Anti-C5 antibodies fused with factor H for treatment of complement mediated diseases

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims the benefit of priority to U.S. Provisional Application No. 63 / 421,993, filed on November 2, 2022, U.S. Provisional Application No. 63 / 486,949, filed on February 24, 2023, International Patent Application No. PCT / US2023 / 063305, filed on February 26, 2023, and U.S. Provisional Application No. 63 / 501,264, filed on May 10, 2023, the contents of each of which are hereby incorporated by reference into this document in their entirety.

[0003] Reference to an electronic sequence listing

[0004] The contents of the electronic sequence listing (792252001241seqlist.xml; size: 153,067 bytes; creation date: October 16, 2023) are incorporated herein by reference in their entirety. Technical Field

[0005] The present invention relates to compositions and methods for treating complement-mediated diseases. Background Art

[0006] The complement system is part of innate immunity and plays a key role in host defense. It enhances (supplements) the ability of antibodies and phagocytes to clear microorganisms and damaged cells from the body, promote inflammation, and attack the cell membranes of pathogens. However, activated complement can also cause severe tissue damage and destruction, and dysregulation of complement activity has been found to be associated with many rare and common diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), rheumatoid arthritis (RA), age-related macular degeneration (AMD), etc. Therefore, anti-complement therapy is a promising method for treating these human disorders.

[0007] Complement activation involves a cascade of target recognition and proteolytic cleavage. It can be activated via three different 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 and involves the sequential activation of C1 and C4 / C2, which then merges with the other pathways at the C3 activation step. The lectin pathway (LP) is triggered by certain pattern recognition molecules, such as mannose-binding lectin (MBL), gelatin, and filocollin, when these molecules bind to microbial surface sugar molecules. It involves the activation of mannan-binding lectin serine proteases (MASPs), which then cleave C4 / C2 at the C3 activation step and join the other pathways. The alternative pathway (AP) has a low level of constitutive activity because spontaneous hydrolysis and activation of C3 produces C3 (H2O). The latter can associate with factor B and, following 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 manner as C3(H2O), thereby initiating another self-amplifying cycle of C3 activation.

[0008] Ongoing efforts to target C3 activation in complement-dependent diseases employ C3 inhibitory cyclic peptides or recombinant short variants of FH, which have very poor pharmacokinetics, requiring large and frequent (eg, daily) dosing.

[0009] C3 activation also leads to the production of the C5 cleavage enzyme complex and initiates the terminal complement activation pathway, ultimately producing effective proinflammatory mediators C5a and membrane attack complex (MAC) C5b-9, which can cause cell lysis and death. In order to prevent complement from causing indiscriminate damage, host cells express many membrane-anchored regulatory factors that work to block complement activation and amplification. Some of these regulatory factors, including decay-accelerating factor (DAF, CD55) and MCP, are used to inhibit C3 activation, while other regulatory factors, such as CD59, are used for other steps of the complement activation cascade. In addition to membrane-anchored complement regulatory factors, there are also fluid-phase regulatory factors in the blood, which are preferentially used to protect host tissues. Fluid-phase inhibitors include factor H (FH) and factor I (FI) (these factors are key inhibitors of the alternative complement activation pathway) as well as C4BP and C1 inhibitor (C1INH) (these inhibitors inhibit classical complement activation). Fluid-phase regulatory proteins and membrane-anchored complement regulatory proteins are typically composed of multiple conserved SCR domains. For example, FH is composed of 20 SCRs.

[0010] Complement C5 is a key protein in the terminal pathway of complement activation and is a precursor protein for the production of the potent proinflammatory mediator C5a and the cytolytic membrane attack complex (MAC).

[0011] Many human inflammatory and autoimmune diseases are mediated by C5a and / or MAC. Blocking C5 activation should prevent the production of C5a and MAC, thus possessing therapeutic value. The humanized mouse 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 reason for this nonresponse is genetic polymorphisms in human C5 that result in the loss of the epitope that eculizumab binds to. Furthermore, due to the high plasma concentration of C5 and the rapid antibody clearance mediated by the target, eculizumab must be administered to patients at high doses and frequencies. Therefore, there is a need for more effective and convenient anti-complement drugs for the treatment of PNH, aHUS, and other complement-mediated diseases.

[0012] 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

[0013] In one aspect, the present application provides a method of treating a complement-mediated disease in a human subject, comprising administering to the human subject an effective amount of a fusion protein comprising i) an antibody portion that specifically binds to human C5 ("anti-C5 antibody portion") and ii) Factor H (FH) or a fragment thereof.

[0014] 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.

[0015] In some embodiments according to any of the methods above, the fusion protein is administered intravenously (IV) or subcutaneously (SC).

[0016] In some embodiments according to any of the methods above, 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).

[0017] In some embodiments according to 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 dosage of about 60 mg to about 1200 mg (e.g., any one of 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 dosage 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.

[0018] In some embodiments according to any one of the above methods, the fusion protein is administered in multiple doses. In some embodiments, the fusion protein is administered once a week (QW). In some embodiments, the fusion protein is administered once every two weeks (Q2W). In some embodiments, the fusion protein is administered with a dosage of about 600 mg to about 2880 mg (for example, 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), each dose being 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. In some embodiments, the fusion protein is administered once a week at a dose of about 600 mg IV for 5 weeks.

[0019] In some embodiments according to any of the above methods, the fusion protein is administered via an initial phase comprising administering the fusion protein with 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 (e.g., weekly or biweekly) for two or more 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 doses). In some embodiments, the initial dose is from about 600 mg to about 3600 mg, such as from about 1200 mg to about 3600 mg (e.g., any one of about 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, 2880 mg, 3000 mg, or 3600 mg). In some embodiments, IV administers the fusion protein of one or more initial doses. In some embodiments, the initial stage includes administering the fusion protein with an initial dose. In some embodiments, the maintenance dose is about 600 mg to about 2880 mg (for example, any one of 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 of two or more maintenance doses is administered once a week. In some embodiments, the maintenance dose (for example, once a week) is about 600 mg to about 1440 mg (for example, any one of about 600 mg, 720 mg, 840 mg, 960 mg, 1080 mg, 1200 mg, 1320 mg, or 1440 mg). In some embodiments, the fusion protein of two or more maintenance doses (e.g., once a week) is each administered with about 600 mg IV to about 1200 mg IV or with about 720 mg SC to about 1440 mg SC (e.g., any one of about 600 mg IV, 1200 mg IV, 720 mg SC, 960 mg SC, or 1440 mg SC). In some embodiments, the fusion protein of two or more maintenance doses is administered once every two weeks. In some embodiments, the maintenance dose (e.g., once every two weeks) is about 960 mg to about 2880 mg (e.g., any one of 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 two weeks) of the fusion protein are each administered at about 960 mg SC to about 1920 mg SC, at about 1920 mg SC to about 2880 mg SC, at about 1800 mg SC to about 2880 mg SC, or at about 1800 mg SC to about 2400 mg SC (e.g., any of 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 longer), such as at least about 12 weeks (e.g., about any of 12, 13, 24, 25, 48, or 49 weeks). In some embodiments, the initial phase includes administering the fusion protein once a week at an initial dose of about 1200 mg for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 or more) doses, and the maintenance phase includes administering the fusion protein once a week or once every two weeks at a maintenance dose of about 720 mg for at least two 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 doses). In some embodiments, the initial phase includes administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and the maintenance phase includes administering the fusion protein once a week at a maintenance dose of about 720 mg SC starting from day 8 for 4 weeks. In some embodiments, the maintenance phase includes administering the fusion protein once a week or once every two weeks at a first maintenance dose within the first maintenance phase time period, followed by administering the fusion protein once a week or once every two weeks at a second maintenance dose within the second maintenance phase time period. In some embodiments, the second maintenance dose is higher than the first maintenance dose. In some embodiments, the second maintenance phase is longer than 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 a week, and the second maintenance dose of the fusion protein is administered at about 1440 mg SC or about 1200 mg IV once a week. In some embodiments, the first maintenance phase is about 4 weeks and 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 for about 4 weeks beginning on day 8, followed by ii) administering the fusion protein at a second maintenance dose of about 1440 mg SC or about 1200 mg IV once weekly for about 44 weeks beginning on day 36.

[0020] In some embodiments according to any 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 comprises administering the fusion protein starting on day 8 at the following maintenance doses: 1) about 600 mg IV or about 1200 mg IV once a week; 2) about 720 mg SC to about 1440 mg SC once a week; 3) about 1920 mg SC to about 2880 mg SC once every two weeks; 4) about 1800 mg SC to about 2400 mg SC once every two weeks; or 5) about 960 mg SC to about 2880 mg SC once every two weeks. 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 period is at least about 48 weeks for weekly maintenance dosing, or at least about 49 weeks for biweekly maintenance dosing.

[0021] In some embodiments according to any 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 comprises administering the fusion protein starting on day 8 at a maintenance dose of: i) about 600 mg IV to about 1200 mg IV once a week for at least about 12 weeks; ii) about 720 mg SC to about 1440 mg SC once a week for at least about 12 weeks; iii) about 1920 mg SC to about 2880 mg SC once every two weeks for at least about 13 weeks; or iv) about 960 mg SC to about 2880 mg SC once every two weeks 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 a week for about 12 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 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 two weeks 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 two weeks 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 two weeks 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 two weeks 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 two weeks for about 13 weeks starting on day 8.In some embodiments, the fusion protein is further administered through an extended phase comprising administering the fusion protein at one or more extended doses after the maintenance phase. In some embodiments, the extended phase comprises administering the fusion protein once every two weeks at an extended dose of about 1920 mg SC for about 9 months.

[0022] In some embodiments according to any of the methods above, 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 two weeks 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 for a first maintenance phase period, followed by a second maintenance dose of about 720 mg SC to about 1440 mg SC once weekly for a second maintenance phase period, and 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 for a first maintenance phase period, followed by a second maintenance dose of about 1920 mg SC to about 2880 mg SC The fusion protein is administered once every two weeks from SC to a second maintenance dose of about 2880 mg SC, and the maintenance phase is at least about 25 weeks. In some embodiments, the first maintenance phase is at least about 1 week in duration and the second maintenance phase is no more than about 23 or about 24 weeks in duration. 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 once weekly starting on day 8 at a maintenance dose of about 960 mg SC for about 24 weeks.

[0023] In some embodiments according to any 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 comprises administering the fusion protein starting on day 8 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 every two weeks for at least about 49 weeks; iv) about 1800 mg SC to about 2400 mg SC every two weeks for at least about 49 weeks; or v) about 960 mg SC to about 2880 mg SC every two weeks for at least 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 wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every two weeks starting on day 8 for about 49 weeks. 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 every two weeks for about 49 weeks beginning 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 beginning on day 8.

[0024] In some embodiments according to any of the methods above, 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; such as the pH in blood) than it does at acidic pH (e.g., about pH 5.8; such as the pH in endosomes).

[0025] In some embodiments according to any of the methods above, the anti-C5 antibody portion is a full-length antibody, Fab, Fab', F(ab)2, F(ab')2, scFv, or a combination thereof.

[0026] In some embodiments according to any 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 one of SEQ ID NOs: 32, 33, and 61, such as SEQ ID NO: 61. In some embodiments, an 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; (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: 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.

[0027] In some embodiments according to any of the methods above, the fusion protein inhibits C3 activation.

[0028] In some embodiments according to any of the above methods, the functional fragment of FH comprises the 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.

[0029] In some embodiments according to any of the above methods, the fusion protein comprises a first FH or a functional fragment thereof and a second FH or a functional fragment thereof, the first FH or a functional fragment thereof is fused to the C-terminus of the 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 the second heavy chain of the 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; (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: (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.

[0030] In some embodiments according to any of the methods above, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises 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.

[0031] 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 DESCRIPTION OF THE DRAWINGS

[0032] Figure 1A Depicted are 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 Different epitope binding of 2G1-3 to eculizumab is depicted.

[0033] Figure 2A Depicted is a C5 inhibition assay demonstrating that anti-C5-FH fusion protein is as effective as Ravulizumab in inhibiting CP-triggered terminal pathway complement activation (sheep red blood cell (RBC) lysis). Figure 2B Depicted is an LPS-based ELISA assay showing that anti-C5-FH fusion protein also inhibits AP complement. Figure 2C Depicted are rabbit RBC lysis assays demonstrating that anti-C5-FH fusion protein is more effective than anti-C5 mAb or FHSCR1-5-Fc alone or in combination in inhibiting AP-triggered terminal pathway complement activation.

[0034] Figure 3 It is shown that anti-C5-FH fusion protein is more potent than Ecu / Rav mAb in inhibiting human PNH RBC lysis and differs from Ecu / Rav in inhibiting opsonization of non-lysed PNH RBCs by C3b fragments.

[0035] Figure 4 It is depicted that anti-C5-FH fusion protein inhibits extravascular hemolysis (EVH) in a dose-dependent manner in an EVH mouse model.

[0036] Figure 5 It is demonstrated that the anti-C5-FH fusion protein has tissue targeting properties to cells with C5b-9 deposition.

[0037] Figure 6A Depicts FH m / m P - / - Mice and FH m / m P - / - Humanized factor D in mice (hFD-FH m / m P - / - ) survival curve. Figure 6B Depicts hFD-FH m / m P - / - Immunofluorescence staining of C3 in mice. Figure 6C Depicts FH m / m P - / - Mice and hFD-FH m / m P - / - Protein levels of C3 and C5 in mice.

[0038] Figure 7A Described are novel bifunctional complement inhibitors comprising an anti-C5 mAb (BB5.1) and a mouse Factor H SCR1-5 fusion protein. Figure 7B Depicted is a sheep red blood cell (RBC) lysis assay using 50% mouse plasma for murine anti-C5-FH fusion protein and BB5.1. Figure 7C Depicted is a rabbit RBC lysis assay using 50% mouse plasma with murine anti-C5-FH fusion protein and BB5.1. Figure 7D Depicted are LPS-based ELISA assays of murine anti-C5-FH fusion protein and BB5.1.

[0039] Figure 8A Depicts hFD-FH treated with mouse anti-C5-FH fusion protein or BB5.1 m / m P - / - Survival curves of mice. Figure 8B Depicts hFD-FH injected with mouse anti-C5-FH fusion protein or BB5.1 m / m P - / - Protein levels of whole-body C3 and factor B depletion in mice. Figure 8C Depicts hFD-FH injected with mouse anti-C5-FH fusion protein or BB5.1 m / m P - / - Scoring of proteinuria and hematuria in mice. Figure 8D Depicts hFD-FH injected with mouse anti-C5-FH fusion protein or BB5.1 m / m P - / - Mice were scored for crescents and fibrin deposition, endocapillary pleocytosis, and mesangial pleocytosis. Figure 8E Depicts hFD-FH injected with mouse anti-C5-FH fusion protein or BB5.1 m / m P - / - Immunofluorescence staining and quantification of glomerular C3 and C9 deposition in mice.

[0040] Figure 9 The protocol for a Phase 1 anti-C5-FH fusion protein clinical study is described.

[0041] Figures 10A-10B Demographic data characteristics table is depicted.

[0042] Figure 11 Table depicting the most frequently reported treatment-emergent adverse events.

[0043] Figure 12A Anti-C5-FH fusion protein concentration-time curves for the SAD cohort are depicted (semi-logarithmic scale). Figure 12BAnti-C5-FH fusion protein concentration-time curves for the MAD cohort are depicted (semi-logarithmic scale).

[0044] Figure 13A Depicted are mean (SD) serum rRBCs over time by dosing regimen in the MAD cohort. Figure 13B Depicted are the mean (SD) C3b over time by dosing regimen for the MAD cohort. Figure 13C Depicted are the mean (SD) free C5 over time by dosing regimen for the MAD cohort.

[0045] Figure 14A Depicted are scatter plots of the percent change from baseline in serum rRBC levels versus serum concentration of anti-C5-FH fusion protein in all subjects. Figure 14B Depicted are scatter plots of the percent change from baseline in serum C3b levels versus anti-C5-FH fusion protein concentration in all subjects. Figure 14C Depicted are scatter plots of the percent change from baseline in free C5 levels versus anti-C5-FH fusion protein concentration in all subjects.

[0046] Figure 15 The systemic lupus erythematosus (SLE)-thrombotic microangiopathy (TMA) clinical study protocol is described.

[0047] Figure 16 Describes clinical research protocols for IgA nephropathy (IgAN) and complement 3 glomerulopathy (C3G).

[0048] Figure 17 The protocol for a Phase 2 paroxysmal nocturnal hemoglobinuria (PNH) clinical study is described.

[0049] Figure 18 Depicted is the mean (± standard deviation) increase in hemoglobin from baseline in cohorts 1, 2, and 3 of treatment-naive PNH patients who were administered a complement inhibitor against a C5-FH fusion protein over 17 weeks. The horizontal dashed line represents a 2 g / dL increase in hemoglobin from baseline. The vertical dashed lines represent the designated time in weeks. The 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, respectively, from baseline in cohorts 1, 2, and 3.

