Treatment of complement-mediated diseases and disorders with C3B antibodies

Abstract

The present invention provides, inter alia, anti-C3b antibodies with increased specificity and potency, and methods of using same to treat C3 glomerulopathy and other complement-mediated diseases and disorders. The present invention provides, inter alia, anti-C3b antibodies and antibody fragments with increased specificity for C3b, and the therapeutic use of such antibodies in the effective treatment of complement-mediated diseases, such as C3 glomerulopathy, dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), wet age-related macular degeneration (wAMD), passive Heymann nephritis (NHP), and collagen antibody-induced arthritis (CAIA).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 376,305, filed September 20, 2022, which is incorporated herein by reference in its entirety.

[0002] Incorporation by reference of sequence listing This application is filed with an electronically filed Sequence Listing in XML format. The Sequence Listing file, named SVI-002WO1_SL.xml, was created on September 19, 2023, and is 25 kilobytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety. [Background technology]

[0003] The complement system is a part of the innate immune system that does not adapt to changes throughout the host's lifetime but is recruited and used by the adaptive immune system. For example, it assists, or complements, the ability of antibodies and phagocytes to eliminate pathogens. This elaborate regulatory pathway allows for a rapid response to pathogenic organisms while protecting host cells from destruction. More than 30 proteins and protein fragments comprise the complement system. These proteins act through opsonization (enhancing the phagocytosis of antigens), chemotaxis (attraction of macrophages and neutrophils), cytolysis (destruction of the membranes of foreign cells), and agglutination (clustering and binding of pathogens together).

[0004] The complement system has three pathways: classical, alternative, and lectin. In the alternative pathway, C3 present in the bloodstream is spontaneously cleaved at a slow rate into C3b and C3a. C3b is the larger of the two components and is considered an important part of the innate immune system. C3b is potent in opsonization, tagging pathogens, immune complexes (antigen-antibody), and apoptotic cells for phagocytosis. Furthermore, C3b plays a role in forming the C3 convertase when bound to factor B (C3bBb complex), or the C5 convertase when bound to C4b and C2b (C4b2b3b complex) or when an additional C3b molecule binds to the C3bBb complex (C3bBb3b complex). C3 glomerulopathy (C3G) is a rare disease characterized by the accumulation of complement factors in the glomerulus due to overactivation and abnormal regulation of the alternative complement pathway (AP). Abnormal regulation of complement AP can result from acquired or genetic abnormalities in complement regulatory proteins. Deposition of complement factors leads to glomerular inflammation, including proliferative glomerulonephritis. The most common diseases under the C3G umbrella are C3 glomerulonephritis (C3GN), characterized by mesangial, subendothelial, and intramembranous deposits, and dense deposit disease (DDD), characterized by dense deposits along the glomerular and tubular basement membranes. Summary of the Invention [Means for solving the problem]

[0005] The present invention provides, inter alia, anti-C3b antibodies and antibody fragments with increased specificity for C3b and therapeutic uses of such antibodies in the effective treatment of complement-mediated diseases such as C3 glomerulopathy, dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), wet age-related macular degeneration (wAMD), passive Heymann nephritis (NHP), and collagen antibody-induced arthritis (CAIA). In some embodiments, the anti-C3b antibody fragment is a VHH or a VHH fused to an Fc domain. As described herein, the present invention is based, in part, on the identification of a new class of anti-C3b-specific VHHs with significantly reduced cross-reactivity to C3. In particular, the anti-C3b VHHs of the present invention have high binding affinity for C3b (e.g., a C3b K of less than 50 nM). D These antibodies are characterized by their potency (e.g., having a greater than 10-fold selectivity for C3b over C3) and minimal cross-reactivity with C3 (e.g., having a greater than 10-fold selectivity for C3b over C3). This is significant because the C3b antibodies and VHHs of the present invention selectively bind to C3b, e.g., via a novel epitope on C3b, and can effectively target C3 convertase in diseased tissues without being saturated by high levels of circulating C3. As a result, the C3b antibodies of the present disclosure can be used at lower doses to achieve therapeutic efficacy compared to other anti-C3b or anti-C3 antibodies. This is demonstrated by the surprisingly high potency observed in functional assays compared to the prior art antibodies described herein. Thus, the present invention provides anti-C3b antibodies and VHHs of the present invention that (i) inhibit C3 convertase formation and mediate clearance of C3 deposits, (ii) target both solid-phase and fluid-phase alternative pathway C3 convertase activity, (iii) block C3b interaction with factor B (fB), (iv) inhibit alternative pathway (AP)-specific activity, (v) limit interference with natural regulators of C3 convertase, such as factor H (fH), DAF, and other inhibitors, (vi) possess favorable biophysical and pharmacokinetic properties to allow for extended therapeutic efficacy (biweekly or monthly administration), and / or (vii) inhibit stabilization of C3 convertase by C3bNef autoantibodies. The anti-C3b antibodies of the present invention promise more potent treatment of complement-mediated diseases and disorders.

[0006] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to complement component 3b (C3b) comprising an amino acid sequence at least 90% identical to SEQ ID NO:10.

[0007] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to complement component 3b (C3b) comprising an amino acid sequence at least 90% identical to SEQ ID NO:11.

[0008] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to complement component 3b (C3b) comprising an amino acid sequence at least 90% identical to SEQ ID NO:12.

[0009] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to complement component 3b (C3b) comprising an amino acid sequence at least 90% identical to SEQ ID NO:13.

[0010] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises NYHMG (SEQ ID NO: 16), CDR2 comprises TIIRTGETIYYADSVKG (SEQ ID NO: 17), and CDR3 comprises ATSGWNIKTVTPYEY (SEQ ID NO: 18).

[0011] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises GRTFSNY (SEQ ID NO: 19), CDR2 comprises IRTGET (SEQ ID NO: 20), and CDR3 comprises ATSGWNIKTVTPYEY (SEQ ID NO: 18).

[0012] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises NYHMG (SEQ ID NO: 16), CDR2 comprises TIIRTGKTIYYADSVKG (SEQ ID NO: 21), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

[0013] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises GRTFSNY (SEQ ID NO: 19), CDR2 comprises IRTGKT (SEQ ID NO: 23), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

[0014] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises NYHMG (SEQ ID NO: 16), CDR2 comprises TIIRTGTTIYYADSVKG (SEQ ID NO: 24), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

[0015] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to C3b, wherein the binding portion comprises three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises GRTFSNY (SEQ ID NO: 19), CDR2 comprises IRTGTT (SEQ ID NO: 25), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

[0016] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises NYHMG (SEQ ID NO: 16), CDR2 comprises TIIRHGTTIYYADSVKG (SEQ ID NO: 26), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

[0017] In one aspect, the present invention provides, inter alia, an antibody or antigen-binding fragment thereof that binds to C3b, wherein the binding portion comprises three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises GRTFSNY (SEQ ID NO: 19), CDR2 comprises IRHGTT (SEQ ID NO: 27), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

[0018] In some embodiments, the antibody or antigen-binding fragment thereof is a nanobody (VHH). In some embodiments, the antibody or antigen-binding fragment thereof is a VHH fused to an Fc domain (VHH-Fc). In some embodiments, the antibody or antigen-binding fragment thereof is an scFv. In some embodiments, the antibody or antigen-binding fragment thereof is a Fab. In some embodiments, the antibody or antigen-binding fragment thereof is an scFv fused to an Fc domain (scFv-Fc). In some embodiments, the antibody or antigen-binding fragment thereof is a bispecific antibody. In some embodiments, the antibody or antigen-binding fragment thereof is a minibody (scFv fused to the CH3 domain of Fc). In some embodiments, the antibody or antigen-binding fragment thereof is an scFab. In some embodiments, the antibody or antigen-binding fragment thereof is a heavy chain antibody.

[0019] In some embodiments, the VHH comprises SEQ ID NO: 10. In some embodiments, the VHH comprises SEQ ID NO: 11. In some embodiments, the VHH comprises SEQ ID NO: 12. In some embodiments, the VHH comprises SEQ ID NO: 13.

[0020] In some embodiments, the antibody or antigen-binding fragment thereof comprises an Fc domain. In some embodiments, the Fc domain is derived from IgG1. In some embodiments, the Fc domain is derived from IgG2. In some embodiments, the Fc domain is derived from IgG3. In some embodiments, the Fc domain is derived from IgG4.

[0021] In some embodiments, the Fc domain is modified. In some embodiments, the Fc domain is modified to increase in vivo half-life. In some embodiments, the Fc domain is modified to reduce in vivo immunogenicity.

[0022] In some embodiments, the Fc domain comprises a T307Q mutation according to EU index numbering. In some embodiments, the Fc domain comprises a Q331V mutation according to EU index numbering. In some embodiments, the Fc domain comprises an A378V mutation according to EU index numbering. In some embodiments, the Fc domain comprises T307Q and Q331V mutations according to EU index numbering. In some embodiments, the Fc domain comprises a T307Q mutation according to EU index numbering. In some embodiments, the Fc domain comprises T307Q and A378V mutations according to EU index numbering. In some embodiments, the Fc domain comprises Q331V and A378V mutations according to EU index numbering. In some embodiments, the Fc domain comprises T307Q, Q331V, and A378V mutations according to EU index numbering.

[0023] In some embodiments, the Fc domain comprises a S228P mutation according to EU index numbering.

[0024] In some embodiments, the Fc domain comprises a substitution at position F234 according to EU index numbering. In some embodiments, the Fc domain comprises a substitution at position L235 according to EU index numbering. In some embodiments, the Fc domain comprises a substitution at position D265 according to EU index numbering. In some embodiments, the Fc domain comprises substitutions at positions F234 and L235 according to EU index numbering. In some embodiments, the Fc domain comprises substitutions at positions F234 and D265 according to EU index numbering. In some embodiments, the Fc domain comprises substitutions at positions L235 and D265 according to EU index numbering. In some embodiments, the Fc domain comprises substitutions at positions F234, L235, and D265 according to EU index numbering.

[0025] In some embodiments, the substitution at position F234 is a hydrophobic amino acid. In some embodiments, the substitution at position F234 is a hydrophobic amino acid selected from the group consisting of alanine, valine, leucine, isoleucine, phenylalanine, and tryptophan, according to EU index numbering. In some embodiments, the substitution at position F234 is alanine. In some embodiments, the substitution at position F234 is valine. In some embodiments, the substitution at position F234 is leucine. In some embodiments, the substitution at position F234 is isoleucine. In some embodiments, the substitution at position F234 is phenylalanine. In some embodiments, the substitution at position F234 is tryptophan.

[0026] In some embodiments, the substitution at position L235 is an acidic amino acid according to EU index numbering. In some embodiments, the substitution at position L235 is an acidic amino acid selected from the group consisting of glutamic acid and aspartic acid. In some embodiments, the substitution at position L235 is glutamic acid. In some embodiments, the substitution at position L235 is aspartic acid.

[0027] In some embodiments, the substitution at position D265 is a non-polar amino acid according to EU index numbering. In some embodiments, the substitution at position D265 is a non-polar amino acid selected from the group consisting of alanine, cysteine, glycine, isoleucine, leucine, methionine, and valine. In some embodiments, the substitution at position D265 is alanine. In some embodiments, the substitution at position D265 is cysteine. In some embodiments, the substitution at position D265 is glycine. In some embodiments, the substitution at position D265 is isoleucine. In some embodiments, the substitution at position D265 is leucine. In some embodiments, the substitution at position D265 is methionine. In some embodiments, the substitution at position D265 is valine.

[0028] In some embodiments, the Fc domain comprises an F234V mutation according to EU index numbering. In some embodiments, the Fc domain comprises an L235E mutation according to EU index numbering. In some embodiments, the Fc domain comprises a D265G mutation according to EU index numbering. In some embodiments, the Fc domain comprises F234V, L235E, and D265G mutations according to EU index numbering. In some embodiments, the Fc domain comprises F234V, L235E, D265G, and S228P mutations according to EU index numbering.

[0029] In some embodiments, the Fc domain comprises T307Q, Q331V, A378V, F234V, L235E, D265G, and S228P mutations according to EU index numbering.

[0030] In some embodiments, the antibody or fragment thereof inhibits the formation of C3 convertase and / or C5 convertase, hi some embodiments, the antibody or fragment thereof does not bind to C3 protein.

[0031] In some embodiments, the antibody or fragment thereof inhibits the activity of a C3 convertase. In some embodiments, the antibody or fragment thereof targets solid-phase alternative pathway C3 convertase activity. In some embodiments, the antibody or fragment thereof targets solution-phase alternative pathway C3 convertase activity. In some embodiments, the antibody or fragment thereof targets both solid-phase and solution-phase alternative pathway C3 convertase activity.

[0032] In some embodiments, the Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence at least 88% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 14. In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO:14.

[0033] In some embodiments, the Fc domain comprises an amino acid sequence at least 80% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence at least 88% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence at least 92% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence at least 93% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence at least 94% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence at least 96% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence at least 97% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence at least 98% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 10. In some embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO:10.

[0034] In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 80% identical to SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 85% identical to SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 88% identical to SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 90% identical to SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 92% identical to SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 95% identical to SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 96% identical to SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 97% identical to SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 98% identical to SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 99% identical to SEQ ID NO:4. In some embodiments, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO:4.

[0035] In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 80% identical to SEQ ID NO:5. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 85% identical to SEQ ID NO:5. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 88% identical to SEQ ID NO:5. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 90% identical to SEQ ID NO:5. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 92% identical to SEQ ID NO:5. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 95% identical to SEQ ID NO:5. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 96% identical to SEQ ID NO:5. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 97% identical to SEQ ID NO:5. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 98% identical to SEQ ID NO:5. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 99% identical to SEQ ID NO:5. In some embodiments, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO:5.

[0036] In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 80% identical to SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 85% identical to SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 88% identical to SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 90% identical to SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 92% identical to SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 95% identical to SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 96% identical to SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 97% identical to SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 98% identical to SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 99% identical to SEQ ID NO:6. In some embodiments, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO:6.

[0037] In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 80% identical to SEQ ID NO:7. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 85% identical to SEQ ID NO:7. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 88% identical to SEQ ID NO:7. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 90% identical to SEQ ID NO:7. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 92% identical to SEQ ID NO:7. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 95% identical to SEQ ID NO:7. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 96% identical to SEQ ID NO:7. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 97% identical to SEQ ID NO:7. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 98% identical to SEQ ID NO:7. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 99% identical to SEQ ID NO:7. In some embodiments, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO:7.

[0038] In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 80% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 85% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 88% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 90% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 92% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 95% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 96% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 97% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 98% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 99% identical to SEQ ID NO:8. In some embodiments, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO:8.

[0039] In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 80% identical to SEQ ID NO:9. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 85% identical to SEQ ID NO:9. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 88% identical to SEQ ID NO:9. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 90% identical to SEQ ID NO:9. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 92% identical to SEQ ID NO:9. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 95% identical to SEQ ID NO:9. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 96% identical to SEQ ID NO:9. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 97% identical to SEQ ID NO:9. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 98% identical to SEQ ID NO:9. In some embodiments, the antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 99% identical to SEQ ID NO:9. In some embodiments, the antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO:9.

[0040] In one aspect, the present invention provides, inter alia, a nucleic acid encoding an antibody of the present invention or an antigen-binding thereof. In some embodiments, the nucleic acid is DNA. In some embodiments, the nucleic acid is cDNA. In some embodiments, the nucleic acid is RNA. In some embodiments, the nucleic acid is messenger RNA (mRNA).

[0041] In one aspect, the invention provides, inter alia, messenger RNA encoding an antibody of the invention or an antigen-binding thereof.

[0042] In one aspect, the invention provides a composition comprising, inter alia, a nucleic acid encoding an antibody or antigen-binding thereof of the invention, and a delivery vehicle.

[0043] In some embodiments, the delivery vehicle is an adeno-associated virus (AAV) vector. In some embodiments, the delivery vehicle is a lipid nanoparticle (LNP).

[0044] In one aspect, the present invention provides a composition comprising, inter alia, a lipid nanoparticle (LNP) encapsulating messenger RNA encoding an anti-C3b antibody or fragment thereof.

[0045] In one aspect, the invention provides, inter alia, a method of treating a complement-mediated disease or disorder, the method comprising administering a therapeutically effective amount of an antibody of the invention or an antibody or antigen-binding fragment thereof to a subject in need thereof.

[0046] In one aspect, the invention provides, inter alia, a method of treating a complement-mediated disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of an anti-C3b antibody or mRNA encoding the antibody or antigen-binding fragment thereof.

[0047] In one aspect, the present invention provides, inter alia, a method of treating a complement-mediated disease or disorder, the method comprising administering a therapeutically effective amount of an anti-C3b antibody or fragment thereof to a subject in need thereof.

[0048] In some embodiments, the complement-mediated disease or disorder is a disease or disorder associated with C glomerulopathy or C3 glomerulopathy. In some embodiments, the disease or disorder associated with C3 glomerulopathy is dense deposit disease (DDD). In some embodiments, the disease or disorder associated with C3 glomerulopathy is C3 glomerulonephritis (C3GN). In some embodiments, the complement-mediated disease or disorder is characterized by accumulation of the C3 component of complement in renal tissue. In some embodiments, the subject has symptomatic hematuria, proteinuria, acute kidney injury (AKI), or chronic kidney disease (CKD). In some embodiments, the complement-mediated disease or disorder is paroxysmal nocturnal hemoglobinuria, geographic atrophy, or autoimmune hemolytic anemia (AIHA). In some embodiments, the complement-mediated disease or disorder is age-related macular degeneration (AMD). In some embodiments, the complement-mediated disease or disorder is wet age-related macular degeneration (wAMD). In some embodiments, the complement-mediated disease or disorder is passive Heymann nephritis (PHN). [Brief explanation of the drawings]

[0049] The drawings are for purposes of illustration only and not limitation.

