control Protein fragment consists of SCR domains 2-4 of decay accelerating factor (DAF), such as described in SEQ ID NO: 42.

[0379] In one or more exemplary embodiments, the Complement Control Protein fragment consists of SCR domains 1-5 of Factor H (CFH / FH), such as described in SEQ ID NO: 43.

[0380] Examples of CCP fragment and SCR domain protein sequences are listed in Table 8.

[0381] Table 8: Examples of CCP fragments and SCR domain protein sequences.

[0382] In one or more exemplary embodiments, a CCP fragment is selected as a protein sequence according to SEQ ID NO: 31 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 31 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 31 .

[0383] In one or more exemplary embodiments, a CCP fragment is selected as a protein sequence according to SEQ ID NO: 42 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 42 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 42.

[0384] In one or more exemplary embodiments, a CCP fragment is selected as a protein sequence according to SEQ ID NO: 43 or a functional homologue thereof having at least 70% sequence identity to SEQ ID NO: 43 such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 43. Regulation of complement activation

[0385] In the present context, the term "regulation of complement activation" is used to represent a process that leads to a reduced activity of any one of the complement activation pathways or a reduction in activity of the complement system proteins. Such processes also include processes that reduces activation of the complement system. An example of a process that reduces activation of the complement system is the activity exerted by DAF reducing the amount of C3 (as demonstrated by the C3 deposition assay in example 4 and figure 4) thereby breaking the complement cascade and reducing complement activation.

[0386] In one or more exemplary embodiments, a regulator of complement activation, is a protein that either reduces the activity of the complement system, a protein that reduces activation of the complement system or a protein that returns complement activity to a normal level.

[0387] A reduction in complement activation within the present context is a reduction in complement activation or activity of at least 5%, such as at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or at least 100%.

[0388] Thus, for example a reduction in complement activation or activity is a reduction of 35-60%, 35- 70%, 35-80%, 35-90% 35-100%, 40-95%, 45-90%, 50-85%, 55-80%, 60-75%, 50-60%, 50-70%, 50-80%, 50-90%, 50-100% 60-70%, 60-80%, 60-90%, 60-100%, 70-80%, 70-95%, 70-100%, 80- 90%, 80-95%, 80-100%, 85-95%, 85-100%, 90-100% or 95-100%.

[0389] In one or more exemplary embodiments, the reduction in complement activation or activity is 40- 80%.

[0390] In one or more exemplary embodiments, the reduction in complement activation or activity is 60- 80%.

[0391] In one or more exemplary embodiments, the reduction in complement activation or activity is 70- 90%.

[0392] In one or more exemplary embodiments, the reduction in complement activation or activity is 80- 95%.

[0393] In one or more exemplary embodiments, the reduction in complement activation or activity is 90- 95%.

[0394] Standard assays such as for example the C3 and TCC deposition assays described in examples 4- 5 can be used to detect and measure Complement activation and / or complement activity.

[0395] A reduction in complement activation or activity can thus be measured by comparing a sample treated with a suspected regulator of complement activation and be compared to negative control sample. If the reduction falls within the interval as described above, the suspected regulator of complement activation is considered a regulator of complement activation in the present context.

[0396] However, there are many methods for comparative testing of samples and the skilled person would be able to set up other assays to the test reductions in complement activity as a matter of routine exercise.

[0397] A return of complement activity to a normal level can for example be detected by comparison of treated samples and control samples to baseline values for complement activity obtained from healthy individuals.

[0398] Thus, if an untreated sample has a higher level of complement activity than the baseline for healthy individuals and said sample undergoes treatment with a protein and said sample after this treatment has a level of complement activity that falls within + / - 5% when compared to the baseline for a healthy individual, then the protein used to treat the sample is, within the present context, considered to have returned complement activity to normal levels.

[0399] Overactivation of the complement system

[0400] The term "overactivation of the complement system" is used in the present disclosure to represent scenarios where activation of the complement cascade to levels above the physiological basal activation results in exhaustion of complement components and have pathological consequences in terms of cell damage and / or complement dysregulation.

[0401] Sequence identity of proteins, functional homologs, and fragments thereof

[0402] In the present context, for proteins, functional homologues, peptides and / or fragments thereof having an amino acid sequence at least, for example 70% identical to a reference amino acid sequence, it is intended that the amino acid sequence of e.g., the peptide is identical to the reference sequence, except that the amino acid sequence may include up to 30 mutations per each 100 amino acids of the reference amino acid sequence.

[0403] In other words, to obtain a sequence at least 70% identical to a reference sequence, up to 30% of the amino acids or nucleotides in the reference sequence may be deleted or substituted with another amino acid / nucleotide, or several amino acids / nucleotides up to 30% of the total amount of the reference sequence.

[0404] These mutations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among amino acids in the reference sequence or in one or more contiguous groups within the reference sequence. Methods to determine identity and similarity are codified in publicly available programs. Preferred computer program methods to determine identity and similarity between two sequences include, but are not limited to, the GCG program package, BLASTP, BLASTN, and FASTA.

[0405] The BLASTX program is publicly available from NCBI and other sources. Each sequence analysis program has a default scoring matrix and default gap penalties. In general, a molecular biologist would be expected to use the default settings established by the software program used.

[0406] Functional homologues

[0407] A functional homologue of a protein / nucleic acid sequence as described herein is a protein / nucleic acid sequence with alterations in the genetic code, which retain its original functionality. A functional homologue may be obtained by mutagenesis or may be natural occurring variants from the same or other species. The functional homologue should have a remaining functionality of at least 50%, such as at least 60%, 70%, 80 %, 90% or 100% compared to the functionality of the protein / nucleic acid sequence. A functional homologue of any one of the disclosed amino acid or nucleic acid sequences can also have a higher functionality than the original amino acid or nucleic acid sequences.

[0408] In the present context, a functional homologue of a Complement Control Protein is able to regulate activation of the complement system. This functionality can be tested in several ways which are known to the skilled person. However, one example of such a method is illustrated in the C3 deposition and TCC deposition assays described in examples 4-6. The adaptation of these assays to individual other Complement Control Proteins is straightforward and would only amount to routine work for the skilled person.

[0409] In the present context, A functional homologue of a Pattern Recognition Molecule or fragment thereof is able to recognize and bind the molecular targets of the Pattern Recognition Molecule. This ability to recognize and bind a molecular target can easily be tested in a ligand binding assays such as that described in example 3. Many other forms of ligand binding assays are known in the prior art and the adaptation of such ligand binding assays to fit a Pattern Recognition Molecule and its molecular target, would represent only routine work for the skilled person.

[0410] Nucleic acids

[0411] The term nucleic acid refers to a group of compounds, the nucleotides (adenine, cytosine, guanine, thymine and uracil), which consists of a pentose sugar (ribose or deoxyribose), a phosphate group and a nucleobase. These nucleotides form biopolymers in nature that make up DNA and RNA molecules. Biopolymers of these nucleotides are referred to as nucleic acid sequences or polynucleotides and are used within the present context to describe DNA and RNA. In one or more exemplary embodiments, a nucleic acid sequence or polynucleotide of the present disclosure relates to a nucleic acid sequence encoding a fusion protein as defined herein.

[0412] A nucleic acid sequence or polynucleotide according to the present disclosure can also further encode an N-terminal signal peptide sequence. This signal peptide can for example be a signal peptide that ensures secretion of the fusion protein.

[0413] In one or more exemplary embodiments, the N-terminal signal peptide is a human serum albumin (HSA) signal peptide according to SEQ ID NO: 30.

[0414] In one or more exemplary embodiments, a nucleic acid sequence encodes a fusion protein having at least 70% sequence identity to SEQ ID NO: 1 , such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 1 .

[0415] In one or more exemplary embodiments, a nucleic acid sequence encodes a fusion protein having at least 70% sequence identity to SEQ ID NO: 2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 2.

[0416] Nucleic acid constructs

[0417] The present disclosure also relates to a nucleic acid construct comprising the polynucleotides operably linked to one or more control sequences. A nucleic acid construct within the present context is an artificial construct comprising a nucleic acid insert that is integrated into or borne by a vector. The vector can be delivered via transformation / transfection to a host cell by for example physical, chemical, or viral methods and allow the nucleic acid inserts to be replicated or expressed in the host cell. Such methods for delivering a vector into a host cell are well known to the skilled person.

[0418] In one or more exemplary embodiments, the present disclosure relates to a nucleic acid construct encoding a fusion-protein as defined herein.

