Bifunctional humanized anti-c5 antibodies and factor h fusion proteins and uses thereof

Abstract

This invention relates to the use of anti-C5 antibodies or their fusion proteins to inhibit complement signaling. Specifically, this invention relates to a method of treating complement-mediated diseases or conditions in an individual by exposing the individual to an anti-C5 antibody fusion protein.

Description

[0001] Statement regarding federally funded research or development

[0002] This invention was carried out with government support from the National Institutes of Health (NIH), grant numbers AI085596 and AI117410. The government holds certain rights to this invention.

[0003] Citation of relevant applications

[0004] This application claims priority to U.S. Provisional Patent Application Serial No. 62 / 837,853, filed April 24, 2019 and U.S. Provisional Patent Application Serial No. 62 / 837,833, filed April 24, 2019, under 35 USC §119(e), the entire contents of which are incorporated herein by reference. Background Technology

[0005] The complement system is part of the innate immune system, which plays a crucial role in host defense. Normally, complement activation is carefully controlled so that it does not cause autologous damage to host tissues. However, in certain cases where the regulatory mechanisms are defective (e.g., mutations in complement regulatory factor genes) or insufficient (e.g., when there is a large amount of autoantibody activation exceeding the capacity of the regulatory factors or when infection-induced complement activation occurs), severe and life-threatening autologous tissue damage can occur through an uncontrolled complement system. Many autoimmune and inflammatory diseases are known to be mediated by malfunctioning complement activation, and extensive work exists in this field to understand the pathogenesis of various complement-mediated diseases and to develop specific anti-complement inhibitors as treatments for these conditions. Activated complement also has the potential to cause significant tissue damage and destruction, and dysregulated complement activity has been found to be associated with a number of rare and common diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), rheumatoid arthritis, and age-related macular degeneration. Therefore, anticomplement therapy is a promising approach for treating these human conditions.

[0006] Complement C5 is a key protein in the terminal complement activation pathway and a precursor protein for the production of the effective pro-inflammatory mediator C5a and the membrane attack complex (MAC). C3 activation also leads to the production of the C5-cleaving enzyme complex and initiates the terminal complement activation pathway, which ends with the production of the effective pro-inflammatory mediator C5a and the membrane attack complex C5b-9, which can induce cytolysis and cell death.

[0007] Several human inflammatory and autoimmune diseases are mediated by C5a and / or MAC, and blocking C5 activation should prevent the production of C5a and MAC and has therapeutic value. Humanized mouse anti-human C5 mAb eculizumab has been used to treat two complement-mediated diseases: PNH and aHUS. However, not all PNH patients respond to eculizumab treatment, and one reason for non-response is the genetic polymorphism of human C5, which results in the loss of the epitope binding to eculizumab. Furthermore, due to the high plasma concentration of C5 and the rapid, target-mediated removal of the antibody, eculizumab must be administered to patients at high doses and frequencies.

[0008] One of the challenges in developing drugs targeting complement proteins lies in their high plasma concentrations and / or rapid turnover. For example, the plasma concentrations of C3 and C5 in humans are approximately 1 mg / mL and 80 μg / mL, respectively. This necessitates the administration of inhibitors of these proteins at high doses and / or frequencies. Indeed, in patients with PNH and aHUS, the anti-C5 mAb drug eculizumab requires maintenance doses of 900 mg and 1200 mg, respectively, administered intravenously every two weeks. Although a more durable second-generation anti-C5 mAb, rivulizumab, has been developed to reduce the injection frequency to every 8 weeks, the maintenance dose of rivulizumab has increased to 3300 mg per injection. Furthermore, neither eculizumab nor rivulizumab normalizes LDH and hemoglobin levels in approximately 50% of treated PNH patients. Breakthrough lysis is frequently observed in PNH patients receiving standard eculizumab therapy, and 20-30% of patients remain transfusion-dependent. These unmet medical needs in PNH patients are related to the fact that defects in DAF and CD59 on affected blood cells make them sensitive to C3 activation and MAC-mediated damage. Although anti-C5 mAbs, such as eculizumab and rivulizumab, can inhibit C5-mediated hemolysis, they do not prevent C3 activation on affected RBCs, and therefore C3b opsonization of RBCs still occurs, leading to the well-recognized extravascular hemolysis (EVH), a process caused by the phagocytosis of C3b-opsonized RBCs in the reticuloendothelial system. Furthermore, studies have shown that blocking complement activation on RBCs at the C5 step has its limitations in terms of efficacy, because if too much C5 convertase assembles on the cell surface, it becomes impossible to completely block C5 cleavage with mAbs having limited affinity. This could explain the breakthrough cytolysis in PNH patients treated with eculizumab and why anti-C5 mAbs fail to prevent complete hemolysis of rabbit and PNH RBCs in ex vivo assays, as both PNH and rabbit RBCs are highly sensitive to C3 complement activation via AP and can readily assemble large amounts of C5 convertases on their surfaces. Although efforts continue to target C3 activation in complement-dependent diseases, for example, through the use of recombinant short variants of C3 inhibitory cyclic peptides or factor H (FH), these molecules have very poor pharmacokinetics and require large and frequent (e.g., daily) doses.

[0009] Therefore, there is a need in the art for a durable, bifunctional complement inhibitor that can inhibit both C3 and C5 activity, thereby achieving greater efficacy in treating terminal complement-mediated lesions and providing the convenience of less frequent dosing. The present invention addresses and satisfies these and other needs. Summary of the Invention

[0010] In one embodiment, the invention includes a fusion protein comprising an antibody that specifically binds to human C5 and a fusion protein chaperone. In one embodiment, C5 is human C5. In one embodiment, the antibody is a monoclonal antibody. In one embodiment, the antibody is a humanized antibody. In one embodiment, the antibody is a chimeric antibody. In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody is an antibody fragment, including but not limited to: Fab, Fab', F(ab)2, F(ab')2, and scFv. In some embodiments, the antibody is part of a construct, for example, a fusion construct comprising an antibody and a targeting or effector portion. In some embodiments, the antibody is part of a conjugated construct, such as an antibody-drug conjugated construct.

[0011] In one aspect of the invention, the antibody fusion protein exhibits pH-dependent binding to C5. In some embodiments, the pH-dependent antibody fusion protein binds to C5 more strongly at a more neutral pH (e.g., about pH 7.4; as present in blood) than it binds at a more acidic pH (e.g., about pH 5.8; as present in endosomes). In some embodiments, the pH-dependent antibody fusion protein dissociates from C5 more rapidly at a more acidic pH (e.g., about pH 5.8; as present in endosomes) than it dissociates at a neutral pH (e.g., about pH 7.4; as present in blood).

[0012] In some embodiments, the anti-C5 antibody exhibits pH-dependent binding to C5. In some embodiments, the pH-dependent anti-C5 antibody binds to C5 more strongly at more neutral pH (e.g., about pH 7.4; as present in blood) than at more acidic pH (e.g., about pH 5.8; as present in endosomes). In some embodiments, the pH-dependent anti-C5 antibody dissociates from C5 more rapidly at more acidic pH (e.g., about pH 5.8; as present in endosomes) than at neutral pH (e.g., about pH 7.4; as present in blood).

[0013] In one embodiment, the fusion protein includes a complement control protein or a fragment thereof. In one embodiment, the complement control protein or a fragment thereof is an inhibitor of C3 convertase. In one embodiment, the C3 convertase is the alternative pathway C3 convertase C3bBb. In one embodiment, the C3 convertase is the classical pathway C3 convertase C4b2a. In one embodiment, the complement control protein or a fragment thereof is an inhibitor of complement activation steps other than C3 or C5 activation. In several embodiments, the fusion protein chaperone includes complement receptor 1 (CR1) or a fragment thereof, membrane cofactor protein (MCP) or a factor thereof, C4b binding protein (C4BP) or a fragment thereof, decay accelerator factor (DAF) or a fragment thereof, apoE (ApoE) or a fragment thereof, FH protein or a fragment thereof, human IgG4 or a fragment thereof, a linker, or any combination thereof. In one embodiment, the fragment of FH includes short concordant repeat (SCR) domains 1-5 of the FH protein. In one embodiment, the fragment of DAF is the extracellular domain of DAF. In one implementation, the fragment of CR1 is a selected SCR of the extracellular domain of CR1.

[0014] In one embodiment, the fusion protein includes a fusion protein chaperone that binds to an antibody. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to an antibody via at least one linker. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to an antibody without using a linker. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the C-terminus of an antibody. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the N-terminus of an antibody.

[0015] In one embodiment, the fusion protein includes a fusion protein chaperone that binds to anti-C5 mAb. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to anti-C5 mAb via at least one linker. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to anti-C5 mAb without using a linker. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the C-terminus of anti-C5 mAb. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the N-terminus of anti-C5 mAb.

[0016] In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the VH sequence of an antibody. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the VH sequence of an antibody using at least one linker. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the VH sequence of an antibody without using a linker. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the C-terminus of the VH sequence of an antibody. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the N-terminus of the VH sequence of an antibody.

[0017] In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the VL sequence of an antibody. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the VL sequence of an antibody using at least one linker. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the VL sequence of an antibody without using a linker. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the C-terminus of the VL sequence of an antibody. In one embodiment, the fusion protein includes a fusion protein chaperone that binds to the N-terminus of the VL sequence of an antibody.

[0018] In one embodiment, the antibody comprises at least one complementarity-determining region (CDR) selected from the group consisting of: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:11, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:11, or one or more variants thereof.

[0019] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:2, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:13, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:2, and a light chain containing the amino acid sequence shown in SEQ ID NO:13, or one or more variants thereof.

[0020] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:14; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:14; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0021] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:2, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:16, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:2, and a light chain containing the amino acid sequence shown in SEQ ID NO:16, or one or more variants thereof.

[0022] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:17; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:17; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0023] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:19, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:7, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:19, and a light chain containing the amino acid sequence shown in SEQ ID NO:7, or one or more variants thereof.

[0024] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:20; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:20; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0025] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:22, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:22, and a light chain containing the amino acid sequence shown in SEQ ID NO:25, or one or more variants thereof.

[0026] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:26; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:29, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:26; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:29, or one or more variants thereof.

[0027] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:28, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:31, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:28, and a light chain containing the amino acid sequence shown in SEQ ID NO:31, or one or more variants thereof.

[0028] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:34; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:34; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0029] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:36, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:7, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:36, and a light chain containing the amino acid sequence shown in SEQ ID NO:7, or one or more variants thereof.

[0030] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:37; VH-CDR2: SEQ ID NO:38; VH-CDR3: SEQ ID NO:39; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:37; VH-CDR2: SEQ ID NO:38; VH-CDR3: SEQ ID NO:39; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0031] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:41, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:41, and a light chain containing the amino acid sequence shown in SEQ ID NO:25, or one or more variants thereof.

[0032] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:42; VH-CDR2: SEQ ID NO:43; VH-CDR3: SEQ ID NO:44; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:42; VH-CDR2: SEQ ID NO:43; VH-CDR3: SEQ ID NO:44; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0033] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:46, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:46, and a light chain containing the amino acid sequence shown in SEQ ID NO:25, or one or more variants thereof.

[0034] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:47; VH-CDR2: SEQ ID NO:48; VH-CDR3: SEQ ID NO:49; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:47; VH-CDR2: SEQ ID NO:48; VH-CDR3: SEQ ID NO:49; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0035] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:51, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:51, and a light chain containing the amino acid sequence shown in SEQ ID NO:25, or one or more variants thereof.

[0036] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:52; VH-CDR2: SEQ ID NO:53; VH-CDR3: SEQ ID NO:54; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:52; VH-CDR2: SEQ ID NO:53; VH-CDR3: SEQ ID NO:54; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0037] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:56, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:56, and a light chain containing the amino acid sequence shown in SEQ ID NO:25, or one or more variants thereof.

[0038] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:47; VH-CDR2: SEQ ID NO:57; VH-CDR3: SEQ ID NO:49; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:47; VH-CDR2: SEQ ID NO:57; VH-CDR3: SEQ ID NO:49; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0039] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:59, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:59, and a light chain containing the amino acid sequence shown in SEQ ID NO:25, or one or more variants thereof.

[0040] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:72, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:74, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:72, and a light chain containing the amino acid sequence shown in SEQ ID NO:74, or one or more variants thereof.

[0041] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:37; VH-CDR2: SEQ ID NO:62; VH-CDR3: SEQ ID NO:39; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:37; VH-CDR2: SEQ ID NO:62; VH-CDR3: SEQ ID NO:39; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0042] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:76, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:74, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:76, and a light chain containing the amino acid sequence shown in SEQ ID NO:74, or one or more variants thereof.

[0043] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:42; VH-CDR2: SEQ ID NO:65; VH-CDR3: SEQ ID NO:44; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO:42; VH-CDR2: SEQ ID NO:65; VH-CDR3: SEQ ID NO:44; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0044] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:78, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:74, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:78, and a light chain containing the amino acid sequence shown in SEQ ID NO:74, or one or more variants thereof.

[0045] In one embodiment, the antibody comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO: 52; VH-CDR2: SEQ ID NO: 68; VH-CDR3: SEQ ID NO: 54; VL-CDR1: SEQ ID NO: 23; VL-CDR2: SEQ ID NO: 9; and VL-CDR3: SEQ ID NO: 10, or one or more variants thereof. In another embodiment, the antibody comprises the following CDRs: VH-CDR1: SEQ ID NO: 52; VH-CDR2: SEQ ID NO: 68; VH-CDR3: SEQ ID NO: 54; VL-CDR1: SEQ ID NO: 23; VL-CDR2: SEQ ID NO: 9; and VL-CDR3: SEQ ID NO: 10, or one or more variants thereof.

[0046] In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:80, or a variant thereof. In one embodiment, the antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:74, or a variant thereof. In one embodiment, the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:80, and a light chain containing the amino acid sequence shown in SEQ ID NO:74, or one or more variants thereof.

[0047] In one embodiment, the antibody is at least one selected from the group consisting of: mAb L3-1, L1-2, H1-4, H1-8 / L1-9, and H2-6 / L3-5. In one embodiment, the antibody is a variant of mAb H1-8 / L1-9.

[0048] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof includes a substitution of the proline residue (i.e., P4) at position #4 in VH CDR2 relative to SEQ ID NO:4. In various embodiments, the substitution at P4 is P4→F4 (i.e., P4F), P4→L4 (i.e., P4L), P4→M4 (i.e., P4M), P4→W4 (i.e., P4W), or P4→I4 (i.e., P4I).

[0049] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a substitution of a threonine residue (i.e., T9) at position #9 in VH CDR2 relative to SEQ ID NO:4. In various embodiments, the substitution at T9 is T9→H9 (i.e., T9H), T9→F9 (i.e., T9F), T9→L9 (i.e., T9L), T9→M9 (i.e., T9M), T9→W9 (i.e., T9W), or T9→I9 (i.e., T9I).

[0050] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a substitution of a proline residue (i.e., P4) at position #4 in VHCDR2 relative to SEQ ID NO:4 and a substitution of a threonine residue at position #9 (i.e., T9) in VHCDR2 relative to SEQ ID NO:4. In various embodiments, the substitution at P4 is P4→F4 (i.e., P4F), P4→L4 (i.e., P4L), P4→M4 (i.e., P4M), P4→W4 (i.e., P4W), or P4→I4 (i.e., P4I); and the substitution at T9 is T9→H9 (i.e., T9H), T9→F9 (i.e., T9F), T9→L9 (i.e., T9L), T9→M9 (i.e., T9M), T9→W9 (i.e., T9W), or T9→I9 (i.e., T9I).

[0051] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a substitution of the valine residue (i.e., V16) at position #16 in VH CDR3 relative to SEQ ID NO:5. In several embodiments, the substitution at V16 is V16→F16 (i.e., V16F), V16→E16 (i.e., V16E), or V16→W16 (i.e., V16W).

[0052] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a substitution of the leucine residue (i.e., L9) at position #9 in VH CDR1 relative to SEQ ID NO: 20. In various embodiments, the substitution at L9 is L9→W9 (i.e., L9W), L9→I9 (i.e., L9I), L9→V9 (i.e., L9V), L9→Y9 (i.e., L9Y), or L9→F9 (i.e., L9F).

[0053] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises substitutions at two or more of the following: proline 4 (i.e., P4) in VH CDR2 relative to SEQ ID NO:4; threonine 9 (i.e., T9) in VH CDR2 relative to SEQ ID NO:4; valine 16 (i.e., V16) in VH CDR3 relative to SEQ ID NO:5; and leucine 9 (i.e., L9) in VH CDR1 relative to SEQ ID NO:20. In various embodiments, substitutions are made at two or more of the following: proline 4 (i.e., P4) in VH CDR2 relative to SEQ ID NO:4; valine 16 (i.e., V16) in VH CDR3 relative to SEQ ID NO:5; and leucine 9 (i.e., L9) in VH CDR1 relative to SEQ ID NO:20. Two or more sites in leucine 9 (L9) of CDR1 contain substitutions for anti-C5 antibodies or their antigen-binding fragments, which include two or more substitutions selected from the group consisting of: L9I / P4M, L9I / P4W, L9I / P4F, L9F / P4M, L9F / P4W, L9F / P4F, L9I / P4M / V16W, L9I / P4W / V16W, L9I / P4F / V16W, L9F / P4M / V16W, L9F / P4W / V16W, L9F / P4F / V16W, L9I / P4M / V16E, L9I / P4W / V16E, L9I / P4F / V16E, L9F / P4M ... M / V16E, L9F / P4W / V16E, L9F / P4F / V16E, L9I / P4M / T9H / V16W, L9I / P4W / T 9H / V16W, L9I / P4F / T9H / V16W, L9F / P4M / T9H / V16W, L9F / P4W / T9H / V16W, L9F / P4F / T9H / V16W, L9I / P4M / T9H / V16E, L9I / P4W / T9H / V16E, L9I / P4F / T9H / V16E, L9F / P4M / T9H / V16E, L9F / P4W / T9H / V16E and L9F / P4F / T9H / V16E.

[0054] In one embodiment, the present invention relates to a method for treating a complement pathway-mediated disease or condition in an individual, comprising the step of administering an anti-C5 antibody or fusion protein to the individual. In one embodiment, the disease or condition is selected from at least the following: macular degeneration (MD), age-related macular degeneration (AMD), ischemia-reperfusion injury, arthritis, rheumatoid arthritis, asthma, allergic asthma, lupus, ulcerative colitis, stroke, postoperative systemic inflammatory syndrome, chronic obstructive pulmonary disease (COPD), PNH syndrome, myasthenia gravis, neuromyelitis optica (NMO), multiple sclerosis, delayed transplantation, antibody-mediated rejection, aHUS, central retinal vein occlusion (CRVO), central retinal artery occlusion (CRAO), bullous epidermal lysis, sepsis, organ transplantation, inflammation (including but not limited to: inflammation associated with cardiopulmonary bypass and kidney dialysis), C3 glomerulonephropathy, membranous nephropathy, IgA nephropathy, glomerulonephritis (including but not limited to: antineutrophil cytoplasmic antibody (ANCA) mediated glomerulonephritis, lupus nephritis, and combinations thereof), ANCA-mediated vasculitis, Shiga toxin-induced HUS, and antiphospholipid antibody-induced pregnancy loss, or any combination thereof. In some embodiments, the AP-mediated disease is C3 glomerulonephropathy. In some embodiments, the AP-mediated disease is macular degeneration, such as age-related macular degeneration. In one embodiment, the administration of an anti-C5 antibody or fusion protein inhibits the production of C3a or C3b proteins. In one embodiment, the administration of a fusion protein inhibits the production of C5a or C5b proteins. In one embodiment, the administration of an anti-C5 antibody or fusion protein inhibits the production of C3a or C3b proteins, or any combination thereof.