[0050] [Figure 1-1] Figures 1A and 1B are exemplary graphs showing the pharmacokinetic effects of Ab1 (repeated twice) and control Ab in cynomolgus monkeys. Figure 1A shows plasma levels of Ab1 and control Ab over a 20-day period. Figure 1B shows the percentage of remaining antibody for Ab1 and control Ab over a 20-day period. Figures 1C and 1D are exemplary graphs showing C3b antibody levels by capture of human and cynomolgus monkey C3b, respectively. Figure 1E is an exemplary graph showing plasma antibody levels in an ex vivo C3 deposition assay. Figure 1F is an exemplary graph showing inhibition of C3 deposition as measured by absorbance at 450 nm. [Figure 1-2] Same as above. [Figure 1-3] Same as above.

[0051] [Figure 2] FIG. 2 is an exemplary schematic diagram of the study design for evaluating the efficacy of anti-C3b antibodies in a mouse laser-induced choroidal neovascularization (CNV) model.

[0052] [Figure 3] Figures 3A and 3B are exemplary graphs showing the effect of C3b antibody on wAMD. Figure 3A is an exemplary graph showing FA leakage area after 7 days of treatment with a test antibody and a control. Figure 3B is an exemplary graph showing OCT area after 7 days of treatment with a test antibody and a control.

[0053] [Figure 4] FIG. 4 is an exemplary schematic diagram of a study design for evaluating the efficacy of anti-C3b antibodies in PHN.

[0054] [Figure 5-1] Figure 5A is an exemplary graph showing albumin:creatinine ratio as a urinary biomarker for measuring the effect of a subject C3b antibody on PHN, and Figure 5B is an exemplary graph showing total protein:creatinine level as a urinary biomarker for measuring the effect of a subject C3b antibody on PHN. [Figure 5-2] Same as above.

[0055] [Figure 6-1] Figure 6A is an exemplary study design schematic for testing the efficacy of C3b antibody in treating a mouse model of collagen antibody-induced arthritis. Figure 6B is an exemplary graph showing the percent change in hind paw volume at different doses of C3b antibody compared to positive and negative controls. [Figure 6-2] Same as above.

[0056] [Figure 7]FIG. 7 is an exemplary graph showing the inhibition of C3 convertase by Ab4, AMY-101, and LNP023 in healthy donors and a representative C3G patient, as measured by a C3 deposition assay. DETAILED DESCRIPTION OF THE INVENTION

[0057] definition In order that the present invention may be more readily understood, certain terms are first defined below. Additional definitions for these terms and other terms are set forth throughout the specification. Publications and other reference materials referred to herein to describe the background of the invention and to provide further details regarding its practice are incorporated herein by reference.

[0058] antibody: As used herein, the term "antibody" refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen-binding site that binds to (immunoreacts with) an antigen. "Binds to" or "immunoreacts with" means that the antibody reacts with one or more desired antigenic determinants. Antibodies include antibody fragments. Antibodies also include, but are not limited to, polyclonal, monoclonal, chimeric dAbs (domain antibodies), single chain, single domain antibodies (VHH), antigen-binding sites fused to a constant region (Fc), Fab, Fab', F(ab')2 fragments, scFv, and Fab expression libraries. Antibodies may be whole antibodies, or immunoglobulins, or antibody fragments.

[0059] amino acid: As used herein, the term "amino acid" in its broadest sense refers to any compound and / or substance that can be incorporated into a polypeptide chain. In some embodiments, an amino acid has the general structure HN-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid, in some embodiments, an amino acid is a d-amino acid, and in some embodiments, an amino acid is an l-amino acid. A "standard amino acid" refers to any of the 20 standard l-amino acids commonly found in naturally occurring peptides. A "non-standard amino acid" refers to any amino acid other than the standard amino acids, whether prepared synthetically or obtained from a natural source. As used herein, a "synthetic amino acid" encompasses chemically modified amino acids, including, but not limited to, salts, amino acid derivatives (such as amides), and / or substitutions. Amino acids, including the carboxyl-terminal and / or amino-terminal amino acids in a peptide, can be modified by methylation, amidation, acetylation, protecting groups, and / or substitutions with other chemical groups that can alter the circulating half-life of the peptide without adversely affecting its activity. Amino acids may participate in disulfide bonds. Amino acids may include mono- or post-translational modifications, such as association with one or more chemical entities (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.). The term "amino acid" is used interchangeably with "amino acid residue" and can refer to free amino acids and / or amino acid residues of peptides. Whether the term refers to a free amino acid or a residue of a peptide will be clear from the context in which it is used.

[0060] Improvement: As used herein, the term "amelioration" refers to the prevention, alleviation, or alleviation of a subject's condition, or improvement of the condition. Improvement includes, but is not limited to, complete recovery or complete prevention of a disease condition. In some embodiments, improvement may refer to partial recovery or prevention of a disease condition. In some embodiments, improvement includes an increase in the level of the relevant protein or its activity that is deficient in the relevant disease tissue.

[0061] Approximately or about: As used herein, the term "approximately" or "about," when applied to one or more subject values, refers to a value similar to a stated reference value.

[0062] Delivery: As used herein, the term "delivery" encompasses both local and systemic delivery.

[0063] Improve, increase, inhibit or decrease: As used herein, the terms "improvement," "increase," or "decrease," or grammatical equivalents, refer to a value relative to a baseline measurement, such as a measurement in the same individual prior to the initiation of a treatment described herein, or a measurement in a control subject (or control subjects) in the absence of a treatment described herein, e.g., a subject receiving a placebo. A "control subject" is a subject suffering from the same type of disease as the subject being treated and who is about the same age as the subject being treated.

[0064] To inhibit or hinder: As used herein, "inhibition" or "inhibiting" or grammatical equivalents refer to a reduction, decrease, or inhibition of biological activity. Neutralization: As used herein, neutralization refers to a reduction or inhibition of the biological activity of a protein to which a neutralizing antibody, in this case an anti-C3b antibody, binds, e.g., a reduction or inhibition of any one of the complement system component signaling, as measured by a C3b-mediated response. The reduction or inhibition of biological activity may be partial or total. The degree to which an antibody neutralizes C3b is referred to as its neutralizing efficacy.

[0065] patient: As used herein, the term "patient" refers to any organism to which a provided composition can be administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. Humans include prenatal and postnatal forms.

[0066] Pharmaceutically acceptable: As used herein, the term "pharmaceutically acceptable" refers to a material that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0067] Substantial Identicality: The phrase "substantial identity" is used herein to refer to the comparison of amino acid sequences or nucleic acid sequences. As understood by those skilled in the art, two sequences are generally considered to be "substantially identical" if they contain identical residues at corresponding positions. As is well known in the art, amino acid sequences or nucleic acid sequences can be compared using any of a variety of algorithms, including those available in commercially available computer programs such as BLAS TN for nucleotide sequences and BLASTP, gapped BLAST, and PSI-BLAST for amino acid sequences. Examples of such programs are described in Altschul, et al., Basic local alignment search tool, J Mal. Biol., 215(3):403-410, 1990; Altschul, et al., Methods in Enzymology, Altschul et al., Nucleic Acids Res. 25:3389-3402, 1997; Baxevanis et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener, et al., (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying identical sequences, the above-mentioned programs typically provide an indication of the degree of identity. In some embodiments, two sequences are considered to be substantially identical if at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more of their corresponding residues are identical over the relevant stretch of residues, which in some embodiments is the entire sequence.In some embodiments, the relevant section is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more residues.

[0068] subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Human includes prenatal and postnatal forms. In many embodiments, the subject is human. A subject can be a patient, which refers to a person who visits a health care provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject can be afflicted with or susceptible to a disease or disorder, but may or may not exhibit symptoms of the disease or disorder.

[0069] In effect: As used herein, the term "substantially" refers to a qualitative condition indicating the extent or degree of the total or near total of a characteristic or property of interest. Those skilled in the biological arts will understand that biological and chemical phenomena rarely, if ever, proceed to completion and / or perfection, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0070] Systemic Distribution or Delivery: As used herein, the terms "systemic distribution," "systemic delivery," or grammatical equivalents refer to a delivery or distribution mechanism or approach that affects the entire body or organism. Typically, systemic distribution or delivery is achieved via the body's circulatory system, e.g., the bloodstream. Compare with the definition of "local distribution or delivery."

[0071] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent refers to an amount sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of a symptom(s) of the disease, disorder, and / or condition. In some embodiments, a "therapeutically effective amount" is sufficient to prevent the progression of a disease state, the onset of one or more symptoms or complications associated with a condition, or a significant increase or decrease in the level of one or more biomarkers associated with a condition from their normal levels. For example, a "therapeutically effective amount" is sufficient to prevent the progression of a symptom or complication associated with the complement system. Those skilled in the art will understand that a therapeutically effective amount is typically administered via a dosing regimen comprising at least one unit dose.

[0072] Treatment: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, alleviate, inhibit, prevent, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to subjects who do not show signs of disease and / or who show only early signs of disease, with the intent of reducing the risk of developing pathology associated with the disease. In some embodiments, the term "treating" or its grammatical equivalents refers to preventing the onset of one or more symptoms associated with a disease state, condition, or a significant increase or decrease from normal levels in the levels of one or more biomarkers associated with a condition. For example, treating a patient with a complement-mediated disorder (e.g., C3 glomerulopathy) includes preventing the progression of symptoms or complications associated with the complement-mediated disorder, such as preventing C3 deposition. (Mode for Carrying Out the Invention)

[0073] The present invention provides, inter alia, anti-C3b antibodies. Antibodies also include, but are not limited to, polyclonal, monoclonal, chimeric dAb (domain antibody), single-chain, single-domain antibody (VHH), single-domain antibody-Fc fusion (VHH-Fc), antigen-binding site fused to a constant region (Fc), Fab, Fab', F(ab')2 fragment, scFv, and Fab expression library. The new class of anti-C3b antibodies of the present invention, such as single-domain antibody (VHH), single-domain antibody-Fc fusion (VHH-Fc), and antigen-binding site fused to a constant region (Fc), can effectively interfere with the formation of the alternative pathway C3 convertase (C3bBP), thereby preventing the cascade from proceeding downstream to the amplification loop of the complement cascade.

[0074] In some embodiments, the C3b antibodies of the invention selectively bind to C3b, inhibit C3 convertase formation, and mediate clearance of C3 deposits. The invention also provides methods for treating complement-mediated diseases and disorders using the anti-C3b antibodies further described herein. The anti-C3b antibodies of the invention have high binding affinity for human C3b (e.g., a C3b K of less than 50 nM). D The present invention is characterized by its ability to selectively bind to C3b (e.g., having a greater than 10-fold selectivity for C3b over C3) and minimal cross-reactivity with C3 (e.g., having a greater than 10-fold selectivity for C3b over C3). For example, selective binding to C3b via a novel epitope on C3b allows it to effectively target C3 convertase in diseased tissues without being saturated by high levels of circulating C3. As a result of the selective binding of the present invention, lower doses can be used to achieve therapeutic efficacy compared to other anti-C3b or anti-C3 antibodies.

[0075] In some embodiments, the antibody or antibody fragment thereof is a single-domain antibody (VHH). The VHH selectively binds to C3b, inhibits C3 convertase formation, and mediates the clearance of C3 deposits. Due to high binding affinity and minimal cross-reactivity with C3b, VHH-Fc fusions inhibit the formation of C3 convertase and mediate the clearance of C3 deposits. The present invention provides anti-C3b antibodies that (i) inhibit C3 convertase formation and mediate the clearance of C3 deposits, (ii) block C3b interaction with factor B (fB), (iii) inhibit alternative pathway (AP)-specific activity, (iv) limit interference with natural regulators of C3 convertase, such as factor H (fH), DAF, and other inhibitors, and / or (v) inhibit the stabilization of C3 convertase by C3bNef autoantibodies.

[0076] In some embodiments, the antibody or antibody fragment thereof is a VHH-Fc fusion. The VHH-Fc fusion selectively binds to C3b, inhibits C3 convertase formation, and mediates the clearance of C3 deposits. Due to its high binding affinity and minimal cross-reactivity with C3b, the VHH-Fc fusion inhibits the formation of C3 convertase and mediates the clearance of C3 deposits. The present invention provides anti-C3b antibodies that (i) inhibit C3 convertase formation and mediate the clearance of C3 deposits, (ii) block C3b interaction with factor B (fB), (iii) inhibit alternative pathway (AP)-specific activity, (iv) limit interference with natural regulators of C3 convertase, such as factor H (fH), DAF, and other inhibitors, and / or (v) inhibit stabilization of C3 convertase by C3bNef autoantibodies.

[0077] In some embodiments, the antibodies of the present invention perform one or more of the following functions: (i) inhibit C3 convertase formation and mediate clearance of C3 deposits, (ii) target both solid-phase and fluid-phase alternative pathway C3 convertase activity, (iii) block C3b interaction with factor B (fB), (iv) inhibit alternative pathway (AP)-specific activity, (v) limit interference with natural regulators of C3 convertase, such as factor H (fH), DAF, and other inhibitors, (vi) possess favorable biophysical and pharmacokinetic properties to allow for extended therapeutic effect (biweekly or monthly administration), and / or (vii) inhibit stabilization of C3 convertase by C3bNef autoantibodies. The present invention also provides a panel of antibodies that specifically and selectively bind human C3b and inhibit C3 convertase activity. This panel includes antibodies that differ in their epitope, affinity, and selectivity for C3b over C3.

[0078] Various aspects of the invention are described in detail in the following sections. The use of the sections is not intended to limit the invention. Each section may be applicable to any aspect of the invention. In this application, the use of "or" means "and / or" unless otherwise stated.

[0079] complement system The complement system is part of the innate immune system, adapting to changes throughout the host's life but supplemented and used by the adaptive immune system. For example, it assists or complements the ability of antibodies and phagocytes to eliminate pathogens. This sophisticated regulatory pathway allows for a rapid response to pathogenic organisms while protecting host cells from destruction. More than 30 proteins and protein fragments comprise the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attraction of macrophages and neutrophils), cytolysis (destruction of the membranes of foreign cells), and agglutination (clustering and binding of pathogens together). The complement system has three pathways: classical, alternative, and lectin. The classical pathway (CP) is activated by specific isotypes of antibodies bound to antigens. The alternative pathway (AP) is activated on the surface of microbial cells in the absence of antibodies. The lectin pathway is activated by plasma lectins that bind to mannose residues on microorganisms. Although the pathways of complement activation differ in how they are initiated, they all result in the production of an enzyme complex capable of cleaving C3, the most abundant complement protein.

[0080] Classical Pathway (CP) The classical pathway, so named because it was first discovered, uses a plasma protein called C1q to detect antibodies bound to the surfaces of microorganisms or other structures. When C1q binds to the Fc portion of an antibody, two related serine proteases, C1r and C1s, become activated and initiate a proteolytic cascade involving other complement proteins. The classical pathway is one of the major effector mechanisms of the humoral arm of the adaptive immune response. Innate immune system soluble proteins called pentraxins can also bind C1q and initiate the classical pathway.

[0081] Lectin pathway The lectin pathway is triggered by a plasma protein called mannose-binding lectin (MBL), which recognizes terminal mannose residues on microbial glycoproteins and glycolipids, similar to the aforementioned mannose receptor on phagocyte membranes. MBL is a member of the complement family with a hexameric structure similar to the C1q component of the complement system. After MBL binds to microorganisms, two enzyme precursors, MASP1 (mannose-associated serine protease 1, or mannan-binding lectin-associated serine protease) and MASP2, which have functions similar to C1r and C1s, associate with MBL and initiate downstream proteolytic steps identical to those in the classical pathway. The central event in complement activation is the proteolysis of the complement protein C3, which generates a biologically active product, C3b, followed by the covalent binding of the C3 product to the microbial cell surface or antigen-bound antibodies. Complement activation depends on the generation of two proteolytic complexes: C3 convertase, which cleaves C3 into two proteolytic fragments called C3a and C3b, and C5 convertase, which cleaves C5 into C5a and C5b.

[0082] Alternate Route (AP) The third pathway of complement activation is called the alternative pathway because it was discovered as a second or "alternative" pathway of complement activation after the classical pathway was defined. This pathway can proceed on many microbial surfaces in the absence of specific antibodies and results in the generation of a separate C3 convertase, designated C3bBb. In contrast to the classical and MB-lectin pathways of complement activation, the alternative pathway does not depend on pathogen-binding proteins for initiation but instead is initiated via spontaneous hydrolysis of C3. Multiple mechanisms ensure that the activation pathway proceeds only on pathogen surfaces.

[0083] C3 convertase and C3b C3 is abundant in plasma, and C3b is produced at a significant rate by spontaneous cleavage (also known as "translocation"). This occurs via spontaneous hydrolysis of the thioester bond in C3, forming C3(HO), which has an altered conformation and allows binding of the plasma protein factor B. The binding of B by C3(HO) then allows a plasma protease called factor D to cleave factor B into Ba and Bb, the latter of which remains bound to C3(HO) to form the C3(HO)Bb complex. This complex, a fluid-phase C3 convertase, forms only in small amounts but is capable of cleaving many molecules of C3 into C3a and C3b. While most of this C3b is inactivated by hydrolysis, some remains covalently bound to the surface of host cells or pathogens via its reactive thioester group. The bound C3b can then bind to factor B, allowing its cleavage by factor D to produce the small fragment Ba and the active protease Bb. This leads to the formation of the alternative pathway C3 convertase, C3b,Bb.