[0419] In one or more exemplary embodiments, a nucleic acid construct encodes a fusion protein as defined herein, having at least 70% sequence identity to SEQ ID NO: 1 , such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 1 .

[0420] In one or more exemplary embodiments, a nucleic acid construct encodes a fusion protein as defined herein, having at least 70% sequence identity to SEQ ID NO: 2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to SEQ ID NO: 2.

[0421] In one or more exemplary embodiments, the present disclosure relates to nucleic acid constructs or vectors that facilitate transformation into a suitable host cell.

[0422] In one or more exemplary embodiments, the nucleic acid constructs or vectors of the present disclosure comprise one or more control elements (expression start / stop / transposable elements). In one or more exemplary embodiments, the nucleic acid constructs or vectors of the present disclosure comprise a signal peptide, the signal peptide ensuring secretion of the encoded fusion protein.

[0423] In one or more exemplary embodiments, the nucleic acid constructs or vectors of the present disclosure, the signal peptide is a HSA (human serum albumin) signal peptide according to SEQ ID NO: 30.

[0424] In one or more exemplary embodiments, the present disclosure relates to nucleic acid constructs and vectors of use in producing fusion proteins as disclosed herein.

[0425] Host cells

[0426] To manufacture biotechnology products, cells can be engineered for production of recombinant proteins including for example fusion proteins. Within the context of the present disclosure a host cell is a cell that is used for harbouring and expressing a polynucleotide, nucleic acid sequence or nucleic acid construct as defined herein. Methods for introducing polynucleotides, nucleic acid sequences and nucleic acid constructs into cells to provide host cells are well known in the prior art.

[0427] Thus, in one or more exemplary embodiments, the present disclosure relates to a host cell comprising a nucleic acid sequence or nucleic acid construct encoding a fusion protein as defined herein.

[0428] Thus, in one or more exemplary embodiments, the present disclosure relates to a host cell comprising a nucleic acid sequence or nucleic acid construct encoding a fusion protein as defined herein, having at least 70% sequence identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 1-2.

[0429] In one or more exemplary embodiments, the host cell expresses a fusion protein as defined herein and encoded by the nucleic acid sequence or nucleic acid construct as disclosed herein.

[0430] In one or more exemplary embodiments, the host cell expresses a fusion protein as defined herein, having at least 70% sequence identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% sequence identity to any one of SEQ ID NOs: 1-2.

[0431] In one or more exemplary embodiments, the host cell that is selected from yeast cells, bacterial cells, mammalian cells and plant cells.

[0432] In one or more exemplary embodiments, the host cell is an eukaryotic cell.

[0433] In one or more exemplary embodiments, the host cell is a yeast cell.

[0434] In one or more exemplary embodiments, the host cell is a mammalian cell. In one or more exemplary embodiments, the host cell is a plant cell.

[0435] Methods for fusion protein production

[0436] In the present context, a method for fusion protein production relates to a method wherein a host cell is cultured / cultivated to produce a fusion protein by expression of a nucleic acid sequence or nucleic acid construct. Such methods for production of fusion proteins in a host cell are well known in the prior art.

[0437] Thus, in one or more exemplary embodiment, the present disclosure relates to a method for producing a fusion protein as disclosed herein, the method comprising:

[0438] • culturing a host cell as defined herein, and

[0439] • recovering the fusion protein.

[0440] In one or more exemplary embodiments, the present disclosure relates to a method for fusion protein production by culturing a host cell comprising a nucleic acid or nucleic acid construct as defined herein.

[0441] However, as the skilled addressee knows, then the fusion protein sequences can also be made via chemical synthesis of peptides. Chemical synthesis of peptides can be carried out using classical solution-phase techniques, although these have been replaced in most research and development settings by solid-phase methods. However, solution-phase synthesis retains its usefulness in large- scale production of peptides for industrial purposes.

[0442] Compositions

[0443] In one or more embodiments, the fusion proteins defined herein, the nucleic acid sequences encoding the fusion proteins defined herein, and / or the nucleic acid constructs encoding the fusion proteins defined herein is / are formulated in a composition.

[0444] In one or more exemplary embodiments, a fusion protein as defined herein is formulated in a composition.

[0445] Pharmaceutical compositions

[0446] In one or more embodiments of the present disclosure, the fusion proteins defined herein, nucleic acid sequences encoding the fusion proteins defined herein, and / or the nucleic acid constructs encoding the fusion proteins defined herein is / are formulated as the active ingredient(s) of a pharmaceutical composition.

[0447] In one or more exemplary embodiments of the present disclosure, a fusion protein as defined herein is formulated as the active ingredient of a pharmaceutical composition. A pharmaceutical composition comprises in addition to the active ingredient, therapeutically inactive ingredients, such as a pharmaceutically acceptable or physiologically acceptable excipient, carrier and / or adjuvants, which are well-known to the person skilled in the art and may include, but are not limited to, solvents, emulsifiers, wetting agents, plasticizers, solubilizers (e.g. solubility enhancing agents) colouring substances, fillers, preservatives, anti-oxidants, anti-microbial agents, viscosity adjusting agents, buffering agents, pH adjusting agents, isotonicity adjusting agents, mucoadhesive substances, and the like. Examples of formulation strategies of pharmaceutical compositions are well-known to the person skilled in the art.

[0448] In the present context a pharmaceutical composition is a mixture of ingredients suitable for administering to a subject that includes an active ingredient.

[0449] Medical use

[0450] The fusion proteins defined herein could be used to treat any disease or disorder that has a complement system component or is related to an inflammatory state, such as e.g. allergic inflammation, asthmatic inflammation, ischemic reperfusion injury or organ damage following organ donation.

[0451] One medical composition developed is the fusion protein MBDAF, that contains a DAF fragment fused to MBL. This fusion protein is an effective regulator of complement activation as demonstrated in examples 4-6. There are different reasons for including a DAF fragment, but mainly DAF is known to prevent formation of the C3 convertases of the complement system, thereby regulating activation of the complement system at an early stage.

[0452] Other fusion protein combinations of PRMs or PRM fragments with CCPs or CCP fragments could also be designed to specifically target different complement activation pathways depending on the PRM used and targeting different stages and / or parts of the complement system depending on the CPP used. This is demonstrated in examples 8-11.

[0453] The complement system is involved in many conditions including immune disorders, inflammatory disorders, injuries and neurodegenerative disorders. Therefore, agents capable of regulating complement activation can also be used for ameliorating, alleviating and / or treatment of these disorders.

[0454] Thus, in one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof, for use as a medicament.

[0455] The medical use within the present context relates to the use of the fusion proteins as defined herein, compositions thereof or pharmaceutical compositions thereof for use in alleviating or ameliorating symptoms of a disease, condition or disorder or in the treatment of a disease, condition, or disorder.

[0456] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use as a medicament.

[0457] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in regulating activation of the complement system.

[0458] In one or more exemplary embodiments, the present disclosure relates to a fusion protein comprising a PRM or a fragment thereof fused to a CCP or a fragment thereof for use in regulating activation of the complement system.

[0459] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in regulating activation of the complement system.

[0460] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in low immunogenicity regulation of the complement system.

[0461] In one or more exemplary embodiments, the present disclosure relates to a fusion protein comprising a PRM or a fragment thereof fused to a CCP or a fragment thereof for use in low immunogenicity regulation of the complement system.

[0462] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in low immunogenicity regulation of the complement system.

[0463] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in regulating overactivation of the complement system.

[0464] In one or more exemplary embodiments, the present disclosure relates to a fusion protein comprising a PRM or a fragment thereof fused to a CCP or a fragment thereof for use in regulating overactivation of the complement system. In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in regulating overactivation of the complement system.

[0465] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in regulating overactivation of the complement system.

[0466] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in controlling, inhibiting, inactivating, limiting, preventing, mitigating, alleviating, ameliorating, or treating inflammation.

[0467] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in controlling, inhibiting, inactivating, limiting, preventing, mitigating, alleviating, ameliorating, or treating inflammation.

[0468] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in controlling, inhibiting, inactivating, limiting, preventing, mitigating, alleviating, ameliorating, or treatment of a disease, disorder or condition associated with inflammation.

[0469] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, inhibition, inactivation, limitation, prevention, mitigation, alleviation, amelioration, or treatment of a disease, disorder or condition associated with inflammation.

[0470] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of a disease, disorder or condition associated with inflammation.

[0471] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of asthmatic inflammation.

[0472] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of asthmatic inflammation.

[0473] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of allergic inflammation.

[0474] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of allergic inflammation.

[0475] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of ischemic reperfusion injury (IRI).

[0476] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of ischemic reperfusion injury (IRI).