[0050] Figure 19Depicted is a graph of mean (± standard deviation) lactate dehydrogenase (LDH) levels in treatment-naive PNH patients who were administered a complement inhibitor against a C5-FH fusion protein over 17 weeks for cohorts 1, 2, and 3. The top horizontal dashed line represents total LDH, which is 1.5 times the upper limit of normal (ULN). The bottom horizontal dashed line represents total LDH, which is 1 times the upper limit of normal. The vertical dashed lines represent the designated time in weeks. The mean (SD) LDH levels in cohorts 1, 2, and 3 decreased by 88.0 (±3.67)%, 83.5 (±7.45)%, and 89.5 (±4.05)% relative to baseline, respectively. DETAILED DESCRIPTION

[0051] 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 comprising an anti-C5 antibody portion and a Factor H (FH) portion (hereinafter referred to as an "anti-C5-FH fusion protein"). The anti-C5-FH fusion protein used herein inhibits complement system activity via a dual mechanism: i) the anti-C5 antibody portion acts 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; such as the pH in blood) than at a more acidic pH (e.g., about pH 5.8; such as the pH in endosomes). In some embodiments, the FH portion is an FH protein or a fragment thereof, such as an FH fragment comprising a short consensus repeat (SCR) domain 1-5 of an FH protein, which is a domain 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 (SLE-TMA) secondary to systemic lupus erythematosus. Anti-C5-FH fusion proteins and anti-C5 antibody portions (e.g., pH-dependent anti-C5 antibody portions) have been described in U.S. Patent Publication No. 20220204602 and International Patent Application No. WO2020 / 219922, and the entire contents of each of these patent documents are incorporated herein by reference as a whole. The treatment methods described herein provide more effective and convenient methods for treating complement-dependent pathologies, such as by reducing the amount and / or frequency of administration, and / or by more effectively blocking the activity of the complement system, which addresses and satisfies previously unmet needs of other complement-mediated disease therapies (e.g., FDA-approved eculizumab).

[0052] I. Definitions

[0053] Generally, the terms used in the claims and description are intended to be interpreted as having their ordinary meaning as understood by one of ordinary skill in the art. Certain terms are defined below to provide additional clarity. In the event of a conflict between the ordinary meaning and the provided definitions, the provided definitions will apply.

[0054] As used herein, the terms "inhibit" and "inhibition" mean to reduce, inhibit, lower, 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, the activity is inhibited or blocked by at least about 50% compared to a control value. In some embodiments, the activity is inhibited or blocked by at least about 75%. In some embodiments, the activity is inhibited or blocked by at least about 95%. In some embodiments, the activity is blocked by 100%.

[0055] The terms "effective amount" and "pharmaceutically effective amount" refer to an amount of a pharmaceutical agent sufficient to provide a desired biological result. The result can be relief (e.g., relief by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or 100%) and / or alleviation of the signs, symptoms or causes of a disease or disorder, or any other desired change in a biological system. In any individual case, an appropriate effective amount can be determined by one of ordinary skill in the art using routine experimentation.

[0056] The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal, in some embodiments a mammal, in some embodiments a human, having a complement system, including humans in need of treatment or susceptible to a disorder or its sequelae. The individual can include, for example, dogs, cats, pigs, cows, sheep, goats, horses, rats, rabbits, hamsters, guinea pigs, monkeys, mice, and humans. In some embodiments, the individual is a human.

[0057] The term "abnormal," when used in the context of organisms, tissues, cells, or components thereof, refers to those organisms, tissues, cells, or components thereof that differ in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from those organisms, tissues, cells, or components thereof that exhibit the "normal" (expected / steady-state) corresponding characteristic. A characteristic that is normal or expected for one cell, tissue type, or subject may be abnormal for a different cell or tissue type.

[0058] A "disease" is a health state of a subject in which the subject is unable to maintain homeostasis and in which the subject's health will continue to deteriorate if the disease is not ameliorated.

[0059] In contrast, a "disorder" in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject's state of health is no more favorable than it would be in the absence of the disorder. If untreated, the disorder does not necessarily cause the subject's state of health to decline further.

[0060] A disease or disorder is "relieved" if the severity of the signs or symptoms of the disease or disorder, the frequency with which the patient experiences such signs or symptoms, or both, is reduced.

[0061] As used herein, the term "treatment" refers to a clinical intervention intended to change the natural process of the treated individual or cell during the course of clinical lesions. Desirable therapeutic effects include reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis. For example, if one or more symptoms associated with a disease or disorder are alleviated or eliminated, including but not limited to a reduction in the frequency and / or severity of signs and / or symptoms caused by the disease, the quality of life of those individuals with the disease is improved, the dosage of other drugs required for treating the disease is reduced, and / or the survival of the individual is prolonged, then the individual is successfully "treated". Treatment can be preventive (to prevent or delay the onset of the disease, or to prevent the manifestation of its clinical or subclinical symptoms), or therapeutically inhibit or alleviate symptoms after the disease manifests.

[0062] A subject who is "likely suitable," including a subject who is "suitable" for a treatment described herein, is a subject who is more likely to benefit than not benefit from administration of the treatment. Conversely, a subject who is "likely not suitable" or "likely unsuitable," including a subject who is "unsuitable" for a treatment described herein, is a subject who is more likely not to benefit than not benefit from administration of the treatment.

[0063] An "effective amount" or "therapeutically effective amount" of a compound is an amount of the compound sufficient to provide a beneficial effect to the subject to which the compound is administered.

[0064] "Therapeutic treatment" is treatment administered to a subject exhibiting signs of a disease or disorder with the purpose of reducing or eliminating those signs.

[0065] As used herein, the term "antibody" refers to an immunoglobulin molecule that is capable of specifically binding to a particular epitope of an antigen. Antibodies can be intact immunoglobulins derived from natural or recombinant sources and can be immunologically active portions of intact immunoglobulins. The antibodies of the present invention can 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).

[0066] As used herein, the term "heavy chain antibody" includes immunoglobulin molecules derived from camelid species by peptide immunization and subsequent isolation of serum, or by cloning and expressing nucleic acid sequences encoding such antibodies. The term "heavy chain antibody" further encompasses immunoglobulin molecules isolated from subjects with heavy chain diseases, or prepared by cloning and expressing the subject's VH (variable heavy chain immunoglobulin) genes.

[0067] A "chimeric antibody" refers to an engineered antibody that contains naturally occurring variable regions (light and heavy chains) derived from a donor antibody associated with light and heavy chain constant regions derived from a recipient antibody.

[0068] "Humanized antibody" refers to an engineered antibody whose CDRs are derived from non-human donor immunoglobulins, and the remaining immunoglobulin-derived portion in the molecule is derived from one (or more) human immunoglobulins. In addition, the framework support residues can be changed to maintain binding affinity (see, for example, 1989, Queen et al., Proc. Natl. Acad Sci USA, 86: 10029-10032; 1991, Hodgson et al., Bio / Technology, 9: 421). Suitable human acceptor antibodies can be antibodies selected from conventional databases (e.g., KABAT database, Los Alamos database, and Swiss protein database) by homology to the nucleotide and amino acid sequences of the donor antibody. Human antibodies characterized by homology (based on amino acids) to the framework region of the donor antibody can be suitable for providing a heavy chain constant region and / or a heavy chain variable framework region for insertion into the donor CDR. Suitable acceptor antibodies capable of supplying a light chain constant or variable framework region can be selected in a similar manner. It should be noted that the acceptor antibody heavy and light chains do not need 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).

[0069] "CDR" is defined as the complementary determining region amino acid sequence of an antibody, which is the hypervariable region of the immunoglobulin heavy and light chains. See, for example, Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, US Department of Health and Human Services, National Institutes of Health (1987). The variable portion of an immunoglobulin has three heavy chain and three light chain CDRs (or CDR regions). Therefore, as used herein, "CDR" refers to all three heavy chain CDRs or all three light chain CDRs (or both all heavy chain and all light chain CDRs, if appropriate). The structure and protein folding of an antibody may mean that other residues are considered to be part of the antigen binding region, and those skilled in the art will understand this. See, for example, Chothia et al., (1989) Conformations of immunoglobulin hypervariable regions; Nature 342, pp. 877-883.

[0070] The terms "natural antibody", "full-length antibody", "intact antibody" and "complete antibody" are used interchangeably herein to refer to an antibody in its substantially intact form, rather than an antibody fragment as defined below. The terms particularly refer to antibodies having heavy chains that contain an Fc region. Natural antibodies are typically heterotetrameric glycoproteins of approximately 150,000 daltons, consisting 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, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (V) at one end. H ), followed by a number of constant domains. Each light chain has a variable domain at one end (V L ) and the constant domain at its other end; The constant domain of the light chain is aligned with the first constant domain of the heavy chain, while the light chain variable domain is aligned with the variable domain of the heavy chain. Specific amino acid residues are considered to form the interface between the light chain variable domain and the heavy chain variable domain.

[0071] 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 may be referred to as "VH." The variable domain of the light chain may be referred to as "VL." These domains are generally the most variable part of the antibody and contain the antigen binding site.

[0072] The term "variable" refers to the fact that some parts of the variable domain are widely different in sequence between antibodies and are used in the binding and specificity of each specific antibody to its specific antigen. However, variability is not evenly distributed throughout the entire variable domain of an antibody. In both the light chain variable domain and the heavy chain variable domain, it is concentrated in three segments called hypervariable regions (HVRs, also referred to as CDRs). The more highly conserved parts of the variable domain are called framework regions (FRs). The variable domains of native heavy and light chains each include four FR regions connected by three HVRs, which form a loop connecting the β-sheet structure and forming a part of the β-sheet structure in some cases. The HVRs in each chain are held together in close proximity by the FR region and, together with the HVRs from the other chain, promote the formation of the antigen-binding site of the antibody (see Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991)).

[0073] The term "constant domain" refers to a portion of an immunoglobulin molecule that has a more conserved amino acid sequence than the other portion of the immunoglobulin containing the antigen binding site, ie, the variable domain. The constant domain comprises the C H 1. C H 2 and C H The constant domains are not directly involved in binding an antibody to an antigen, but exhibit various effector functions, such as the antibody's participation in antibody-dependent cellular toxicity.

[0074] 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.

[0075] The term IgG "isotype" or "subclass" as used herein refers to any subclass of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions.

[0076] Depending on the amino acid sequence of the constant domain of the heavy chain of the antibody (immunoglobulin), the antibody (immunoglobulin) can be designated as different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and some of these classes can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are respectively referred to as α, δ, ε, γ and μ. The subunit structure and three-dimensional configuration of the immunoglobulins of different classes are well known and are generally described in, for example, Abbas et al. Cellular and Mol. Immunology, 4th edition (WB Saunders, Co., 2000). Antibodies can be part of a larger fusion molecule formed by the covalent or non-covalent association of the antibody with one or more other proteins or peptides.

[0077] "Antibody fragments" comprise a portion of an intact antibody, preferably comprising the antigen-binding region of the intact antibody. 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 (such as single-chain variable fragments scFv); miniature bifunctional antibodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0078] 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, whose name reflects its ability to readily crystallize. Pepsin treatment produces an F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.

[0079] "Fv" is the smallest antibody fragment containing a complete antigen binding site. In some embodiments, the double-chain Fv species is composed of a dimer of a heavy chain variable domain and a light chain variable domain in a tight, non-covalent association. In the single-chain Fv (scFv) species, a heavy chain variable domain and a light chain variable domain can be covalently linked by a flexible peptide linker so that the light chain and the heavy chain can associate into a "dimerization" structure similar to the structure in the double-chain Fv species. It is in this configuration that the three HVRs of each variable domain interact to define the antigen binding site on the surface of the VH-VL dimer. Together, the six HVRs confer antigen binding specificity to the antibody. However, even a single variable domain (or only half an Fv comprising three HVRs specific for an antigen) can recognize and bind antigens, but the affinity is lower than the entire binding site.

[0080] Fab fragments have two polypeptide chains, containing heavy chain variable domains and light chain variable domains (VH, VL), and also contain the constant domain (CL) of the light chain and the first constant domain (CH1) of the heavy chain. The difference between Fab' fragments and Fab fragments is that a few residues are added to the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation for Fab' herein, in which the one or more cysteine ​​residues of the constant domains carry a free thiol group. F(ab')2 antibody fragments were originally produced as paired Fab' fragments with hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0081] "Single-chain Fv" or "scFv" antibody fragments comprise the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Typically, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains that enables the scFv to form the required structure for antigen binding. For a review of scFvs, see, e.g., Pluckthün, The Pharmacology of Monoclonal Antibodies. Springer Berlin Heidelberg, 1994. 269-315.

[0082] The "Fc" fragment comprises the carboxyl-terminal portions of two heavy chains held together by disulfide bonds. The effector functions of an antibody are determined by sequences in the Fc region, which is also the part recognized by Fc receptors (FcRs) found on certain types of cells.

[0083] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, for example, the individual antibodies constituting the population are identical, with the exception of possible mutations that may exist in small amounts, such as naturally occurring mutations. Therefore, the modifier "monoclonal" indicates that the characteristic of the antibody is not a mixture of unrelated antibodies. In some embodiments, such monoclonal antibodies generally include antibodies comprising a polypeptide sequence that binds to a target, wherein the target binding polypeptide sequence is obtained by including a process of selecting a single target binding polypeptide sequence from a plurality of polypeptide sequences. For example, the selection process can be a unique clone selected from a plurality of clones such as a hybridoma clone, a phage clone, or a recombinant DNA clone. It should be understood that the selected target binding sequence can be further changed, for example, to improve affinity to the target, humanize the target binding sequence, improve its yield in cell culture, reduce its in vivo immunogenicity, create multispecific antibodies, etc., and antibodies comprising a changed target binding sequence are also monoclonal antibodies of the present invention. Unlike polyclonal antibody preparations that generally include different antibodies for different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed to a single determinant on the antigen. In addition to their specificity, monoclonal antibody preparations are advantageous because they are generally free of contamination by other immunoglobulins.

[0084] 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, monoclonal antibodies to be used in accordance with the present invention can be made by a variety of techniques, including, for example, the hybridoma method (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 methods (see, e.g., U.S. Patent No. 4,816,567), phage display technology (see, e.g., Clackson et al., Nature 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et 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)), and techniques for producing human antibodies or human-like antibodies in animals that have part or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, e.g., WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 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 Huszar, Intern. Rev. Immunol. 13: 65-93 (1995)).

[0085] Monoclonal antibodies (mAbs) herein specifically include "chimeric" antibodies, in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of one or more chains is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass; and fragments of such antibodies, as long as they exhibit the desired biological activity (see, e.g., U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)). Chimeric antibodies include PRIMATTZED® antibodies, in which the antigen-binding region of the antibody is derived from an antibody generated, for example, by immunizing a macaque with the antigen of interest.

[0086] The structure and location of immunoglobulin variable regions can be determined by reference to Kabat, EA et al., Sequences of Proteins of Immunological Interest. 4th ed. US Department of Health and Human Services. 1987 and updates thereof, now available on the Internet (immuno.bme.nwu.edu).

[0087] As used herein, the term "specific binding" about an antibody means identifying and binding a specific target molecule, but does not substantially identify or bind the antibody of other molecules in the sample. In some cases, the term "specific binding" or "specifically binding" is used to mean that identification and binding depend on the presence of a specific structure (e.g., antigenic determinant or epitope) on the target molecule. If, for example, an antibody specifically binds to an epitope "A," then in the reaction containing labeled "A" and an antibody, the presence of an unlabeled molecule (or free unlabeled A) containing an epitope A will reduce the amount of the labeled A bound to the antibody. An antibody that binds or specifically binds to a target (e.g., an epitope) is an antibody that binds to a target with greater affinity, avidity, and is more susceptible to and / or to a longer duration than it binds to other targets. In some embodiments, the degree to which an antibody is bound to an unrelated target is less than about 10% of the binding of the antibody to the target, as measured by, for example, 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 between proteins from different species. In some embodiments, specific binding may include but does not require exclusive binding.

[0088] 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 many sites through weak non-covalent forces; the more interactions, the stronger the affinity.

[0089] The term "multispecific" as used in conjunction with an antibody or antigen-binding protein refers to an antibody or antigen-binding protein that has polyepitopic specificity (i.e., is capable of specifically binding to two, three, or more different epitopes on one biological molecule, or is capable of specifically binding to epitopes on two, three, or more different biological molecules).

[0090] As used herein, "percent (%) amino acid sequence identity" and "homology" with respect to peptide, polypeptide or antibody sequences are defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a particular peptide or polypeptide sequence, after aligning the sequences and, if necessary, introducing gaps to achieve the maximum percentage of sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining percent amino acid sequence identity can be achieved in various ways that are within the skill of 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 parameters suitable for measuring alignment, including any algorithm required for achieving maximum alignment over the full length of the compared sequences.

[0091] Amino acid substitutions may include, but are not limited to, replacement of one amino acid in a polypeptide by another amino acid. Exemplary substitutions are shown in Table A. Amino acid substitutions can be introduced into the antibody of interest, and the product can be screened for desired activity, such as maintained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC.

[0092] Table A

[0093]

[0094] Amino acids can be grouped according to 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 affecting chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe. Non-conservative substitutions would require exchanging a member of one of these classes for another.

[0095] As used herein, the term "covalently linked" refers to a direct connection through one or more chemical bonds or an indirect connection through one or more linkers. Any suitable chemical bond can be used to create a direct connection, 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.

[0096] As used herein, the "C-terminus" of a polypeptide refers to the last amino acid residue of the polypeptide that donates its amine group to form a peptide bond with the carboxyl group of its adjacent amino acid residue. The "N-terminus" of a polypeptide, as used herein, refers to the first amino acid of the polypeptide that donates its carboxyl group to form a peptide bond with the amine group of its adjacent amino acid residue.

[0097] Range: Throughout this disclosure, various aspects of the invention are presented in range format. It should be understood that descriptions in range format are merely for convenience and brevity and should not be construed as inflexible limitations on the scope of the invention. Thus, descriptions of ranges should be considered to have specifically disclosed all possible subranges and individual values ​​within the range. For example, descriptions of ranges such as 1 to 6 should be considered to specifically disclose subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and individual values ​​within the ranges, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the size of the range.

[0098] It is to be understood that the embodiments of the present invention described herein include "consisting of" and / or "consisting essentially of" the embodiments.

[0099] As used herein, reference to "not" a value or parameter generally means and describes "other than" a value or parameter. For example, a method is not for treating type X cancer and means that the method is for treating a type other than X cancer.

