Anti-C5 antibodies fused to factor H for use in the treatment of complement-mediated diseases

Abstract

The present application provides a method for treating a complement-mediated disease in a human individual, the method comprising administering to the individual an effective amount of a fusion protein comprising: i) an antibody portion that specifically binds to human C5; and ii) factor H (FH) or a functional fragment thereof. The complement-mediated disease can be, for example, paroxysmal nocturnal hemoglobinuria (PNH) syndrome, C3 glomerulopathy (C3G), IgA nephropathy (IgAN), and thrombotic microangiopathy secondary to systemic lupus erythematosus (SLE-TMA).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 421,993, filed November 2, 2022, U.S. Provisional Patent Application No. 63 / 486,949, filed February 24, 2023, International Patent Application No. PCT / US2023 / 063305, filed February 26, 2023, and U.S. Provisional Patent Application No. 63 / 501,264, filed May 10, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Electronic Sequence Listing Reference The contents of the electronic sequence listing (792252001241seqlist.xml; size: 153,067 bytes; and creation date: October 16, 2023) are incorporated herein by reference in their entirety.

[0003] FIELD OF THE INVENTION The present invention relates to compositions and methods for treating complement-mediated diseases. [Background technology]

[0004] The complement system is part of innate immunity and plays a key role in host defense. It enhances (complements) the ability of antibodies and phagocytes to remove microorganisms and damaged cells from the organism, promote inflammation, and attack pathogen cell membranes. However, activated complement can also cause significant tissue damage and destruction, and dysregulation of complement activity has been found to be associated with several rare and common diseases, including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), rheumatoid arthritis (RA), and age-related macular degeneration (AMD). Therefore, anti-complement therapy is a promising approach to treat these human disorders.

[0005] Complement activation involves a cascade of target recognition and proteolytic cleavage. It can be activated through three distinct pathways, all of which converge at the C3 activation step. These pathways are the classical pathway, the alternative pathway, and the lectin pathway. The classical pathway (CP) is activated by antigen-antibody complexes, sequentially activating C1 and C4 / C2, before converging with other pathways at the C3 activation step. The lectin pathway (LP) is triggered when specific pattern recognition molecules, such as mannose-binding lectin (MBL), collectins, and ficolins, bind to microbial surface sugar molecules. This activates mannan-binding lectin serine proteases (MASPs), which then cleave C4 / C2 and join with other pathways at the C3 activation step. The alternative pathway (AP) is constitutively active at a low level due to spontaneous hydrolysis and activation of C3 to produce C3(HO). The latter can associate with factor B and, upon proteolytic activation by factor D, generate the initial C3-cleaving enzyme complex, C3(H2O)Bb. In the absence of regulatory proteins, the product of the C3(H2O)Bb complex, C3b, can associate with factor B in the same way as C3(H2O), thus initiating another self-amplifying cycle of C3 activation.

[0006] Ongoing efforts to target C3 activation in complement-dependent diseases use C3-inhibitory cyclic peptides or short recombinant variants of FH, but these have very poor pharmacokinetics and require large and frequent (e.g., daily) dosing.

[0007] C3 activation also leads to the generation of the C5-cleavage enzyme complex, which initiates the terminal complement activation pathway and ultimately leads to the production of potent proinflammatory mediators C5a and the membrane attack complex (MAC) C5b-9, which can cause cell lysis and death. To prevent complement from causing indiscriminate damage, host cells express several membrane-anchored regulators that function to block complement activation and amplification. Some of these regulators, including decay-accelerating factor (DAF, CD55) and MCP, act to inhibit C3 activation, while others, such as CD59, act at other stages of the complement activation cascade. In addition to membrane-anchored complement regulators, fluid-phase regulators also exist in the blood that act to preferentially protect host tissues. Fluid-phase inhibitors include factor H (FH) and factor I (FI), which are essential inhibitors of the alternative pathway of complement activation, and C4BP and C1 inhibitor (C1INH), which inhibit classical pathway complement activation. Both fluid-phase and membrane-anchored complement regulatory proteins are often composed of multiple conserved SCR domains, for example, FH is composed of 20 SCRs.

[0008] Complement C5 is an essential protein in the terminal pathway of complement activation and is the precursor protein for generating the potent proinflammatory mediator C5a and the cytolytic membrane attack complex (MAC).

[0009] Several human inflammatory and autoimmune diseases are mediated by C5a and / or MAC, and blocking C5 activation would prevent the production of C5a and MAC and be of therapeutic value. The humanized murine anti-human C5 mAb, eculizumab (e.g., Soliris®), has been used to treat two complement-mediated diseases: paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). However, not all PNH patients respond to eculizumab treatment, and one of the reasons for this non-responsiveness is a genetic polymorphism in human C5 that has lost the epitope that binds to eculizumab. In addition, because the plasma concentration of C5 is high and the antibody is rapidly cleared via targeting, eculizumab must be administered to patients at high doses and frequently. Therefore, more effective and easier-to-use anti-complement drugs are needed for the treatment of both PNH and aHUS, as well as other complement-mediated diseases.

[0010] The disclosures of all publications, patents, patent applications and published patent applications mentioned herein are hereby incorporated by reference in their entirety. Summary of the Invention [Means for solving the problem]

[0011] In one aspect, the present application provides a method for treating a complement-mediated disease in a human individual, the method comprising administering to the human individual an effective amount of a fusion protein comprising: i) an antibody portion that specifically binds to human C5 (an "anti-C5 antibody portion"); and ii) factor H (FH) or a fragment thereof.

[0012] In some embodiments according to any one of the above methods, the complement-mediated disease is selected from the group consisting of paroxysmal nocturnal hemoglobinuria (PNH) syndrome, C3 glomerulopathy (C3G), IgA nephropathy (IgAN), and thrombotic microangiopathy secondary to systemic lupus erythematosus (SLE-TMA). In some embodiments, the complement-mediated disease is PNH. In some embodiments, the complement-mediated disease is C3G. In some embodiments, the complement-mediated disease is IgAN. In some embodiments, the complement-mediated disease is SLE-TMA.

[0013] In some embodiments according to any one of the above methods, the fusion protein is administered intravenously (IV) or subcutaneously (SC).

[0014] In some embodiments according to any one of the above methods, the fusion protein is administered at a dose of about 60 mg to about 3600 mg (e.g., about 60 mg to about 1200 mg, about 600 mg to 1200 mg, about 600 mg to about 2880 mg, about 600 mg to about 3600 mg, about 1200 mg to about 3600 mg, about 2400 mg to about 3600 mg, about 720 mg to about 1440 mg, about 1920 mg to about 2880 mg, or about 1800 mg to about 2400 mg).

[0015] In some embodiments of any one of the above methods, the fusion protein is administered in a single dose. In some embodiments, the fusion protein is administered in a dose of about 60 mg to about 1200 mg (e.g., about 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720, 780, 840, 900, 960, or 1200 mg). In some embodiments, the fusion protein is administered in a dose of about 60 mg IV, about 180 mg IV, about 180 mg SC, about 360 mg IV, about 600 mg IV, about 720 mg SC, or about 1200 mg IV.

[0016] In some embodiments of any one of the above methods, the fusion protein is administered in multiple doses. In some embodiments, the fusion protein is administered once every week (QW). In some embodiments, the fusion protein is administered once every other week (Q2W). In some embodiments, the fusion protein is administered at a dose of about 600 mg to about 2880 mg (e.g., about 600 mg to 1200 mg, about 600 mg to about 2400 mg, about 1200 mg to about 2880 mg, about 2400 mg to about 2880 mg, about 720 mg to about 1440 mg, about 720 mg to about 1920 mg, about 1920 mg to about 2880 mg, or about 1800 mg to about 2400 mg). In some embodiments, the fusion protein is administered in multiple doses (e.g., QW or Q2W) of about 600 mg, 660 mg, 720 mg, 780 mg, 840 mg, 900 mg, 960 mg, 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, 2880 mg, 3000 mg, or 3600 mg each. In some embodiments, the fusion protein is administered at a dose of about 600 mg IV once weekly for 5 weeks.

[0017] In some embodiments according to any one of the above methods, the fusion protein is administered in an initial phase comprising administering the fusion protein in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or more) initial doses, followed by a maintenance phase comprising administering the fusion protein in two or more (e.g., 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 23, 24, 25, 26, 40, 44, 47, 48, 49, 50 or more) doses (e.g., once every week or once every other week). In some embodiments, the initial dose is about 600 mg to about 3600 mg, e.g., about 1200 mg to about 3600 mg (e.g., about 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, 2880 mg, 3000 mg, or 3600 mg). In some embodiments, one or more initial doses of the fusion protein are administered IV. In some embodiments, the initial phase comprises administering a single initial dose of the fusion protein. In some embodiments, the maintenance dose is about 600 mg to about 2880 mg (e.g., about 600 mg, 720 mg, 960 mg, 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, or 2880 mg). In some embodiments, two or more maintenance doses of the fusion protein are administered weekly. In some embodiments, the maintenance dose (e.g., once weekly) is about 600 mg to about 1440 mg (e.g., about 600 mg, 720 mg, 840 mg, 960 mg, 1080 mg, 1200 mg, 1320 mg, or 1440 mg). In some embodiments, two or more maintenance doses (e.g., once weekly) of the fusion protein are each administered at about 600 mg IV to about 1200 mg IV, or about 720 mg SC to about 1440 mg SC (e.g., about 600 mg IV, 1200 mg IV, 720 mg SC, 960 mg SC, or 1440 mg SC). In some embodiments, two or more maintenance doses of the fusion protein are administered every other week.In some embodiments, the maintenance dose (e.g., once every other week) is about 960 mg to about 2880 mg (e.g., about 960 mg, 1800 mg, 1920 mg, 2000 mg, 2200 mg, 2400 mg, 2600 mg, or 2880 mg). In some embodiments, two or more maintenance doses (e.g., once every other week) of the fusion protein are each administered at about 960 mg SC to about 1920 mg SC, about 1920 mg SC to about 2880 mg SC, about 1800 mg SC to about 2880 mg SC, or about 1800 mg SC to about 2400 mg SC (e.g., about 960 mg SC, 1800 mg SC, 1920 mg SC, 2400 mg SC, or 2880 mg SC). In some embodiments, the maintenance phase is at least about 4 weeks (e.g., at least about any of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 36, 38, 40, 42, 44, 45, 46, 47, 48, 49, 50, 52 weeks or more), e.g., at least about 12 weeks (e.g., at least about any of 12, 13, 24, 25, 48, or 49 weeks). In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg once weekly one or more times (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or more times), and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg once weekly or once every other week at least two times (e.g., 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 23, 24, 25, 26, 40, 44, 47, 48, 49, 50 or more times). In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC once weekly for four weeks starting on day 8. In some embodiments, the maintenance phase comprises administering the fusion protein at a first maintenance dose once every week or once every other week during a first maintenance phase, followed by administering the fusion protein at a second maintenance dose once every week or once every other week during a second maintenance phase.In some embodiments, the second maintenance dose is higher than the first maintenance dose. In some embodiments, the duration of the second maintenance phase is longer than the duration of the first maintenance phase. In some embodiments, the first maintenance dose of the fusion protein is administered at about 720 mg SC or about 600 mg IV once weekly, and the second maintenance dose of the fusion protein is administered at about 1440 mg SC or about 1200 mg IV once weekly. In some embodiments, the duration of the first maintenance phase is about 4 weeks, and the duration of the second maintenance phase is at least about 44 weeks. In some embodiments, the complement-mediated disease is C3G or IgAN. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises i) administering the fusion protein at a first maintenance dose of about 720 mg SC or about 600 mg IV once weekly starting on day 8 for about 4 weeks, followed by ii) administering the fusion protein at a second maintenance dose of about 1440 mg SC or about 1200 mg IV once weekly starting on day 36 for about 44 weeks.

[0018] In some embodiments of any one of the above methods, the initial phase comprises administering the fusion protein at an initial dose of about 600 mg IV to about 3600 mg IV on day 1, and the maintenance phase, beginning on day 8, comprises administering the fusion protein at a maintenance dose of: i) about 600 mg IV to about 1200 mg IV once weekly; ii) about 720 mg SC to about 1440 mg SC once weekly; iii) about 1920 mg SC to about 2880 mg SC once every other week; iv) about 1800 mg SC to about 2400 mg SC once every other week; or v) about 960 mg SC to about 2880 mg SC once every other week. In some embodiments, the maintenance phase is at least about 12 weeks for weekly maintenance dosing, or at least about 13 weeks for biweekly maintenance dosing. In some embodiments, the maintenance phase is at least about 24 weeks for weekly maintenance dosing, or at least about 25 weeks for biweekly maintenance dosing. In some embodiments, the maintenance phase is at least about 48 weeks for once-weekly maintenance dosing, or at least about 49 weeks for once-every-weekly maintenance dosing.

[0019] In some embodiments of any one of the above methods, the complement-mediated disease is PNH. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV on day 1, and the maintenance phase, starting on day 8, comprises administering the fusion protein at a maintenance dose of: i) about 600 mg IV to about 1200 mg IV once weekly for at least about 12 weeks; ii) about 720 mg SC to about 1440 mg SC once weekly for at least about 12 weeks; iii) about 1920 mg SC to about 2880 mg SC once every other week for at least about 13 weeks; or iv) about 960 mg SC to about 2880 mg SC once every other week for at least about 13 weeks. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC or about 600 mg IV once weekly for about 12 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC once weekly for about 12 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 3600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC (e.g., about 2880 mg SC) once every other week for about 13 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV to about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC to about 2880 mg SC once every other week for about 13 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC to about 2880 mg SC once every other week for about 13 weeks starting on day 8.In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV to about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC once every other week for about 13 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC once every other week for about 13 weeks starting on day 8. In some embodiments, the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extended doses after the maintenance phase. In some embodiments, the extension phase comprises administering the fusion protein at an extended dose of about 1920 mg SC once every other week for about 9 months.

[0020] In some embodiments according to any one of the above methods, the complement-mediated disease is SLE-TMA. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV on day 1, and the maintenance phase comprises: i) administering the fusion protein at a maintenance dose of about 720 mg SC to about 1440 mg SC once weekly starting on day 8 for at least about 24 weeks; ii) administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week starting on day 8 for at least about 25 weeks; iii) administering the fusion protein at a first maintenance dose of about 600 mg IV to about 1200 mg IV once weekly for the duration of the first maintenance phase, followed by administering the fusion protein at a second maintenance dose of about 720 mg SC to about 1440 mg SC once weekly for the duration of the second maintenance phase, wherein the maintenance phase is at least about 24 weeks; or iv) administering the fusion protein at about 600 mg IV to about 1200 mg IV once weekly for the duration of the first maintenance phase. The maintenance phase comprises administering the fusion protein at a first maintenance dose of about 1200 mg IV to about 1200 mg SC, followed by administering the fusion protein at a second maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week during a second maintenance phase, the maintenance phase being at least about 25 weeks. In some embodiments, the duration of the first maintenance phase is at least about 1 week, and the duration of the second maintenance phase is not more than about 23 or about 24 weeks. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC once weekly starting on day 8 for about 24 weeks.

[0021] In some embodiments of any one of the above methods, the complement-mediated disease is C3G or IgAN. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 600 mg IV to about 3600 mg IV (e.g., about 1200 mg IV to about 3600 mg IV) on day 1, and the maintenance phase, starting on day 8, comprises administering the fusion protein at a maintenance dose of: i) about 600 mg IV to about 1200 mg IV once weekly for at least about 48 weeks; ii) about 720 mg SC to about 1440 mg SC once weekly for at least about 48 weeks; iii) about 1920 mg SC to about 2880 mg SC once every other week for at least about 49 weeks; iv) about 1800 mg SC to about 2400 mg SC once every other week for at least about 49 weeks; or v) about 960 mg SC to about 2880 mg SC once every other week for about 49 weeks. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC or about 600 mg IV once weekly for about 48 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1440 mg SC or about 1200 mg IV once weekly for about 48 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 2400 mg IV to about 3600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week for about 49 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC to about 2880 mg SC once every other week for about 49 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC once weekly for about 48 weeks starting on day 8.

[0022] In some embodiments according to any one of the above methods, binding of the anti-C5 antibody portion to human C5 is pH-dependent, and the anti-C5 antibody portion binds to human C5 more strongly at neutral pH (e.g., about pH 7.4, e.g., the pH found in blood) than at acidic pH (e.g., about pH 5.8, e.g., the pH found in endosomes).

[0023] In some embodiments according to any one of the above methods, the anti-C5 antibody portion is a full-length antibody, a Fab, a Fab', a F(ab)2, a F(ab')2, an scFv, or a combination thereof.

[0024] In some embodiments according to any one of the above methods, the anti-C5 antibody portion is a full-length antibody ("anti-C5 full-length antibody"). In some embodiments, the anti-C5 full-length antibody comprises an Fc fragment derived from human IgG4. In some embodiments, the Fc fragment comprises the amino acid sequence of any of SEQ ID NOs: 32, 33, and 61, e.g., SEQ ID NO: 61. In some embodiments, the anti-C5 full-length antibody comprises a heavy chain and a light chain, wherein (i) the heavy chain comprises the amino acid sequence of SEQ ID NO: 119 and the light chain comprises the amino acid sequence of SEQ ID NO: 74; (ii) the heavy chain comprises the amino acid sequence of SEQ ID NO: 121 and the light chain comprises the amino acid sequence of SEQ ID NO: 74; (iii) the heavy chain comprises the amino acid sequence of SEQ ID NO: 123 and the light chain comprises the amino acid sequence of SEQ ID NO: 74; or (iv) the heavy chain comprises the amino acid sequence of SEQ ID NO: 125 and the light chain comprises the amino acid sequence of SEQ ID NO: (v) the heavy chain comprises the amino acid sequence of SEQ ID NO: 120 and the light chain comprises the amino acid sequence of SEQ ID NO: 90; (vi) the heavy chain comprises the amino acid sequence of SEQ ID NO: 122 and the light chain comprises the amino acid sequence of SEQ ID NO: 90; (vii) the heavy chain comprises the amino acid sequence of SEQ ID NO: 124 and the light chain comprises the amino acid sequence of SEQ ID NO: 90; or (viii) the heavy chain comprises the amino acid sequence of SEQ ID NO: 126 and the light chain comprises the amino acid sequence of SEQ ID NO: 90.

[0025] In some embodiments according to any one of the above methods, the fusion protein inhibits activation of C3.

[0026] In some embodiments according to any one of the above methods, the functional fragment of FH comprises short consensus repeat (SCR) domains 1-5 of the FH protein. In some embodiments, the functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 85.

[0027] In some embodiments according to any one of the above methods, the fusion protein comprises a first FH or functional fragment thereof and a second FH or functional fragment thereof, wherein the first FH or functional fragment thereof is fused to the C-terminus of a first heavy chain of an anti-C5 full-length antibody, and the second FH or functional fragment thereof is fused to the C-terminus of a second heavy chain of an anti-C5 full-length antibody. In some embodiments, (i) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 72, and each light chain comprises the amino acid sequence of SEQ ID NO: 74; (ii) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 76, and each light chain comprises the amino acid sequence of SEQ ID NO: 74; (iii) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 78, and each light chain comprises the amino acid sequence of SEQ ID NO: 74; or (iv) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 80, and each light chain comprises the amino acid sequence of SEQ ID NO: 74. (v) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 89, and each light chain comprises the amino acid sequence of SEQ ID NO: 90; (vi) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 116, and each light chain comprises the amino acid sequence of SEQ ID NO: 90; (vii) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 117, and each light chain comprises the amino acid sequence of SEQ ID NO: 90; or (viii) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 118, and each light chain comprises the amino acid sequence of SEQ ID NO: 90.

[0028] In some embodiments according to any one of the above methods, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0.

[0029] The methods described herein can use any of the fusion proteins described herein. The anti-C5 antibody portion and the FH portion are described in more detail below. [Brief explanation of the drawings]

[0030] [Figure 1A] 1 illustrates the bifunctional structure of the anti-C5-FH fusion protein and the SDS-PAGE separation of the humanized anti-C5 mAb and the anti-C5-FH fusion protein. [Figure 1B] 1 illustrates the binding of 2G1-3 to a distinct epitope from eculizumab.

[0031] [Figure 2] (A) Illustrates a C5 inhibition assay (sheep red blood cell (RBC) lysis) showing that the anti-C5-FH fusion protein is as potent as ravulizumab in inhibiting terminal pathway complement activation triggered by CP. (B) Illustrates an LPS-based ELISA assay showing that the anti-C5-FH fusion protein also inhibits AP complement. (C) Illustrates a rabbit RBC lysis assay showing that the anti-C5-FH fusion protein, alone or in combination, is more potent than anti-C5 mAb or FH SCR1-5-Fc in inhibiting terminal pathway complement activation triggered by AP.

[0032] [Figure 3] 1 illustrates that anti-C5-FH fusion protein is more potent than Ecu / Rav mAb in inhibiting lysis of human PNH RBCs and differs from Ecu / Rav in inhibiting opsonization of C3b fragments of non-lysed PNH RBCs.

[0033] [Figure 4-1] 1 illustrates that anti-C5-FH fusion protein dose-dependently inhibited extravascular hemolysis (EVH) in a mouse model of EVH. [Figure 4-2] 1 illustrates that anti-C5-FH fusion protein dose-dependently inhibited extravascular hemolysis (EVH) in a mouse model of EVH.

[0034] [Figure 5-1] 1 illustrates that anti-C5-FH fusion proteins have tissue targeting properties to cells with C5b-9 deposits. [Figure 5-2] 1 illustrates that anti-C5-FH fusion proteins have tissue targeting properties to cells with C5b-9 deposits.

[0035] [Figure 6A] Illustrated are survival curves for FHm / mP− / − and FHm / mP− / − factor D humanized mice (hFD-FHm / mP− / −). [Figure 6B] Immunofluorescence staining of C3 in hFD-FHm / mP− / − mice is depicted. [Figure 6C] 1 depicts protein levels of C3 and C5 in FHm / mP− / − and hFD-FHm / mP− / − mice.