[0477] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of a disease or condition associated with ischemic reperfusion injury (IRI).

[0478] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of a disease or condition associated with ischemic reperfusion injury (IRI).

[0479] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of renal ischemic reperfusion or intestinal ischemic reperfusion.

[0480] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of renal ischemic reperfusion or intestinal ischemic reperfusion.

[0481] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of inflammation caused by ischemic reperfusion injury (IRI).

[0482] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of inflammation caused by ischemic reperfusion injury (IRI).

[0483] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of ischemic reperfusion injury (IRI) following organ transplantation.

[0484] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of ischemic reperfusion injury (IRI) following organ transplantation.

[0485] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of organ damage caused by inflammation following organ transplantation.

[0486] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of organ damage caused by inflammation following organ transplantation.

[0487] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of membranous nephropathy (MN).

[0488] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of membranous nephropathy (MN).

[0489] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of complement activation or complement overactivation in subjects suffering from membranous nephropathy (MN).

[0490] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of complement activation or complement overactivation in subjects suffering from membranous nephropathy (MN).

[0491] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of proteinuria.

[0492] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of proteinuria.

[0493] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of proteinuria in subjects suffering from membranous nephropathy (MN).

[0494] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of proteinuria in subjects suffering from membranous nephropathy (MN).

[0495] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of conditions associated with inflammation, apoptosis, autoimmunity, coagulation, and / or thrombotic or coagulopathic related diseases.

[0496] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of conditions associated with inflammation, apoptosis, autoimmunity, coagulation, and / or thrombotic or coagulopathic related diseases.

[0497] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of any inflammatory disorder selected from the group consisting of immune complex disease, organ ischemia, reperfusion injury, sepsis, septicemia, preeclampsia, HELP syndrome, disseminated bacteremia, disseminated aspergillosis, disseminated fungal infections, myocardial ischemia, necrotizing fasciitis, rheumatoid arthritis, systemic lupus erythematosus, graft-versus-host disease, hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA), myocardial infarction, reperfusion injury, stroke, dermatomyositis, disseminated intravascular coagulation, Vascular complication and nephropathy associated with type 1 and / or type 2 diabetes, atypic haemolytic uremic syndrome, haemolytic uremic syndrome, age related macular degeneration, burn injury, complications related to organ transplantations, IgA nephropathy, membranous nephropathy, and acute kidney injury.

[0498] In a preferred embodiment, the composition according to the invention is for use in the treatment of IgA nephropathy. IgA nephropathy is the most common form of glomerulonephritis worldwide. It is driven by deposits of galactose-deficient lgA1 in the kidney, which trigger inflammation, leading to scarring, tissue damage, and potentially kidney failure. Deposits of complement components, notably the PRIVI IVIBL, have been observed in the glomeruli of affected patients. A recent phase 3 clinical trial of the factor B inhibitor Iptacopan demonstrated that complement inhibition significantly reduced proteinuria in patients with IgA nephropathy.

[0499] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, limitation, prevention, mitigation, alleviation, amelioration, or treatment of any inflammatory disorder selected from the group consisting of immune complex disease, organ ischemia, reperfusion injury, sepsis, septicemia, preeclampsia, HELP syndrome, disseminated bacteremia, disseminated aspergillosis, disseminated fungal infections, myocardial ischemia, necrotizing fasciitis, rheumatoid arthritis, systemic lupus erythematosus, graft-versus-host disease, hematopoietic stem cell transplant- associated thrombotic microangiopathy (TA-TMA), myocardial infarction, reperfusion injury, stroke, dermatomyositis, disseminated intravascular coagulation, Vascular complication and nephropathy associated with type 1 and / or type 2 diabetes, atypic haemolytic uremic syndrome, haemolytic uremic syndrome, age related macular degeneration, burn injury, complications related to organ transplantations, IgA nephropathy, membranous nephropathy, and acute kidney injury.

[0500] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in regulation of the lectin pathway of the complement system with enhanced avidity and enhanced modulatory potency.

[0501] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in regulation of the lectin pathway of the complement system with enhanced avidity and enhanced modulatory potency.

[0502] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in low immunogenicity regulation of lectin pathway of the complement system. In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in low immunogenicity regulation of lectin pathway of the complement system.

[0503] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in immunogenicity-free regulation of the lectin pathway of the complement system.

[0504] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in immunogenicity-free regulation of the lectin pathway of the complement system.

[0505] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in immunogenicity-free regulation of the lectin pathway of the complement system.

[0506] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in immunogenicity-free regulation of the lectin pathway of the complement system.

[0507] In one or more exemplary embodiments, the present disclosure relates to fusion proteins as defined herein, compositions thereof, and / or pharmaceutical compositions thereof for use in control, inhibition, inactivation, limitation, prevention, mitigation, alleviation, amelioration, or treatment of complement system overactivation by targeted modulation of the lectin pathway.

[0508] In one or more exemplary embodiments, the present disclosure relates to a fusion protein according to any one of SEQ ID NOs: 1 -2 or a functional homologue thereof having at least 70% identity to any one of SEQ ID NOs: 1-2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to any one of SEQ ID NOs: 1-2 for use in control, inhibition, inactivation, limitation, prevention, mitigation, alleviation, amelioration, or treatment of complement system overactivation by targeted modulation of the lectin pathway.

[0509] In a preferred embodiment, the fusion protein is for use in a mammal, preferably a human subject. Other aspects of the invention

[0510] An aspect of the invention relates to a method for treating or alleviating a disease or disorder in a subject that has a complement system component or is related to an inflammatory state, the method comprising administering to the subject a fusion protein according to the invention to the subject.

[0511] In an embodiment, the disease or disorder is selected from allergic inflammation, asthmatic inflammation, ischemic reperfusion injury and organ damage following organ donation.

[0512] General

[0513] It should be understood that any feature and / or aspect discussed above in connections with the compounds according to the invention apply by analogy to the methods described herein.

[0514] The terms "CCP" and "CCPs" are used respectively throughout this disclosure as abbreviations for the singular form and the plural form of Complement Control Protein.

[0515] The terms "PRM" and "PRMs" are used respectively throughout this disclosure as abbreviations for the singular form and the plural form of Pattern Recognition Molecule.

[0516] The terms membrane attack complex (MAC) and terminal complement complex (TCC) refer to the same protein complex and are used interchangeably in the present disclosure.

[0517] The following figures and examples are provided below to illustrate the present invention. They are intended to be illustrative and are not to be construed as limiting in any way.

[0518] BRIEF DESCRIPTION OF THE FIGURES

[0519] Figure 1

[0520] Figure 1 shows a western blot under reducing and non-reducing conditions of MBDAF, MBL and DAF with an MBL specific antibody. Lane 1) MBDAF produced in Expi293. Lane 2) MBDAF produced in ExpiCHO. Lane 3) MBL produced in Expi293, Lane 4) MBL produced in Expi CHO. Lane 5) MBL produced in DG44 CHO. Lane 6) DAF.

[0521] Figure 2

[0522] Figure 2 shows a western blot under reducing and non-reducing conditions of MBDAF, MBL and DAF with a DAF specific antibody. Lane 1) MBDAF produced in Expi293. Lane 2) MBDAF produced in ExpiCHO. Lane 3) MBL produced in Expi293, Lane 4) MBL produced in ExpiCHO. Lane 5) MBL produced in DG44 CHO. Lane 6) DAF. Figure 3 shows a ligand binding assay of MBL and MBDAF against mannan on a solid phase surface.

[0523] Figure 4 shows a C3 deposition assay of a human serum sample / pool incubated on mannan coated plates in the presence of varying concentrations of MBDAF, MBL, DAF, MBL+DAF, and Eculizumab respectively.

[0524] Figure 5 shows a TCC deposition assay of a human serum sample / pool incubated on mannan- coated plates in the presence of varying concentrations of MBDAF, MBL, DAF, MBL+DAF and Eculizumab respectively.

[0525] Figure 6 shows a TCC deposition assay of varying concentrations of human serum / pool incubated on mannan-coated plates in the presence of 2.5 pg / ml MBDAF or Eculizumab.

[0526] Figure 7 shows an illustration of the MBDAF fusion protein with an N-terminal HSA signal peptide attached to SCR domain 1 of the DAF fragment.

[0527] Figure 8

[0528] Figure 8 shows an illustration of an MBDAF oligomer.

[0529] Figure 9

[0530] Figure 9 shows a C3 deposition assay of a human serum sample / pool incubated on mannan- coated plates in the presence of varying concentrations of MBDAF and MAP1 :CD55 respectively.