[0100] Reference herein to "about" a value or parameter includes (and describes) variations involving that value or parameter itself. For example, reference to a description of "about X" includes a description of "X." As used herein, the term "about XY" has the same meaning as "about X to about Y."

[0101] As used herein and in the appended claims, the singular forms "a," "an," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0102] II. Treatment Methods

[0103] The present invention relates to the use of anti-C5-FH fusion proteins (e.g., FMEH-IgG4-PLA-FH) to inhibit complement signaling and complement-related diseases or disorders in individuals (e.g., humans), the anti-C5-FH fusion proteins 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 use of any of the anti-C5 antibody portions described herein to inhibit complement signaling and complement-related diseases or disorders in individuals (e.g., humans). 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; such as the pH in blood) than at a more acidic pH (e.g., about pH 5.8; such as the pH in endosomes). This pH-dependent binding provides greater persistence of the administered antibody molecule because the cellularly taken up immune complex (i.e., anti-C5 mAb bound to C5) will dissociate in the acidic environment of the endosome and allow the released antibody to recycle out of the cell via the neonatal Fc receptor (FcRn), where it can bind to new C5 molecules. In some embodiments, the individual is a complement inhibitor naive individual.

[0104] In some embodiments, the present invention relates to inhibiting the complement signaling cascade by specifically targeting the complement component C5 protein or protein fragment C5a or C5b, such as by inhibiting (e.g., inhibiting at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or 100% of any one of) C5a-mediated inflammation and cell activation, or inhibiting C5b-mediated cell lysis. In some embodiments, the present invention relates to inhibiting the complement signaling cascade by specifically targeting the complement component C3b protein, such as for preventing (e.g., preventing at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or 100% of any one of) complement C3b deposition and amplification. In some embodiments, the present invention relates to methods for treating and preventing inflammatory and autoimmune diseases mediated by unwanted, uncontrolled, excessive complement activation. In some embodiments, the present invention relates to treating a complement-mediated disease or a complement-mediated disorder in an individual (e.g., a human) by administering (e.g., intravenously or subcutaneously) an anti-C5-FH fusion protein (e.g., FMEH-IgG4-PLA-FH) to the individual. In some embodiments, the present invention relates to treating a complement-mediated disease or a complement-mediated disorder in an individual (e.g., a human) by administering (e.g., intravenously or subcutaneously) an anti-C5 antibody portion (such as any of the anti-C5 antibodies or antigen-binding fragments thereof described herein) to the individual.

[0105] Any complement-related disease, such as a disease associated with C3 (or C3b) and / or C5 (or C5a, C5b) activity or AP and / or terminal pathway activity, can be treated using the methods described herein. Complement function defects are the cause of several human glomerular diseases, including atypical hemolytic uremic syndrome (aHUS), antineutrophil cytoplasmic antibody-mediated vasculitis (ANCA), C3 glomerulopathy, IgA nephropathy, immune complex membranoproliferative glomerulonephritis, renal ischemia-reperfusion injury, lupus nephritis, membranous nephropathy, and chronic transplant-mediated glomerulopathy. Abnormal activation of complement components has also been proposed as a marker for various types of cancer and their clinical outcomes. Lung cancer patients show significantly higher plasma levels of complement proteins and activation fragments than control donors, and elevated complement levels are correlated with lung tumor size. Complement-related proteins are also elevated in the biofluids of patients with other types of tumors. See, eg, 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.

[0106] In some embodiments, the complement-associated 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, postoperative 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), retinal ... ), central retinal artery occlusion (CRAO), epidermolysis bullosa, sepsis, organ transplantation, inflammation (including but not limited to inflammation associated with cardiopulmonary bypass and renal dialysis), C3 glomerulopathy (C3G), membranous nephropathy, IgA nephropathy (IgAN), glomerulonephritis (including but not limited to anti-neutrophil cytoplasmic antibody (ANCA)-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, such as AMD.

[0107] In some embodiments, the present 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 proteins and the formation of MAC. Examples of complement-mediated diseases that can be treated using the methods of the present invention include, but are not limited to, PNH syndrome, C3G, IgAN, and SLE-TMA.

[0108] In some embodiments, a method of treating a complement-mediated disease in a human subject (e.g., a complement inhibitor-naive human subject) is provided, comprising administering to the human subject 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 domains of FH, such as SEQ ID NO: 85), such as 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 at a dose of about 60 mg to about 3600 mg, such as about 60 mg to about 1200 mg, about 60 mg to about 3000 mg, about 60 mg to about 2880 mg, about 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., any one 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 doses). In some embodiments, the fusion protein is administered once a week (QW). In some embodiments, the fusion protein is administered once every two weeks (Q2W).In some embodiments, the fusion protein is administered in multiple doses (e.g., QW or Q2W), each dose of about 600 mg to about 2880 mg, such as any of about 600 mg to 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 protein is administered in multiple doses (e.g., QW or Q2W), each dose being 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. In some embodiments, the fusion protein is administered once a week at a dose of about 600 mg IV for 5 weeks. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an 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., two) 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 in 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 to the abdominal wall using standard techniques for SC administration.

[0109] In some embodiments, a method of treating a complement-mediated disease in a human subject (e.g., a complement inhibitor naive human subject) is provided, comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH) comprising i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, such as FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domains of FH, such as SEQ ID NO: 85), wherein the fusion protein is administered through an initial phase comprising administering the fusion protein with one or more (e.g., one) initial doses followed by a maintenance phase comprising administering the fusion protein (e.g., weekly or biweekly) for 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. 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 from about 600 mg to about 3600 mg, such as from about 1200 mg to about 3600 mg, from about 600 mg to about 1200 mg, from about 600 mg to about 2880 mg, from about 1200 mg to about 3600 mg, from about 720 mg to about 1440 mg, from about 720 mg to about 3000 mg, from about 1920 mg to about 2880 mg, from about 1800 mg to about 3600 mg, or from about 1800 mg to about 2400 mg. In some embodiments, the initial dose is from about 1200 mg to about 3600 mg, such as from about 1200 mg, 1440 mg, 1800 mg, 1920 mg, 2400 mg, 2880 mg, 3000 mg, or 3600 mg. In some embodiments, IV administers one or more (e.g., one) initial dose of the fusion protein. In some embodiments, the initial phase comprises administering the fusion protein in 1, 2, 3, 4, 5, 6, 10, 12, 14, 16 or more initial doses. In some embodiments, the initial phase comprises administering the fusion protein in one initial dose.In some embodiments, the maintenance dose is about 600 mg to about 2880 mg, such as 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 fusion protein are administered once a week. In some embodiments, maintenance dose (for example, once a week) is about 600 mg to about 1440 mg, such as about 600 mg to about 1200 mg, about 720 mg to about 1440 mg, about 600 mg, about 720 mg, about 840 mg, about 960 mg, about 1080 mg, about 1200 mg, about 1320 mg or about 1440 mg. In some embodiments, the fusion protein of two or more maintenance doses is each administered (for example, once a week) with about 600 mg IV to about 1200 mg IV or with about 720 mg SC to about 1440 mg SC. For example, the fusion protein of two or more maintenance doses is each administered (for example, once a week) with about 600 mg IV, about 1200 mg IV, about 720 mg SC, about 960 mg SC or about 1440 mg SC. In some embodiments, the fusion protein of two or more maintenance doses is administered once every two weeks. In some embodiments, the maintenance dose (e.g., once every two weeks) is about 960 mg to about 2880 mg, such as any of 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, the fusion protein of two or more maintenance doses is each administered (for example, once every two weeks) at about 1920 mg SC to about 2880 mg SC or at about 1800 mg SC to about 2400 mg SC, such as any one of about 960 mg SC, about 1800 mg SC, about 1920 mg SC, about 2400 mg SC, or about 2880 mg SC. In some embodiments, the maintenance phase is at least about 4 weeks, such as 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, any one of 52 weeks or longer. In some embodiments, the maintenance phase is at least about 12 weeks, such as any one of 12 weeks, 13 weeks, 24 weeks, 25 weeks, 48 ​​weeks or 49 weeks. In some embodiments, the initial phase includes administering the fusion protein once a week for one or more (e.g., one) dosages with an initial dose of about 1200 mg, and wherein the maintenance phase includes administering the fusion protein once a week or once every two weeks for at least two (e.g., at least 4, 5, 12, 13, 24, 25, 48 or 49) dosages with a maintenance dose of about 720 mg. In some embodiments, the initial phase includes administering the fusion protein with an initial dose of about 1200 mg IV on the 1st day, and the maintenance phase includes administering the fusion protein once a week for 4 weeks with a maintenance dose of about 720 mg SC starting from the 8th day. In some embodiments, the maintenance phase includes administering the fusion protein (e.g., once a week or once every two weeks) with a first maintenance dose in the first maintenance phase time period, followed by administering the fusion protein (e.g., once a week or once every two weeks) with a second maintenance dose in the second maintenance phase time period. In some embodiments, the second maintenance dose is higher than the first maintenance dose, such as any one of at least about 1.5, 2, 3, 4, 5, 10 times or more. In some embodiments, the second maintenance phase time period is longer than the first maintenance phase time period, such as any one of 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 first maintenance phase time period is at least 1 week, and the second maintenance phase time period is no more than about 23 or about 24 weeks. In some embodiments, the fusion protein of the first maintenance dose is administered once a week with about 720 mg SC or about 600 mg IV, and the fusion protein of the second maintenance dose is administered once a week with about 1440 mg SC or about 1200 mg IV.In some embodiments, the first maintenance phase period is about 4 weeks and the second maintenance phase period is at least about 44 weeks. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an amino acid sequence of SEQ ID NO: 90. In some embodiments, FH or its functional fragment is fused to the C-terminus of one or two (e.g., two) heavy chains of an anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH or its functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises about 120 mg / mL of fusion protein, sodium phosphate, sodium chloride, L-Lys-HCL, and polysorbate 80, with 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 can be administered without further preparation and is administered to the abdominal wall using standard techniques for SC administration.

[0110] In some embodiments, a method of treating a complement-mediated disease in a human subject (e.g., a complement inhibitor naive human subject) is provided, the method comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH) comprising i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, such as FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, such as 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 subject is provided, the method comprising administering to the human subject 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, such as FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85), wherein the fusion protein is administered once weekly for 5 weeks at a dose of about 600 mg IV. In some embodiments, a method of treating a complement-mediated disease in a human subject is provided, the method comprising administering to the human subject 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, such as FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domains of FH, such as SEQ ID NO: 85), wherein the fusion protein is administered through an initial phase comprising administering the fusion protein once weekly (e.g., IV) for one or more doses (e.g., only one dose) at an initial dose of about 1200 mg followed by a maintenance phase comprising administering the fusion protein once weekly (e.g., IV) for one or more doses (e.g., only one dose) at an initial dose of about 720 mg. The fusion protein is administered weekly or biweekly (e.g., SC) for 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 at a maintenance dose of mg.In some embodiments, a method of treating a complement-mediated disease in a human subject is provided, the method comprising administering to the human subject 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, such as FMEH-IgG4-PLA) and ii) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85), wherein the fusion protein is administered through 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 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an 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., two) 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 in 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 to the abdominal wall using standard techniques for SC administration.

[0111] In some embodiments, a method of treating a complement-mediated disease in a human subject (e.g., a complement inhibitor naive human subject) is provided, the method comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH) comprising (a) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, such as FMEH-IgG4-PLA) and (b) FH or a fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85), wherein the fusion protein is administered through 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 maintenance phase comprising administering the fusion protein starting on day 8 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 IV once every two weeks. SC to about 2880 mg SC; iv) about 1800 mg SC to about 2400 mg SC every two weeks; or v) about 960 mg SC to about 2880 mg SC 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 of the fusion protein is administered IV at any of 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; such as any of 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 administering the fusion protein once weekly at a 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 once weekly at a 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 at a biweekly 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; such as any of 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 weeks or longer, such as 12 weeks) for 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 weeks or longer, such as 13 weeks) for biweekly maintenance dosing. In some embodiments, the maintenance phase is at least about 24 weeks (e.g., 24 weeks) for weekly maintenance dosing, or at least about 25 weeks (e.g., 25 weeks) for biweekly maintenance dosing. In some embodiments, the maintenance period is at least about 48 weeks (e.g., 48 weeks) for weekly maintenance dosing, or at least about 49 weeks (e.g., 49 weeks) for biweekly maintenance dosing. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having the amino acid sequence of SEQ ID NO: 87 and a VL having 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 having the amino acid sequence of SEQ ID NO: 120 and ii) a light chain having the amino acid sequence of SEQ ID NO: 90.In some embodiments, FH or its functional fragment is fused to the C-terminus of one or two (e.g., two) heavy chains of an anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH or its functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises about 120 mg / mL of fusion protein, sodium phosphate, sodium chloride, L-Lys-HCL, and polysorbate 80, with 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 can be administered without further preparation and is administered to the abdominal wall using standard techniques for SC administration.

[0112] In some embodiments, the method includes administering the anti-C5-FH fusion protein with a high initial loading dose, such as from about 600 mg to about 3600 mg (including, for example, any one of 600, 1200, 1440, 1800, 1920, 2400, and 3600 mg or any range therebetween) to mitigate the effects of target-mediated drug disposition (TMDD). The pharmacokinetics of mAbs have shown that higher antigen mass is associated with higher mAb clearance, which prolongs the time to reach steady-state drug concentrations (see, for example, Ternant et al., Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans. Clinical Pharmacokinetics, 2019 Feb;58(2)). Using a high loading dose upfront can reduce the contribution of clearance due to nonlinear TMDD to total clearance (nonlinear clearance due to TMDD + linear nonspecific clearance), thereby allowing steady-state drug concentrations to be reached more quickly.

[0113] In some embodiments, the methods described herein further include selecting an individual suitable for this treatment. In some embodiments, the methods described herein further include excluding individuals that are not suitable for this treatment. In some embodiments, the human individual to be treated has previously been treated with a C5 inhibitor (e.g., an anti-C5 antibody therapy). In some embodiments, the human individual to be treated has not previously been treated with a C5 inhibitor (e.g., an anti-C5 antibody therapy). In some embodiments, the method further includes determining the hemoglobin level, transfusion status, and / or FACIT fatigue scale score of the subject at baseline and after treatment. For exemplary selection / elimination methods, see, e.g., Examples 4-6.

[0114] In some embodiments, the methods described herein further include measuring the toxicity or side effects of the treatment method, including but not limited to adverse events (TEAEs) occurring during treatment, serious adverse events (TESAEs) occurring during treatment, and adverse events of particular interest (AESIs), such as those based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). In some embodiments, according to CTCAE v5.0, the treatment methods described herein will not cause adverse events of >= 3 grades. In some embodiments, the method also includes measuring one or more of clinical laboratory values, electrocardiograms (ECGs), physical examinations, and vital signs. Regarding exemplary methods, see, for example, Examples 4-6.

[0115] Treatment options for PNH

[0116] In some embodiments, a method of treating PNH in a human subject (e.g., a complement inhibitor-naive human subject) is provided, comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH), the fusion protein comprising i) an antibody portion that specifically binds to human C5 (e.g., a full-length anti-human C5 antibody, such as FMEH-IgG4-PLA) and ii) FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as 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 at a dosage of about 60 to about 3600 mg (including, for example, any one 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 at a single dose (such as a dosage of about 60 mg to about 1200 mg). In some embodiments, the fusion protein is administered at 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 at multiple doses. In some embodiments, the fusion protein is administered weekly or biweekly, such as at a dosage of about 600 mg to about 2880 mg. In some embodiments, the fusion protein is administered through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein with one or more (e.g., one) initial dose (e.g., about 600 mg to about 3600 mg or about 1200 mg to about 3600 mg per dose, such as IV administration), the maintenance phase comprising administering the fusion protein (e.g., once a week or once every two weeks) for 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). In some embodiments, two or more maintenance doses of the fusion protein are administered once a week, such as at about 600 mg to about 2880 mg per dose. In some embodiments, two or more maintenance doses of the fusion protein are each administered once weekly 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 biweekly, such as at about 960 mg to about 2880 mg. In some embodiments, two or more maintenance doses of the fusion protein are each administered 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, about 1700 mg SC to about 2100 mg SC, and about 1800 mg SC to about 2880 mg SC. In some embodiments, the maintenance phase is at least about 12 weeks. In some embodiments, the initial dosing phase comprises administering to an individual a dose of about 1200 mg to about 3600 mg (e.g., IV) once weekly for one or more doses (e.g., only one dose), followed by a maintenance phase comprising administering to an individual about 720 mg to about 2880 mg (e.g., SC) or about 600 mg to about 1200 mg SC once weekly for one or more doses (e.g., only one dose). The fusion protein is administered (e.g., IV) weekly or biweekly for at least two doses, e.g., for 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 weeks or longer, such as 12 weeks) for weekly maintenance dosing, or for 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 weeks or longer, such as 13 weeks) for biweekly maintenance dosing.In some embodiments, the fusion protein is further administered by an extended phase, which is included in the administration of the fusion protein with one or more extended doses after the maintenance phase. In some embodiments, the maintenance phase is followed by an extended phase, which is 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 longer, such as 9 months. In some embodiments, the extended dose is identical to the maintenance dose. In some embodiments, the extended dose is lower than the maintenance dose. In some embodiments, the extended dose is higher than the maintenance dose. In some embodiments, the extended dose is about 1920 mg SC. In some embodiments, the extended phase includes administering the fusion protein once every two weeks with an extended dose of about 1920 mg SC for about 9 months. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an 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., two) 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 in 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 to the abdominal wall using standard techniques for SC administration.