[0036] [Figure 7] A illustrates a novel bifunctional complement inhibitor comprising an anti-C5 mAb (BB5.1) and a mouse factor H SCR1-5 fusion protein. B illustrates a sheep red blood cell (RBC) lysis assay performed with 50% mouse plasma for mouse anti-C5-FH fusion protein and BB5.1. C illustrates a rabbit RBC lysis assay performed with 50% mouse plasma for mouse anti-C5-FH fusion protein and BB5.1. D illustrates an LPS-based ELISA assay for mouse anti-C5-FH fusion protein and BB5.1.

[0037] [Figure 8A]1 illustrates survival curves of hFD-FHm / mP− / − mice treated with either mouse anti-C5-FH fusion protein or BB5.1. [Figure 8B] 1 depicts protein levels of systemic C3 and factor B consumption in hFD-FHm / mP− / − mice injected with mouse anti-C5-FH fusion protein or BB5.1. [Figure 8C] 1 illustrates the proteinuria and hematuria scores in hFD-FHm / mP− / − mice injected with mouse anti-C5-FH fusion protein or BB5.1. [Figure 8D] Illustrates the scores of crescents and fibrin deposition, intraductal pleocytosis, and mesangial pleocytosis in hFD-FHm / mP− / − mice injected with mouse anti-C5-FH fusion protein or BB5.1. [Figure 8E] 1 depicts immunofluorescence staining and quantification of glomerular C3 and C9 deposition in hFD-FHm / mP− / − mice injected with mouse anti-C5-FH fusion protein or BB5.1.

[0038] [Figure 9] The phase 1 anti-C5-FH fusion protein clinical trial scheme is illustrated.

[0039] [Figure 10A] A table of demographic characteristics is illustrated. [Figure 10B] A table of demographic characteristics is illustrated.

[0040] [Figure 11-1] A table of the most frequently reported treatment-emergent adverse events is illustrated. [Figure 11-2] A table of the most frequently reported treatment-emergent adverse events is illustrated.

[0041] [Figure 12A] 1 depicts anti-C5-FH fusion protein concentration-time profiles (semi-logarithmic scale) for the SAD cohort. [Figure 12B]Illustrates anti-C5-FH fusion protein concentration-time profiles (semi-logarithmic scale) for the MAD cohort.

[0042] [Figure 13A] Illustrates mean (SD) serum rRBC over time by dosing regimen in the MAD cohort. [Figure 13B] Illustrates mean (SD) C3b over time by dosing regimen for the MAD cohort. [Figure 13C] Illustrates mean (SD) free C5 over time by dosing regimen for the MAD cohort.

[0043] [Figure 14A] Scatter plots of percent change from baseline in serum rRBC levels versus serum concentrations of anti-C5-FH fusion protein for all subjects are shown. [Figure 14B] Scatter plots of percent change from baseline in serum C3b levels versus concentration of anti-C5-FH fusion protein for all subjects are shown. [Figure 14C] Scatter plots of percent change from baseline in free C5 levels versus concentration of anti-C5-FH fusion protein for all subjects are shown.

[0044] [Figure 15] This diagram illustrates the systemic lupus erythematosus (SLE)-thrombotic microangiopathy (TMA) clinical trial scheme.

[0045] [Figure 16] The clinical trial scheme for IgA nephropathy (IgAN) and complement 3 glomerulopathy (C3G) is illustrated.

[0046] [Figure 17] The phase 2 clinical trial scheme for paroxysmal nocturnal hemoglobinuria (PNH) is illustrated.

[0047] [Figure 18]Figure 1 illustrates a graph of the mean (±standard deviation) hemoglobin increase from baseline in complement inhibitor-naive PNH patients administered anti-C5-FH fusion protein over 17 weeks for cohorts 1, 2, and 3. The horizontal dashed line represents a 2 g / dL increase in hemoglobin from baseline. The vertical dashed lines indicate the indicated time in weeks. Mean (SD) hemoglobin levels increased by 4.9 (±1.7) g / dL, 5.8 (±1.6) g / dL, and 5.8 (±2.8) g / dL from baseline in cohorts 1, 2, and 3, respectively.

[0048] [Figure 19] Figure 1 illustrates a graph of mean (±standard deviation) lactate dehydrogenase (LDH) levels in complement inhibitor-naive PNH patients administered anti-C5-FH fusion protein over 17 weeks for cohorts 1, 2, and 3. The upper horizontal dashed line represents total LDH at 1.5 times the upper limit of normal (ULN). The lower horizontal dashed line represents total LDH at 1 times the upper limit of normal. The vertical dashed lines indicate the indicated time in weeks. Mean (SD) LDH levels were reduced by 88.0 (±3.67)%, 83.5 (±7.45)%, and 89.5 (±4.05)% from baseline in cohorts 1, 2, and 3, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0049] In one aspect, the present application provides a method for treating complement-mediated diseases by inhibiting complement signaling using an anti-C5 / factor H fusion protein (hereinafter referred to as an "anti-C5-FH fusion protein") comprising an anti-C5 antibody portion and a factor H (FH) portion. The anti-C5-FH fusion protein used herein inhibits complement system activity through a dual mechanism: i) the anti-C5 antibody portion functions as an anti-C5 antibody to block C5 activity; and ii) the FH portion acts as a C3 complement activation inhibitor. In some embodiments, the anti-C5 antibody portion exhibits pH-dependent binding to C5 (hereinafter referred to as a "pH-dependent anti-C5 antibody portion"). In some embodiments, the pH-dependent anti-C5 antibody portion binds to C5 more strongly at a more neutral pH (e.g., about pH 7.4, e.g., the pH found in blood) than at a more acidic pH (e.g., about pH 5.8, e.g., the pH found in endosomes). In some embodiments, the FH portion is an FH protein or a fragment thereof, for example, an FH fragment containing short consensus repeat (SCR) domains 1-5 of the FH protein, which are domains involved in regulating C3 activation. Complement-mediated diseases include, but are not limited to, paroxysmal nocturnal hemoglobinuria (PNH) syndrome, C3 glomerulopathy (C3G), IgA nephropathy (IgAN), and thrombotic microangiopathy secondary to systemic lupus erythematosus (SLE-TMA). Anti-C5-FH fusion proteins and anti-C5 antibody portions (e.g., pH-dependent anti-C5 antibody portions) are described in U.S. Patent Publication No. 20220204602 and International Patent Application No. WO2020 / 219922 (the entire contents of each of which are specifically incorporated herein by reference in their entirety). The treatment methods described herein provide a more effective and convenient way to treat complement-dependent pathologies, e.g., by reducing dosage and / or frequency and / or by more effectively blocking the activity of the complement system, which addresses and fills a need not previously met by other complement-mediated disease therapies (e.g., FDA-approved eculizumab).

[0050] I. Definition In general, the terms used in the claims and the specification are intended to be interpreted as having their ordinary meanings as understood by those of ordinary skill in the art. However, certain terms are defined below for clarity. If there is a conflict between the ordinary meaning and a given definition, the given definition shall control.

[0051] The terms "inhibit" and "inhibition," as used herein, mean to reduce, suppress, decrease, or block an activity or function by at least about 10% (e.g., at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%) relative to a control value. In some embodiments, activity is inhibited or blocked by at least about 50% compared to a control value. 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%. In some embodiments, activity is blocked by 100%.

[0052] The terms "effective amount" and "pharmaceutically effective amount" refer to an amount of an agent sufficient to produce a desired biological result. That result can be a reduction (e.g., at least about any of a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% reduction) and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. An appropriate effective amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0053] The terms "patient," "subject," "individual," and the like, are used interchangeably herein and refer to any animal, in some embodiments a mammal, and in some embodiments a human, having a complement system, including humans in need of therapy for or susceptible to a condition or its sequelae. Individuals can include, for example, dogs, cats, pigs, cows, sheep, goats, horses, rats, rabbits, hamsters, guinea pigs, monkeys, mice, and humans. In some embodiments, an individual is a human.

[0054] The term "abnormal," when used in the context of an organism, tissue, cell, or component thereof, refers to an organism, tissue, cell, or component thereof that has at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) that differs from an organism, tissue, cell, or component thereof that exhibits the "normal" (expected / regular) respective characteristic. A characteristic that is normal or expected for one cell, tissue type, or subject could be abnormal for a different cell or tissue type.

[0055] A "disease" is a state of health in a subject where the subject is unable to maintain homeostasis and where the subject's health will continue to deteriorate unless the disease is ameliorated.

[0056] In contrast, a "disorder" in a subject is a state in which the subject is able to maintain homeostasis, but in which the subject's health status is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily cause a further deterioration in the subject's health status.

[0057] A disease or disorder is "alleviated" if the severity of a sign or symptom of the disease or disorder, the frequency with which the patient experiences such sign or symptom, or both, is reduced.

[0058] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural history of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include a reduction in the rate of disease progression, an improvement or palliative of the disease state, and remission or improved prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with a disease or disorder are reduced or eliminated. These include, but are not limited to, a reduction in the frequency and / or severity of signs and / or symptoms attributable to the disease, an increase in the quality of life of a person suffering from the disease, a reduction in the dose of other pharmaceuticals required to treat the disease, and / or an extension of the individual's survival. Treatment may be prophylactic (preventing or delaying the onset of the disease or preventing the manifestation of its clinical or subclinical symptoms) or therapeutic suppression or alleviation of symptoms after the manifestation of the disease.

[0059] A subject who is "potentially suitable," including a subject who is "suitable" for a treatment(s) described herein, is a subject who is likely to benefit from administration of the treatment. Conversely, a subject who is "potentially unsuitable," including a subject who is "unsuitable" for a treatment(s) described herein, is a subject who is likely not to benefit from administration of the treatment.

[0060] An "effective amount" or "therapeutically effective amount" of a compound is the amount of compound sufficient to confer a beneficial effect on the subject to which it is administered.

[0061] A "therapeutic treatment" is a treatment administered to a subject who exhibits symptoms of a disease or disorder with the intent of reducing or eliminating those symptoms.

[0062] The term "antibody," as used herein, refers to an immunoglobulin molecule capable of specifically binding to a specific epitope of an antigen. Antibodies can be intact immunoglobulins from natural sources or from recombinant sources, and immunoreactive portions of intact immunoglobulins. Antibodies in the present invention may exist in a variety of forms, including, for example, polyclonal antibodies, monoclonal antibodies, intracellular antibodies ("intrabodies"), Fv, Fab, Fab', F(ab)2, and F(ab')2, as well as single-chain antibodies (scFv), heavy-chain antibodies such as camelid 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, NY; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426).

[0063] As used herein, the term "heavy chain antibody" or "heavy chain antibodies" includes immunoglobulin molecules derived from Camelidae species by immunization with a peptide and subsequent isolation of serum, or by cloning and expression of nucleic acid sequences encoding such antibodies. The term "heavy chain antibody" or "heavy chain antibodies" further encompasses immunoglobulin molecules isolated from a subject with a heavy chain disease or prepared by cloning and expression of a VH (variable heavy chain immunoglobulin) gene from a subject.

[0064] "Chimeric antibody" refers to a type of engineered antibody that contains naturally occurring variable regions (light and heavy chains) from a donor antibody associated with light and heavy chain constant regions from an acceptor antibody.

[0065] A "humanized antibody" refers to a type of engineered antibody whose CDRs are derived from a non-human donor immunoglobulin and the remaining immunoglobulin-derived portions of the molecule are derived from one or more human immunoglobulin(s). In addition, framework support residues may be modified to preserve binding affinity (see, e.g., 1989, Queen et al., Proc. Natl. Acad Sci USA, 86:10029-10032; 1991, Hodgson et al., Bio / Technology, 9:421). Suitable human acceptor antibodies may be selected from conventional databases, such as the KABAT database, the Los Alamos database, and the Swiss Protein database, based on their homology to the nucleotide and amino acid sequences of the donor antibody. Human antibodies characterized by homology (on an amino acid basis) to the framework regions of the donor antibody may be suitable for providing heavy chain constant and / or heavy chain variable framework regions for insertion of donor CDRs. A suitable acceptor antibody capable of donating light chain constant or variable framework regions may be selected similarly. Note that the heavy and light chains of the acceptor antibody do not have to be derived from the same acceptor antibody. The prior art describes several methods for producing such humanized antibodies (see, for example, EP-A-0239400 and EP-A-054951).

[0066] "CDR" is defined as the complementarity-determining region amino acid sequences of an antibody, which are the hypervariable regions of the immunoglobulin heavy and light chains. See, e.g., 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. Thus, "CDR," as used herein, refers to all three heavy chain CDRs or all three light chain CDRs (or, where appropriate, both all heavy chain CDRs and all light chain CDRs). The structure and protein folding of an antibody may mean that other residues are considered part of the antigen-binding region, as would be understood by one of skill in the art. See, e.g., Chothia et al., (1989) Conformations of immunoglobulin hypervariable regions; Nature 342, pp. 877-883.

[0067] The terms "native antibody," "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein and refer to an antibody in its substantially intact form, rather than an antibody fragment as defined hereinafter. The term specifically refers to an antibody having a heavy chain containing an Fc region. Naturally occurring antibodies are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, although the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain contains at one end a variable domain (V H ) followed by multiple constant domains. Each light chain has a variable domain (V L) and a constant domain at its other end, with the light-chain constant domain aligned with the first constant domain of the heavy chain and the light-chain variable domain aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light- and heavy-chain variable domains.

[0068] The "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domain of the heavy chain is sometimes referred to as "VH." The variable domain of the light chain is sometimes referred to as "VL." These domains are generally the most variable parts of an antibody and contain the antigen-binding sites.

[0069] The term "variable" refers to the fact that certain portions of the variable domains differ significantly in sequence among antibodies and are responsible for the binding and specificity of each particular antibody for its particular antigen. However, the variability is not uniformly distributed throughout the variable domains of antibodies. It is concentrated in three segments called hypervariable regions (HVRs, also called CDRs) in both the light-chain and heavy-chain variable domains. The more highly conserved portions of the variable domains are called framework regions (FRs). Naturally occurring heavy-chain and light-chain variable domains each contain four FR regions, which primarily adopt a beta-sheet configuration with three HVRs connected to the beta-sheet structure, forming loops that in some cases form part of the beta-sheet structure. The HVRs within each chain are held in close proximity by the FR regions and, together with the HVRs of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institutes of Health, Bethesda, Md. (1991)).

[0070] The term "constant domain" refers to the portion of an immunoglobulin molecule that has a more conserved amino acid sequence compared to the other portion of the immunoglobulin, the variable domain, which contains the antigen-binding site. The constant domain is the C H 1. C H 2 and C H The constant domains contain three domains (collectively, CH), as well as the CL domain of the light chain. The constant domains are not directly involved in binding the antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0071] The "light chains" of antibodies (immunoglobulins) from any mammalian species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequences of their constant domains.

[0072] The term IgG "isotype" or "subclass" as used herein means any of the subclasses of immunoglobulins defined by the chemical and antigenic properties of their constant regions.

[0073] Depending on the amino acid sequence in the constant domain of their heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of various classes of immunoglobulins are well known and are generally described, for example, in Abbas et al. Cellular and Mol. Immunology, 4th ed. (WB Saunders, Co., 2000). An antibody may be part of a larger fusion molecule formed by covalent or noncovalent association of the antibody with one or more other proteins or peptides.

[0074] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding region thereof. In some embodiments, the antibody fragments described herein are antigen-binding fragments. Examples of antibody fragments or antigen-binding fragments include Fab, Fab', F(ab')2, and Fv fragments (single-chain variable fragments, such as scFv); diabodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0075] Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site, and a residual "Fc" fragment, the "Fc" designation reflecting its ability to crystallize readily. Pepsin treatment yields an F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.

[0076] An "Fv" is the minimum antibody fragment that contains a complete antigen-binding site. In some embodiments, two-chain Fv species consist of a dimer of one heavy-chain variable domain and one light-chain variable domain in tight, non-covalent association. In single-chain Fv (scFv) species, one heavy-chain variable domain and one light-chain variable domain can be covalently linked by a flexible peptide linker so that the light and heavy chains can associate in a "dimeric" structure similar to that of two-chain Fv species. It is in this configuration that the three HVRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six HVRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three HVRs specific for an antigen) has the ability to recognize and bind antigen, albeit with lower affinity than the entire binding site.

[0077] Fab fragments have two polypeptide chains containing heavy and light chain variable domains (VH, VL), as well as a light chain constant domain (CL) and the first heavy chain constant domain (CH1). Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation used herein to represent Fab' in which the cysteine ​​residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0078] "Single-chain Fv" or "scFv" antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain. Generally, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding. For a review of scFvs, see, e.g., Pluckthun, The Pharmacology of Monoclonal Antibodies. Springer Berlin Heidelberg, 1994, pp. 269-315.

[0079] The "Fc" fragment contains the carboxy-terminal portions of both heavy chains held together by disulfides. The effector functions of the antibody are determined by sequences in the Fc region, which is also the region recognized by Fc receptors (FcRs) found on certain cell types.

[0080] The term "monoclonal antibody," as used herein, refers to an antibody obtained from a substantially homogeneous antibody population, e.g., the individual antibodies comprising the population are identical except for possible mutations, e.g., naturally occurring mutations, that may be present in minor amounts. Thus, the modifier "monoclonal" indicates the character of the antibody as not being a mixture of distinct antibodies. In some embodiments, such monoclonal antibodies typically comprise an antibody comprising a polypeptide sequence that binds to a target, where the target-binding polypeptide sequence was obtained by a process that includes selecting a single target-binding polypeptide sequence from a plurality of polypeptide sequences. For example, the selection process can be the selection of a unique clone from a pool of multiple clones, e.g., hybridoma clones, phage clones, or recombinant DNA clones. The selected target-binding sequence can be further modified, e.g., to improve affinity for the target, humanize the target-binding sequence, improve its production in cell culture, reduce its immunogenicity in vivo, generate multispecific antibodies, etc., and it is understood that antibodies comprising modified target-binding sequences are also monoclonal antibodies of the present invention. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. In addition to their specificity, monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins.

[0081] The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies used in accordance with the present invention can be produced using, for example, hybridoma techniques (e.g., Kohler and Milstein, Nature 256:495-97 (1975); Hongo et al., Hybridoma 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA techniques (see, for example, U.S. Pat. No. 4,816,567), phage display techniques (e.g., Clackson et al., Nature 352:624-628 (1991); Marks et al., Nature 352:624-628 (1991)), or other methods. al.,J.Mol.Biol.222:581-597(1992);Sidhu et al.,J.Mol.Biol.338(2):299-310(2004);Lee et al. al.,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004);and Lee et al.,J.Immunol.Methods 284(1-2):119-132 (2004)), as well as techniques for producing human or human-like antibodies in animals that have some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (e.g., WO1998 / 24893; WO1996 / 34096; WO1996 / 33735; WO1991 / 10741; Jakobovits et al., Proc. Natl. Acad. Sci. USA 90:2551 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016; Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-813 (1994); Fishwild et al., Nature Biotechnol. 14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and These antibodies may be produced by a variety of techniques, including immunohistochemistry (see Huszar, Intern. Rev. Immunol. 13:65-93 (1995)).

[0082] Monoclonal antibodies (mAbs), as used herein, specifically include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies so long as they exhibit the desired biological activity (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)). Chimeric antibodies include the PRIMATTZED® antibody, the antigen-binding region of which is derived from an antibody generated, for example, by immunizing macaque monkeys with an antigen of interest.

[0083] The structure and location of immunoglobulin variable regions may be determined by reference to Kabat, EA et al., Sequences of Proteins of Immunological Interest. 4th Edition. US Department of Health and Human Services. 1987, and the latest edition thereof currently available on the internet (immuno.bme.nwu.edu).

[0084] The term "specifically binds," as used herein with respect to antibodies, refers to an antibody that recognizes and binds to a specific target molecule but does not substantially recognize or bind to other molecules in a sample. In some cases, the terms "specific binding" or "specifically binds" are used to mean that recognition and binding are dependent on the presence of a particular structure (e.g., an antigenic determinant or epitope) on the target molecule. For example, if an antibody specifically binds to epitope "A," the presence of an unlabeled molecule containing epitope A (or free unlabeled A) in a reaction containing labeled "A" and the antibody will reduce the amount of labeled A that binds to the antibody. An antibody that binds or specifically binds to a target (e.g., an epitope) is an antibody that binds to this target with higher affinity, avidity, more readily, and / or with a longer duration than it binds to other targets. In some embodiments, the extent of binding of an antibody to an unrelated target is less than about 10% of the antibody's binding to the target, as measured, for example, by radioimmunoassay (RIA). In some embodiments, an antibody that specifically binds to a target has a dissociation constant (K) of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, or ≦0.1 nM. d ). In some embodiments, the antibody specifically binds to an epitope on a protein that is conserved among proteins from different species. In some embodiments, specific binding can, but need not, include exclusive binding.

[0085] As used herein, the term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable regions of the antibody "arms" interact with the antigen at multiple sites through weak non-covalent forces. The more interactions, the stronger the affinity.

[0086] The term "multispecific," when used in reference to an antibody or antigen-binding protein, refers to an antibody or antigen-binding protein that has polyepitopic specificity (i.e., capable of specifically binding to two, three, or more different epitopes on a single biomolecule, or capable of specifically binding to epitopes on two, three, or more different biomolecules).

[0087] As used herein, "percent (%) amino acid sequence identity" and "homology" with respect to a peptide, polypeptide, or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences to be compared.

[0088] Amino acid substitutions may include, but are not limited to, the replacement of one amino acid in a polypeptide with another. Exemplary substitutions are shown in Table A. Amino acid substitutions can be introduced into an antibody of interest and the product screened for a desired activity, such as retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. [Table A]

[0089] Amino acids may be grouped by common side chain properties: (1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile, (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln, (3) acidic: Asp, Glu, (4) basic: His, Lys, Arg, (5) residues that affect chain orientation: Gly, Pro, (6) aromatic: Trp, Tyr, Phe. Non-conservative substitutions involve exchanging a member of one of these classes for another class.