[0055] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0056] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:11, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0057] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:14; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0058] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:17; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0059] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:20; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0060] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:26; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:29, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0061] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:37; VH-CDR2: SEQ ID NO:38; VH-CDR3: SEQ ID NO:39; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0062] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:42; VH-CDR2: SEQ ID NO:43; VH-CDR3: SEQ ID NO:44; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0063] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:47; VH-CDR2: SEQ ID NO:48; VH-CDR3: SEQ ID NO:49; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0064] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:52; VH-CDR2: SEQ ID NO:53; VH-CDR3: SEQ ID NO:54; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0065] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering a fusion protein to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the fusion protein comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:47; VH-CDR2: SEQ ID NO:57; VH-CDR3: SEQ ID NO:49; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the fusion protein comprises an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0066] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering an antibody, or a fusion protein or fragment thereof, to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the antibody comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:37; VH-CDR2: SEQ ID NO:62; VH-CDR3: SEQ ID NO:39; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0067] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering an antibody, or a fusion protein or fragment thereof, to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the antibody comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO:42; VH-CDR2: SEQ ID NO:65; VH-CDR3: SEQ ID NO:44; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0068] In one embodiment, the present invention relates to a method for reducing the activity of an individual's complement system, wherein the method comprises administering an antibody, or a fusion protein or fragment thereof, to the individual via an administration route selected from: enteral administration, parenteral administration, and combinations thereof, and wherein the antibody comprises six complementation-determining regions having the following amino acid sequences: VH-CDR1: SEQ ID NO: 52; VH-CDR2: SEQ ID NO: 68; VH-CDR3: SEQ ID NO: 54; VL-CDR1: SEQ ID NO: 23; VL-CDR2: SEQ ID NO: 9; and VL-CDR3: SEQ ID NO: 10, or one or more variants thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0069] In some embodiments, the present invention comprises a fusion protein containing an anti-human C5 antibody, wherein the antibody has a heavy chain variable (VH) region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:2, or a variant thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0070] In some embodiments, the present invention is a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a light chain variable (VL) region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:7, or a variant thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0071] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:2, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:7. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0072] In some embodiments, the present invention comprises a fusion protein containing an anti-human C5 antibody, wherein the antibody has a VL region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:13, or a variant thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0073] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:2, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:13. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0074] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VL region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:16. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0075] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:2, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:16. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0076] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:19. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0077] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VL region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:7. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0078] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:19, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:7. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0079] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:22. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0080] In one embodiment, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VL region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:25. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0081] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:22, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:25. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0082] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:28. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0083] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VL region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:31. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0084] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:28, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:31. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0085] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:41. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0086] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:41, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:25. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0087] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:46. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0088] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:46, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:25. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0089] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:51. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0090] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:51, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:25. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0091] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:56. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0092] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:56, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:25. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0093] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:59. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0094] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, wherein the antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:59, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:25. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0095] In some embodiments, the present invention comprises a fusion protein containing an anti-human C5 antibody, an antibody fusion protein having inhibitory activity against human C3, or a combination thereof, wherein the antibody or antibody fusion protein has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:72, or a variant thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0096] In some embodiments, the present invention comprises a fusion protein containing an anti-human C5 antibody, an antibody fusion protein having inhibitory activity against human C3, or a combination thereof, wherein the antibody or antibody fusion protein has a VL region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:74, or a variant thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0097] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, an antibody fusion protein having inhibitory activity against human C3, or a combination thereof, wherein the antibody or antibody fusion protein has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:72, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:74. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0098] In some embodiments, the present invention comprises a fusion protein containing an anti-human C5 antibody, an antibody fusion protein having inhibitory activity against human C3, or a combination thereof, wherein the antibody or antibody fusion protein has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:76, or a variant thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0099] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, an antibody fusion protein having inhibitory activity against human C3, or a combination thereof, wherein the antibody or antibody fusion protein has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:76, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:74. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0100] In some embodiments, the present invention comprises a fusion protein containing an anti-human C5 antibody, an antibody fusion protein having inhibitory activity against human C3, or a combination thereof, wherein the antibody or antibody fusion protein has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:78, or a variant thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0101] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, an antibody fusion protein having inhibitory activity against human C3, or a combination thereof, wherein the antibody or antibody fusion protein has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:78, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:74. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0102] In some embodiments, the present invention comprises a fusion protein containing an anti-human C5 antibody, an antibody fusion protein having inhibitory activity against human C3, or a combination thereof, wherein the antibody or antibody fusion protein has a VH region having an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:80, or a variant thereof. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0103] In some embodiments, the present invention relates to a fusion protein comprising an anti-human C5 antibody, an antibody fusion protein having inhibitory activity against human C3, or a combination thereof, wherein the antibody or antibody fusion protein has a VH region and a VL region, wherein the VH region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:80, and wherein the VL region has an amino acid sequence having greater than about 90% (e.g., greater than any one of 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identity with SEQ ID NO:74. In one embodiment, the antibody is an antibody fragment selected from Fab, Fab', F(ab)2, F(ab')2, scFv, and combinations thereof.

[0104] In one embodiment, the present invention relates to cells comprising at least one of the fusion proteins described elsewhere herein. In some embodiments, the cells produce at least one of the fusion proteins described elsewhere herein. In one embodiment, the cells are hybridomas.

[0105] In one embodiment, the invention is a cell line comprising at least one of the fusion proteins described elsewhere herein. In some embodiments, the cell line produces at least one of the fusion proteins described elsewhere herein. In some embodiments, the cell line is a hybridoma cell line.

[0106] In one embodiment, the present invention relates to genetically modified non-human animals. In one embodiment, the genetically modified non-human animal expresses human C5. In one embodiment, the genetically modified non-human animal is a rodent. In one embodiment, the genetically modified non-human animal is a mouse. In one embodiment, the genetically modified non-human animal is a NOD / SCID mouse. In one embodiment, the genetically modified non-human animal is an FcRn / SCID mouse.

[0107] In one embodiment, the present invention relates to a fusion protein comprising an anti-C5 antibody moiety and FH or a functional fragment thereof. In some embodiments, the anti-C5 moiety comprises at least one histidine substitution. In one embodiment, the anti-C5 moiety comprises an IgG4 chain. In one embodiment, the IgG4 chain comprises a PLA mutation. In one embodiment, FH or a functional fragment thereof comprises domains 1-5 of the FH protein. Attached Figure Description

[0108] The above summary of the invention and the following detailed description of exemplary embodiments will be better understood when read in conjunction with the accompanying drawings. However, it should be understood that the invention is not limited to the exact embodiments and tools shown in the drawings. In the drawings:

[0109] Figure 1 The nucleotide and amino acid sequences of the humanized variable heavy chain (VH) (humanized 2G1 VH-11801) and the humanized variable light chain (VL) (humanized 2G1 VL-1901) of mAb 2G1 are shown. Humanization was achieved by CDR transplantation from murine mAb 2G1 VH to the germline-encoded human VH framework (11801) and from murine mAb 2G1 VL to the germline-encoded human VL framework (1901). The amino acid sequences of the signal peptide are underlined, and the amino acid sequences of CDR1, CDR2, and CDR3 are bolded and shaded.

[0110] Figure 2 The nucleotide and amino acid sequences of mAb L3-1, humanized VH-11801, and humanized VL-1901 with Q→H substitution in VL-CDR3 are shown.

[0111] Figure 3 The nucleotide and amino acid sequences of mAb L1-2, humanized VH-11801, and humanized VL-1901 with T→H substitution in VL-CDR1 are shown.

[0112] Figure 4 The nucleotide and amino acid sequences of mAb H1-4, humanized VH-11801, and humanized VL-1901 with I→H substitution in VH-CDR1 are shown.

[0113] Figure 5 The nucleotide and amino acid sequences of mAb H1-8 / L1-9, humanized VH-11801, and humanized VL-1901 with N→H substitution in VH-CDR1 and Y→H substitution in VL-CDR1 are shown.

[0114] Figure 6 The nucleotide and amino acid sequences of mAb H2-6 / L3-5, humanized VH-11801, and humanized VL-1901 with Y→H substitution in VH-CDR2 and E→H substitution in VL-CDR3 are shown.

[0115] Figure 7Octet traces of C5 binding and dissociation of parental humanized mAb 11801 (VH-11801(SEQ ID NO:2) and VL-1901(SEQ ID NO:7)) at pH 5.8 and pH 7.4 are shown.

[0116] Figure 8 Octet traces of C5 binding and dissociation of mAb L3-1 at pH 5.8 and pH 7.4 are shown.

[0117] Figure 9 Octet traces of C5 binding and dissociation of mAb L1-2 at pH 5.8 and pH 7.4 are shown.

[0118] Figure 10 Octet traces of C5 binding and dissociation of mAb H1-4 at pH 5.8 and pH 7.4 are shown.

[0119] Figure 11 Octet traces of C5 binding and dissociation of mAb H2-6 / L3-5 at pH 5.8 and pH 7.4 are shown.

[0120] Figure 12 Octet traces of C5 binding and dissociation of mAb H1-8 / L1-9 at pH 5.8 and pH 7.4 are shown.

[0121] Figure 13 The results of a classical complement-mediated sheep erythrocyte cytolysis assay evaluating the C5 inhibitory effects of parental humanized mAb 11801 (VH-11801(SEQ ID NO:2) and VL-1901(SEQ ID NO:7)) and its variants mAb L1-2, mAb L3-1 and mAb H2-6 / L3-5 are presented.

[0122] Figure 14 The results of a classical complement-mediated sheep erythrocyte cytolysis assay evaluating the C5 inhibitory effects of parental humanized mAb 11801 (VH-11801 (SEQ ID NO:2) and VL-1901 (SEQ ID NO:7)) and variant mAb H1-8 / L1-9 are presented.

[0123] Figure 15 The results of a classical complement-mediated sheep erythrocyte cytolysis assay evaluating the C5 inhibitory effects of parental humanized mAb 11801 (VH-11801 (SEQ ID NO:2) and VL-1901 (SEQ ID NO:7)) and variants mAb H1-4 and mAb L3-1 are presented.

[0124] Figure 16 The results of ELISA assays evaluating human C5 levels in the plasma of NOD / SCID mice genetically modified to express human C5 are shown. M1, M3, M4, and M5 represent four representative mouse strains.

[0125] Figure 17 The results show the determination of human IgG4 levels in the plasma of NOD / SCID mice genetically modified to express human C5 after injection with recombinant chimeric human IgG4 mAb H1-4, H1-8 / L1-9, H2-6 / L3-5, L3-1, or L1-2.

[0126] Figure 18 The results of a classical complement-mediated chicken erythrocyte assay evaluating the pharmacodynamics of parental humanized mAb 2G1 (VH-11801 (SEQ ID NO:2) and VL-1901 (SEQ ID NO:7)) in two NOD / SCID mice (Mo-03 and Mo-05) that were genetically modified to express human C5 are presented.

[0127] Figure 19 The results of a classical complement-mediated chicken erythrocyte assay evaluating the pharmacodynamics of recombinant chimeric human IgG4mAb L3-1, L1-2, H1-4, H1-8 / L1-9, and H2-6 / L3-5 in NOD / SCID mice genetically modified to express human C5 are presented.

[0128] Figure 20 The results show ELISA assays demonstrating improved binding of the mAb H1-8 / L1-9 ScFV variant to C5 at pH 7.4 with at least one alternative at the following positions: leucine 9 (i.e., L9) in VH CDR1 relative to SEQ ID NO:20, proline 4 (i.e., P4) in VH CDR2 relative to SEQ ID NO:4, and / or relative to SEQ ID NO:20. NO:5, valine 16 (i.e., V16) in VHCDR3 (i.e., L9→W9 (i.e., L9W), L9→I9 (i.e., L9I), L9→V9 (i.e., L9V), L9→Y9 (i.e., L9Y), L9→F9 (i.e., L9F), P4→F4 (i.e., P4F), P4→L4 (i.e., P4L), P4→M4 (i.e., P4M), P4→W4 (i.e., P4W), P4→I4 (i.e., P4I), V16→F16 (i.e., V16F), V16→E16 (i.e., V16E) and V16→W16 (i.e., V16W)). The binding of the mAb H1-8 / L1-9ScFV variant is shown in columns 3 (OD450) and 4 (OD450 confirmed), and the binding of the parent mAb H1-8 / L1-9ScFV is shown in column 8 (WT / OD450).

[0129] Figure 21 Octet assay results evaluating the relative C5 binding affinity of the mAb H1-8 / L1-9 variant as human IgG4 expression in Expi-CHO cells are shown. Expi-CHO cells were transfected with the H1-8 VH variant as indicated, and cell culture supernatants were evaluated 2 days post-transfection. For a given cell culture supernatant, the ratio of C5 binding reaction to antibody binding reaction was calculated and used as a measure of C5 binding affinity. The figure shows the ratios calculated based on two different Octet assays using transfection experiments with at least one alternative mAb H1-8 / L1-9 IgG4 variant at the following positions: leucine 9 (i.e., L9) in VH CDR1 relative to SEQ ID NO:20, proline 4 (i.e., P4) in VH CDR2 relative to SEQ ID NO:4, and / or leucine 9 (i.e., P4) in VH CDR1 relative to SEQ ID NO:5. The valine 16 (i.e., V16) in CDR3 includes L9→W9 (i.e., L9W), L9→I9 (i.e., L9I), L9→V9 (i.e., L9V), L9→Y9 (i.e., L9Y), L9→F9 (i.e., L9F), P4→F4 (i.e., P4F), P4→L4 (i.e., P4L), P4→M4 (i.e., P4M), P4→W4 (i.e., P4W), P4→I4 (i.e., P4I), V16→F16 (i.e., V16F), V16→E16 (i.e., V16E), and V16→W16 (i.e., V16W)).

[0130] Figure 22Octet assay results evaluating the dissociation rates of C5 and mAb H1-8 / L1-9 variants at pH 7.4 and pH 5.8, respectively, are shown. The percentage reduction from peak C5 binding rate for each mAb at pH 7.4 and pH 5.8 was calculated after switching from the binding phase to the dissociation phase. The figure shows the percentage reduction calculated based on two different Octet assays using transfection experiments with at least one replacement mAb H1-8 / L1-9 IgG4 variant at the following positions: leucine 9 (i.e., L9) in VH CDR1 relative to SEQ ID NO:20, proline 4 (i.e., P4) in VH CDR2 relative to SEQ ID NO:4, and / or leucine 9 (i.e., P4) in VH CDR2 relative to SEQ ID NO:5. The valine 16 (i.e., V16) in CDR3 includes L9→W9 (i.e., L9W), L9→I9 (i.e., L9I), L9→V9 (i.e., L9V), L9→Y9 (i.e., L9Y), L9→F9 (i.e., L9F), P4→F4 (i.e., P4F), P4→L4 (i.e., P4L), P4→M4 (i.e., P4M), P4→W4 (i.e., P4W), P4→I4 (i.e., P4I), V16→F16 (i.e., V16F), V16→E16 (i.e., V16E), and V16→W16 (i.e., V16W)).

[0131] Figure 23 Eighteen combined substitution variants are listed (i.e., L9I / P4M, L9I / P4W, L9I / P4F, L9F / P4M, L9F / P4W, L9F / P4F, L9I / P4M / V16W, L9I / P4W / V16W, L9I / P4F / V16W, L9F / P4M / V16W, L9F / P4W / V16W, L9F / P4F / V16W, L9I / P4M / V16E, L9I / P4W / V16E, L9I / P4F / V16E, L9F / P4M / V16E, L9F / P4W / V16E, and L9F / P4F / V16E). These combined variants are derived from seven single variants of mAb H1-8 / L1-9IgG4 (i.e., L9I, L9F, P4M, P4W, P4F, V16E, and V16W), exhibiting improved C5 binding affinity relative to the parental H1-8 / L1-9 mAb, while simultaneously maintaining differential dissociation rates at pH 7.4 and pH 5.8. Figure 21 and Figure 22 ).

[0132] Figure 24Octet assay results are shown to evaluate the relative C5 binding affinity of the mAb H1-8 / L1-9 co-alternative variant for human IgG4 expression in Expi-CHO cells. Expi-CHO cells were transfected with the H1-8VH co-alternative variant, and cell culture supernatants were evaluated 2 days post-transfection. For a given cell culture supernatant, the ratio of C5 binding reaction to antibody binding reaction was calculated and used as a measure of C5 binding affinity. The figure shows the ratios calculated based on transfection experiments using the following mAb H1-8 / L1-9 combination variants: L9I / P4M, L9I / P4W, L9I / P4F, L9F / P4M, L9F / P4W, L9F / P4F, L9I / P4M / V16W, L9I / P4W / V16W, L9I / P4F / V16W, L9F / P4M / V16W, L9F / P4W / V16W, L9F / P4F / V16W, L9I / P4M / V16E, L9I / P4W / V16E, L9I / P4F / V16E, L9F / P4M / V16E, L9F / P4W / V16E, and L9F / P4F / V16E.

[0133] Figure 25 Octet assay results evaluating the dissociation rates of C5 and mAb H1-8 / L1-9 combined substitution variants at pH 7.4 and pH 5.8 are presented. The percentage reduction of each mAb from the peak C5 binding reaction at pH 7.4 and pH 5.8 was calculated after switching from the binding to the dissociation phase. The figure shows the calculated percentage reduction in transfection experiments using the following mAb H1-8 / L1-9 IgG4 combination replacement variants: L9I / P4M, L9I / P4W, L9I / P4F, L9F / P4M, L9F / P4W, L9F / P4F, L9I / P4M / V16W, L9I / P4W / V16W, L9I / P4F / V16W, L9F / P4M / V16W, L9F / P4W / V16W, L9F / P4F / V16W, L9I / P4M / V16E, L9I / P4W / V16E, L9I / P4F / V16E, L9F / P4M / V16E, L9F / P4W / V16E, and L9F / P4F / V16E.

[0134] Figure 26 The results of the mAb 1819 affinity maturation assays evaluating the affinity of other scFv mutants, including clone 14C6, which corresponds to the T-to-H mutation at position 9 of VHCDR2, are shown. The results were obtained from the C5-binding affinity assays at pH 7.4.

[0135] Figure 27The results of differential affinity assays for C5-binding of other scFv mutants, including clone 14C6, which corresponds to the T-to-H mutation at position 9 of VHCDR2, are shown from mAb 1819 affinity maturation assays at pH 7.4 and pH 5.8.

[0136] Figure 28 The results of the mAb 1819 affinity maturation assay, based on differential binding at pH 7.4 and pH 5.8, show that clone 14C6 is the top-ranked mutant in this group. Clone 14C6 corresponds to the T-to-H mutation at position 9 of VH CDR2.

[0137] Figure 29 The nucleotide and amino acid sequences of humanized VH-11801 with N→H and L→I substitutions in VH-CDR1, P→W substitutions in VH-CDR2, and V→W substitutions in VH-CDR3 are shown; and the nucleotide and amino acid sequences of humanized VH-11801 with N→H and L→I substitutions in VH-CDR1, P→F substitutions in VH-CDR2, and V→W substitutions in VH-CDR3 are shown.

[0138] Figure 30 The nucleotide and amino acid sequences of the mAb H1-8 / L1-9 variant FME-VH (top) with N→H and L→F substitutions in VH-CDR1, P→M substitution in VH-CDR2, and V→E substitution in VH-CDR3 are shown; and the nucleotide and amino acid sequences of the mAb H1-8 / L1-9 variant FMW-VH (bottom) with N→H and L→F substitutions in VH-CDR1, P→M substitution in VH-CDR2, and V→W substitution in VH-CDR3 are shown.

[0139] Figure 31 The nucleotide and amino acid sequences of humanized VH-11801 with N→H and L→F substitutions in VH-CDR1, P→M and T→H substitutions in VH-CDR2, and V→E substitution in VH-CDR3 are shown.

[0140] Figure 32 Octet traces of C5 binding and dissociation of recombinant chimeric human IgG4 mAb H1-8 / L1-9, FMW, IFW, FME, and IWW at pH 5.8 and pH 7.4 are shown.

[0141] Figure 33 The binding of recombinant chimeric human IgG4 mAb 11801 (VH-11801 (SEQ ID NO:2)) and VL-1901 (SEQ ID NO:7), H1-8 / L1-9, FMW, IFW, FME and IWW at C5 from the peak dissociation at pH 7.4 and pH 5.8 is shown.

[0142] Figure 34 The results of a classical complement-mediated sheep erythrocyte cytolysis assay were presented to evaluate the C5 inhibitory effects of parental humanized recombinant chimeric human IgG4 mAb H1-8 / L1-9 (VH-11801(SEQ ID NO:22) and VL-1901(SEQ ID NO:25)) and its variants IFW PLA (VH-11801(SEQ ID NO:46) and VL-1901(SEQ ID NO:25), FME, PLA (SEQ ID NO:51) and VL-1901(SEQ ID NO:25)), IWW PLA (SEQ ID NO:41) and VL-1901(SEQ ID NO:25)) and FMW PLA (SEQ ID NO:56) and VL-1901(SEQ ID NO:25)).

[0143] Figure 35 Octet traces of C5 binding and dissociation of recombinant chimeric human IgG4 mAb H1-8 / L1-9, FME, FMEH, FMW, and IFW at pH 5.8 and pH 7.4 are shown.

[0144] Figure 36 The purified recombinant chimeric human IgG4 PLA (SEQ ID NO:61), mAb H1-8 / L1-9, FME, FMEH, FMW, and IFW were shown to bind at C5 from the peak dissociation at pH 5.8 and pH 7.4.

[0145] Figure 37 The results of a classical complement-mediated sheep erythrocyte cytolysis assay evaluating the C5 inhibitory effects of recombinant chimeric human IgG4 mAb FME PLA (SEQ ID NO:51 and VL-1901 (SEQ ID NO:25)), FMEH PLA (SEQ ID NO:59 and VL-1901 (SEQ ID NO:25)), FMW PLA (SEQ ID NO:56 and VL-1901 (SEQ ID NO:25)), and IFW PLA (VH-11801 (SEQ ID NO:46 and VL-1901 (SEQ ID NO:25)) are presented.

[0146] Figure 38 The nucleotide and amino acid sequences of the human IgG4-Fc domain mutation in the recombinant chimeric human IgG4 PLAmAb used for PK / PD testing in C5 humanized FcRn / SCID mice are shown.

[0147] Figure 39 Plasma C5 levels in C5 humanized mice induced by hydrodynamic injection of human C5 cDNA are shown.

[0148] Figure 40 The results show the determination of total human C5 levels in the plasma of FcRn / SCID mice genetically modified to express human C5 after injection with recombinant chimeric human IgG4 PLA (SEQ ID NO:61) mAb IFW-PLA, FMW-PLA, or FMEH-PLA.

[0149] Figure 41 The results show the determination of total IgG4 levels in the plasma of FcRn / SCID mice genetically modified to express human C5 after injection with recombinant chimeric human IgG4 PLA (SEQ ID NO:61) mAb IFW-PLA, FMW-PLA or FMEH-PLA.

[0150] Figure 42 The results of a classical complement-mediated chicken erythrocyte assay are presented to evaluate the pharmacodynamics of recombinant chimeric human IgG4 PLA (SEQ ID NO:61) mAb IFW-PLA, FMW-PLA, or FMEH-PLA in FcRn / SCID mice genetically modified to express human C5.

[0151] Figure 43 Three distinct pathways were shown that can lead to complement activation, including target recognition and proteolytic cleavage cascades. All pathways converge at the C3 activation step.

[0152] Figure 44 The structures of human FH, consisting of 20 SCR domains, and human IgG4 anti-C5mAb / FH SCR1-5 fusion protein are shown.

[0153] Figure 45 The nucleotide and amino acid sequences of the mAb H1-8 / L1-9 variant FMEH-IgG4PLA-FH1-5, with the VH sequence of humanized VH-11801 having N→H and L→F substitutions in VH-CDR1, P→M and T→H substitutions in VH-CDR2, and V→E substitution in VH-CDR3 are shown.