[0117] In some embodiments, a method of treating PNH in a human subject (e.g., a complement inhibitor naive human subject) is provided, the method comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH) comprising (a) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, such as FMEH-IgG4-PLA) and (b) FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85), wherein the fusion protein is administered through 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 comprising administering the fusion protein starting on day 8 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 IV once weekly In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and wherein the maintenance phase comprises administering the fusion protein weekly starting on day 8 at a maintenance dose of about 720 mg SC or about 600 mg IV for about 12 weeks. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1 to about 2400 mg IV, and wherein the maintenance phase comprises administering the fusion protein once every two weeks starting on day 8 at a maintenance dose of about 960 mg SC to about 2880 mg SC for about 13 weeks. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 2400 mg IV on day 1, and wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC to about 2880 mg SC once every two weeks 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 wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC once every two weeks 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 wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every two weeks 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 on day 1, and wherein 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. In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 2400 mg IV on day 1, and wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC once every two weeks 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 3600 mg IV on day 1, and wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 2880 mg SC once every two weeks starting on day 8 for about 13 weeks. In some embodiments, the fusion protein is further administered via an extended phase comprising administering the fusion protein at one or more extended doses following the maintenance phase. In some embodiments, the maintenance phase is followed by an extension phase that is 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 longer, for example, about 9 months. In some embodiments, the extended dose is the same as the maintenance dose. In some embodiments, the extended dose is lower than the maintenance dose. In some embodiments, the extended dose is higher than the maintenance dose. In some embodiments, the extended phase comprises administering the fusion protein once every two weeks at an extended dose of about 1920 mg SC for about 9 months. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an 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., two) 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 in 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 to the abdominal wall using standard techniques for SC administration.

[0118] In some embodiments, a method for treating PNH in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through 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 once weekly starting on day 8 at a maintenance dose of about 720 mg SC or about 600 mg IV for about 12 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises SEQ ID NO: 89 amino acid sequence. In some embodiments, the fusion protein is further administered through an extended phase, which includes administering the fusion protein with one or more extended doses after the maintenance phase. In some embodiments, the extended phase includes administering the fusion protein once every two weeks at an extended dose of about 1920 mg SC for about 9 months. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises about 120 mg / mL of fusion protein, sodium phosphate, sodium chloride, L-Lys-HCL and polysorbate 80, with 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 can be administered without further formulation and is administered to the abdominal wall using standard techniques for SC administration.

[0119] In some embodiments, a method for treating PNH in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV on day 1, the maintenance phase comprising administering the fusion protein once weekly for about 12 weeks starting on day 8 at a maintenance dose of about 720 mg SC; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered through an extended phase, which includes administering the fusion protein with one or more extended doses after the maintenance phase. In some embodiments, the extended phase includes administering the fusion protein once every two weeks at an extended dose of about 1920 mg SC for about 9 months. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises about 120 mg / mL of fusion protein, sodium phosphate, sodium chloride, L-Lys-HCL, and polysorbate 80, with 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 can be administered without further preparation and is administered to the abdominal wall using standard techniques for SC administration.

[0120] In some embodiments, a method for treating PNH in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 3600 mg IV on day 1, the maintenance phase comprising administering the fusion protein at a maintenance dose of about 2880 mg SC once every two weeks starting on day 8 for about 13 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered through an extended phase, which includes administering the fusion protein with one or more extended doses after the maintenance phase. In some embodiments, the extended phase includes administering the fusion protein once every two weeks at an extended dose of about 1920 mg SC for about 9 months. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises about 120 mg / mL of fusion protein, sodium phosphate, sodium chloride, L-Lys-HCL, and polysorbate 80, with 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 can be administered without further preparation and is administered to the abdominal wall using standard techniques for SC administration.

[0121] In some embodiments, a method for treating PNH in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase, followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 2400 mg IV on day 1, the maintenance phase comprising administering the fusion protein once every two weeks starting on day 8 at a maintenance dose of about 960 mg SC to about 2880 mg SC for about 13 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90 amino acid sequence; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered through an extended phase, which includes administering the fusion protein in one or more extended doses after the maintenance phase. In some embodiments, the extended phase includes administering the fusion protein once every two weeks at an extended dose of about 1920 mg SC for about 9 months. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises about 120 mg / mL of 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 preparation and is administered to the abdominal wall using standard techniques for SC administration.

[0122] In some embodiments, a method for treating PNH in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 2400 mg IV on day 1, the maintenance phase comprising administering the fusion protein once every two weeks starting on day 8 at a maintenance dose of about 960 mg SC to about 2880 mg SC for about 13 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises SEQ ID NO: 89 amino acid sequence. In some embodiments, the fusion protein is formulated in 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, the fusion protein is further administered through an extended phase comprising administering the fusion protein with one or more extended doses after the maintenance phase. In some embodiments, the extended phase comprises administering the fusion protein once every two weeks at an extended dose of about 1920 mg SC 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 preparation and is administered to the abdominal wall using standard techniques for SC administration.

[0123] In some embodiments, a method for treating PNH in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase, followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV to about 2400 mg IV on day 1, the maintenance phase comprising administering the fusion protein at a maintenance dose of about 1920 mg SC once every two weeks starting on day 8 for about 13 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises SEQ ID NO: 89 amino acid sequence. In some embodiments, the fusion protein is further administered through an extended phase, which includes administering the fusion protein with one or more extended doses after the maintenance phase. In some embodiments, the extended phase includes administering the fusion protein once every two weeks at an extended dose of about 1920 mg SC for about 9 months. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises about 120 mg / mL of fusion protein, sodium phosphate, sodium chloride, L-Lys-HCL and polysorbate 80, with 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 can be administered without further formulation and is administered to the abdominal wall using standard techniques for SC administration.

[0124] In some embodiments, a method for treating PNH in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 2400 mg IV on day 1, the maintenance phase comprising administering the fusion protein at a maintenance dose of about 1920 mg SC once every two weeks starting on day 8 for about 13 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is further administered through an extended phase, which includes administering the fusion protein with one or more extended doses after the maintenance phase. In some embodiments, the extended phase includes administering the fusion protein once every two weeks at an extended dose of about 1920 mg SC for about 9 months. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises about 120 mg / mL of fusion protein, sodium phosphate, sodium chloride, L-Lys-HCL, and polysorbate 80, with 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 can be administered without further preparation and is administered to the abdominal wall using standard techniques for SC administration.

[0125] In some embodiments, a method of treating PNH in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 3600 mg IV on day 1, the maintenance phase comprising administering the fusion protein once every two weeks starting on day 8 at a maintenance dose of about 1920 mg SC to about 2880 mg SC for about 13 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: NO: 89 amino acid sequence. In some embodiments, the fusion protein is further administered by an extended phase, which is included in the administration of the fusion protein with one or more extended doses after the maintenance phase. In some embodiments, the extended phase includes administering the fusion protein once every two weeks with an extended dose of about 1920 mg SC for about 9 months. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises about 120 mg / mL of fusion protein, sodium phosphate, sodium chloride, L-Lys-HCL and polysorbate 80, and the pH is 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 can be administered without further preparation, and is administered to the abdominal wall using the standard technique of SC administration.

[0126] PNH

[0127] Complement-mediated hemolytic anemia contributes to many red blood cell disorders, such as paroxysmal nocturnal hemoglobinuria (PNH). PNH is a blood disorder characterized by the clonal expansion of one or more hematopoietic stem cells that are unable to undergo glycosylphosphatidylinositol (GPI)-anchored biosynthesis due to acquired somatic mutations in the phosphatidylinositol glycan A (PIG-A) gene. Affected progeny cells lack all GPI-anchored surface proteins, including the complement regulatory factors CD55 and CD59. Therefore, PNH red blood cells (RBCs) are susceptible to activated complement, particularly the membrane attack complex (MAC), leading to chronic intravascular hemolysis with repeated exacerbations.

[0128] PNH is a disorder 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 may 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 intestines) are sequelae of such events (Hillmen, P. et al., Am. J. Hematol. 2010;85(8):553-559). Due to these adverse pathological processes, patients with PNH have a reduced quality of life (QoL), which can include debilitating fatigue, chronic pain, poor physical function, shortness of breath, abdominal pain, erectile dysfunction, the need for anticoagulation, blood transfusions, and in some cases, dialysis (Weitz, IC. et al., Thromb Res. 2012; 130(3): 361-368). Patients with PNH are at significant risk for morbidity and mortality.

[0129] Patients with PNH may exhibit at least one of the following characteristics, which may be symptoms of residual anemia and / or complement-mediated extravascular hemolysis (EVH) and / or incomplete control of intravascular hemolysis: a) exhibit signs or symptoms of ongoing RBC loss due to persistent or intermittent intravascular hemolysis and / or extravascular hemolysis; b) have RBC opsonization by C3 fragments; c) require regular blood transfusions; d) have lower normal or lower normal levels of hemoglobin; e) have lower normal or lower normal levels of platelets; f) have higher normal or higher normal levels of reticulocytes; g) have higher normal or higher normal levels of bilirubin; or h) have iron overload or are at risk for iron overload.

[0130] The above characteristics can also be used to monitor the progression of a PNH patient's response to treatment according to the present invention and to modify the dosage regimen if deemed clinically appropriate. In certain embodiments, the subject with PNH has previously been treated with a terminal complement inhibitor but still exhibits at least one of the above characteristics.

[0131] In some embodiments, the methods of treating PNH described herein can prevent (e.g., prevent at least about any of a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% chance), delay (e.g., delay for at least about any of 1, 2, 3, 6, 12, 18, 24, 30, 36, 42, 48, 52 months or longer), or reduce (e.g., reduce at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) the severity of one or more of the signs / symptoms / characteristics of PNH discussed above, including, but not limited to, 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 result in a reduction in one or more of the following in a subject (e.g., a reduction of at least about 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 crises observed in patients treated with terminal complement inhibitors. In some embodiments, the methods of treating PNH described herein result in an improvement (e.g., an improvement of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) in one or more of the following in a subject: i) FACIT fatigue scale score; ii) serum LDH and hemoglobin (HgB) levels; iii) quality of life; iv) absolute reticulocyte count; v) bilirubin levels; and vi) haptoglobin levels. In some embodiments, the methods of treating PNH described herein reduce (e.g., by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) one or more of the following: (a) C3b deposition and (b) plasma free C5 levels. In some embodiments, the methods of treating PNH described herein reduce (e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) lactate dehydrogenase (LDH) levels compared to baseline. In some embodiments, the methods of 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 of treating PNH described herein increase (e.g., by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) HgB levels compared to baseline. In some embodiments, the methods of treating PNH described herein achieve an increase in Hgb of at least about 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 compared to baseline. In some embodiments, the methods of treating PNH described herein increase (e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) the proportion of PNH red blood cells that can survive complement attack. In some embodiments, the human subject to be treated has extravascular hemolysis (EVH).Thus, in some embodiments, the present disclosure also relates to methods of treating clinically apparent EVH in a human subject suffering from PNH.

[0132] In some embodiments, the efficacy of the methods described herein for treating PNH can be assessed by one or more of the following: i) an increase in hemoglobin level (e.g., in the absence of a blood transfusion) compared to baseline (e.g., an increase of ≥ 2 g / dL); ii) a decrease in serum lactate dehydrogenase (LDH) level compared to baseline (e.g., a decrease of at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); iii) the proportion of subjects with breakthrough hemolysis, defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin < 10 g / dL], MAVEs including thrombosis, dysphagia, or erectile dysfunction) in the presence of an elevated LDH ≥ 2 × upper limit of normal (ULN) after the previous LDH was reduced to < 1.5 × ULN with treatment; iv) a decrease in hemoglobin ≥ 10 g / dL; and v) an improvement (e.g., an improvement of at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) in quality of life as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and the EQ-5D-3L.Pharmacodynamic and biomarker changes can also be measured to reflect treatment efficacy, including but not limited to: 1) a decrease in C3b activity assay compared to baseline (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 in total and free serum C5 levels compared to baseline (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 in rabbit RBC assay compared to baseline; 4) a change in factor H serum levels compared to baseline; 5) a change in d-dimer compared to baseline; 6) an increase in free hemoglobin compared to baseline (e.g., an increase of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%). 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); 7) an increase in serum total and direct bilirubin compared to baseline (e.g., an increase of at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); 8) an increase in serum haptoglobin level compared to baseline (e.g., an increase of at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%); and 9) an increase in reticulocyte count compared to baseline (e.g., an increase of at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%).

[0133] In some embodiments, the methods of treating PNH described herein further comprise selecting a human subject suitable for such treatment. In some embodiments, the human subject to be treated is a complement inhibitor-naive subject with PNH. In some embodiments, the human subject to be treated is a complement inhibitor-naive subject with PNH who has LDH, hemoglobin, and transfusion dependency. In some embodiments, the human subject further receives antibiotic prophylaxis during treatment. In some embodiments, the human subject is at least about 18 years old. In some embodiments, the human subject meets one or more of the following criteria: 1) a diagnosis of PNH within 6 months of screening, confirmed by flow cytometric evaluation of white blood cells and red blood cells, e.g., granulocyte or monocyte clone size ≥ 10%; 2) the presence of one or more PNH-associated signs or symptoms, e.g., within 3 months of screening; 3) LDH ≥ 2.0 × ULN at screening; 4) hemoglobin ≤ 10.0 g / dL at screening; 5) effective contraception during treatment; 6) negative pregnancy test for females during treatment; 7) BMI < 35 kg / m 2 8) Previous vaccination against Neisseria meningitidis at screening (subjects who do not provide evidence of previous vaccination should be vaccinated after the start of anti-C5-FH fusion protein administration, but need to receive appropriate antibiotic prophylaxis until 2 weeks after vaccination); and 9) vaccination against Streptococcus pneumoniae and Hemophilus influenzae (if anti-C5-FH fusion protein is started within 2 weeks of vaccination, appropriate antibiotics should be given for prophylaxis).

[0134] In some embodiments, the methods for treating PNH described herein further include excluding human subjects who are not suitable for such treatment. In some embodiments, human subjects who are not suitable for the treatment methods described herein meet one or more of the following criteria: 1) any clinically significant underlying illness other than PNH that is poorly controlled; 2) any infection treated with IV (within 30 days of screening) or oral (within 14 days of screening) antibiotics, antivirals, or antifungals; 3) history of meningococcal infection; 4) history of untreated tuberculosis; 5) history of splenectomy; 6) hepatitis C virus (HCV) ribonucleic acid (RNA) or human immunodeficiency virus (HIV) seropositivity at screening; 7) history of bone marrow or stem cell transplantation; 8) absolute neutrophil count (ANC) <500 cells / μL; 9) reticulocyte count <100 × 10 3cells / μL; 10) platelet count < 30,000 cells / μL; 11) history of systemic autoimmune disease; 12) estimated glomerular filtration rate (eGFR) calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation < 30 mL / min / 1.73 m 2 ; 13) known allergy to penicillin antibiotics; 14) history of drug or alcohol abuse within 1 year of screening; 15) before screening < 1) Receipt of any type of live attenuated vaccine within 1 month, or plan to receive any such live attenuated vaccine during treatment; 16) Use of rituximab in the past 3 months or use of any complement inhibitor before screening; 17) Use of steroids (topical use is allowed), EPO, iron supplements, folic acid, vitamin B12, androgens, HIF-PHI within 4 weeks before screening, and use of immunosuppressants within 3 months before screening (if the dose of the above drugs can be maintained stable during this period, it is acceptable); 18) History of malignancy, except for adequately treated basal cell carcinoma or carcinoma in situ of the cervix; 19) Bone marrow failure and / or candidates for bone marrow transplantation; 20) Any pregnant or breastfeeding woman, or any woman who plans to become pregnant during treatment; 21) QT interval after correction for heart rate by Fridericia's formula (QTcF) based on single or average QTcF values ​​of three ECGs obtained at 3-minute intervals > 450 milliseconds (msec) for men and > 470 for women msec; and 22) prior treatment with complement inhibitors.