[0090] The term "covalently linked," as used herein, refers to a direct linkage through one or more chemical bonds or an indirect linkage through one or more linkers. Any suitable chemical bond can be used to create the direct linkage, including, but not limited to, covalent bonds, such as peptide bonds and disulfide bonds, or non-covalent bonds, such as hydrogen bonds, hydrophobic bonds, ionic bonds, or van der Waals bonds.

[0091] As used herein, the "C-terminus" of a polypeptide refers to the last amino acid residue of the polypeptide, which donates its amine group to form a peptide bond with the carboxyl group of the adjacent amino acid residue. The "N-terminus" of a polypeptide, as used herein, refers to the first amino acid of the polypeptide, which donates its carboxyl group to form a peptide bond with the amine group of the adjacent amino acid residue.

[0092] Ranges: Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is for convenience and brevity only and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numerical values ​​within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0093] It will be understood that embodiments of the invention described herein include "consisting of" and / or "consisting essentially of" embodiments.

[0094] As used herein, "not" a value or parameter generally means and describes "other than" a value or parameter. For example, "the method is not used to treat cancer type X" means that the method is used to treat cancer types other than X.

[0095] Reference herein to "about" a value or parameter includes (and describes) a variation about that value or parameter itself. For example, a description that refers to "about X" includes the description of "X." As used herein, the term "about X to Y" has the same meaning as "about X to about Y."

[0096] As used in this specification and the appended claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0097] II. Treatment Methods The present invention relates to the inhibition of complement signaling and a complement-related disease or disorder in an individual (e.g., a human) using an anti-C5-FH fusion protein (e.g., FMEH-IgG4-PLA-FH) comprising i) an anti-C5 antibody portion that specifically binds to C5 (e.g., human C5) and ii) FH or a functional fragment thereof. The present invention also relates to the inhibition of complement signaling and a complement-related disease or disorder in an individual (e.g., a human) using any of the anti-C5 antibody portions described herein. In some embodiments, the anti-C5 antibody portion exhibits pH-dependent binding to C5 (e.g., human C5). In some embodiments, the pH-dependent anti-C5 antibody portion binds to C5 more strongly at a more neutral pH (e.g., about pH 7.4, e.g., the pH found in blood) than at a more acidic pH (e.g., about pH 5.8, e.g., the pH found in endosomes). Such pH-dependent binding enhances the persistence of the administered antibody molecule. This is because immune complexes (i.e., anti-C5 mAb bound to C5) taken up by the cell dissociate in the acidic environment of the endosome, and the free antibody is recycled back out of the cell via fetal Fc receptors (FcRn), where it can bind to new C5 molecules. In some embodiments, the individual is complement inhibitor-naive.

[0098] In some embodiments, the invention is directed to inhibiting the complement signaling cascade by specifically targeting complement component C5 protein, or fragments of proteins C5a or C5b, e.g., by inhibiting C5a-mediated inflammation and cell activation (e.g., at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% inhibition) or by inhibiting C5b-mediated cell lysis. In some embodiments, the invention is directed to inhibiting the complement signaling cascade by specifically targeting complement component C3b protein, e.g., to prevent complement C3b deposition and amplification (e.g., at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% prevention). In some embodiments, the present invention is directed to methods of treating and preventing inflammation and autoimmune diseases mediated by unwanted, uncontrolled, and excessive complement activation. In some embodiments, the present invention is directed to treating a complement-mediated disease or disorder in an individual (e.g., a human) by administering (e.g., intravenously or subcutaneously) to the individual an anti-C5-FH fusion protein (e.g., FMEH-IgG4-PLA-FH). In some embodiments, the present invention is directed to treating a complement-mediated disease or disorder in an individual (e.g., a human) by administering (e.g., intravenously or subcutaneously) to the individual an anti-C5 antibody portion (e.g., any of the anti-C5 antibodies or antigen-binding fragments thereof described herein).

[0099] The methods described herein can be used to treat any complement-related disease, such as diseases associated with C3 (or C3b) and / or C5 (or C5a, C5b) activity, or AP and / or terminal pathway activity. Impaired complement function is the cause of several human glomerular diseases, including atypical hemolytic uremic syndrome (aHUS), antineutrophil cytoplasmic antibody-mediated vasculitis (ANSA), C3 glomerulopathy, IgA nephropathy, immune complex membranoproliferative glomerulonephritis, renal ischemia-reperfusion injury, lupus nephritis, membranous nephropathy, and chronic transplant-mediated glomerulopathy. Abnormal complement component activation has also been proposed as a marker for various types of cancer and their clinical outcomes. Lung cancer patients exhibit significantly higher plasma levels of complement proteins and activation fragments than control donors, and elevated complement levels correlate with lung tumor size. Complement-related proteins are also elevated in biological fluids from patients with other types of tumors. See, e.g., Pio et al. Semin Immunol. 2013 Feb;25(1):54-64. Inhibition of the complement cascade has been proposed for the treatment of glomerular diseases and cancer.

[0100] In some embodiments, the complement-related disease is selected from the group consisting of macular degeneration (MD), age-related macular degeneration (AMD), ischemia-reperfusion injury, arthritis, rheumatoid arthritis, asthma, allergic asthma, lupus, ulcerative colitis, stroke, post-operative systemic inflammatory syndrome, chronic obstructive pulmonary disease (COPD), PNH syndrome, myasthenia gravis, neuromyelitis optica (NMO), multiple sclerosis, delayed graft function, antibody-mediated rejection, aHUS, central retinal vein occlusion (CRVO), central retinal artery occlusion (CRAO), epidermolysis bullosa, sepsis, organ transplant, inflammation (including but not limited to). In some embodiments, the AP-mediated disease is selected from the group consisting of: inflammation associated with cardiopulmonary bypass surgery and kidney dialysis, C3 glomerulopathy (C3G), membranous nephropathy, IgA nephropathy (IgAN), glomerulonephritis (including, but not limited to, antineutrophil cytoplasmic antibody (ANCEA)-mediated glomerulonephritis, lupus nephritis, and combinations thereof), thrombotic microangiopathy secondary to systemic lupus erythematosus (SLE-TMA), 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 C3G. In some embodiments, the AP-mediated disease is macular degeneration, e.g., AMD.

[0101] In some embodiments, the invention is a method of treating a complement-mediated disease or disorder in an individual (e.g., a human), comprising administering to the human individual an anti-C5 antibody portion (e.g., any of the anti-C5 antibodies or antigen-binding fragments thereof described herein), thereby inhibiting the production of C5a or C5b protein and the formation of MAC. Examples of complement-mediated diseases that can be treated using the methods of the invention include, but are not limited to, PNH syndrome, C3G, IgAN, and SLE-TMA.

[0102] In some embodiments, methods are provided for treating a complement-mediated disease in a human individual (e.g., a complement inhibitor-naive human individual), comprising administering to the human individual an effective amount of a fusion protein comprising: i) an antibody portion that specifically binds to human C5 (an anti-human C5 antibody portion; e.g., FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), e.g., any of the anti-C5-FH fusion proteins described herein (e.g., FMEH-IgG4-PLA-FH). In some embodiments, the complement-mediated disease is selected from the group consisting of PNH syndrome, C3G, IgAN, and SLE-TMA. In some embodiments, the fusion protein is administered intravenously (IV). In some embodiments, the fusion protein is administered subcutaneously (SC). In some embodiments, the fusion protein is administered in a dose of about 60 mg to about 3600 mg, e.g., about 60 mg to about 1200 mg, about 60 mg to about 3000 mg, about 60 mg to about 2880 mg, 600 mg to about 1200 mg, about 600 mg to about 2880 mg, about 600 mg to about 3600 mg, about 1200 mg to about 3600 mg, about 720 mg to about 1440 mg, about 720 mg to about 3000 mg, about 1920 mg to about 2880 mg, about 1800 mg to about 3600 mg, or about 1800 mg to about 2400 mg. In some embodiments, the fusion protein is administered in a single dose. In some embodiments, the fusion protein is administered at a dose (e.g., a single dose) of about 60 mg to about 1200 mg (e.g., about any of about 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, 600 mg, 660 mg, 720 mg, 780 mg, 840 mg, 900 mg, 960 mg, or 1200 mg). In some embodiments, the fusion protein is administered at a dose (e.g., a single dose) of about 60 mg IV, about 180 mg IV, about 180 mg SC, about 360 mg IV, about 600 mg IV, about 720 mg SC, or about 1200 mg IV.In some embodiments, the fusion protein is administered in multiple doses (e.g., 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 23, 24, 25, 26, 40, 44, 47, 48, 49, 50 or more times). In some embodiments, the fusion protein is administered once every week (QW). In some embodiments, the fusion protein is administered once every other week (Q2W). In some embodiments, the fusion proteins are administered in repeated doses (e.g., QW or Q2W) of about 600 mg to about 2880 mg, e.g., about 600 mg to about 1200 mg, about 1200 mg to about 2880 mg, about 720 mg to about 1440 mg, about 720 mg to about 2880 mg, about 960 mg to about 1920 mg, about 960 mg to about 2880 mg, about 1920 mg to about 2880 mg, about 1400 mg to about 2880 mg, about 1800 mg to about 2880 mg, or about 1800 mg to about 2400 mg. In some embodiments, the fusion proteins are administered in repeated doses (e.g., QW or Q2W) of about 600 mg, 660 mg, 720 mg, 780 mg, 840 mg, 900 mg, 960 mg, 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, 2880 mg, 3000 mg, or 3600 mg each. In some embodiments, the fusion protein is administered at a dose of about 600 mg IV once weekly for 5 weeks. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, the FH, or functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody.In some embodiments, the heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0103] In some embodiments, a method for treating a complement-mediated disease in a human individual (e.g., a complement inhibitor-naive human individual) is provided, comprising administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-Ig) comprising i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85). G4-PLA-FH), wherein the fusion protein is administered in an initial phase comprising administering one or more (e.g., one) initial doses of the fusion protein, followed by a maintenance phase comprising administering two or more (e.g., 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 23, 24, 25, 26, 40, 44, 47, 48, 49, 50 or more) maintenance doses of the fusion protein (e.g., once weekly or once every two weeks). In some embodiments, the complement-mediated disease is selected from the group consisting of PNH, C3G, IgAN, and SLE-TMA. In some embodiments, the initial dose is about 600 mg to about 3600 mg, e.g., about 1200 mg to about 3600 mg, about 600 mg to about 1200 mg, about 600 mg to about 2880 mg, about 1200 mg to about 3600 mg, about 720 mg to about 1440 mg, about 720 mg to about 3000 mg, about 1920 mg to about 2880 mg, about 1800 mg to about 3600 mg, or about 1800 mg to about 2400 mg. In some embodiments, the initial dose is about 1200 mg to about 3600 mg, e.g., about 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, 2880 mg, 3000 mg, or 3600 mg. In some embodiments, one or more (e.g., one) initial doses of the fusion protein are administered IV. In some embodiments, the initial phase comprises administering 1, 2, 3, 4, 5, 6, 10, 12, 14, 16 or more initial doses of the fusion protein, hi some embodiments, the initial phase comprises administering a single initial dose of the fusion protein.In some embodiments, the maintenance dose is about 600 mg to about 2880 mg, e.g., about 1200 mg to about 2880 mg, about 600 mg to about 1200 mg, about 960 mg to about 1440 mg, about 960 mg to about 1920 mg, about 960 mg to about 2880 mg, about 600 mg to about 2000 mg, about 720 mg to about 2400 mg, about 720 mg to about 1440 mg, about 1920 mg to about 2880 mg, about 1800 mg to about 2880 mg, or about 1800 mg to about 2400 mg. In some embodiments, the maintenance dose is about 600 mg, 720 mg, 960 mg, 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, or 2880 mg. In some embodiments, two or more maintenance doses of the fusion protein are administered weekly. In some embodiments, the maintenance dose (e.g., weekly) is about 600 mg to about 1440 mg, e.g., about 600 mg to about 1200 mg, about 720 mg to about 1440 mg, about 600 mg, about 720 mg, 840 mg, about 960 mg, about 1080 mg, about 1200 mg, about 1320 mg, or about 1440 mg. In some embodiments, two or more maintenance doses of the fusion protein are each administered at about 600 mg IV to about 1200 mg IV, or about 720 mg SC to about 1440 mg SC (e.g., weekly). For example, two or more maintenance doses of the fusion protein are each administered at about 600 mg IV, about 1200 mg IV, about 720 mg SC, about 960 mg SC, or about 1440 mg SC (e.g., once weekly). In some embodiments, two or more maintenance doses of the fusion protein are administered every other week. In some embodiments, the maintenance dose (e.g., every other week) is about 960 mg to about 2880 mg, e.g., about 960 mg to about 1920 mg, about 1920 mg to about 2880 mg, about 1800 mg to about 2400 mg, about 1800 mg to about 1920 mg, about 1800 mg to about 2880 mg, about 1800 mg, about 1920 mg, about 2000 mg, about 2200 mg, about 2400 mg, about 2600 mg, or about 2880 mg.In some embodiments, two or more maintenance doses of fusion protein are each administered at about 1920 mg SC to about 2880 mg SC, or about 1800 mg SC to about 2400 mg SC, e.g., about 960 mg SC, about 1800 mg SC, about 1920 mg SC, about 2400 mg SC, or about 2880 mg SC (e.g., once every other week). In some embodiments, the maintenance phase is at least about 4 weeks, e.g., at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 34, 36, 38, 40, 42, 44, 45, 46, 47, 48, 49, 50, 52 weeks or more. In some embodiments, the maintenance phase is at least about 12 weeks, e.g., 12, 13, 24, 25, 48, or 49 weeks. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg once weekly or once every other week for at least two times (e.g., at least 4, 5, 12, 13, 24, 25, 48, or 49 times) at a maintenance dose of about 720 mg. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC once weekly for four weeks, starting on day 8. In some embodiments, the maintenance phase comprises administering the fusion protein at a first maintenance dose (e.g., once weekly or once every other week) during the first maintenance phase, followed by administering the fusion protein at a second maintenance dose (e.g., once weekly or once every other week) during the second maintenance phase. In some embodiments, the second maintenance dose is higher than the first maintenance dose, e.g., at least about 1.5, 2, 3, 4, 5, 10, or more times higher. In some embodiments, the duration of the second maintenance phase is longer than the duration of the first maintenance phase, e.g., at least about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 weeks or more.In some embodiments, the duration of the first maintenance phase is at least 1 week, and the duration of the second maintenance phase is about 23 or about 24 weeks or less. In some embodiments, the first maintenance dose of the fusion protein is administered at about 720 mg SC or about 600 mg IV once weekly, and the second maintenance dose of the fusion protein is administered at about 1440 mg SC or about 1200 mg IV once weekly. In some embodiments, the duration of the first maintenance phase is about 4 weeks, and the duration of the second maintenance phase is at least about 44 weeks. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0104] In some embodiments, methods are provided for treating a complement-mediated disease in a human individual (e.g., a complement inhibitor-naive human individual), comprising administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the fusion protein is administered in a single dose of about 60 mg IV, about 180 mg IV, about 180 mg SC, about 360 mg IV, about 600 mg IV, about 720 mg SC, or about 1200 mg IV. In some embodiments, a method of treating a complement-mediated disease in a human individual is provided, comprising administering to the human individual an effective amount of a fusion protein (e.g., FMEH-IgG4-PLA-FH) comprising i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the fusion protein is administered at a dose of about 600 mg IV once weekly for 5 weeks. In some embodiments, a method of treating a complement-mediated disease in a human individual is provided, comprising administering to the human individual an effective amount of a fusion protein (e.g., FMEH-IgG4-PLA-FH) comprising i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the fusion protein is administered at a dose of about 1200 mg IV once weekly for 5 weeks. In some embodiments, the fusion protein is administered in an initial phase comprising one or more (e.g., only one) administration of an initial dose (e.g., IV) of the fusion protein, followed by a maintenance phase comprising at least two (e.g., 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 23, 24, 25, 26, 40, 44, 47, 48, 49, 50 or more) administrations of the fusion protein at a maintenance dose of about 720 mg once weekly or once every other week (e.g., SC).In some embodiments, a method of treating a complement-mediated disease in a human individual is provided, comprising administering to the human individual an effective amount of a fusion protein (e.g., FMEH-IgG4-PLA-FH) comprising i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV on day 1, followed by a maintenance phase comprising administering the fusion protein at a maintenance dose of about 720 mg SC once weekly for 4 weeks starting on day 8. In some embodiments, the complement-mediated disease is selected from the group consisting of PNH, C3G, IgAN, and SLE-TMA. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, an FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to an FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion.In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0105] In some embodiments, a method of treating a complement-mediated disease in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising (a) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and (b) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 600 mg IV to about 3600 mg IV on day 1, followed by a series of doses, starting on day 8, of: i) about 600 mg IV to about 1200 mg IV once weekly; ii) about 720 mg SC to about 1440 mg SC once weekly; or iii) about 1920 mg SC to about 2880 mg SC once every other week. SC; iv) about 1800 mg SC to about 2400 mg SC once every other week; or v) about 960 mg SC to about 2880 mg SC once every other week, in a maintenance phase comprising administering the fusion protein. In some embodiments, the complement-mediated disease is selected from the group consisting of PNH, C3G, IgAN, and SLE-TMA. In some embodiments, the initial dose of the fusion protein is administered IV at about 600 mg to about 1200 mg, about 600 mg to about 2880 mg, about 720 mg to about 1440 mg, about 720 mg to about 3000 mg, about 1200 mg to about 3600 mg, about 1200 mg to about 2400 mg, about 1200 mg to about 1800 mg, about 2000 mg to about 2800 mg, about 1800 mg to about 3600 mg, or about 2400 mg to about 3600 mg, e.g., about 1200 mg, about 1600 mg, about 1800 mg, about 2000 mg, about 2400 mg, about 2800 mg, about 3000 mg, or about 3600 mg. In some embodiments, the maintenance phase comprises IV administration of the fusion protein at a once-weekly maintenance dose of about 600 mg, about 720 mg, about 840 mg, about 960 mg, about 1080 mg, about 1200 mg, or any range therebetween.In some embodiments, the maintenance phase comprises administering the fusion protein SC at a once-weekly maintenance dose of about 720 mg, about 840 mg, about 960 mg, about 1080 mg, about 1200 mg, about 1320 mg, about 1440 mg, or any range therebetween. In some embodiments, the maintenance phase comprises administering the fusion protein SC once every other week at a maintenance dose of any of about 960 mg to about 1920 mg, about 960 mg to about 2880 mg, about 1920 mg to about 2880 mg, about 1800 mg to about 2400 mg, about 1800 mg to about 2880 mg, about 1800 mg to about 1920 mg, about 1920 mg to about 2400 mg, or about 2000 mg to about 2400 mg, e.g., about 1800 mg, about 1920 mg, about 2040 mg, about 2160 mg, about 2280 mg, about 2400 mg, about 2520 mg, about 2640 mg, about 2760 mg, about 2880 mg, or any range therebetween. In some embodiments, the maintenance phase is at least about 12 weeks (e.g., 12, 13, 14, 15, 16, 18, 20, 22, 23, 24, 25, 26, 28, 30, 34, 38, 40, 42, 44, 46, 47, 48, 49, 50 or more weeks, e.g., 12 weeks) for once-weekly maintenance dosing, or at least about 13 weeks (e.g., 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51 or more weeks, e.g., 13 weeks) for once-every-weekly maintenance dosing. In some embodiments, the maintenance phase is at least about 24 weeks (e.g., 24 weeks) for once-weekly maintenance dosing, or at least about 25 weeks (e.g., 25 weeks) for once-every-weekly maintenance dosing. In some embodiments, the maintenance phase is at least about 48 weeks (e.g., 48 weeks) for once-weekly maintenance dosing, or at least about 49 weeks (e.g., 49 weeks) for once-every-weekly maintenance dosing.In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, an FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to an FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0106] In some embodiments, the method includes administering a high initial loading dose of an anti-C5-FH fusion protein, e.g., about 600 mg to about 3600 mg (e.g., 600, 1200, 1440, 1800, 1920, 2400, and 3600 mg, or any range therebetween), to mitigate the effects of target-mediated drug elimination (TMDD). The pharmacokinetics of mAbs has revealed that higher antigen mass is associated with higher mAb clearance, thereby increasing the time to reach steady-state drug concentrations (see, e.g., Ternant et al., Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans. Clinical Pharmacokinetics, 2019 Feb;58(2)). Using a high initial loading dose can reduce the contribution of nonlinear TMDD clearance to total clearance (nonlinear TMDD clearance + linear nonspecific clearance), thereby allowing steady-state drug concentrations to be reached more quickly.

[0107] In some embodiments, the methods described herein further comprise selecting individuals suitable for such treatment. In some embodiments, the methods described herein further comprise excluding individuals unsuitable for such treatment. In some embodiments, the human individual to be treated has previously been treated with a C5 inhibitor, e.g., anti-C5 antibody therapy. In some embodiments, the human individual to be treated has not previously been treated with a C5 inhibitor, e.g., anti-C5 antibody therapy. In some embodiments, the methods further comprise determining the subject's hemoglobin level, transfusion status, and / or FACIT fatigue scale score at baseline and after treatment. See, e.g., Examples 4-6 for exemplary selection / exclusion methods.

[0108] In some embodiments, the methods described herein further comprise measuring toxicity or side effects of the treatment method, including, but not limited to, treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and adverse events of special interest (AESIs), e.g., based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). In some embodiments, the treatment methods described herein do not induce adverse events of grade ≥ 3 according to CTCAE v5.0. In some embodiments, the methods also comprise measuring one or more of clinical laboratory values, electrocardiogram (ECG), physical examination, and vital signs. For exemplary methods, see, e.g., Examples 4-6.