[0531] Figure 10

[0532] Figure 10 shows a TCC deposition assay of a human serum sample / pool incubated on mannan- coated plates in the presence of varying concentrations of MBDAF, MAPI and MAP1 :CD55 respectively.

[0533] Figure 11

[0534] Figure 11 shows a TCC deposition assay of a human serum sample at different concentrations incubated on mannan-coated plates in the presence of varying concentrations of MBDAF, or FH1-5 + MBL (MBH). A) 2%, and B) 10%. Figure 12 shows a C3 deposition assay using A) a human serum sample or B) a mouse serum sample incubated on manna-coated plates in the presence of varying concentrations of MBDAF (Human MBDAF) or mouse DAF + human MBL (Mouse MBDAF).

[0535] Figure 13 shows a TCC deposition assay using a human serum sample at different concentrations incubated on mannan-coated plates in the presence of varying concentrations of MBDAF, DAF fragment + MBL (MBL_DAFfrgmt), DAF fragment + MBL fragment (MBLfrgmt_DAFfrgmt), DAF fragment + MBL fragment without linker (MBLfrgmt_DAFfrgmt_NL), or Eculizumab. A) 2%, and B) 10%.

[0536] Figure 14

[0537] Figure 14 shows a C3 and TCC deposition assay using a human serum sample incubated on acetylated-BSA coated plates in the presence of varying concentrations of a DAF + ficolin-3 fusion protein (FCN-3:DAF).

[0538] EXAMPLES

[0539] Example 1 : Evaluating complement activation regulatory function of fusion proteins

[0540] Example 1a: Complement deposition assay on mannan-coated plates with 2 % human serum.

[0541] Nunc MaxiSorp flat-bottom microtiter 96-wellplates (ThermoFisher Scientific) were coated with 10 pg / ml of mannan (M7504 Merck) in PBS overnight at 4 °C.

[0542] The samples (MBDAF and controls) were diluted 3-fold in a predilution plate using Barbital-Tw (5.5 mM sodium barbiturate, 145 mM NaCI, 2.7 mM CaCI2, 2.1 mM MgCI2, pH 7.4 + 0.05 % Tween- 20).

[0543] Normal human serum collected into clot activator tubes (from a pool of healthy individuals) was diluted in Barbital-Tw to a 4% concentration and then added to the predilution plate in a 1 :1 proportion (final serum concentration 2%).

[0544] The samples were incubated together with human serum in mannan-coated plates for 45 (TCC) or 15 min (C3) at 37 °C. Complement activation was measured using 2 pg / ml of monoclonal antibodies against C3 (BH6 anti-human C3b / c antibody) or TCC (aE11 anti-human C5b-9 antibody) for 1 .5 h, followed by HRP-conjugated streptavidin (1 :2000 dilution, RPN1231 v MilliporeSigma) for 1 h at RT.

[0545] The plates were developed with TMB One (Kementec Diagnostics, Taastrup, Denmark), and stopped with 0.3 M sulfuric acid. The optical density was read at 450 nm and 630 nm using a Synergy HT plate reader (BioTek, Winooski, VT, USA). OD was corrected by subtracting the 630 nm value to the 450 nm value.

[0546] Example 1 b: Ficolin-2 and -3 testing

[0547] For the evaluation of Ficolin-1 , Ficolin-2, Ficolin-3 or ficolin fragment containing fusion proteins, the assay of example 1a can for example be used where 96-well microtiter plates are coated with 5 pg / ml of acetylated bovine serum albumin instead of mannan.

[0548] Example 1c: C1q testing

[0549] Similarly, for the evaluation of C1q containing fusion proteins, the assay of example 1a can for example be used, wherein 96-well microtiter plates are coated overnight with 10 pg / ml of human serum albumin followed by 2 h incubation with 1 :2000 dilution of rabbit anti-human serum albumin (Dako 0001) should be used instead.

[0550] Other PRMs can also be tested using the assay described in example 1a, but will require a different coating of the 96-well plate with molecules that the PRMs in question has binding activity towards. Incubation times with serum may need to be corrected depending on serum source and PRM used.

[0551] Example 2: Western blotting of MBDAF, MBL and DAF produced in different cell lines

[0552] Aim of study

[0553] To demonstrate that the fusion protein MBDAF contains covalently bound MBL and DAF molecules.

[0554] Materials and methods

[0555] Proteins were subjected to SDS-PAGE electrophoresis using NuPAGE™ 3-8 % Tris-Acetate gels. Blotting was performed onto Amersham™ Hybond™ 0.45 pm PVDF membranes (GE Healthcare) according to the manufacturer’s instructions. Membranes were blocked using 5 % skim milk (MilliporeSigma, Burlington, MA, USA) and probed overnight at 4 °C with 1 pg / ml 131-1 anti-MBL (Garred et al. 1992) or 1 pg / ml anti-CD-55 mAb clone 278803 (MAB2009; R&D Systems, Minneapolis, MN, USA) diluted in PBS-Tw, and subsequently probed for 1 h at room temperature (RT) with rabbit anti-mouse HRP polyclonal antibody in PBS-Tw (P0260, 0,65pg / ml in PBS-Tw; Agilent Technologies, Santa Clara, CA, USA). After every antibody incubation, the membranes were washed six times with PBS-Tw. Membranes were developed using SuperSignal WestFemto maximum-sensitivity substrate (Thermo Fisher Scientific) and analyzed with Odyssey® XF (Ll- COR, Lincoln, Nebraska, USA)

[0556] Results Western blot under reducing and non-reducing conditions of the fusion protein MBDAF (SEQ ID NO: 1) produced in two different cell lines (ExpiCHO and Expi293). MBL (SEQ ID: 3) produced in three different cell lines (ExpiCHO, Expi293 and CHO DG44), and DAF (SEQ ID: 22) CCP domains 1-4. The membranes were probed with an MBL-specific antibody (figure 1) or a DAF-specific antibody (figure 2).

[0557] Conclusions

[0558] The results demonstrate that MBDAF is comprised of covalently bound MBL and DAF molecules.

[0559] Example 3: Binding of MBDAF to a mannan coated solid phase

[0560] Aim of study

[0561] To demonstrate binding of the fusion protein MBDAF to the carbohydrate ligand mannan on the solid phase.

[0562] Materials and methods

[0563] MaxiSorp microtiter 96-well plates were coated with 10 pg / ml of mannan (M7504 Merck) in PBS overnight. MBL (SEQ ID NO: 3) and MBDAF (SEQ ID NO: 1) were applied in a 2-fold dilution series in Barbital-Tw (5.5 mM sodium barbiturate, 145 mM NaCI, 2.7 mM CaCI2, 2.1 mM MgCI2, pH 7.4 + 0.05 % Tween-20), with a starting concentration of 4.34 pM (MBL) and 3.77 pM (MBDAF) — calculated assuming they form tetramers of trimers — and incubated for 1 :45 h at RT. Protein binding to was quantified using 2 pg / ml of biotinylated Hyb-131-1 for 1 :30 h at RT. Biotinylated mAb detection and plate development was performed as described before.

[0564] Results

[0565] MBDAF maintains the lectin binding activity of its constituent PRM MBL as shown in figure 3.

[0566] Conclusion

[0567] The fusion protein MBDAF maintains the lectin binding activity, demonstrating that addition of the regulatory molecule DAF in the N-terminus of the PRM MBL does not impair its binding activity.

[0568] Example 4: Complement regulation of C3 by MBDAF

[0569] Aim of study

[0570] To demonstrate that MBDAF is an effective regulator of complement activation at the C3 level

[0571] Materials and methods

[0572] MaxiSorp microtiter 96-well plates were coated with 10 pg / ml of mannan in PBS overnight at 4 °C. The samples (MBDAF and controls) were diluted 3-fold in a predilution plate using Barbital-Tw (5.5 mM sodium barbiturate, 145 mM NaCI, 2.7 mM CaCI2, 2.1 mM MgCI2, pH 7.4 + 0.05 % Tween- 20). Normal human serum collected into clot activator tubes (from a pool of healthy individuals) was diluted in Barbital-Tw to a 4% concentration and then added to the predilution plate in a 1 :1 proportion (final serum concentration 2%). The samples were incubated together with human serum in mannan-coated plates for 45 (TCC) or 15 min (C3) at 37 °C. Complement activation was measured using 2 pg / ml of biotinylated monoclonal antibody against C3 (BH6 anti-human C3b / c antibody) for 1 .5 h, followed by HRP-conjugated streptavidin (1 :2000 dilution, RPN1231 v MilliporeSigma) for 1 h at RT.