[0135] Treatment options for SLE-TMA

[0136] In some embodiments, a method of treating SLE-TMA in a human subject (e.g., a complement inhibitor-naive human subject) is provided, comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH), the fusion protein comprising i) an antibody portion that specifically binds to human C5 (e.g., an anti-human C5 full-length antibody, such as FMEH-IgG4-PLA) and ii) FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as 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 at a dosage of about 60 to about 3600 mg (including, for example, any one 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 at a single dose (such as a dosage of about 60 mg to about 1200 mg). In some embodiments, the fusion protein is administered at 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 at multiple doses. In some embodiments, the fusion protein is administered weekly or biweekly, such as at a dosage of about 600 mg to about 2880 mg. In some embodiments, the fusion protein is administered through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein with one or more (e.g., one) initial dose (e.g., about 600 mg to about 3600 mg per dose or about 1200 mg to about 3600 mg, such as IV administration), the maintenance phase comprising administering the fusion protein (e.g., once a week or once every two weeks) for 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). In some embodiments, two or more maintenance doses of the fusion protein are administered once a week, such as 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 once weekly at about 600 mg IV to about 1200 mg IV or at about 720 mg SC to about 1440 mg SC.In some embodiments, two or more maintenance doses of the fusion protein are administered once every two weeks, such as at about 1800 mg to about 2880 mg. In some embodiments, two or more maintenance doses of the fusion protein are each administered once every two weeks at about 1920 mg SC to about 2880 mg SC or at about 1800 mg SC to about 2400 mg SC. In some embodiments, the maintenance phase is at least about 24 weeks. In some embodiments, an initial dosing phase comprises administering to a subject a dose of about 1200 mg to about 3600 mg (e.g., about 1200 mg to about 2400 mg, such as IV) once weekly for one or more doses (e.g., only one dose), followed by a maintenance phase comprising administering the fusion protein at about 720 mg to about 2880 mg (e.g., SC) once weekly or once every two weeks for at least two doses, e.g., for at least about 24 weeks (e.g., 24, 25, 26, 28, 30, 34, 38, 40, 42, 44, 46, 47, 48, 49, 50 weeks or longer, such as 24 weeks) for weekly maintenance dosing, or for at least about 25 weeks (e.g., 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51 weeks or longer, such as 25 weeks) for biweekly maintenance dosing. In some embodiments, the maintenance phase includes administering the fusion protein (for example, once a week or once every two weeks) with the first maintenance dose in the first maintenance phase time period, and then administering the fusion protein (for example, once a week or once every two weeks) with the second maintenance dose in the second maintenance phase time period. In some embodiments, the first maintenance dose and / or the second maintenance dose is about 600 mg to about 2880 mg, such as 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, the first maintenance dose, and / or the second maintenance dose of the fusion protein are administered IV or SC.In some embodiments, the fusion protein of the first maintenance dose and / or the second maintenance dose is used with 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 with about 1800 mg SC to about 2400 mg SC. In some embodiments, the second maintenance dose is higher than the first maintenance dose, such as high at least about 1.5, 2, 3, 4, 5, 10 times or more any one. In some embodiments, the second maintenance phase time period is longer than the first maintenance phase time period, such as long 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 any one. In some embodiments, the first maintenance phase time period is at least about 1 week, and the second maintenance phase time period is no more than about 23 or about 24 weeks. In some embodiments, a first maintenance dose of the fusion protein is administered at about 600 mg IV or about 1200 mg IV once weekly during the first maintenance phase, followed by a second maintenance dose of the fusion protein at about 720 mg SC or about 1440 mg SC once weekly during the second maintenance phase. In some embodiments, a first maintenance dose of the fusion protein is administered at about 600 mg IV or about 1200 mg IV once weekly during the first maintenance phase, followed by a second maintenance dose of the fusion protein at about 1920 mg SC or about 2880 mg SC once every two weeks during the second maintenance phase. In some embodiments, the first maintenance phase period 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 longer, such as 1 week), and the second maintenance phase period is no more than about 24 weeks (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, such as 23 or 24 weeks). In some embodiments, the maintenance phase is at least about 24 or about 25 weeks (including the first maintenance phase period and the second maintenance phase period). In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96.In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an 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 two (e.g., two) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH or a functional fragment thereof comprises an amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises 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 to the abdominal wall using standard techniques for SC administration.

[0137] In some embodiments, a method of treating SLE-TMA in a human subject (e.g., a complement inhibitor naive human subject) is provided, comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH) comprising i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, such as FMEH-IgG4-PLA) and ii) FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85), wherein the fusion protein is administered through an initial phase comprising administering the drug to the human subject 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) followed by a maintenance phase. In some embodiments, the fusion protein is administered IV to about 3600 mg IV, the maintenance phase comprising administering the fusion protein for two or more (e.g., 24, 25, 26, 27, 28, 29, 30 weeks or longer) maintenance doses starting on day 8; and wherein the maintenance phase comprises administering the fusion protein at a first maintenance dose (e.g., weekly or biweekly) for a first maintenance phase time period (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 23, 24 weeks or longer) followed by administering the fusion protein at a second maintenance dose (e.g., weekly or biweekly) for a second maintenance phase time period (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 25 weeks or longer). 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, such as 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 are any one of 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 IV or SC of the initial dose, the first maintenance dose and / or the second maintenance dose is administered. In some embodiments, the fusion protein of the first maintenance dose and / or the second maintenance dose is administered with 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 with 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 second maintenance phase time period is longer than the first maintenance phase time period. In some embodiments, the first maintenance dose of the fusion protein is administered at about 600 mg IV or about 1200 mg IV once a week, and the second maintenance dose of the fusion protein is administered at about 720 mg SC to about 1440 mg SC once a week, or at about 1920 mg SC to about 2880 mg SC once every two weeks. In some embodiments, the maintenance phase (including the first maintenance phase time period and the second maintenance phase time period) is at least about 24 weeks or about 25 weeks. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an 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 two (e.g., two) 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 in 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 to the abdominal wall using standard techniques for SC administration.

[0138] In some embodiments, a method of treating SLE-TMA in a human subject (e.g., a complement inhibitor naive human subject) is provided, the method comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH) comprising (a) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, such as FMEH-IgG4-PLA) and (b) FH or a functional fragment thereof (e.g., the SCR1-5 domains of FH, such as SEQ ID NO: 85), wherein the fusion protein is administered through 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 a maintenance phase comprising: i) administering the fusion protein at a dose of about 720 mg SC to about 1440 mg IV starting on day 8; The invention further comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every two weeks beginning 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 a first maintenance phase period, followed by administering the fusion protein at a second maintenance dose of about 720 mg SC to about 1440 mg SC once weekly for a second maintenance phase period, and 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 for a first maintenance phase period, followed by administering the fusion protein at a second maintenance dose of about 1920 mg SC to about 2880 mg SC once every two weeks beginning on day 8 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 wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC once weekly for about 24 weeks starting on day 8. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 96.In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an 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 two (e.g., two) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH or a functional fragment thereof comprises an amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises 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 to the abdominal wall using standard techniques for SC administration.

[0139] In some embodiments, a method of treating SLE-TMA in a human subject (e.g., a complement inhibitor naive human subject) is provided, the method comprising administering to the human subject 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 through an initial phase followed by a maintenance phase, 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, the maintenance phase comprising administering the fusion protein once weekly starting on day 8 at a maintenance dose of about 720 mg SC to about 1440 mg SC for at least about 24 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90 amino acid sequence; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises 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 to the abdominal wall using standard techniques for SC administration.

[0140] In some embodiments, a method of treating SLE-TMA in a human subject (e.g., a complement inhibitor naive human subject) is provided, the method comprising administering to the human subject 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 through an initial phase followed by a maintenance phase, 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, the maintenance phase comprising administering the fusion protein once every two weeks starting on day 8 at a maintenance dose of about 1920 mg SC to about 2880 mg SC for at least about 25 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises 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 to the abdominal wall using standard techniques for SC administration.

[0141] In some embodiments, a method for treating SLE-TMA in a human subject (e.g., a complement inhibitor naive human subject) is provided, the method comprising administering to the human subject 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 through an initial phase followed by a maintenance phase, 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, the maintenance phase being at least about 24 weeks, wherein the maintenance phase comprises administering the fusion protein once weekly starting on day 8 at a first maintenance dose of about 600 mg IV to about 1200 mg IV during the first maintenance phase period, followed by administering the fusion protein once weekly at a second maintenance dose of about 720 mg SC to about 1440 mg SC during the second maintenance phase period; wherein the first FH functional fragment is fused to the C-terminus of a first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises SEQ ID NO: In some embodiments, the fusion protein comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition comprising approximately 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80 at a pH of approximately 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 subcutaneous administration, the anti-C5-FH fusion protein is administered without further formulation and is administered to the abdominal wall using standard techniques for subcutaneous administration. In some embodiments, the second maintenance dose is higher than the first maintenance dose. In some embodiments, the second maintenance phase is longer than the first maintenance phase. In some embodiments, the first maintenance phase is at least about 1 week, and the second maintenance phase is no more than about 23 weeks.

[0142] In some embodiments, a method for treating SLE-TMA in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase followed by a maintenance phase, 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, the maintenance phase being at least about 25 weeks, wherein the maintenance phase comprises administering the fusion protein once weekly starting on day 8 at a first maintenance dose of about 600 mg IV to about 1200 mg IV during the first maintenance phase period, followed by administering the fusion protein once every two weeks during the second maintenance phase period at a second maintenance dose of about 1920 mg SC to about 2880 mg SC; wherein the first FH functional fragment is fused to the C-terminus of a first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of a second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises SEQ In some embodiments, the fusion protein comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition comprising approximately 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80 at a pH of approximately 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 subcutaneous administration, the anti-C5-FH fusion protein is administered without further formulation and is administered to the abdominal wall using standard techniques for subcutaneous administration. In some embodiments, the second maintenance dose is higher than the first maintenance dose. In some embodiments, the second maintenance phase is longer than the first maintenance phase. In some embodiments, the first maintenance phase is at least about one week long, and the second maintenance phase is no longer than about 24 weeks long.

[0143] In some embodiments, a method for treating SLE-TMA in a human subject (e.g., a complement inhibitor naive human subject) is provided, the method comprising administering to the human subject 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 through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV on day 1, the maintenance phase comprising administering the fusion protein once weekly starting on day 8 at a maintenance dose of about 960 mg SC for about 24 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises SEQ ID NO: 89 amino acid sequence. In some embodiments, the fusion protein is formulated in 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 to the abdominal wall using standard techniques for SC administration.

[0144] SLE-TMA

[0145] Thrombotic microangiopathy (TMA) is a serious complication that may occur in patients with systemic lupus erythematosus (SLE), adversely affecting prognosis and increasing mortality. SLE is a chronic autoimmune disease of unknown etiology. Renal involvement is usually caused by immune complex-mediated glomerular disease, however, vascular disease may also occur, usually adversely affecting prognosis and increasing mortality. TMA is a severe renal vascular injury that manifests as progressive, life-threatening thrombocytopenia, microangiopathic hemolytic anemia, and end-stage renal failure. The differential diagnosis of TMA in patients with SLE includes antiphospholipid antibody syndrome (APS), thrombocytopenic purpura, complement-mediated and infection-related hemolytic uremic syndrome, drug-mediated TMA (particularly due to calcineurin inhibitor toxicity), and malignant hypertension. TMA is characterized by endothelial damage, leading to thrombosis in capillaries and arterioles, and leading to Coombs-negative hemolytic anemia, thrombocytopenia, and end-organ damage, often affecting the kidneys. TMA encompasses several entities: thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and complement-mediated TMA. Typically, renal complications are particularly prominent in Shiga toxin-associated hemolytic uremic syndrome (STx-HUS) and atypical HUS, while TTP is more likely to present with neurological complications. Individuals with mild TTP may have recurrent symptomatic episodes, including seizures and vision loss. SLE and / or APS are common autoimmune diseases associated with secondary HUS. Dysregulation of terminal complement activation, leading to tissue damage, is the common thread in the pathophysiology of all forms of complement-mediated TMA. Although the clinical manifestations of TMA depend on the type, they generally include: fever, microangiopathic hemolytic anemia, renal failure, thrombocytopenia, and neurological manifestations. As TMA progresses, multi-organ failure or damage is possible because hyaline thrombi can spread and affect the brain, kidneys, heart, liver, and other major organs. Typical organ damage associated with TMA includes malignant hypertension, kidney damage, abdominal pain, diarrhea, stroke, mental confusion, heart damage, and eye damage. See, for example, Figueiredo et al., CEN Case Rep. 2022;11(1):26-30; Kello et al., SeminArthritis Rheum. 2019;49(1):74-83.

[0146] In some embodiments, the methods of treating SLE-TMA described herein can prevent (e.g., prevent at least about any of a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% chance), delay (e.g., delay for at least about any of 1, 2, 3, 6, 12, 18, 24, 30, 36, 42, 48, 52 months or longer), or reduce (e.g., reduce at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) the severity of one or more of the signs / symptoms / characteristics of SLE-TMA discussed above, including, but not limited to, APS, thrombocytopenic purpura, complement-mediated and infection-related hemolytic uremic syndrome, drug-mediated TMA, malignant hypertension, thrombocytopenia, microangiopathic hemolytic anemia, renal injury, and end-stage renal failure. In some embodiments, the methods for treating SLE-TMA described herein result in one or more reduction (e.g., reduction by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) of the subject's: i) proteinuria; ii) need for hemodialysis; iii) mortality; iv) complement activity; and v) systemic lupus erythematosus disease activity index (SLEDAI) score. In some embodiments, the methods for treating SLE-TMA described herein result in one or more improvements (e.g., improvement by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) of the subject's: i) FACIT fatigue scale score; ii) renal function; iii) eGFR; and iv) quality of life.

[0147] In some embodiments, the efficacy of the methods described herein for treating SLE-TMA 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) level; 3) percent change from baseline in estimated glomerular filtration rate (eGFR); 4) percent change from baseline in urine protein / creatinine ratio (UPCR); 5) time to first hematologic response, e.g., platelet count > 100,000 / μL with normalization of LDH; 6) an increase of at least 25% in platelet count compared to baseline. 7) the percentage of subjects whose platelet count increases by at least 25% (e.g., at least about any of 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%) compared to baseline; 8) the change from baseline in haptoglobin, hemoglobin, albumin, 24-hour proteinuria, bilirubin, and / or reticulocyte count; 9) the change in dialysis status throughout the treatment course; 10) Changes in RBC or platelet transfusion requirements (e.g., number of transfusions required and total number of units); 11) overall survival; 12) incidence of extrarenal complications related to TMA; 13) percentage of subjects with resolution of schistocytosis; 14) markers of healthcare utilization and morbidity, including but not limited to: duration of inpatient hospitalization (number of days) and / or duration of ICU stay during treatment and quality of life (QoL; Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]); 15) incidence of treatment failure, as defined by any of the following criteria: doubling of creatinine from baseline in the setting of a renal-related SAE or an increase in Common Terminology Criteria for Adverse Events (CTCAE) > Grade 1: worsening of renal function requiring new dialysis; worsening of renal or hematologic function requiring use of another complement inhibitor; worsening of renal, hematologic, neurologic, or other function due to TMA requiring use of IVIG, belimumab, or rituximab; major extrarenal adverse events secondary to TMA; and death of the subject due to TMA, TMA-related complications, or the fusion protein; 16) change from baseline in SLEDAI score; 17) renal biopsy status; 18) presence of autoantibodies to factor H; 19) pharmacodynamic and biomarker changes 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.

[0148] In some embodiments, subjects receiving anti-C5-FH fusion protein will 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 / without azathioprine maintenance therapy, calcineurin inhibitors, or mycophenolate mofetil. SOC will exclude other complement inhibitors, IVIG, and rituximab. In some embodiments, individuals may further receive rescue therapy via plasma exchange, plasmapheresis, and / or plasma transfusion.

[0149] In some embodiments, the methods for treating SLE-TMA described herein further include selecting a human subject suitable for such treatment (e.g., a complement inhibitor-naive human subject). In some embodiments, the human subject to be treated has previously been vaccinated with one or all of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. In some embodiments, the human subject is further treated with antibiotic prophylaxis during treatment. In some embodiments, individuals who have not been vaccinated with the above-mentioned vaccinations will begin receiving prophylactic antibiotics no later than the first dose of the anti-C5-FH fusion protein, and will continue to receive the antibiotic prophylaxis until 2 weeks after vaccination. In some embodiments, the human subject is about 18 to about 65 years old. In some embodiments, the human subject meets one or more of the following criteria: 1) meets criteria for SLE according to the 2019 European League Against Rheumatism (EULAR) / American College of Rheumatology (ACR) criteria; 2) platelet count is reduced to <100,000 / μL and exhibits a decrease of at least 25% (e.g., at least about any of 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%) compared to pre-treatment platelet count. Pre-treatment platelet count was defined as the platelet count within the 6 months prior to screening, or the median of all platelet counts if more than 1 measurement was taken during that 6-month period (if no pre-screening platelet value was available, a platelet count < 100,000 / μL at screening and a renal biopsy with evidence of TMA within 6 months would be sufficient); 3) LDH ≥ 2× upper limit of normal (ULN); 4) presence of schistocytes on the peripheral blood smear within 14 days of screening; 5) abnormal renal function as defined by creatinine above ULN or proteinuria as defined below. Subjects were eligible if they had acute kidney injury due to SLE-TMA requiring dialysis within 4 weeks of screening (urine protein ≥ 1.0 g / 24 h; or UPCR ≥ 1.0 g / g (or ≥ 113 mg / mmol) on 2 separate assessments during the screening period; for example, these assessments should be at least 3 days apart, and the difference between the higher value and the lower value should be < 20%); 6) practiced effective contraception from screening until the end of treatment; 7) had a negative pregnancy test in women at screening and / or within 24 hours before the first dose of anti-C5-FH fusion protein; 8) had evidence of previous vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae at screening (subjects who did not provide evidence of previous vaccination should be vaccinated after the start of anti-C5-FH fusion protein administration, but should receive appropriate antibiotic prophylaxis until 2 weeks after vaccination); 9) had evidence of microangiopathic hemolytic anemia.

[0150] In some embodiments, the methods for 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) diagnosed with other TMA syndromes, including but not limited to ADAMTS13 deficiency-mediated TMA, metabolic-mediated TMA, Shiga toxin-mediated TMA, coagulation-mediated TMA, hematopoietic stem cell transplantation-mediated TMA, and drug-mediated TMA; 2) renal biopsy showing only chronic changes in TMA within 7 days of screening, such as myxoid changes and onion-skin lesions in arterioles and / or arteries without any acute component (as defined by at least 1 fibrin microthrombus in the glomerulus, arteriole, and / or artery); 3) any history or signs of severe chronic active or recurrent infection within 6 months prior to screening, or screening laboratory evidence consistent with severe chronic active or recurrent infection requiring treatment with antibiotics, antivirals, or antifungals; 4) a positive Coombs test at the time of TMA diagnosis; 5) a history of nephropathy with IV Any infection treated with antibiotics (within 30 days of screening) or oral antibiotics (within 14 days of screening), antivirals, or antifungals; 6) positive nasopharyngeal swab for Neisseria meningitidis at screening or previous history of meningitis; 7) history of meningococcal infection; 8) untreated tuberculosis; 9) HCV or HIV seropositivity; 10) history of splenectomy; 11) known hypersensitivity to penicillin antibiotics; 12) known or suspected immunodeficiency, including hereditary complement deficiencies; 13) history of transplantation, including heart, lung, small bowel, pancreatic, liver, kidney, bone marrow, or stem cell transplantation; 14) absolute neutrophil count < 1000 cells / mm 3 ;15) eGFR < 30 mL / min / 1.73 m 2 , except for subjects who required acute dialysis within 4 weeks of screening for a new diagnosis of SLE-TMA; 16) Platelet count < 30,000 / mm 3; 17) History of drug or alcohol abuse within 1 year of screening; 18) Before screening < 19) Receipt of any type of live attenuated vaccine within 1 month, or plan to receive any such live attenuated vaccine during treatment; 20) Use of IVIG within 7 days of starting anti-C5-FH fusion protein; 21) Use of rituximab within 3 months of starting anti-C5-FH fusion protein; 22) Use of belimumab within 3 months of starting anti-C5-FH fusion protein; 23) History of malignancy, except for adequately treated basal cell carcinoma or carcinoma in situ of the cervix; 24) Any pregnant or breastfeeding woman, or any woman who plans to become pregnant during or shortly after treatment; 25) Any condition that may impair treatment, pose a safety risk to the subject, or may interfere with the interpretation of treatment results, such as active symptomatic COVID infection; 26) QT interval after heart rate correction by Fridericia's formula (QTcF) > 450 milliseconds (msec) for men, or > 470 for women, based on a single or average QTcF value of three ECGs obtained within 3 minutes. msec; and 27) unwillingness to receive vaccinations against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae.