[0109] How to treat PNH In some embodiments, methods are provided for treating PNH in a human individual (e.g., a complement inhibitor-naive human individual), comprising administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising: i) an antibody portion that specifically binds human C5 (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85). In some embodiments, the fusion protein is administered intravenously. In some embodiments, the fusion protein is administered subcutaneously. In some embodiments, the fusion protein is administered in a dose of about 60 mg to about 3600 mg (e.g., including any of 60, 180, 360, 600, 720, 960, 1200, 1440, 1800, 1920, 2400, 1920, 2880, 3000, 3200, and 3600 mg). In some embodiments, the fusion protein is administered in a single dose, e.g., about 60 mg to about 1200 mg. In some embodiments, the fusion protein is administered in a single dose of about 60 mg IV, about 180 mg IV, about 180 mg SC, about 360 mg IV, about 600 mg IV, about 720 mg SC, or about 1200 mg IV. In some embodiments, the fusion protein is administered in multiple doses. In some embodiments, the fusion protein is administered weekly or biweekly, e.g., at a dose of about 600 mg to about 2880 mg. In some embodiments, the fusion protein is administered in an initial phase comprising one or more (e.g., single) initial doses (e.g., about 600 mg to about 3600 mg, or about 1200 mg to about 3600 mg per IV dose) of the fusion protein, followed by a maintenance phase comprising at least two (e.g., 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 23, 24, 25, 26, 40, 44, 47, 48, 49, 50, or more) doses (e.g., about 600 mg to about 2880 mg per dose) of the fusion protein (e.g., weekly or biweekly).In some embodiments, two or more maintenance doses of the fusion protein are administered weekly, e.g., at about 600 mg to about 2880 mg per dose. In some embodiments, two or more maintenance doses of the fusion protein are administered weekly, e.g., at about 600 mg IV to about 1200 mg IV, about 960 mg SC to about 2880 mg SC, or about 720 mg SC to about 1440 mg SC. In some embodiments, two or more maintenance doses of the fusion protein are administered weekly, e.g., at about 960 mg to about 2880 mg. In some embodiments, the two or more maintenance doses of fusion protein are each administered once every other week at about 960 mg SC to about 2880 mg SC, about 1200 mg SC to about 2880 mg SC, about 1400 mg SC to about 2880 mg SC, about 1600 mg SC to about 2880 mg SC, about 1800 mg SC to about 2880 mg SC, about 2000 mg SC to about 2800 mg SC, about 2200 mg SC to about 2600 mg SC, about 2300 mg SC to about 2500 mg SC, about 2320 mg SC to about 2480 mg SC, about 2340 mg SC to about 2460 mg SC, about 2360 mg SC to about 2440 mg SC, about 2380 mg SC to about 2420 mg SC, about 1500 mg SC to about 2300 mg SC, or about 1700 mg SC to about 2100 mg SC, about 1800 mg SC to about 2000 mg SC, about 1820 mg SC to about 1980 mg SC, about 1840 mg SC to about 1960 mg SC, about 1860 mg SC to about 1940 mg SC, about 1880 mg SC to about 1940 mg SC, about 1900 mg SC to about 1940 mg SC, about 1920 mg SC to about 2880 mg SC, or about 1800 mg SC to about 2400 mg SC. In some embodiments, the maintenance phase is at least about 12 weeks.In some embodiments, the initial dosing phase comprises administering to the individual one or more (e.g., only one) dose of about 1200 mg to about 3600 mg (e.g., IV) once weekly, followed by a maintenance phase comprising administering to the individual at least two doses of about 720 mg to about 2880 mg (e.g., SC) or about 600 mg to about 1200 mg (e.g., IV) of the fusion protein once weekly or once every other week for at least about 12 weeks (e.g., 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 1 In some embodiments, the maintenance phase comprises administering the fusion protein in one or more extended doses after the maintenance phase. In some embodiments, the maintenance phase is followed by an extension phase of at least about 1 week, 2 weeks, 3 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 months or more, e.g., 9 months. In some embodiments, the extension dose is the same as the maintenance dose. In some embodiments, the extension dose is less than the maintenance dose. In some embodiments, the extension dose is greater than the maintenance dose. In some embodiments, the extension dose is about 1920 mg SC. In some embodiments, the extension phase comprises administering the fusion protein at an extended dose of about 1920 mg SC once every other week for about 9 months. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO:87 and a VL comprising the amino acid sequence of SEQ ID NO:88.In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and administered intraperitoneally using standard techniques for SC administration.

[0110] In some embodiments, a method of treating PNH in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising (a) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and (b) FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV on day 1, followed by: i) about 600 mg IV to about 1200 mg IV once weekly for at least about 12 weeks; ii) about 720 mg SC to about 1440 mg SC once weekly for at least about 12 weeks, starting on day 8. SC; iii) about 1920 mg SC to about 2880 mg SC once every other week for at least 13 weeks; or iv) a maintenance phase comprising administering the fusion protein at a maintenance dose of about 960 mg SC to about 2880 mg SC once every other week for at least 13 weeks. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC or about 600 mg IV once every week for about 12 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV to about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC to about 2880 mg SC once every other week for about 13 weeks starting on day 8. In some embodiments, the initial phase involves administering the fusion protein at an initial dose of about 2400 mg IV on day 1, and the maintenance phase involves administering the fusion protein at a maintenance dose of about 960 mg SC to about 2880 mg SC once every other week starting on day 8 for about 13 weeks.In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV to about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC once every other week for about 13 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 3600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week for about 13 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC once every week for about 12 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC once every other week for about 13 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 3600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 2880 mg SC once every other week for about 13 weeks starting on day 8. In some embodiments, the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extension doses after the maintenance phase. In some embodiments, the maintenance phase is followed by an extension phase of at least about 1 week, 2 weeks, 3 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 months or more, e.g., about 9 months. In some embodiments, the extension dose is the same as the maintenance dose. In some embodiments, the extension dose is less than the maintenance dose. In some embodiments, the extension dose is greater than the maintenance dose. In some embodiments, the extension phase comprises administering the fusion protein at an extended dose of about 1920 mg SC once every other week for about 9 months.In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, an FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to an FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0111] In some embodiments, a method of treating PNH in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV on day 1, followed by administration of about 720 mg SC or about 600 mg SC once weekly for about 12 weeks starting on day 8. The method further includes administering a fusion protein in a maintenance phase comprising administering an IV maintenance dose of a fusion protein, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extension doses after the maintenance phase. In some embodiments, the extension phase comprises administering the fusion protein in an extension dose of about 1920 mg SC once every other week for about 9 months. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0112] In some embodiments, a method of treating PNH in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV on day 1, followed by administration of about 720 mg IV once weekly starting on day 8 for about 12 weeks. The method further comprises administering a fusion protein in a maintenance phase comprising administering a maintenance dose of about 1920 mg SC once every other week for about 9 months, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extension doses after the maintenance phase. In some embodiments, the extension phase comprises administering the fusion protein in an extension dose of about 1920 mg SC once every other week for about 9 months. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0113] In some embodiments, a method of treating PNH in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 3600 mg IV on day 1, followed by administration of about 2880 mg IV once every other week starting on day 8 for about 13 weeks. The method further comprises administering a fusion protein in a maintenance phase comprising administering a maintenance dose of about 1920 mg SC once every other week for about 9 months, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extension doses after the maintenance phase. In some embodiments, the extension phase comprises administering the fusion protein in an extension dose of about 1920 mg SC once every other week for about 9 months. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0114] In some embodiments, a method of treating PNH in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 2400 mg IV on day 1, followed by about 960 mg SC to about 2880 mg SC once every other week for about 13 weeks starting on day 8. The method further comprises administering a fusion protein in a maintenance phase comprising administering a maintenance dose of about 1920 mg SC once every other week for about 9 months, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extension doses after the maintenance phase. In some embodiments, the extension phase comprises administering the fusion protein in an extension dose of about 1920 mg SC once every other week for about 9 months. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0115] In some embodiments, a method of treating PNH in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 2400 mg IV on day 1, followed by administration of about 960 mg SC to about 2880 mg SC once every other week for about 13 weeks starting on day 8. and a maintenance phase comprising administering a fusion protein at a SC maintenance dose, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and a pH of about 6.0. In some embodiments, the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extension doses after the maintenance phase. In some embodiments, the extension phase involves administering the fusion protein at an extended dose of about 1920 mg SC once every other week for about 9 months. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0116] In some embodiments, a method of treating PNH in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 2400 mg IV on day 1, followed by an initial dose of about 1920 mg IV once every other week starting on day 8 for about 13 weeks. The method further comprises administering a fusion protein in a maintenance phase comprising administering a maintenance dose of about 1920 mg SC once every other week for about 9 months, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extension doses after the maintenance phase. In some embodiments, the extension phase comprises administering the fusion protein in an extension dose of about 1920 mg SC once every other week for about 9 months. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0117] In some embodiments, a method of treating PNH in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising (i) an anti-human C5 full-length antibody, (ii) a first FH functional fragment, and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 2400 mg IV on day 1, followed by administration of about 1920 mg IV once every other week starting on day 8 for about 13 weeks. The method further comprises administering a fusion protein in a maintenance phase comprising administering a maintenance dose of about 1920 mg SC once every other week for about 9 months, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extension doses after the maintenance phase. In some embodiments, the extension phase comprises administering the fusion protein in an extension dose of about 1920 mg SC once every other week for about 9 months. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0118] In some embodiments, a method of treating PNH in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 3600 mg IV on day 1, followed by about 1920 mg SC to about 2880 mg SC once every other week for about 13 weeks starting on day 8. The method further comprises administering a fusion protein in a maintenance phase comprising administering a maintenance dose of about 1920 mg SC once every other week for about 9 months, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extension doses after the maintenance phase. In some embodiments, the extension phase comprises administering the fusion protein in an extension dose of about 1920 mg SC once every other week for about 9 months. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0119] PNH Complement-mediated hemolytic anemia contributes to numerous red blood cell disorders, including paroxysmal nocturnal hemoglobinuria (PNH). PNH is a hematologic disorder characterized by the clonal expansion of one or a few hematopoietic stem cells that are incapable of glycosylphosphatidylinositol (GPI) anchor biosynthesis due to acquired somatic mutations in the phosphatidylinositol glycan class A (PIG-A) gene. Affected progeny cells lack all GPI-anchored surface proteins, including the complement regulators CD55 and CD59. Therefore, PNH red blood cells (RBCs) are vulnerable to activated complement, particularly the membrane attack complex (MAC), resulting in chronic intravascular hemolysis with recurring exacerbations.

[0120] PNH is a condition in which uncontrolled complement activity leads to systemic complications, primarily through intravascular hemolysis and platelet activation (see Socie G, et al., French Society of Haematology. Lancet. 1996;348(9027):573-577 and Brodsky, R., Blood. 2014;124(18):2804-2811). Persistent intravascular hemolysis can be triggered by various stressors, such as infection or physical exertion, which leads to smooth muscle contraction (free hemoglobin), chronic anemia, and an increased risk of severe thromboembolism. Thromboembolism is the most common cause of death in patients with PNH, and pulmonary hypertension and end-organ damage to vital organs such as the liver, kidneys, brain, and intestine are sequelae of such events (Hillmen, P., et al., Am. J. Hematol. 2010;85(8):553-559). These deleterious pathological processes result in a decreased quality of life (QoL) in patients with PNH, including debilitating fatigue, chronic pain, decreased physical function, shortness of breath, abdominal pain, erectile dysfunction, anticoagulation, the need for blood transfusions, and in some cases, dialysis (Weitz, I. C., et al., Thromb Res. 2012;130(3):361-368). Patients with PNH are at significant risk of morbidity and mortality.

[0121] Patients with PNH may exhibit at least one of the following characteristics, which may be symptoms of residual anemia and / or incomplete control of complement-mediated extravascular hemolysis (EVH) and / or intravascular hemolysis: a) exhibiting signs or symptoms of constant loss of RBCs due to continuous or intermittent intravascular and / or extravascular hemolysis; b) having RBCs opsonized with fragments of C3; c) requiring regular transfusions; d) having low-normal or below-normal hemoglobin; e) having low-normal or below-normal platelets; f) having high-normal or above-normal reticulocytes; g) having high-normal or above-normal bilirubin; or h) having or being at risk for iron overload.

[0122] The above characteristics can also be used to monitor the progress of PNH patients in response to treatment according to the present invention and to modify the dosing regimen if deemed clinically appropriate. In certain embodiments, a subject with PNH has been previously treated with a terminal complement inhibitor but continues to exhibit at least one of the above characteristics.

[0123] In some embodiments, the methods of treating PNH described herein can prevent (e.g., prevent at least about any of the following: EVH, fatigue, abdominal pain, dyspnea, anemia, dysphagia, chest pain, pallor, jaundice, cytopenias, and erectile dysfunction), delay (e.g., delay by at least about any of the following: EVH, fatigue, abdominal pain, dyspnea, anemia, dysphagia, chest pain, pallor, jaundice, cytopenias, and erectile dysfunction), or reduce the severity (e.g., reduce by at least about any of the following: EVH, fatigue, abdominal pain, dyspnea, anemia, dysphagia, chest pain, pallor, jaundice, cytopenias, and erectile dysfunction). In some embodiments, the methods of treating PNH described herein reduce one or more of the following in a subject (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%): (a) persistent EVH; (b) anemia; (c) transfusion dependence; (d) intravascular hemolysis; (e) uncontrolled C3 activation and opsonization; and (f) the occurrence of "breakthrough" hemolytic acute episodes observed in patients treated with terminal complement inhibitors. In some embodiments, the methods of treating PNH described herein improve one or more of the following in a subject (e.g., by at least about any of about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% improvement): i) FACIT fatigue scale score; ii) serum LDH and hemoglobin (HgB) levels; iii) quality of life; iv) absolute reticulocyte count; v) bilirubin level; and vi) haptoglobin level. In some embodiments, the methods of treating PNH described herein reduce one or more of the following (e.g., by at least about any of about a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction): (a) C3b deposition and (b) plasma free C5 levels.In some embodiments, the methods for treating PNH described herein reduce lactate dehydrogenase (LDH) levels compared to baseline (e.g., by at least about any of a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction). In some embodiments, the methods for treating PNH described herein reduce LDH levels to less than 0.5, 1.0, or 1.5 times the upper limit of normal (ULN). In some embodiments, the methods for treating PNH described herein increase HgB levels compared to baseline (e.g., by at least about any of a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% increase). In some embodiments, the methods for treating PNH described herein achieve an increase in Hgb from baseline of at least about any of 2 g / dL, 3 g / dL, 4 g / dL, 5 g / dL, 6 g / dL, 7 g / dL, 8 g / dL, 9 g / dL, 10 g / dL, 11 g / dL, or 12 g / dL. In some embodiments, the methods for treating PNH described herein increase the percentage of PNH red blood cells that can survive complement attack (e.g., an increase of at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%). In some embodiments, the human individual to be treated has extravascular hemolysis (EVH). Thus, in some embodiments, the present disclosure also relates to methods for treating clinically evident EVH in a human individual suffering from PNH.

[0124] In some embodiments, the efficacy of the methods of treating PNH described herein can be assessed by one or more of the following: i) an increase from baseline in hemoglobin levels (e.g., an increase of ≥ 2 g / dL) (e.g., without transfusion); ii) a decrease from baseline in serum lactate dehydrogenase (LDH) levels (e.g., a decrease of at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); iii) a decrease in intravascular hemolysis when there is an increase in LDH of ≥ 2 x the upper limit of normal (ULN) after a prior treatment reduced LDH to < 1.5 x ULN. iv) the proportion of subjects with breakthrough hemolysis, defined as at least one new or worsening symptom or sign (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 g / dL], MAVE including thrombosis, dysphagia, or erectile dysfunction); iv) a change in the proportion of subjects with hemoglobin ≥ 12 g / dL; and v) an increase in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue score and EQ-5D-3L (e.g., an increase of at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%). Changes in pharmacodynamics and biomarkers can also be measured to reflect the effectiveness of treatment.These include, but are not limited to: 1) a decrease from baseline in a C3b activity assay (e.g., a decrease of at least about any of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); 2) a decrease from baseline in total and free serum C5 levels (e.g., a decrease of at least about any of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); 3) a change from baseline in a rabbit RBC assay; 4) a change from baseline in factor H serum levels; 5) a change from baseline in d-dimer; 6) an increase from baseline in free hemoglobin (e.g., at least 7) An increase from baseline in serum total bilirubin and direct bilirubin (e.g., an increase of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); 8) An increase from baseline in serum total bilirubin and direct bilirubin (e.g., an increase of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); 8) an increase from baseline in serum haptoglobin levels (e.g., an increase of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); and 9) an increase from baseline in reticulocyte count (e.g., an increase of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%).

[0125] In some embodiments, the methods of treating PNH described herein further comprise selecting a human individual suitable for such treatment. In some embodiments, the human individual to be treated is a complement inhibitor-naïve subject with PNH. In some embodiments, the human individual to be treated is a complement inhibitor-naïve subject with LDH, hemoglobin, and transfusion-dependent PNH. In some embodiments, the human individual further receives antibiotic prophylaxis during treatment. In some embodiments, the human individual is at least about 18 years of age. In some embodiments, the human individual meets one or more of the following criteria: 1) a diagnosis of PNH confirmed by flow cytometry assessment of white blood cells and red blood cells, e.g., with a clonal size of ≥10% granulocytes or monocytes within 6 months of screening; 2) the presence of one or more PNH-related signs or symptoms, e.g., within 3 months of screening; 3) LDH ≥ 2.0 x ULN at screening; 4) hemoglobin ≤ 10.0 g / dL at screening; 5) the practice of effective contraception during treatment; 6) a negative pregnancy test in women undergoing treatment; or 7) a body weight < 35 kg / m 2 BMI of ; 8) prior vaccination against Neisseria meningitidis at screening (subjects who do not provide evidence of prior vaccination must be vaccinated after initiation of anti-C5-FH fusion protein administration but are required to receive appropriate antibiotic prophylaxis for up to two weeks after vaccination); and 9) vaccination against Streptococcus pneumoniae and Hemophilus influenzae (if anti-C5-FH fusion protein administration is initiated within two weeks of vaccination, appropriate antibiotics must be given for prophylaxis).

[0126] In some embodiments, the methods of treating PNH described herein further comprise excluding human individuals who are ineligible for such treatment. In some embodiments, human individuals who are ineligible for the methods of treatment described herein meet one or more of the following criteria: 1) any clinically significant, uncontrolled underlying condition other than PNH; 2) treatment of any infection with an IV (within 30 days of screening) or oral (within 14 days of screening) antibiotic, antiviral, or antifungal agent; 3) a history of meningococcal infection; 4) a history of untreated tuberculosis; 5) a history of splenectomy; 6) a positive serology for hepatitis C virus (HCV) ribonucleic acid (RNA) or human immunodeficiency virus (HIV) at screening; 7) a history of bone marrow or stem cell transplant; 8) an absolute neutrophil count (ANC) <500 cells / μL; 9) a reticulocyte count <100×10 3 cells / μL; 10) platelet count <30,000 cells / μL; 11) history of systemic autoimmune disease; 12) estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula 213) known allergy to penicillin antibiotics; 14) history of drug or alcohol abuse within 1 year of screening; 15) received any type of live attenuated vaccine <1 month prior to screening or planned to receive any such live attenuated vaccine during treatment; 16) use of rituximab within 3 months immediately prior to screening or any complement inhibitors prior to screening; 17) use of steroids (topical use is permitted), EPO, iron supplements, folic acid, vitamin B12, androgens, HIF-PHI within 4 weeks prior to screening, and immunosuppression within 3 months prior to screening. 18) history of malignancy (except adequately treated basal cell carcinoma or cervical intraepithelial neoplasia); 19) bone marrow failure and / or bone marrow transplant candidates; 20) any women who are pregnant or nursing, or who plan to become pregnant during treatment; 21) heart rate-corrected QT interval (QTcF) by the Fridericia formula of >450 milliseconds (msec) for men and >470 msec for women, based on either a single or mean QTcF value of three ECGs obtained at 3-minute intervals; and 22) previous treatment with a complement inhibitor.