[0573] Biotinylated mAb detection and plate development was performed as described before. MBL, DAF, MBL and DAF applied together, and eculizumab were used as controls.

[0574] Results

[0575] The combination of a PRM and a fragment of a CCP in a fusion protein is vastly superior to the use of both proteins as separate entities (see figure 4).

[0576] Conclusion

[0577] The fusion protein MBDAF is superior in reducing complement activation (compared to the separate entities), illustrated as inhibition of C3 deposition.

[0578] Example 5: Complement regulation of TCC by MBDAF

[0579] Aim of study

[0580] To demonstrate that MBDAF is an effective regulator of complement activation at the TCC level.

[0581] Materials and methods

[0582] MaxiSorp microtiter 96-well plates were coated with mannan, and serial dilutions of MBDAF mixed with 2% serum were incubated for 15 min at 37 °C as described above. Plates were washed and complement activation was measured using 2 pg / ml of biotinylated monoclonal antibody against TCC (aE11 anti-human C5b-9 antibody) for 1 .5 h, followed by HRP-conjugated streptavidin (1 :2000 dilution, RPN1231 v MilliporeSigma) for 1 h at RT. Biotinylated mAb detection and plate development was performed as described before. MBL, DAF, MBL and DAF applied together, and eculizumab were used as controls.

[0583] Results

[0584] The combination of a PRM and a fragment of a CCP in a fusion protein is vastly superior to the use of both proteins as separate entities (figure 5).

[0585] Conclusion

[0586] The fusion protein MBDAF is superior in reducing complement activation (compared to the separate entities), illustrated as inhibition of TCC deposition. Example 6: Complement regulation by MBDAF at varying serum concentrations

[0587] Aim of study

[0588] To demonstrate that MBDAF is superior in reducing complement activation.

[0589] Materials and methods

[0590] Maxisorp microtiter 96-well plates were coated with 10 pg / ml mannan, and a fixed concentration of MBDAF or eculizumab (2.5 pg / ml) mixed with serial dilutions of serum were incubated for 45 min at 37 °C. Plates were washed and complement activation was measured as deposited TCC as described above.

[0591] Results

[0592] The results demonstrate that MBDAF is an effective regulator of complement activation over a range of serum concentrations with a potency comparable to eculizumab (figure 6).

[0593] Conclusion

[0594] The fusion protein MBDAF can effectively reduce complement activation with a potency comparable to eculizumab, illustrated as inhibition of TCC deposition.

[0595] Example 7: Comparative data to MAPI and MAP1 :CD55

[0596] Aim of study

[0597] To demonstrate that MBDAF is superior in reducing complement activation compared to the MAPI and MAP1 :CD55.

[0598] Materials and methods

[0599] MaxiSorp microtiter 96-well plates were coated with mannan, and serial dilutions of MBDAF, MAP- 1 , or MAP-1 :CD55, mixed with 2% serum were incubated for 15 or 45 min at 37 °C as described above for C3 and TCC, respectively. Plates were washed and complement activation was measured using biotinylated monoclonal antibodies against C3 and TCC for 1.5 h. Biotinylated mAb detection and plate development was performed as described before.

[0600] Results

[0601] The results demonstrate that MBDAF is a superior regulator of complement activation compared to MAPI and MAPI :CD55 both at the C3 and TCC levels (figures 9 and 10).

[0602] Conclusion

[0603] The fusion protein MBDAF can effectively reduce complement activation with a potency much superior to MAPI and MAP1 :CD55, illustrated as inhibition of C3 and TCC deposition. Example 8: Testing different complement control proteins (CCPs)

[0604] Aim of study

[0605] To validate that the concept of the invention is applicable using different CCPs.

[0606] Materials and methods

[0607] MaxiSorp microtiter 96-well plates were coated with mannan, and serial dilutions of MBDAF, MBL:FH1 5(MBH) mixed with 2 (figure 11 A) or 10% (figure 11 B) human serum were incubated for 45 min at 37 °C. Detection of TCC was measured as described in example 5.

[0608] To evaluate the species-specific activity of DAF, MaxiSorp microtiter 96-well plates were coated with mannan, and serial dilutions of MBDAF (SEQ ID NO: 1) or MBL:mouse DAF1 4(SEQ ID NO: 41) (mouse MBDAF) mixed with 2% human (figure 12 A) or mouse serum (figure 12 B) were incubated for 10 or 15 min at RT (for mouse and human serum, respectively). Plates were washed and complement activation was measured using antibodies against C3 (biotinylated BH6 for human serum, and Dako A0063 for mouse serum), followed by HRP-conjugated streptavidin (1 :2000 dilution, RPN1231v MilliporeSigma) or swine anti-rabbit lmmunoglobulin-HRP(Dako P0399) for 1 h at RT.

[0609] Results

[0610] MBH can reduce activation of the complement system, illustrated as inhibition of TCC deposition (figure 11). Moreover, since DAF demonstrates a species-specific activity, orthologous CCPs can be used to generate regulators for different animal species. As shown in figure 12, mouse MBDAF is a potent inhibitor of C3 deposition in mouse serum, while human MBDAF remains ineffective. In human serum, mouse MBDAF is capable of inhibiting C3 deposition, but to a lesser extent than human MBDAF.

[0611] Conclusion

[0612] Different CCPs can be fused to MBL to provide alternative modes of action by regulating different steps of the complement cascade, or to control complement activation in different animal species.

[0613] Example 9: Testing different fragments of the pattern recognition molecule (PRM) MBL and the complement control protein (CCP) DAF.

[0614] Aim of study

[0615] To validate that the concept of the invention is applicable using fragments of a PRM or CCPs instead of full-length proteins.

[0616] Materials and methods MaxiSorp microtiter 96-well plates were coated with mannan, and serial dilutions of MBDAF (SEQ ID NO: 1), DAF2-4(SEQ ID NO: 42) + MBL (SEQ ID NO: 3) (MBDAFfr0mt; SEQ ID NO: 46), DAF2 4(SEQ ID NO: 42) + MBL without collagen-like region (SEQ ID NO: 44) (MBLfr9mt_DAFfr9mt; SEQ ID NO: 47), MBLfr9mt_DAFfrsmtwithout a linker (MBLfr9mt_DAFfr9mt_NL; SEQ ID NO: 48), and Eculizumab mixed with 2 (figure 13 A) or 10% (figure 13 B) human serum were incubated for 45 min at 37 °C. Detection of TCC was measured as described in example 5.

[0617] Results

[0618] MBDAFfrgmtwas the most potent regulator of complement activation, while MBLfr9mt_DAFfrsmtand MBLfr9mt_DAFfrsmt_NL were as effective as the original MBDAF molecule (figure 13). Moreover, a fusion protein without a linker showed a comparable activity to MBDAF.

[0619] Conclusion

[0620] Different CCPs can be fused to full-length MBL or a fragment of MBL lacking the collagen-like region to generate fusion proteins of various sizes, functionality, and regulatory potencies. Moreover, a linker between CCP and PRM is not required to generate functional fusion proteins to regulate the complement system.

[0621] Example 10: Testing different pattern recognition molecules (PRMs) using ficolin-3 as a PRM in the fusion protein ficolin-3:DAF (FCN-3:DAF)

[0622] Aim of study

[0623] To validate that the concept of the invention is applicable using different PRMs.

[0624] Materials and methods

[0625] MaxiSorp microtiter 96-well plates were coated with acetylated bovine serum albumin, and serial dilutions of DAF + ficolin-3 (FCN-3:DAF; SEQ ID NO: 49) mixed with 2% human serum were incubated for 30-45 min at 37 °C. Detection of C3 and TCC was measured as described in examples 4 and 5.

[0626] Results

[0627] The results demonstrate that FCN-3:DAF is an effective regulator of complement activation (Figure 14).

[0628] Conclusion

[0629] FCN-3:DAF is an effective regulator of complement activation, confirming that different PRMs can be used to target the fusion proteins to different ligands or surfaces. ITEMS

[0630] 1 . A fusion protein comprising a pattern recognition molecule (PRM) or a fragment thereof and a complement control protein (CCP) or a fragment thereof.

[0631] 2. A fusion protein according to item 1 , wherein the fusion protein further comprises a linker.

[0632] 3. A fusion protein according to item 2, wherein the linker is a hydrophilic linker.

[0633] 4. A fusion protein according to any one of items 2-3, wherein the linker is flexible.

[0634] 5. A fusion protein according to any one of items 2-4, wherein the linker does not generate a secondary structure.