[0151] Treatment options for C3G and / or IgAN

[0152] In some embodiments, a method of treating C3G in a human subject (e.g., a complement inhibitor-naive human subject) is provided, comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH), the fusion protein comprising i) an antibody portion that specifically binds to human C5 (e.g., a full-length anti-human C5 antibody, such as FMEH-IgG4-PLA) and ii) FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as 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 at a dosage of about 60 to about 3600 mg (including, for example, any one 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 at a single dose (such as a dosage of about 60 mg to about 1200 mg). In some embodiments, the fusion protein is administered at 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 at multiple doses. In some embodiments, the fusion protein is administered weekly or biweekly, such as at a dosage of about 600 mg to about 2880 mg. In some embodiments, the fusion protein is administered through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein with one or more (e.g., one) initial dose (e.g., about 600 mg to about 3600 mg or about 1200 mg to about 3600 mg per dose, such as IV administration), the maintenance phase comprising administering the fusion protein (e.g., once a week or once every two weeks) for 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). In some embodiments, two or more maintenance doses of the fusion protein are administered once a week, such as 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 at about 720 mg SC to about 1440 mg SC. In some embodiments, two or more maintenance doses of the fusion protein are administered once every two weeks, such as at about 1800 mg to about 2880 mg.In some embodiments, two or more maintenance doses of the fusion protein are each administered at about 1920 mg SC to about 2880 mg SC or at about 1800 mg SC to about 2400 mg SC every two weeks. In some embodiments, the maintenance phase is at least about 48 weeks. In some embodiments, an initial dosing phase comprises administering to a subject a dose of about 600 mg to about 3600 mg (e.g., IV) once weekly for one or more doses (e.g., only one dose), followed by a maintenance phase comprising administering the fusion protein at about 720 mg to about 2880 mg (e.g., SC) or about 600 mg to about 1200 mg (e.g., IV) once weekly or once every two weeks for at least two doses, e.g., for at least about 48 weeks (e.g., 48, 49, 50, 51, 52, 54, 56, 58, 60 weeks or longer, such as 48 weeks) for weekly maintenance dosing, or for at least about 49 weeks (e.g., 49, 51, 53, 55, 57, 59, 61, 63, 65 weeks or longer, such as 49 weeks) for biweekly maintenance dosing. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an 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., two) 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 in 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 to the abdominal wall using standard techniques for SC administration.

[0153] In some embodiments, a method of treating IgAN in a human subject (e.g., a complement inhibitor-naive human subject) is provided, comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH), the fusion protein comprising i) an antibody portion that specifically binds to human C5 (e.g., a full-length anti-human C5 antibody, such as FMEH-IgG4-PLA) and ii) FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as 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 at a dosage of about 60 to about 3600 mg (including, for example, any one 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 at a single dose (such as a dosage of about 60 mg to about 1200 mg). In some embodiments, the fusion protein is administered at 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 at multiple doses. In some embodiments, the fusion protein is administered weekly or biweekly, such as at a dosage of about 600 mg to about 2880 mg. In some embodiments, the fusion protein is administered through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein with one or more (e.g., one) initial dose (e.g., about 600 mg to about 3600 mg or about 1200 mg to about 3600 mg per dose, such as IV administration), the maintenance phase comprising administering the fusion protein (e.g., once a week or once every two weeks) for 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). In some embodiments, two or more maintenance doses of the fusion protein are administered once a week, such as about 600 mg to about 1440 mg per dose. In some embodiments, two or more maintenance doses of the fusion protein are each administered once weekly at about 600 mg IV to about 1200 mg IV or at about 720 mg SC to about 1440 mg SC.In some embodiments, two or more maintenance doses of the fusion protein are administered once every two weeks, such as at about 1800 mg to about 2880 mg. In some embodiments, two or more maintenance doses of the fusion protein are each administered once every two weeks at about 1920 mg SC to about 2880 mg SC or at about 1800 mg SC to about 2400 mg SC. In some embodiments, the maintenance phase is at least about 48 weeks. In some embodiments, an initial dosing phase comprises administering to a subject a dose of about 600 mg to about 3600 mg (e.g., IV) once weekly for one or more doses (e.g., only one dose), followed by a maintenance phase comprising administering the fusion protein at about 720 mg to about 2880 mg (e.g., SC) or about 600 mg to about 1200 mg (e.g., IV) once weekly or once every two weeks for at least two doses, e.g., for at least about 48 weeks (e.g., 48, 49, 50, 51, 52, 54, 56, 58, 60 weeks or longer, such as 48 weeks) for weekly maintenance dosing, or for at least about 49 weeks (e.g., 49, 51, 53, 55, 57, 59, 61, 63, 65 weeks or longer, such as 49 weeks) for biweekly maintenance dosing. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an 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., two) 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 in a pharmaceutical composition, wherein the pharmaceutical composition comprises 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 to the abdominal wall using standard techniques for SC administration.

[0154] In some embodiments, a method of treating C3G or IgAN in a human subject (e.g., a complement inhibitor naive human subject) is provided, the method comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH) comprising i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, such as FMEH-IgG4-PLA) and ii) FH or a functional fragment thereof (e.g., the SCR1-5 domains of FH, such as SEQ ID NO: 85), wherein the fusion protein is administered through an initial phase comprising administering the drug IV to the human subject 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) followed by a maintenance phase. In some embodiments, the fusion protein is administered IV to about 3600 mg IV, the maintenance phase comprising administering the fusion protein starting on day 8 for two or more (e.g., 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 weeks or longer) maintenance doses; and wherein the maintenance phase comprises administering the fusion protein at a first maintenance dose (e.g., weekly or biweekly) for a first maintenance phase time period (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 40, 42, 44 weeks or longer) followed by administering the fusion protein at a second maintenance dose (e.g., weekly or biweekly) for a second maintenance phase time period (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 40, 42, 44, 46, 48, 50 weeks or longer). 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, such as 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 are any one of 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 IV or SC of the initial dose, the first maintenance dose and / or the second maintenance dose is used. In some embodiments, the fusion protein of the first maintenance dose and / or the second maintenance dose is used with 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 with 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 second maintenance phase time period is longer than the first maintenance phase time period. In some embodiments, the fusion protein of the first maintenance dose is used once a week with about 720 mg SC or about 600 mg IV, and the fusion protein of the second maintenance dose is used once a week with about 1440 mg SC or about 1200 mg IV. In some embodiments, the first maintenance phase time period is about 4 weeks, and the second maintenance phase time period is at least about 44 weeks. In some embodiments, the initial stage includes administering the fusion protein with an initial dose of about 600 mg IV to about 1200 mg IV (e.g., about 1200 mg IV) on the 1st day, and wherein the maintenance phase includes: i) administering the fusion protein once a week with the first maintenance dose of about 720 mg SC or about 600 mg IV from the 8th day and continuing about 4 weeks, subsequently ii) administering the fusion protein once a week with the second maintenance dose of about 1440 mg SC or about 1200 mg IV from the 36th day and continuing about 44 weeks. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an amino acid sequence of SEQ ID NO: 90.In some embodiments, FH or its functional fragment is fused to the C-terminus of one or two (e.g., two) heavy chains of an anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH or its functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises about 120 mg / mL of fusion protein, sodium phosphate, sodium chloride, L-Lys-HCL, and polysorbate 80, with 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 can be administered without further preparation and is administered to the abdominal wall using standard techniques for SC administration.

[0155] In some embodiments, a method of treating C3G or IgAN in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through 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 maintenance phase comprising (a) administering the fusion protein once weekly for about 4 weeks starting on day 8 at a first maintenance dose of about 720 mg SC or about 600 mg IV, followed by (b) administering the fusion protein once weekly for about 4 weeks starting on day 36 at a first maintenance dose of about 1440 mg SC or about 1200 mg IV. The second maintenance dose of IV is administered once weekly for about 44 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in 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 to the abdominal wall using standard techniques for SC administration.

[0156] In some embodiments, a method of treating C3G or IgAN in a human subject (e.g., a complement inhibitor naive human subject) is provided, the method comprising administering to the human subject an effective amount of a fusion protein (e.g., any of the anti-C5-FH fusion proteins described herein, such as FMEH-IgG4-PLA-FH) comprising i) an anti-human C5 antibody portion (e.g., an anti-human C5 full-length antibody, such as FMEH-IgG4-PLA) and ii) FH or a functional fragment thereof (e.g., the SCR1-5 domains of FH, such as SEQ ID NO: 85), wherein the fusion protein is administered through an initial phase comprising administering to the human subject 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 followed by a maintenance phase. In some embodiments, the fusion protein is administered at an initial dose of about 600 mg IV to about 1200 mg IV (e.g., about 1200 mg IV), the maintenance phase comprising administering the fusion protein starting on day 8 at a maintenance dose of: (a) about 600 mg IV to about 1200 mg IV once a week for at least about 48 weeks; (b) about 720 mg SC to about 1440 mg SC once a week for at least about 48 weeks; (c) about 1920 mg SC to about 2880 mg SC once every two weeks for at least about 49 weeks; or (d) about 1800 mg SC to about 2400 mg SC once every two weeks for at least about 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 wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 720 mg SC or about 600 mg IV once a week for about 48 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 wherein 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 beginning 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 wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every two weeks beginning on day 8 for about 49 weeks.In some embodiments, the initial phase comprises administering the fusion protein at an initial dose of about 600 mg IV on day 1, and wherein the maintenance phase comprises administering the fusion protein once weekly for about 48 weeks starting on day 8 at a maintenance dose of about 720 mg SC. In some embodiments, the anti-C5 antibody portion comprises a VH-CDR1 having the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises a VH having the amino acid sequence of SEQ ID NO: 87 and a VL having 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 having an amino acid sequence of SEQ ID NO: 120 and ii) a light chain having an 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 two (e.g., two) heavy chains of the anti-C5 full-length antibody. In some embodiments, the heavy chain fused to FH or a functional fragment thereof comprises an amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition comprising approximately 120 mg / mL of the fusion protein, sodium phosphate, sodium chloride, L-Lys-HCl, and polysorbate 80 at a pH of approximately 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 preparation and is administered to the abdominal wall using standard techniques for SC administration.

[0157] In some embodiments, a method of treating C3G or IgAN in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV on day 1, the maintenance phase comprising administering the fusion protein once weekly starting on day 8 at a maintenance dose of about 720 mg SC or about 600 mg IV for about 48 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: NO: 89 amino acid sequence. In some embodiments, the fusion protein is formulated in 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 to the abdominal wall using standard techniques for SC administration.

[0158] In some embodiments, a method of treating C3G or IgAN in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 600 mg IV on day 1, the maintenance phase comprising administering the fusion protein once weekly starting on day 8 at a maintenance dose of about 720 mg SC for about 48 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises SEQ ID NO: 89 amino acid sequence. In some embodiments, the fusion protein is formulated in 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 to the abdominal wall using standard techniques for SC administration.

[0159] In some embodiments, a method of treating C3G or IgAN in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through an initial phase followed by a maintenance phase, the initial phase comprising administering the fusion protein at an initial dose of about 1200 mg IV on day 1, the maintenance phase comprising administering the fusion protein once weekly starting on day 8 at a maintenance dose of about 1440 mg SC or about 1200 mg IV for about 48 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 121. NO:90 amino acid sequence; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises 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 to the abdominal wall using standard techniques for SC administration.

[0160] In some embodiments, a method of treating C3G or IgAN in a human individual (e.g., a complement inhibitor naive human individual) is provided, the method comprising 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 through 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 a maintenance phase comprising administering the fusion protein once every two weeks starting on day 8 at a maintenance dose of about 1920 mg SC to about 2880 mg SC for about 49 weeks; wherein the first FH functional fragment is fused to the C-terminus of the first heavy chain of the anti-human C5 full-length antibody, and the second FH functional fragment is fused to the C-terminus of the second heavy chain of the anti-human C5 full-length antibody; wherein each heavy chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 120, and each light chain of the anti-human C5 full-length antibody comprises the amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the FH functional fragment comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises 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 to the abdominal wall using standard techniques for SC administration.

[0161] C3G

[0162] Complement 3 glomerulopathy (C3G) is a rare kidney disease (estimated to be 2-3 cases per 1,000,000 people) with two forms: dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). C3G is characterized by deposition of C3 in the filtering units (glomeruli) of the kidney, suggesting that complement is involved in causing kidney damage. C3 glomerulopathy is characterized by evidence of alternative complement activation based on C3 deposition in the glomeruli. Genetic lesions that lead to complement regulation defects in these patients have been described, including mutations in complement factor H. Common signs and symptoms of C3G (DDD or C3GN) associated with loss of normal renal function include the following: blood in the urine (hematuria), excess protein in the urine (proteinuria), acute nephritic syndrome or nephrotic syndrome, low levels of the complement component C3, swelling (edema), gout, recurrent infections, decreased urine output (oliguria), high blood pressure, fatigue and decreased alertness, drusen, abnormal distribution of fat under the skin (acquired partial lipodystrophy), and any combination thereof. C3G (DDD or C3GN) can also lead to renal failure, with signs and symptoms including loss of appetite, nausea and vomiting, difficulty sleeping, dry, itchy skin, and nocturnal muscle cramps. There is no approved treatment for patients with C3 glomerulopathy (including C3GN). Without treatment, C3G always leads to renal failure, and kidney transplantation is usually the only option. Even after transplantation, the new kidney will often fail due to recurrence of the disease.

[0163] In some embodiments, the methods of treating C3G described herein can prevent (e.g., prevent at least about any of a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% chance), delay (e.g., delay for at least about any of 1, 2, 3, 6, 12, 18, 24, 30, 36, 42, 48, 52 months or longer), or reduce (e.g., reduce at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) the severity of one or more of the signs and symptoms of C3G discussed above, including, but not limited to, hematuria, proteinuria, nephritic syndrome, renal failure, drusen. In some embodiments, the methods for treating C3G described herein can improve (e.g., reduce at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) one or more renal pathologies, including but not limited to proteinuria, hematuria, crescents and fibrin deposition, C3 deposition, capillary endocellularity, and mesangial cellularity. In some embodiments, the methods for treating C3G described herein can reduce (e.g., reduce at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) one or more of the following: C3 deposition score, C3b activity, free serum C5 level, eGFR, urine protein to creatinine ratio (UPCR; calculated as the percentage change in protein (Pr) / creatinine (Cr)), and RBC lysis. In some embodiments, the methods of treating C3G described herein can improve (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) quality of life, such as assessed by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and the Kidney Disease Quality of Life (KDQoL) scale and / or histology and histopathology of a renal biopsy.

[0164] IgAN

[0165] IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. 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. Aggregates of immune complexes are formed in situ and / or deposited in the glomerular mesangium. This promotes the proliferation of mesangial cells, increases the synthesis of extracellular matrix proteins, cytokines, and chemokines, and allows immune cells to infiltrate into surrounding tissues. Therefore, disease progression involves (1) the production of Gd-IgA1; (2) its recognition by anti-glycan autoantibodies; (3) its formation of immune complexes in the kidney; and (4) activation of mesangial cells. See, for example, Penfold et al., Int. J. Nephrol. and Renovascular Dis. 11, pp. 137-148 (2017).

[0166] IgAN primarily occurs in subjects in their 20s and 30s. Patients present with a range of symptoms, typically including microhematuria or macrohematuria and increased urinary protein excretion. Patients may also present with hypertension due to ongoing renal damage. Current treatments offer only supportive care, including administration of maximum tolerated doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or immunosuppressive drugs, the benefits of which are largely offset by adverse reactions. Ultimately, 30%-40% of patients will develop end-stage renal disease (ESRD) within 20-30 years of IgAN diagnosis. During this period, in addition to decreased renal function, patients also experience many symptoms that significantly reduce their quality of life. Patients with IgAN typically 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.