[0127] Treatment of SLE-TMA In some embodiments, methods are provided for treating SLE-TMA in a human individual (e.g., a complement inhibitor-naive human individual), comprising administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising: i) an antibody portion that specifically binds human C5 (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85). In some embodiments, the fusion protein is administered intravenously. In some embodiments, the fusion protein is administered subcutaneously. In some embodiments, the fusion protein is administered in a dose of about 60 mg to about 3600 mg (e.g., including any of 60, 180, 360, 600, 720, 960, 1200, 1440, 1800, 1920, 2400, 1920, 2880, 3000, 3200, and 3600 mg). In some embodiments, the fusion protein is administered in a single dose, e.g., about 60 mg to about 1200 mg. In some embodiments, the fusion protein is administered in a single dose of about 60 mg IV, about 180 mg IV, about 180 mg SC, about 360 mg IV, about 600 mg IV, about 720 mg SC, or about 1200 mg IV. In some embodiments, the fusion protein is administered in multiple doses. In some embodiments, the fusion protein is administered weekly or biweekly, e.g., at a dose of about 600 mg to about 2880 mg. In some embodiments, the fusion protein is administered in an initial phase comprising one or more (e.g., single) initial doses (e.g., about 600 mg to about 3600 mg, or about 1200 mg to about 3600 mg per IV dose) of the fusion protein, followed by a maintenance phase comprising at least two (e.g., 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 23, 24, 25, 26, 40, 44, 47, 48, 49, 50, or more) doses (e.g., about 600 mg to about 2880 mg per dose) of the fusion protein (e.g., weekly or biweekly).In some embodiments, two or more maintenance doses of the fusion protein are administered weekly, e.g., at about 600 mg to about 1440 mg per dose, or about 600 mg to about 1200 mg per dose. In some embodiments, two or more maintenance doses of the fusion protein are each administered weekly at about 600 mg IV to about 1200 mg IV, or about 720 mg SC to about 1440 mg SC. In some embodiments, two or more maintenance doses of the fusion protein are administered biweekly, e.g., at about 1800 mg to about 2880 mg. In some embodiments, two or more maintenance doses of the fusion protein are each administered biweekly at about 1920 mg SC to about 2880 mg SC, or about 1800 mg SC to about 2400 mg SC. In some embodiments, the maintenance phase is at least about 24 weeks. In some embodiments, the initial dosing phase comprises administering to the individual one or more (e.g., only one) dose of about 1200 mg to about 3600 mg (e.g., about 1200 mg to about 2400 mg, e.g., IV) once weekly, followed by a maintenance phase comprising administering to the individual at least two doses of about 720 mg to about 2880 mg (e.g., SC) of the fusion protein once weekly or once every other week, e.g., once weekly for a maintenance dose. In some embodiments, the maintenance phase comprises administering the fusion protein at a first maintenance dose (e.g., once every week or once every other week) for a first maintenance phase, followed by administering the fusion protein at a second maintenance dose (e.g., once every week or once every other week) for a second maintenance phase.In some embodiments, the first maintenance dose and / or the second maintenance dose is about 600 mg to about 2880 mg, e.g., about 600 mg to about 1200 mg, about 720 mg to about 1440 mg, about 1800 mg to about 2880 mg, about 1920 mg to about 2880 mg, about 1800 mg to about 2400 mg, about 600 mg to about 2400 mg, or about 720 mg to about 2400 mg. In some embodiments, the first maintenance dose and / or the second maintenance dose is about 600 mg, 720 mg, 960 mg, 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, or 2880 mg. In some embodiments, the initial dose, first maintenance dose, and / or second maintenance dose of the fusion protein are administered IV or SC. In some embodiments, the first and / or second maintenance dose of fusion protein is administered at about 600 mg IV to about 1200 mg IV, about 720 mg SC to about 1440 mg SC, about 1920 mg SC to about 2880 mg SC, or about 1800 mg SC to about 2400 mg SC. In some embodiments, the second maintenance dose is higher than the first maintenance dose, e.g., at least about 1.5, 2, 3, 4, 5, 10, or more times higher. In some embodiments, the duration of the second maintenance phase is longer than the duration of the first maintenance phase, e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 weeks or more. In some embodiments, the duration of the first maintenance phase is at least about 1 week and the duration of the second maintenance phase is not more than about 23 or about 24 weeks. In some embodiments, a first maintenance dose of the fusion protein is administered weekly at about 600 mg IV to about 1200 mg IV during the first maintenance phase, followed by a second maintenance dose of the fusion protein is administered weekly or every other week at about 720 mg SC to about 1440 mg SC during the second maintenance phase.In some embodiments, a first maintenance dose of the fusion protein is administered weekly at about 600 mg IV to about 1200 mg IV during a first maintenance phase, followed by a second maintenance dose of the fusion protein administered once every two weeks at about 1920 mg SC to about 2880 mg SC during a second maintenance phase. In some embodiments, the duration of the first maintenance phase is at least about 1 week (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 weeks or more, e.g., 1 week), and the duration of the second maintenance phase is about 24 weeks or less (e.g., 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 week, e.g., 23 or 24 weeks). In some embodiments, the maintenance phase is at least about 24 or about 25 weeks (including the duration of the first maintenance phase and the duration of the second maintenance phase). In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, an FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to an FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0.In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0128] In some embodiments, a method for treating SLE-TMA in a human individual (e.g., a complement inhibitor-naive human individual) includes administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising (i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and (ii) FH or a functional fragment thereof (e.g., the SCR1-5 domains of FH, e.g., SEQ ID NO: 85), wherein the fusion protein is administered at an initial dose (e.g., about 600 mg to about 1200 mg, about 600 mg to about 2880 mg, about 720 mg to about 1440 mg, about 720 mg to about 3000 mg, about 1200 mg IV to about 3600 mg IV, about 1200 mg IV to about 2400 mg IV, or about 2400 mg IV) on day 1. IV to about 3600 mg IV), followed by a maintenance phase beginning on day 8, comprising administering the fusion protein at two or more maintenance doses (e.g., 24, 25, 26, 27, 28, 29, 30 or more weeks), wherein the maintenance phase comprises administering the fusion protein at a first maintenance dose (e.g., once weekly or once every other week) for the duration of the first maintenance phase (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 23, 24 or more weeks), followed by administering the fusion protein at a second maintenance dose (e.g., once weekly or once every other week) for the duration of the second maintenance phase (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 25 or more weeks). In some embodiments, the initial dose is about 600 mg, 720 mg, 1200 mg, 1440 mg, 1600 mg, 1800 mg, 1920 mg, 2400 mg, 2880 mg, 3000 mg, 3240 mg, or 3600 mg. In some embodiments, the first maintenance dose and / or the second maintenance dose is about 600 mg to about 2880 mg, for example, about 600 mg to about 1200 mg, about 720 mg to about 1440 mg, about 1800 mg to about 2880 mg, about 1920 mg to about 2880 mg, about 1800 mg to about 2400 mg, about 600 mg to about 2400 mg, or about 720 mg to about 2400 mg.In some embodiments, the first maintenance dose and / or the second maintenance dose is about 600 mg, 720 mg, 960 mg, 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, or 2880 mg. In some embodiments, the fusion protein for the initial dose, first maintenance dose, and / or second maintenance dose is administered IV or SC. In some embodiments, the fusion protein for the first maintenance dose and / or second maintenance dose is administered at about 600 mg IV to about 1200 mg IV, about 720 mg SC to about 1440 mg SC, about 1920 mg SC to about 2880 mg SC, or about 1800 mg SC to about 2400 mg SC. In some embodiments, the second maintenance dose is higher than the first maintenance dose. In some embodiments, the duration of the second maintenance phase is longer than the duration of the first maintenance phase. In some embodiments, the first maintenance dose of the fusion protein is administered at about 600 mg IV or about 1200 mg IV once weekly, and the second maintenance dose of the fusion protein is administered at about 720 mg SC to about 1440 mg SC once weekly or about 1920 mg SC to about 2880 mg SC once every other week. In some embodiments, the maintenance phase (including the duration of the first maintenance phase and the duration of the second maintenance phase) is at least about 24 or about 25 weeks. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, the FH, or functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to the FH, or functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89.In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0129] In some embodiments, a method of treating SLE-TMA in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising (a) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and (b) FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV (e.g., about 1200 mg IV to about 2400 mg IV) on day 1, followed by: i) about 720 mg SC to about 1440 mg SC once weekly starting on day 8 for at least about 24 weeks. ii) administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week starting on day 8 for at least about 25 weeks; iii) administering the fusion protein at a first maintenance dose of about 600 mg IV to about 1200 mg IV once weekly starting on day 8 during a first maintenance phase, followed by administering the fusion protein at a second maintenance dose of about 720 mg SC to about 1440 mg SC once weekly during a second maintenance phase, wherein the maintenance phase is at least about 24 weeks; or iv) administering the fusion protein at a first maintenance dose of about 600 mg IV to about 1200 mg IV once weekly starting on day 8 during a first maintenance phase, followed by administering the fusion protein at a second maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week during a second maintenance phase, wherein the maintenance phase is at least about 24 weeks. and administering the fusion protein at a second maintenance dose SC, and the maintenance phase is for at least about 25 weeks. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC once weekly starting on day 8 for about 24 weeks.In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, an FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to an FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0130] In some embodiments, a method of treating SLE-TMA in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV on day 1, followed by administration of about 720 mg SC to about 1440 mg SC once weekly starting on day 8 for at least about 24 weeks. and a maintenance phase comprising administering a fusion protein at a SC maintenance dose, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0131] In some embodiments, a method of treating SLE-TMA in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV on day 1, followed by about 1920 mg SC to about 2880 mg SC once every other week starting on day 8 for at least about 25 weeks. and a maintenance phase comprising administering a fusion protein at a SC maintenance dose, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0132] In some embodiments, a method of treating SLE-TMA in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV on day 1, followed by a maintenance phase of at least about 24 weeks, wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 600 mg IV to about 1200 mg IV once weekly starting on day 8 for the duration of the first maintenance phase, followed by about 720 mg SC to about 1440 mg SC once weekly for the duration of the second maintenance phase. and administering a fusion protein with a second maintenance dose SC, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration. In some embodiments, the second maintenance dose is higher than the first maintenance dose. In some embodiments, the duration of the second maintenance phase is longer than the duration of the first maintenance phase. In some embodiments, the duration of the first maintenance phase is at least about 1 week, and the duration of the second maintenance phase is about 23 weeks or less.

[0133] In some embodiments, a method of treating SLE-TMA in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV on day 1, followed by a maintenance phase of at least about 25 weeks, wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 600 mg IV to about 1200 mg IV once weekly starting on day 8 for the duration of a first maintenance phase, followed by about 1920 mg SC to about 2880 mg SC once every other week for the duration of a second maintenance phase. and administering a fusion protein with a second maintenance dose SC, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration. In some embodiments, the second maintenance dose is higher than the first maintenance dose. In some embodiments, the duration of the second maintenance phase is longer than the duration of the first maintenance phase. In some embodiments, the duration of the first maintenance phase is at least about 1 week, and the duration of the second maintenance phase is about 24 weeks or less.

[0134] In some embodiments, a method of treating SLE-TMA in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV on day 1, followed by administration of about 960 mg IV once weekly starting on day 8 for about 24 weeks. and a maintenance phase comprising administering a fusion protein at a SC maintenance dose, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0135] SLE-TMA Thrombotic microangiopathy (TMA) is a serious complication that can occur in patients with systemic lupus erythematosus (SLE), adversely affecting prognosis and increasing mortality. SLE is a chronic autoimmune disease of unknown etiology. Renal disease is typically caused by immune complex-mediated glomerular disease, but vascular disease can also occur, commonly adversely affecting prognosis and increasing mortality. TMA is a severe renal vascular injury manifesting as progressive, life-threatening thrombocytopenia, microangiopathic hemolytic anemia, and advanced renal failure. The differential diagnosis of TMA in patients with SLE includes antiphospholipid syndrome (APS), thrombocytopenic purpura, complement-mediated and infection-associated hemolytic uremic syndrome, drug-mediated TMA (particularly due to calcineurin inhibitor toxicity), and malignant hypertension. TMA is characterized by endothelial damage leading to thrombosis of capillaries and arterioles, resulting in Coombs-negative hemolytic anemia, thrombocytopenia, and end-organ damage, often affecting the kidneys. TMA encompasses several entities: thrombotic thrombocytopenia (TTP), hemolytic uremic syndrome (HUS), and complement-mediated TMA. Renal complications are generally more prevalent in Shiga toxin-associated hemolytic uremic syndrome (STx-HUS) and atypical HUS, whereas neurological complications are more prevalent in TTP. Individuals with milder forms of TTP may experience recurrent symptomatic episodes, including seizures and vision loss. Systemic lupus erythematosus (SLE) and / or acute pulmonary syndrome (APS) are common autoimmune disorders associated with secondary HUS. Dysregulation of terminal complement activation, resulting in tissue damage, is a common feature in the pathophysiology of all forms of complement-mediated TMA. Clinical symptoms of TMA vary depending on the type, but typically include fever, microangiopathic hemolytic anemia, renal failure, thrombocytopenia, and neurological symptoms. As TMA progresses, hyaline clots can spread to and affect the brain, kidneys, heart, liver, and other major organs, potentially resulting in multiple organ failure or damage. Typical organ damage associated with TMA includes malignant hypertension, kidney damage, abdominal pain, diarrhea, stroke, confusion, cardiac damage, and eye damage.See, e.g., Figueiredo et al., CEN Case Rep. 2022; 11(1): 26-30; Kello et al., Semin Arthritis Rheum. 2019; 49(1): 74-83.

[0136] In some embodiments, the methods of treating SLE-TMA described herein prevent (e.g., at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, 500%, 510%, 520%, 530%, 540%, 550%, 560%, 570%, 580%, 590%, 600%, 610%, 620%, 630%, 640%, 650%, 660%, 670%, 680%, 690%, 700%, 710%, 720%, 730%, 740%, 750%, 760%, 770%, 780%, 790%, 800%, 810%, 820%, 830%, 840%, 850%, 860%, 870%, 880%, 890%, 900%, 910%, 920%, 930%, 940%, 950%, 960%, 970%, 980%, 990%, 1000 or 100% probability), delay (e.g., by at least about 1, 2, 3, 6, 12, 18, 24, 30, 36, 42, 48, 52 months or more), or reduce its severity (e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction). In some embodiments, the methods of treating SLE-TMA described herein reduce one or more of the following in a subject (e.g., by at least about any of a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction): i) proteinuria; ii) the need for hemodialysis; iii) morality rate; iv) complement activity; and v) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. In some embodiments, the methods of treating SLE-TMA described herein improve one or more of the following in a subject (e.g., by at least about any of a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% improvement): i) FACIT fatigue scale score; ii) renal function; iii) eGFR; and iv) quality of life.

[0137] In some embodiments, the efficacy of the methods of treating SLE-TMA described herein can be assessed by one or more of the following: 1) change from baseline in platelet count; 2) percent change from baseline in serum lactate dehydrogenase (LDH) levels; 3) percent change from baseline in estimated glomerular filtration rate (eGFR); 4) percent change from baseline in urinary protein-to-creatinine ratio (UPCR); 5) time to first hematologic response, e.g., time to platelet count >100,000 / μL with normalized LDH; 6) time to first hematologic response, e.g., ... 7) time to at least a 25% (e.g., at least about any of 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%) improvement in platelet count from baseline; 8) change from baseline in haptoglobin, hemoglobin, albumin, 24-hour proteinuria, bilirubin, and / or reticulocyte count; 9) change in dialysis status throughout the treatment period; 10) Changes in RBC or platelet transfusion requirements (e.g., number of transfusions and total units required); 11) overall survival; 12) incidence of extrarenal complications associated with TMA; 13) percentage of subjects with resolution of schistocytosis; 14) markers of healthcare utilization and morbidity, including, but not limited to, patient duration of hospitalization (days) and / or duration of ICU stay during the procedure, and quality of life (QoL; Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT]-F); 15) incidence of procedural failure, as defined by any of the following: status of renal-related SAE. doubling of creatinine from baseline or an increase equivalent to >1 Common Terminology Criteria for Adverse Events (CTCAE) grade in the TMA; worsening of renal function requiring new dialysis; worsening of renal or hematologic function requiring the use of another complement inhibitor; worsening of renal, hematologic, neurologic, or other function as a result of TMA; need for the use of IVIG, belimumab, or rituximab; major extrarenal adverse events secondary to TMA; and death of the subject attributable to TMA, TMA-related complications, or fusion protein; 16) change from baseline in SLEDAI score;17) renal biopsy status; 18) presence of autoantibodies to factor H; 19) changes in pharmacodynamics and biomarkers of the anti-C5-FH fusion protein, including, but not limited to, changes from baseline in serum C3b and free and total C5, changes from baseline in rabbit RBC assays (alternative complement pathway [AP] and terminal complement pathway [TP] activity), changes in endogenous serum levels of factor H, and changes in serum C5b-9; and 20) immunogenicity of the anti-C5-FH fusion protein.

[0138] In some embodiments, subjects receiving the anti-C5-FH fusion protein continue to receive standard of care (SOC) therapy for SLE-TMA. SOC includes any combination of the following: IV or PO corticosteroids, cyclophosphamide induction with or without azathioprine maintenance therapy, calcineurin inhibitors, or mycophenolate mofetil. SOC excludes other complement inhibitors, IVIG, and rituximab. In some embodiments, individuals may further receive salvage therapy via plasma exchange, plasmapheresis, and / or plasma infusion.

[0139] In some embodiments, the methods of treating SLE-TMA described herein further include selecting a human individual suitable for such treatment (e.g., a complement inhibitor-naive human individual). In some embodiments, the human individual to be treated has previously been vaccinated against one or all of Neisseria meningitidis, Streptococcus pneumoniae, and Hemophilus influenzae. In some embodiments, the human individual further receives antibiotic prophylaxis during treatment. In some embodiments, individuals not vaccinated with the above-described vaccinations will receive antibiotic prophylaxis starting no later than the first administration of anti-C5-FH fusion protein and will continue to receive this antibiotic prophylaxis treatment for up to two weeks after vaccination. In some embodiments, the human individual is between about 18 and about 65 years of age. In some embodiments, the human individual meets one or more of the following criteria: 1) meets criteria for SLE according to the 2019 European Association of Rheumatology (EULAR) / American College of Rheumatology (ACR) criteria; 2) has a platelet count <100,000 / μL and is at least a 25% (e.g., about any of 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%) decrease from the pre-treatment platelet count. Pre-treatment platelet count is defined as the platelet count within 6 months prior to screening, or the median of all platelet counts if multiple measurements were taken within that 6-month period (if a pre-screening platelet value is not available, a platelet count <100,000 / μL at screening and evidence of TMA on a renal biopsy within 6 months is sufficient); 3) LDH ≥ 2x upper limit of normal (ULN); 4) presence of schistocytes on a peripheral blood smear within 14 days of screening; 5) abnormal renal function defined by creatinine above ULN or proteinuria as defined below.Eligible subjects were those with acute kidney injury due to SLE-TMA requiring dialysis within 4 weeks of screening (urine protein ≥ 1.0 g / 24 hours on two separate assessments during the screening period; or UPCR ≥ 1.0 g / g (or ≥ 113 mg / mmol); e.g., these assessments must be at least 3 days apart, and the difference between the higher and lower values ​​must be < 20%); 6) effective contraception practice from screening to the end of treatment; 7) a negative pregnancy test in women at screening and / or within 24 hours prior to the first dose of anti-C5-FH fusion protein; 8) evidence of prior vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Hemophilus influenzae at screening (subjects who do not provide evidence of prior vaccination must be vaccinated after initiating anti-C5-FH fusion protein administration but are required to receive appropriate antibiotic prophylaxis for up to 2 weeks after vaccination); and 9) evidence of microangiopathic hemolytic anemia.

[0140] In some embodiments, the methods of treating PNH described herein further include excluding human individuals who are not suitable for such treatment. In some embodiments, human individuals who are not suitable for the methods of treatment described herein meet one or more of the following criteria: 1) a diagnosis of other TMA syndromes, including but not limited to ADAMTS13 deficiency-mediated TMA, metabolism-mediated TMA, Shiga toxin-mediated TMA, coagulation-mediated TMA, hematopoietic stem cell transplantation-mediated TMA, and drug-mediated TMA; 2) a kidney biopsy within 7 days of screening shows only chronic changes in TMA (such as those defined by mucus changes and onion skin lesions of small arteries and / or arteries) and at least 3) any history or signs of significant chronic active or recurrent infection requiring treatment with antibiotics, antivirals, or antifungals in the 6 months prior to screening, or screening laboratory values ​​consistent with significant chronic active or recurrent infection; 4) a positive Coombs test at the time of TMA diagnosis; 5) treatment of any infection with IV (within 30 days of screening) or oral (within 14 days of screening) antibiotics, antivirals, or antifungals; 6) Neisseria at the time of screening meningitidis nasopharyngeal swab positive or history of meningitis; 7) history of meningococcal infection; 8) untreated tuberculosis; 9) positive serology for HCV or HIV; 10) history of splenectomy; 11) known allergy to penicillin antibiotics; 12) known or suspected immunodeficiency, including inherited complement deficiency; 13) history of transplant, including heart, lung, small intestine, pancreas, liver, kidney, bone marrow, or stem cell transplant; 14) absolute neutrophil count <1000 cells / mm 3 ;15)eGFR<30mL / min / 1.73m 2 , except for subjects requiring acute dialysis within 4 weeks of screening due to a new diagnosis of SLE-TMA; 16) platelet count <30,000 / mm 317) History of drug or alcohol abuse within 1 year of screening; 18) Received any type of live attenuated vaccine within 1 month before screening or plan to receive any such live attenuated vaccine during the treatment period; 19) Use of any complement inhibitor; 20) Use of IVIG within 7 days of initiating anti-C5-FH fusion protein; 21) Use of rituximab within 3 months of initiating anti-C5-FH fusion protein; 22) Use of belimumab within 3 months of initiating anti-C5-FH fusion protein; 23) History of malignancy (adequately treated basal cell carcinoma or uterine cancer) 24) any women who are pregnant or breastfeeding, or who plan to become pregnant during or immediately after treatment; 25) any condition that may interfere with treatment, pose a safety risk to the subject, or confound interpretation of treatment results, such as active symptomatic COVID infection; 26) QT interval (QtcF) corrected for heart rate by the Fridericia formula of >450 milliseconds (msec) for men or >470 msec for women, based on either single or mean QTcF values ​​of three ECGs obtained 3 minutes apart; and 27) unwillingness to be vaccinated against Neisseria meningitidis, Streptococcus pneumoniae, and Hemophilus influenzae.

[0141] Methods for treating C3G and / or IgAN In some embodiments, methods are provided for treating C3G in a human individual (e.g., a complement inhibitor-naive human individual), comprising administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising: i) an antibody portion that specifically binds human C5 (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85). In some embodiments, the fusion protein is administered intravenously. In some embodiments, the fusion protein is administered subcutaneously. In some embodiments, the fusion protein is administered in a dose of about 60 mg to about 3600 mg (e.g., including any of 60, 180, 360, 600, 720, 960, 1200, 1440, 1800, 1920, 2400, 1920, 2880, 3000, 3200, and 3600 mg). In some embodiments, the fusion protein is administered in a single dose, e.g., about 60 mg to about 1200 mg. In some embodiments, the fusion protein is administered in a single dose of about 60 mg IV, about 180 mg IV, about 180 mg SC, about 360 mg IV, about 600 mg IV, about 720 mg SC, or about 1200 mg IV. In some embodiments, the fusion protein is administered in multiple doses. In some embodiments, the fusion protein is administered weekly or biweekly, e.g., at a dose of about 600 mg to about 2880 mg. In some embodiments, the fusion protein is administered in an initial phase comprising one or more (e.g., single) initial doses (e.g., about 600 mg to about 3600 mg, or about 1200 mg to about 3600 mg per IV dose) of the fusion protein, followed by a maintenance phase comprising at least two (e.g., 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 23, 24, 25, 26, 40, 44, 47, 48, 49, 50, or more) doses (e.g., about 600 mg to about 2880 mg per dose) of the fusion protein (e.g., weekly or biweekly).In some embodiments, two or more maintenance doses of the fusion protein are administered weekly, e.g., at about 600 mg to about 1440 mg per dose. In some embodiments, two or more maintenance doses of the fusion protein are each administered weekly at about 600 mg IV to about 1200 mg IV, or about 720 mg SC to about 1440 mg SC. In some embodiments, two or more maintenance doses of the fusion protein are administered biweekly, e.g., at about 1800 mg to about 2880 mg. In some embodiments, two or more maintenance doses of the fusion protein are each administered biweekly at about 1920 mg SC to about 2880 mg SC, or about 1800 mg SC to about 2400 mg SC. In some embodiments, the maintenance phase is at least about 48 weeks. In some embodiments, the initial dosing phase comprises administering to the individual one or more (e.g., only one) dose of about 600 mg to about 3600 mg (e.g., IV) once weekly, followed by a maintenance phase comprising administering at least two doses of about 720 mg to about 2880 mg (e.g., SC) or about 600 mg to about 1200 mg (e.g., IV) of the fusion protein once weekly or once every other week, for example, for at least about 48 weeks (e.g., 48, 49, 50, 51, 52, 54, 56, 58, 60 or more weeks, e.g., 48 weeks) for weekly maintenance dosing, or at least about 49 weeks (e.g., 49, 51, 53, 55, 57, 59, 61, 63, 65 or more weeks, e.g., 49 weeks) for biweekly maintenance dosing. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87, and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90.In some embodiments, FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of an anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and administered intraperitoneally using standard techniques for SC administration.