[0154] Figure 46 The nucleotide and amino acid sequences of the mAb H1-8 / L1-9 variant FMEH-IgG4PLA-FH1-5, a humanized VL-1901 with Y→H substitution in VL-CDR1, are shown.

[0155] Figure 47 SDS gels showing the VH and VL chains of anti-C5 mAb FMEH-IgG4PLA (lane 1) and anti-C5 mAb / FH SCR1-5 fusion protein (FMEH-IgG4PLA-FH1-5) (lane 2).

[0156] Figure 48 Octet baselines of C5 binding and dissociation of anti-C5 mAb FMEH-IgG4PLA and anti-C5 mAb / FH SCR1-5 fusion protein FMEH-IgG4PLA-FH1-5 at pH 5.8 and pH 7.4 are shown.

[0157] Figure 49 The dissociation of C5 binding from the peak values ​​of anti-C5 mAb FMEH-IgG4 and anti-C5 mAb / FH SCR1-5 fusion protein, FMEH-IgG4PLA-FH1-5, at pH 7.4 and pH 5.8 is shown.

[0158] Figure 50 The results of a complement-mediated rabbit erythrocyte cytolysis assay, which evaluated the inhibitory effects of anti-C5 mAb FMEH-IgG4PLA, anti-C5 mAb / FH SCR1-5 fusion protein, FMEH-IgG4PLA-FH1-5, and the baseline anti-C5 mAb eculizumab and revlizumab on hemolytic activity, are presented.

[0159] Figure 51 The levels of C3 fragment deposition on unlysaturated rabbit RBCs treated with FMEH-IgG4PLA, FMEH-IgG4PLA-FH1-5, eculizumab, and rivlizumab are shown.

[0160] Figure 52 The results show the determination of human IgG4 levels in plasma of C5 humanized FcRn / SCID mice at multiple time points following injections of FMEH-IgG4PLA, FMEH-IgG4PLA-FH1-5, eculizumab, and rivulizumab.

[0161] Figure 53The results of the determination of FMEH-IgG4PLA-FH1-5 levels in plasma of C5 humanized FcRn / SCID mice at multiple time points after injection were presented by using a detection mAb specific to the human IgG4 portion of the molecule.

[0162] Figure 54 The results of the determination of FMEH-IgG4PLA-FH1-5 levels in plasma of C5 humanized FcRn / SCID mice at multiple time points after injection were presented by using a detection mAb specific to the FH SCR1-5 portion of the molecule.

[0163] Figure 55 The results of ELISA assays evaluating human C5 levels in plasma from C5-humanized FcRn / SCID mice at multiple time points following injections of FMEH-IgG4PLA, FMEH-IgG4PLA-FH1-5, eculizumab, and rivulizumab are presented.

[0164] Figure 56 The results show the cytolysis of rabbit RBCs via the alternative complement pathway at multiple time points following injections of FMEH-IgG4PLA, FMEH-IgG4PLA-FH1-5, eculizumab, rivulizumab, and C5-removed human serum, using serum collected from C5 humanized FcRn / SCID mice.

[0165] Figure 57 Representative in vitro results of RBC hemolysis in PNH patients are shown (Patient #2). 2E7 RBCs from PNH patients were mixed in AP buffer with 35% HCl-acidified normal human serum in the presence of varying amounts of FMEH-IgG4PLA-FH1-5, eculizumab, or rivulizumab. The mixture was incubated at 37°C for 40 min, and hemolysis was measured at OD405. The percentage of cell lysis was calculated using the formula (OD405(specific ab concentration) - OD405(40mM EDTA)) / ((OD405(ab concentration = 0) - OD405(40mM EDTA))*100%). FMEH-IgG4PLA-FH1-5 blocked RBC cell lysis in PNH patients more effectively in vitro than eculizumab and rivulizumab. Figure 57 The comparative inhibitory activities and IC50 (mg / mL) of FMEH-IgG4PLA-FH1-5, eculizumab, rivulizumab, and control IgG4 on complement-mediated cytolysis in normal human serum (35% AB blood type) with acidified human PNH erythrocytes were shown.

[0166] Figure 58Representative FACS analysis results of C3b coatings on RBCs of PNH patients after in vitro treatment with anti-C5 mAb are shown. Following hemolysis assays (see [link to FACS analysis]). Figure 57 In vitro hemolysis of RBCs from PNH patients was performed. Unlyzed RBCs were collected and washed with DPBS. 2E6 cells were incubated on ice for 30 min with anti-C3b antibody, followed by FACS analysis. The C3b+ / CD59- cell population was gated and analyzed. Results were from PNH patient #2. ND indicates not detected. FMEH-IgG4PLA-FH1-5 effectively blocked C3b deposition on RBCs from PNH patients, while eculizumab and revlizumab did not. C3b-opsonized PNH erythrocytes were detected in samples treated with eculizumab or revlizumab instead of FMEH-IgG4PLA-FH1-5 (Q4).

[0167] Figure 59 Representative results of in vitro RBC hemolysis in PNH patients are shown (Patient #3). 5E6 PNH RBCs in AP buffer were mixed with 50% HCl-acidified normal human serum in the presence of different amounts of FMEH-IgG4PLA-FH1-5, eculizumab, or rivulizumab as specified. Hemolysis occurred at 37°C for 90 min, and hemolysis readings were taken at OD405 using a spectrometer. The percentage of lysate was calculated using the formula (OD405(specific ab concentration) - OD405(40mM EDTA)) / ((OD405(ab concentration = 0) - OD405(40mM EDTA))*100%. FMEH-IgG4PLA-FH1-5 blocked RBC lysate in PNH patients more effectively in vitro than eculizumab and rivulizumab.

[0168] Figure 60 Representative FACS analysis results of C3b coating on #3 RBCs from PNH patients after in vitro treatment with anti-C5 mAb are shown. Following a hemolysis assay in which 5E6 #3 RBCs from PNH patients were mixed with 50% HCl-acidified normal human serum and various concentrations of the specified antibody and incubated, unlysaturated RBCs were collected and washed with DPBS. 2E6 unlysaturated cells were incubated with anti-C3b antibody on ice for 30 min, followed by FACS analysis. C3b+ cell populations were gated and analyzed. ND indicates not detected. FMEH-IgG4PLA-FH1-5 blocked C3b deposition on PNH patient RBCs in a dose-dependent manner, while eculizumab and rivulizumab did not.

[0169] Figure 61The effects of the FMEH-IgG4PLA and FMEH-IgG4PLA-FH1-5 fusion proteins on complement-mediated cytolysis in cynomolgus monkeys were demonstrated. Hemolysis of rabbit erythrocytes was measured using 50% cynomolgus monkey serum in the presence of multiple concentrations of either FMEH-IgG4PLA or FMEH-IgG4PLA-FH1-5 fusion protein. Two baseline anti-human C5 mAbs (eculizumab and rivulizumab) that were unresponsive to cynomolgus C5 were used as negative controls.

[0170] Figure 62 ,include Figure 62 A and Figure 62 B shows a representative Biacore measurement of the affinity of FMEH-IgG4PLA for human FcRn at pH 6.0. Purified human FcRn was coupled to a CM5 chip (280 RU) using an amine coupling method. Biacore analysis was performed on a Biacore-3000 instrument. The chip was regenerated with pH 7.4 buffer between each binding. The kD of FMHE-IgG4PLA was determined to be 6.47 E-9M. Figure 62 A shows representative results confirming that FMEH binds to human FcRn. Figure 62 B shows a representative Biacore measurement and corresponding analysis of the affinity of FMEH-IgG4PLA for human FcRn at pH 6.0.

[0171] Figure 63 ,include Figure 63 A and Figure 63 B shows a representative Biacore measurement of the affinity of FMEH-IgG4PLA-FH1-5 for human FcRn at pH 6.0. Purified human FcRn was coupled to a CM5 chip (280 RU) using an amine coupling method. Biacore analysis was performed on a Biacore-3000 instrument. The chip was regenerated with pH 7.4 buffer between each binding. The kD of FMEH-IgG4PLA-FH1-5 was determined to be 8.88E-9M. Figure 63 A shows representative results confirming the binding of FMEH-FH1-5 to human FcRn. Figure 63 B shows representative Biacore measurements and corresponding analyses of the affinity of FMEH-IgG4PLA-FH1-5 for human FcRn at pH 6.0.

[0172] Figure 64 ,include Figure 64 A and Figure 64B shows a representative Biacore measurement of the affinity of FMEH-IgG4PLA for canine FcRn at pH 6.0. Purified canine FcRn was coupled to a CM5 chip (280 RU) using an amine coupling method. Biacore analysis was performed on a Biacore-3000 instrument. The chip was regenerated with pH 7.4 buffer between each binding. The kD of FMHE-IgG4PLA was determined to be 1.4E-8M. Figure 64 A shows representative results confirming FMEH binding to canine FcRn. Figure 64 B shows a representative Biacore measurement and corresponding analysis of the affinity of FMEH-IgG4PLA for canine FcRn at pH 6.0.

[0173] Figure 65 ,include Figure 65 A and Figure 65 B shows a representative Biacore measurement of the affinity of FMEH-IgG4PLA-FH1-5 for canine FcRn at pH 6.0. Purified canine FcRn was coupled to a CM5 chip (280 RU) using an amine coupling method. Biacore analysis was performed on a Biacore-3000 instrument. The chip was regenerated with pH 7.4 buffer between each binding. The kD of FMEH-IgG4PLA-FH1-5 was determined to be 3.91E-8M. Figure 65 A shows representative results confirming the binding of FMEH-FH1-5 to canine FcRn. Figure 65 B shows a representative Biacore measurement and corresponding results of the affinity of FMEH-IgG4PLA-FH1-5 for canine FcRn at pH 6.0.

[0174] Figure 66 Representative pharmacokinetics of FMEH-IgG4PLA-FH1-5 in C5 humanized FcRn / Scid mice (n=2) are shown, as measured using detection antibodies against either the human IgG4 Fc or FH fusion protein. In both assays, FMEH-IgG4PLA-FH1-5 in mouse plasma was captured by an anti-human κ light chain antibody, but different detection antibodies were used for either the human IgG4 portion of the molecule (left panel) or the human FH1-5 portion of the molecule (right panel). Mouse plasma samples were collected at multiple time points following injection of FMEH-IgG4PLA-FH1-5 as specified. Both assays confirmed similar pharmacokinetics, indicating that the anti-C5 mAb and FH1-5 fusion protein maintained its integrity.

[0175] Figure 67 ,include Figure 67 A to Figure 67Figure C shows representative results of the characterization of FMEH-FH1-5 by SDS-PAGE and SEC-HPLC. Characterization of FMEH-IgG4PLA-FH1-5 by SDS-PAGE and SEC-HPLC. FMEH-IgG4PLA-FH1-5 expressed from HEK293 cell transfection medium was purified using protein A affinity chromatography. Figure 67 A shows representative results from the reducing SDS-PAGE. In the reducing SDS-PAGE, the ~85 kDa and ~25 kDa bands represent the expected heavy chain-FH1-5 fusion protein and the light chain, respectively. Figure 67 B shows representative results from non-reducing SDS-PAGE. In non-reducing SDS-PAGE, bands with markers greater than 200 kDa are expected to be intact FMEH-IgG4PLA-FH1-5 molecules. Figure 67 C shows representative results from SEC-HPLC. In SEC-HPLC, FMEH-IgG4PLA-FH1-5 was eluted at 6.54 min, and it was greater than 95% pure.

[0176] Figure 68 Representative results from the mass spectrometry analysis of FMEH-IgG4PLA-FH1-5 are presented. Mass spectrometry analysis was performed on FMEH-IgG4PLA-FH1-5 purified from HEK293 transfected cell culture medium via protein A to determine its molecular weight. The molecular weights of the intact, reduced heavy chain, reduced light chain, and deglycosylated intact, reduced, and deglycosylated heavy chain, as well as the reduced and deglycosylated light chain of FMEH-IgG4PLA-FH1-5, were determined. For all samples, the experimental and theoretical molecular weights were perfectly matched. The results indicate the presence of two glycosylation modifications on FMEH-IgG4PLA-FH1-5. Considering the typical N-glycosylation site in CH2 of Fc, no glycosylation occurs in FH domains 1-5.

[0177] Figure 69 ,include Figure 69 A and Figure 69Figure B shows the representative binding affinity of FMEH-IgG4PLA-FH1-5 for human and canine C5 protein at pH 7.4 and pH 5.8. Binding affinity of FMEH-IgG4PLA-FH1-5 purified from HEK293 transfected cell culture medium was determined using the Gator (Probe Life Inc., China) biomembrane interference technique. Experiments were conducted under pH 7.4 or pH 5.8 buffer conditions to determine the effect of pH on binding kinetics. Data were analyzed using a 1:1 binding model and the Gator evaluation software (Probe Life Inc., China). FMEH-IgG4PLA-FH1-5 dissociates from the C5 binding complex approximately 10 times faster at pH 5.8 than at pH 7.4. Figure 69 A shows a graph illustrating the binding affinity of FMEH-IgG4PLA-FH1-5 to human and canine C5 protein at pH 7.4 and pH 5.8. Figure 69 B shows a tabular illustration of the binding affinity of FMEH-IgG4PLA-FH1-5 to human and canine C5 protein at pH 7.4 and pH 5.8. Detailed Implementation

[0178] This invention relates to the inhibition of complement signaling transduction using anti-C5 antibodies, fusion proteins, or combinations thereof. The invention relates in part to bifunctional complement inhibitors that can inhibit both C3 and C5 activity, thereby achieving greater efficacy and providing the convenience of less frequent dose administration in the treatment of terminal complement-mediated lesions. In some embodiments, the anti-C5 antibody, fusion protein, or combination thereof exhibits pH-dependent binding to C5. In some embodiments, the pH-dependent anti-C5 antibody or fusion protein binds to C5 more strongly at more neutral pH (e.g., about pH 7.4; such as the pH present in blood) than it binds at more acidic pH (e.g., about pH 5.8; such as the pH present in endosomes). In several embodiments, the invention relates to compositions and methods for treating complement-mediated diseases or conditions in an individual by contacting the individual with an anti-C5 antibody, fusion protein, or combination thereof. Complement-mediated lesions and conditions that can be treated with the compositions and methods described in this invention include, but are not limited to: MD, AMD, ischemia-reperfusion injury, arthritis, rheumatoid arthritis, lupus, ulcerative colitis, stroke, postoperative systemic inflammatory syndrome, asthma, allergic asthma, COPD, PNH syndrome, myasthenia gravis, NMO, multiple sclerosis, delayed transplantation, antibody-mediated rejection, aHUS, CRVO, CRAO, bullous epidermolysis bullosa, sepsis, organ transplantation, inflammation (including but not limited to: inflammation associated with cardiopulmonary bypass and renal dialysis), C3 glomerulonephropathy, membranous nephropathy, IgA nephropathy, glomerulonephritis (including but not limited to: ANCA-mediated glomerulonephritis, lupus nephritis, and combinations thereof), ANCA-mediated vasculitis, Shiga toxin-induced HUS, and antiphospholipid antibody-induced pregnancy loss, or any combination thereof.

[0179] definition

[0180] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this invention, exemplary methods and materials are described.

[0181] As used herein, each of the following terms has the meaning relating to it in this section.

[0182] The article “a” is used in this text to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an element” means one element or more.

[0183] As used herein, the term "inhibition" means a reduction, inhibition, weakening, or blocking of activity or function by at least about 10% relative to a control. In some embodiments, activity is inhibited or blocked by at least about 50% compared to a control. In some embodiments, activity is inhibited or blocked by at least about 75%. In some embodiments, activity is inhibited or blocked by at least about 95%.

[0184] The terms "effective amount" and "effective amount of a drug" refer to the amount of reagent sufficient to provide the desired biological outcome. This outcome can be a reduction and / or alleviation of the signs, symptoms, or cause of a disease or condition, or any other desired change in a biological system. Those skilled in the art can determine the appropriate effective amount in any individual case using routine laboratory methods.

[0185] The terms “patient,” “subject,” “individual,” etc., are used interchangeably herein and refer to any animal having a complement system, in some embodiments, a mammal, and in some embodiments, a human, including individuals requiring treatment for a condition or its sequelae, or individuals susceptible to a condition or its sequelae. The individuals may include, for example, dogs, cats, pigs, cattle, sheep, goats, horses, rats, monkeys, and mice, as well as humans.

[0186] When used in the context of organisms, tissues, cells, or components thereof, the term "abnormal" means that at least one observable or detectable characteristic (e.g., age, treatment, time, etc.) differs from those of organisms, tissues, cells, or components thereof that exhibit "normal" (expected / self-balancing) characteristics. A characteristic that is normal or expected for one cell or tissue type or subject may be abnormal for different cell or tissue types.

[0187] "Disease" is a health condition of a subject in which the subject is unable to maintain homeostasis, and in which the subject's health continues to deteriorate if the disease is not improved.

[0188] Conversely, a "condition" in a subject refers to a state where the subject is able to maintain homeostasis, but their health is not as good as it would be without the condition. If left untreated, the condition does not necessarily lead to a further decline in the subject's health.

[0189] The disease or condition is said to be "reduced" if the severity of the symptoms or signs of the disease or condition, the frequency with which the patient experiences such symptoms or signs, or both, are reduced.

[0190] The “effective amount” or “therapeutic effective amount” of a compound is the amount of the compound sufficient to provide a beneficial effect to a subject who is given the compound.

[0191] As used herein, “illustrating material” includes publications, records, charts, or any other medium of expression that can be used to convey the usefulness of the compounds, compositions, carriers, or delivery systems of the present invention in the kit for producing an effect that alleviates one or more of the diseases or conditions listed herein. Optionally or alternatively, the illustrating material may describe one or more methods for alleviating a disease or condition in mammalian cells or tissues. The illustrating material of the kit of the present invention may, for example, be affixed to a container containing the compounds, compositions, carriers, or delivery systems identified in the present invention, or may be shipped together with the container containing the identified compounds, compositions, carriers, or delivery systems. Alternatively, the illustrating material may be shipped separately from the container, with the aim of enabling the recipient to use the illustrating material and the compounds collaboratively.

[0192] As used herein, "operably linked" or "operably linked" can mean that gene expression is controlled by a promoter to which it is spatially linked. The promoter can be located at the 5' (upstream) or 3' (downstream) end of the gene it controls. The distance between the promoter and the gene can be approximately the same as the distance between the promoter and the gene it controls in the gene from which the promoter originates. As is known in the art, variations in this distance are acceptable without loss of promoter function.

[0193] "Therapeutic treatment" is treatment administered to a subject who exhibits symptoms of a disease or condition in order to alleviate or eliminate those symptoms.

[0194] As used in this article, “treating a disease or condition” means reducing the frequency and / or severity of the signs and / or symptoms of a disease or condition experienced by a patient.

[0195] As used herein, the phrases “biological sample,” “sample,” or “sample” are intended to include any sample containing cells, tissues, or body fluids in which nucleic acid expression or polypeptides can be detected. The biological sample may contain any biological material suitable for detecting a desired biomarker and may include cellular and / or non-cellular material derived from the individual. Examples of such biological samples include, but are not limited to, blood, lymph, bone marrow, biopsies, and smears. Samples that are essentially liquid are referred to herein as “body fluids.” Biological samples can be obtained from a patient using a variety of techniques, including (e.g., by scraping or wiping an area) or by using a needle. Methods for collecting various bodily samples are well known in the art.

[0196] As used herein, the term "antibody" refers to an immunoglobulin molecule capable of specifically binding to a specific epitope of an antigen. Antibodies can be complete immunoglobulins derived from natural or recombinant sources, and can be the immunologically active portion of a complete immunoglobulin. The antibodies described in this invention can exist in various forms, including, for example, polyclonal antibodies, monoclonal antibodies, intracellular antibodies (“intramural antibodies”), Fv, Fab, Fab', F(ab)2 and F(ab')2, as well as single-chain antibodies (scFv), heavy-chain antibodies, such as camel antibodies and humanized antibodies (Harlow et al., 1999, Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426).

[0197] As used herein, the term "synthetic antibody" refers to an antibody produced using DNA recombination techniques, such as, for example, antibodies expressed by bacteriophages. The term should also be considered as referring to an antibody produced by the synthesis of a DNA molecule encoding the antibody, and said DNA molecule expressing an antibody protein or amino acid sequence specifying the antibody, wherein said DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence techniques available and well known in the art.

[0198] As used herein, the term "heavy chain antibody" includes immunoglobulin molecules derived from camelids through peptide immunization and subsequent serum isolation, or through the cloning and expression of nucleic acid sequences encoding these antibodies. The term "heavy chain antibody" also encompasses immunoglobulin molecules isolated from subjects with heavy chain disease or prepared through the cloning and expression of the VH (variable heavy chain immunoglobulin) gene from subjects.

[0199] "Chimeric antibodies" refer to a class of engineered antibodies that contain naturally occurring variable regions (light and heavy chains) derived from donor antibodies and constant regions of light and heavy chains derived from recipient antibodies.

[0200] "Humanized antibodies" refer to a class of engineered antibodies that have a core-derived receptor (CDR) derived from a non-human donor immunoglobulin, with the remaining immunoglobulin-derived portion of the molecule derived from one (or more) human immunoglobulins. Additionally, the framework support residues can be modified to maintain binding affinity (see, for example, 1989, Queen et al., Proc. Natl. Acad Sci USA, 86:10029-10032; 1991, Hodgson et al., Bio / Technology, 9:421). Suitable human receptor antibodies can be selected from conventional databases, such as the KABAT database, the Los Alamos database, and the Swiss protein database, based on homology with the nucleotide and amino acid sequences of the donor antibody. Human antibodies characterized by homology (based on amino acids) with the framework region of the donor antibody can be adapted to provide a heavy chain constant region and / or a heavy chain variable framework region for donor CDR insertion. Suitable receptor antibodies capable of providing a light chain constant or variable framework region can be selected in a similar manner. It should be noted that the heavy and light chains of the receptor antibody do not need to be derived from the same receptor antibody. Several methods for generating these humanized antibodies have been described in the prior art (see, for example, EP-A-0239400 and EP-A-054951).