[0635] 6. A fusion protein according to any one of items 2-5, wherein the linker does not interfere with the folding of either the Pattern Recognition Molecule or fragment thereof or the Complement Control Protein or fragment thereof.

[0636] 7. A fusion protein according to any one of items 2-6, wherein the linker consists of serine and glycine residues.

[0637] 8. A fusion protein according to any one of items 2-7, wherein the linker is a (G4S1)n-linker, wherein n is a number selected from the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0638] 9. A fusion protein according to any one of items 2-8, wherein the linker is a (GsS^n-linker, wherein n is as one of the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0639] 10. A fusion protein according to any one of items 2-9, wherein the linker is a (G2S1)n-linker, wherein n is as one of the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0640] 11 . A fusion protein according to any one of items 2-10, wherein the linker is a (G^ n-linker, wherein n is as one of the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0641] 12. A fusion protein according to any one of items 2-11 , wherein the linker is selected from

[0642] GGGGS (SEQ ID NO: 34), GGGGSGGGGS (SEQ ID NO: 35) and GGGGSGGGGSGGGGS (SEQ ID NO: 36).

[0643] 13. A fusion protein according to any one of items 2-12, wherein the linker is selected as GGGGSGGGGSGGGGS (SEQ ID NO: 36).

[0644] 14. A fusion protein according to any one of items 2-13, wherein the linker consists of glycine residues.

[0645] 15. A fusion protein according to any of the preceding items, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Collectins, Ficolins, Pentraxins and C1q, or fragments thereof.

[0646] 16. A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Collectins, Ficolins, Pentraxins and C1q, or fragments thereof.

[0647] 17. A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Collectins, Ficolins and Pentraxins, or fragments thereof. 18. A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Collectins, Ficolins and C1q, or fragments thereof.

[0648] 19. A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Collectins, Pentraxins and C1q, or fragments thereof.

[0649] 20. A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Ficolins, Pentraxins and C1q, or fragments thereof.

[0650] 21 . A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Collectins and Ficolins, or fragments thereof.

[0651] 22. A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Collectins and Pentraxins, or fragments thereof.

[0652] 23. A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Collectins and C1q, or fragments thereof.

[0653] 24. A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Ficolins and Pentraxins, or fragments thereof.

[0654] 25. A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Ficolins and C1 q, or fragments thereof.

[0655] 26. A fusion protein according to any one of items 1-14, wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Pentraxins and C1q, or fragments thereof.

[0656] 27. A fusion protein according to any one of items 1-19 and 21-23, wherein the pattern recognition molecule (PRM) or a fragment thereof is a Collectin or a fragment thereof.

[0657] 28. A fusion protein according to item 27, wherein the Collectin or a fragment thereof is selected from the group consisting of mannose-binding lectin (MBL / mannan-binding lectin), Collectin 10 (CL10 / CL-L1), Collectin 11 (CL-11 / CL-K1), CL-12 (CL12 / CL-P1), SP-A (surfactant protein A) and SP-D (surfactant protein D), or fragments thereof.

[0658] 29. A fusion protein according to any one of items 27-28, wherein the pattern recognition molecule (PRM) or a fragment thereof is a protein encoding mannose / mannan binding lectin (MBL) according to SEQ ID NO:3, a functional homologue thereof having at least 70% identity to SEQ ID NO: 3, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 3 or a fragment thereof. 30. A fusion protein according to any one of items 1-18, 20-21 and 24-25, wherein the pattern recognition molecule (PRM) or a fragment thereof is a Ficolin or a fragment thereof.

[0659] 31 . A fusion protein according to item 30, wherein the Ficolin or a fragment thereof is selected from the group consisting of ficolin-1 (FCN-1 / M-ficolin), ficolin-2 (FCN-2 / L-ficolin) and ficolin-3 (FCN3 / H-ficolin), or fragments thereof.

[0660] 32. A fusion protein according any one of items 30-31 , wherein the Ficolin or a fragment thereof is selected as Ficolin 3 or a fragment thereof

[0661] 33. A fusion protein according to any one of items 1-17, 19-20, 22, 24 and 26, wherein the pattern recognition molecule or a fragment thereof is a pentraxin or a fragment thereof.

[0662] 34. A fusion protein according to item 33, wherein the pentraxin or a fragment thereof is selected from the group consisting of CRP, SAP, PTX3, GPR144, nervous system pentraxins: NPTXI, NPTXII and NPTXR or fragments thereof.

[0663] 35. A fusion protein according to any one of items 33-34, wherein the pentraxin or a fragment thereof is selected from the group consisting of CRP, SAP and PTX3, or fragments thereof.

[0664] 36. A fusion protein according to any one of items 1-16, 18-20, 23 and 25-26, wherein the pattern recognition molecule (PRM) or a fragment thereof is C1q or a fragment thereof.

[0665] 37. A fusion protein according to any one of items 36, wherein the C1q or a fragment thereof is selected from the group consisting of C1q, C1qA, C1qB and C1qC, or fragments thereof.

[0666] 38. A fusion protein according to anyone of the preceding items comprising a Pattern recognition molecule (PRM) fragment containing one or more sections of a Pattern recognition molecule (PRM) corresponding to at least 30%, such as at least 35%, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 98% of the pattern recognition molecule (PRM) protein sequence.

[0667] 39. A fusion protein according to any one of the preceding items comprising a pattern recognition molecule (PRM) fragment containing the pattern recognition motif(s) responsible for recognition of polysaccharides, oligosaccharides, carbohydrates, acetylated ligands and / or lipids in the pattern recognition molecule (PRM).

[0668] 40. A fusion protein according to any one of the preceding items comprising a pattern recognition molecule (PRM) fragment containing the motif(s) responsible for interaction with the complement system in the pattern recognition molecule (PRM).

[0669] 41 . A fusion protein according to any one of the preceding items, comprising a pattern recognition molecule (PRM) fragment containing a. the motif(s) responsible for pattern recognition molecule (PRM) interaction with the complement system, and b. the pattern recognition motif(s) responsible for pattern recognition molecule (PRM) recognition of polysaccharides, oligosaccharides, carbohydrates, acetylated ligands and / or lipids.

[0670] 42. A fusion protein according to any one of the preceding items, comprising a Complement Control Protein (CCP) or a fragment thereof selected from the group consisting of Decay Accelerating Factor (DAF / CD55), Membrane Cofactor Protein (MCP / CD46), Protectin (CD59), Complement Receptor type 1 (CR1 / CD35 / Complement C3b / C4b receptor), Complement Regulator of the Immunoglobulin Superfamily (CRIg), Factor H, C4-Binding Protein (C4bp), Complement Receptor 2 (CR2 / CD21), a DAF-CD59 fusion protein, a MCP- DAF fusion protein, a solubilized DAF (sDAF) fragment, a solubilized MCP (sMCP) fragment, a solubilized CD59 (sCD59) fragment, solubilized Complement Receptor type 1 (sCR1) fragment, a soluble Complement Receptor type 2 (sCR2) fragment, a solubilized CRIg (sCRIg) fragment, a DAF-CD59 fusion, a MCP-DAF fusion protein and a solubilized MCP-DAF fusion protein (sMCP-DAF), or fragments thereof.

[0671] 43. A fusion protein according to any one of the preceding items, wherein the Complement Control Protein (CCP) or a fragment thereof is selected from the group consisting of Membrane Cofactor Protein (MCP / CD46), Decay Accelerating Factor (DAF / CD55), Protectin (CD59), Complement Receptor type 1 (CR1 / CD35 / Complement C3b / C4b receptor), Complement Regulator of the Immunoglobulin Superfamily (CRIg), Factor H, C4-Binding Protein (C4bp), and CR2, or fragments thereof.

[0672] 44. A fusion protein according to any one of the preceding items, wherein the Complement Control Protein (CCP) or a fragment thereof is selected from the group consisting of Membrane Cofactor Protein (MCP / CD46), Decay Accelerating Factor (DAF / CD55), Protectin (CD59), Complement Receptor type 1 (CR1 / CD35 / Complement C3b / C4b receptor), or Complement Regulator of the Immunoglobulin Superfamily (CRIg), and complement receptor 2 (CR2 / CD21), or fragments thereof.

[0673] 45. A fusion protein according to any one of the preceding items, wherein the Complement Control Protein (CCP) or a fragment thereof is selected from the group consisting of CD46, DAF, CD35, and FH, or fragments thereof.

[0674] 46. A fusion protein according to any one of the preceding items, wherein the complement control protein (CCP) or a fragment thereof is CD46 or a fragment thereof.