[0084] Upon C3b binding to host cells, numerous complement regulatory proteins present in plasma and on host cell membranes bind and prevent complement activation from proceeding. These proteins interact with C3b and either prevent the formation of convertases or promote their rapid dissociation. Thus, membrane-bound proteins known as complement receptor 1 (CR1) and decay-accelerating factor (DAF or CD55) compete with factor B for binding to C3b on the cell surface and can displace Bb from the already formed convertase. Convertase formation can also be prevented by cleaving C3b into its inactive derivative, iC3b. This is achieved by the plasma protease factor I and another host cell membrane protein, CR1, and C3b-binding proteins that can act as cofactors, such as membrane cofactors for proteolysis (MCP or CD46). Factor H is another complement regulatory protein in plasma that binds C3b and, like CR1, acts as a cofactor for factor I, as well as competing with factor B and displacing Bb from the convertase. Factor H binds preferentially to C3b bound to vertebrate cells due to its affinity for sialic acid residues present on these cells.

[0085] In contrast, pathogen surfaces lack these regulatory proteins and sialic acid residues, allowing the C3bBb convertase to form and persist. Indeed, this process may be supported by a positive regulatory factor known as properdin or P factor, which binds to many microbial surfaces and stabilizes the convertase. Deficiency of P factor is associated with increased susceptibility to infection with Neisseria species. Once formed, the C3bBb convertase rapidly cleaves further C3 into C3b, which can bind to pathogens and act as an opsonin, or restart the pathway to form another molecule of C3bBb convertase. Thus, the alternative pathway is activated through an amplification loop that can proceed on pathogen surfaces but not on host cells. This same amplification loop allows the alternative pathway to contribute to complement activation initially triggered through the classical or MB-lectin pathways.

[0086] The C3 convertases resulting from activation of the classical and MB-lectin pathways (C4b, 2b) and the alternative pathway (C3b, Bb) are clearly distinct. Only one component of the alternative pathway appears to be completely unrelated to its functional equivalents in the classical and MB-lectin pathways: the initiating serine protease, factor D. Factor D can also be selected as the sole activating protease of the complement system, circulating as an active enzyme rather than a proenzyme. This is necessary for initiation of the alternative pathway via natural C3 cleavage, and when bound to C3b, factor D is safe for the host because it has no substrates other than factor B. This means that factor D only finds its substrates at very low levels in plasma and on the surface of pathogens, where the alternative pathway of complement activation can proceed.

[0087] The formation of the C3 convertase is the point at which the three pathways of complement activation converge, as both the classical and MB-lectin pathway convertases C4b, 2b, and the alternative pathway convertase C3bBb possess the same activity and initiate the same subsequent events. Both cleave C3 into C3b and C3a. C3b covalently binds to adjacent molecules on the pathogen surface via its thioester bond and would otherwise be inactivated by hydrolysis. C3 is the most abundant complement protein in plasma, occurring at a concentration of 1.2 mg ml-1, and up to 1,000 molecules of C3b can bind in close proximity to a single active C3 convertase. Thus, the primary effect of complement activation is the deposition of large amounts of C3b on the surface of infectious pathogens, forming a covalent coating that can signal their eventual destruction by phagocytes.

[0088] The next step in the cascade is the generation of C5 convertase. In the classical and MB-lectin pathways, C5 convertase is formed by the binding of C3b to C4b,2b, yielding C4b,2b,3b. By the same token, the C5 convertase in the alternative pathway is formed by the binding of C3b to C3 convertase, forming C3b2Bb. C5 is captured by the C5 convertase complex through binding to an acceptor site on C3b and then becomes susceptible to cleavage by the serine protease activity of C2b or Bb. This reaction, which generates C5b and C5a, is much more limited than the cleavage of C3, because C5 can be cleaved only when bound to C3b, which is part of the C5 convertase complex. Thus, complement activation by both the alternative, MB-lectin, and classical pathways results in the binding of large numbers of C3b molecules on the surface of pathogens, the generation of more limited numbers of C5b molecules, and the release of C3a and C5a.

[0089] C3b antagonists and anti-C3b antibodies C3b antagonists suitable for the present invention include therapeutic agents capable of reducing, inhibiting, or neutralizing one or more C3b-mediated signaling, including those described herein. For example, suitable C3b antagonists according to the present invention include, but are not limited to, anti-C3b antibodies or fragments thereof, anti-C3b VHH-Fc, soluble C3b-binding proteins, soluble C3b-binding protein-Fc fusion proteins or fragments thereof.

[0090] Anti-C3b antibodies and fragments Conventional antibodies, also known as immunoglobulins, have a Y-shaped structure consisting of four polypeptides: two heavy chains and two light chains. This structure allows antibody molecules to perform the dual functions of antigen binding and mediating biological activity. Each function is carried out by a different portion of the antibody: the fragment antigen-binding (Fab fragment) and the fragment crystallizable region (Fc region). The Fab fragment is the region of the antibody that binds to antigen. It consists of one constant domain and one variable domain from each of the heavy and light chains. These domains form the paratope, or antigen-binding site, at the amino terminus of the monomer. The Fc region is the tail region of the antibody that interacts with cell surface receptors called Fc receptors and with proteins in the complement system. This property allows antibodies to activate the immune system. The Fc region of immunoglobulin G contains highly conserved N-glycosylation sites.

[0091] Within the VH and VL regions, three CDRs, hypervariable amino acid sequences, are present that form the antigen-binding site of each Fab. The interface between each heavy and light chain CDR and the constant segment creates a three-dimensional binding structure with high specificity for distinct antigenic determinants, or epitopes.

[0092] Single domain antibodies (VHH) Single-domain antibodies (VHHs) are fragments that represent the smallest antigen-binding domain of an antibody. Despite typically having a smaller molecular weight (12-15 kDa) than their parent antibodies, these antibodies retain their binding specificity and affinity. These single-domain antibodies are characterized by their high physical and thermal stability, as well as by their manufacturing process.

[0093] In some embodiments, the VHH is fused to an Fc domain. In some embodiments, the VHH is fused to a CH2 domain. In some embodiments, the VHH is fused to a CH3 domain. In some embodiments, the VHH is fused to both a CH2 and a CH3 domain.

[0094] Constant region (Fc) The Fc region of an antibody interacts with several Fc receptors and ligands, conferring a number of important functional capabilities called effector functions. For IgG, the Fc region includes Ig domains Cγ2 and Cγ3, as well as the N-terminal hinge leading to Cγ2. An important family of Fc receptors for the IgG class are Fc gamma receptors (FcγRs). These receptors mediate communication between antibodies and the cellular arm of the immune system (Raghavan et al., 1996, Annu Rev Cell Dev Biol 12:181-220; Ravetch et al., 2001, Annu Rev Immunol 19:275-290). In humans, this protein family includes FcγRI (CD64), which includes the isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), which includes the isoforms FcγRIIa (including allotypes H131 and R131), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16), which includes the isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIIb-NA1 and FcγRIIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65, incorporated by reference). These receptors typically have an extracellular domain that mediates Fc binding, a transmembrane region, and an intracellular domain that can mediate some intracellular signaling events. These receptors are expressed on a variety of immune cells, including monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, B cells, large granular lymphocytes, Langerhans cells, natural killer (NK) cells, and γδ T cells. Formation of the Fc / FcγR complex recruits these effector cells to the site of bound antigen, typically resulting in intracellular signaling events and important subsequent immune responses, such as the release of inflammatory mediators, B cell activation, endocytosis, phagocytosis, and cytotoxic attack. The ability to mediate cytotoxic and phagocytic effector functions is a potential mechanism by which antibodies destroy target cells.The cell-mediated reaction in which non-specific cytotoxic cells expressing FcγR recognize bound antibodies on target cells and subsequently cause lysis of the target cells is called antibody-dependent cell-mediated cytotoxicity (ADCC) (Raghavan et al., 1996, Annu Rev Cell Dev Biol 12:181-220; Ghetie et al., 2000, Annu Rev Immunol 18:739-766; Ravetch et al., 2001, Annu Rev Immunol 19:275-290, incorporated by reference). The cell-mediated reaction in which non-specific cytotoxic cells expressing FcγR recognize bound antibodies on target cells and subsequently cause phagocytosis of the target cells is called antibody-dependent cell-mediated phagocytosis (ADCP). Several structures of the extracellular domains of human FcγRs have been solved, including FcγRIIa (pdb accession code 1H9V) (Sondermann et al., 2001, J Mol Biol 309:737-749) (pdb accession code 1FCG) (Maxwell et al., 1999, Nat Struct Biol 6:437-442), FcγRIIb (pdb accession code 2FCB) (Sondermann et al., 1999, Embo J 18:1095-1103), and FcγRIIIb (pdb accession code 1E4J) (Sondermann et al., 2000, Nature 406:267-273, incorporated by reference). All FcγRs bind to the same region on Fc, at the N-terminus of the Cγ2 domain and preceding hinge.This interaction has been structurally well characterized (Sondermann et al., 2001, J Mol Biol 309:737-749, incorporated by reference), with several structures of human Fc bound to the extracellular domain of human FcγRIIIb being solved (pdb accession code 1E4K) (Sondermann et al., 2000, Nature 406:267-273) (pdb accession codes 1IIS and 1IIX) (Radaev et al., 2001, J Biol Chem 276:16469-16477, incorporated by reference), as well as the structure of the human IgE Fd / FcεRIa complex (pdb accession code 1F6A) (Garman et al., 2000, Nature 406:259-266, incorporated by reference).

[0095] An overlapping but distinct site on Fc serves as an interface for the complement protein C1q. Similar to how Fc / FcγR binding mediates ADCC, Fc / C1q binding mediates complement-dependent cytotoxicity (CDC). C1q complexes with the serine proteases C1r and C1s to form the C1 complex. C1q can bind six antibodies, but binding to two IgGs is sufficient to activate the complement cascade. Similar to Fc interactions with FcγR, different IgG subclasses have different affinities for C1q, with IgG1 and IgG3 typically binding substantially better to FcγR than IgG2 and IgG4.

[0096] The site on Fc between the Cγ2 and Cγ3 domains mediates interaction with the neonatal receptor FcRn, which recycles internalized antibodies from endosomes back into the bloodstream (Raghavan et al., 1996, Annu Rev Cell Dev Biol 12:181-220; Ghetie et al., 2000, Annu Rev Immunol 18:739-766, incorporated by reference). This process, coupled with kidney filtration due to the large size of full-length molecules, results in favorable antibody serum half-lives ranging from 1 to 3 weeks. Binding of Fc to FcRn also plays an important role in antibody transport. The FcRn binding site on Fc is also the site of bacterial protein A and G binding. Tight binding by these proteins is typically exploited as a means of purifying antibodies by employing protein A or protein G affinity chromatography during protein purification. Therefore, the fidelity of this region on Fc is important for both the clinical properties of antibodies and their purification. Available structures of the rat Fc / FcRn complex (Martin et al., 2001, Mol Cell 7:867-877, incorporated by reference) and complexes of Fc with proteins A and G (Deisenhofer, 1981, Biochemistry 20:2361-2370; Sauer-Eriksson et al., 1995, Structure 3:265-278; Tashiro et al., 1995, Curr Opin Struct Biol 5:471-481, incorporated by reference) provide insight into the interactions of Fc with these proteins.

[0097] In some embodiments, the antibody or fragment thereof comprises an optimized Fc variant that is useful in various situations. As outlined above, current antibody therapy suffers from various problems. The present invention provides a promising means for enhancing the therapeutic efficacy of antibodies through the abrogation of their ability to mediate cytotoxic effector functions such as ADCC, ADCP, and CDC.

[0098] Fc variants Fc polypeptides comprising an Fc variant described herein are referred to as "Fc polypeptides." Fc polypeptides of the present invention include polypeptides comprising an Fc variant in the context of a larger polypeptide, such as an antibody or Fc fusion. That is, Fc polypeptides include antibodies and Fc fusions comprising an Fc variant of the present invention. Fc polypeptides of the present invention also include polypeptides that contain little or no additional polypeptide sequence beyond the Fc region, referred to as isolated Fc. Fc polypeptides described in the present invention also include fragments of the Fc region. As described below, any of the foregoing Fc polypeptides may be fused to one or more fusion or conjugate partners to provide desired functional properties.

[0099] The parent Fc polypeptides described herein may be derived from a wide variety of sources and may be substantially encoded by one or more Fc genes from any organism, including, but not limited to, rodents, including but not limited to, humans, mice, and rats; lagomorphs, such as rabbits and hares; camelids, such as camels, llamas, and dromedaries; and non-human primates, including but not limited to, prosimians, platyrrhines (New World monkeys), Cercopithecinoidea (Old World monkeys), and hominoidea, including gibbons, lesser apes, and greater apes, with humans being the most preferred. The parent Fc polypeptides of the present invention may be substantially encoded by immunoglobulin genes belonging to any of the antibody classes, including, but not limited to, sequences belonging to the IgG (including human subclasses IgG1, IgG2, IgG3, or IgG4), IgA (including human subclasses IgA1 and IgA2), IgD, IgE, IgG, or IgM classes of antibodies. The parent Fc polypeptides of the present invention comprise sequences belonging to the human IgG class of antibodies. For example, the parent Fc polypeptide can be a parent antibody, such as a human IgG1 antibody, a human IgA antibody, or a mouse IgG2a or IgG2b antibody. The parent antibody can be non-human, chimeric, humanized, or fully human, as described in detail below. The parent Fc polypeptide can be modified or engineered in some way; for example, the parent antibody can be affinity matured or have engineered glycoforms, all of which are described more fully below. Alternatively, the parent Fc polypeptide can be an Fc fusion, e.g., an Fc fusion in which the fusion partner targets a cell surface receptor. Alternatively, the parent Fc polypeptide can be an isolated Fc region that contains little or no other polypeptide sequence outside the Fc region. The parent Fc polypeptide can be a naturally occurring Fc region or an existing engineered variant of an Fc polypeptide. Importantly, the parent Fc polypeptide contains an Fc region, which can then be mutated to generate an Fc variant.

[0100] Optimized characteristics The Fc variants described herein are optimized for several therapeutically relevant properties. The Fc variants comprise one or more amino acid modifications relative to a parent Fc polypeptide, where the amino acid modification(s) provide one or more optimized properties. The Fc variants of the present invention differ in amino acid sequence from their parent Fc polypeptide by at least one amino acid modification. In some embodiments, the Fc variants have at least one amino acid modification relative to the parent. Alternatively, in some embodiments, the Fc variants may have multiple amino acid modifications relative to the parent, e.g., about 1 to 50 amino acid modifications, about 1 to 10 amino acid modifications, or about 1 to about 5 amino acid modifications relative to the parent. Thus, the sequences of the Fc variant and the parent Fc polypeptide are substantially homologous. For example, the variant Fc variant sequences herein will have about 80% homology, preferably at least about 90% homology, and most preferably at least about 95% homology to the parent Fc variant sequence.

[0101] Fc variants can be optimized for various properties. Fc variants engineered or predicted to exhibit one or more optimized properties are referred to herein as "optimized Fc variants." Properties that can be optimized include, but are not limited to, enhanced or reduced affinity for FcγRs. In some embodiments, Fc variants are optimized to have reduced or ablated affinity for human FcγRs, including, but not limited to, FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, and FcγRIIIb. These embodiments are expected to provide Fc polypeptides with enhanced therapeutic properties in humans, e.g., reduced effector function and reduced toxicity. In other embodiments, Fc variants provide enhanced affinity for one or more FcγRs but reduced affinity for one or more other FcγRs. For example, an Fc variant may have enhanced binding to FcγRIIIa but reduced binding to FcγRIIb. Alternatively, an Fc variant may have enhanced binding to FcγRIIa and FcγRI, but reduced binding to FcγRIIb, hi yet another embodiment, an Fc variant may have enhanced affinity for FcγRIIb, but reduced affinity for one or more activating FcγRs.

[0102] In some embodiments, the Fc variants have reduced or truncated affinity for FcγRI. In some embodiments, the Fc variants have reduced or truncated affinity for FcγRIIa. In some embodiments, the Fc variants have reduced or truncated affinity for FcγRIIb. In some embodiments, the Fc variants have reduced or truncated affinity for FcγRIIc. In some embodiments, the Fc variants have reduced or truncated affinity for FcγRIIIa. In some embodiments, the Fc variants have reduced or truncated affinity for FcγRIIIb. In some embodiments, the Fc variants have reduced or truncated affinity for C1q. In some embodiments, the Fc variants have enhanced affinity for FcRn. In some embodiments, the Fc variants maintain affinity for FcRn. In some embodiments, the Fc variants have reduced or truncated affinity for FcγRI, FcγRIIa, FcγRIIb, FcγRIIIa, FcγRIIIb, and C1q, hi some embodiments, the Fc variants have reduced or truncated affinity for FcγRI, FcγRIIa, FcγRIIb, FcγRIIIa, FcγRIIIb, and C1q and retain binding to FcRn.

[0103] Fc variants may also be optimized for enhanced function and / or solution properties in the aglycosylated form. In a preferred embodiment, the aglycosylated Fc variant binds to an Fc ligand with reduced affinity relative to the aglycosylated form of the parent Fc variant. The Fc ligand may be derived from any source, including, but not limited to, FcγR, C1q, FcRn, and proteins A and G, including, but not limited to, human, mouse, rat, rabbit, or monkey, preferably human. Alternatively, in a preferred embodiment, the Fc variant is optimized to be more stable and / or soluble than the aglycosylated form of the parent Fc variant.