[0201] The term "donor antibody" refers to an antibody (monoclonal and / or recombinant) that provides the amino acid sequence of its variable region, CDR, or other functional fragments or analogs to the first immunoglobulin partner, thereby providing an altered immunoglobulin coding region and resulting in an antibody with the antigen specificity and neutralizing activity characteristics of the donor antibody.

[0202] The term "receptor antibody" refers to an antibody (monoclonal and / or recombinant) that is heterologous to a donor antibody and contributes the entire (or any portion, but in some embodiments, the entire) amino acid sequence encoding its heavy and / or light chain framework region and / or its heavy and / or light chain constant region to the first immunoglobulin chaperone. In some embodiments, the human antibody is a receptor antibody.

[0203] The term "fusion protein" refers to a protein resulting from the linking of two or more polypeptides derived from individual proteins. In some embodiments, fusion proteins are produced using recombinant DNA techniques (e.g., by linking nucleic acids encoding each part of the fusion protein), and fusion proteins are commonly used in biological research or therapeutics. In some embodiments, fusion proteins are produced by chemical conjugation (e.g., covalent conjugation) between the polypeptide moieties of the fusion protein, with or without a linker.

[0204] As used herein, the term “link” or “connection” refers to a connection or union of two or more components held together by a bond, link, force or binding, encompassing direct or indirect connections, such as (e.g.) directly binding a first polypeptide to a second polypeptide or material, and (e.g.) placing one or more intermediate compounds (e.g., amino acids, peptides, polypeptides, etc.) between the first polypeptide and the second polypeptide or material.

[0205] The “CDR” is defined as the complementarity-determining region amino acid sequence of an antibody, which is a hypervariable region of the heavy and light chains of an immunoglobulin. See, for example, Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., USDapartment of Health and Human Services, National Institutes of Health (1987). There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Therefore, as used herein, “CDR” refers to all three heavy chain CDRs, or all three light chain CDRs (or, if applicable, both heavy chain and light chain CDRs). The structure and protein folding of an antibody can be interpreted to include other residues as part of the antigen-binding region, and this will be understood by those skilled in the art. See, for example, Chothia et al., (1989) Conformations of immunoglobulin hypervariable regions; Nature 342, pp. 877-883.

[0206] As used herein, “immunoassay” refers to any binding assay that uses an antibody capable of specifically binding to a target molecule to detect and quantify said target molecule.

[0207] For antibodies, the term "specific binding," as used herein, refers to antibodies that recognize and bind to a specific target molecule, but substantially do not recognize and bind to other molecules in the sample. In some cases, the term "specific binding" is used to indicate that recognition and binding depend on the presence of a specific structure on the target molecule (e.g., an antigenic determinant or epitope). If, for example, an antibody specifically binds to epitope "A," then in a reaction containing labeled "A" and the antibody, the presence of an unlabeled molecule containing epitope A (or free unlabeled A) will reduce the amount of labeled A bound to the antibody.

[0208] The “coding region” of a gene includes nucleotide residues in the coding strand of the gene and nucleotides in the non-coding strand of the gene, which are homologous to or complementary to the coding region of the mRNA molecule produced by transcription of the gene.

[0209] The “coding region” of the mRNA molecule also includes nucleotide residues of the mRNA molecule that match the anticodon region of the transfer RNA molecule during translation of the mRNA molecule or that encode a stop codon. Therefore, the coding region may include nucleotide residues containing codons for amino acid residues not present in the mature protein encoded by the mRNA molecule (e.g., amino acid residues in the protein output signal sequence).

[0210] "Differentially reduced expression" or "downregulation" means that the level of a biomarker product is at least 10% or more lower than that of a control, for example, 20%, 30%, 40%, or 50%, 60%, 70%, 80%, 90% or less, and / or 2.0-fold, 1.8-fold, 1.6-fold, 1.4-fold, 1.2-fold, 1.1-fold or less, and any and all of these increments.

[0211] "Differentially increased expression" or "upregulation" means that the level of a biomarker product is at least 10% or more higher than that of a control, for example, 20%, 30%, 40%, or 50%, 60%, 70%, 80%, 90% or more, and / or 1.1-fold, 1.2-fold, 1.4-fold, 1.6-fold, 1.8-fold, 2.0-fold or more, and any and all of these increments.

[0212] As used herein, "complementary" for nucleic acids refers to the broad concept of sequence complementarity between regions of two nucleic acid strands or between two regions of the same nucleic acid strand. It is known that adenine residues in a first nucleic acid region can form specific hydrogen bonds ("base pairing") with residues in a second nucleic acid region (if the residues are thymine or uracil) that are antiparallel to the first region. Similarly, it is known that cytosine residues in a first nucleic acid strand can pair with bases of residues in a second nucleic acid strand (if the residues are guanine) that are antiparallel to the first strand. If, when the two regions are arranged in an antiparallel manner, at least one nucleotide residue in the first region is capable of pairing with a base of a residue in the second region, then the first region of the nucleic acid is complementary to the second region having the same or different nucleic acids. In some embodiments, the first region comprises a first portion, and the second region comprises a second portion, wherein, when the first and second portions are arranged in an antiparallel manner, at least about 50%, and / or at least about 75%, or at least about 90%, or at least about 95% of the nucleotide residues in the first portion are capable of pairing with nucleotide bases in the second portion. In some embodiments, all nucleotide residues in the first portion are capable of pairing with nucleotide bases in the second portion.

[0213] As used in this article, the term "DNA" is defined as deoxyribonucleic acid.

[0214] "Encoding" refers to the inherent property of a specific nucleotide sequence in a polynucleotide, such as a gene, cDNA, or mRNA, as a template for the synthesis of other polymers and macromolecules having a defined nucleotide sequence (i.e., rRNA, tRNA, and mRNA) or a defined amino acid sequence and the biological properties derived therefrom in biological processes. Therefore, if the transcription and translation of mRNA corresponding to a gene produces a protein in a cell or other biological system, then the gene encodes that protein. Both the coding strand, whose nucleotide sequence is identical to the mRNA sequence and is typically provided in the sequence listing, and the non-coding strand, which serves as a template for the transcription of the gene or cDNA, can be referred to as the protein or other product encoding that gene or cDNA.

[0215] Unless otherwise stated, "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate forms of each other and encode the same amino acid sequence. A nucleotide sequence encoding a protein or RNA phrase may also include introns, so that in some forms, the nucleotide sequence encoding said protein may contain introns.

[0216] "Separated" means altered or removed from its natural state. For example, nucleic acids or peptides that are naturally present in a living subject in their normal background are not "separated," but the same nucleic acids or peptides that are partially or completely separated from the material coexisting with their natural background are "separated." Separated nucleic acids or proteins may be in a substantially purified form or may exist in a non-natural environment, such as (e.g.) host cells.

[0217] As used herein, the term "hybridoma" refers to a cell resulting from the fusion of B lymphocytes and a fusion partner, such as myeloma cells. Hybridomas can be cloned and maintained indefinitely in cell culture and are capable of producing monoclonal antibodies. Hybridomas can also be considered hybrid cells.

[0218] "Isolated nucleic acid" refers to a segment or fragment of nucleic acid that has been separated from the sequence flanked to it in its naturally occurring state, i.e., a DNA fragment that has been removed from the sequence normally adjacent to said fragment (i.e., the sequence adjacent to said fragment in its naturally occurring genome). The term also applies to nucleic acids that have been purified substantially from other components naturally accompanying said nucleic acid (i.e., RNA, DNA, or proteins naturally accompanying said nucleic acid in cells). Therefore, the term includes, for example, recombinant DNA introduced into vectors, into autonomously replicating plasmids or viruses, or into the genomic DNA of prokaryotes or eukaryotes, or as a separate molecule independent of other sequences (i.e., as cDNA or a fragment of genome or cDNA produced by PCR or restriction endonuclease digestion). It also includes recombinant DNA as part of a hybrid gene encoding other polypeptide sequences.

[0219] In the context of this invention, the following abbreviations for common nucleic acid bases are used: "A" refers to adenosine, "C" refers to cytosine, "G" refers to guanine nucleoside, "T" refers to thymidine nucleoside, and "U" refers to uracil nucleoside.

[0220] As used herein, the term "polynucleotide" is defined as a nucleotide chain. Furthermore, nucleic acids are polymers of nucleotides. Therefore, as used herein, nucleic acids and polynucleotides are interchangeable. Those skilled in the art will understand that nucleic acids are polynucleotides that can be hydrolyzed into monomeric "nucleotides." These monomeric nucleotides can be hydrolyzed into nucleosides. Polynucleotides as used herein include, but are not limited to, all nucleic acid sequences obtained by any means available in the art, including, without limitation, recombination methods, i.e., cloning of nucleic acid sequences from recombinant libraries or cell genomes using conventional cloning techniques such as PCR, and synthetic methods.

[0221] As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably and refer to a compound consisting of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limitation on the maximum number of amino acids a protein or peptide sequence can contain. A polypeptide includes any peptide or protein containing two or more amino acids linked together by peptide bonds. As used herein, the term refers to both short chains and long chains, where short chains are generally referred to in the art as, for example, peptides, oligopeptides, and oligomers, and long chains are generally referred to in the art as proteins, which exist in various types. “Polypeptide” includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, mimics, fusion proteins or variants thereof, or fragments thereof. Polypeptides include natural peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0222] As used herein, the term "offspring" means offspring or progeny, and includes the offspring of mammals, as well as differentiated or undifferentiated progeny cells derived from the mother cell. In one usage, the term "offspring" refers to a progeny cell that is genetically identical to its parent. In another usage, the term "offspring" refers to a progeny cell that is genetically and phenotypically identical to its parent. In yet another usage, the term "offspring" refers to a progeny cell that differentiates from a parent cell.

[0223] As used in this article, the term "RNA" is defined as ribonucleic acid.

[0224] As used in this article, “recombinant DNA” is defined as DNA produced by linking DNA fragments from different sources.

[0225] As used in this article, the term "recombinant polypeptide" is defined as a polypeptide produced using recombinant DNA methods.

[0226] As used in this article, “combined” refers to the covalent connection of one molecule to a second molecule.

[0227] As used herein, a “variant” is a nucleic acid or peptide sequence that differs from a reference nucleic acid or peptide sequence in sequence, but retains the essential biological properties of the reference molecule. Sequence changes in nucleic acid variants may not alter the amino acid sequence of the peptide encoded by the reference nucleic acid, or may result in amino acid substitutions, additions, deletions, fusions, and truncations. Sequence changes in peptide variants are generally limited or conserved, such that the sequences of the reference peptide and the variant are very similar overall and identical in several regions. Variants and reference peptides may differ in any combination of amino acid sequences from one or more substitutions, additions, or deletions. Variants of nucleic acids or peptides may be naturally occurring, such as allelic variants, or may be variants known not to be naturally occurring. Non-natural variants of nucleic acids and peptides can be prepared by mutagenesis techniques or by direct synthesis. In several embodiments, the variant sequence has at least 99%, at least 98%, at least 97%, at least 96%, at least 95%, at least 94%, at least 93%, at least 92%, at least 91%, at least 90%, at least 89%, at least 88%, at least 87%, at least 86%, or at least 85% identity with the reference sequence.

[0228] As used herein, the term "regulation" can refer to any method that alters substrate levels or activity. For proteins, non-limiting examples of regulation include affecting expression (including transcription and / or translation), affecting folding, affecting degradation or protein turnover, and affecting protein localization. For enzymes, non-limiting examples of regulation also include affecting enzyme activity. A "regulatory factor" is a molecule whose activity includes affecting substrate levels or activity. Regulatory factors can be direct or indirect. Regulatory factors can act to activate, inhibit, or otherwise regulate their substrates.

[0229] As used in this paper, a "scan window" refers to a segment of adjacent positions in a sequence that can be evaluated independently of any side-connected sequences. The scan window typically changes gradually along the length of the sequence to be evaluated, with each new segment being evaluated independently. The incremental change can be one or more positions.

[0230] As used in this article, "vector" can refer to a nucleic acid sequence containing an origin of replication. Vectors can be plasmids, bacteriophages, bacterial artificial chromosomes, or yeast artificial chromosomes. Vectors can be DNA or RNA vectors. Vectors can be self-replicating extrachromosomal vectors or vectors integrated into the host genome.

[0231] Scope: Throughout this disclosure, various aspects of the invention may be presented in a scope format. It should be understood that the scope format is for convenience and brevity only and should not be considered a rigid limitation on the scope of the invention. Therefore, a description of the scope should be considered to have all possible sub-scopes specifically disclosed, as well as the individual values ​​within those scopes. For example, a description of a scope such as 1 to 6 should be considered to have specifically disclosed sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and the individual values ​​within those scopes, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This is applicable regardless of the width of the scope.

[0232] describe

[0233] This invention relates to the inhibition of complement signaling transduction using an anti-C5 antibody or a fusion protein thereof. In some embodiments, the invention relates to the inhibition of complement signaling transduction using a bifunctional complement inhibitor capable of inhibiting both C3 and C5 activity. In several embodiments, the invention relates in part to a method of treating a complement-mediated disease or condition in an individual by contacting the individual with its anti-C5 antibody fusion protein.

[0234] complement inhibitors and bifunctional antibodies

[0235] This invention relates to the inhibition of complement signaling and complement-related disorders using anti-human C5 antibodies, fusion proteins, or antigen-binding fragments thereof (e.g., anti-C5 antibodies or variants or fragments thereof, anti-C5 fusion protein antibodies or variants or fragments thereof, etc.). In some embodiments, anti-C5 antibodies, fusion proteins, or combinations thereof exhibit bifunctional activity in inhibiting C5 and C3 activation. In some embodiments, anti-C5 antibodies, fusion proteins, or combinations thereof exhibit pH-dependent binding to C5.

[0236] In some embodiments, anti-C5 antibodies, fusion proteins, or combinations thereof exhibit pH-dependent binding to C5. In some embodiments, pH-dependent anti-C5 antibodies, fusion proteins, or combinations thereof bind to C5 more strongly at more neutral pH (e.g., about pH 7.4; as present in blood) than at more acidic pH (e.g., about pH 5.8; as present in endosomes). This pH-dependent binding provides longer persistence of the applied antibody or antibody fusion protein molecule because the immune complex absorbed by the cell (i.e., anti-C5 mAb bound to C5 and / or anti-C5mAb-FH fusion protein bound to C5) will dissociate in the acidic environment of the endosome, allowing the free antibody or antibody-FH fusion protein to recycle out of the cell via the neonatal Fc receptor (FcRn), where it is available for binding to new C5 molecules.

[0237] In one embodiment, the present invention relates to the inhibition of complement signaling cascades by specifically targeting fragments of complement component C3 protein or proteins C3a or C3b. In one embodiment, the present invention relates to the inhibition of complement signaling cascades by specifically targeting fragments of complement component C5 protein or proteins C5a or C5b. In one embodiment, the present invention relates to the inhibition of complement signaling cascades by specifically targeting fragments of complement component C3 protein, proteins C3a or C3b, C5 protein, fragments of proteins C5a or C5b, or any combination thereof. In one embodiment, the present invention relates to methods for treating and preventing inflammation and autoimmune diseases mediated by unwanted, uncontrolled, excessive complement activation. In one embodiment, the present invention relates to the treatment of complement-mediated diseases or complement-mediated conditions in an individual by exposing the individual to an anti-C5 antibody. In one embodiment, the present invention relates to the treatment of complement-mediated diseases or complement-mediated conditions in an individual by exposing the individual to an anti-C5 fusion protein antibody. In one embodiment, the present invention relates to the treatment of complement-mediated diseases or conditions in an individual by contacting the individual with an anti-C5 antibody or an anti-C5 fusion protein antibody.

[0238] In one embodiment, the present invention is a method for treating complement-mediated diseases or conditions in an individual, comprising the step of administering an anti-C5 antibody, a fusion protein, or a combination thereof to the individual, thereby inhibiting the production of C3a or C3b proteins and the formation of MAC. In another embodiment, the present invention is a method for treating complement-mediated diseases or conditions in an individual, comprising the step of administering an anti-C5 antibody, a fusion protein, or a combination thereof to the individual, thereby inhibiting the production of C3a or C3b proteins and the formation of MAC. In yet another embodiment, the present invention is a method for treating complement-mediated diseases or conditions in an individual, comprising the step of administering an anti-C5 antibody, a fusion protein, or a combination thereof to the individual, thereby inhibiting the production of C3a or C3b proteins, inhibiting the production of C5a or C5b proteins, and inhibiting the formation of MAC. Examples of complement-mediated lesions that can be treated using the methods described in this invention include, but are not limited to: MD, AMD, ischemia-reperfusion injury, arthritis, rheumatoid arthritis, lupus, ulcerative colitis, stroke, postoperative systemic inflammatory syndrome, asthma, allergic asthma, COPD, PNH syndrome, myasthenia gravis, NMO, multiple sclerosis, delayed transplantation, antibody-mediated rejection, aHUS, CRVO, CRAO, bullous epidermolysis bullosa, sepsis, organ transplantation, inflammation (including but not limited to: inflammation associated with cardiopulmonary bypass and renal dialysis), C3 glomerulonephropathy, membranous nephropathy, IgA nephropathy, glomerulonephritis (including but not limited to: ANCA-mediated glomerulonephritis, lupus nephritis, and combinations thereof), ANCA-mediated vasculitis, Shiga toxin-induced HUS, and antiphospholipid antibody-induced pregnancy loss, or any combination thereof. In some embodiments, the compositions and methods described herein are useful for treating subjects who do not respond adequately to treatment with eculizumab or revlizumab, including subjects with PNH. By way of non-limiting example, some subjects may have mutations in the α chain of C5 that could make them resistant to eculizumab or revlizumab treatment (see Genetic variants in C5 and poor response to eculizumab. Nishimura J, et al., N Engl J Med. 2014 Feb 13; 370(7):632-9).

[0239] The immune system's ability to distinguish between "self" and "non-self" antigens is crucial for its function as a specific defense against invasive microorganisms. "Non-self" antigens are those antigens that enter or are present on substances in the body that are detectably different from the subject's own components, or are exogenous to the subject's own components. "Self" antigens, however, are those that are undetectably different from or not exogenous to the self-components of healthy subjects. In various embodiments of the method, suppressed complement activation is complement activation triggered by at least one of microbial antigens, non-biological exogenous surfaces, altered autologous tissue, or combinations thereof. An example of a non-biological exogenous surface is blood tubing, such as blood vessels used in heart-lung bypass surgery or kidney dialysis. Examples of altered autologous tissue include apoptotic, necrotic, and ischemic-stressed tissues and cells, tissues and cells lacking functional complement regulatory proteins, or combinations thereof.

[0240] In some embodiments, the anti-C5 antibody of the present invention (e.g., anti-C5 antibody, anti-C5 fusion protein antibody, antibody fragment, antibody variant, etc.) inhibits downstream activation of the alternative complement pathway (AP), the classical pathway (CP), or the lectin pathway (LP). Typically, CP is initiated by an antigen-antibody complex, and LP is activated by the binding of lectins to sugar molecules on the surface of microorganisms. AP is constitutively active at low levels but can be rapidly amplified on the surface of bacterial, viral, and parasitic cells due to the lack of regulatory proteins. Host cells are typically protected against AP complement activation by regulatory proteins. However, in some cases, such as when the regulatory proteins are defective or absent, AP can be uncontrollably activated on host cells, leading to complement-mediated diseases or symptoms. CP consists of components C1, C2, and C4 and merges with AP in the C3 activation step. LP consists of mannose-binding lectin (MBL) and MBL-associated serine protease (MASP) and shares components C4 and C2 with CP. Complement activation (AP) consists of component C3 and several factors, such as factor B, factor D, propertin, C5, and the fluid phase regulator FH. Complement activation comprises three phases: (a) recognition, (b) enzymatic activation, and (c) membrane attack, leading to cell death. The first phase of CP complement activation begins at C1. C1 consists of three distinct proteins: the recognition subunit C1q, and the serine protease subfractions C1r and C1s, which are bound together in the calcium-dependent tetrameric complex C1r2s2. The intact C1 complex is essential for the physiological activation of C1. Activation occurs when the intact C1 complex binds to an immunoglobulin complexed with an antigen. This binding activates C1s, which then cleaves both C4 and C2 proteins to produce C4a and C4b, and C2a and C2b. The C4b and C2a fragments merge to form the C3 convertase C4b2a, which in turn cleaves C3 to form C3a and C3b. LP activation is initiated by MBL binding to certain sugars on the target surface, which in turn triggers MASP activation, which then cleaves C4 and C2 in a manner similar to the C1 activity of CP, resulting in the production of the C3 convertase C4b2a. Thus, CP and LP are activated through different mechanisms, but they share the same components C4 and C2, and both pathways lead to the production of the same C3 convertase C4b2a. The cleavage of C3 into C3b and C3a via C4b2a is a central event in the complement pathway for two reasons. It initiates the AP amplification loop, as surface-deposited C3b is a central intermediate of AP. Both C3a and C3b are biologically important. C3a is pro-inflammatory and, along with C5a, is known as an anaphylatoxin. C3b and its further cleavage products also bind to complement receptors present on neutrophils, eosinophils, monocytes, and macrophages, thereby facilitating the phagocytosis and clearance of C3b-opsonized particles.Ultimately, C3b can bind to C4b2a to form the C5 convertase of CP and LP to activate the terminal complement sequence, thereby leading to the production of the effective pro-inflammatory mediator C5a and the assembly of cytolytic MAC C5-C9.