[0142] In some embodiments, methods are provided for treating IgAN in a human individual (e.g., a complement inhibitor-naive human individual), comprising administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising: i) an antibody portion that specifically binds human C5 (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85). In some embodiments, the fusion protein is administered intravenously. In some embodiments, the fusion protein is administered subcutaneously. In some embodiments, the fusion protein is administered in a dose of about 60 mg to about 3600 mg (e.g., including any of 60, 180, 360, 600, 720, 960, 1200, 1440, 1800, 1920, 2400, 1920, 2880, 3000, 3200, and 3600 mg). In some embodiments, the fusion protein is administered in a single dose, e.g., about 60 mg to about 1200 mg. In some embodiments, the fusion protein is administered in a single dose of about 60 mg IV, about 180 mg IV, about 180 mg SC, about 360 mg IV, about 600 mg IV, about 720 mg SC, or about 1200 mg IV. In some embodiments, the fusion protein is administered in multiple doses. In some embodiments, the fusion protein is administered weekly or biweekly, e.g., at a dose of about 600 mg to about 2880 mg. In some embodiments, the fusion protein is administered in an initial phase comprising one or more (e.g., single) initial doses (e.g., about 600 mg to about 3600 mg, or about 1200 mg to about 3600 mg per IV dose) of the fusion protein, followed by a maintenance phase comprising at least two (e.g., 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 23, 24, 25, 26, 40, 44, 47, 48, 49, 50, or more) doses (e.g., about 600 mg to about 2880 mg per dose) of the fusion protein (e.g., weekly or biweekly).In some embodiments, two or more maintenance doses of the fusion protein are administered weekly, e.g., at about 600 mg to about 1440 mg per dose. In some embodiments, two or more maintenance doses of the fusion protein are each administered weekly at about 600 mg IV to about 1200 mg IV, or about 720 mg SC to about 1440 mg SC. In some embodiments, two or more maintenance doses of the fusion protein are administered biweekly, e.g., at about 1800 mg to about 2880 mg. In some embodiments, two or more maintenance doses of the fusion protein are each administered biweekly at about 1920 mg SC to about 2880 mg SC, or about 1800 mg SC to about 2400 mg SC. In some embodiments, the maintenance phase is at least about 48 weeks. In some embodiments, the initial dosing phase comprises administering to the individual one or more (e.g., only one) dose of about 600 mg to about 3600 mg (e.g., IV) once weekly, followed by a maintenance phase comprising administering at least two doses of about 720 mg to about 2880 mg (e.g., SC) or about 600 mg to about 1200 mg (e.g., IV) of the fusion protein once weekly or once every other week, for example, for at least about 48 weeks (e.g., 48, 49, 50, 51, 52, 54, 56, 58, 60 or more weeks, e.g., 48 weeks) for weekly maintenance dosing, or at least about 49 weeks (e.g., 49, 51, 53, 55, 57, 59, 61, 63, 65 or more weeks, e.g., 49 weeks) for biweekly maintenance dosing. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87, and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90.In some embodiments, FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of an anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and administered intraperitoneally using standard techniques for SC administration.

[0143] In some embodiments, a method for treating C3G or IgAN in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising (i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and (ii) FH or a functional fragment thereof (e.g., the SCR1-5 domains of FH, e.g., SEQ ID NO: 85), wherein the fusion protein is administered at an initial dose (e.g., about 600 mg to about 1200 mg, about 600 mg to about 2880 mg, about 720 mg to about 1440 mg, about 720 mg to about 3000 mg, about 1200 mg IV to about 3600 mg IV, about 1200 mg IV to about 2400 mg IV, or about 2400 mg IV) on day 1. The fusion protein may be administered in an initial phase comprising administering the fusion protein at a dose of about 3600 mg IV to about 3600 mg IV, followed by a maintenance phase comprising administering the fusion protein at two or more maintenance doses (e.g., 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or more weeks) beginning on day 8, wherein the maintenance phase continues for a period of time (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 or more weeks) during the first maintenance phase. In some embodiments, the initial dose is about 600 mg, 720 mg, 1200 mg, 1440 mg, 1600 mg, 1800 mg, 1920 mg, 2400 mg, 2880 mg, 3000 mg, 3240 mg, or 3600 mg.In some embodiments, the first maintenance dose and / or the second maintenance dose is about 600 mg to about 2880 mg, e.g., about 600 mg to about 1200 mg, about 720 mg to about 1440 mg, about 1800 mg to about 2880 mg, about 1920 mg to about 2880 mg, about 1800 mg to about 2400 mg, about 600 mg to about 2400 mg, or about 720 mg to about 2400 mg. In some embodiments, the first maintenance dose and / or the second maintenance dose is about 600 mg, 720 mg, 960 mg, 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, or 2880 mg. In some embodiments, the initial dose, first maintenance dose, and / or second maintenance dose of the fusion protein are administered IV or SC. In some embodiments, the first and / or second maintenance dose of fusion protein is administered at about 600 mg IV to about 1200 mg IV, about 720 mg SC to about 1440 mg SC, about 1920 mg SC to about 2880 mg SC, or about 1800 mg SC to about 2400 mg SC. In some embodiments, the second maintenance dose is higher than the first maintenance dose. In some embodiments, the duration of the second maintenance phase is longer than the duration of the first maintenance phase. In some embodiments, the first maintenance dose of fusion protein is administered at about 720 mg SC or about 600 mg IV once weekly, and the second maintenance dose of fusion protein is administered at about 1440 mg SC or about 1200 mg IV once weekly. In some embodiments, the duration of the first maintenance phase is about 4 weeks, and the duration of the second maintenance phase is at least about 44 weeks. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 600 mg IV to about 1200 mg IV (e.g., about 1200 mg IV) on day 1, and the maintenance phase comprises i) administering the fusion protein at a first maintenance dose of about 720 mg SC or about 600 mg IV once weekly starting on day 8 for about 4 weeks, followed by ii) administering the fusion protein at a second maintenance dose of about 1440 mg SC or about 1200 mg IV once weekly starting on day 36 for about 44 weeks.In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, an FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to an FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, at a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0144] In some embodiments, a method of treating C3G or IgAN in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 600 mg IV to about 1200 mg IV (e.g., about 1200 mg IV) on day 1, followed by (a) administering the fusion protein at a first maintenance dose of about 720 mg SC or about 600 mg IV once weekly for about 4 weeks starting on day 8, followed by (b) administering the fusion protein at a first maintenance dose of about 1440 mg SC or about 1200 mg IV once weekly for about 44 weeks starting on day 36. and a maintenance phase comprising administering a fusion protein via IV with a second maintenance dose, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0145] In some embodiments, a method for treating C3G or IgAN in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, e.g., FMEH-IgG4-PLA-FH) comprising (i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, e.g., FMEH-IgG4-PLA) and (ii) FH or a functional fragment thereof (e.g., the SCR1-5 domains of FH, e.g., SEQ ID NO: 85), wherein the fusion protein is administered in an amount of about 600 mg IV to about 3600 mg IV (e.g., about 600 mg to about 1200 mg, about 600 mg to about 2880 mg, about 720 mg to about 1440 mg, about 720 mg to about 3000 mg, about 1200 mg IV to about 2400 mg IV, or about 2400 mg IV) on day 1. In some embodiments, methods are provided in which the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 600 mg IV to about 3600 mg IV, followed by a maintenance phase, starting on day 8, comprising administering the fusion protein at a maintenance dose of about 600 mg IV to about 1200 mg IV once weekly for at least about 48 weeks; (b) about 720 mg SC to about 1440 mg SC once weekly for at least about 48 weeks; (c) about 1920 mg SC to about 2880 mg SC once every other week for at least 49 weeks; or (d) about 1800 mg SC to about 2400 mg SC once every other week for at least 49 weeks. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 600 mg IV to about 1200 mg IV (e.g., about 1200 mg IV) on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC or about 600 mg SC once weekly for about 48 weeks, starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 600 mg IV to about 1200 mg IV (e.g., about 1200 mg IV) on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1440 mg SC or about 1200 mg IV once weekly starting on day 8 for about 48 weeks.In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 2400 mg IV to about 3600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week for about 49 weeks starting on day 8. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC once every week for about 48 weeks starting on day 8. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:96. In some embodiments, the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 antibody portion is a full-length antibody comprising i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and ii) a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, FH, or a functional fragment thereof, is fused to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH, or a functional fragment thereof, comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0146] In some embodiments, a method of treating C3G or IgAN in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV on day 1, followed by administration of about 720 mg SC or about 600 mg SC once weekly starting on day 8 for about 48 weeks. and a maintenance phase comprising administering an IV maintenance dose of a fusion protein, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody and a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0147] In some embodiments, a method of treating C3G or IgAN in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 600 mg IV on day 1, followed by administration of about 720 mg IV once weekly starting on day 8 for about 48 weeks. and a maintenance phase comprising administering a fusion protein at a SC maintenance dose, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0148] In some embodiments, a method of treating C3G or IgAN in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV on day 1, followed by administration of about 1440 mg SC or about 1200 mg SC once weekly for about 48 weeks starting on day 8. and a maintenance phase comprising administering an IV maintenance dose of a fusion protein, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody and a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0149] In some embodiments, a method of treating C3G or IgAN in a human individual (e.g., a complement inhibitor-naive human individual) comprises administering to the human individual an effective amount of a fusion protein comprising: (i) an anti-human C5 full-length antibody; (ii) a first FH functional fragment; and (iii) a second FH functional fragment, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein at an initial dose of about 2400 mg IV to about 3600 mg IV on day 1, followed by about 1920 mg SC to about 2880 mg SC once every other week for about 49 weeks starting on day 8. and a maintenance phase comprising administering a fusion protein at a SC maintenance dose, wherein a first FH functional fragment is fused to the C-terminus of a first heavy chain of an anti-human C5 full-length antibody, a second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody, each heavy chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 120, each light chain of the anti-human C5 full-length antibody comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to an FH functional fragment comprising the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80, and having a pH of about 6.0. In some embodiments, for IV administration, the anti-C5-FH fusion protein is diluted in an infusion bag containing 100 mL of 0.9% sodium chloride for infusion. In some embodiments, for SC administration, the anti-C5-FH fusion protein is administered without further formulation and is administered intraperitoneally using standard techniques for SC administration.

[0150] C3G Complement 3 glomerulopathy (C3G) is a rare kidney disease (estimated to affect 2–3 per 1,000,000 people) with two forms: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). C3G is characterized by the deposition of C3 in the filtering units of the kidney (glomeruli), implicating complement in causing kidney damage. C3 glomerulopathy is characterized by evidence of alternative complement activation based on C3 deposition in the glomeruli. Genetic lesions leading to complement dysregulation, including mutations in complement factor H, have been reported in these patients. Common signs and symptoms of C3G (DDD or C3GN) associated with loss of normal kidney function include: blood in the urine (hematuria), excess protein in the urine (proteinuria), acute nephrotic syndrome or nephrotic syndrome, low levels of complement component C3, swelling (edema), gout, recurrent infections, decreased urine production (oliguria), hypertension, fatigue and decreased alertness, drusen, abnormal distribution of subcutaneous fat (acquired partial lipodystrophy), and any combination thereof. C3G (DDD or C3GN) can also lead to kidney failure, and signs and symptoms include loss of appetite, nausea and vomiting, difficulty sleeping, dry and itchy skin, and nighttime muscle cramps. There is no approved treatment for patients with C3 glomerulopathies, including C3GN. Without treatment, C3G invariably leads to kidney failure, and kidney transplantation is often the only option. Even after transplantation, the new kidney often fails due to recurrence of the disease.

[0151] In some embodiments, the methods of treating C3G described herein can prevent (e.g., prevent at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the time), delay (e.g., delay by at least about 1, 2, 3, 6, 12, 18, 24, 30, 36, 42, 48, 52 months or more), or reduce the severity (e.g., reduce by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) of one or more of the signs and symptoms of C3G discussed above (including, but not limited to, hematuria, proteinuria, nephrotic syndrome, renal failure, and drusen). In some embodiments, the C3G treatment methods described herein can improve one or more kidney lesions (including, but not limited to, proteinuria, hematuria, crescent and fibrin deposition, C3 deposition, intraductal pleocytosis, and mesangial pleocytosis) (e.g., by at least about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction). In some embodiments, the C3G treatment methods described herein can reduce one or more of the following: C3 deposition score, C3b activity, free serum C5 level, eGFR, urinary protein / creatinine ratio (UPCR; calculated as the percentage change (%) of protein (Pr) / creatinine (Cr)), and RBC lysis (e.g., by at least about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction). In some embodiments, the C3G treatment methods described herein can improve quality of life, such as that assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and the Kidney Disease Quality of Life (KDQoL) scale, and / or histological and histopathological findings of kidney biopsies (e.g., an improvement of about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%).

[0152] IgAN IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Abnormal glycosylation of IgA1 leads to increased serum levels of galactose-deficient IgA1 (Gd-IgA1), which is recognized by glycan-specific IgA and IgG autoantibodies. Immune complex aggregates form in situ and / or are deposited in the glomerular mesangium. This promotes mesangial cell proliferation, increased synthesis of extracellular matrix proteins, cytokines, and chemokines, and immune cell infiltration into surrounding tissues. Therefore, disease progression involves (1) production of Gd-IgA1; (2) its recognition by anti-glycan autoantibodies; (3) immune complex formation in the kidney; and (4) mesangial cell activation. See, for example, Penfold et al., Int. J. Nephrol. and Renovascular Dis. 11, pp. 137-148 (2017).

[0153] IgAN primarily affects patients in their 20s and 30s. Patients present with a variety of symptoms, typically including microscopic or gross hematuria and increased urinary protein excretion. Patients may also present with hypertension as a result of persistent renal damage. Current treatment approaches offer supportive care, including administration of maximally tolerated angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or immunosuppressants, but the side effects far outweigh the benefits. Ultimately, 30–40% of patients develop end-stage renal disease (ESRD) within 20–30 years of IgAN diagnosis. During this time, patients experience a number of symptoms, including declining renal function, that significantly deteriorate their quality of life. Patients with IgAN often exhibit significantly increased expression of endothelin-1 (ET-1) and ET-RA in the kidneys. Increased endothelin expression is positively correlated with proteinuria, one of the hallmark symptoms of IgAN.

[0154] In some embodiments, the methods of treating IgAN described herein can prevent (e.g., prevent at least about any of the following: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% probability), delay (e.g., delay by at least about any of the following: 1, 2, 3, 6, 12, 18, 24, 30, 36, 42, 48, 52 months or more), or reduce the severity (e.g., reduce by at least about any of the following: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% probability) of one or more of the signs and symptoms of IgAN discussed above (including, but not limited to, proteinuria, hematuria, back pain, edema, high blood pressure, and complications such as high cholesterol, acute renal failure, chronic renal failure, and nephrotic syndrome). In some embodiments, the methods of treating IgAN described herein may achieve one or more of the following effects: i) reduction in renal inflammation and / or fibrosis (e.g., a reduction of about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); ii) reduction in the production of Gd-IgA1 (e.g., a reduction of at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); iii) reduction in the occurrence of hematuria (e.g., a reduction of at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); iv) stabilization of eGFR (e.g., a reduction of about 30%, 20%, 10%, 5%, or 100%). or no greater fluctuation than 50%, 60%, 70%, 80%, 90%, or 100%; v) delay in the onset of ESRD (e.g., a delay of at least about 1, 2, 3, 6, 12, 18, 24, 30, 36, 42, 48, 52 months or more); vi) reduction in the number of IgA nephropathy-associated disease flares (e.g., a reduction of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); vii) reduction in proteinuria (e.g., a reduction of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); viii) reduction in fatigue (e.g., a reduction of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%);ix) inhibition of mesangial cell activation (e.g., at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% inhibition); x) reduction of mesangial cell activation upon contact with IgA immune complexes (e.g., at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction); xi) in the kidney. and xii) an improvement in renal function and / or renal lesion score (e.g., at least about any of an improvement of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%). In some embodiments, the methods of treating IgAN described herein can reduce one or more of C3 deposition score, C3b activity, free serum C5 level, eGFR, UPCR, and RBC lysis (e.g., at least about any of an improvement of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%). In some embodiments, the methods of treating IgAN described herein can improve quality of life, such as that assessed by the FACIT-Fatigue score and the KDQoL scale, and / or renal biopsy histology and histopathology (e.g., by about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% improvement);

[0155] In some embodiments, the efficacy of the C3G or IgA treatment methods described herein can be assessed by one or more of the following: i) percent change from baseline in 24-hour UPCR; ii) change from baseline in rabbit RBC assay, C3b activity assay, serum and urinary factor H levels, urinary MCP-1, C3a, C5a, properdin, or C5b-9 levels, and / or free serum C5 levels; iii) change in eGFR; iv) change in quality of life as assessed by the FACIT-Fatigue score and the KDQoL scale; and v) change in histological and histopathological findings in subjects undergoing repeat kidney biopsies. Such methods are known in the art. In some embodiments, changes from baseline in markers involved in the alternative complement pathway, such as C3, C3d, C3c, C3adesArg, C5, C5a, C5b-9, C5adesArg, and other inflammatory markers, can be assessed in plasma / serum or urine during the treatment period.

[0156] In some embodiments, the methods of treating C3G or IgAN described herein further comprise selecting a human individual suitable for such treatment (e.g., a complement inhibitor-naive human individual). In some embodiments, the human individual to be treated has had prior vaccination against one or all of Neisseria meningitidis, Streptococcus pneumoniae, and Hemophilus influenzae. In some embodiments, the human individual further receives antibiotic prophylaxis during treatment. In some embodiments, individuals not vaccinated with the above-described vaccinations will receive antibiotic prophylaxis starting no later than the first administration of anti-C5-FH fusion protein and will continue to receive this antibiotic prophylaxis treatment for up to two weeks after vaccination. In some embodiments, the human individual is between about 18 and about 75 years of age. In some embodiments, the human individual meets one or more of the following criteria: 1) weight >35 kilograms (kg) at screening; 2) body mass index (BMI) <35 kilograms per square meter (kg / m 2 3) UPCR > 1.5 grams per gram (g / g) by 24-hour urine collection at screening; 4) documented diagnosis and clinical status of IgAN or C3G; 5) negative pregnancy test and effective contraception for the entire treatment period; 6) vaccination; and 7) ability to provide informed consent. In some embodiments, C3G or IgAN is confirmed by biopsy in the human individual to be treated. In some embodiments, the human individual is on a stable regimen of 12 weeks of angiotensin-converting enzyme or angiotensin blocker and / or 6 weeks of sodium-glucose cotransporter 2 (SGLT2) inhibitor at screening.

[0157] In some embodiments, the methods of treating C3G or IgAN described herein further comprise excluding human individuals who are unsuitable for such treatment. In some embodiments, human individuals who are unsuitable for the methods of treatment described herein meet one or more of the following criteria: 1) any clinically significant, poorly controlled underlying disease other than IgAN or C3G; 2) any history or signs of significant chronic active or recurrent infection, such as those requiring or being treated with antibiotics, antivirals, or antifungals; 3) a history of infection with encapsulated organisms; 4) a history of untreated tuberculosis; 5) a known allergy to penicillin-based antibiotics. 6) known or suspected immunodeficiency disease, including inherited complement deficiencies; 7) positive serology for hepatitis C virus (HCV) ribonucleic acid (RNA) or human immunodeficiency virus (HIV) at screening; 8) history of bone marrow or stem cell transplant; 9) absolute neutrophil count (ANC) < 500 cells / microliter (cells / μL); 10) eGFR < 30 milliliters per minute (mL / min / 1.73 m) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula 2 11) Presence of crescent formation in >50 percent (%) of glomeruli as assessed by renal biopsy; 12) Nephrotic syndrome; 13) Glomerular urinary tract infection >30 mL / min / 1.73 m within 24 weeks prior to the screening visit 214) receiving or anticipated need for renal replacement therapy during the duration of treatment; 15) a history of drug or alcohol abuse within 1 year of screening; 16) having received any type of live attenuated vaccine <4 weeks prior to screening or intending to receive any such live attenuated vaccine during the treatment period; 17) use of rituximab within the past 12 weeks or previous use of any complement inhibitor; 18) use of systemic corticosteroids (prednisone or equivalent) >10 mg / day within 4 weeks prior to screening or use of immunosuppressants (e.g., steroids) within 3 months prior to screening. 19) history of malignancy (except adequately treated basal cell carcinoma or intraepithelial carcinoma of the cervix); 20) any woman who is pregnant or breastfeeding, or any woman who plans to become pregnant during treatment; 21) QT interval (QTcF) corrected for heart rate by the Fridericia formula of >450 milliseconds (msec) for men and >470 msec for women, based on either a single or mean QTcF value of three ECGs obtained at 3-minute intervals; 22) diagnosed with a secondary form of IgAN (e.g., Henoch-Schönlein purpura, IgA-associated vasculitis); and 23) use of any complement inhibitors.

[0158] The anti-C5-FH fusion protein and its components are described in further detail below.