[0104] In some embodiments, the antibody or fragment thereof comprises an Fc variant comprising an L235E mutation. In some embodiments, the antibody or fragment thereof comprises an Fc variant comprising a D265G mutation. In some embodiments, the antibody or fragment thereof comprises an Fc variant comprising an F234V mutation. In some embodiments, the antibody or fragment thereof comprises an Fc variant comprising F234V, L235E, and D265G mutations.

[0105] Engineered Fc mutations In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG1 Fc region, wherein the Fc variant comprises amino acid substitutions L234F / L235E / D265G, where residues are numbered according to the EU index.

[0106] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG1 Fc region, wherein the Fc variant comprises amino acid substitutions T307Q / Q311V / A378V, where residues are numbered according to the EU index.

[0107] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG1 Fc region, wherein the Fc variant comprises amino acid substitutions L234F / L235E / D265G / S228P / T307Q / Q311V / A378V, where residues are numbered according to the EU index.

[0108] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG1 Fc region, wherein the Fc variant comprises amino acid substitutions L234F / L235E / G237A / D265G, where residues are numbered according to the EU index.

[0109] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG1 Fc region, wherein the Fc variant comprises amino acid substitutions L234V / L235E / G237A / D265G, where residues are numbered according to the EU index.

[0110] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG1 Fc region, wherein the Fc variant comprises amino acid substitutions L234F / L235E / D265G / A330S / P331S, where residues are numbered according to the EU index.

[0111] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG1 Fc region, wherein the Fc variant comprises amino acid substitutions L234V / L235A / G237A / D265G, where residues are numbered according to the EU index.

[0112] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG1 Fc region, wherein the Fc variant comprises amino acid substitutions L234V / L235A / G237A / D265G / A330S / P331S, where residues are numbered according to the EU index.

[0113] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG1 Fc region, wherein the Fc variant comprises the amino acid substitution D265G, where residues are numbered according to the EU index.

[0114] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG4 Fc region, wherein the Fc variant comprises amino acid substitutions L235E / D265G / S228P, where residues are numbered according to the EU index.

[0115] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG4 Fc region, wherein the Fc variant comprises the amino acid substitutions F234V / L235E / D265G / S228P, where residues are numbered according to the EU index.

[0116] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG4 Fc region, wherein the Fc variant comprises the amino acid substitutions F234V / L235A / G237A / D265G / S228P, where residues are numbered according to the EU index.

[0117] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG4 Fc region, wherein the Fc variant comprises amino acid substitutions L235E / G237A / D265G / S228P, where residues are numbered according to the EU index.

[0118] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG4 Fc region, wherein the Fc variant comprises amino acid substitutions L235E / G237A / P329G / S228P, where residues are numbered according to the EU index.

[0119] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG4 Fc region, wherein the Fc variant comprises amino acid substitutions L235E / G237A / L328R / S228P, where residues are numbered according to the EU index.

[0120] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG2 Fc region, wherein the Fc variant comprises amino acid substitutions D265G / A330S / P331S, where residues are numbered according to the EU index.

[0121] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG2 Fc region, wherein the Fc variant comprises amino acid substitutions A235E / D265G / A330S / P331S, where residues are numbered according to the EU index.

[0122] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG2 Fc region, wherein the Fc variant comprises amino acid substitutions A235E / D265G / P329G, where residues are numbered according to the EU index.

[0123] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises amino acid substitutions at positions 235 and 265, wherein the amino acid at position 265 is substituted with a Gly, and wherein residues are numbered according to the EU index.

[0124] In some embodiments, the Fc variants further comprise one or more amino acid substitutions at positions 234, 237, 329, 330, or 331. In some embodiments, the Fc variants further comprise an amino acid substitution at position 234. In some embodiments, the Fc variants further comprise amino acid substitutions at positions 234 and 237. In some embodiments, the Fc variants further comprise amino acid substitutions at positions 234, 330, and 331. In some embodiments, the Fc variants further comprise amino acid substitutions at positions 234, 237, 330, and 331. In some embodiments, the Fc variants further comprise an amino acid substitution at position 237. In some embodiments, the Fc variants further comprise amino acid substitutions at positions 330 and 331. In some embodiments, the Fc variants further comprise an amino acid substitution at position 329.

[0125] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises amino acid substitutions at positions 234 and 265, wherein the amino acid at position 234 is substituted with Val, and wherein residues are numbered according to the EU index.

[0126] In some embodiments, the Fc variant further comprises amino acid substitutions at positions 235 and 237. In some embodiments, the Fc variant further comprises amino acid substitutions at positions 235, 237, 330, and 331. In some embodiments, the Fc variant further comprises an amino acid substitution at position 235.

[0127] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG4 Fc region, wherein the Fc variant comprises amino acid substitutions at positions F234, L235, and D265, where residues are numbered according to the EU index.

[0128] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: 234V, L235E, and D265G, where residues are numbered according to the EU index.

[0129] In some embodiments, the Fc variant is an IgG4 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: S228P, F234V, L235E, and D265G. In some embodiments, the Fc variant is an IgG4 Fc region and comprises the following amino acid substitutions: S228P, F234V, L235E, and D265G.

[0130] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: 234F, L235E, and D265G, where residues are numbered according to the EU index.

[0131] In some embodiments, the Fc variant is an IgG1 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: L234F, L235E, and D265G. In some embodiments, the Fc variant is an IgG1 Fc region and comprises the following amino acid substitutions: L234F, L235E, and D265G.

[0132] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: 234F, L235E, G237A, and D265G, where residues are numbered according to the EU index.

[0133] In some embodiments, the Fc variant is an IgG1 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: L234F, L235E, G237A, and D265G. In some embodiments, the Fc variant is an IgG1 Fc region and comprises the following amino acid substitutions: L234F, L235E, G237A, and D265G.

[0134] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: 234V, L235E, G237A, and D265G, where residues are numbered according to the EU index.

[0135] In some embodiments, the Fc variant is an IgG1 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: L234V, L235E, G237A, and D265G. In some embodiments, the Fc variant is an IgG1 Fc region and comprises the following amino acid substitutions: L234V, L235E, G237A, and D265G.

[0136] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: 234F, L235E, D265D, A330S, and P331S, where residues are numbered according to the EU index.

[0137] In some embodiments, the Fc variant is an IgG1 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: L234F, L235E, D265D, A330S, and P331S. In some embodiments, the Fc variant is an IgG1 Fc region and comprises the following amino acid substitutions: L234F, L235E, D265D, A330S, and P331S.

[0138] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: 234V, L235A, G237A, and D265G, where residues are numbered according to the EU index.

[0139] In some embodiments, the Fc variant is an IgG1 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: L234V, L235A, G237A, and D265G. In some embodiments, the Fc variant is an IgG1 Fc region and comprises the following amino acid substitutions: 234F, L234V, L235A, G237A, and D265G. In some embodiments, the Fc variant is an IgG4 Fc region and comprises the following amino acid substitutions: S228P, L234V, L235A, G237A, and D265G. In some embodiments, the Fc variant is an IgG4 Fc region and comprises the following amino acid substitutions: S228P, L234V, L235A, G237A, and D265G.

[0140] In some embodiments, the Fc variant comprises the following amino acid substitutions: S228P, L234V, L235A, G237A, D265G, T307Q, Q311V, and A378V, hi some embodiments, the Fc variant is an IgG4 Fc region and comprises the following amino acid substitutions: L234V, L235A, G237A, D265G, T307Q, Q311V, and A378V.

[0141] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: 234V, L235A, G237A, D265G, A330S, and P331S, where residues are numbered according to the EU index.

[0142] In some embodiments, the Fc variant is an IgG1 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: L234V, L235A, G237A, D265G, A330S, and P331S. In some embodiments, the Fc variant is an IgG1 Fc region and comprises the following amino acid substitutions: L234V, L235A, G237A, D265G, A330S, and P331S.

[0143] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises amino acid substitutions L235E and D265G, where residues are numbered according to the EU index.

[0144] In some embodiments, the Fc variant is an IgG4 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: S228P, L235E, and D265G. In some embodiments, the Fc variant is an IgG4 Fc region and comprises the following amino acid substitutions: S228P, L235E, and D265G.

[0145] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: L235E, G237A, and D265G, where residues are numbered according to the EU index.

[0146] In some embodiments, the Fc variant is an IgG4 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: S228P, L235E, G237A, and D265G. In some embodiments, the Fc variant is an IgG4 Fc region and comprises the following amino acid substitutions: S228P, L235E, G237A, and D265G.

[0147] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: L235E, G237A, and P329G, where residues are numbered according to the EU index.

[0148] In some embodiments, the Fc variant is an IgG4 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: S228P, L235E, G237A, and P329G. In some embodiments, the Fc variant is an IgG4 Fc region and comprises the following amino acid substitutions: S228P, L235E, G237A, and P329G.

[0149] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises amino acid substitutions of L235E, G237A, and L328R, where residues are numbered according to the EU index.

[0150] In some embodiments, the Fc variant is an IgG4 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: S228P, L235E, G237A, and L328R. In some embodiments, the Fc variant is an IgG4 Fc region and comprises the following amino acid substitutions: S228P, L235E, G237A, and L328R.

[0151] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: D265G, A330S, and P331S, where residues are numbered according to the EU index.

[0152] In some embodiments, the Fc variant is an IgG2 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: D265G, A330S, and P331S. In some embodiments, the Fc variant is an IgG2 Fc region and comprises the following amino acid substitutions: D265G, A330S, and P331S.

[0153] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises the following amino acid substitutions: 235E, D265G, A330S, and P331S, where residues are numbered according to the EU index.

[0154] In some embodiments, the Fc variant is an IgG2 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: A235E, D265G, A330S, and P331S. In some embodiments, the Fc variant is an IgG2 Fc region and comprises the following amino acid substitutions: A235E, D265G, A330S, and P331S.

[0155] In some embodiments, the antibody or fragment thereof comprises an Fc variant of a wild-type human IgG Fc region, wherein the Fc variant comprises amino acid substitutions 235E, D265G, and P329G, where residues are numbered according to the EU index.

[0156] In some embodiments, the Fc variant is an IgG2 Fc region. In some embodiments, the Fc variant comprises the following amino acid substitutions: A235E, D265G, and P329G. In some embodiments, the Fc variant is an IgG2 Fc region and comprises the following amino acid substitutions: A235E, D265G, and P329G.

[0157] In some embodiments, the Fc variant comprises SEQ ID NO:14. ESKYGPPCPPCPA PEVEGGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLQVLHVDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIVVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 14)

[0158] In some embodiments, the Fc variant comprises an amino acid sequence 85% identical to SEQ ID NO: 14. In some embodiments, the Fc variant comprises an amino acid sequence 90% identical to SEQ ID NO: 14. In some embodiments, the Fc variant comprises an amino acid sequence 92% identical to SEQ ID NO: 14. In some embodiments, the Fc variant comprises an amino acid sequence 95% identical to SEQ ID NO: 14. In some embodiments, the Fc variant comprises an amino acid sequence 96% identical to SEQ ID NO: 14. In some embodiments, the Fc variant comprises an amino acid sequence 97% identical to SEQ ID NO: 14. In some embodiments, the Fc variant comprises an amino acid sequence 98% identical to SEQ ID NO: 14. In some embodiments, the Fc variant comprises an amino acid sequence 99% identical to SEQ ID NO: 14. In some embodiments, the Fc variant comprises an amino acid sequence identical to SEQ ID NO: 14.

[0159] Anti-C3b antibody sequence In some embodiments, the antibody is composed of two light chains and two heavy chains. In some embodiments, the heavy and light chains each comprise a complementarity determining region (CDR) and a framework region. In some embodiments, the antibody or fragment thereof is a VHH.

[0160] In some embodiments, the VHH comprises three CDRs: CDR1, CDR2, and CDR3, as specified by the amino acid sequences in Tables A and B.

[0161] Exemplary anti-C3b antibody sequences are provided below. [Table A] [Table B]

[0162] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises the VHH sequence of SEQ ID NO:10. EVQLLESGGGLVQPGGSLRLSCAASGRTFSNYHMGWFRQAPGQGREFVATIIRTGETIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATSGWNIKTVTPYEYWGQGTLVTVSS (SEQ ID NO: 10)

[0163] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises the VHH sequence of SEQ ID NO:11. EVQLLESGGGLVQPGGSLRLSCAASGRTFSNYHMGWFRQAPGQGREFVATIIRTGKTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATSGWHIKTVTPYEYWGQGTLVTVSS (SEQ ID NO: 11)

[0164] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises the VHH sequence of SEQ ID NO:12. EVQLLESGGGLVQPGGSLRLSCAASGRTFSNYHMGWFRQAPGQGREFVATIIRTGTTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATSGWHIKTVTPYEYWGQGTLVTVSS (SEQ ID NO: 12)

[0165] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises the VHH sequence of SEQ ID NO:13. EVQLLESGGGLVQPGGSLRLSCAASGRTFSNYHMGWFRQAPGQGREFVATIIRHGTTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATSGWHIKTVTPYEYWGQGTLVTVSS (SEQ ID NO: 13)

[0166] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH fused to an Fc domain.

[0167] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain fusion of SEQ ID NO:4. EVQLLESGGGLVQPGGSLRLSCAASGRTFSNYHMGWFRQAPGQGREFVATIIRTGETIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATSGWNIKTVTPYEYWGQGTLVTVSSESKYGPPCPPCPAPEVEGGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLQVLHVDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIVVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 4)

[0168] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain fusion of SEQ ID NO:5. EVQLLESGGGLVQPGGSLRLSCAASGRTFSNYHMGWFRQAPGQGREFVATIIRTGKTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATSGWHIKTVTPYEYWGQGTLVTVSSESKYGPPCPPCPAPEVEGGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLQVLHVDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIVVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 5)

[0169] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain fusion of SEQ ID NO:6. EVQLLESGGGLVQPGGSLRLSCAASGRTFSNYHMGWFRQAPGQGREFVATIIRTGTTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATSGWHIKTVTPYEYWGQGTLVTVSSESKYGPPCPPCPAPEVEGGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLQVLHVDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIVVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 6)

[0170] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain fusion of SEQ ID NO:7. EVQLLESGGGLVQPGGSLRLSCAASGRTFSNYHMGWFRQAPGQGREFVATIIRHGTTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATSGWHIKTVTPYEYWGQGTLVTVSSESKYGPPCPPCPAPEVEGGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLQVLHVDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIVVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 7)

[0171] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain fusion of SEQ ID NO:8. EVQLLESGGGLVQPGGSLRLSCAASGRTFSNYHMGWFRQAPGQGREFVATIIRTGETIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATSGWNIKTVTPYEYWGQGTLVTVSSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 8)

[0172] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain fusion of SEQ ID NO:9. EVQLLESGGGLVQPGGSLRLSCAASGRTFSNYHMGWFRQAPGQGREFVATIIRTGTTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAATSGWHIKTVTPYEYWGQGTLVTVSSESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 9)

[0173] In some embodiments, an anti-C3b antibody according to the invention comprises a CDR amino acid sequence having at least 75%, 78%, 80%, 82%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity to one or more of SEQ ID NOs: 16-27.

[0174] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 75% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 78% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 80% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 82% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 85% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 85% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 87% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 90% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 91% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 92% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 93% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 94% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 95% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 96% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 97% identity to SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 98% identity to SEQ ID NO: 16.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 99% identity to SEQ ID NO:16.

[0175] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 75% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 78% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 80% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 82% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 87% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 90% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 91% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 92% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 93% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 94% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 95% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 96% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 97% identity to SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 98% identity to SEQ ID NO: 17.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 99% identity to SEQ ID NO:17.

[0176] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 75% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 78% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 80% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 82% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 85% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 85% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 87% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 90% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 91% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 92% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 93% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 94% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 95% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 96% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 97% identity to SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 98% identity to SEQ ID NO: 18.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 99% identity to SEQ ID NO:18.

[0177] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 75% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 78% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 80% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 82% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 85% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 85% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 87% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 90% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 91% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 92% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 93% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 94% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 95% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 96% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 97% identity to SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 98% identity to SEQ ID NO: 19.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 amino acid sequence having at least 99% identity to SEQ ID NO:19.

[0178] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 75% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 78% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 80% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 82% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 87% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 90% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 91% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 92% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 93% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 94% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 95% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 96% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 97% identity to SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 98% identity to SEQ ID NO: 20.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 99% identity to SEQ ID NO:20.

[0179] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 75% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 78% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 80% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 82% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 87% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 90% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 91% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 92% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 93% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 94% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 95% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 96% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 97% identity to SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 98% identity to SEQ ID NO: 21.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 99% identity to SEQ ID NO:21.

[0180] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 75% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 78% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 80% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 82% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 85% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 85% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 87% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 90% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 91% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 92% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 93% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 94% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 95% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 96% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 97% identity to SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 98% identity to SEQ ID NO: 22.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 amino acid sequence having at least 99% identity to SEQ ID NO:22.

[0181] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 75% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 78% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 80% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 82% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 87% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 90% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 91% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 92% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 93% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 94% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 95% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 96% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 97% identity to SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 98% identity to SEQ ID NO: 23.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 99% identity to SEQ ID NO:23.

[0182] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 75% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 78% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 80% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 82% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 87% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 90% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 91% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 92% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 93% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 94% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 95% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 96% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 97% identity to SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 98% identity to SEQ ID NO: 24.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 99% identity to SEQ ID NO:24.

[0183] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 75% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 78% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 80% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 82% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 87% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 90% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 91% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 92% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 93% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 94% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 95% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 96% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 97% identity to SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 98% identity to SEQ ID NO: 25.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 99% identity to SEQ ID NO:25.