[0241] In one embodiment, the complement pathway activity inhibited by the method of the present invention is complement pathway activation induced by at least one selected from lipopolysaccharide (LPS), lipooligosaccharide (LOS), pathogen-associated molecular patterns (PAMPs), and danger-associated molecular patterns (DAMPs). In another embodiment, the complement signaling activity inhibited by the method of the present invention is the production of C5a protein. In another embodiment, the complement signaling activity inhibited by the method of the present invention is the production of C5b protein. In another embodiment, the complement signaling activity inhibited by the method of the present invention is the production of C3a protein. In another embodiment, the complement signaling activity inhibited by the method of the present invention is the production of C3b protein. In several embodiments, the complement signaling activity inhibited by the method of the present invention is the production of C5a protein, C5b protein, C3a protein, C3b protein, or any combination thereof. In another embodiment, the complement signaling activity inhibited by the method of the present invention is the formation of MAC. In another embodiment, the complement pathway activity inhibited by the method of the present invention is C5-dependent. In another embodiment, the activity of the complement pathway inhibited by the method of the present invention is C3-dependent. In yet another embodiment, the activity of the complement pathway inhibited by the method of the present invention is C3-dependent, C5-dependent, or both.

[0242] In one embodiment, the present invention is a method for inhibiting the initiation of terminal complement activation in an individual, comprising the step of administering an anti-C5 antibody, a fusion protein, or a combination thereof to the individual, thereby inhibiting the initiation of terminal complement activation in the individual due to CP, LP, or AP activation. Examples of these embodiments are patients with complement-mediated hemolysis of PNH and individuals with complement-mediated aHUS, asthma, ischemia / reperfusion injury, rheumatoid arthritis, and ANCA-mediated nephropathy. In various embodiments of the invention, diseases and conditions that can be treated using the compositions and methods of the present invention include, but are not limited to: complement-mediated hemolysis, complement-mediated aHUS, C3 glomerulonephropathy, neuromyelitis optica, myasthenia gravis, asthma, ischemia / reperfusion injury, rheumatoid arthritis, and ANCA-mediated nephropathy or conditions.

[0243] In several other embodiments, this document provides methods for identifying potential anti-C5 antibodies, fusion proteins, or combinations thereof that inhibit terminal complement activation. One such method is the sheep erythrocyte cytolysis assay as described below. Briefly, at 37°C, 1 × 10⁻⁶ sheep RBCs (prepared in PBS) are... 7 One cell / sample, incubated with 50% normal human serum (NHS, from Complement Technology Inc.) in gelatin-flora buffer (GVB2+, Sigma; total assay volume: 100 μL) for 20 min. Before addition to sheep RBCs, NHS was pre-incubated with anti-C5 mAb at 4°C for 1 hour. The cytolysis reaction was terminated by adding ice-cold 40 mM EDTA in PBS. The incubation mixture was centrifuged at 1500 rpm for 5 min, and the supernatant was collected and OD405 nm was measured. Samples without NHS or with EDTA were used as negative cytolysis controls, and sheep RBC samples completely lysed with distilled water were used as positive controls (100% cytolysis). The cytolysis percentage in other samples was normalized. A separate method that can be used for confirmatory screening of anti-human C5 blocking mAbs includes the following steps: a) plating with LPS; b) washing the plate to remove unbound LPS; c) adding a solution of bovine serum albumin (BSA) in phosphate-buffered saline (PBS); d) washing the plate to remove unbound BSA; e) adding a mixture of candidate anti-C5 antibody compounds that have been pre-cultured with serum and mixed into normal human serum; f) washing the plate; g) adding HRP-conjugated anti-human C5b-9 or anti-C5b-9 antibody. h) Human C6 antibody (anti-human TCC antibody, clone aE11 or biotin-labeled anti-human C6 antibody, both from Quidel); i) washing the plate to remove unbound antibodies; j) adding HRP substrate reagent; k) adding sulfuric acid to terminate the reaction; l) measuring the optical density at 450 nm; l) comparing the optical density of the plate containing the candidate anti-C5 antibody compound with the optical densities of the positive and negative controls; wherein an anti-C5 antibody is identified when the optical density decreases compared to the positive control.

[0244] Anti-C5 antibody and anti-C5 fusion protein antibody

[0245] In some embodiments, the present invention includes a composition comprising an antibody or fusion protein that specifically inhibits C3 activation by C3 convertase. In some embodiments, the present invention includes a composition comprising an antibody or fusion protein that specifically binds to and inhibits C5 activation. In some embodiments, the present invention includes a composition comprising an antibody or fusion protein that specifically inhibits the activation of C3, C5, or both. In some embodiments, the anti-C5 antibody or fusion protein is a polyclonal antibody, a monoclonal antibody, a chimeric antibody, or a humanized antibody.

[0246] In some embodiments, the antibody or fusion protein is an antibody fragment. In some embodiments, C3 is human C3. In some embodiments, C5 is human C5. In some embodiments, the anti-C5 antibody fusion protein is an anti-C5 mAb linked to an FH fragment. In some embodiments, the anti-C5 antibody fusion protein is an anti-C5 mAb linked to an FH fragment. In some embodiments, FH is human FH. In some embodiments, the anti-C5 antibody or fusion protein exhibits pH-dependent binding to C5. In some embodiments, the pH-dependent anti-C5 antibody or fusion protein binds to C5 more strongly at more neutral pH (e.g., about pH 7.4; such as the pH present in blood) than it binds at more acidic pH (e.g., about pH 5.8; such as the pH present in endosomes).

[0247] In some embodiments, the binding of antibodies, fusion proteins, or antibody fragments to human C5 is associated with a reduction in the production of C3a or C3b in the complement activation pathway and a decrease in the formation of MAC in the intact organism.

[0248] In some embodiments, the present invention comprises a protein or polypeptide capable of inhibiting the activation of human C3. In some embodiments, the present invention comprises a protein or polypeptide capable of binding to and inhibiting the activation of human C5. In some embodiments, the present invention comprises a protein or polypeptide capable of binding to and / or inhibiting the activation of human C3, human C5, or both. In some embodiments, an antibody, fusion protein, or antibody fragment; said protein or polypeptide binding to a relevant portion or fraction or epitope of human C3 convertase; and the interaction of the antibody, fusion protein, or antibody fragment thereof, or said protein or polypeptide with the relevant portion of human C3 convertase, is associated with a reduction in the production of C3a or C3b and the formation of MAC in the intact organism. In some embodiments, an antibody, fusion protein, or antibody fragment; said protein or polypeptide binding to a relevant portion or fraction or epitope of human C5; and the binding of the antibody, fusion protein, or antibody fragment thereof, or said protein or polypeptide with the relevant portion of human C5, is associated with a reduction in the production of C5a or C5b and the formation of MAC in the intact organism.

[0249] In some embodiments, the antibody, fusion protein, or fragment thereof having inhibitory activity against human C3 convertase is further conjugated to a protein, peptide, or other compound. In some embodiments, the human C3 convertase inhibitory antibody, fusion protein, or antibody fragment thereof is conjugated to a protein, peptide, or other compound. In some embodiments, the protein, peptide, or other compound conjugated to the human C3 convertase inhibitory antibody, fusion protein, or antibody fragment thereof is a targeting moiety (i.e., the targeting moiety specifically binds to molecules other than human C3). In some embodiments, the protein, peptide, or other compound conjugated to the human C3 convertase inhibitory antibody, fusion protein, or antibody fragment thereof is an effector molecule (e.g., a cytotoxic molecule).

[0250] In some embodiments, the human C5-binding antibody, fusion protein, or C5-binding antibody fragment thereof is further conjugated to a protein, peptide, or another compound. In some embodiments, the human C5-binding antibody, fusion protein, or antibody fragment thereof is conjugated to a protein, peptide, or other compound. In some embodiments, the protein, peptide, or other compound conjugated to the human C5-binding antibody, fusion protein, or antibody fragment thereof is a targeting moiety (i.e., the targeting moiety specifically binds to molecules other than human C5). In some embodiments, the protein, peptide, or other compound conjugated to the human C5-binding antibody, fusion protein, or antibody fragment thereof is an effector molecule (e.g., a cytotoxic molecule).

[0251] In some embodiments, the human C3 convertase inhibitory antibody and the human C5 binding antibody, the fusion protein, or fragments thereof are further conjugated to a protein, peptide, or another compound. In some embodiments, the human C3 convertase inhibitory antibody and the human C5 binding antibody, the fusion protein, or fragments thereof are conjugated to a protein, peptide, or other compound. In some embodiments, the protein, peptide, or other compound conjugated to the human C3 convertase inhibitory antibody and the human C5 binding antibody, the fusion protein, or fragments thereof is a targeting moiety (i.e., the targeting moiety specifically binds to molecules other than human C3 and human C5). In some embodiments, the protein, peptide, or other compound conjugated to the human C3 convertase inhibitory antibody and the human C5 binding antibody, the fusion protein, or fragments thereof is an effector molecule (e.g., a cytotoxic molecule).

[0252] In several embodiments, the antibody is a fusion protein. In one embodiment, the fusion protein comprises a complement control protein. In one embodiment, the fusion protein comprises CR1 or a fragment thereof. In one embodiment, the fusion protein comprises MCP or a fragment thereof. In one embodiment, the fusion protein comprises C4BP or a fragment thereof. In one embodiment, the fusion protein comprises DAF or a fragment thereof. In one embodiment, the fusion protein comprises ApoE or a fragment thereof. In one embodiment, the fusion protein comprises FH protein or a fragment thereof. In one embodiment, the fusion protein comprises human IgG4 or a fragment thereof. In one embodiment, the fusion protein comprises a linker. In several embodiments, the fusion protein comprises CR1 or a fragment thereof, MCP or a fragment thereof, C4BP or a fragment thereof, DAF or a fragment thereof, ApoE or a fragment thereof, FH protein or a fragment thereof, human IgG4 or a fragment thereof, a linker, or any combination thereof.

[0253] In one embodiment, the FH fragment contains at least one SCR domain of the FH protein. In one embodiment, the FH fragment contains at least two SCR domains of the FH protein. In one embodiment, the FH fragment contains at least three SCR domains of the FH protein. In one embodiment, the FH fragment contains at least four SCR domains of the FH protein. In one embodiment, the FH fragment contains at least five SCR domains of the FH protein. In one embodiment, the FH fragment contains at least six SCR domains of the FH protein. In one embodiment, the FH fragment contains at least seven SCR domains of the FH protein. In one embodiment, the FH fragment contains at least eight SCR domains of the FH protein. In one embodiment, the FH fragment contains at least nine SCR domains of the FH protein. In one embodiment, the FH fragment contains at least ten SCR domains of the FH protein. In one embodiment, the FH fragment contains at least eleven SCR domains of the FH protein. In one embodiment, the FH fragment contains at least twelve SCR domains of the FH protein. In one embodiment, the FH fragment contains at least 13 SCR domains of the FH protein. In one embodiment, the FH fragment contains at least 14 SCR domains of the FH protein. In one embodiment, the FH fragment contains at least 15 SCR domains of the FH protein. In one embodiment, the FH fragment contains at least 16 SCR domains of the FH protein. In one embodiment, the FH fragment contains at least 17 SCR domains of the FH protein. In one embodiment, the FH fragment contains at least 18 SCR domains of the FH protein. In one embodiment, the FH fragment contains at least 19 SCR domains of the FH protein. In one embodiment, the FH fragment contains at least 20 SCR domains of the FH protein.

[0254] In one embodiment, the FH fragment includes SCR domains 1-20 of the FH protein. In one embodiment, the FH fragment includes SCR domains 1-5 of the FH protein. In one embodiment, the FH fragment includes SCR domains 2-5 of the FH protein. In one embodiment, the FH fragment includes SCR domains 3-5 of the FH protein. In one embodiment, the FH fragment includes SCR domains 4 and 5 of the FH protein. In one embodiment, the FH fragment includes SCR domain 5 of the FH protein.

[0255] In one embodiment, the fusion protein comprises an antibody and a fusion protein chaperone (e.g., FH or a functional fragment thereof). In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) bound to an antibody. In some embodiments, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused directly to (e.g., bound to) an antibody via a linker. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) bound to an antibody via at least one linker. In one embodiment, the linker is not a cleavable linker. In one embodiment, the linker is a cleavable linker. For example, in some embodiments, the cleavable linker is a chemically cleavable linker, an enzyme-cleavable linker, a peptide-based linker, or any combination thereof.

[0256] In some embodiments, the chemically cleavable adapter is an acid-cleavable adapter or a reducible adapter. In one embodiment, the acid-cleavable adapter is specifically designed to remain stable in the neutral pH of the bloodstream but undergo hydrolysis and release of cytotoxic drugs in the acidic environment of the cellular compartment. In one embodiment, the reducible adapter is designed to remain stable in the oxygen-rich environment of the bloodstream and to be selectively cleaved in the reducing environment of the cell. In another embodiment, the peptide-based adapter is designed to remain intact in systemic circulation and to be cleaved by a specific intracellular protease, such as cathepsin B. Examples of linkers include, but are not limited to: linkers containing lysosome-specific protease cleavage sites, linkers containing mixed disulfide bonds, aminoethoxyethoxyacetate (AEEA), β-glucuronide linkers, peptide linkers cleavable by intracellular proteases, such as lysosomal proteases or erythrocyte plasma proteases, dipeptide linkers (e.g., valine-citrulline or phenylalanine-lysine linkers), aminohexanoates, hydrazones, thiomaleimides, and dibenzocyclooctylene (DBCO).

[0257] In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to the antibody without a connector. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to the C-terminus of the antibody. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to the N-terminus of the antibody.

[0258] In one embodiment, the fusion protein includes a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to anti-C5 mAb. In another embodiment, the fusion protein includes a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to anti-C5 mAb via at least one linker.

[0259] In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to the anti-C5 mAb without using a linker. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to the C-terminus of the anti-C5 mAb. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to the N-terminus of the anti-C5 mAb.

[0260] In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to a variant of the antibody. For example, in one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to a variant of anti-C5 mAb. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to a variant of the antibody via at least one linker.

[0261] In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to a variant of the antibody without using a linker. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to the C-terminus of a variant of the antibody. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that binds to the N-terminus of a variant of the antibody.

[0262] In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused (e.g., bound) to an antibody fragment. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to an antibody fragment with or without a linker. For example, in one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to an anti-C5 mAb fragment. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to an antibody fragment via at least one linker.

[0263] In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that is fused to the antibody fragment without using a linker. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to the C-terminus of the antibody fragment. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to the N-terminus of the antibody fragment.

[0264] In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to the VH sequence of an antibody. For example, in one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to the VH sequence of an anti-C5 mAb. In another embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to the VH sequence of an antibody via at least one linker.

[0265] In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that is fused to the VH sequence of the antibody without using a linker. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that is fused to the C-terminus of the VH sequence of the antibody. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that is fused to the N-terminus of the VH sequence of the antibody.

[0266] In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to the VL sequence of an antibody. For example, in one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to the VL sequence of an anti-C5 mAb. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) fused to the VL sequence of an antibody via at least one linker.

[0267] In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that is fused to the VL sequence of the antibody without using a linker. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that is fused to the C-terminus of the VL sequence of the antibody. In one embodiment, the fusion protein comprises a fusion protein chaperone (e.g., FH or a functional fragment thereof) that is fused to the N-terminus of the VL sequence of the antibody.

[0268] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0269] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR1: SEQ ID NO:8, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3; and VL-CDR1: SEQ ID NO:8.

[0270] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4; and VL-CDR2: SEQ ID NO:9.

[0271] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3: SEQ ID NO:10, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; and VL-CDR3: SEQ ID NO:10.

[0272] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH ...3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0273] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0274] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0275] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3: SEQ ID NO:11, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; and VL-CDR3: SEQ ID NO:11.

[0276] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH ...3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant VL-CDR3, which represents the amino acid sequence shown in NO:11, or a variant thereof containing up to about three amino acid substitutions (such as any one of about 1, 2 or 3).

[0277] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:11.

[0278] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:11.

[0279] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:2, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:13, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb L3-1, or a variant thereof. Monoclonal anti-C5 antibody mAb L3-1 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:2, and a light chain containing the amino acid sequence shown in SEQ ID NO:13. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0280] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:14; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:14; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0281] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR1: SEQ ID NO:14, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3; and VL-CDR1: SEQ ID NO:14.

[0282] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:14, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH ...3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0283] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:14, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0284] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:14; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0285] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:2, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:16, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb L1-2, or a variant thereof. The monoclonal anti-C5 antibody mAb L1-2 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:2, and a light chain containing the amino acid sequence shown in SEQ ID NO:16. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0286] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:17; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:17; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0287] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:17, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR1: SEQ ID NO:8, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:17; and VL-CDR1: SEQ ID NO:8.

[0288] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:17, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:17 ... VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0289] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:17, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0290] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:17; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0291] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:19, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:7, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-4, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-4 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:19, and a light chain containing the amino acid sequence shown in SEQ ID NO:7. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0292] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:20; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:20; VH-CDR2: SEQ ID NO:4; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0293] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:20, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR1: SEQ ID NO:23, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:20; and VL-CDR1: SEQ ID NO:23.

[0294] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:20, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:20 ... VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0295] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:20, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0296] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:20; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:4; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0297] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:22, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:22, and a light chain containing the amino acid sequence shown in SEQ ID NO:25. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0298] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:26; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:29, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:26; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:29, or one or more variants thereof.

[0299] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:26, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:26; and VL-CDR2: SEQ ID NO:9.

[0300] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3: SEQ ID NO:29, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; and VL-CDR3: SEQ ID NO:29.

[0301] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:26, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:26 ... VL-CDR3, which has the amino acid sequence shown in NO:29, or a variant thereof containing up to about three amino acid substitutions (such as any one of about 1, 2 or 3).

[0302] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:26, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:29.

[0303] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:26; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:29.

[0304] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:28, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:31, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H2-6 / L3-5, or a variant thereof. The monoclonal anti-C5 antibody mAb H2-6 / L3-5 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:28, and a light chain containing the amino acid sequence shown in SEQ ID NO:31. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0305] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:34; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:3; VH-CDR2: SEQ ID NO:34; VH-CDR3: SEQ ID NO:5; VL-CDR1: SEQ ID NO:8; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0306] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:34, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:34; and VL-CDR2: SEQ ID NO:9.

[0307] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:34, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:34 ... VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0308] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:34, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0309] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:3; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:34; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:5; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:8; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0310] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:36, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:7, or a variant thereof. In some embodiments, the monoclonal anti-C5 antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:36, and a light chain containing the amino acid sequence shown in SEQ ID NO:7. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0311] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:37; VH-CDR2: SEQ ID NO:38; VH-CDR3: SEQ ID NO:39; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:37; VH-CDR2: SEQ ID NO:38; VH-CDR3: SEQ ID NO:39; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0312] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:37, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR1: SEQ ID NO:23, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:37; and VL-CDR1: SEQ ID NO:23.

[0313] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:38, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:38; and VL-CDR2: SEQ ID NO:9.

[0314] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:39, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3: SEQ ID NO:10, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:39; and VL-CDR3: SEQ ID NO:10.

[0315] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:37, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:38, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:39, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:37 ... VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0316] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:37, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:38, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:39; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0317] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:37; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:38; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:39; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0318] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:41, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:41, and a light chain containing the amino acid sequence shown in SEQ ID NO:25. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0319] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:42; VH-CDR2: SEQ ID NO:43; VH-CDR3: SEQ ID NO:44; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:42; VH-CDR2: SEQ ID NO:43; VH-CDR3: SEQ ID NO:44; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0320] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:42, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR1: SEQ ID NO:23, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:42; and VL-CDR1: SEQ ID NO:23.

[0321] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:43, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:43; and VL-CDR2: SEQ ID NO:9.

[0322] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:44, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3: SEQ ID NO:10, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:44; and VL-CDR3: SEQ ID NO:10.

[0323] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:42, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:43, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:44, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:42, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:43 ... VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0324] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:42, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:43, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:44; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0325] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:42; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:43; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:44; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0326] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:46, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:46, and a light chain containing the amino acid sequence shown in SEQ ID NO:25. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0327] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:47; VH-CDR2: SEQ ID NO:48; VH-CDR3: SEQ ID NO:49; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:47; VH-CDR2: SEQ ID NO:48; VH-CDR3: SEQ ID NO:49; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0328] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:47, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR1: SEQ ID NO:23, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:47; and VL-CDR1: SEQ ID NO:23.

[0329] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:48, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:48; and VL-CDR2: SEQ ID NO:9.

[0330] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:49, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3: SEQ ID NO:10, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:49; and VL-CDR3: SEQ ID NO:10.

[0331] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:47, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:48, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:49, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:47 ... VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0332] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:47, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:48, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:49; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0333] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:47; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:48; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:49; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0334] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:51, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:51, and a light chain containing the amino acid sequence shown in SEQ ID NO:25. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0335] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO: 52; VH-CDR2: SEQ ID NO: 53; VH-CDR3: SEQ ID NO: 54; VL-CDR1: SEQ ID NO: 23; VL-CDR2: SEQ ID NO: 9; and VL-CDR3: SEQ ID NO: 10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO: 52; VH-CDR2: SEQ ID NO: 53; VH-CDR3: SEQ ID NO: 54; VL-CDR1: SEQ ID NO: 23; VL-CDR2: SEQ ID NO: 9; and VL-CDR3: SEQ ID NO: 10, or one or more variants thereof.

[0336] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:52, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR1: SEQ ID NO:23, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:52; and VL-CDR1: SEQ ID NO:23.

[0337] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:53, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:53; and VL-CDR2: SEQ ID NO:9.

[0338] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:54, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3: SEQ ID NO:10, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:54; and VL-CDR3: SEQ ID NO:10.