[0167] In some embodiments, the methods of treating IgAN described herein can prevent (e.g., prevent at least about any of a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% chance), delay (e.g., delay for at least about any of 1, 2, 3, 6, 12, 18, 24, 30, 36, 42, 48, 52 months or longer), or reduce (e.g., reduce at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) the severity of one or more of the signs and symptoms of IgAN discussed above, including, but not limited to, proteinuria, hematuria, back pain, edema, hypertension, and complications (e.g., high cholesterol, acute renal failure, chronic renal failure, nephrotic syndrome).In some embodiments, the methods of treating IgAN described herein can achieve one or more of the following: i) reduction (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) of renal inflammation and / or fibrosis; ii) reduction (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) of Gd-IgA1 production; iii) reduction (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) of the occurrence of hematuria; iv) stabilization (e.g., by no more than about 30%, 20%, 10%, 5%, or less) of renal inflammation and / or fibrosis; eGFR; v) delay (e.g., by at least about any of 1, 2, 3, 6, 12, 18, 24, 30, 36, 42, 48, 52 months or longer) the onset of ESRD; vi) reduce (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) the number of acute attacks of IgA nephropathy-related disease; vii) reduce (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) proteinuria; viii) reduce (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) fatigue; ix) inhibit (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) fatigue; , 90% or 100%) mesangial cell activation; x) reducing (e.g., reducing by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) the activation of mesangial cells in contact with IgA immune complexes; xi) reducing (e.g., reducing by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) the expression of endothelin 1 (ET-1) and ET-RA in the kidney; and xii) improving (e.g., improving by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%) renal function and / or renal pathology scores. In some embodiments, the methods of treating IgAN described herein can reduce (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) one or more of: C3 deposition score, C3b activity, free serum C5 levels, eGFR, UPCR, and RBC lysis.In some embodiments, the methods of treating IgAN described herein can improve (e.g., by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%) quality of life, such as assessed by the FACIT-Fatigue score and KDQoL scale and / or histology and histopathology of renal biopsy.

[0168] In some embodiments, the efficacy of the methods described herein for treating C3G or IgAN 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, change from baseline in C3b activity assay, change from baseline in serum and urine factor H levels, change from baseline in urine MCP-1, C3a, C5a, properdin, or C5b-9 levels, and / or change from baseline in 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) changes in histology and histopathology in subjects undergoing repeat renal biopsies. Such methods are known in the art. In some embodiments, changes from baseline in markers of alternative complement pathway involvement, e.g., C3, C3d, C3c, C3adesArg, C5, C5a, C5b-9, C5adesArg, and other markers of inflammation, can be assessed in plasma / serum or urine during the treatment period.

[0169] In some embodiments, the methods of treating C3G or IgAN described herein further comprise selecting a human subject suitable for such treatment (e.g., a complement inhibitor naive human subject). In some embodiments, the human subject to be treated has previously been vaccinated against one or all of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. In some embodiments, the human subject further receives antibiotic prophylaxis during treatment. In some embodiments, individuals who have not received the above-mentioned vaccinations will begin receiving prophylactic antibiotics no later than the first dose of anti-C5-FH fusion protein and will continue to receive the antibiotic prophylaxis until 2 weeks after vaccination. In some embodiments, the age of the human subject is from about 18 to about 75 years old. In some embodiments, the human subject meets one or more of the following criteria: 1) weight > 35 kilograms (kg) at screening; 2) body mass index (BMI) < 35 kilograms / square meter (kg / m 2); 3) UPCR >1.5 grams / 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 throughout the treatment period; 6) vaccination; and 7) ability to provide informed consent. In some embodiments, C3G or IgAN is confirmed by biopsy of the human subject to be treated. In some embodiments, the human subject is on a stable regimen of angiotensin-converting enzyme or angiotensin blocker for 12 weeks and / or a sodium glucose cotransporter-2 (SGLT2) inhibitor for 6 weeks at screening.

[0170] In some embodiments, the methods of treating C3G or IgAN described herein further comprise excluding human subjects who are not suitable for such treatment. In some embodiments, human subjects who are not suitable for the treatment methods 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 severe chronic active or recurrent infection, such as those requiring or currently being treated with antibiotics, antivirals, or antifungals; 3) history of infection with an encapsulated organism; 4) history of untreated tuberculosis; 5) known hypersensitivity to penicillin antibiotics; 6) known or suspected immunodeficiency, including hereditary complement deficiencies; 7) seropositivity for hepatitis C virus (HCV) RNA or human immunodeficiency virus (HIV) at screening; 8) history of bone marrow or stem cell transplantation; 9) absolute neutrophil count (ANC) <500 cells / microliter (cells / μL); 10) eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula <30 mL / min / 1.73 m 2 ); 11) presence of crescentic forms in >50 percent (%) of glomeruli assessed on renal biopsy; 12) nephrotic syndrome; 13) rapidly progressive glomerulonephritis, defined as an eGFR falling to >30 mL / min / 1.73 m2 within 24 weeks prior to the screening visit. 2; 14) receiving renal replacement therapy or expected to need renal replacement therapy during the treatment duration; 15) a history of drug or alcohol abuse within 1 year of screening; 16) receiving any type of live attenuated vaccine < 4 weeks before screening, or planning to receive any such live attenuated vaccine during treatment; 17) using rituximab or any previous use of complement inhibitors in the past 12 weeks; 18) using >10 mg / day of systemic corticosteroids (prednisone or equivalent) or use of immunosuppressants (e.g., mycophenolate mofetil, hydroxychloroquine, cyclosporine, etc.) within 3 months prior to screening; 19) history of malignancy, except for adequately treated basal cell carcinoma or carcinoma in situ of the cervix; 20) any pregnant or breastfeeding woman, or any woman planning to become pregnant during the treatment period; 21) QT interval corrected for heart rate by the Fridericia formula (QTcF) based on a single or average QTcF value of three ECGs obtained at 3-minute intervals >450 milliseconds (msec) for men and >470 msec for women; 22) diagnosis of secondary IgAN (e.g., Henoch Schönlein purpura, IgA vasculitis); and 23) use of any complement inhibitors.

[0171] The anti-C5-FH fusion protein and its components are described in more detail below.

[0172] Anti-C5-fH fusion protein

[0173] Any anti-C5-FH fusion protein and anti-C5 antibody portion (e.g., pH-dependent anti-C5 antibody portion) described in US20220204602, US20220177556, US11578137, and WO2020219922 may be used herein, the contents of each of which are incorporated herein by reference in their entirety.

[0174] The methods described herein utilize a fusion protein comprising an anti-C5 antibody portion (such as any 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, FH or a functional fragment thereof is fused to one or both heavy chains (e.g., at the C-terminus of the heavy chain) of the anti-C5 full-length antibody. 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 one of SEQ ID NOs: 32, 33, and 61. In some embodiments, the IgG4 Fc fragment comprising PLA mutations comprises the amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the FH fragment inhibits C3 activation. In some embodiments, the functional fragment of FH comprises the short consensus repeat (SCR) domains 1-5 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.

[0175] In some embodiments, the fusion protein comprises an anti-C5 antibody portion (such as any 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 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.

[0176] In some embodiments, the fusion protein comprises an anti-C5 antibody portion and FH or a functional fragment thereof, wherein the anti-C5 antibody portion is pH-sensitive or pH-dependent (such as any 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 a higher affinity at a neutral pH (e.g., about pH 7.4) than at an acidic pH (e.g., about pH 5.8). In some embodiments, the pH-dependent anti-C5 antibody portion has a binding affinity for C5 (e.g., human C5) at about pH 7.4 that is at least about 3 times (such as at least about 4, 5, 6, 7, 8, 9, 10 times, or more) higher than the pH-dependent anti-C5 antibody portion has a binding affinity for 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 comprising 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.

[0177] In some embodiments, the fusion protein comprises an anti-C5 antibody portion and FH or a functional fragment thereof, wherein the anti-C5 antibody portion is pH-sensitive or pH-dependent (such as any of the pH-sensitive or pH-dependent anti-C5 antibodies described herein), for example, binds to C5 (e.g., human C5) with a higher affinity at pH 7.4 than at pH 5.8, 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 FH or a functional fragment thereof, wherein the anti-C5 antibody portion is pH-sensitive or pH-dependent (such as any of the pH-sensitive or pH-dependent anti-C5 antibodies or antigen-binding fragments thereof described herein), for example, binds to C5 (e.g., human C5) with a higher affinity at pH 7.4 than at pH 5.8, and wherein FH or a functional fragment thereof comprises the SCR1-5 domain of FH. In some embodiments, the fusion protein comprises an anti-C5 antibody portion and FH or a functional fragment thereof, wherein the anti-C5 antibody portion is pH-sensitive or pH-dependent (such as any of the pH-sensitive or pH-dependent anti-C5 antibodies described herein), for example, binds to C5 (e.g., human C5) with higher affinity at pH 7.4 than at pH 5.8, wherein the anti-C5 antibody portion comprises an IgG4 Fc fragment (e.g., an IgG4 Fc fragment comprising a PLA mutation), and wherein FH or a 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.

[0178] In some embodiments, the fusion protein comprises an anti-C5 antibody portion (such as any of the anti-C5 antibodies or antigen-binding fragments thereof described herein) and FH or a functional fragment thereof, wherein the anti-C5 antibody portion comprises a histidine substitution in one or more CDR regions thereof (such as any 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 FH or a functional fragment thereof, wherein the anti-C5 antibody portion comprises a histidine substitution in one or more CDR regions thereof (such as any 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 FH or a functional fragment thereof, wherein the anti-C5 antibody portion comprises a histidine substitution in one or more CDR regions thereof (such as any of the histidine-containing anti-C5 antibodies or antigen-binding fragments thereof described herein), and wherein the FH or a functional fragment thereof comprises the SCR1-5 domain of FH. In some embodiments, the fusion protein comprises an anti-C5 antibody portion and FH or a functional fragment thereof, wherein the anti-C5 portion comprises a histidine substitution in one or more CDR regions thereof (such as any of the histidine-containing anti-C5 antibodies described herein), wherein the anti-C5 antibody portion comprises an IgG4 Fc fragment (e.g., an IgG4 Fc fragment comprising a PLA mutation), and wherein FH or a 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.

[0179] 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 of the anti-C5 antibodies or antigen-binding fragments thereof described herein) via a linker (e.g., a peptide linker), such as via a linker to the C-terminus of the anti-C5 antibody portion. Any suitable peptide linker can 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 an anti-C5 antibody portion (e.g., any of the anti-C5 antibodies or antigen-binding fragments thereof described herein), such as 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 to the C-terminus of one or both heavy chains of an anti-C5 full-length antibody, directly or via a peptide linker, such as 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 the 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 the second heavy chain of the anti-C5 full-length antibody.

[0180] In some embodiments, the fusion protein further comprises a signal peptide at the N-terminus of one or more polypeptide chains thereof. Any signal peptide suitable for protein / polypeptide export 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, the FH or a functional fragment thereof is fused (e.g., directly fused) to the C-terminus of one or two (e.g., two) 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 two VH or heavy chains and / or one or two VL or light chains (e.g., two heavy chains and two light chains) of the anti-C5 full-length antibody. In some embodiments, the signal peptide fused to the VH or heavy chain of the anti-C5 antibody or its antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 91. In some embodiments, the signal peptide fused to the VL or light chain of the anti-C5 antibody or its antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 92. In some embodiments, the signal peptide is cleaved in the form of a mature or secreted fusion protein. In some embodiments, the fusion protein does not comprise any signal peptide.

[0181] In some embodiments, a fusion protein is provided, which comprises 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, such as SEQ ID NO: 85), wherein the anti-C5 antibody portion comprises: (i) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 11; and (ii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 11. (iii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 17, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; (iv) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 20, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 24 (v) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 26, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 29;(vi) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 34, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; (vii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 37, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 38, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 39, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; (viii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 37, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 38, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 39, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10 and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; (ix) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 47, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 48, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; (x) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 52, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 53, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 54, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 55. a VH-CDR2 having the amino acid sequence of SEQ ID NO: 53, a VH-CDR3 having the amino acid sequence of SEQ ID NO: 54, a VL-CDR1 having the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 10;(xi) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 47, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; (xii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96; (xiii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96; (i) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 42, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 65, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 44, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; (ii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 42, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 65, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 44, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; (iii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 42, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 65, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 44, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; a VH-CDR1 having the amino acid sequence of SEQ ID NO: 52, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 68, a VH-CDR3 having the amino acid sequence of SEQ ID NO: 54, a VL-CDR1 having the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 10;(xvi) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; (xvii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96; (xviii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 95, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 97; NO: 94, a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 97; (xix) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 14, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96; (xx) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 17, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 18, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 19, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 20. NO: 4, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having the amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having the amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 96;(xxi) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 102, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96; (xxii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 26, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 105; (xxiii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 26, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 105 (xxiv) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 108, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 38, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 39, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96; (xxv) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 108, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 38, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 39, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96; (xxv) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 108, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 38, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 39, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 108, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 43, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 44, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9; and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96;(xxvi) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 48, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96; (xxvii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 53, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 54, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96; (xxviii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 53, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 54, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: (xxix) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 108, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 65, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 44, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96; or (xxx) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 108, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 65, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 44, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96. 86, a VH-CDR1 having the amino acid sequence of SEQ ID NO: 68, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 54, a VL-CDR1 having the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-C5 antibody portion comprises: (i) a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having the amino acid sequence of VL of SEQ ID NO: 98;(ii) a VH having an amino acid sequence of SEQ ID NO: 93 and a VL having an amino acid sequence of SEQ ID NO: 99; (iii) a VH having an amino acid sequence of SEQ ID NO: 101 and a VL having an amino acid sequence of SEQ ID NO: 95; (iv) a VH having an amino acid sequence of SEQ ID NO: 103 and a VL having an amino acid sequence of SEQ ID NO: 88; (v) a VH having an amino acid sequence of SEQ ID NO: 104 and a VL having an amino acid sequence of SEQ ID NO: 106; (vi) a VH having an amino acid sequence of SEQ ID NO: 107 and a VL having an amino acid sequence of SEQ ID NO: 95; (vii) a VH having an amino acid sequence of SEQ ID NO: 109 and a VL having an amino acid sequence of SEQ ID NO: 88; (viii) a VH having an amino acid sequence of SEQ ID NO: 110 and a VL having an amino acid sequence of SEQ ID NO: 88; (ix) a VH having an amino acid sequence of SEQ ID NO: 111 and a VL having an amino acid sequence of SEQ ID NO: 88 NO: 111 and a VL having an amino acid sequence of SEQ ID NO: 88; (x) a VH having an amino acid sequence of SEQ ID NO: 112 and a VL having an amino acid sequence of SEQ ID NO: 88; (xi) a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an amino acid sequence of SEQ ID NO: 88; (xii) a VH having an amino acid sequence of SEQ ID NO: 113 and a VL having an amino acid sequence of SEQ ID NO: 88; (xiii) a VH having an amino acid sequence of SEQ ID NO: 114 and a VL having an amino acid sequence of SEQ ID NO: 88; (xiv) a VH having an amino acid sequence of SEQ ID NO: 115 and a VL having an amino acid sequence of SEQ ID NO: 88;or (xv) a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having 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 a FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85), wherein the anti-C5 antibody portion comprises: (i) a VH-CDR1 having the amino acid sequence of SEQ ID NO: 47, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 10;or (ii) a VH-CDR1 having the amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 96. In some embodiments, a fusion protein is provided, which comprises 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, such as SEQ ID NO: 85), wherein the anti-C5 antibody portion comprises a VH having the amino acid sequence of SEQ ID NO: 87 and a VL having the amino acid sequence of SEQ ID NO: 88. In some embodiments, FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as 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, such as an Fc fragment comprising the amino acid sequence of any one 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, such as SEQ ID NO: 85) is fused (e.g., directly fused) to the C-terminus of one or two (e.g., two) heavy chains of the anti-C5 full-length antibody. In some embodiments, the anti-C5 full-length antibody comprises a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 120, 122, 124, and 126 and a light chain having the amino acid sequence of SEQ ID NO: 90. In some embodiments, the anti-C5 full-length antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 120 and a light chain having the amino acid sequence of SEQ ID NO: 90.

[0182] In some embodiments, a fusion protein is provided, which comprises an anti-C5 full-length antibody and FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85); wherein FH or a functional fragment thereof is fused (e.g., directly fused) to the C-terminus of one or two (e.g., two) heavy chains of the anti-C5 full-length antibody; and wherein the anti-C5 full-length antibody comprises: (i) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 47, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10; or (ii) a VH-CDR1 having an amino acid sequence of SEQ ID NO: 86, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-C5 antibody comprises a VH-CDR2 having an amino acid sequence of SEQ ID NO: 57, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 49, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 23, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an 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, such as SEQ ID NO: 85); wherein the FH or a functional fragment thereof is fused (e.g., directly fused) to the C-terminus of one or two (e.g., two) heavy chains of the anti-C5 full-length antibody; and wherein the anti-C5 full-length antibody comprises a VH having an amino acid sequence of SEQ ID NO: 87 and a VL having an amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-C5 full-length antibody comprises an Fc fragment having an amino acid sequence of SEQ ID NO: 61. In some embodiments, a fusion protein is provided, which comprises an anti-C5 full-length antibody and FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85); wherein FH or a functional fragment thereof is fused (e.g., directly fused) to the C-terminus of one or two (e.g., two) heavy chains of the anti-C5 full-length antibody; and wherein the anti-C5 full-length antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 120 and a light chain having the amino acid sequence of SEQ ID NO: 90.

[0183] 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 having 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, such as SEQ ID NO: 85) is fused (e.g., directly fused) to the C-terminus of one or two (e.g., two) heavy chains of the anti-C5 full-length antibody. In some embodiments, a fusion protein is provided that comprises 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, such as SEQ ID NO: 85); wherein FH or a functional fragment thereof is fused (e.g., directly fused) to the C-terminus of one heavy chain of the anti-C5 full-length antibody. In some embodiments, a fusion protein is provided, which comprises an anti-C5 full-length antibody and FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85); wherein FH or a functional fragment thereof is fused to the C-terminus of one heavy chain of the anti-C5 full-length antibody (e.g., directly fused); and wherein the anti-C5 full-length antibody comprises a heavy chain having an amino acid sequence of any one of SEQ ID NOs: 120, 122, 124 and 126 and a light chain having an amino acid sequence of SEQ ID NO: 90. In some embodiments, a fusion protein is provided, which comprises a first FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85), a second FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as 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 a functional fragment thereof is fused to the C-terminus of the first heavy chain of the anti-C5 full-length antibody (e.g., directly fused), and the second FH or a functional fragment thereof is fused to the C-terminus of the second heavy chain of the anti-C5 full-length antibody (e.g., directly fused). In some embodiments, a fusion protein is provided, which comprises a first FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85), a second FH or a functional fragment thereof (e.g., the SCR1-5 domain of FH, such as SEQ ID NO: 85), and an anti-C5 full-length antibody; wherein the first FH or a functional fragment thereof is fused to the C-terminus of the first heavy chain of the anti-C5 full-length antibody (e.g., directly fused), and the second FH or a functional fragment thereof is fused to the C-terminus of the second heavy chain of the anti-C5 full-length antibody (e.g., directly fused); and wherein the anti-C5 full-length antibody comprises a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 120, 122, 124 and 126 and a light chain having the amino acid sequence of SEQ ID NO: 90.