[0184] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 75% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 78% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 80% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 82% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 87% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 90% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 91% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 92% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 93% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 94% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 95% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 96% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 97% identity to SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 98% identity to SEQ ID NO: 26.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 99% identity to SEQ ID NO:26.

[0185] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 75% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 78% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 80% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 82% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 85% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 87% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 90% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 91% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 92% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 93% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 94% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 95% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 96% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 97% identity to SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 98% identity to SEQ ID NO: 27.In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 amino acid sequence having at least 99% identity to SEQ ID NO:27.

[0186] In some embodiments, anti-C3b antibodies according to the invention comprise up to one, two, three, or four amino acid substitutions in one or more of the CDR sequences of SEQ ID NOs: 16-27. In some embodiments, anti-C3b antibodies according to the invention comprise up to one, two, three, four, or five amino acid substitutions in one or more of the CDR sequences selected from SEQ ID NOs: 16-27.

[0187] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR1 of SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR1 of SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR1 of SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR1 of SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR1 of SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR1 of SEQ ID NO: 16.

[0188] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR2 of SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR2 of SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR2 of SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR2 of SEQ ID NO: 17.

[0189] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR3 of SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR3 of SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR3 of SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR3 of SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR3 of SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR3 of SEQ ID NO: 18.

[0190] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR1 of SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR1 of SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR1 of SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR1 of SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR1 of SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR1 of SEQ ID NO: 19.

[0191] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR2 of SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR2 of SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR2 of SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR2 of SEQ ID NO: 20.

[0192] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR2 of SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR2 of SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR2 of SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR2 of SEQ ID NO: 21.

[0193] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR3 of SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR3 of SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR3 of SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR3 of SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR3 of SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR3 of SEQ ID NO: 22.

[0194] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR2 of SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR2 of SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR2 of SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR2 of SEQ ID NO: 23.

[0195] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR2 of SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR2 of SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR2 of SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR2 of SEQ ID NO: 24.

[0196] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR2 of SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR2 of SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR2 of SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR2 of SEQ ID NO: 25.

[0197] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR2 of SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR2 of SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR2 of SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR2 of SEQ ID NO: 26.

[0198] In some embodiments, the anti-C3b antibody or fragment thereof comprises one amino acid substitution in CDR2 of SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises two amino acid substitutions in CDR2 of SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises three amino acid substitutions in CDR2 of SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises four amino acid substitutions in CDR2 of SEQ ID NO: 27. In some embodiments, the anti-C3b antibody or fragment thereof comprises five amino acid substitutions in CDR2 of SEQ ID NO: 27.

[0199] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 defined by SEQ ID NO: 16. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 defined by SEQ ID NO: 17. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 defined by SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 defined by SEQ ID NO: 19. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 defined by SEQ ID NO: 20. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 defined by SEQ ID NO: 21. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR3 defined by SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 defined by SEQ ID NO: 23. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 defined by SEQ ID NO: 24. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 defined by SEQ ID NO: 25. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 defined by SEQ ID NO: 26. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR2 defined by SEQ ID NO:27.

[0200] In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 17, and a CDR3 defined by SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 20, and a CDR3 defined by SEQ ID NO: 18. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 21, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 23, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 24, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 25, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 26, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, the anti-C3b antibody or fragment thereof comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 27, and a CDR3 defined by SEQ ID NO: 22.

[0201] In some embodiments of the invention, the heavy chain constant region of the anti-C3b antibody comprises a CH1, hinge, and CH2 domain from an IgG4 antibody fused to a CH3 domain from an IgG1 antibody. In some embodiments of the invention, the heavy chain constant region of the anti-C3b antibody is an IgG1, IgG2, IgG3, or IgG4 heavy chain constant region, or is derived from an IgG1, IgG2, IgG3, or IgG4 heavy chain constant region. In some embodiments of the invention, the light chain constant region of the anti-C3b antibody is a lambda or kappa light chain constant region, or is derived from a lambda or kappa light chain constant region.

[0202] In some embodiments, the antibody or antigen-binding fragment thereof is a single-chain variable fragment (ScFv) comprising at least one of the CDR sequences of SEQ ID NOs: 16-27. In some embodiments, the antibody or antigen-binding fragment thereof is a fusion molecule comprising at least one of the CDR sequences of SEQ ID NOs: 16-27. In some embodiments, the antibody or antigen-binding fragment thereof is a bispecific antibody comprising at least one of the CDR sequences of SEQ ID NOs: 16-27. In some embodiments, the antibody or antigen-binding fragment thereof is a VHH comprising at least one of the CDR sequences of SEQ ID NOs: 16-27.

[0203] In some embodiments, a VHH that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 17, and a CDR3 defined by SEQ ID NO: 18. In some embodiments, a VHH that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 20, and a CDR3 defined by SEQ ID NO: 18. In some embodiments, a VHH that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 21, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, a VHH that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 23, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, a VHH that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 24, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, a VHH that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 25, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, a VHH that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 26, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, a VHH that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 27, and a CDR3 defined by SEQ ID NO: 22.

[0204] In some embodiments, the antibody or antigen-binding fragment thereof is a VHH-Fc fusion comprising at least one of the CDR sequences of SEQ ID NOs: 16-27.

[0205] In some embodiments, a VHH-Fc fusion that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 17, and a CDR3 defined by SEQ ID NO: 18. In some embodiments, a VHH-Fc fusion that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 20, and a CDR3 defined by SEQ ID NO: 18. In some embodiments, a VHH-Fc fusion that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 21, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, a VHH-Fc fusion that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 23, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, a VHH-Fc fusion that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 24, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, a VHH-Fc fusion that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 25, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, a VHH-Fc fusion that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 16, a CDR2 defined by SEQ ID NO: 26, and a CDR3 defined by SEQ ID NO: 22. In some embodiments, a VHH-Fc fusion that binds Cb3 comprises a CDR1 defined by SEQ ID NO: 19, a CDR2 defined by SEQ ID NO: 27, and a CDR3 defined by SEQ ID NO: 22.

[0206] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 85% identical to SEQ ID NO: 10. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 88% identical to SEQ ID NO: 10. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 90% identical to SEQ ID NO: 10. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 92% identical to SEQ ID NO: 10. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 95% identical to SEQ ID NO: 10. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 97% identical to SEQ ID NO: 10. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 98% identical to SEQ ID NO: 10. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 99% identical to SEQ ID NO: 10.

[0207] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 85% identical to SEQ ID NO: 11. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 88% identical to SEQ ID NO: 11. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 90% identical to SEQ ID NO: 11. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 92% identical to SEQ ID NO: 11. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 95% identical to SEQ ID NO: 11. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 97% identical to SEQ ID NO: 11. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 98% identical to SEQ ID NO: 11. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 99% identical to SEQ ID NO: 11.

[0208] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 85% identical to SEQ ID NO: 12. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 88% identical to SEQ ID NO: 12. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 90% identical to SEQ ID NO: 12. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 92% identical to SEQ ID NO: 12. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 95% identical to SEQ ID NO: 12. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 97% identical to SEQ ID NO: 12. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 98% identical to SEQ ID NO: 12. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 99% identical to SEQ ID NO: 12.

[0209] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 85% identical to SEQ ID NO: 13. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 88% identical to SEQ ID NO: 13. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 90% identical to SEQ ID NO: 13. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 92% identical to SEQ ID NO: 13. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 95% identical to SEQ ID NO: 13. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 97% identical to SEQ ID NO: 13. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 98% identical to SEQ ID NO: 13. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH sequence that is at least 99% identical to SEQ ID NO: 13.

[0210] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 85% identical to SEQ ID NO:4. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 88% identical to SEQ ID NO:4. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 90% identical to SEQ ID NO:4. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 92% identical to SEQ ID NO:4. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 95% identical to SEQ ID NO:4. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 96% identical to SEQ ID NO:4. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 97% identical to SEQ ID NO:4. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 98% identical to SEQ ID NO: 4. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 99% identical to SEQ ID NO: 4.

[0211] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 85% identical to SEQ ID NO:5. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 88% identical to SEQ ID NO:5. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 90% identical to SEQ ID NO:5. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 92% identical to SEQ ID NO:5. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 95% identical to SEQ ID NO:5. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 96% identical to SEQ ID NO:5. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 97% identical to SEQ ID NO:5. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 98% identical to SEQ ID NO: 5. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 99% identical to SEQ ID NO: 5.

[0212] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 85% identical to SEQ ID NO:6. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 88% identical to SEQ ID NO:6. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 90% identical to SEQ ID NO:6. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 92% identical to SEQ ID NO:6. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 95% identical to SEQ ID NO:6. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 96% identical to SEQ ID NO:6. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 97% identical to SEQ ID NO:6. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 98% identical to SEQ ID NO: 6. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 99% identical to SEQ ID NO: 6.

[0213] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 85% identical to SEQ ID NO:7. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 88% identical to SEQ ID NO:7. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 90% identical to SEQ ID NO:7. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 92% identical to SEQ ID NO:7. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 95% identical to SEQ ID NO:7. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 96% identical to SEQ ID NO:7. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 97% identical to SEQ ID NO:7. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 98% identical to SEQ ID NO: 7. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 99% identical to SEQ ID NO: 7.

[0214] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 85% identical to SEQ ID NO: 8. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 88% identical to SEQ ID NO: 8. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 90% identical to SEQ ID NO: 8. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 92% identical to SEQ ID NO: 8. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 95% identical to SEQ ID NO: 8. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 96% identical to SEQ ID NO: 8. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 97% identical to SEQ ID NO: 8. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 98% identical to SEQ ID NO: 8. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 99% identical to SEQ ID NO: 8.

[0215] In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 85% identical to SEQ ID NO:9. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 88% identical to SEQ ID NO:9. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 90% identical to SEQ ID NO:9. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 92% identical to SEQ ID NO:9. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 95% identical to SEQ ID NO:9. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 96% identical to SEQ ID NO:9. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 97% identical to SEQ ID NO:9. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 98% identical to SEQ ID NO: 9. In some embodiments, the anti-C3b antibody or antigen-binding fragment thereof comprises a VHH-Fc domain that is at least 99% identical to SEQ ID NO: 9.

[0216] In other embodiments, a suitable C3b antagonist is an anti-C3b antibody. The anti-C3b antibody of the present disclosure may be multispecific, e.g., bispecific. The antibody of the present disclosure may be mammalian (e.g., human, llama, or mouse), humanized, chimeric, recombinant, synthetically produced, or naturally isolated. Exemplary antibodies of the present disclosure include, but are not limited to, IgG (e.g., IgG1, IgG2, IgG3, and IgG4), IgM, IgA (e.g., IgA1, IgA2, and IgAsec), IgD, IgE, Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, scFv, scFv-Fc, and SMIP-binding moieties. In certain embodiments, the antibody is an scFv. The scFv may include a flexible linker that allows the scFv to orient in different directions, for example, to enable antigen binding. In various embodiments, the antibody may be a cytosol-stable scFv or intrabody that retains its structure and function in the reducing environment within the cell (e.g., Fisher and DeLisa, J. Mol. Biol. 385(1):299-311, 2009, incorporated herein by reference). In certain embodiments, the scFv is converted into an IgG or chimeric antigen receptor according to methods known in the art. In embodiments, the antibody binds to both denatured and native protein targets. In embodiments, the antibody binds to either denatured or native proteins.

[0217] In most mammals, including humans, whole antibodies have at least two heavy (H) chains and two light (L) chains connected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains (CH1, CH2, and CH3) and a hinge region between CH1 and CH2. Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region consists of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs), interspersed with more conserved regions called "framework regions" (FRs). Each VH and VL contains three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens.

[0218] Antibodies include all known forms of antibodies and other protein scaffolds with antibody-like properties. For example, anti-C3b antibodies can be monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, bispecific antibodies, monovalent antibodies, chimeric antibodies, or protein scaffolds with antibody-like properties, such as fibronectin or ankyrin repeats. Antibodies can have any of the following isotypes: IgG (e.g., IgG1, IgG2, IgG3, and IgG4), IgM, IgA (e.g., IgA1, IgA2, and IgAsec), IgD, or IgE.

[0219] An antibody fragment may comprise one or more segments derived from an antibody. Segments derived from an antibody may retain the ability to specifically bind to a particular antigen. An antibody fragment may be, for example, a Fab, Fab', Fab'2, F(ab')2, Fd, Fv, Feb, scFv, or SMIP. An antibody fragment may be, for example, a diabody, triabody, affibody, nanobody (VhH), aptamer, domain antibody, linear antibody, single-chain antibody, or any of a variety of multispecific antibodies that can be formed from antibody fragments.

[0220] Examples of antibody fragments include: (i) a Fab fragment: a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment: a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment: a fragment consisting of the VH and CH1 domains; (iv) a Fv fragment: a fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment: a fragment comprising the VH and VL domains; (vi) a dAb fragment: a fragment which is a VH domain; (vii) a dAb fragment: a fragment which is a VL domain; (viii) an isolated complementarity-determining region (CDR); and (ix) a combination of two or more isolated CDRs which may optionally be linked by one or more synthetic linkers. Furthermore, the two domains of an Fv fragment, VL and VH, are encoded by separate genes but can be linked using recombinant methods, for example, by a synthetic linker that allows them to be expressed as a single protein, with the VL and VH regions pairing to form a monovalent binding moiety (known as a single-chain Fv (scFv)). Antibody fragments may be obtained using conventional techniques known to those skilled in the art and, in some cases, may be used in the same manner as intact antibodies. Antigen-binding fragments can be produced by recombinant DNA technology or by enzymatic or chemical cleavage of intact immunoglobulins. Antibody fragments may further include any of the above-described antibody fragments with the addition of additional C-terminal amino acids, N-terminal amino acids, or amino acids separating the individual fragments.

[0221] An antibody may be called chimeric if it contains one or more antigenic determining regions or constant regions from a first species and one or more antigenic determining regions or constant regions from a second species. Chimeric antibodies may be constructed, for example, by genetic engineering. Chimeric antibodies may contain immunoglobulin gene segments belonging to different species (e.g., from mouse and human).

[0222] The antibody may be a human antibody. A human antibody refers to a binding moiety having variable regions in which both the framework and CDR regions are derived from human immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region is also derived from a human immunoglobulin sequence. A human antibody may contain one or more sequence variations, such as mutations, of amino acid residues not specified in human immunoglobulin sequences. The variations or additional amino acids may be introduced, for example, by human engineering. The human antibodies of the present disclosure are not chimeric.

[0223] An antibody may be humanized, meaning that an antibody containing one or more antigen-determining regions (e.g., at least one CDR) substantially derived from a non-human immunoglobulin or antibody has been engineered to contain at least one immunoglobulin domain substantially derived from a human immunoglobulin or antibody. An antibody may be humanized using the conversion methods described herein, e.g., by inserting an antigen-recognition sequence from a non-human antibody encoded by a first vector into a human framework encoded by a second vector. For example, a first vector may contain a polynucleotide encoding a non-human antibody (or fragment thereof) and site-specific recombination motifs, while a second vector may contain a polynucleotide encoding a human framework and site-specific recombination motifs complementary to the site-specific recombination motifs on the first vector. The site-specific recombination motifs may be positioned on each vector such that a recombination event results in the insertion of one or more antigen-determining regions from the non-human antibody into the human framework, thereby forming a polynucleotide encoding a humanized antibody.

[0224] In certain embodiments, the antibody is converted from scFv to IgG (e.g., IgG1, IgG2, IgG3, and IgG4). Various methods exist in the art for converting scFv fragments to IgG. One such method for converting scFv fragments to IgG is disclosed in U.S. Patent Application Publication No. 20160362476, the contents of which are incorporated herein by reference.

[0225] Specificity of anti-C3b antibodies In some embodiments, the anti-C3b antibody has a dissociation constant (K D ) binds to human or cynomolgus C3b. In some embodiments, K D is determined by surface plasma resonance assay (SPR). D is determined by ELISA.

[0226] In some embodiments, the anti-C3b antibody has selectivity for C3b over C3. In some embodiments, the anti-C3b antibody binds to C3b but not C3. In some embodiments, the anti-C3b antibody described herein binds to C3b with a binding affinity for C3b that is more than 5-fold higher than its binding affinity for C3. In some embodiments, the anti-C3b antibody described herein binds to C3b with a binding affinity for C3b that is more than 6-fold higher than its binding affinity for C3. In some embodiments, the anti-C3b antibody described herein binds to C3b with a binding affinity for C3b that is more than 7-fold higher than its binding affinity for C3. In some embodiments, the anti-C3b antibody described herein binds to C3b with a binding affinity for C3b that is more than 8-fold higher than its binding affinity for C3. In some embodiments, the anti-C3b antibody described herein binds to C3b with a binding affinity for C3b that is more than 9-fold higher than its binding affinity for C3. In some embodiments, the anti-C3b antibodies described herein bind to C3b with a binding affinity for C3b that is more than 10-fold higher than its binding affinity for C3. In some embodiments, the anti-C3b antibodies described herein bind to C3b with a binding affinity for C3b that is more than 12-fold higher than its binding affinity for C3. In some embodiments, the anti-C3b antibodies described herein bind to C3b with a binding affinity for C3b that is more than 15-fold higher than its binding affinity for C3. In some embodiments, the anti-C3b antibodies described herein bind to C3b with a binding affinity for C3b that is more than 17-fold higher than its binding affinity for C3. In some embodiments, the anti-C3b antibodies described herein bind to C3b with a binding affinity for C3b that is more than 20-fold higher than its binding affinity for C3. In some embodiments, the anti-C3b antibodies described herein bind to C3b with a binding affinity for C3b that is more than 7-fold higher, more than 10-fold higher, more than 15-fold higher, more than 20-fold higher, more than 25-fold higher, or more than 30-fold higher than its binding affinity for C3b. In some embodiments, the anti-C3b antibodies described herein have more than 2-fold higher selectivity for C3b over C3. In some embodiments, the anti-C3b antibodies described herein have more than 5-fold higher selectivity for C3b over C3.In some embodiments, the anti-C3b antibodies described herein have greater than 7-fold selectivity for C3b over C3. In some embodiments, the anti-C3b antibodies described herein have greater than 8-fold selectivity for C3b over C3. In some embodiments, the anti-C3b antibodies described herein have greater than 10-fold selectivity for C3b over C3. In some embodiments, the anti-C3b antibodies described herein have greater than 12-fold selectivity for C3b over C3. In some embodiments, the anti-C3b antibodies described herein have greater than 15-fold selectivity for C3b over C3. In some embodiments, the anti-C3b antibodies described herein have greater than 18-fold selectivity for C3b over C3. In some embodiments, the anti-C3b antibodies described herein have greater than 20-fold selectivity for C3b over C3. In some embodiments, the anti-C3b antibodies described herein have greater than 25-fold selectivity for C3b over C3. In some embodiments, the anti-C3b antibodies described herein are more than 30-fold more selective for C3b than C3.