[0339] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:52, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:53, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:54, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:52 ...3, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:52, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0340] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:52, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:53, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:54; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0341] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:52; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:53; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:54; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0342] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:56, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:56, and a light chain containing the amino acid sequence shown in SEQ ID NO:25. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0343] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:47; VH-CDR2: SEQ ID NO:57; VH-CDR3: SEQ ID NO:49; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:47; VH-CDR2: SEQ ID NO:57; VH-CDR3: SEQ ID NO:49; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0344] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:57, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:57; and VL-CDR2: SEQ ID NO:9.

[0345] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:47, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:57, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:49, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:47 ... VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0346] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:47, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:57, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:49; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0347] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:47; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:57; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:49; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0348] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:59, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:59, and a light chain containing the amino acid sequence shown in SEQ ID NO:25. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0349] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:76, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:74, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:76, and a light chain containing the amino acid sequence shown in SEQ ID NO:74. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0350] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:37; VH-CDR2: SEQ ID NO:62; VH-CDR3: SEQ ID NO:39; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:37; VH-CDR2: SEQ ID NO:62; VH-CDR3: SEQ ID NO:39; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0351] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:62, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:62; and VL-CDR2: SEQ ID NO:9.

[0352] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:37, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:62, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:39, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:37 ... VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0353] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:37, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:62, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:39; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0354] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:37; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:62; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:39; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0355] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:64, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:64, and a light chain containing the amino acid sequence shown in SEQ ID NO:25. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0356] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:72, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:74, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:72, and a light chain containing the amino acid sequence shown in SEQ ID NO:74. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0357] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO:42; VH-CDR2: SEQ ID NO:65; VH-CDR3: SEQ ID NO:44; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO:42; VH-CDR2: SEQ ID NO:65; VH-CDR3: SEQ ID NO:44; VL-CDR1: SEQ ID NO:23; VL-CDR2: SEQ ID NO:9; and VL-CDR3: SEQ ID NO:10, or one or more variants thereof.

[0358] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:65, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:65; and VL-CDR2: SEQ ID NO:9.

[0359] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:42, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:65, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:44, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:42 ...4, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0360] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:42, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:65, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:44; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0361] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:42; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:65; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:44; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0362] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO: 67, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO: 25, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain, 67, and a light chain containing the amino acid sequence shown in SEQ ID NO: 67, said light chain containing the amino acid sequence shown in SEQ ID NO: 25. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0363] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:78, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:74, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:78, and a light chain containing the amino acid sequence shown in SEQ ID NO:74. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0364] In one embodiment, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises at least one CDR selected from the group consisting of: VH-CDR1: SEQ ID NO: 52; VH-CDR2: SEQ ID NO: 68; VH-CDR3: SEQ ID NO: 54; VL-CDR1: SEQ ID NO: 23; VL-CDR2: SEQ ID NO: 9; and VL-CDR3: SEQ ID NO: 10, or one or more variants thereof. In another embodiment, the anti-C5 antibody comprises all of the following CDRs: VH-CDR1: SEQ ID NO: 52; VH-CDR2: SEQ ID NO: 68; VH-CDR3: SEQ ID NO: 54; VL-CDR1: SEQ ID NO: 23; VL-CDR2: SEQ ID NO: 9; and VL-CDR3: SEQ ID NO: 10, or one or more variants thereof.

[0365] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:68, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR2: SEQ ID NO:9, or a variant thereof comprising up to about three amino acid substitutions (such as any one of about 1, 2, or 3). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:68; and VL-CDR2: SEQ ID NO:9.

[0366] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:52, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:68, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:54, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:52, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:68 ... VL-CDR3, which has the amino acid sequence shown in NO:10, or a variant thereof containing up to about 3 amino acid substitutions (such as any one of about 1, 2 or 3).

[0367] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:52, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:68, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:54; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9, or a variant thereof comprising up to about 3 amino acid substitutions (such as any one of about 1, 2, or 3); and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0368] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises: VH-CDR1 comprising the amino acid sequence shown in SEQ ID NO:52; VH-CDR2 comprising the amino acid sequence shown in SEQ ID NO:68; VH-CDR3 comprising the amino acid sequence shown in SEQ ID NO:54; VL-CDR1 comprising the amino acid sequence shown in SEQ ID NO:23; VL-CDR2 comprising the amino acid sequence shown in SEQ ID NO:9; and VL-CDR3 comprising the amino acid sequence shown in SEQ ID NO:10.

[0369] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:70, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:25, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:70, and a light chain containing the amino acid sequence shown in SEQ ID NO:25. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0370] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:80, or a variant thereof. In other embodiments, the anti-C5 antibody comprises a light chain containing the amino acid sequence shown in SEQ ID NO:74, or a variant thereof. In yet another embodiment, the anti-C5 antibody is mAb H1-8 / L1-9, or a variant thereof. The monoclonal anti-C5 antibody mAb H1-8 / L1-9 comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO:78, and a light chain containing the amino acid sequence shown in SEQ ID NO:74. In some embodiments, the monoclonal anti-C5 antibody is humanized. In some embodiments, the monoclonal anti-C5 antibody is a chimeric antibody.

[0371] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a substitution of proline (i.e., P4) at position #4 in VH CDR2 relative to SEQ ID NO:4. In various embodiments, the substitution at P4 is P4→F4 (i.e., P4F), P4→L4 (i.e., P4L), P4→M4 (i.e., P4M), P4→W4 (i.e., P4W), or P4→I4 (i.e., P4I).

[0372] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a substitution of threonine (i.e., T9) at position #9 in VH CDR2 relative to SEQ ID NO:4. In various embodiments, the substitution at T9 is T9→H9 (i.e., T9H), T9 is T9→F9 (i.e., T9F), T9→L9 (i.e., T9L), T9→M9 (i.e., T9M), T9→W9 (i.e., T9W), or T9→I9 (i.e., T9I).

[0373] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a substitution of proline (i.e., P4) at position #4 in VH CDR2 relative to SEQ ID NO:4; and a substitution of threonine at position #9 (i.e., T9) in VH CDR2 relative to SEQ ID NO:4. In various embodiments, the substitution at P4 is P4→F4 (i.e., P4F), P4→L4 (i.e., P4L), P4→M4 (i.e., P4M), P4→W4 (i.e., P4W), or P4→I4 (i.e., P4I); and the substitution at T9 is T9→H9 (i.e., T9H), T9 is T9→F9 (i.e., T9F), T9→L9 (i.e., T9L), T9→M9 (i.e., T9M), T9→W9 (i.e., T9W), or T9→I9 (i.e., T9I).

[0374] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a substitution of valine (i.e., V16) at position #16 in VH CDR3 relative to SEQ ID NO:5. In several embodiments, the substitution at V4 is V16→F16 (i.e., V16F), V16→E16 (i.e., V16E), or V16→W16 (i.e., V16W).

[0375] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof includes a substitution of asparagine (i.e., N8) at position #8 in VH CDR1 relative to SEQ ID NO:3. In various embodiments, the substitution at N8 is N8→H8 (i.e., N8H), N8→W8 (i.e., N8W), N8→I8 (i.e., N8I), N8→V8 (i.e., N8V), N8→Y8 (i.e., N8Y), or N8→F8 (i.e., N8F).

[0376] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises a substitution of leucine (i.e., L9) at position #9 in VH CDR1 relative to SEQ ID NO: 20. In various embodiments, the substitution at L9 is L9→W9 (i.e., L9W), L9→I9 (i.e., L9I), L9→V9 (i.e., L9V), L9→Y9 (i.e., L9Y), or L9→F9 (i.e., L9F).

[0377] In some embodiments, the anti-C5 antibody, fusion protein, or antigen-binding fragment thereof comprises substitutions at two or more of the following: proline 4 (i.e., P4) in VH CDR2 relative to SEQ ID NO:4; threonine 9 (i.e., T9) in VH CDR2 relative to SEQ ID NO:4; valine 16 (i.e., V16) in VH CDR3 relative to SEQ ID NO:5; and leucine 9 (i.e., L9) in VH CDR1 relative to SEQ ID NO:20. In various embodiments, substitutions are made at two or more of the following: proline 4 (i.e., P4) in VH CDR2 relative to SEQ ID NO:4; threonine 9 (i.e., T9) in VH CDR2 relative to SEQ ID NO:4; valine 16 (i.e., V16) in VH CDR3 relative to SEQ ID NO:5; and leucine 9 (i.e., L9) in VH CDR1 relative to SEQ ID NO:20. Two or more sites in leucine 9 (L9) of CDR1 contain substitutions for anti-C5 antibodies or their antigen-binding fragments, which include two or more substitutions selected from the group consisting of: L9I / P4M, L9I / P4W, L9I / P4F, L9F / P4M, L9F / P4W, L9F / P4F, L9I / P4M / V16W, L9I / P4W / V16W, L9I / P4F / V16W, L9F / P4M / V16W, L9F / P4W / V16W, L9F / P4F / V16W, L9I / P4M / V16E, L9I / P4W / V16E, L9I / P4F / V16E, L9F / P4M ... M / V16E, L9F / P4W / V16E, L9F / P4F / V16E, L9I / P4M / T9H / V16W, L9I / P4W / T 9H / V16W, L9I / P4F / T9H / V16W, L9F / P4M / T9H / V16W, L9F / P4W / T9H / V16W, L9F / P4F / T9H / V16W, L9I / P4M / T9H / V16E, L9I / P4W / T9H / V16E, L9I / P4F / T9H / V16E, L9F / P4M / T9H / V16E, L9F / P4W / T9H / V16E and L9F / P4F / T9H / V16E.

[0378] In some embodiments, the antibody or fusion protein is a chimeric antibody. In some embodiments, the anti-human C5 antibody may comprise human light chain and human heavy chain constant regions, as well as variable region CDR sequences as described above. Those skilled in the art will be able to prepare and obtain chimeric antibodies using known techniques for exchanging relevant domains of the specific antibody of interest. Such antibodies are readily prepared by transplanting xenogeneic antibody domains and introducing one or more CDR sequences as described in this application. Using known recombinant techniques, it is possible to obtain and prepare recombinant antibodies comprising heavy chain and light chain constant regions encoded by nucleic acid sequences of human heavy chain and light chain constant regions; and this disclosure describes heavy chain and light chain variable regions comprising CDRs encoded by nucleic acid sequences corresponding to CDR sequences. Those skilled in the art can prepare anti-human C5 antibodies comprising one or more CDR sequences as described in this disclosure, wherein the light chain portion is replaced individually or the heavy chain portion is replaced individually by a region from an antibody belonging to another species, such as (e.g.) human. Human anti-human C5 antibodies comprising a variable region having one or more CDR sequences and murine or non-murretic antibody structural elements located outside the CDR region can be prepared using conventional methods known in the art. The CDR sequences are selected from SEQ ID NO: 3-5, 8-11, 14, 17, 20, 23, 26, 29, 34, 37-39, 42-44, 47-49, 52-54, 57, 62, 65, and 68, or variants thereof. In some embodiments, the antibody or antibody fragment is further humanized using techniques known in the art.

[0379] In several embodiments, any antibody or fusion protein of the present invention described herein, having any of the variable regions described herein, may comprise a human IgG4 constant heavy chain. SEQ ID NO:32 is an example amino acid sequence of a human IgG4 constant heavy chain. In some embodiments, the antibody or fusion protein of the present invention comprises a human IgG4 constant heavy chain having an S228P mutation. SEQ ID NO:33 is an example amino acid sequence of a human IgG4 constant heavy chain having an S228P mutation. In some embodiments, the antibody of the present invention comprises a human IgG4 constant heavy chain having an Fc PLA mutation. SEQ ID NO:61 is an example amino acid sequence of a human IgG4 constant heavy chain having an Fc PLA mutation.

[0380] In some embodiments, the anti-C5 antibody or fusion protein comprises an antibody having at least about 85% (such as at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid identity with the CDR sequences described herein listed in SEQ ID NO 3-5, 8-11, 14, 17, 20, 23, 26, 29, 34, 37-39, 42-44, 47-49, 52-54, 57, 62, 65, and 68).

[0381] In one embodiment, the present invention discloses an anti-C5 antibody or fusion protein having a CDR sequence having at least about 85% (such as at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identity with the CDR sequence described above. In one embodiment, the anti-human C5 antibody has a VH region and a VL region, wherein the VH region has an amino acid sequence that is more than 90% (e.g., more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a sequence selected from SEQ ID NO 2, 19, 22, 28, 36, 41, 46, 51, 56, and 59, and wherein the VL region has an amino acid sequence that is more than 90% (e.g., more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a sequence selected from SEQ ID NO 7, 13, 16, 17, 25, 31, and 74.

[0382] In some embodiments, the antibody or antibody fragment is modified. In some embodiments, the modification includes the fusion of the antibody or its antigen-binding fragment with a portion or fragment of another protein. In some embodiments, the antibody or antibody fragment of the present invention is modified to improve its circulating half-life in vivo. For example, the antibody fragment may be fused with an FcRn molecule (also known as a neonatal Fc receptor) to stabilize the antibody in vivo (Nature Reviews Immunology 7:715-725). In some embodiments, the antibody or its antigen-binding fragment is conjugated (e.g., fused) to an effector molecule and / or another targeting moiety (such as an antibody or antibody fragment that recognizes a different molecule, a different antigen, or a different epitope).

[0383] Those skilled in the art will be able to prepare human C5-binding scFv comprising at least one specific CDR sequence or a variant thereof selected from SEQ ID NO:3-5, 8-11, 14, 17, 20, 23, 26, 29, 34, 37-39, 42-44, 47-49, 52-54, 57, 62, 65, and 68. The scFv may comprise the heavy chain variable region sequence or one or more variants thereof represented in SEQ ID NO:3-5, 17, 20, 26, 34, 37-39, 42-44, 47-49, 52-54, 57, 62, 65, and 68, and the light chain variable region, or one or more variants thereof represented in SEQ ID NO:8-11, 14, 23, and 29. CDR sequences within scFv that introduce at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with the CDR sequences described in this invention are covered within the scope of this invention.

[0384] In some embodiments, the isolated antibody binds to human C5, wherein the antibody binds to an epitope of human C5. In some embodiments, the human C5 antibody of the present invention is an antibody that binds to a human C5-specific epitope. In some embodiments, the epitope comprises at least one amino acid in the α-chain of C5. In some embodiments, the epitope comprises at least one amino acid in the β-chain of C5.

[0385] In some embodiments, the present invention provides a fusion protein comprising an anti-C5 antibody moiety (as described herein with any of the anti-C5 antibodies) and FH or a functional fragment thereof. In some embodiments, the anti-C5 antibody moiety is a full-length antibody. In some embodiments, FH is fused to one or both of the heavy chains of the full-length antibody (e.g., at the C-terminus of the heavy chain). In some embodiments, the full-length antibody comprises an IgG4 chain (e.g., an IgG4 chain containing a PLA mutation). For example, in one embodiment, the IgG4 chain containing a PLA mutation comprises a constant human IgG4 heavy chain containing an Fc PLA mutation. In one embodiment, the IgG4 chain containing a PLA mutation comprises the amino acid sequence shown in SEQ ID NO:61.

[0386] In some embodiments, the present invention provides a fusion protein comprising an anti-C5 antibody moiety (as described herein) and an FH containing an SCR1-5 domain or a functional fragment thereof. In some embodiments, the present invention provides a fusion protein comprising an anti-C5 antibody moiety containing an IgG4 chain (e.g., an IgG4 chain containing a PLA mutation) and an FH containing an SCR1-5 domain or a functional fragment thereof.

[0387] In some embodiments, the present invention provides a fusion protein comprising an anti-C5 antibody moiety and an FH or a functional fragment thereof, wherein the anti-C5 antibody moiety is pH-sensitive (as described herein as any of the pH-sensitive anti-C5 antibodies). For example, in some embodiments, the pH-sensitive anti-C5 antibody moiety is an anti-C5 antibody moiety that has a higher binding affinity for C5 at pH 7.4 than at pH 5.8. In some embodiments, the anti-C5 antibody moiety has a binding affinity for C5 (e.g., human C5) at pH 7.4 that is at least about 3 times higher (e.g., at least about 4, 5, 6, 7, 8, or 10 times higher) than the anti-C5 antibody moiety has at pH 5.8.

[0388] In some embodiments, the fusion protein comprises an anti-C5 antibody moiety and FH or a functional fragment thereof, wherein the anti-C5 antibody moiety is pH-sensitive (as described herein with any of the pH-sensitive anti-C5 antibodies), for example, exhibiting a higher binding affinity for C5 at pH 7.4 than at pH 5.8, and wherein the anti-C5 moiety comprises an IgG4 chain (e.g., an IgG4 chain containing a PLA mutation). In some embodiments, the fusion protein comprises an anti-C5 antibody moiety and FH or a functional fragment thereof, and wherein the anti-C5 antibody moiety is pH-sensitive (as described herein with any of the pH-sensitive anti-C5 antibodies), for example, exhibiting a higher binding affinity for C5 at pH 7.4 than at pH 5.8, and wherein the FH or a functional fragment thereof comprises the SCR1-5 domain of FH. In some embodiments, the fusion protein comprises an anti-C5 antibody moiety and FH or a functional fragment thereof, wherein the anti-C5 antibody moiety is pH sensitive (as described herein as any of the pH-sensitive anti-C5 antibodies), for example, having a higher binding affinity for C5 at pH 7.4 than at pH 5.8, wherein the anti-C5 moiety comprises an IgG4 chain (e.g., an IgG4 chain containing a PLA mutation), and wherein the FH or a functional fragment thereof comprises the SCR1-5 domain of FH.

[0389] In some embodiments, the present invention provides a fusion protein comprising an anti-C5 antibody moiety (as described herein with any of the anti-C5 antibodies) and FH or a functional fragment thereof, wherein the anti-C5 moiety comprises histidine substitutions in one or more of its CDR regions (as described herein with any of the histidine-containing anti-C5 antibodies). In some embodiments, the fusion protein comprises an anti-C5 antibody moiety and FH or a functional fragment thereof, wherein the anti-C5 moiety comprises histidine substitutions in one or more of its CDR regions (as described herein with any of the histidine-containing anti-C5 antibodies), and wherein the anti-C5 moiety comprises an IgG4 chain (e.g., an IgG4 chain comprising a PLA mutation). In some embodiments, the fusion protein comprises an anti-C5 antibody moiety and FH or a functional fragment thereof, wherein the anti-C5 moiety comprises histidine substitutions in one or more of its CDR regions (as described herein with any of the histidine-containing anti-C5 antibodies), and wherein the FH or a functional fragment thereof comprises the SCR1-5 domain of FH. In some embodiments, the fusion protein comprises an anti-C5 antibody portion and FH or a functional fragment thereof, wherein the anti-C5 portion comprises a histidine substitution in one or more of its CDR regions (as described herein as any of the histidine-containing anti-C5 antibodies), wherein the anti-C5 portion comprises an IgG4 chain (e.g., an IgG4 chain containing a PLA mutation), and wherein the FH or a functional fragment thereof comprises the SCR1-5 domain of FH.

[0390] In several embodiments, FH or a functional fragment thereof comprises complement FH. Complement FH is a single-chain plasma glycoprotein. This protein consists of 20 repeating SCR domains arranged in a continuous manner like a string of 20 beads, each SCR domain having approximately 60 amino acids. In some embodiments, FH binds to C3b, accelerating the decay of the alternative pathway C3-convertase (C3Bb), and acts as a cofactor for the hydrolytic inactivation of C3b. In the presence of FH, C3b hydrolysis leads to the cleavage of C3b. In some embodiments, FH has at least three distinct binding domains for C3b, located within SCRs 1-4, 5-8, and 19-20. In some embodiments, each site of FH binds to a different region within the C3b protein: the N-terminal site binds to native C3b; a second site within the middle region of FH binds to the C3c fragment; and sites within SCRs 19 and 20 bind to the C3d region. In some embodiments, FH also contains a heparin binding site located within SCR 7, SCR 5-12, and SCR20 of FH and overlapping with the C3b binding site. For example, in some embodiments, structural and functional analyses show that the complement-inhibiting domain of FH is located within the first four N-terminal SCR domains.

[0391] The FH or functional fragments thereof described herein refer to any part of an FH protein that has some or all of the complement-inhibiting activity of the FH protein, and as described in detail below, include, but are not limited to: the full-length FH protein, biologically active fragments of the FH protein, FH fragments containing SCR1-4, or any homologs of naturally occurring FH or fragments thereof.

[0392] In several embodiments, FH is a full-length human FH protein comprising the amino acid sequence described in SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, or SEQ ID NO:84. Amino acids 1-18 correspond to the leader peptide, amino acids 21-80 correspond to SCR1, amino acids 85-141 correspond to SCR2, amino acids 146-205 correspond to SCR3, amino acids 210-262 correspond to SCR4, and amino acids 267-320 correspond to SCR5.

[0393] In some embodiments, the FH portion has one or more of the following properties: (1) binding to C-reactive protein (CRP), (2) binding to C3b, (3) binding to heparin, (4) binding to sialic acid, (5) binding to the surface of endothelial cells, (6) binding to cytokine receptors, (7) binding to pathogens, (8) C3b cofactor activity, (9) C3b attenuation-accelerating activity, and (10) inhibition of alternative complement pathways.

[0394] In some embodiments, the FH portion comprises the first four N-terminal SCR domains of the FH (SCR1-4). In some embodiments, the construct comprises the first five N-terminal SCR domains of the FH (SCR1-5). In some embodiments, the construct comprises the first six N-terminal SCR domains of the FH (SCR1-6). In some embodiments, the FH portion comprises (and in some embodiments, constitutes or substantially constitutes) at least the first four N-terminal SCR domains of the FH, including, for example, any one of at least the 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th or more N-terminal SCR domains of the FH.