[0159] Anti-C5-fH fusion protein Any of the anti-C5-FH fusion proteins and anti-C5 antibody moieties (e.g., pH-dependent anti-C5 antibody moieties) described in US20220204602, US20220177556, US11578137, and WO2020219922 can be used herein, the contents of each of which are incorporated by reference in their entirety.

[0160] The methods described herein utilize a fusion protein comprising an anti-C5 antibody portion (such as any one of the anti-C5 antibodies or antigen-binding fragments thereof described herein) and FH or a functional fragment thereof. In some embodiments, the anti-C5 antibody portion is a full-length antibody (hereinafter referred to as an "anti-C5 full-length antibody"). In some embodiments, the FH or a functional fragment thereof is fused to one or both (e.g., both) heavy chains of the anti-C5 full-length antibody (e.g., to the C-terminus of the heavy chain(s)). In some embodiments, the anti-C5 full-length antibody comprises an Fc fragment derived from human IgG4 (such as an IgG4 Fc fragment comprising PLA mutations (S228P / M428L / N434A)). In some embodiments, the IgG4 Fc fragment comprises the amino acid sequence of any of SEQ ID NOs: 32, 33, and 61. In some embodiments, the IgG4 Fc fragment comprises a PLA mutation comprising the amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the fragment of FH inhibits C3 activation. In some embodiments, the functional fragment of FH comprises short consensus repeat (SCR) domains 1 to 5 of FH. In some embodiments, the functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 85. In some embodiments, the nucleic acid encoding the IgG4 Fc comprising the amino acid sequence of SEQ ID NO: 61 comprises the nucleic acid sequence of SEQ ID NO: 60.

[0161] In some embodiments, the fusion protein comprises an anti-C5 antibody portion (such as any one of the anti-C5 antibodies or antigen-binding fragments thereof described herein) and FH or a functional fragment thereof comprising the SCR1-5 domain of FH. In some embodiments, the fusion protein comprises i) an anti-C5 antibody portion (such as any one of the anti-C5 antibodies described herein) comprising an IgG4 Fc fragment (e.g., an IgG4 Fc fragment comprising a PLA mutation), and ii) FH or a functional fragment thereof comprising the SCR1-5 domain of FH. In some embodiments, the functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 85. In some embodiments, the IgG4 Fc fragment comprises the amino acid sequence of SEQ ID NO: 61.

[0162] In some embodiments, the fusion protein comprises an anti-C5 antibody portion and an FH or functional fragment thereof, wherein the anti-C5 antibody portion is pH-sensitive or pH-dependent (e.g., any one of the pH-sensitive or pH-dependent anti-C5 antibodies or antigen-binding fragments thereof described herein). For example, in some embodiments, the pH-sensitive anti-C5 antibody portion is an anti-C5 antibody portion that binds to C5 with higher affinity at neutral pH (e.g., about pH 7.4) than at acidic pH (e.g., about pH 5.8). In some embodiments, the binding affinity of the pH-dependent anti-C5 antibody portion to C5 (e.g., human C5) at about pH 7.4 is at least about three times (e.g., at least about any of 4, 5, 6, 7, 8, 9, 10, or more) higher than the binding affinity of the pH-dependent anti-C5 antibody portion to C5 (e.g., human C5) at about pH 5.8. In some embodiments, the pH-dependent anti-C5 antibody portion comprises an Fc fragment derived from human IgG4 (e.g., an IgG4 Fc fragment containing a PLA mutation). In some embodiments, the functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 85. In some embodiments, the IgG4 Fc fragment comprises the amino acid sequence of SEQ ID NO:61.

[0163] In some embodiments, the fusion protein comprises an anti-C5 antibody portion and an FH or functional fragment thereof, wherein the anti-C5 antibody portion is pH-sensitive or pH-dependent (such as any one of the pH-sensitive or pH-dependent anti-C5 antibodies described herein) and binds to C5 (e.g., human C5) with greater affinity at pH 7.4 than at pH 5.8, and the anti-C5 antibody portion comprises an IgG4 Fc fragment (e.g., an IgG4 Fc fragment comprising a PLA mutation). In some embodiments, the fusion protein comprises an anti-C5 antibody portion and an FH or functional fragment thereof, wherein the anti-C5 antibody portion is pH-sensitive or pH-dependent (such as any one of the pH-sensitive or pH-dependent anti-C5 antibodies or antigen-binding fragments thereof described herein) and binds to C5 (e.g., human C5) with greater affinity at pH 7.4 than at pH 5.8, and the FH or functional fragment thereof comprises the SCR1-5 domains of FH. In some embodiments, the fusion protein comprises an anti-C5 antibody portion and an FH or functional fragment thereof, wherein the anti-C5 antibody portion is pH-sensitive or pH-dependent (such as any one of the pH-sensitive or pH-dependent anti-C5 antibodies described herein) and binds to C5 (e.g., human C5) with higher affinity at pH 7.4 than at pH 5.8, for example, the anti-C5 antibody portion comprises an IgG4 Fc fragment (e.g., an IgG4 Fc fragment comprising a PLA mutation), and the FH or functional fragment thereof comprises the SCR1-5 domains of FH. In some embodiments, the functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 85. In some embodiments, the IgG4 Fc fragment comprises the amino acid sequence of SEQ ID NO: 61.

[0164] In some embodiments, the fusion protein comprises an anti-C5 antibody portion (such as any one of the anti-C5 antibodies or antigen-binding fragments thereof described herein) and an FH or functional fragment thereof, wherein the anti-C5 antibody portion comprises a histidine substitution in one or more of its CDR regions (such as any one of the histidine-containing anti-C5 antibodies or antigen-binding fragments thereof described herein). In some embodiments, the fusion protein comprises an anti-C5 antibody portion and an FH or functional fragment thereof, wherein the anti-C5 antibody portion comprises a histidine substitution in one or more of its CDR regions (such as any one of the histidine-containing anti-C5 antibodies described herein), and wherein the anti-C5 antibody portion comprises an IgG4 Fc fragment (e.g., an IgG4 Fc fragment comprising a PLA mutation). In some embodiments, the fusion protein comprises an anti-C5 antibody portion and an FH or functional fragment thereof, wherein the anti-C5 antibody portion comprises a histidine substitution in one or more of its CDR regions (e.g., any one of the histidine-containing anti-C5 antibodies or antigen-binding fragments thereof described herein), and the FH or functional fragment thereof comprises the SCR1-5 domain of FH. In some embodiments, the fusion protein comprises an anti-C5 antibody portion and an FH or functional fragment thereof, wherein the anti-C5 antibody portion comprises a histidine substitution in one or more of its CDR regions (e.g., any one of the histidine-containing anti-C5 antibodies described herein), the anti-C5 antibody portion comprises an IgG4 Fc fragment (e.g., an IgG4 Fc fragment comprising a PLA mutation), and the FH or functional fragment thereof comprises the SCR1-5 domain of FH. In some embodiments, the functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 85. In some embodiments, the IgG4 Fc fragment comprises the amino acid sequence of SEQ ID NO: 61.

[0165] In some embodiments, FH or a functional fragment thereof (e.g., SEQ ID NO: 85) is fused to an anti-C5 antibody portion (e.g., any one of the anti-C5 antibodies or antigen-binding fragments thereof described herein) via a linker (e.g., a peptide linker), e.g., fused to the C-terminus of the anti-C5 antibody portion via a linker. Any suitable peptide linker may be used herein, including, but not limited to, a GS linker. In some embodiments, FH or a functional fragment thereof (e.g., SEQ ID NO: 85) is fused directly to the anti-C5 antibody portion (e.g., any one of the anti-C5 antibodies or antigen-binding fragments thereof described herein), e.g., fused directly to the C-terminus of the anti-C5 antibody portion. In some embodiments, the anti-C5 antibody portion is a full-length antibody. In some embodiments, FH or a functional fragment thereof is fused, e.g., directly to the C-terminus of one or both heavy chains of the anti-C5 full-length antibody, either directly or via a peptide linker, e.g., fused directly. In some embodiments, the fusion protein comprises a first FH or a functional fragment thereof and a second FH or a functional fragment thereof, wherein the first FH or a functional fragment thereof is fused to the C-terminus of a first heavy chain of an anti-C5 full-length antibody, and the second FH or a functional fragment thereof is fused to the C-terminus of a second heavy chain of an anti-C5 full-length antibody.

[0166] In some embodiments, the fusion protein further comprises a signal peptide at the N-terminus of one or more of its polypeptide chain(s). Any suitable signal peptide for protein / polypeptide transport or expression can be used herein, including, but not limited to, SEQ ID NO: 91 or 92. In some embodiments, the anti-C5 antibody portion is a full-length antibody, and the FH or functional fragment thereof is fused (e.g., directly fused) to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody, and the fusion protein comprises one or more signal peptides fused to the N-terminus of one or both VH or heavy chains and / or one or both VL or light chains (e.g., both heavy chains and both light chains) of the anti-C5 full-length antibody. In some embodiments, the signal peptide fused to the VH(s) or heavy chain(s) of the anti-C5 antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 91. In some embodiments, the signal peptide fused to the VL(s) or light chain(s) of the anti-C5 antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 92. In some embodiments, the signal peptide is cleaved in the form of the mature or secreted fusion protein. In some embodiments, the fusion protein does not include any signal peptide.

[0167] In some embodiments, a fusion protein comprising an anti-C5 antibody portion (e.g., an anti-C5 full-length antibody) and FH or a functional fragment thereof (e.g., the SCR1-5 domains of FH, e.g., SEQ ID NO: 85), wherein the anti-C5 antibody portion comprises: (i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 11. (ii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; (iii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, and VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8 , VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; (iv) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; (v) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 26 R2, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 29; (vi) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;(vii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; (viii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 42, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 43, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 44 (ix) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 47, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 48, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; 3; (x) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 52, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; (xi) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 47, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, and VH-CDR 3. VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; (xii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96;(xiii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; (xiv) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 42, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 65, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 44 (xv) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 52, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; (xvi) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 52, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10 DR3; (xvi) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; (xvii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5 R3, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96; (xviii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97;(xix) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96; (xx) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96; (xxi) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 102, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23 ... i) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 105; (xxiii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, (xxiv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96; (xxiv) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 108, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96;(xxv) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 108, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 43, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 44, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96; (xxvi) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 48, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, (xxvii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96; (xxviii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96; VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 108, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96; (xxix) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 108, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 65, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 44, VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 23 or (xxx) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises: (i) a VH comprising the amino acid sequence of SEQ ID NO: 93, and a VL comprising the amino acid sequence of SEQ ID NO: 98;(ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 99; (iii) a VH comprising the amino acid sequence of SEQ ID NO: 101 and a VL comprising the amino acid sequence of SEQ ID NO: 95; (iv) a VH comprising the amino acid sequence of SEQ ID NO: 103 and a VL comprising the amino acid sequence of SEQ ID NO: 88; (v) a VH comprising the amino acid sequence of SEQ ID NO: 104 and a VL comprising the amino acid sequence of SEQ ID NO: 106; (vi) a VH comprising the amino acid sequence of SEQ ID NO: 107 and a VL comprising the amino acid sequence of SEQ ID NO: 95; (vii) a VH comprising the amino acid sequence of SEQ ID NO: 108 and a VL comprising the amino acid sequence of SEQ ID NO: 109; (viii) a VH comprising the amino acid sequence of SEQ ID NO: 110 and a VL comprising the amino acid sequence of SEQ ID NO: 88; (ix) a VH comprising the amino acid sequence of SEQ ID NO: 111 and a VL comprising the amino acid sequence of SEQ ID NO: 88; (x) a VH comprising the amino acid sequence of SEQ ID NO: 112 and a VL comprising the amino acid sequence of SEQ ID NO: 88; (xi) a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88; (xii) SEQ ID NO: 1; (xiii) a VH comprising the amino acid sequence of SEQ ID NO: 114 and a VL comprising the amino acid sequence of SEQ ID NO: 88; (xiv) a VH comprising the amino acid sequence of SEQ ID NO: 115 and a VL comprising the amino acid sequence of SEQ ID NO: 88; or (xv) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 95. In some embodiments, a fusion protein is provided comprising an anti-C5 antibody portion (e.g., an anti-C5 full-length antibody) and FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the anti-C5 antibody portion comprises (i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 47, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, or (ii) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, a fusion protein is provided comprising an anti-C5 antibody portion (e.g., an anti-C5 full-length antibody) and an FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the anti-C5 antibody portion comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85) is fused to the C-terminus of the anti-C5 antibody portion. In some embodiments, the anti-C5 antibody portion is a full-length antibody. In some embodiments, the anti-C5 full-length antibody comprises an Fc fragment derived from human IgG4, e.g., an Fc fragment comprising the amino acid sequence of any of SEQ ID NOs: 32, 33, and 61, e.g., SEQ ID NO: 61.In some embodiments, FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85) is fused (e.g., directly fused) to the C-terminus of one or both (e.g., both) heavy chains of an anti-C5 full-length antibody. In some embodiments, the anti-C5 full-length antibody comprises a heavy chain comprising the amino acid sequence of any of SEQ ID NOs: 120, 122, 124, and 126, and a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, the anti-C5 full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 120, and a light chain comprising the amino acid sequence of SEQ ID NO: 90.

[0168] In some embodiments, a fusion protein comprising an anti-C5 full-length antibody and FH or a functional fragment thereof (e.g., the SCR1-5 domains of FH, e.g., SEQ ID NO: 85), wherein the FH or functional fragment thereof is fused (e.g., directly fused) to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody, and the anti-C5 full-length antibody comprises (i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 47, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, and a VH-CDR4 comprising the amino acid sequence of SEQ ID NO: 23. and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; or (ii) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 86, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96. In some embodiments, a fusion protein is provided comprising an anti-C5 full-length antibody and FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the FH or functional fragment is fused (e.g., directly fused) to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody, and the anti-C5 full-length antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 87 and a VL comprising the amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 full-length antibody comprises an Fc fragment comprising the amino acid sequence of SEQ ID NO: 61. In some embodiments, a fusion protein is provided comprising an anti-C5 full-length antibody and FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the FH or functional fragment thereof is fused (e.g., directly fused) to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody, and the anti-C5 full-length antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 120 and a light chain comprising the amino acid sequence of SEQ ID NO: 90.

[0169] In some embodiments, the anti-C5 antibody portion is a full-length antibody. In some embodiments, the anti-C5 full-length antibody comprises an Fc fragment comprising the amino acid sequence of SEQ ID NO: 61. In some embodiments, FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85) is fused (e.g., directly fused) to the C-terminus of one or both (e.g., both) heavy chains of the anti-C5 full-length antibody. In some embodiments, a fusion protein is provided comprising an anti-C5 full-length antibody (such as any of the anti-C5 full-length antibodies described herein) and FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the FH or functional fragment is fused (e.g., directly fused) to the C-terminus of one of the heavy chains of the anti-C5 full-length antibody. In some embodiments, a fusion protein is provided comprising an anti-C5 full-length antibody and FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, e.g., SEQ ID NO: 85), wherein the FH or functional fragment thereof is fused (e.g., directly fused) to one C-terminus of the heavy chain of the anti-C5 full-length antibody, and the anti-C5 full-length antibody comprises a heavy chain comprising the amino acid sequence of any of SEQ ID NOs: 120, 122, 124, and 126, and a light chain comprising the amino acid sequence of SEQ ID NO: 90. In some embodiments, a fusion protein is provided comprising a first FH or a functional fragment thereof (e.g., the SCR1-5 domain of an FH, e.g., SEQ ID NO: 85), a second FH or a functional fragment thereof (e.g., the SCR1-5 domain of an FH, e.g., SEQ ID NO: 85), and an anti-C5 full-length antibody (such as any of the anti-C5 full-length antibodies described herein), wherein the first FH or functional fragment thereof is fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody (e.g., a direct fusion), and the second FH or functional fragment thereof is fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody (e.g., a direct fusion).In some embodiments, a fusion protein is provided comprising a first FH or a functional fragment thereof (e.g., the SCR1-5 domain of an FH, e.g., SEQ ID NO: 85), a second FH or a functional fragment thereof (e.g., the SCR1-5 domain of an FH, e.g., SEQ ID NO: 85), and an anti-C5 full-length antibody, wherein the first FH or functional fragment thereof is fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody (e.g., direct fusion), and the second FH or functional fragment thereof is fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody (e.g., direct fusion), and the anti-C5 full-length antibody comprises a heavy chain comprising the amino acid sequence of any of SEQ ID NOs: 120, 122, 124, and 126, and a light chain comprising the amino acid sequence of SEQ ID NO: 90.

[0170] In some embodiments, a fusion protein is provided comprising: i) an anti-C5 full-length antibody; ii) a first functional fragment of FH fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody; and iii) a second functional fragment of FH fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody, wherein the anti-C5 full-length antibody comprises two heavy chains each comprising the amino acid sequence of SEQ ID NO: 120 and two light chains each comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to a functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 89. This fusion protein is hereinafter referred to as "FMEH-IgG4-PLA-FH." In some embodiments, the fusion protein further comprises a signal peptide (e.g., SEQ ID NO: 91 or 92) at the N-terminus of one or both heavy chains and / or one or both light chains of the anti-C5 full-length antibody, e.g., both heavy chains and both light chains of the anti-C5 full-length antibody. In some embodiments, a fusion protein is provided comprising: i) an anti-C5 full-length antibody; ii) a first functional fragment of FH fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody; and iii) a second functional fragment of FH fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody, wherein the anti-C5 full-length antibody comprises two heavy chains each comprising the amino acid sequence of SEQ ID NO: 119 and two light chains each comprising the amino acid sequence of SEQ ID NO: 74, and each heavy chain fused to a functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 72.

[0171] In some embodiments, a fusion protein is provided comprising: i) an anti-C5 full-length antibody; ii) a first functional fragment of FH fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody; and iii) a second functional fragment of FH fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody, wherein the anti-C5 full-length antibody comprises two heavy chains each comprising the amino acid sequence of SEQ ID NO: 122 and two light chains each comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to a functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 116. In some embodiments, the fusion protein further comprises a signal peptide (e.g., SEQ ID NO: 91 or 92) at the N-terminus of one or both heavy chains and / or one or both light chains of the anti-C5 full-length antibody, e.g., both heavy chains and both light chains of the anti-C5 full-length antibody. In some embodiments, a fusion protein is provided comprising: i) an anti-C5 full-length antibody; ii) a first functional fragment of FH fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody; and iii) a second functional fragment of FH fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody, wherein the anti-C5 full-length antibody comprises two heavy chains each comprising the amino acid sequence of SEQ ID NO: 121 and two light chains each comprising the amino acid sequence of SEQ ID NO: 74, and each heavy chain fused to a functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 76.

[0172] In some embodiments, a fusion protein is provided comprising: i) an anti-C5 full-length antibody; ii) a first functional fragment of FH fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody; and iii) a second functional fragment of FH fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody, wherein the anti-C5 full-length antibody comprises two heavy chains each comprising the amino acid sequence of SEQ ID NO: 124 and two light chains each comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to a functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 117. In some embodiments, the fusion protein further comprises a signal peptide (e.g., SEQ ID NO: 91 or 92) at the N-terminus of one or both heavy chains and / or one or both light chains of the anti-C5 full-length antibody, e.g., both heavy chains and both light chains of the anti-C5 full-length antibody. In some embodiments, a fusion protein is provided comprising: i) an anti-C5 full-length antibody; ii) a first functional fragment of FH fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody; and iii) a second functional fragment of FH fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody, wherein the anti-C5 full-length antibody comprises two heavy chains each comprising the amino acid sequence of SEQ ID NO: 123 and two light chains each comprising the amino acid sequence of SEQ ID NO: 74, and each heavy chain fused to the functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 78.

[0173] In some embodiments, a fusion protein is provided comprising: i) an anti-C5 full-length antibody; ii) a first functional fragment of FH fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody; and iii) a second functional fragment of FH fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody, wherein the anti-C5 full-length antibody comprises two heavy chains each comprising the amino acid sequence of SEQ ID NO: 126 and two light chains each comprising the amino acid sequence of SEQ ID NO: 90, and each heavy chain fused to a functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 118. In some embodiments, the fusion protein further comprises a signal peptide (e.g., SEQ ID NO: 91 or 92) at the N-terminus of one or both heavy chains and / or one or both light chains of the anti-C5 full-length antibody, e.g., both heavy chains and both light chains of the anti-C5 full-length antibody. In some embodiments, a fusion protein is provided comprising: i) an anti-C5 full-length antibody; ii) a first functional fragment of FH fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody; and iii) a second functional fragment of FH fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody, wherein the anti-C5 full-length antibody comprises two heavy chains each comprising the amino acid sequence of SEQ ID NO: 125 and two light chains each comprising the amino acid sequence of SEQ ID NO: 74, and each heavy chain fused to a functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 80.

[0174] Anti-C5 antibody part The fusion proteins described herein comprise an antibody portion that specifically binds to C5. In some embodiments, the anti-C5 antibody portion is a chimeric antibody. In further embodiments, the anti-C5 antibody portion is a humanized antibody. In some embodiments, the anti-C5 antibody portion is a full-length antibody, Fab, Fab', F(ab)2, F(ab')2, scFv, or a combination thereof. In some embodiments, the anti-C5 antibody portion is an antibody fragment (e.g., Fab, scFv). In some embodiments, the anti-C5 antibody portion is a full-length antibody, e.g., a full-length antibody comprising an Fc fragment derived from IgG4 (e.g., an IgG4 Fc comprising a PLA mutation). In some embodiments, the IgG4 Fc fragment comprises the amino acid sequence of any of SEQ ID NOs: 32, 33, and 61, e.g., SEQ ID NO: 61. In some embodiments, the binding of the anti-C5 antibody portion to C5 is pH-dependent, and the anti-C5 antibody portion binds to C5 more strongly at neutral pH (e.g., about pH 7.4) than at acidic pH (e.g., about pH 5.8). In some embodiments, the C5 is human C5. In some embodiments, the anti-C5 antibody portion comprises (or consists of, or consists essentially of) an anti-C5 antibody or antigen-binding fragment thereof. In some embodiments, the anti-C5 antibody portion consists of any of the anti-C5 antibodies or antigen-binding fragments thereof described herein.