[0227] In some embodiments, the anti-C3b antibody has a dissociation constant (K D In some embodiments, the anti-C3b antibody binds to C3 with a dissociation constant (K) of greater than 150 nM. D In some embodiments, the anti-C3b antibody binds to C3 with a dissociation constant (K) of greater than 200 nM. D In some embodiments, the anti-C3b antibody binds to C3 with a dissociation constant (K) of greater than 250 nM. D In some embodiments, the anti-C3b antibody binds to C3 with a dissociation constant (K) of greater than 300 nM. D In some embodiments, the anti-C3b antibody binds to C3 with a dissociation constant (K) of greater than 350 nM. D In some embodiments, the anti-C3b antibody binds to C3 with a dissociation constant (K) of greater than 400 nM. D In some embodiments, the anti-C3b antibody binds to C3 with a dissociation constant (K) of greater than 450 nM. D In some embodiments, the anti-C3b antibody binds to C3 with a dissociation constant (K) of greater than 500 nM. D) binds to C3. In some embodiments, K D is determined by surface plasma resonance assay (SPR). D is determined by ELISA.

[0228] In some embodiments, the anti-C3b antibody lacks effector functions to prevent C3b-bound cells from a cytotoxic effect.

[0229] Efficacy of anti-C3b antibodies In some embodiments, the anti-C3b antibody or fragment thereof has an EC50 of 0.1 ng / mL to 100 ng / mL.

[0230] In some embodiments, the anti-C3b antibody or fragment thereof has an IC50 of 0.1 nM to 100 nM. In some embodiments, the IC50 is measured by a C3 deposition assay. In some embodiments, the IC50 is measured by a hemolytic assay.

[0231] Anti-C3b antibody epitope The exemplary anti-C3b antibodies described herein have characteristics based on the distinct epitopes on C3b that are bound by the anti-C3b antibodies. The term "epitope" refers to the amino acids of a target molecule that are bound by the anti-C3b antibody when the antibody is bound to the target molecule. Epitopes can be contiguous or discontinuous (e.g., (i) in a single-chain polypeptide, amino acid residues that are not contiguous with each other in the polypeptide sequence but are bound by the antibody within the context of the target molecule, or (ii) in a multimeric protein comprising two or more individual components (e.g., an amino acid residue is present in one or more of the individual components but is still bound by the antibody)). Epitope determinants can include chemically active surface groups of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and can have specific three-dimensional structural features and / or specific charge characteristics. Generally, an antigen-binding protein specific for a particular target molecule will preferentially recognize an epitope on the target molecule in a complex mixture of proteins and / or macromolecules.

[0232] Methods for characterizing epitopes bound by antigen-binding proteins are well known in the art and include binning (cross-competition) (Miller et al., "Epitope binning of murine monoclonal antibodies by a multiplexed pairing assay," J. Immunol. Methods (2011) 365, 118-25), peptide mapping (e.g., PEPSPOT™) (Albert et al., "The B-cell Epitope of the Monoclonal Anti-Factor VIII Antibody ESH8 Characterized by Peptide Array Analysis," 2008 Thromb. Haemost. 99, 634-7), and mutagenesis methods such as chimeras (Song et al., "Epitope Mapping of Ibalizumab, a Humanized Anti-CD4 Monoclonal Antibody with Anti-HIV-1 Activity in Infected Patients," J. Virol.(2010) 84, 6935-6942), alanine scanning (Cunningham and Wells, "High-resolution epitope mapping of HGH-receptor interactions by alanine-scanning mutagenesis," Science (1989) 244, 1081-1085), arginine scanning (Lim et al., "A diversity of antibody epitopes can induce signaling through the erythropoietin receptor," Biochemistry (2010) 49, 3797-3804), HD exchange method (Coates et al., "Epitope mapping by amide hydrogen / deuterium exchange coupled with immobilization of antibody, on-line proteolysis, liquid chromatography, and mass spectrometry," Rapid Commun. Mass Spectrom. (2009) 23, 639-647), NMR cross-saturation method (Morgan et al., "Precise epitope mapping of malaria parasite inhibitory These include, but are not limited to, "antibodies by TROSY NMR cross-saturation" Biochemistry (2005) 44, 518-23), and crystallography (Gerhardt et al. "Structure of IL-17A in complex with a potent, fully human neutralizing antibody" J. Mol. Biol (2009) 394, 905-21). The level of detail they provide regarding the amino acids that comprise the epitope varies depending on the method.

[0233] Antibodies with identical or overlapping epitopes often cross-compete for binding to an antigen. Thus, in certain embodiments, an antibody of the present invention cross-competes with any one of Ab3-Ab35. "Cross-compete" or "cross-compete" means that an antibody competes for the same epitope or binding site on a target. Such competition can be determined by an assay in which a reference antigen-binding protein (e.g., an antibody or antigen-binding portion thereof) prevents or inhibits the specific binding of a test antibody, or vice versa. Many types of competitive binding assays can be used to determine whether a test molecule competes with a reference molecule for binding. Examples of assays that can be utilized include solid-phase direct or indirect radioimmunoassays (RIA), solid-phase direct or indirect enzyme immunoassays (EIA), sandwich competitive assays (see, e.g., Stahl et al. (1983) Methods in Enzymology 9:242-253), solid-phase direct biotin-avidin EIA (see, e.g., Kirkland et al., (1986) J. Immunol. 137:3614-9), solid-phase direct labeling assays, solid-phase direct labeling sandwich assays, Luminex (Jia et al. "A novel method of Multiplexed Competitive Antibody Binning for the characterization of monoclonal antibodies" J. Immunological Methods (2004) 288, 91-98), and surface plasmon resonance (Song et al. "Epitope Mapping of Ibalizumab, a Humanized Anti-CD4 Monoclonal Antibody with Anti-HIV-1 Activity in Examples include "Competitive Antibody in Infected Patients," J. Virol. (2010) 84, 6935-42. Typically, when a competing antibody is present in excess, it will inhibit binding of a reference antigen-binding protein to a common antigen by at least 50%, 55%, 60%, 65%, 70%, or 75%.In some instances, binding is inhibited by at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more.

[0234] Nucleic acids encoding C3b antagonists and anti-C3b antibodies In some embodiments, the present invention provides nucleic acids encoding, inter alia, C3b antagonists or anti-C3b antibodies. In some embodiments, the nucleic acids encode the CDRs of an anti-C3b antibody of the present invention. In some embodiments, the nucleic acids encode fragments of an anti-C3b antibody of the present invention. In some embodiments, the nucleic acids encode the variable regions of an anti-C3b antibody of the present invention. In some embodiments, the nucleic acids encode the variable heavy chain and / or variable light chain of an anti-C3b antibody of the present invention. In some embodiments, the nucleic acids encode VHHs of an anti-C3b antibody of the present invention. In some embodiments, the nucleic acids encode anti-C3b VHHs fused to an Fc domain.

[0235] In some embodiments, the nucleic acid is DNA. In some embodiments, the nucleic acid is cDNA. In some embodiments, the nucleic acid is RNA. In some embodiments, the nucleic acid is messenger RNA (mRNA).

[0236] In some embodiments, the present invention provides messenger RNA (mRNA) encoding, inter alia, a C3b antagonist or an anti-C3b antibody. In some embodiments, the mRNA encodes the CDRs of an anti-C3b antibody of the present invention. In some embodiments, the mRNA encodes a fragment of an anti-C3b antibody of the present invention. In some embodiments, the mRNA encodes the variable region of an anti-C3b antibody of the present invention. In some embodiments, the mRNA encodes the variable heavy chain and / or variable light chain of an anti-C3b antibody of the present invention. In some embodiments, the mRNA encodes a VHH of an anti-C3b antibody of the present invention. In some embodiments, the mRNA encodes an anti-C3b VHH fused to an Fc domain.

[0237] mRNA encoding anti-C3b antibody and its antigen-binding fragment In some embodiments, the present invention provides mRNA encoding an anti-C3b antibody or antigen-binding fragment thereof. In some embodiments, the mRNA encoding the anti-C3b antibody or antigen-binding fragment thereof is codon-optimized. In some embodiments, the present invention provides methods and compositions for delivering codon-optimized mRNA encoding an anti-C3b antibody or antigen-binding fragment thereof to a subject for the treatment of complement-mediated diseases. Suitable codon-optimized mRNA encodes any full-length, fragment, or portion of an anti-C3b antibody, such as a CDR, variable region, variable heavy chain, variable light chain, scFv, VHH, or VHH-Fc fusion.

[0238] mRNA synthesis The mRNA of the present invention can be synthesized according to any of various known methods.For example, the mRNA of the present invention can be synthesized through in vitro transcription (IVT).Briefly, IVT is typically carried out using a linear or circular DNA template containing a promoter, a pool of ribonucleotide triphosphates, a buffer system that may contain DTT and magnesium ions, and an appropriate RNA polymerase (for example, T3, T7, or SP6 RNA polymerase), DNAse I, pyrophosphatase, and / or RNAse inhibitor.The exact conditions vary depending on the specific application.

[0239] Exemplary mRNA Constructs Building design: 5'UTR-mRNA encoding antibody or fragment thereof-3'UTR Codon optimization Increasing research has shown that mRNA contains multiple layers of information that overlap with the amino acid code. Traditionally, codon optimization has been used to remove rare codons that are thought to be rate-limiting for protein expression. While rapidly growing bacteria and yeast both exhibit strong codon bias in highly expressed genes, higher eukaryotes exhibit much less codon bias, making it more difficult to identify codons that may be rate-limiting. Furthermore, it has been found that codon bias itself does not necessarily result in high expression, but rather requires other characteristics.

[0240] For example, rare codons are involved in translation slowing and the formation of pause sites, which may be required for correct protein folding. Therefore, variation in codon usage may provide a mechanism for fine-tuning the temporal pattern of elongation and thus increasing the time available for proteins to undergo correct folding. Codon optimization can interfere with this fine-tuning mechanism, resulting in less efficient protein translation or increased amounts of incorrectly folded protein. Similarly, codon optimization can disrupt normal patterns of cognate and wobble tRNA usage, thereby affecting protein structure and function, since wobble-dependent slowing of elongation may similarly be selected as a mechanism for achieving correct protein folding.

[0241] Various methods for performing codon optimization are known in the art, but each has significant drawbacks and limitations from a computational and / or therapeutic perspective. In particular, known methods of codon optimization often involve, for each amino acid, replacing each codon with the codon with the highest usage for that amino acid, resulting in an "optimized" sequence containing only one codon encoding each amino acid (and thus may be referred to as a one-to-one sequence). Increased expression is not limited to mammalian cell cultures, but has also been observed in vivo in mouse models. The observed improvement in expression of codon-optimized coding sequences is expected to provide improved, more cost-effective mRNA replacement therapy to patients in need thereof, as it does not require the use of modified nucleotides in mRNA preparation, allowing treatment with reduced doses and / or extended administration intervals.

[0242] In some embodiments, codon-optimized mRNA is produced according to methods known in the art.

[0243] nucleotide Various naturally occurring or modified nucleosides may be used to produce mRNA according to the present invention. In some embodiments, mRNA is prepared using natural nucleosides (e.g., adenosine, guanosine, cytidine, uridine), nucleoside analogs (e.g., 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyladenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 7-deazaguanosine, 7-deaza-uridine, 7-methylcytidine, C-5 propynyl-uridine, C-5 propynyl-uridine, C-5 propynyl-uridine, C-5 propynyl-uridine, C-5 propynyl-uridine, C-5 propynyl-uridine, C-5 propynyl-uridine, C-5 methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 7-methylcytidine, C-5 propynyl-ur ... methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-methylcytidine, C-5 propynyl-uridine, C-5 propynyl-uridine, C-5 propynyl-uridine, C-5 The bases may be or contain nucleotides such as 2'-amino-2'-methyl-2'-pyridinone, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, pseudouridine (e.g., N-1-methyl-pseudouridine), 2-thiouridine, and 2-thiocytidine), chemically modified bases, biologically modified bases (e.g., methylated bases), intercalated bases, modified sugars (e.g., 2'-fluororibose, ribose, 2'-deoxyribose, arabinose, and hexose), and / or modified phosphate groups (e.g., phosphorothioate and 5'-N-phosphoramidite linkages).

[0244] In some embodiments, the mRNA contains one or more non-standard nucleotide residues. Non-standard nucleotide residues can include, for example, 5-methyl-cytidine ("5mC"), pseudouridine ("ψU"), and / or 2-thio-uridine ("2sU"). For a discussion of such residues and their incorporation into mRNA, see, for example, U.S. Pat. No. 8,278,036 or WO2011012316. The mRNA can also be RNA, which is defined as RNA in which 25% of U residues are 2-thio-uridine and 25% of C residues are 5-methylcytidine. Teachings for the use of RNA are disclosed in U.S. Patent Publication No. US20120195936 and International Publication No. WO2011012316, both of which are incorporated herein by reference in their entireties. The presence of non-standard nucleotide residues can make an mRNA more stable and / or less immunogenic than a control mRNA with the same sequence but containing only standard residues. In further embodiments, the mRNA can contain one or more non-standard nucleotide residues selected from isocytosine, pseudoisocytosine, 5-bromouracil, 5-propynyluracil, 6-aminopurine, 2-aminopurine, inosine, diaminopurine, and 2-chloro-6-aminopurine cytosine, as well as combinations of these and other nucleobase modifications. Some embodiments can further include additional modifications to the furanose ring or nucleobase. Additional modifications can include, for example, sugar modifications or substitutions (e.g., one or more of 2'-O-alkyl modifications, locked nucleic acids (LNAs)). In some embodiments, the RNA can be complexed or hybridized with additional polynucleotides and / or peptide polynucleotides (PNAs). In some embodiments, where the sugar modification is a 2'-O-alkyl modification, such modifications may include, but are not limited to, 2'-deoxy-2'-fluoro, 2'-O-methyl, 2'-O-methoxyethyl, and 2'-deoxy modifications. In some embodiments, any of these modifications may be present individually or in combination in 0-100% of the nucleotides, e.g., 0%, 1%, 10%, 25%, 50%, 75%, 85%, 90%, 95%, or greater than 100% of the constituent nucleotides.

[0245] Post-synthesis processing Typically, a 5' cap and / or 3' tail can be added post-synthetically. The presence of a cap is important in providing resistance to nucleases found in most eukaryotic cells. The presence of a "tail" helps protect the mRNA from exonuclease degradation.

[0246] A 5' cap is typically added as follows: first, an RNA terminal phosphatase removes one of the terminal phosphate groups from the 5' nucleotide, leaving two terminal phosphates; then, guanosine triphosphate (GTP) is added to the terminal phosphate via a guanylyltransferase, resulting in a 5'5'5 triphosphate linkage; then, the 7 nitrogen of guanine is methylated by a methyltransferase. Examples of cap structures include, but are not limited to, mG(5')ppp(5'(A), G(5')ppp(5')A, and G(5')ppp(5')G. Additional cap structures are described in published U.S. patent application Ser. No. 2016 / 0032356 and U.S. provisional patent application Ser. No. 62 / 464,327, filed Feb. 27, 2017, which are incorporated herein by reference.

[0247] Typically, the tail structure comprises a poly(A) and / or poly(C) tail. The poly(A) or poly(C) tail on the 3' end of an mRNA typically comprises at least 50 adenosine or cytosine nucleotides, at least 150 adenosine or cytosine nucleotides, at least 200 adenosine or cytosine nucleotides, at least 250 adenosine or cytosine nucleotides, at least 300 adenosine or cytosine nucleotides, at least 350 adenosine or cytosine nucleotides, at least 400 adenosine or cytosine nucleotides, at least 450 adenosine or cytosine nucleotides, at least 500 adenosine or cytosine nucleotides, At least 550 adenosine or cytosine nucleotides, at least 600 adenosine or cytosine nucleotides, at least 650 adenosine or cytosine nucleotides, at least 700 adenosine or cytosine nucleotides, at least 750 adenosine or cytosine nucleotides, at least 800 adenosine or cytosine nucleotides, at least 850 adenosine or cytosine nucleotides, at least 900 adenosine or cytosine nucleotides, at least 950 adenosine or cytosine nucleotides, or at least 1 kb of adenosine or cytosine nucleotides.In some embodiments, the polyA or polyC tail comprises about 10 to 800 adenosine or cytosine nucleotides, respectively (e.g., about 10 to 200 adenosine or cytosine nucleotides, about 10 to 300 adenosine or cytosine nucleotides, about 10 to 400 adenosine or cytosine nucleotides, about 10 to 500 adenosine or cytosine nucleotides, about 10 to 550 adenosine or cytosine nucleotides, about 10 to 600 adenosine or cytosine nucleotides, about 50 to 600 adenosine or cytosine nucleotides, about 100 to 600 adenosine or cytosine nucleotides, about 150 to 600 adenosine or cytosine nucleotides, about 20 ...200 to 300 adenosine or cytosine nucleotides, about 200 to 300 adenosine or cytosine nucleotides, about The poly(A) tail may be 600 adenosine or cytosine nucleotides, about 250-600 adenosine or cytosine nucleotides, about 300-600 adenosine or cytosine nucleotides, about 350-600 adenosine or cytosine nucleotides, about 400-600 adenosine or cytosine nucleotides, about 450-600 adenosine or cytosine nucleotides, about 500-600 adenosine or cytosine nucleotides, about 10-150 adenosine or cytosine nucleotides, about 10-100 adenosine or cytosine nucleotides, about 20-70 adenosine or cytosine nucleotides, or about 20-60 adenosine or cytosine nucleotides. In some embodiments, the tail structure comprises a combination of poly(A) and poly(C) tails of various lengths as described herein. In some embodiments, the tail structure comprises at least 50%, 55%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, or 99% adenosine nucleotides, hi some embodiments, the tail structure comprises at least 50%, 55%, 65%, 70%, 75%, 80%, 85%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, or 99% cytosine nucleotides.