[0395] In some embodiments, FH is wild-type FH. In some embodiments, FH is a variant of naturally occurring FH or a variant thereof. Variants of naturally occurring FH proteins or fragments thereof include proteins that differ from naturally occurring FH or fragments thereof, by at least one or more of the following: deletion (e.g., a truncated form of the protein, such as a peptide or fragment), insertion, inversion, substitution, and / or derivatization (e.g., by glycosylation, phosphorylation, acetylation, myristylation, isopentenylation, palmitation, amidation, and / or addition of glycosylphosphatidylinositol. For example, the FH variant may have at least about 70% identity with the amino acid sequence of naturally occurring FH (e.g., SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, or SEQ ID NO:84), for example, having at least about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence of naturally occurring FH (e.g., SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, or SEQ ID NO:84). In some embodiments, the FH variant or fragment thereof retains all the complement-inhibiting activity of naturally occurring FH or fragment thereof. In some embodiments, the FH variant or fragment thereof retains at least about 50% of the complement-inhibiting activity of naturally occurring FH or fragment thereof, for example, at least about 60%, 70%, 80%, 90%, or 95%. In some embodiments, the FH or fragment thereof comprises at least the first five N-terminal SCR domains of human FH, such as an FH portion having an amino acid sequence of 21 to 320 amino acids containing at least human FH (e.g., SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, or SEQ ID NO:84). In some embodiments, the FH or a fragment thereof comprises at least the first 5 N-terminal SCR domains of human FH, wherein the human FH has an amino acid sequence that is at least about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identical to amino acids 21 to 320 of human FH (e.g., SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, or SEQ ID NO:84).

[0396] Screening assay

[0397] This invention has applications in various screening assays, including determining whether candidate anti-C5 antibodies (e.g., anti-C5 antibodies, anti-C5 fusion protein antibodies, etc.) can inhibit complement activity.

[0398] In some embodiments, the complement activity level in the presence of the candidate anti-C5 antibody is compared with the complement activity detected in a positive control. The positive control includes complement activation in the absence of the added test compound. In some embodiments, the candidate anti-C5 antibody is identified as a complement inhibitor when the complement activity in the presence of the candidate anti-C5 antibody is less than about 70% of the complement activity detected in the positive control; this corresponds to greater than about 30% inhibition of complement activity in the presence of the test compound. In other embodiments, the candidate anti-C5 antibody is identified as a complement inhibitor when the complement activity in the presence of the candidate anti-C5 antibody is less than about 80% of the complement activity detected in the positive control; this corresponds to greater than about 20% inhibition of complement activity in the presence of the test compound. In other embodiments, the candidate anti-C5 antibody is identified as a complement inhibitor when, in the presence of the candidate anti-C5 antibody, the complement activity is less than about 90% of the complement activity detected in the positive control; this corresponds to greater than about 10% inhibition of complement activity in the presence of the test compound. In some embodiments, the complement inhibition level by the candidate anti-C5 antibody is compared with the inhibition level detected in the negative control.

[0399] Various immunoassays, including competitive and non-competitive immunoassays, antigen capture assays, double-antibody sandwich assays, and triple-antibody sandwich assays, are useful methods of this invention (Self et al., 1996, Curr. Opin. Biotechnol. 7:60-65). This invention should not be considered limited to any known or previously unknown type of assay, as long as the assay can detect complement inhibition.

[0400] Enzyme-linked immunosorbent assay (ELISA) is useful in the methods of the present invention. Enzymes, such as (but not limited to) horseradish peroxidase (HRP), alkaline phosphatase, β-galactosidase, or urease, can be linked (e.g.) to an anti-C5 antibody or a second antibody used in the methods of the present invention. A horseradish-peroxidase detection system can be used with (e.g.) a chromogenic substrate, tetramethylbenzidine (TMB), which produces a soluble product detectable at 450 nm in the presence of hydrogen peroxide. Other convenient ELISA systems include (e.g.) an alkaline phosphatase detection system, which can be used with a chromogenic substrate, p-nitrophenyl phosphate, to produce a soluble product readily detectable at 405 nm. Similarly, a β-galactosidase detection system can be used with a chromogenic substrate, o-nitrobenzene-β-D-galactopyranoside (ONPG), to produce a soluble product detectable at 410 nm. As an alternative, the urinary enzyme detection system can be used with a substrate, such as urea-bromocresol purple (Sigma Immunochemicals, St. Louis, MO). Useful enzyme-linked primary and secondary antibodies are available from several commercial sources.

[0401] Chemiluminescence detection is also useful for detecting inhibition of the terminal complement pathway. Chemiluminescent secondary antibodies are available from multiple commercial sources.

[0402] Fluorescence detection is also useful for detecting terminal complement inhibition. Useful fluoresceins include, but are not limited to: DAPI, fluorescein, Hoechst 33258, R-phycocyanin, B-phycoerythrin, R-phycoerythrin, rhodamine, Texas red, and fluorescein- or rhodamine-labeled antibodies.

[0403] Radioimmunoassay (RIA) is also useful in the methods of this invention. These assays are well known in the art and, for example, in Brophy et al. (1990, Biochem. Biophys. Res. Comm. 167:898-903) and Guechot et al. (1996, Clin. Chem. 42:558-563). For example, radioimmunoassays can be performed using iodine-125-labeled primary or secondary antibodies (Harlow et al., as above, 1999).

[0404] The signals emitted by detectable antibodies can be analyzed, for example, by detecting the color from a chromogenic substrate using a spectrophotometer; by detecting radiation using a radiation counter, such as a gamma particle counter used to detect iodine-125; or by detecting fluorescence using a fluorometer in the presence of light of a specific wavelength. When using an enzyme-linked assay, quantitative analysis is performed using a spectrophotometer. It should be understood that the assays of this invention can be performed manually, or automatically if desired, and signals emitted by multiple samples can be detected simultaneously in multiple commercially available systems.

[0405] The method of this invention also covers the use of capillary electrophoresis-based immunoassays (CEIA), which can be automated if desired. The immunoassay can also be used in conjunction with laser-induced fluorescence, as described, for example, in Schmalzing et al. (1997, Electrophoresis 18:2184-2193) and Bao (1997, J. Chromatogr. B. Biomed. Sci. 699:463-480). Liposome immunoassays, such as flow-injection liposome immunoassays and liposome immunosensors, can also be used according to the method of this invention (Rongen et al., 1997, J. Immunol. Methods 204:105-133).

[0406] Quantitative immunoblotting can also be used in the method of this invention to determine the level of terminal complement inhibition. Well-known methods, such as scanning microscopy-based quantitative immunoblotting (Parra et al., 1998, J. Vasc. Surg. 28:669-675), can be used.

[0407] Application method

[0408] The method of the present invention includes administering a therapeutically effective amount of at least one anti-C5 antibody (e.g., an anti-C5 antibody, an anti-C5 fusion protein antibody, etc.) or a binding fragment thereof (as described elsewhere herein) to an individual identified as having a complement-mediated disease or condition. In one embodiment, the individual is a mammal with a complement system. In one embodiment, the individual is a human. In several embodiments, the at least one anti-C5 antibody or a binding fragment thereof is administered locally, regionally, or systemically.

[0409] In several embodiments, the disease or condition is selected from at least the following: MD, AMD, ischemia-reperfusion injury, arthritis, rheumatoid arthritis, lupus, ulcerative colitis, stroke, postoperative systemic inflammatory syndrome, asthma, allergic asthma, COPD, PNH syndrome, myasthenia gravis, NMO, multiple sclerosis, delayed transplantation, antibody-mediated rejection, aHUS, CRVO, CRAO, bullous epidermolysis bullosa, sepsis, organ transplantation, inflammation (including but not limited to inflammation associated with cardiopulmonary bypass and renal dialysis), C3 glomerulonephropathy, membranous nephropathy, IgA nephropathy, glomerulonephritis (including but not limited to ANCA-mediated glomerulonephritis, lupus nephritis, and combinations thereof), ANCA-mediated vasculitis, Shiga toxin-induced HUS, and antiphospholipid antibody-induced pregnancy loss, or any combination thereof. In some embodiments, the complement-mediated disease is C3 glomerulonephropathy. In some embodiments, the complement-mediated disease is macular degeneration, such as age-related macular degeneration. In one embodiment, administration of the anti-C5 antibody fusion protein inhibits the production of C3a or C3b protein. In another embodiment, administration of the anti-C5 antibody fusion protein inhibits the production of C5a or C5b protein. In some embodiments, the compositions and methods of the present invention are useful for treating subjects who do not respond to treatment with eculizumab, including subjects with PNH. By way of non-limiting example, some subjects may have mutations in the α chain of C5 that could make them resistant to eculizumab treatment (see Genetic variants in C5 and poor response to eculizumab (Nishimura J et al., N Engl J Med. 2014 Feb 13; 370(7):632-9).

[0410] The methods of the present invention may include the administration of at least one anti-C5 antibody fusion protein or a binding fragment thereof, but the invention should in no way be construed as limited to the anti-C5 antibody fusion proteins described herein, but should be considered as encompassing any known and unknown anti-C5 antibody fusion proteins that attenuate and reduce complement activation.

[0411] The method of the present invention includes administering to an individual a therapeutically effective amount of at least one anti-C5 antibody fusion protein or a binding fragment thereof, wherein the composition of the present invention, alone or in combination with at least one other therapeutic agent, comprises at least one anti-C5 antibody fusion protein or a binding fragment thereof. The present invention can be combined with other therapeutic modalities, such as (e.g.) anti-inflammatory therapies. Examples of anti-inflammatory therapies that can be used in combination with the method of the present invention include (e.g.) therapies using steroidal drugs and therapies using non-steroidal drugs.

[0412] The method of the present invention includes administering a therapeutically effective amount of an anti-C5 antibody fusion protein or its antigen-binding fragment to a subject. In some embodiments, the present invention covers a method for treating complement-related diseases involving abnormal complement signaling regulation by administering a therapeutically effective amount of the antibody fusion protein of the present invention or its antibody fragment, thereby reducing the formation of C3a, C3b, C5a or C5b or MAC in the subject. In some embodiments, the present invention covers a method for treating complement-related diseases involving abnormal complement signaling regulation by administering a therapeutically effective amount of an antibody fusion protein or antibody fragment. In some embodiments, the present invention covers a method for treating complement-related diseases involving abnormal complement signaling regulation by administering an effective amount of an antibody fusion protein, antibody fragment, polypeptide, peptide, or conjugated peptide to a subject, thereby reducing the activation of complement activation pathways in the subject. In some embodiments, the treatment method covers administering a systemically effective dose of an antibody fusion protein or antibody fragment to a subject, thereby systemically reducing the formation of C3a, C3b, C5a or C5b or MAC in the subject.

[0413] Pharmaceutical compositions useful for practicing the present invention can be administered to deliver at least about 1 ng / kg, at least about 5 ng / kg, at least about 10 ng / kg, at least about 25 ng / kg, at least about 50 ng / kg, at least about 100 ng / kg, at least about 500 ng / kg, at least about 1 g / kg, at least about 5 g / kg, at least about 10 g / kg, at least about 25 g / kg, at least about 50 g / kg, at least about 100 g / kg, at least about 500 g / kg, at least about 1 mg / kg, at least about 5 mg / kg, at least about 10 mg / kg, at least about 25 mg / kg, at least about 50 mg / kg, at least about 100 mg / kg, at least about 200 mg / kg, at least about 300 mg / kg, at least about 400 mg / kg, and at least 500 mg / kg of subject body weight. In one embodiment, the present invention applies a dose that results in the production of the following concentrations of the anti-C5 antibody fusion protein of the present invention in an individual: at least about 1 pM, at least about 10 pM, at least about 100 pM, at least about 1 nM, at least about 10 nM, at least about 100 nM, at least about 1 μM, at least about 2 μM, at least about 3 μM, at least about 4 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, and at least about 10 μM. In another embodiment, the invention envisions dosages that result in the production of the following concentrations of the anti-C5 antibody fusion protein of the invention in an individual's plasma: at least about 1 pM, at least about 10 pM, at least about 100 pM, at least about 1 nM, at least about 10 nM, at least about 100 nM, at least about 1 μM, at least about 2 μM, at least about 3 μM, at least about 4 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, and at least about 10 μM.

[0414] In some embodiments, pharmaceutical compositions useful for practicing the present invention may be administered to deliver no more than about 1 ng / kg, no more than about 5 ng / kg, no more than about 10 ng / kg, no more than about 25 ng / kg, no more than about 50 ng / kg, no more than about 100 ng / kg, no more than about 500 ng / kg, no more than about 1 g / kg, no more than about 5 g / kg, no more than about 10 g / kg, no more than about 25 g / kg, no more than about 50 g / kg, no more than about 100 g / kg, no more than about 500 g / kg, no more than about 1 mg / kg, no more than about 5 mg / kg, no more than about 10 mg / kg, no more than about 25 mg / kg, no more than about 50 mg / kg, no more than about 100 mg / kg, no more than about 200 mg / kg, no more than about 300 mg / kg, no more than about 400 mg / kg, and no more than about 500 mg / kg of the subject's body weight. In one embodiment, the present invention applies a dose that results in the production of the following concentrations of the anti-C5 antibody fusion protein of the present invention in an individual: not greater than about 1 pM, not greater than about 10 pM, not greater than about 100 pM, not greater than about 1 nM, not greater than about 10 nM, not greater than about 100 nM, not greater than about 1 μM, not greater than about 2 μM, not greater than about 3 μM, not greater than about 4 μM, not greater than about 5 μM, not greater than about 6 μM, not greater than about 7 μM, not greater than about 8 μM, not greater than about 9 μM, and not greater than about 10 μM. In another embodiment, the invention contemplates dosages that result in the production of the following concentrations of the anti-C5 antibody fusion protein of the invention in an individual's plasma: not greater than about 1 pM, not greater than about 10 pM, not greater than about 100 pM, not greater than about 1 nM, not greater than about 10 nM, not greater than about 100 nM, not greater than about 1 μM, not greater than about 2 μM, not greater than about 3 μM, not greater than about 4 μM, not greater than about 5 μM, not greater than about 6 μM, not greater than about 7 μM, not greater than about 8 μM, not greater than about 9 μM, and not greater than about 10 μM. Dosage ranges between any of the doses disclosed herein are also considered.

[0415] Typically, the dose administered to a subject (in some embodiments, a human) in the method of the present invention ranges from 0.5 μg to approximately 50 mg per kilogram of subject body weight. However, the exact dose administered will vary based on a number of factors, including but not limited to: the type of subject and the type of disease state to be treated, the subject's age, and the route of administration. In some embodiments, the dose of the compound will vary between approximately 1 μg and approximately 10 mg per kilogram of subject body weight. In other embodiments, the dose will vary between approximately 3 μg and approximately 1 mg per kilogram of subject body weight.

[0416] The antibody fusion protein can be administered to the subject several times a day, or less frequently, such as once a day, twice a day, three times a day, once a week, twice a week, three times a week, once every two weeks, twice every two weeks, three times every two weeks, once a month, twice a month, three times a month, or even less frequently, such as once every few months, or even once a year, or a few times or less. The frequency of the dosage will be obvious to a person skilled in the art and will depend on a variety of factors, such as (but not limited to) the type and severity of the disease to be treated, the type and age of the subject, etc. The pharmaceutical composition formulation can be prepared by any method known in or subsequently developed in the pharmaceutical field. Generally, these methods of preparation involve the step of binding the active ingredient with a carrier or one or more other auxiliary ingredients, and then, if necessary or desired, shaping or packaging the product into the desired single-dose or multi-dose units.

[0417] Although the description of the pharmaceutical compositions provided herein primarily relates to pharmaceutical compositions suitable for ethical administration to humans, those skilled in the art will understand that these compositions are generally suitable for administration to a wide variety of subjects. It is well understood that modifications can be made to pharmaceutical compositions suitable for human administration to make said compositions suitable for administration to a wide range of subjects, and that conventional veterinary pharmacologists can design and implement these modifications simply through routine experiments (if any). Individuals contemplated for administration of the pharmaceutical compositions of the present invention include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as non-human primates, cattle, pigs, horses, sheep, cattle, and dogs.

[0418] Pharmaceutical compositions useful in the methods of the present invention can be prepared, packaged, or sold in formulations suitable for ocular, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, oral, intraocular, vitreous, intramuscular, intradermal, and intravenous administration. Other formulations considered include projected nanoparticles, liposome formulations, re-encapsulated red blood cells containing the active ingredient, and immunologically based formulations.

[0419] The pharmaceutical compositions of the present invention can be prepared, packaged, or sold as a whole, as a single unit dose, or as multiple single unit doses. A unit dose is a single amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient to be administered to an individual or a convenient fraction of such doses, such as, for example, half or one-third of such doses.

[0420] In the pharmaceutical compositions of the present invention, the relative amounts of the active ingredient, the pharmaceutically available carrier, and any other components will vary based on the identity, body type, and condition of the individual being treated, and also based on the route of administration of the composition. For example, the composition may comprise between 0.1% and 100% (w / w) of the active ingredient. In various embodiments, the composition comprises at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 21%, at least about 22%, at least about 23%, at least about 24%, and at least about 25%. At least approximately 26%, at least approximately 27%, at least approximately 28%, at least approximately 29%, at least approximately 30%, at least approximately 31%, at least approximately 32%, at least approximately 33%, at least approximately 34%, at least approximately 35%, at least approximately 36%, at least approximately 37%, at least approximately 38%, at least approximately 39%, at least approximately 40%, at least approximately 41%, at least approximately 42%, at least approximately 43%, at least approximately 44%, at least approximately 45%, at least approximately 46%, at least approximately 47%, at least approximately 48%, at least approximately 49%, at least approximately 50%, at least approximately 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59%, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, At least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% (w / w) of active ingredient.

[0421] In addition to the active ingredient, the pharmaceutical compositions of the present invention may also include one or more other pharmaceutical active agents.

[0422] Controlled-release or sustained-release formulations of the pharmaceutical compositions of the present invention can be prepared using conventional techniques.

[0423] Parenteral administration of a pharmaceutical composition includes any route of administration, characterized by physical disruption of individual tissue and administration of the pharmaceutical composition through an opening in said tissue. Parenteral administration can be local, regional, or systemic. Therefore, parenteral administration includes, but is not limited to, administration of the pharmaceutical composition by injection, application of the composition through a surgical incision, application of the composition through a non-surgical wound that penetrates tissue, etc. Specifically, parenteral administration is considered, including but not limited to: intravenous, intraocular, intravitreal, subcutaneous, intraperitoneal, intramuscular, intradermal, intrasternal injection, and intratumoral administration.

[0424] Pharmaceutical compositions suitable for parenteral administration include the active ingredient combined with a carrier suitable for the drug, such as sterile water or sterile isotonic saline. These formulations can be prepared, packaged, or sold in forms suitable for pellet administration or for continuous administration. Injectable formulations can be prepared, packaged, or sold in unit dose forms, such as in ampoules or in multi-dose containers containing preservatives. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions, pastes, and implantable sustained-release or biodegradable formulations in oily or aqueous media. These formulations may also include one or more other components, including, but not limited to, suspensions, stabilizers, or dispersants. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in a dry (i.e., powder or granule) form reconstituted with a suitable media (e.g., sterile, pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0425] The pharmaceutical compositions are prepared, packaged, or sold as sterile, injectable aqueous or oily suspensions or solutions. Such suspensions or solutions can be formulated according to known techniques and may include other components besides the active ingredient, such as dispersants, wetting agents, or suspending agents. These sterile injectable formulations can be prepared using non-toxic, parenteral-applicable diluents or solvents, such as, for example, water or 1,3-butanediol. Other available diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixing oils, such as synthetic mono- or diglycerides. Other useful parenteral-applicable formulations include those containing an active ingredient in microcrystalline form, in liposome formulations, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may include pharmaceutically available polymers or hydrophobic materials, such as emulsions, ion exchange resins, slightly soluble polymers, or slightly soluble salts.

[0426] The pharmaceutical compositions of the present invention can be prepared, packaged, or marketed in formulations suitable for administration to the lungs via the buccal interstitial space. Such formulations may comprise dried particles containing an active ingredient and having a diameter in the range of about 0.5 to about 7 nanometers, and in some embodiments, about 1 to about 6 nanometers. These compositions are conveniently available in dry powder form for application using an apparatus or a self-propelling solvent / powder dispensing container, the apparatus comprising a dry powder reservoir to which a propellant stream can be directed to disperse the powder, and the self-propelling solvent / powder dispensing container, such as an apparatus comprising an active ingredient dissolved or suspended in a low-boiling-point propellant in a sealed container. In some embodiments, the powder comprises particles wherein at least 98% by weight of the particles have a diameter greater than 0.5 nanometers and at least 95% by number of the particles have a diameter less than 7 nanometers. In some embodiments, at least 95% by weight of the particles have a diameter greater than 1 nanometer and at least 90% by number of the particles have a diameter less than 6 nanometers. In some embodiments, the dry powder composition includes a solid fine powder diluent, such as sugar, and the dry powder composition is conveniently provided in unit dose form.

[0427] Low-boiling-point propellants typically comprise liquid propellants having a boiling point of less than 65°F at atmospheric pressure. Typically, the propellant may comprise 50 to 99.9% (w / w) of the composition, and the active ingredient may comprise 0.1 to 20% (w / w) of the composition. The propellant may also include other components such as liquid nonionic or solid anionic surfactants or solid diluents (in some embodiments, having a particle size on the same order of magnitude as the particles containing the active ingredient).

[0428] The pharmaceutical compositions of the present invention formulated for transpulmonary delivery may also provide the active ingredient in the form of a solution or suspension droplets. These formulations may be prepared, packaged, or sold as optionally sterile aqueous solutions or diluted solutions or suspensions of an alcohol containing the active ingredient, and may be conveniently administered using any nebulizer or spray device. These formulations may also include one or more other ingredients, including but not limited to: flavoring agents such as sodium saccharin, volatile oils, buffers, surfactants, or preservatives such as methylparaben. In some embodiments, the average diameter of the droplets provided via this route of administration is in the range of about 0.1 to about 200 nanometers.