[0184] 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 the first heavy chain of the anti-C5 full-length antibody, and iii) a second functional fragment of FH fused to the C-terminus of the second heavy chain of the anti-C5 full-length antibody; wherein the anti-C5 full-length antibody comprises two heavy chains, each having an amino acid sequence of SEQ ID NO: 120, and two light chains, each having an amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the functional fragment of FH comprises an amino acid sequence of SEQ ID NO: 89. The 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 (such as both heavy chains and both light chains) of the anti-C5 full-length antibody. In some embodiments, a fusion protein is provided, which comprises i) an anti-C5 full-length antibody, ii) a first functional fragment of FH fused to the C-terminus of the first heavy chain of the anti-C5 full-length antibody, and iii) a second functional fragment of FH fused to the C-terminus of the second heavy chain of the anti-C5 full-length antibody; wherein the anti-C5 full-length antibody comprises two heavy chains, each having an amino acid sequence of SEQ ID NO: 119, and two light chains, each having an amino acid sequence of SEQ ID NO: 74; and wherein each heavy chain fused to the functional fragment of FH comprises the amino acid sequence of SEQ ID NO: 72.

[0185] 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 the first heavy chain of the anti-C5 full-length antibody, and iii) a second functional fragment of FH fused to the C-terminus of the second heavy chain of the anti-C5 full-length antibody; wherein the anti-C5 full-length antibody comprises two heavy chains, each having an amino acid sequence of SEQ ID NO: 122, and two light chains, each having an amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the functional fragment of FH comprises an 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 (such as both heavy chains and both light chains of the anti-C5 full-length antibody). In some embodiments, a fusion protein is provided, which comprises i) an anti-C5 full-length antibody, ii) a first functional fragment of FH fused to the C-terminus of the first heavy chain of the anti-C5 full-length antibody, and iii) a second functional fragment of FH fused to the C-terminus of the second heavy chain of the anti-C5 full-length antibody; wherein the anti-C5 full-length antibody comprises two heavy chains, each having an amino acid sequence of SEQ ID NO: 121, and two light chains, each having an amino acid sequence of SEQ ID NO: 74; and wherein each heavy chain fused to the functional fragment of FH comprises an amino acid sequence of SEQ ID NO: 76.

[0186] 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 having an amino acid sequence of SEQ ID NO: 124, and two light chains, each having an amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the functional fragment of FH comprises an 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 (such as both heavy chains and both light chains of the anti-C5 full-length antibody). In some embodiments, a fusion protein is provided, which comprises i) an anti-C5 full-length antibody, ii) a first functional fragment of FH fused to the C-terminus of the first heavy chain of the anti-C5 full-length antibody, and iii) a second functional fragment of FH fused to the C-terminus of the second heavy chain of the anti-C5 full-length antibody; wherein the anti-C5 full-length antibody comprises two heavy chains, each having an amino acid sequence of SEQ ID NO: 123, and two light chains, each having an amino acid sequence of SEQ ID NO: 74; and wherein each heavy chain fused to the functional fragment of FH comprises an amino acid sequence of SEQ ID NO: 78.

[0187] 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 having an amino acid sequence of SEQ ID NO: 126, and two light chains, each having an amino acid sequence of SEQ ID NO: 90; and wherein each heavy chain fused to the functional fragment of FH comprises an 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 (such as both heavy chains and both light chains of the anti-C5 full-length antibody). In some embodiments, a fusion protein is provided, which comprises i) an anti-C5 full-length antibody, ii) a first functional fragment of FH fused to the C-terminus of the first heavy chain of the anti-C5 full-length antibody, and iii) a second functional fragment of FH fused to the C-terminus of the second heavy chain of the anti-C5 full-length antibody; wherein the anti-C5 full-length antibody comprises two heavy chains, each having an amino acid sequence of SEQ ID NO: 125, and two light chains, each having an amino acid sequence of SEQ ID NO: 74; and wherein each heavy chain fused to the functional fragment of FH comprises an amino acid sequence of SEQ ID NO: 80.

[0188] Anti-C5 antibody part

[0189] The fusion protein described herein comprises an antibody portion that specifically binds to C5. In some embodiments, the anti-C5 antibody portion is a chimeric antibody. In other 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, such as 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 one of SEQ ID NOs: 32, 33, and 61, such as SEQ ID NO: 61. In some embodiments, the binding of the anti-C5 antibody portion to C5 is pH-dependent, and wherein 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, 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 an 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.

[0190] 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.

[0191] It will be understood that the anti-C5 antibody portions described herein can be derived from any of the anti-C5 antibodies or antibody fragments thereof discussed in more detail below.

[0192] 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; such as the pH in blood) than at a more acidic pH (e.g., about pH 5.8; such as the pH in endosomes). In some embodiments, the pH-dependent anti-C5 antibody portion is a variant of a humanized anti-C5 antibody (e.g., comprising one or more amino acid substitutions, such as conservative substitutions) comprising a VH having the amino acid sequence of SEQ ID NO: 2 and a VL having the amino acid sequence of SEQ ID NO: 7.

[0193] In some embodiments, binding of an anti-C5 antibody or antibody fragment to human C5 is associated with a reduction in C5a or C5b production and MAC formation in the complement activation pathway 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, component, or epitope of human C5; and binding of the anti-C5 antibody or antibody fragment to a relevant portion of human C5 is associated with a reduction in C5a or C5b production and MAC formation in an intact organism.

[0194] In some embodiments, the anti-C5 antibody or its antibody fragment is further conjugated to a protein, peptide or another compound. In some embodiments, the anti-C5 antibody or its antibody fragment is conjugated to a protein, peptide or another compound. In some embodiments, the protein, peptide or another compound to which the anti-C5 antibody or its antibody fragment 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 another compound to which the anti-C5 antibody or its antibody fragment is conjugated is an effector molecule (e.g., a cytotoxic molecule).

[0195] In various embodiments, any of the anti-C5 antibodies described herein, having any of the variable regions described herein, may 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 fragment of 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 an S108P mutation, an M308L mutation, and an N314A mutation relative to SEQ ID NO: 32. In some embodiments, the anti-C5 antibody comprises a human IgG4 Fc fragment having an S108P mutation, an M308L mutation, and an N314A mutation relative to SEQ ID NO: 32 (also referred to herein as having an IgG4 Fc "PLA" mutation). SEQ ID NO: 61 is an exemplary amino acid sequence of a human IgG4 Fc fragment having an S108P mutation, an M308L mutation, and an N314A mutation relative to SEQ ID NO: 32.

[0196] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10, or a variant thereof comprising up to 5 (e.g., 5, 4, 3, 2, or 1) amino acid variations (e.g., insertions, deletions, substitutions, such as conservative substitutions) in one or more CDRs.

[0197] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about 3 Variants comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions) thereof; and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 10, or a variant thereof comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions).

[0198] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10.

[0199] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96, or a variant thereof comprising up to 5 (e.g., 5, 4, 3, 2, or 1) amino acid variations (e.g., insertions, deletions, substitutions, such as conservative substitutions) in one or more CDRs.

[0200] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about 3 Variants comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions) thereof; and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 96 or a variant thereof comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions).

[0201] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96.

[0202] In some embodiments, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 2, or a variant thereof having 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 having the amino acid sequence of SEQ ID NO: 7, or a variant thereof having 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, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 2, and a VL having the amino acid sequence of SEQ ID NO: 7. In some embodiments, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 93, or a variant thereof having 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 having the amino acid sequence of SEQ ID NO: 95, or a variant thereof having 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, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having 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.

[0203] In some embodiments, the anti-C5 antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 2, or a variant thereof having at least about 80% (e.g., at least about 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 having the amino acid sequence of SEQ ID NO: 7, or a variant thereof having at least about 80% (e.g., at least about 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 having the amino acid sequence of SEQ ID NO: 2 and a light chain having the amino acid sequence of SEQ ID NO: 7; or ii) a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having 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 having the amino acid sequence of SEQ ID NO: 2 and a light chain having the amino acid sequence of SEQ ID NO: 7; or ii) a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having the amino acid sequence of SEQ ID NO: 95; and a human IgG4 Fc fragment having 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 having the amino acid sequence of SEQ ID NO: 2 and a light chain having the amino acid sequence of SEQ ID NO: 7; or ii) a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having the amino acid sequence of SEQ ID NO: 95; and a human IgG4 Fc fragment (having 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 having an S108P mutation, an M308L mutation, and an N314A 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 having the amino acid sequence of SEQ ID NO: 2 and a light chain having the amino acid sequence of SEQ ID NO: 7; or ii) a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having the amino acid sequence of SEQ ID NO: 95; and a human IgG4 Fc fragment (having the amino acid sequence of SEQ ID NO: 61) having an S108P mutation, an M308L mutation, and an N314A mutation relative to SEQ ID NO: 32.

[0204] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 11, or a variant thereof comprising up to 5 (e.g., 5, 4, 3, 2, or 1) amino acid variations (e.g., insertions, deletions, substitutions, e.g., conservative substitutions) in one or more CDRs.

[0205] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about 3 Variants comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions) thereof; and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 11 or a variant thereof comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions).

[0206] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 11.

[0207] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 97, or a variant thereof comprising up to 5 (e.g., 5, 4, 3, 2, or 1) amino acid variations (e.g., insertions, deletions, substitutions, such as conservative substitutions) in one or more CDRs.

[0208] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about 3 Variants comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions) thereof; and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 97 or a variant thereof comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions).

[0209] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 8, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 97.

[0210] In some embodiments, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 2, or a variant thereof having 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 having the amino acid sequence of SEQ ID NO: 13, or a variant thereof having 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, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 2, and a VL having the amino acid sequence of SEQ ID NO: 13. In some embodiments, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 93, or a variant thereof having 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 having the amino acid sequence of SEQ ID NO: 98, or a variant thereof having 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, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having 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.

[0211] In some embodiments, the anti-C5 antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 2, or a variant thereof having at least about 80% (e.g., at least about 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 having the amino acid sequence of SEQ ID NO: 13, or a variant thereof having at least about 80% (e.g., at least about 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 having the amino acid sequence of SEQ ID NO: 2 and a light chain having the amino acid sequence of SEQ ID NO: 13; or ii) a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having 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 having the amino acid sequence of SEQ ID NO: 2 and a light chain having the amino acid sequence of SEQ ID NO: 13; or ii) a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having the amino acid sequence of SEQ ID NO: 98; and a human IgG4 Fc fragment having 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 having the amino acid sequence of SEQ ID NO: 2 and a light chain having the amino acid sequence of SEQ ID NO: 13; or ii) a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having the amino acid sequence of SEQ ID NO: 98; and a human IgG4 Fc fragment (having 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 having an S108P mutation, an M308L mutation, and an N314A 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 having the amino acid sequence of SEQ ID NO: 2 and a light chain having the amino acid sequence of SEQ ID NO: 13; or ii) a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having the amino acid sequence of SEQ ID NO: 98; and a human IgG4 Fc fragment (having the amino acid sequence of SEQ ID NO: 61) having an S108P mutation, an M308L mutation, and an N314A mutation relative to SEQ ID NO: 32.

[0212] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 14, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10, or a variant thereof comprising up to 5 (e.g., 5, 4, 3, 2, or 1) amino acid variations (e.g., insertions, deletions, substitutions, such as conservative substitutions) in one or more CDRs.

[0213] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR1 having an amino acid sequence of SEQ ID NO: 14, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about 3 Variants comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions) thereof; and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 10, or a variant thereof comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions).

[0214] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 3, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 14, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 10.

[0215] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 14, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96, or a variant thereof comprising up to 5 (e.g., 5, 4, 3, 2, or 1) amino acid variations (e.g., insertions, deletions, substitutions, such as conservative substitutions) in one or more CDRs.

[0216] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR1 having an amino acid sequence of SEQ ID NO: 14, or a variant thereof comprising up to about 3 (such as any one of about 1, 2, or 3) amino acid substitutions (e.g., conservative substitutions); a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to about 3 Variants comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions) thereof; and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 96 or a variant thereof comprising at most about 3 (such as about any one of 1, 2 or 3) amino acid substitutions (e.g., conservative substitutions).

[0217] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises: a VH-CDR1 having an amino acid sequence of SEQ ID NO: 94, a VH-CDR2 having an amino acid sequence of SEQ ID NO: 4, a VH-CDR3 having an amino acid sequence of SEQ ID NO: 5, a VL-CDR1 having an amino acid sequence of SEQ ID NO: 14, a VL-CDR2 having an amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 having an amino acid sequence of SEQ ID NO: 96.

[0218] In some embodiments, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 2, or a variant thereof having 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 having the amino acid sequence of SEQ ID NO: 16, or a variant thereof having 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, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 2, and a VL having the amino acid sequence of SEQ ID NO: 16. In some embodiments, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 93, or a variant thereof having 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 having the amino acid sequence of SEQ ID NO: 99, or a variant thereof having 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, an anti-C5 antibody or antigen-binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 93 and a VL having 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.

[0219] In some embodiments, the anti-C5 antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 2, or a variant thereof having at least about 80% (e.g., at least about 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 having the amino acid sequence of SEQ ID NO: 16, or a variant thereof having at least about 80% (e.g., at least about 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 antibod...

Claims

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

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 method of claim 1 or 2, wherein the fusion protein is administered in the following manner: (i) intravenous (IV) or subcutaneous (SC); and / or (ii) at a dose of about 60 mg to about 3600 mg.

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

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

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

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

8. The method of claim 7, wherein: (i) the initial dose is from about 600 mg to about 3600 mg; (ii) IV administration of the one or more initial doses of the fusion protein; (iii) the initial phase comprises administering the fusion protein at an 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 once a week or once every two weeks; and / or (vi) the maintenance phase is at least about 4 weeks.

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

10. The method of any one of claims 7-9, wherein 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 wherein the maintenance phase comprises administering the fusion protein starting on day 8 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 every 2 weeks; iv) about 1800 mg SC to about 2400 mg SC every two weeks; or v) about 960 mg SC to about 2880 mg SC once every two weeks.

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

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

13. The method of claim 12, wherein 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 wherein the maintenance phase comprises administering the fusion protein starting on day 8 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 every two weeks for at least about 13 weeks; or iv) about 960 mg SC to about 2880 mg SC once every two weeks for at least about 13 weeks.

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

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

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

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

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

19. The method of claim 18, wherein 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 wherein the maintenance phase comprises: i) administering the fusion protein once weekly starting on day 8 at a maintenance dose of about 720 mg SC to about 1440 mg SC 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 two weeks for at least about 25 weeks starting on day 8; iii) administering the fusion protein once weekly starting on day 8 at a first maintenance dose of about 600 mg IV to about 1200 mg IV for a first maintenance phase, followed by administering the fusion protein once weekly at a second maintenance dose of about 720 mg SC to about 1440 mg SC for a second maintenance phase, wherein the maintenance phase is at least about 24 weeks; or iv) administering the fusion protein once weekly during a first maintenance phase starting on day 8 at a first maintenance dose of about 600 mg IV to about 1200 mg IV, followed by administering the fusion protein once every two weeks during a second maintenance phase at a second maintenance dose of about 1920 mg SC to about 2880 mg SC, wherein the maintenance phase is at least about 25 weeks.

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 wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 960 mg SC once weekly for about 24 weeks starting on day 8.

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

22. The method of claim 21, wherein 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 wherein the maintenance phase comprises administering the fusion protein starting on day 8 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 every two weeks for at least about 49 weeks; or iv) about 1800 mg SC to about 2400 mg SC once every two weeks for at least about 49 weeks.

23. The method of claim 22, (i) wherein the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and wherein the maintenance phase comprises administering the fusion protein once weekly starting on day 8 at a maintenance dose of about 720 mg SC or about 600 mg IV for about 48 weeks; (ii) wherein the initial phase comprises administering the fusion protein at an initial dose of about 1200 mg IV on day 1, and wherein the maintenance phase comprises administering the fusion protein once weekly starting on day 8 at a maintenance dose of about 1440 mg SC or about 1200 mg IV for about 48 weeks; (iii) wherein 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 wherein the maintenance phase comprises administering the fusion protein at a maintenance dose of about 1920 mg SC to about 2880 mg SC once every two weeks starting on day 8 for about 49 weeks; or (iv) wherein the initial phase comprises administering the fusion protein at an initial dose of about 600 mg IV on day 1, and wherein 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.

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

25. The method of any one of claims 1-24, wherein the anti-C5 antibody portion is a full-length antibody, Fab, Fab', F(ab)2, F(ab')2, scFv, or a combination thereof.

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

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

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

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

61.

30. The method of any one of claims 26-29, wherein the anti-C5 full-length antibody comprises a heavy chain and a light chain, and 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; (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.

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

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 the 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 the second heavy chain of the anti-C5 full-length antibody.

34. The method of claim 33, wherein: (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.

35. The method of any one of claims 1-34, wherein the fusion protein is formulated in a pharmaceutical composition, wherein the pharmaceutical composition comprises 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.

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