[0248] As described herein, the addition of a 5' cap and / or 3' tail facilitates the detection of abortive transcripts generated during in vitro synthesis, since without capping and / or tailing, these prematurely terminated mRNA transcripts may be too small to be detected. Thus, in some embodiments, a 5' cap and / or 3' tail is added to a synthesized mRNA before the mRNA is tested for purity (e.g., the level of abortive transcripts present in the mRNA). In some embodiments, a 5' cap and / or 3' tail is added to a synthesized mRNA before the mRNA is purified as described herein. In other embodiments, a 5' cap and / or 3' tail is added to a synthesized mRNA after the mRNA is purified as described herein.

[0249] Delivery Vehicle According to the present invention, mRNA encoding the anti-C3b antibodies or antigen-binding fragments described herein can be delivered as naked RNA (unpackaged) or via a delivery vehicle. As used herein, the terms "delivery vehicle," "carrier vehicle," "nanoparticle," or grammatical equivalents are used interchangeably.

[0250] The delivery vehicle may be formulated in a pharmacological composition in combination with one or more additional nucleic acids, carriers, targeting ligands, or stabilizing reagents, or mixed with a suitable excipient. Techniques for drug formulation and administration can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., latest edition. A particular delivery vehicle is selected based on its ability to facilitate transfection of the nucleic acid into target cells.

[0251] Liposomal Delivery Vehicles In some embodiments, a suitable delivery vehicle is a liposome delivery vehicle, such as a lipid nanoparticle (LNP). As used herein, a liposome delivery vehicle, such as a lipid nanoparticle, is generally characterized as a microscopic vesicle having an internal aqueous space separated from the external medium by one or more bilayer membranes. The bilayer membrane of a liposome is typically formed by amphiphilic molecules, such as lipids of synthetic or natural origin, containing spatially separated hydrophilic and hydrophobic domains (Lasic, Trends Biotechnol., 16:307-321, 1998). The bilayer membrane of a liposome can also be formed by amphiphilic polymers and surfactants (e.g., polymersomes, niosomes, etc.). In the context of the present invention, a liposome delivery vehicle typically serves to transport the desired mRNA to target cells or tissues. In some embodiments, the nanoparticle delivery vehicle is a liposome. In some embodiments, the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids, and one or more PEG-modified lipids.

[0252] Therapeutic Uses of the Composition In one aspect, the present invention provides methods for inducing anti-C3b antibody expression in vivo, particularly by administering a nucleic acid encoding an anti-C3b antibody or a fragment thereof, or by administering an anti-C3b antibody. In some embodiments, the composition comprises a nucleic acid encapsulated or complexed with a delivery vehicle. In some embodiments, the delivery vehicle is selected from the group consisting of a liposome, a lipid nanoparticle, a solid lipid nanoparticle, a polymer, a virus, a sol-gel, and a nanogel. In some embodiments, the nucleic acid encoding the anti-C3b antibody or a fragment thereof is packaged in a viral particle.

[0253] gene therapy In some embodiments, a pharmaceutical composition containing a nucleic acid encoding an anti-C3b antibody or a fragment thereof is used to treat a subject in need thereof. In some embodiments, a pharmaceutical composition containing the rAAV vector described herein is used to treat a subject in need thereof. Pharmaceutical compositions containing the rAAV vectors or particles of the present invention contain a pharmaceutically acceptable excipient, diluent, or carrier. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate-buffered saline, water, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions, etc. The pharmaceutical composition may be in lyophilized form. Such carriers can be formulated by conventional methods and administered to a subject in a therapeutically effective amount.

[0254] The rAAV vector is administered to a subject in need thereof via a suitable route. In some embodiments, the rAAV vector is administered intravenously, intraperitoneally, subcutaneously, or intradermally. In one embodiment, the rAAV vector is administered intravenously. In embodiments, intradermal administration includes administration using a "gene gun" or biolistic particle delivery system. In some embodiments, the rAAV vector is administered via a non-viral lipid nanoparticle. For example, a composition comprising an rAAV vector may include one or more diluents, buffers, liposomes, lipids, or lipid complexes. In some embodiments, the rAAV vector is contained within a microparticle or nanoparticle, such as a lipid nanoparticle or an inorganic nanoparticle.

[0255] In some embodiments, the rAAV is pseudotyped. Pseudotyped rAAV is an infectious virus containing any combination of AAV capsid proteins and rAAV genomes. Pseudotyped rAAV is useful for changing the tissue or cell specificity of rAAV and can be used alone or in conjunction with non-pseudotyped rAAV to deliver one or more genes to cells, for example, mammalian cells. For example, pseudotyped rAAV can be used following administration of non-pseudotyped rAAV in mammals that have generated an immune response against the non-pseudotyped rAAV. Capsid proteins from any AAV serotype can be derived from or obtainable from wild-type AAV genomes of different serotypes, or can be used with rAAV genomes that are chimeric genomes, i.e., rAAV genomes that are chimeric genomes with two ITRs, where each ITR is derived from a different serotype or a chimeric ITR. The use of chimeric genomes, such as those containing ITRs from two AAV serotypes or chimeric ITRs, can result in oriented recombination, which can further enhance the production of transcriptionally active intermolecular concatemers. Thus, the 5' and 3' ITRs in the rAAV vectors of the invention can be homologous, i.e., from the same serotype, heterologous, i.e., from different serotypes, or chimeric, i.e., from ITRs with ITR sequences from more than two AAV serotypes.

[0256] In some embodiments, the rAAV vector is an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, or AAV11 vector. In some embodiments, the rAAV vector is AAV1. In some embodiments, the rAAV vector is AAV2. In some embodiments, the rAAV vector is AAV3. In some embodiments, the rAAV vector is AAV4. In some embodiments, the rAAV vector is AAV5. In some embodiments, the rAAV vector is AAV6. In some embodiments, the rAAV vector is AAV7. In some embodiments, the rAAV vector is AAV8. In some embodiments, the rAAV vector is AAV9. In some embodiments, the rAAV vector is AAV10. In some embodiments, the rAAV vector is AAV11. In some embodiments, the rAAV vector is sequence optimized. In some embodiments, the rAAV capsid is modified. For example, in some embodiments, the rAAV8 capsid is modified.

[0257] Treatment with C3b antagonists or anti-C3b antibodies In some embodiments, the invention provides methods of treating complement-mediated disorders (e.g., C3 glomerulopathy) by administering, inter alia, a C3b antagonist or anti-C3b antibody. In some embodiments, the invention provides methods of treating complement-mediated disorders in a subject comprising, inter alia, administering to the subject a C3b antagonist or anti-C3b antibody at a therapeutically effective dose and between doses for a treatment period sufficient to ameliorate, stabilize, or reduce one or more symptoms of the disorder. In some embodiments, the invention provides methods of treating complement-mediated disorders in a subject comprising, inter alia, administering to the subject a composition comprising a nucleic acid encoding a C3b antagonist or anti-C3b antibody at a therapeutically effective dose and between doses for a treatment period sufficient to ameliorate, stabilize, or reduce one or more symptoms of the disorder. In some embodiments, the present invention provides, inter alia, methods for treating a complement-mediated disorder in a subject comprising administering to the subject a composition comprising mRNA encoding a C3b antagonist or an anti-C3b antibody at a therapeutically effective dose and at a treatment interval sufficient to ameliorate, stabilize, or reduce one or more symptoms of the disorder.

[0258] Complement-mediated disorders Many autoimmune diseases are characterized by the production of autoantibodies that bind to host proteins or deposits in tissues as components of immune complexes. Autoantibodies can activate the complement system, which can mediate tissue damage and induce systemic inflammation. Therefore, complement inhibitors may be beneficial across a number of different autoimmune diseases.

[0259] C3 glomerulopathy (C3G) is a rare disease characterized by the accumulation of complement factors in the glomerulus due to overactivation and abnormal regulation of the alternative complement pathway (AP). It is an ultra-rare disease with an annual incidence of approximately 1 to 3 million cases. C3 glomerulopathy is an umbrella term for a spectrum of related diseases or disorders characterized by the accumulation of the C3 component of complement in renal tissue. Abnormal regulation of the AP of complement can result from acquired or genetic abnormalities in complement regulatory proteins. Complement factor deposition leads to glomerular inflammation and may also result in proliferative glomerulonephritis. The most common diseases under the C3G umbrella are C3 glomerulonephritis (C3GN), which is characterized by mesangial, subendothelial, and intramembranous deposits, and dense deposit disease (DDD), which is characterized by dense deposits along the glomerular and tubular basement membranes. Disease presentation ranges from asymptomatic hematuria and proteinuria to acute presentation with classic signs and symptoms of glomerulonephritis. C3 glomerulopathy is driven by acquired factors (anti-C3 and C5 convertase autoantibodies) and genetic mutations in complement-related genes. These autoantibodies drive complement dysregulation by prolonging the half-life of vital but usually short-lived enzymes. Genetic mutations in factor H, complement factor H-related (CFHR) protein, and C3 can result in impaired regulation of C3 convertase.

[0260] Other diseases associated with AP overactivation include paroxysmal nocturnal hemoglobinuria (PNH) with extravascular hemolysis, a rare acquired blood disorder in which RBCs are targeted by C3b rather than MAC. C5 inhibitors are ineffective in patients with PNH, and this remains a major unmet medical need. Geographic atrophy (GA) is another complication associated with AP overactivation. It is a progressive symptom of age-related macular degeneration (AMD), characterized by the progressive and irreversible loss of retinal pigment epithelium and photoreceptors and is the leading cause of legal blindness. 98% of patients with wet AMD develop GA despite anti-VEGF treatment.

[0261] In one aspect, the present invention provides a method of treating a disease or disorder, the method comprising administering a therapeutically effective amount of an anti-C3b antibody or fragment thereof to a subject in need thereof. In some embodiments, the disease or disorder is a complement-mediated disorder. In some embodiments, the disease or disorder is C3 glomerulopathy. In some embodiments, the disease or disorder is associated with C3 glomerulopathy. In some embodiments, the disease or disorder is dense deposit disease. In some embodiments, the disease or disorder is C3 glomerulonephritis (C3GN). In some embodiments, the disease or disorder is a disorder characterized by accumulation of the C3 component of complement in renal tissue. In some embodiments, the disease or disorder is hematuria. In some embodiments, the disease or disorder is proteinuria. In some embodiments, the disease or disorder is acute kidney injury (AKI). In some embodiments, the disease or disorder is chronic kidney disease (CKD). In some embodiments, the disease or disorder is associated with AP hyperactivation. In some embodiments, the disease or disorder is paroxysmal nocturnal hemoglobinuria. In some embodiments, the disease or disorder is geographic atrophy (GA). In some embodiments, the disease or disorder is autoimmune hemolytic anemia (AIHA). In some embodiments, the disease or disorder is age-related macular degeneration (AMD). In some embodiments, the disease or disorder is wet age-related macular degeneration (wAMD). In some embodiments, the disease or disorder is passive Heymann nephritis (PHN). In some embodiments, the disease or disorder is rheumatoid arthritis (RA). In some embodiments, the disease or disorder is collagen antibody-induced arthritis (CAIA). In some embodiments, the disease or disorder is caused by a genetic mutation in factor H. In some embodiments, the disease or disorder is caused by a genetic mutation in the CFHR protein. In some embodiments, the disease or disorder is caused by a genetic mutation in C43. In some embodiments, the disease is driven by an acquired factor. In some embodiments, the acquired factor is an anti-C3 autoantibody. In some embodiments, the acquired factor is a C5 convertase autoantibody.

[0262] Effect of anti-C3b antibody In some embodiments, administration of the anti-C3b antibody or fragment thereof inhibits C3 deposition in the subject. In some embodiments, administration of the anti-C3b antibody or fragment thereof inhibits C3 activity or C3 activation.

[0263] In some embodiments, administration of an anti-C3b antibody or a fragment thereof inhibits the alternative pathway (AP). In some embodiments, administration of an anti-C3b antibody or a fragment thereof inhibits the classical pathway (CP). In some embodiments, administration of an anti-C3b antibody or a fragment thereof inhibits both the alternative pathway (AP) and the classical pathway (CP). In some embodiments, administration of an anti-C3b antibody or a fragment thereof inhibits the alternative pathway (AP) but not the classical pathway (CP). In some embodiments, the level of AP inhibition is higher than the level of CP inhibition. In some embodiments, the level of AP inhibition is about 2-fold or more than the level of CP inhibition. In some embodiments, the level of AP inhibition is about 3-fold or more than the level of CP inhibition. In some embodiments, the level of AP inhibition is about 4-fold or more than the level of CP inhibition. In some embodiments, the level of AP inhibition is about 5-fold or more than the level of CP inhibition. In some embodiments, the level of AP inhibition is about 8-fold or more than the level of CP inhibition. In some embodiments, the level of AP inhibition is about 10-fold or more than the level of CP inhibition.

[0264] In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits complement factor B binding to C3. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 10% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 15% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 20% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 25% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 30% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 40% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 45% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 50% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 60% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 70% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 80% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 85% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 90% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 95% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits factor B binding to C3 by about 99% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof completely inhibits binding of factor B to C3b.In some embodiments, administration of an anti-C3b antibody or fragment thereof partially inhibits binding of factor B to C3b.

[0265] In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 10% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 15% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 20% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 25% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 30% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 40% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 45% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3 by about 50% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 60% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 70% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 80% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 85% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 90% compared to baseline. In some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 95% compared to baseline, hi some embodiments, administration of an anti-C3b antibody or fragment thereof inhibits P factor binding to C3bBb by about 99% compared to baseline.In some embodiments, administration of an anti-C3b antibody or fragment thereof completely inhibits binding of factor P to C3bBb. In some embodiments, administration of an anti-C3b antibody or fragment thereof partially inhibits binding of factor P to C3bBb.

[0266] Pharmaceutical Compositions and Administration The antibodies or agents of the present invention (also referred to herein as "active compounds"), as well as their derivatives, fragments, analogs, and homologs, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the antibody or agent and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles, such as liposomes and fixed oils, can also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, its use in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0267] The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, intravitreal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents such as sterile water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium sulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, or phosphates; and agents for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0268] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0269] Sterile injectable solution can be prepared by incorporating the required amount of active compound in one or combination of the above-listed components in suitable solvent, as needed, and then sterilize by filtration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains basic dispersion medium and other components that are required from the above-listed components.For the preparation of sterile powder for sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which obtains powder of active ingredient and any additional desired components from the solution that has been previously sterilized and filtered.

[0270] Oral compositions generally contain an inert diluent or edible carrier.They can be enclosed in gelatin capsules or compressed into tablets.For the purpose of oral therapeutic administration, active compounds can be incorporated with excipients and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the compound in the fluid carrier is orally applied, swished, expectorated or swallowed.Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavor, or the like.

[0271] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0272] Systemic administration can also be via transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, and include, for example, for transmucosal administration, surfactants, bile salts, and fusidic acid derivatives.Transmucosal administration can be achieved through the use of nasal sprays or suppositories.For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams generally known in the art.

[0273] The compounds can also be prepared in the form of suppositories (eg, with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0274] In one embodiment, the active compound may be prepared with a carrier that protects the compound from rapid release from the body, such as a controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such formulations will be apparent to those skilled in the art. Materials are commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeting infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0275] For ease of administration and uniformity of dosage, it is particularly advantageous to prepare oral or parenteral compositions in unit dosage form.As used herein, unit dosage form refers to a physically separate unit that is suitable as a unit dose for the subject to be treated, and each unit contains a predetermined amount of active compound that is calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification of unit dosage form of the present invention is determined and directly depends on the inherent characteristics of active compound and the specific therapeutic effect that should be achieved, and the inherent limitation of the technology that combines this active compound for individual treatment.

[0276] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0277] Administration method In certain embodiments, the anti-C3b antibody is administered by any route suitable for administering an anti-C3b antibody, such as, for example, intravenously or subcutaneously.

[0278] In some embodiments, a single administration of anti-C3b antibody is sufficient to improve, stabilize, or reduce one or more symptoms for 5 days, 1 week, 2 weeks, 4 weeks, 5 weeks, 7 weeks, 12 weeks, or more.

[0279] In some embodiments, a single administration of anti-C3b antibody is sufficient to ameliorate, stabilize, or reduce one or more symptoms such that the subject does not require repeated administrations.