[0429] The formulation is also useful for intranasal delivery of the pharmaceutical compositions of the present invention.

[0430] Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient and having an average particle size of about 0.2 to 500 micrometers. This formulation is administered by nasal inhalation, i.e., by rapid inhalation through the nasal passage from a powder container kept close to the nostrils.

[0431] Formulations suitable for nasal application may, for example, contain as little as 0.1% (w / w) to as much as 100% (w / w) of an active ingredient, and may also contain one or more other ingredients.

[0432] The pharmaceutical compositions of the present invention can be prepared, packaged, or marketed in formulations suitable for oral administration. These formulations may, for example, be in the form of tablets or lozenges prepared using conventional methods, and may, for example, comprise 0.1 to 20% (w / w) of the active ingredient, the remainder comprising an orally soluble or biodegradable component and optionally, one or more other ingredients. Alternatively, formulations suitable for oral administration may comprise powders containing the active ingredient or solutions or suspensions that are sprayed or atomized. In some embodiments, when dispersed, these powder, spray, or atomized formulations have an average particle or droplet size in the range of about 0.1 to about 200 nanometers, and may also include one or more other ingredients.

[0433] As used herein, “other ingredients” include, but are not limited to, one or more of the following: excipients; surfactants; dispersants; inert diluents; granulators and disintegrants; binders; lubricants; sweeteners; flavorings; colorants; preservatives; physiologically degradable components such as gelatin; aqueous media and solvents; oily media and solvents; suspending agents; dispersants or wetting agents; emulsifiers, analgesics; buffers; salts; thickeners; fillers; emulsifiers; antioxidants; antibiotics; antifungals; stabilizers; and pharmaceutically available polymers or hydrophobic materials. Other “additional ingredients” that may be included in the pharmaceutical compositions of the present invention are known in the art and described, for example, in Remington’s Pharmaceutical Sciences (1985, edited by Genaro, Mack Publishing Co., Easton, PA), which is incorporated herein by reference.

[0434] Cells that produce antibodies, fusion proteins, or their antigen-binding fragments

[0435] In some embodiments, the present invention comprises a cell or cell line (e.g., a host cell) that produces at least one of the anti-C5 antibodies (e.g., anti-C5 antibodies, anti-C5 fusion protein antibodies, etc.) or antigen-binding fragments described herein. In one embodiment, the cell or cell line is a genetically modified cell that produces at least one of the anti-C5 antibodies or antigen-binding fragments described herein. In one embodiment, the cell or cell line is a hybridoma that produces at least one of the anti-C5 antibodies or antigen-binding fragments described herein.

[0436] Hybrid cells (hybridomas) are typically generated from the fusion of clumps of murine spleen cells (highly enriched with B lymphocytes) and myeloma "fusion companion cells" (Alberts et al., Molecular Biology of the Cell (Garland Publishing, Inc., 1994); Harlow et al., Antibodies. A Laboratory Manual (Cold Spring Harbor Laboratory, Cold Spring Harbor, 1988). The fused cells are then divided into pools that can be analyzed for the production of antibodies with the desired specificity. Positive pools can be further subdivided until single-cell clones producing antibodies with the desired specificity are identified. Antibodies produced by these clones are called monoclonal antibodies.

[0437] Nucleic acids encoding any antibody or antibody fragment disclosed herein, and vectors comprising said nucleic acids, are also provided. Therefore, the antibodies and fragments of the present invention can be generated by expressing said nucleic acids in cells or cell lines, such as those commonly used for the expression of recombinant or humanized immunoglobulins. Therefore, the antibodies and fragments of the present invention can also be generated by cloning said nucleic acids into one or more expression vectors and transforming the vectors into cell lines, such as those commonly used for the expression of recombinant or humanized immunoglobulins.

[0438] Genes encoding the heavy and light chains or fragments thereof of immunoglobulins can be engineered according to methods known in the art, including but not limited to: polymerase chain reaction (PCR) (see, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor, NY, 1989; Berger & Kimmel, Methods in Enzymology, Vol. 152: Guide to Molecular Cloning Techniques, Academic Press, Inc., San Diego, Calif., 1987; Co et al., 1992, J. Immunol. 148: 1149). For example, genes encoding the heavy and light chains or fragments thereof can be cloned from the genomic DNA of antibody-secreting cells, or cDNA can be generated by reverse transcription of cellular RNA. Cloning is accomplished by conventional methods, including the use of PCR primers that hybridize to sequences flanked or overlapping with the gene or gene segment to be cloned.

[0439] Nucleic acids encoding the antibodies of the present invention, or their heavy or light chains or fragments, can be obtained and used according to recombinant nucleic acid technologies for generating specific immunoglobulins, immunoglobulin chains, or fragments or variants thereof in various host cells or in in vitro translation systems. For example, nucleic acids encoding antibodies, or fragments thereof, can be placed in suitable prokaryotic or eukaryotic vectors, such as expression vectors, and introduced into suitable host cells by appropriate methods (e.g., transformation, transfection, electroporation, infection), thereby operatively linking the nucleic acids to one or more expression control elements in the vector or integrating them into the host cell genome.

[0440] In some embodiments, the heavy and light chains or fragments thereof can be assembled in two different expression vectors that can be used for co-transfection of recipient cells. In some embodiments, each vector may contain two or more selectable genes, one for selection in a bacterial system and one for selection in a eukaryotic system. These vectors enable the genes to be generated and amplified in bacterial systems and enable subsequent eukaryotic cell co-transfection and selection of co-transfected cells. The selection procedure can be used to select the expression of antibody nucleic acids introduced onto two different DNA vectors in eukaryotic cells.

[0441] Alternatively, nucleic acids encoding the heavy and light chains or fragments thereof can be expressed from a vector. Although the heavy and light chains are encoded by different genes, they can be linked using recombination methods. For example, two polypeptides can be linked by a synthetic adapter that allows them to be prepared as a single protein chain, wherein V L and V H The regions pair up to form monovalent molecules (called scFv; see, for example, Bird et al., 1988, Science 242:423-426; and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883).

[0442] This invention provides isolated nucleic acid molecules comprising nucleic acid sequences encoding heavy chains and / or light chains and fragments thereof. When produced in cells, nucleic acid molecules comprising sequences encoding both light and heavy chains or fragments thereof can be engineered to include synthetic signal sequences for antibody or fragment secretion. Furthermore, the nucleic acid molecules may contain specific DNA links that allow the insertion of other antibody sequences and maintain the translation reading frame, thereby not altering the amino acids typically present in antibody sequences.

[0443] According to the present invention, a nucleic acid sequence encoding an antibody can be inserted into a suitable expression vector. In several embodiments, the expression vector contains elements necessary for the transcription and translation of the inserted nucleic acid encoding the antibody to produce a recombinant DNA molecule that directs the expression of an antibody sequence for the formation of an antibody or a fragment thereof.

[0444] Nucleic acids encoding antibodies or fragments thereof can be subjected to a variety of recombinant nucleic acid techniques known to those skilled in the art, such as site-directed mutagenesis.

[0445] Nucleic acids can be expressed in cells using various methods. Nucleic acids can be cloned into several vector types. However, this invention should not be considered limited to any specific vector. Instead, it should be considered to encompass a variety of readily available and / or known vectors in the art. For example, the nucleic acids of this invention can be cloned into vectors, including but not limited to: plasmids, phages, phage derivatives, animal viruses, and entrapments. Vectors of particular interest include expression vectors, replication vectors, probe-generating vectors, and sequencing vectors.

[0446] In specific embodiments, the expression vector is selected from viral vectors, bacterial vectors, and mammalian cell vectors. Various expression vector systems exist that include at least some or all of the components discussed above. Systems based on prokaryotic and / or eukaryotic vectors can be used in conjunction with this invention to produce polynucleotides or their homologous polypeptides. Numerous such systems are commercially available and widely applicable.

[0447] Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (2012) and Ausubel et al. (1999) and in other virology and molecular biology handbooks. Viruses useful as vectors include, but are not limited to, retroviruses, adenoviruses, adenovirus-associated viruses, herpesviruses, and lentiviruses. In some embodiments, murine stem cell virus (MSCV) vectors are used to express the desired nucleic acid. MSCV vectors have been shown to express the desired nucleic acid efficiently in cells. However, the invention should not be limited to the use of MSCV vectors, but any method of retroviral expression is included in the invention. Other examples of viral vectors are those based on Moloney mouse leukemia virus (MoMuLV) and human immunodeficiency virus (HIV). In some embodiments, suitable vectors contain an origin of replication that functions in at least one organism, a promoter sequence, a convenient restriction endonuclease site, and one or more optional markers. (See, for example, WO 01 / 96584; WO 01 / 29058; and U.S. Patent No. 6,326,193).

[0448] Other regulatory elements, such as enhancers, can be used to regulate the frequency of transcription initiation. A promoter can be a promoter that naturally binds to a gene or nucleic acid sequence, such as one obtained by isolating a 5' non-coding sequence located upstream of the coding segment and / or exon. Such a promoter can be referred to as "endogenous." Similarly, an enhancer can be an enhancer that naturally binds to a nucleic acid sequence, located downstream or upstream of the sequence. Alternatively, certain advantages can be gained by placing the coding nucleic acid segment under the control of a recombinant or heterologous promoter, which refers to a promoter that does not normally bind to the nucleic acid sequence in its natural environment. A recombinant or heterologous enhancer also refers to an enhancer that does not normally bind to the nucleic acid sequence in its natural environment. These promoters or enhancers can include promoters or enhancers of other genes, and promoters or enhancers isolated from any other prokaryotic, viral, or eukaryotic cells, as well as non-"naturally occurring" promoters or enhancers, such as promoters or enhancers containing different elements of different transcriptional regulatory regions and / or mutants that alter expression. In addition to synthesizing nucleic acid sequences that generate promoters and enhancers, recombinant cloning and / or nucleic acid amplification techniques, including PCR-generated sequences, can be used in conjunction with the components disclosed herein (US Patent Nos. 4,683,202 and 5,928,906). Furthermore, control sequences that guide transcription and / or expression of sequences in non-nuclear organelles, such as mitochondria and chloroplasts, can also be considered.

[0449] Naturally, it is important to use promoters and / or enhancers that effectively direct the expression of DNA segments in the chosen cell type, organelle, and organism for expression. Those skilled in the art of molecular biology are generally familiar with how combinations of promoters, enhancers, and cell types can be used for protein expression; see, for example, Sambrook et al. (2012). The promoters used can be constitutive, tissue-specific, inducible, and / or useful under appropriate conditions to direct high-level expression of the introduced DNA segment, as is advantageous in the large-scale production of recombinant proteins and their fragments.

[0450] An example of a promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high-level expression of any polynucleotide sequence operatively linked thereto. However, other constitutive promoter sequences may also be used, including but not limited to: simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), HIV long terminal repeat (LTR) promoter, Moloney virus promoter, avian leukosis virus promoter, E. coli / Bard's virus immediate early promoter, Raul's sarcoma virus promoter, and human gene promoters such as (but not limited to) actin promoter, myosin promoter, hemoglobin promoter, and muscle creatine promoter. Furthermore, the invention should not be limited to the use of constitutive promoters. Inducible promoters are also contemplated as part of the invention. The use of inducible promoters in the invention provides a molecular switch that can turn on the expression of the polynucleotide sequence operatively linked thereto when such expression is desired, or turn off expression when expression is not desired. Examples of inducible promoters include, but are not limited to, metallothionine promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters. Furthermore, the present invention includes the use of tissue-specific or cell-type-specific promoters, which are promoters that are active only in the desired tissue or cell. Tissue-specific promoters are well known in the art and include, but are not limited to, HER-2 promoters and PSA-related promoter sequences.

[0451] To evaluate the expression of the nucleic acid, the expression vector to be introduced into the cell may also contain an optional marker gene or a reporter gene, or both, to facilitate the identification and selection of expressing cells from a population of cells attempting to be transfected or infected by a viral vector. In other embodiments, the optional marker may be carried on a separate nucleic acid and used in a co-transfection procedure. Both the optional marker and the reporter gene may be side-linked with appropriate regulatory sequences to enable expression in host cells. Useful optional markers are known in the art and include, for example, antibiotic resistance genes suc...

Claims

1. Fusion protein, comprising: a) The anti-human C5 antibody portion that specifically binds to human C5, and b) Factor H (FH) or its functional fragment; in, The anti-human C5 antibody portion comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: The VH comprises: VH-CDR1, listed in the amino acid sequence of SEQ ID NO: 47, VH-CDR2, listed in the amino acid sequence of SEQ ID NO: 57, and VH-CDR3, listed in the amino acid sequence of SEQ ID NO: 49; and the VL comprises: VL-CDR1, listed in the amino acid sequence of SEQ ID NO: 23, VL-CDR2, listed in the amino acid sequence of SEQ ID NO: 9, and VL-CDR3, listed in the amino acid sequence of SEQ ID NO: 10; and The functional fragment of FH includes short common repeat (SCR) domains 1-4 or 1-5 of the FH protein.

2. The fusion protein according to claim 1, wherein: The VH comprises amino acid residues 20-144 of the amino acid sequence of SEQ ID NO: 59 or a variant thereof having at least 85% sequence identity with amino acid residues 20-144 of the amino acid sequence of SEQ ID NO: 59; and the VL comprises amino acid residues 21-127 of the amino acid sequence of SEQ ID NO: 25 or a variant thereof having at least 85% sequence identity with amino acid residues 21-127 of the amino acid sequence of SEQ ID NO:

25.

3. The fusion protein according to claim 2, wherein: The VH comprises amino acid residues 20-144 of the amino acid sequence of SEQ ID NO: 59, and the VL comprises amino acid residues 21-127 of the amino acid sequence of SEQ ID NO:

25.

4. The fusion protein of claim 1, wherein the binding of the anti-human C5 antibody portion to human C5 is pH-dependent, and The anti-human C5 antibody moiety described therein binds to human C5 more strongly at neutral pH than it does at acidic pH.

5. The fusion protein according to claim 1, wherein the functional fragment of FH comprises: (i) amino acid residues 474-773 of the amino acid sequence of SEQ ID NO: 72, or (ii) amino acid residues 21-320 of the amino acid sequence of SEQ ID NO:

81.

6. The fusion protein according to claim 1, wherein, The anti-human C5 antibody is a full-length antibody, Fab, Fab', F(ab)2, F(ab')2, scFv, or a combination thereof.

7. The fusion protein according to claim 6, wherein, The FH or its functional fragment is fused to the C-terminus of the anti-human C5 antibody moiety.

8. The fusion protein according to claim 7, wherein, The FH or its functional fragment is fused to the C-terminus of the anti-human C5 antibody moiety via a linker.

9. The fusion protein according to claim 6, wherein, The anti-human C5 antibody is partly a full-length anti-C5 antibody.

10. The fusion protein according to claim 9, wherein, The full-length anti-C5 antibody contains a human IgG4 Fc fragment.

11. The fusion protein according to claim 10, wherein, The Fc fragment contains the amino acid sequence of any one of SEQ ID NO: 32, 33 and 61.

12. The fusion protein according to claim 11, wherein, The Fc fragment contains the amino acid sequence of SEQ ID NO:

61.

13. The fusion protein according to claim 9, wherein, The FH or its functional fragment is fused to the C-terminus of one or both heavy chains of the full-length anti-C5 antibody to form one or two FH or its functional fragment-heavy chain fusion peptides.

14. The fusion protein according to claim 13, wherein, The fusion protein comprises a first functional fragment of FH and a second functional fragment of FH, wherein the first functional fragment of FH is fused to the C-terminus of the first heavy chain of the full-length anti-C5 antibody to form a first FH functional fragment-heavy chain fusion polypeptide, and the second functional fragment of FH is fused to the C-terminus of the second heavy chain of the full-length anti-C5 antibody to form a second FH functional fragment-heavy chain fusion polypeptide.

15. The fusion protein according to claim 14, wherein, The full-length anti-C5 antibody comprises two light chains, each containing amino acid residues 21-234 of SEQ ID NO: 74, wherein the first FH functional fragment-heavy chain fusion polypeptide and the second FH functional fragment-heavy chain fusion polypeptide each contain amino acid residues 20-777 of the amino acid sequence of SEQ ID NO:

72.

16. An isolated nucleic acid encoding a fusion protein according to any one of claims 1-15.

17. The isolated nucleic acid according to claim 16, wherein, The isolated nucleic acid contains a nucleic acid sequence of any one of SEQ ID NO: 24, 58, 71 and 73.

18. A vector comprising the isolated nucleic acid according to claim 16 or 17.

19. The vector according to claim 18, wherein it is a viral vector.

20. The carrier according to claim 19, wherein, The viral vector is a retroviral vector, an adenovirus vector, an adenovirus-associated viral vector, or a herpesvirus vector.

21. The carrier according to claim 19, wherein, The viral vector is a retroviral vector.

22. The carrier according to claim 19, wherein, The viral vector is a lentiviral vector.

23. The carrier according to claim 19, wherein, The viral vector is a human immunodeficiency virus vector.

24. The carrier according to claim 22, wherein, The lentiviral vector is either a murine stem cell virus vector or a Moloney mouse leukemia virus vector.

25. A host cell expressing a fusion protein according to any one of claims 1-15, or a vector comprising the nucleic acid according to claim 16 or 17, or any one of claims 18-24.

26. A pharmaceutical composition comprising: a fusion protein according to any one of claims 1-15, a nucleic acid according to claim 16 or 17, or a vector according to any one of claims 18-24.

27. The use of the fusion protein according to any one of claims 1-15, the nucleic acid according to claim 16 or 17, the vector according to any one of claims 18-24, or the pharmaceutical composition according to claim 26 in the preparation of a medicament for treating complement pathway-mediated diseases or conditions in an individual. The diseases or conditions mediated by the complement pathway are selected from the group consisting of: macular degeneration (MD), ischemia-reperfusion injury, stroke, asthma, chronic obstructive pulmonary disease (COPD), paroxysmal nocturnal hemoglobinuria (PNH) syndrome, myasthenia gravis, multiple sclerosis, delayed graft function recovery, antibody-mediated rejection, atypical hemolytic uremic syndrome (aHUS), central retinal vein occlusion (CRVO), central retinal artery occlusion (CRAO), bullous epidermolysis, sepsis, inflammation, organ transplantation, C3 glomerulonephropathy (C3G), membranous nephropathy, IgA nephropathy, Shiga toxin-induced HUS, antiphospholipid antibody-induced pregnancy loss, and any combination thereof.

28. The application according to claim 27, wherein: i) Diseases or conditions mediated by the complement pathway include inflammation, and said inflammation includes one or more of the following: inflammation associated with cardiopulmonary bypass, inflammation associated with renal dialysis, glomerulonephritis, arthritis, neuromyelitis optica (NMO), postoperative systemic inflammatory syndrome, antineutrophil cytoplasmic antibody (ANCA)-mediated vasculitis, lupus, and / or ulcerative colitis; and / or ii) Diseases or conditions mediated by the complement pathway include macular degeneration, and said macular degeneration includes age-related macular degeneration (AMD); and / or iii) Diseases or conditions mediated by the complement pathway include asthma, and the asthma includes allergic asthma.

29. The application of claim 28, wherein the complement pathway-mediated disease or condition includes inflammation, wherein: i) The inflammation includes glomerulonephritis, and the glomerulonephritis includes anti-neutrophil cytoplasmic antibody (ANCA)-mediated glomerulonephritis, lupus nephritis, or any combination thereof; and / or ii) The inflammation includes arthritis, and the arthritis is rheumatoid arthritis.

30. The use of the fusion protein according to any one of claims 1-15, the isolated nucleic acid according to claim 16 or 17, the carrier according to any one of claims 18-24, or the pharmaceutical composition according to claim 26 in the preparation of a medicament for reducing individual complement system activity, wherein... The activity of the complement system is associated with diseases or conditions selected from the group consisting of: macular degeneration (MD), ischemia-reperfusion injury, stroke, asthma, chronic obstructive pulmonary disease (COPD), paroxysmal nocturnal hemoglobinuria (PNH) syndrome, myasthenia gravis, multiple sclerosis, delayed graft function recovery, antibody-mediated rejection, atypical hemolytic uremic syndrome (aHUS), central retinal vein occlusion (CRVO), central retinal artery occlusion (CRAO), bullous epidermolysis, sepsis, inflammation, organ transplantation, C3 glomerulonephropathy (C3G), membranous nephropathy, IgA nephropathy, Shiga toxin-induced HUS, antiphospholipid antibody-induced pregnancy loss, and any combination thereof.

31. The application according to claim 30, wherein: i) The disease or condition includes inflammation, and the inflammation includes one or more of the following: inflammation associated with cardiopulmonary bypass, inflammation associated with kidney dialysis, glomerulonephritis, arthritis, neuromyelitis optica (NMO), postoperative systemic inflammatory syndrome, antineutrophil cytoplasmic antibody (ANCA)-mediated vasculitis, lupus, and / or ulcerative colitis; and / or ii) The disease or condition includes macular degeneration, and the macular degeneration includes age-related macular degeneration (AMD); and / or iii) The disease or condition mentioned includes asthma, and the asthma includes allergic asthma.

32. The application according to claim 31, wherein the disease or condition includes inflammation, wherein: i) The inflammation includes glomerulonephritis, and said glomerulonephritis includes anti-neutrophil cytoplasmic antibody (ANCA)-mediated glomerulonephritis, lupus nephritis, or any combination thereof; and / or ii) The inflammation includes arthritis, and the arthritis mentioned therein is rheumatoid arthritis.

33. The application according to claim 27, wherein the individual is a person.

34. The application according to claim 30, wherein the individual is a person.

35. A method for producing a fusion protein, comprising: a) Culturing host cells containing the nucleic acid of claim 16 or 17 or the vector of any one of claims 18-24, or the host cells of claim 25, under conditions suitable for the expression of the fusion protein; and b) Recover the expressed fusion protein from the host cell.

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