[0675] 47. A fusion protein according to any one of the preceding items, wherein the complement control protein (CCP) or a fragment thereof is CD35 or a fragment thereof.

[0676] 48. A fusion protein according to any one of the preceding items, wherein the complement control protein (CCP) or a fragment thereof is FH or a fragment thereof.

[0677] 49. A fusion protein according to any one of the preceding items, wherein the complement control protein (CCP) or a fragment thereof is Decay Accelerating Factor (DAF / CD55) or a fragment thereof.

[0678] 50. A fusion protein according to any one of the preceding items comprising a membrane associated Complement Control Protein (CCP) or a fragment thereof.

[0679] 51 . A fusion protein according to item 50, wherein the membrane associated Complement Control Protein (CCP) or a fragment thereof is selected from the group consisting of Decay Accelerating Factor (DAF / CD55), Membrane Cofactor Protein (MCP / CD46), Protectin (CD59), Complement Receptor type 1 (CR1 / CD35 / Complement C3b / C4b receptor), Complement Regulator of the Immunoglobulin Superfamily (CRIg) and Complement Receptor 2 (CR2 / CD21), or fragments thereof.

[0680] 52. A fusion protein according to any one of the preceding items comprising a circulating Complement Control Protein (CCP) or a fragment thereof.

[0681] 53. A fusion protein according to item 52, wherein the circulating Complement Control Protein (CCP) or a fragment thereof is selected from the group consisting of Factor H and C4- Binding Protein (C4bp), or fragments thereof.

[0682] 54. A fusion protein according to any one of the preceding items comprising a Complement Control Protein (CCP) fragment containing one or more sections of a Complement Control Protein (CCP) corresponding to at least 30%, such as at least 35%, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 98% of the Complement Control Protein (CCP) protein sequence.

[0683] 55. A fusion protein according to any one of the preceding items comprising a Complement Control Protein (CCP) fragment containing the motif(s) responsible for regulation, control and / or interaction with the complement system.

[0684] 56. A fusion protein according to any of the preceding items comprising a solubilized fragment of a membrane associated Complement Control Protein (CPP).

[0685] 57. A fusion protein according to item 56, wherein at least one transmembrane domain has been deleted from a membrane associated Complement Control Protein (CCP).

[0686] 58. A fusion protein according to any one of items 56-57, wherein the solubilized Complement Control Protein (CCP) fragment is selected from the group consisting of a solubilized DAF (sDAF) fragment, a solubilized MCP (sMCP) fragment, a solubilized CD59 (sCD59) fragment, a solubilized CR1 (sCR1) fragment, a solubilized Complement Receptor 2 (CR2 / CD21) fragment, and a solubilized CRIg (sCRIg) fragment.

[0687] 59. A fusion protein according to item 58, wherein the solubilized Complement Control Protein (CCP) fragment is a solubilized Decay Accelerating Factor (DAF / CD55) fragment.

[0688] 60. A fusion protein according to any one of the preceding items comprising a solubilized Decay Accelerating Factor (DAF / CD55) fragment as defined according to SEQ ID NO: 31 or a functional homologue thereof having at least 70% identity to SEQ ID NO: 31 , such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 31 .

[0689] 61 . A fusion protein according to any one of the preceding items, wherein the pattern recognition molecule (PRM) is mannose / mannan binding lectin (MBL) and the Complement Control Protein (CCP) is Decay Accelerating Factor (DAF / CD55).

[0690] 62. A fusion protein according to any one of the preceding items, wherein the pattern recognition molecule (PRM) is mannose / mannan binding lectin (MBL) and the Complement Control Protein (CCP) is a solubilized Decay Accelerating Factor (DAF / CD55) fragment.

[0691] 63. A fusion protein according to item 62, wherein; a. The fusion protein is encoded by SEQ ID NOs: 1 or 2 , or b. The fusion protein is a functional homologue thereof having at least 70% identity to SEQ ID NOs: 1 or 2, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 1 or 2.

[0692] 64. A fusion protein according to any one of the preceding items, wherein the pattern recognition molecule (PRM) is C1q and the Complement Control Protein (CCP) is Decay Accelerating Factor (DAF / CD55).

[0693] 65. A fusion protein according to any one of the preceding items, wherein the pattern recognition molecule (PRM) is C1q and the Complement Control Protein (CCP) is a solubilized Decay Accelerating Factor (DAF / CD55) fragment.

[0694] 66. A fusion protein according to any one of the preceding items, wherein the pattern recognition molecule (PRM) is C1q and the Complement Control Protein (CCP) is Decay Accelerating Factor (DAF / CD55).

[0695] 67. A fusion protein according to any one of the preceding items, wherein the pattern recognition molecule (PRM) is C1q and the Complement Control Protein (CCP) is a solubilized Decay Accelerating Factor (DAF / CD55) fragment.

[0696] 68. A fusion protein according to any one of the preceding items, wherein the pattern recognition molecule (PRM) is Ficolin-3 and the Complement Control Protein (CCP) is Decay Accelerating Factor (DAF / CD55).

[0697] 69. A fusion protein according to any one of the preceding items, wherein the pattern recognition molecule (PRM) is Ficolin-3 and the Complement Control Protein (CCP) is a solubilized Decay Accelerating Factor (DAF / CD55) fragment.

[0698] 70. A nucleic acid sequence encoding a fusion protein according to any one of the preceding items.

[0699] 71 . A nucleic acid construct comprising a nucleic acid sequence encoding a fusion protein according to any one of the preceding items.

[0700] 72. A nucleic acid construct according to item 71 comprising a nucleic acid sequence operably linked to one or more control sequences.

[0701] 73. A host cell comprising a nucleic acid sequence or nucleic acid construct according to items 70-72.

[0702] 74. A host cell according to item 73, wherein said host cell expresses a fusion protein encoded by a nucleic acid sequence or nucleic acid construct according to items 70-72.

[0703] 75. A method for producing a fusion protein, the method comprising culturing the host cell according to any one of items 73-74, and recovering the fusion protein.

[0704] 76. A composition comprising a fusion protein according to any of items 1-69, a nucleic acid sequence or nucleic acid construct according to items 70-72, a host cell according to items 73-74, a fusion protein expressed by the host cell of item 74, or a fusion protein produced by the method of item 75. 77. A pharmaceutical composition comprising a fusion protein according to any of items 1-69, a nucleic acid sequence or nucleic acid construct according to items 70-72, a host cell according to items 73-74, a fusion protein expressed by the host cell of item 74, or a fusion protein produced by the method of item 75.

[0705] 78. A composition comprising a fusion protein according to any of items 1-69, a fusion protein expressed by the host cell of item 74 or a fusion protein produced by the method of item 75.

[0706] 79. A pharmaceutical composition comprising a fusion protein according to any of items 1-69, a fusion protein expressed by the host cell of item 74 or a fusion protein produced by the method of item 75.

[0707] 80. The composition according to any one of items 76-79 for use as a medicament.

[0708] 81 . The composition according to any one of items 76-79 for use in targeted modulation of the complement system.

[0709] 82. The composition according to any one of items 76-79 for use in controlling, inhibiting or inactivating the complement system.

[0710] 83. The composition according to any one of items 76-79 for use in modulation of the complement system with enhanced avidity and enhanced modulatory potency.

[0711] 84. The composition according to any one of items 76-79 for use in low immunogenicity modulation of the complement system.

[0712] 85. The composition according to any one of items 76-79 for use in immunogenicity-free modulation of the complement system.

[0713] 86. The composition according to any one of items 76-79 for use in controlling, inhibiting, inactivating, limiting, preventing, mitigating, alleviating, ameliorating, or treating complement system overactivation.

[0714] 87. The composition according to any one of items 76-79 for use in targeted modulation of the lectin pathway complement system.

[0715] 88. The composition according to any one of items 76-79 for use in controlling, inhibiting or inactivating the lectin pathway of the complement system.

[0716] 89. The composition according to any one of items 76-79 for use in modulation of the lectin pathway of the complement system with enhanced avidity and enhanced modulatory potency.

[0717] 90. The composition according to any one of items 76-79 for use in low immunogenicity modulation of lectin pathway of the complement system.

[0718] 91 . The composition according to any one of items 76-79 for use in immunogenicity-free modulation of the lectin pathway of the complement system.

[0719] 92. The composition according to any one of items 76-79 for use in controlling, inhibiting, inactivating, limiting, preventing, mitigating, alleviating, ameliorating, or treating complement system overactivation by targeted modulation of the lectin pathway. 93. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating inflammation.

[0720] 94. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating a disease or condition associated with inflammation.