[0280] The therapeutically effective amount of the anti-C3b antibody-containing pharmaceutical composition to be used will depend, for example, on the therapeutic situation and purpose. Those skilled in the art will understand that appropriate dosage levels for treatment will vary, in part, depending on the molecule being delivered, the indication for which the anti-C3b antibody is being used, the route of administration, and the patient's size (weight, body surface, or organ size) and / or condition (age and general health). In certain embodiments, clinicians may titrate the dosage and modify the route of administration to obtain optimal therapeutic effects. Typical dosages can range from about 0.1 μg / kg up to about 1000 mg / kg or more, depending on the factors described above.

[0281] In some embodiments, the therapeutically effective dose is between about 1 mg and 1000 mg. In some embodiments, the therapeutically effective dose is between about 10 mg and 500 mg. [Example]

[0282] Although certain compounds, compositions, and methods of the invention have been described as being particular in accordance with certain embodiments, the following examples serve only to illustrate the invention and are not intended to limit the invention. Although certain compounds, compositions, and methods of the invention have been described as being particular in accordance with certain embodiments, the following examples serve only to illustrate the invention and are not intended to limit the invention.

[0283] Example 1. Pharmacokinetic analysis of anti-C3b antibodies. In this study, the pharmacokinetics of anti-C3b antibodies were determined in non-human primates. First, Ab1 (anti-C3b VHH fused to modified IgG4 Fc) and control Ab (IC12, control antibody) were administered intravenously at 10 mg / kg to cynomolgus monkeys. The characteristics of each antibody are shown in Table 1. Plasma samples were collected before administration and at 30 minutes, 6 hours, 24 hours, 48 ​​hours, 120 hours, 336 hours, 456 hours, 672 hours, and 792 hours after administration, and the percentage of remaining antibody was measured. [Table 1]

[0284] Figure 1A shows plasma levels of Ab1 (repeated twice) and control Ab over a 20-day period. Ab1 was observed to persist in serum for more than 15 days. Figure 1B shows the percentage of Ab1 (repeated twice) and control Ab over a 20-day period. The data show that a significantly higher percentage of antibody remained over time for Ab1 compared to the control Ab.

[0285] To confirm that the C3b antibodies of the present invention bind to human C3b with high affinity in addition to cynomolgus monkey C3b, the concentrations of human C3b or antibodies to cynomolgus monkey C3b were measured. As shown in Figures 1C and 1D, Ab1 binds to human C3b with high affinity, approximately 100-fold higher than that of cynomolgus monkey C3b.

[0286] Next, the pharmacodynamic effects of anti-C3b Ab1 and a control Ab were evaluated. Ex vivo C3 deposition studies were performed at 3% serum concentration, and inhibition of C3 deposition was measured over time. Figure 1E shows plasma antibody levels, and Figure 1F shows inhibition of C3 deposition. Under these conditions, the PD effect observed for Ab1 lasted for more than 14 days. Furthermore, the PK / PD of the control Ab demonstrates the importance of inhibition of the C3(HO)-mediated migration mechanism for target-mediated drug disposal (TMDD).

[0287] Example 2. Inhibition of C3 convertase in wet age-related macular degeneration (AMD) by C3b antibodies Wet age-related macular degeneration (wAMD) is the less common but most severe form of AMD and is one of the leading causes of blindness in older adults. wAMD is characterized by choroidal neovascularization (CMV) and acute vision loss. The retina is particularly vulnerable to oxidative damage, which leads to complement activation and histogenesis of AMD. Current treatment involves monthly intravitreal injections of anti-VEGF antibodies.

[0288] This example demonstrates the efficacy of the C3b antibody of the present invention in treating wAMD using a mouse laser-induced choroidal neovascularization (CNV) model. wAMD-like disease is induced in mice by laser-induced damage to the retinal basement membrane (Bruch's membrane) located at four spots around the optic nerve. The damage induces neovascularization from the underlying capillary layer (choroid) to the retina, resulting in an inflammatory response. [Table 2]

[0289] Mice were intravitreally administered vehicle or antibody as shown in Table 2, and ocular imaging was performed on days 0, 1, 3, and 7 according to the study design shown in Figure 2. Specifically, two ocular imaging techniques were used in this example. First, surface imaging by fluorescein angiography (FA), which uses sodium fluorescein to visualize the ocular vasculature. The extent of CNV is determined by a vasculopathy-based scoring system and by the size of the CNV surface area, as shown below. Second, ocular imaging is performed by cross-sectional imaging by optical coherence tomography (OTC). The extent of CNV is determined by the size of the CNV cross-sectional area. [Table 5]

[0290] Figure 3A shows the FA leakage area after treatment with each antibody on day 7. Figure 3B shows the OCT leakage area after treatment with each antibody on day 7. Table 3 shows the percent reduction in OCT area and FA leakage compared to vehicle control. The data show that both Ab2 and Ab3 provided at least approximately 30% protection in mice on day 7. The alternative pathway is only partially involved in CNV pathology (approximately 35%). Thus, a 30% reduction in disease suggests that the C3b antibody of the present invention was highly effective in blocking the contribution of AP to disease progression. [Table 3]

[0291] Example 3. Efficacy of C3b antibody against passive Heymann nephritis (PHN) Passive Heymann nephritis (PHN) mimics human idiopathic membranous nephritis (iMN), which is induced by autoantibodies against the podocyte antigen PLA2-R. PHN is induced in rats by nephrotoxic serum (Fx1A), which targets megalin, a nephrite protein found on the surface of podocytes and proximal tubules.

[0292] This experiment evaluated the use of C3b antibody in a PHN mouse model. The study design for this experiment is shown in Figure 4. The PHN phenotype was induced in PHN model mice by challenge with nephrotoxic serum (Fx1A) that targets megalin. PHN mice were treated with the antibodies shown in Table 4 on day 2, administered intravenously twice a week. Serum and urinary biomarkers, as well as renal histology, were evaluated to assess the efficacy of the treatment groups. [Table 4]

[0293] Figure 5A shows the albumin to creatinine ratio (urinary biomarker) in PHN mouse models treated with different doses of Ab2 compared with mice treated with positive and negative controls. We observed that treatment with 50 mg / kg Ab2 resulted in a significantly lower albumin to creatinine ratio. Then, the total protein to creatinine ratio was determined, as shown in Figure 5B.

[0294] Example 4. Efficacy of C3b antibody against collagen antibody-induced arthritis (CAIA) mouse model of RA This experiment evaluated the use of C3b antibodies in collagen type II-specific monoclonal antibody-induced arthritis (CAIA). A schematic diagram of the study design is shown in Figure 6A. Anti-C3b VHH fused to Fc (Ab2) was administered at various concentrations on days 6, 9, and 13. MVZ antibody was used as a positive control, and dexamethasone was used as a negative control. Figure 6B shows a dose-dependent reduction in paw volume in mice in response to treatment with Ab2. The data indicate that protection appears to be primarily correlated with the first dose given on day 6 of the study.

[0295] Example 5. Efficacy of C3b antibodies against C3 convertase activity in C3G patients This experiment evaluated the effectiveness of C3b antibodies in inhibiting C3 convertase activity in the serum of human complement 3 glomerulopathy (C3G) patients. C3G patient samples were collected, and ex vivo C3 convertase inhibition was measured by a C3 deposition assay according to methods known in the art. AMY-101 (a C3 inhibitor) and LNP023 were used as controls. The anti-C3b antibody used in this particular assay was Ab4, which comprises the VHH of SEQ ID NO: 13 fused to the Fc domain of SEQ ID NO: 14. As shown in Figure 7, Ab4 was particularly effective at inhibiting C3 deposition compared to the control.

[0296] equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the following claims.

Claims

1. An antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity-determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises NYHMG (SEQ ID NO: 16), CDR2 comprises TIIRTGETIYYADSVKG (SEQ ID NO: 17), and CDR3 comprises ATSGWNIKTVTPYEY (SEQ ID NO: 18).

2. An antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity-determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises GRTFSNY (SEQ ID NO: 19), CDR2 comprises IRTGET (SEQ ID NO: 20), and CDR3 comprises ATSGWNIKTVTPYEY (SEQ ID NO: 18).

3. An antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises NYHMG (SEQ ID NO: 16), CDR2 comprises TIIRHGTTIYYADSVKG (SEQ ID NO: 26), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

4. An antibody or antigen-binding fragment thereof that binds to C3b, wherein the binding portion comprises three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises GRTFSNY (SEQ ID NO: 19), CDR2 comprises IRHGTT (SEQ ID NO: 27), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

5. An antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity-determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises NYHMG (SEQ ID NO: 16), CDR2 comprises TIIRTGKTIYYADSVKG (SEQ ID NO: 21), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

6. An antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity-determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises GRTFSNY (SEQ ID NO: 19), CDR2 comprises IRTGKT (SEQ ID NO: 23), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

7. An antibody or antigen-binding fragment thereof that binds to C3b, comprising three complementarity-determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises NYHMG (SEQ ID NO: 16), CDR2 comprises TIIRTGTTIYYADSVKG (SEQ ID NO: 24), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

8. An antibody or antigen-binding fragment thereof that binds to C3b, wherein the binding portion comprises three complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR1 comprises GRTFSNY (SEQ ID NO: 19), CDR2 comprises IRTGTT (SEQ ID NO: 25), and CDR3 comprises ATSGWHIKTVTPYEY (SEQ ID NO: 22).

9. An antibody or antigen-binding fragment thereof that binds to complement component 3b (C3b), comprising an amino acid sequence that is at least 90% identical to any of SEQ ID NOs: 10-13.

10. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, wherein the antibody or antigen-binding fragment thereof is a VHH.

11. The antibody or antigen-binding fragment thereof of claim 10, wherein the VHH comprises SEQ ID NO:

10.

12. The antibody or antigen-binding fragment thereof of claim 10, wherein the VHH comprises SEQ ID NO:

11.

13. The antibody or antigen-binding fragment thereof of claim 10, wherein the VHH comprises SEQ ID NO:

12.

14. The antibody or antigen-binding fragment thereof of claim 10, wherein the VHH comprises SEQ ID NO:

13.

15. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 14, further comprising an Fc domain, wherein the Fc domain is derived from IgG1, IgG2, IgG3, or IgG4.

16. The antibody or antigen-binding fragment thereof of claim 15, wherein the Fc domain is derived from IgG4.

17. The antibody or antigen-binding fragment thereof according to any one of claims 15 to 16, wherein the Fc domain is modified.

18. The antibody or antigen-binding fragment thereof according to claim 17, wherein the Fc domain comprises T307Q, Q311V and / or A378V mutations, and the numbering of the Fc domain is according to the EU index.

19. The antibody or antigen-binding fragment thereof according to any one of claims 17 to 18, wherein the Fc domain comprises an S228P mutation and the Fc domain numbering is according to the EU index.

20. The antibody or antigen-binding fragment thereof according to any one of claims 17 to 19, wherein the Fc domain comprises a substitution at positions F234, L235 and / or D265, and the Fc domain numbering is according to the EU index.

21. 21. The antibody or antigen-binding fragment thereof of claim 20, wherein the substitution at position F234 is a hydrophobic amino acid selected from the group consisting of alanine, valine, leucine, isoleucine, phenylalanine, and tryptophan, and the Fc domain numbering is according to the EU index.

22. The antibody or antigen-binding fragment thereof according to any one of claims 20 to 21, wherein the substitution at position F234 is valine and the Fc domain numbering is according to the Kabat EU index.

23. The antibody or antigen-binding fragment thereof according to any one of claims 20 to 22, wherein the substitution at position L235 is an acidic amino acid and the Fc domain numbering is according to the EU index.

24. The antibody or antigen-binding fragment thereof according to any one of claims 20 to 23, wherein the substitution at position L235 is an acidic amino acid selected from the group consisting of glutamic acid and aspartic acid, and the Fc domain numbering is according to the EU index.

25. The antibody or antigen-binding fragment thereof according to any one of claims 20 to 24, wherein the substitution at position L235 is aspartic acid and the Fc domain numbering is according to the EU index.

26. The antibody or antigen-binding fragment thereof according to any one of claims 20 to 25, wherein the substitution at position D265 is a non-polar amino acid and the Fc domain numbering is according to the EU index.

27. The antibody or antigen-binding fragment thereof according to any one of claims 20 to 26, wherein the substitution at position D265 is a non-polar amino acid selected from the group consisting of alanine, cysteine, glycine, isoleucine, leucine, methionine, and valine, and the Fc domain numbering is according to the EU index.

28. The antibody or antigen-binding fragment thereof according to any one of claims 20 to 27, wherein the substitution at position D265 is glycine and the Fc domain numbering is according to the EU index.

29. The antibody or antigen-binding fragment thereof according to any one of claims 20 to 28, wherein the Fc domain comprises S228P, F234V, L235E, D265G, T307Q, Q311V, and A378V mutations.

30. The antibody or antigen-binding fragment thereof of claim 29, wherein the Fc domain comprises the amino acid sequence of SEQ ID NO:

14.

31. The antibody or antigen-binding fragment thereof of any one of claims 1 to 30, wherein the antibody or fragment thereof inhibits the formation of C3 convertase and / or C5 convertase.

32. The antibody or antigen-binding fragment thereof of any one of claims 1 to 31, wherein the antibody or fragment thereof does not bind to C3 protein.

33. The antibody or antigen-binding fragment thereof of any one of claims 1 to 32, wherein the antibody or fragment thereof inhibits the activity of C3 convertase.

34. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 33, comprising an amino acid sequence at least 90% identical to SEQ ID NO:

4.

35. 35. The antibody or antigen-binding fragment thereof of claim 34, comprising SEQ ID NO:

4.

36. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 33, comprising an amino acid sequence at least 90% identical to SEQ ID NO:

5.

37. 37. The antibody or antigen-binding fragment thereof of claim 36, comprising SEQ ID NO:

5.

38. The antibody or fragment thereof according to any one of claims 1 to 33, comprising an amino acid sequence at least 90% identical to SEQ ID NO:

6.

39. 39. The antibody or antigen-binding fragment thereof of claim 38, comprising SEQ ID NO:

6.

40. The antibody or fragment thereof according to any one of claims 1 to 33, comprising an amino acid sequence at least 90% identical to SEQ ID NO:

7.

41. 41. The antibody or antigen-binding fragment thereof of claim 40, comprising SEQ ID NO:

7.

42. The antibody or fragment thereof according to any one of claims 1 to 33, comprising an amino acid sequence at least 90% identical to SEQ ID NO:

8.

43. 42. The antibody or antigen-binding fragment thereof of claim 41, comprising SEQ ID NO:

8.

44. The antibody or fragment thereof according to any one of claims 1 to 33, comprising an amino acid sequence at least 90% identical to SEQ ID NO:

9.

45. 41. The antibody or antigen-binding fragment thereof of claim 40, comprising SEQ ID NO:

9.

46. A nucleic acid encoding the antibody or antigen-binding fragment thereof of any one of claims 1 to 45.

47. 47. The nucleic acid of claim 46, wherein the nucleic acid is DNA, cDNA, RNA, or messenger RNA (mRNA).

48. 48. The nucleic acid of claim 47, wherein the nucleic acid is mRNA.

49. A composition comprising the nucleic acid of any one of claims 46 to 48 and a delivery vehicle.

50. 50. The composition of claim 49, wherein the delivery vehicle is an adeno-associated virus (AAV) vector or a lipid nanoparticle (LNP).

51. 51. The composition of claim 50, wherein the mRNA is encapsulated in an LNP.

52. 46. ​​A method of treating a complement-mediated disease or disorder, comprising administering a therapeutically effective amount of the antibody or antibody or antigen-binding fragment thereof of any one of claims 1 to 45 to a subject in need thereof.

53. 53. The method of claim 52, wherein the complement-mediated disease or disorder is a C3 glomerulopathy or a disease or disorder associated with a C3 glomerulopathy.

54. 54. The method of claim 53, wherein the disease or disorder associated with C3 glomerulopathy is dense deposit disease (DDD).

55. 54. The method of claim 53, wherein the disease or disorder associated with C3 glomerulopathy is C3 glomerulonephritis (C3GN).

56. 53. The method of claim 52, wherein the complement-mediated disease or disorder is characterized by accumulation of the C3 component of complement in renal tissue.

57. 57. The method of any one of claims 52-56, wherein the subject has symptomatic hematuria, proteinuria, acute kidney injury (AKI), or chronic kidney disease (CKD).

58. 53. The method of claim 52, wherein the complement-mediated disease or disorder is paroxysmal nocturnal hemoglobinuria, geographic atrophy, or autoimmune hemolytic anemia (AIHA).

59. 53. The method of claim 52, wherein the complement-mediated disease or disorder is age-related macular degeneration (AMD).

60. 53. The method of claim 52, wherein the complement-mediated disease or disorder is passive Heymann nephritis (PHN).

61. A method for treating a complement-mediated disease or disorder, comprising administering a therapeutically effective amount of an anti-C3b antibody or fragment thereof to a subject in need thereof.

62. 62. The method of claim 61, wherein the complement-mediated disease or disorder is a C3 glomerulopathy or a disease or disorder associated with a C3 glomerulopathy.

63. 63. The method of claim 62, wherein the disease or disorder associated with C3 glomerulopathy is dense deposit disease (DDD).

64. 63. The method of claim 62, wherein the disease or disorder associated with C3 glomerulopathy is C3 glomerulonephritis (C3GN).

65. 62. The method of claim 61, wherein the complement-mediated disease or disorder is age-related macular degeneration (AMD).

66. 62. The method of claim 61, wherein the complement-mediated disease or disorder is passive Heymann nephritis (PHN).

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