[0175] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof binds to an epitope in the alpha chain of C5 and / or an epitope in the beta chain of C5.

[0176] It is understood that the anti-C5 antibody portions described herein can be derived from either the anti-C5 antibodies or antibody fragments thereof, as discussed in more detail below.

[0177] In some embodiments, the anti-C5 antibody portion exhibits pH-dependent binding to C5. In some embodiments, the pH-dependent anti-C5 antibody portion binds to C5 more strongly at a more neutral pH (e.g., about pH 7.4, e.g., the pH found in blood) than at a more acidic pH (e.g., about pH 5.8, e.g., the pH found in endosomes). In some embodiments, the pH-dependent anti-C5 antibody portion is a variant (e.g., containing one or more amino acid substitutions, e.g., conservative substitutions) of a humanized anti-C5 antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:2 and a VL comprising the amino acid sequence of SEQ ID NO:7.

[0178] In some embodiments, binding of an anti-C5 antibody or a fragment thereof to human C5 is associated with reduced generation of C5a or C5b in the complement activation pathway and reduced MAC formation in an intact organism. In some embodiments, the anti-C5 antibody portion is capable of binding to human C5. In some embodiments, the anti-C5 antibody or antibody fragment binds to a relevant portion or fraction or epitope of human C5, and binding of the anti-C5 antibody or antibody fragment thereof to a relevant portion of human C5 is associated with reduced C5a or C5b generation and MAC formation in an intact organism.

[0179] In some embodiments, the anti-C5 antibody or antibody fragment thereof is further conjugated to a protein, peptide, or another compound. In some embodiments, the anti-C5 antibody or antibody fragment thereof is conjugated to a protein, peptide, or other compound. In some embodiments, the protein, peptide, or other compound to which the anti-C5 antibody or antibody fragment thereof is conjugated is a targeting moiety (i.e., the targeting moiety specifically binds to a molecule other than human C5). In some embodiments, the protein, peptide, or other compound to which the anti-C5 antibody or antibody fragment thereof is conjugated is an effector molecule (e.g., a cytotoxic molecule).

[0180] In various embodiments, any of the anti-C5 antibodies described herein having any of the variable regions described herein can comprise an Fc fragment or Fc domain. For example, in some embodiments, the anti-C5 antibodies described herein comprise an Fc fragment of an immunoglobulin. Exemplary immunoglobulins include, but are not limited to, IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and IgD. In some embodiments, the anti-C5 antibody comprises the Fc of a human IgG4. SEQ ID NO: 32 is an exemplary amino acid sequence of a human IgG4 Fc fragment. In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment having an S108P mutation relative to SEQ ID NO: 32. SEQ ID NO: 33 is an exemplary amino acid sequence of a human IgG4 Fc fragment having an S108P mutation relative to SEQ ID NO: 32. In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment having one or more of the following mutations relative to SEQ ID NO: 32: an S108P mutation, an M308L mutation, and an N314A mutation. In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment with S108P, M308L, and N314A mutations relative to SEQ ID NO: 32 (also referred to herein as with IgG4 Fc "PLA" mutations). SEQ ID NO: 61 is an exemplary amino acid sequence of a human IgG4 Fc fragment with S108P, M308L, and N314A mutations relative to SEQ ID NO: 32.

[0181] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; or a variant thereof comprising up to five (e.g., 5, 4, 3, 2, or 1) amino acid mutations (e.g., insertions, deletions, substitutions, e.g., conservative substitutions) in one or more of the CDRs.

[0182] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof has a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions). a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions).

[0183] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0184] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96, or a variant thereof comprising up to five (e.g., 5, 4, 3, 2, or 1) amino acid mutations (e.g., insertions, deletions, substitutions, e.g., conservative substitutions) in one or more of the CDRs.

[0185] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof has a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions). a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions).

[0186] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96.

[0187] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 2, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 2, and a VL comprising the amino acid sequence of SEQ ID NO: 7, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 7. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 2, and a VL comprising the amino acid sequence of SEQ ID NO: 7. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 93, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 93, and a VL comprising the amino acid sequence of SEQ ID NO: 95, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 95. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 93, and a VL comprising the amino acid sequence of SEQ ID NO: 95. In some embodiments, the VH and VL do not comprise a signal peptide at the N-terminus.

[0188] In some embodiments, the anti-C5 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO:2. In some embodiments, the anti-C5 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:7, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO:7. In some embodiments, the anti-C5 antibody is humanized. In some embodiments, the anti-C5 antibody is a chimeric antibody. In some embodiments, the anti-C5 antibody is mAb 2G1, or a variant thereof (e.g., humanized 2G1). In some embodiments, the anti-C5 antibody mAb 2G1 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO:2 and a light chain comprising the amino acid sequence of SEQ ID NO:7; or ii) a VH comprising the amino acid sequence of SEQ ID NO:93 and a VL comprising the amino acid sequence of SEQ ID NO:95. In some embodiments, the anti-C5 antibody comprises an Fc fragment. In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment or a variant thereof. In some embodiments, the anti-C5 antibody mAb 2G1 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO:2 and a light chain comprising the amino acid sequence of SEQ ID NO:7; or ii) a VH comprising the amino acid sequence of SEQ ID NO:93 and a VL comprising the amino acid sequence of SEQ ID NO:95, and a human IgG4 Fc fragment comprising the amino acid sequence of SEQ ID NO:32. In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment having an S108P mutation relative to SEQ ID NO:32, or a variant thereof. In some embodiments, the anti-C5 antibody mAb 2G1 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 7; or ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 95, and a human IgG4 Fc fragment comprising the amino acid sequence of SEQ ID NO: 33, with an S108P mutation relative to SEQ ID NO: 32.In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment, or a variant thereof, having S108P, M308L, and N314A mutations relative to SEQ ID NO: 32. In some embodiments, the anti-C5 antibody mAb 2G1 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 7; or ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 95, and a human IgG4 Fc fragment comprising the amino acid sequence of SEQ ID NO: 61, which has S108P, M308L, and N314A mutations relative to SEQ ID NO: 32.

[0189] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 11; or a variant thereof comprising up to five (e.g., 5, 4, 3, 2, or 1) amino acid mutations (e.g., insertions, deletions, substitutions, e.g., conservative substitutions) in one or more of the CDRs.

[0190] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof has a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions). a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 11, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions).

[0191] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 11.

[0192] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97, or a variant thereof comprising up to five (e.g., 5, 4, 3, 2, or 1) amino acid mutations (e.g., insertions, deletions, substitutions, e.g., conservative substitutions) in one or more of the CDRs.

[0193] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof has a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions). a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions).

[0194] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97.

[0195] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 2, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 2, and a VL comprising the amino acid sequence of SEQ ID NO: 13, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 13. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 2, and a VL comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 93, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 93, and a VL comprising the amino acid sequence of SEQ ID NO: 98, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 98. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 93, and a VL comprising the amino acid sequence of SEQ ID NO: 98. In some embodiments, the VH and VL do not comprise a signal peptide at the N-terminus.

[0196] In some embodiments, the anti-C5 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO:2. In some embodiments, the anti-C5 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:13, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO:13. In some embodiments, the anti-C5 antibody is humanized. In some embodiments, the anti-C5 antibody is a chimeric antibody. In some embodiments, the anti-C5 antibody is mAb L3-1, or a variant thereof. In some embodiments, the anti-C5 antibody mAb L3-1 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 13; or ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 98. In some embodiments, the anti-C5 antibody comprises an Fc fragment. In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment or a variant thereof. In some embodiments, the anti-C5 antibody mAb L3-1 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 13; or ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 98, and a human IgG4 Fc fragment comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment having an S108P mutation relative to SEQ ID NO: 32, or a variant thereof. In some embodiments, the anti-C5 antibody mAb L3-1 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 13; or ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 98, and a human IgG4 Fc fragment comprising the amino acid sequence of SEQ ID NO: 33, having an S108P mutation relative to SEQ ID NO: 32.In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment, or a variant thereof, having S108P, M308L, and N314A mutations relative to SEQ ID NO: 32. In some embodiments, the anti-C5 antibody mAb L3-1 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 13; or ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 98, and a human IgG4 Fc fragment comprising the amino acid sequence of SEQ ID NO: 61, which has S108P, M308L, and N314A mutations relative to SEQ ID NO: 32.

[0197] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 14; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; or a variant thereof comprising up to five (e.g., 5, 4, 3, 2, or 1) amino acid mutations (e.g., insertions, deletions, substitutions, e.g., conservative substitutions) in one or more of the CDRs.

[0198] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof has a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions). a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions).

[0199] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 14; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0200] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 14; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96, or a variant thereof comprising up to five (e.g., 5, 4, 3, 2, or 1) amino acid mutations (e.g., insertions, deletions, substitutions, e.g., conservative substitutions) in one or more of the CDRs.

[0201] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof has a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions). a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions); and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96, or a variant thereof comprising up to about three (such as about any of one, two, or three) amino acid substitutions (e.g., conservative substitutions).

[0202] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 94; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 14; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 96.

[0203] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 2, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 2, and a VL comprising the amino acid sequence of SEQ ID NO: 16, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 16. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 2, and a VL comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 93, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 93, and a VL comprising the amino acid sequence of SEQ ID NO: 99, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO: 99. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 93, and a VL comprising the amino acid sequence of SEQ ID NO: 99. In some embodiments, the VH and VL do not comprise a signal peptide at the N-terminus.

[0204] In some embodiments, the anti-C5 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:2, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO:2. In some embodiments, the anti-C5 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:16, or a variant thereof comprising at least about 80% (e.g., at least about any of 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) sequence identity to SEQ ID NO:16. In some embodiments, the anti-C5 antibody is humanized. In some embodiments, the anti-C5 antibody is a chimeric antibody. In some embodiments, the anti-C5 antibody is mAb L1-2, or a variant thereof. In some embodiments, the anti-C5 antibody mAb L1-2 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 16; or ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 99. In some embodiments, the anti-C5 antibody comprises an Fc fragment. In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment or a variant thereof. In some embodiments, the anti-C5 antibody mAb L1-2 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 16; or ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 99, and a human IgG4 Fc fragment comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment having an S108P mutation relative to SEQ ID NO: 32, or a variant thereof. In some embodiments, the anti-C5 antibody mAb L1-2 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 16; or ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 99, and a human IgG4 Fc fragment comprising the amino acid sequence of SEQ ID NO: 33, which has an S108P mutation relative to SEQ ID NO: 32.In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment, or a variant thereof, having S108P, M308L, and N314A mutations relative to SEQ ID NO: 32. In some embodiments, the anti-C5 antibody mAb L1-2 comprises i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO: 16; or ii) a VH comprising the amino acid sequence of SEQ ID NO: 93 and a VL comprising the amino acid sequence of SEQ ID NO: 99, and a human IgG4 Fc fragment comprising the amino acid sequence of SEQ ID NO: 61, which has S108P, M308L, and N314A mutations relative to SEQ ID NO: 32.

[0205] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 17; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; or a variant thereof comprising up to five (e.g., 5, 4, 3, 2, or 1) amino acid mutations (e.g., insertions, deletions, substitutions, e.g., conservative substitutions) in one or more of the CDRs.

[0206] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof has a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about three (such as about any of 1, 2, or 3) amino acid substitutions (e.g., con...

Claims

1. A method for treating a complement-mediated disease in a human individual, comprising administering to the human individual an effective amount of a fusion protein comprising: i) an antibody portion that specifically binds to human C5 (an "anti-C5 antibody portion"); and ii) factor H (FH) or a functional fragment thereof.

2. 2. The method of claim 1, wherein the complement-mediated disease is selected from the group consisting of paroxysmal nocturnal hemoglobinuria (PNH) syndrome, C3 glomerulopathy (C3G), IgA nephropathy (IgAN), and thrombotic microangiopathy secondary to systemic lupus erythematosus (SLE-TMA).

3. the fusion protein (i) administered intravenously (IV) or subcutaneously (SC); and / or (ii) administered at a dose of about 60 mg to about 3600 mg; The method according to claim 1 or 2.

4. The method of any one of claims 1 to 3, wherein the fusion protein is administered in a single dose.

5. The method of any one of claims 1 to 3, wherein the fusion protein is administered in multiple doses.

6. 6. The method of claim 5, wherein the fusion protein is administered once weekly (QW) or once every other week (Q2W).

7. 7. The method of claim 5 or 6, wherein the fusion protein is administered in an initial phase comprising administering the fusion protein in one or more initial doses, followed by a maintenance phase comprising administering the fusion protein in two or more maintenance doses.

8. (i) the initial dose is from about 600 mg to about 3600 mg; (ii) the one or more initial doses of the fusion protein are administered IV; (iii) the initial phase comprises administering the fusion protein in a single initial dose; (iv) the maintenance dose is from about 600 mg to about 2880 mg; (v) the two or more maintenance doses of the fusion protein are administered weekly or biweekly; and / or (vi) the maintenance phase is at least about 4 weeks. The method of claim 7.

9. 9. The method of claim 7 or 8, wherein the maintenance phase comprises administering the fusion protein at a first maintenance dose once every week or once every other week during a first maintenance phase, followed by administering the fusion protein at a second maintenance dose once every week or once every other week during a second maintenance phase.

10. the initial phase comprising administering the fusion protein at an initial dose of about 600 mg IV to about 3600 mg IV on day 1, and the maintenance phase beginning on day 8 i) about 600 mg IV to about 1200 mg IV once weekly; ii) about 720 mg SC to about 1440 mg SC once weekly; iii) about 1920 mg SC to about 2880 mg SC once every other week; iv) about 1800 mg SC to about 2400 mg SC once every other week; or v) about 960 mg SC to about 2880 mg SC once every other week 10. The method of any one of claims 7 to 9, comprising administering the fusion protein at a maintenance dose of

11. 11. The method of any one of claims 7 to 10, wherein the maintenance phase is for at least about 12 weeks with weekly maintenance dosing or at least about 13 weeks with biweekly maintenance dosing.

12. The method of any one of claims 7 to 11, wherein the complement-mediated disease is PNH.

13. the initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV on day 1, and the maintenance phase beginning on day 8 i) about 600 mg IV to about 1200 mg IV once weekly for at least about 12 weeks; ii) about 720 mg SC to about 1440 mg SC once weekly for at least about 12 weeks; iii) about 1920 mg SC to about 2880 mg SC once every other week for at least about 13 weeks; or iv) about 960 mg SC to about 2880 mg SC once every other week for at least about 13 weeks 13. The method of claim 12, comprising administering the fusion protein at a maintenance dose of

14. (i) the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC or about 600 mg IV once weekly starting on day 8 for about 12 weeks; (ii) the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV to about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC to about 2880 mg SC once every other week starting on day 8 for about 13 weeks; (iii) the initial phase comprises administering the fusion protein at an initial dose of about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC to about 2880 mg SC once every other week starting on day 8 for about 13 weeks; (iv) the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV to about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC once every other week starting on day 8 for about 13 weeks; or (v) the initial phase comprises administering the fusion protein at an initial dose of about 3600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week starting on day 8 for about 13 weeks; The method of claim 13.

15. (i) the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC once weekly starting on day 8 for about 12 weeks; (ii) the initial phase comprises administering the fusion protein at an initial dose of about 2400 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC once every other week starting on day 8 for about 13 weeks; or (iii) the initial phase comprises administering the fusion protein at an initial dose of about 3600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 2880 mg SC once every other week starting on day 8 for about 13 weeks; 15. The method of claim 14.

16. 16. The method of any one of claims 12 to 15, wherein the fusion protein is further administered in an extension phase comprising administering the fusion protein in one or more extension doses after the maintenance phase.

17. 17. The method of claim 16, wherein the extension phase comprises administering the fusion protein at an extended dose of about 1920 mg SC once every other week for about 9 months.

18. The method of any one of claims 7 to 11, wherein the complement-mediated disease is SLE-TMA.

19. the initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 3600 mg IV on day 1, and the maintenance phase comprising: i) administering the fusion protein at a maintenance dose of about 720 mg SC to about 1440 mg SC once weekly starting on day 8 for at least about 24 weeks; ii) administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week starting on day 8 for at least about 25 weeks; iii) administering the fusion protein at a first maintenance dose of about 600 mg IV to about 1200 mg IV once weekly during a first maintenance phase starting on day 8, followed by administering the fusion protein at a second maintenance dose of about 720 mg SC to about 1440 mg SC once weekly during a second maintenance phase, wherein the maintenance phase is for at least about 24 weeks; or iv) administering the fusion protein at a first maintenance dose of about 600 mg IV to about 1200 mg IV once weekly during a first maintenance phase starting on day 8, followed by administering the fusion protein at a second maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week during a second maintenance phase, wherein the maintenance phase is for at least about 25 weeks.

20. The method of claim 18.

20. 20. The method of claim 19, wherein the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC once weekly starting on day 8 for about 24 weeks.

21. The method of any one of claims 7 to 11, wherein the complement-mediated disease is C3G or IgAN.

22. the initial phase comprising administering the fusion protein at an initial dose of about 600 mg IV to about 3600 mg IV on day 1, and the maintenance phase beginning on day 8 i) about 600 mg IV to about 1200 mg IV once weekly for at least about 48 weeks; ii) about 720 mg SC to about 1440 mg SC once weekly for at least about 48 weeks; iii) about 1920 mg SC to about 2880 mg SC once every other week for at least about 49 weeks; or iv) about 1800 mg SC to about 2400 mg SC once every other week for at least about 49 weeks 22. The method of claim 21, comprising administering the fusion protein at a maintenance dose of

23. (i) the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC or about 600 mg IV once weekly starting on day 8 for about 48 weeks; (ii) the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1440 mg SC or about 1200 mg IV once weekly starting on day 8 for about 48 weeks; (iii) the initial phase comprises administering the fusion protein at an initial dose of about 2400 mg IV to about 3600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every other week starting on day 8 for about 49 weeks; or (iv) the initial phase comprises administering the fusion protein at an initial dose of about 600 mg IV on day 1, and the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC once weekly starting on day 8 for about 48 weeks.

23. The method of claim 22.

24. 24. The method of any one of claims 1 to 23, wherein the binding of the anti-C5 antibody portion to human C5 is pH dependent, and the anti-C5 antibody portion binds to human C5 more strongly at neutral pH than at acidic pH.

25. The anti-C5 antibody portion may be a full-length antibody, Fab, Fab', F(ab) ２ , F(ab') ２ , scFv, or a combination thereof.

26. 26. The method of claim 25, wherein the anti-C5 antibody portion is a full-length antibody ("anti-C5 full-length antibody").

27. 27. The method of claim 26, wherein the anti-C5 full-length antibody comprises an Fc fragment derived from human IgG4.

28. 28. The method of claim 27, wherein the Fc fragment comprises the amino acid sequence of any of SEQ ID NOs: 32, 33, and 61.

29. 29. The method of claim 28, wherein the Fc fragment comprises the amino acid sequence of SEQ ID NO:

61.

30. the anti-C5 full-length antibody comprises a heavy chain and a light chain; (i) the heavy chain comprises the amino acid sequence of SEQ ID NO: 119 and the light chain comprises the amino acid sequence of SEQ ID NO: 74; (ii) the heavy chain comprises the amino acid sequence of SEQ ID NO: 121 and the light chain comprises the amino acid sequence of SEQ ID NO: 74; (iii) the heavy chain comprises the amino acid sequence of SEQ ID NO: 123 and the light chain comprises the amino acid sequence of SEQ ID NO: 74; (iv) the heavy chain comprises the amino acid sequence of SEQ ID NO: 125 and the light chain comprises the amino acid sequence of SEQ ID NO: 74; (v) the heavy chain comprises the amino acid sequence of SEQ ID NO: 120 and the light chain comprises the amino acid sequence of SEQ ID NO: 90; (vi) the heavy chain comprises the amino acid sequence of SEQ ID NO: 122 and the light chain comprises the amino acid sequence of SEQ ID NO: 90; (vii) the heavy chain comprises the amino acid sequence of SEQ ID NO: 124 and the light chain comprises the amino acid sequence of SEQ ID NO: 90; or (viii) the heavy chain comprises the amino acid sequence of SEQ ID NO: 126 and the light chain comprises the amino acid sequence of SEQ ID NO:

90.

30. The method according to any one of claims 26 to 29.

31. The method of any one of claims 1 to 30, wherein the functional fragment of FH comprises short consensus repeat (SCR) domains 1 to 5 of FH.

32. 32. The method of claim 31, wherein the functional fragment of FH comprises the amino acid sequence of SEQ ID NO:

85.

33. The method of any one of claims 26 to 32, wherein the fusion protein comprises a first FH or a functional fragment thereof and a second FH or a functional fragment thereof, wherein the first FH or a functional fragment thereof is fused to the C-terminus of a first heavy chain of the anti-C5 full-length antibody, and the second FH or a functional fragment thereof is fused to the C-terminus of a second heavy chain of the anti-C5 full-length antibody.

34. (i) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 72 and each light chain comprises the amino acid sequence of SEQ ID NO: 74; (ii) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 76 and each light chain comprises the amino acid sequence of SEQ ID NO: 74; (iii) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 78 and each light chain comprises the amino acid sequence of SEQ ID NO: 74; (iv) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 80 and each light chain comprises the amino acid sequence of SEQ ID NO: 74; (v) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 89 and each light chain comprises the amino acid sequence of SEQ ID NO: 90; (vi) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 116 and each light chain comprises the amino acid sequence of SEQ ID NO: 90; (vii) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 117 and each light chain comprises the amino acid sequence of SEQ ID NO: 90; or (viii) each heavy chain fused to FH or a functional fragment thereof comprises the amino acid sequence of SEQ ID NO: 118, and each light chain comprises the amino acid sequence of SEQ ID NO: 90; 34. The method of claim 33.

35. 35. The method of any one of claims 1 to 34, wherein the fusion protein is formulated into a pharmaceutical composition comprising about 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCL, and polysorbate 80, and at a pH of about 6.0.

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