[0721] 95. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating inflammation caused by complement system overactivation.

[0722] 96. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating a disease or condition associated with complement system overactivation.

[0723] 97. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating asthmatic inflammation.

[0724] 98. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating allergic inflammation.

[0725] 99. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating ischemic reperfusion injury (IRI).

[0726] 100. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating a disease or condition associated with ischemic reperfusion injury (IRI).

[0727] 101. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating renal ischemic reperfusion or intestinal ischemic reperfusion.

[0728] 102. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating inflammation caused by ischemic reperfusion injury (IRI).

[0729] 103. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating ischemic reperfusion injury (IRI) following organ transplantation.

[0730] 104. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating organ damage caused by inflammation following organ transplantation.

[0731] 105. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating organ damage caused by ischemic reperfusion injury (IRI) following organ transplantation. 106. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating membranous nephropathy (MN).

[0732] 107. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating complement activation or complement overactivation in subjects suffering from membranous nephropathy (MN).

[0733] 108. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating proteinuria.

[0734] 109. The composition according to any one of items 76-79 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating proteinuria in subjects suffering from membranous nephropathy (MN).

[0735] 110. The composition according to any one of items 76-79 for use in the treatment of conditions associated with inflammation, apoptosis, autoimmunity, coagulation, and / or thrombotic or coagulopathic related diseases.

[0736] 111. The composition according to any one of items 76-79 for use in the treatment of any inflammatory disorder selected from the group consisting of immune complex disease, organ ischemia, reperfusion injury, sepsis, septicemia, preeclampsia, HELP syndrome, disseminated bacteremia, disseminated aspergillosis, dissiminated fungal infections, myocardial ischemia, necrotizing fasciitis, rheumatoid arthritis, systemic lupus erythematosis, graft-versus-host disease, hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA), myocardial infarction, reperfusion injury, stroke, dermatomyositis, disseminated intravascular coagulation, Vascular complication and nephropathy associated with type 1 and / or type 2 diabetes, atypic haemolytic uremic syndrome, haemolytic uremic syndrome, age related macular degeneration, burn injury, complications related to organ transplantations, IgA nephropathy, membranous nephropathy and acute kidney injury.

[0737] SEQUENCE OVERVIEW

[0738] SEQ ID Nos: 31 and 41 are identical and may be used interchangeably.

Claims

CLAIMS1. A fusion protein comprising a pattern recognition molecule (PRM) or a fragment thereof and a complement control protein (CCP) or a fragment thereof.

2. The fusion protein according to claim 1 , wherein the pattern recognition molecule (PRM) or a fragment thereof is a protein encoding mannose / mannan binding lectin (MBL) according to SEQ ID NO: 3, a functional homologue thereof having at least 70% identity to SEQ ID NO: 3, or a fragment thereof.

3. The fusion protein according to claim 1 or 2, wherein the pattern recognition molecule (PRM) or a fragment thereof is a protein encoding mannose / mannan binding lectin (MBL) according to SEQ ID NO: 3, or a functional homologue thereof having at least 90% identity to SEQ ID NO: 3.

4. The fusion protein according to claim 1 , wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of the Collectins, Ficolins, Pentraxins and C1q, or fragments thereof.

5. The fusion protein according to claim 1 , wherein the pattern recognition molecule (PRM) or a fragment thereof is selected from the group consisting of Ficolins, or fragments thereof, preferably being ficolin-3, such as SEQ ID NO: 11 , or a functional homologue thereof having at least 70% identity to SEQ ID NO: 11 , or a fragment thereof, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 11 .

6. The fusion protein according to any one of the preceding claims, wherein the Complement Control Protein (CCP) fragment is a solubilized Decay Accelerating Factor (DAF / CD55) fragment.

7. The fusion protein according to any one of the preceding claims comprising a solubilized Decay Accelerating Factor (DAF / CD55) fragment as defined according to SEQ ID NO: 41 or a functional homologue thereof having at least 70% identity to SEQ ID NO: 41 , such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 41 .

8. The fusion protein according to any one of the preceding claims comprising a solubilized Decay Accelerating Factor (DAF / CD55) fragment as defined according to SEQ ID NO: 42 or a functional homologue thereof having at least 70% identity to SEQ ID NO: 42, such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to SEQ ID NO: 42.

9. The fusion protein according to claim 1 , wherein the pattern recognition molecule (PRM) is mannose / mannan binding lectin (MBL) and the Complement Control Protein (CCP) is a solubilized Decay Accelerating Factor (DAF / CD55) fragment.

10. The fusion protein according to claim 1 , wherein; a) the fusion protein is encoded by SEQ ID NOs: 1 , 2, 45, 46, 47, 48, or 49, or b) the fusion protein is a functional homologue thereof having at least 70% identity to a fusion protein according to a), such as at least 75%, 80%, 85%, 90%, 95%, 98% or 99% identity to a fusion protein according to a).11 . A nucleic acid sequence or nucleic acid construct encoding a fusion protein according to any one of the preceding claims.

12. A host cell comprising a nucleic acid sequence or nucleic acid construct according to claim 11 .

13. A method for producing a fusion protein, the method comprising• culturing the host cell according to claim 12, and• recovering the fusion protein.

14. A composition comprising a fusion protein according to any one of claims 1-10, a nucleic acid sequence or nucleic acid construct according to claim 11 , a fusion protein expressed by the host cell of claim 12, or a fusion protein produced by the method of claim 13.

15. A composition comprising a fusion protein according to any of claims 1-10, a fusion protein expressed by the host cell of claim 12 or a fusion protein produced by the method of claim 13.

16. A pharmaceutical composition comprising a fusion protein according to any of claims 1-10, a fusion protein expressed by the host cell of claim 12 or a fusion protein produced by the method of claim 13.

17. The composition according to any one of claims 14-16 for use as a medicament.

18. The composition according to any one of claims 14-16 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating inflammation or a disease or condition associated with inflammation.

19. The composition for use according to claim 18, wherein the inflammation is caused by complement system overactivation.

20. The composition for use according to claim 18, wherein the inflammation is asthmatic inflammation.21 . The composition for use according to claim 18, wherein the inflammation is allergic inflammation.

22. The composition for use according to claim 18, wherein the inflammation is caused by ischemic reperfusion injury (IRI).

23. The composition according to any one of claims 14-16 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating ischemic reperfusion injury (IRI) or a disease or condition associated with ischemic reperfusion injury (IRI).

24. The composition for use according to claim 23, wherein the ischemic reperfusion injury (IRI) is renal ischemic reperfusion or intestinal ischemic reperfusion.

25. The composition for use according to claim 23, wherein the ischemic reperfusion injury (IRI) is ischemic reperfusion injury (IRI) following organ transplantation.

26. The composition according to any one of claims 14-16 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating organ damage caused by inflammation following organ transplantation.

27. The composition for use according to claim 26, wherein the wherein the organ damage is caused by ischemic reperfusion injury (IRI) following organ transplantation.

28. The composition according to any one of claims 14-16 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating membranous nephropathy (MN).

29. The composition according to any one of claims 14-16 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating complement activation or complement overactivation in subjects suffering from membranous nephropathy (MN).

30. The composition according to any one of claims 14-16 for use in controlling, limiting, preventing, mitigating, alleviating, ameliorating, or treating proteinuria.31 . The composition for use according to claim 30, wherein the proteinuria is in subjects suffering from membranous nephropathy (MN).

32. The composition according to any one of claims 14-16 for use in the treatment of conditions associated with inflammation, apoptosis, autoimmunity, coagulation, and / or thrombotic or coagulopathic related diseases.

33. The composition according to any one of claims 14-16 for use in the treatment of any inflammatory disorder selected from the group consisting of immune complex disease, organ ischemia, reperfusion injury, sepsis, septicemia, preeclampsia, HELP syndrome, disseminated bacteremia, disseminated aspergillosis, disseminated fungal infections, myocardial ischemia, necrotizing fasciitis, rheumatoid arthritis, systemic lupus erythematosus, graft-versus-host disease, hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA), myocardial infarction, reperfusion injury, stroke, dermatomyositis, disseminated intravascular coagulation, Vascular complication and nephropathy associated with type 1 and / or type 2 diabetes, atypic haemolytic uremic syndrome, haemolytic uremic syndrome, age related macular degeneration, burn injury, complications related to organ transplantations, IgA nephropathy, membranous nephropathy and acute kidney injury.

34. The composition according to any one of claims 14-16 for use in the treatment of IgA nephropathy.

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