RU2802307C2 - C3 binding agents and methods of their use - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: antibody variants that specifically bind the C3 component of human complement, compositions containing such antibodies, and methods of their use are provided. Also the polynucleotides and vectors encoding antibodies and cells containing them are provided.

EFFECT: invention can be used in the treatment of eye diseases in which complement activation is involved.

31 cl, 6 dwg, 22 tbl, 13 ex

Description

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority over U.S. Provisional Application No. 62/652253, filed April 3, 2018, the entire contents of which are incorporated herein by reference.

SEQUENCE LIST

[0002] This description is provided with a copy of the Sequence Listing in Machine Readable Format (MFF). The FFM, 47702-0011WO1_SL.txt, which was created on March 26, 2019 and has a size of 216032 bytes, is identical to the paper copy of the Sequence Listing and is incorporated herein by reference in its entirety.

FIELD OF TECHNOLOGY

[0003] This invention generally relates to agents that bind the C3 (C3) component of complement, in particular antibodies that bind to human C3, as well as therapeutic methods of using the agents.

BACKGROUND OF THE INVENTION

[0004] The complement cascade is primarily involved in the detection and removal of foreign pathogens such as bacteria. The complement system includes more than 30 cell-associated and circulating proteins (eg, C1, C1q, C1r, C1s, C2, C3, C3a, C3b, C4, factor B, factor D, factor H, factor I). There are three main pathways that activate complement: the classical pathway (CP), the lectin pathway (MBL), and the alternative pathway (AP).

[0005] The three complement pathways are initiated by different factors, each leading to cleavage of the C3 component of complement. The classical complement pathway is activated when the C1 complex binds specific antigen-antibody complexes, often immunoglobulin M (IgM), IgG3, or IgG1. This causes a conformational change in the C1 complex, allowing it to cleave C4 and C2 to form the C4bC2b complex. C4bC2b acts as the classical pathway C3 convertase. The lectin complement pathway is activated when mannose-binding lectin (MBL) binds mannose-containing polysaccharides on microorganisms, initiating cleavage of C4 and C2 by the serine protease complex associated with MBL-MBL. As in the classical pathway, the C4bC2b complex forms the C3 convertase of the lectin pathway. The oldest of the three evolutionary signaling pathways, the alternative complement pathway, operates independently of the classical and lectin pathways, and as an amplification loop for them. The alternative complement pathway undergoes low-level self-activation through slow spontaneous hydrolysis of C3. After hydrolysis, C3( _H2O ) binds complement factor B, which is subsequently cleaved by complement factor D to C3( _H2O )Bb, forming the alternative complement pathway C3 convertase. These different pathways combine to split the C3 complement component into C3a and C3b. In host cells, endogenous factors shut down the complement cascade. On pathogens, the complement cascade continues with cleavage of complement component C5, which induces cell death through phagocytosis, inflammation, and ultimately activation of the membrane attack complex (MAC). ( Immunobiology: The Immune System in Health and Disease. 5th edition; Chapter: The complement system and innate immunity ; New York: Garland Science; 2001.)

[0006] Although the complement system has traditionally been considered part of the immune system, ie defense against foreign pathogens, complement activity also plays a role in maintaining tissue health. For example, the clearance of apoptotic cells is facilitated by the complement pathway. However, inappropriate or excessive complement activation is thought to be a cause or contributing factor to a number of diseases and disorders.

[0007] It is believed that diseases in which complement activation is involved include age-related macular degeneration (AMD). AMD is the leading cause of vision loss among older people in developed countries and affects approximately 9% of the world's population. There are two types of AMD: dry (approximately 85-90% of patients) and wet (approximately 10-15% of patients). Wet AMD occurs when abnormal blood vessels (known as choroidal neovascularization or CNV) grow under the retina and macula. These new blood vessels can bleed and leak fluid, causing the macula to bulge or rise from its normally flat position, distorting or destroying central vision. Under these circumstances, vision loss can be rapid and severe. Dry AMD is characterized by the formation of drusen under the retina. Geographic atrophy (GA) is an advanced (late) form of dry AMD. GA is characterized by progressive loss of retinal pigment epithelium (RPE), loss of photoreceptors (rods and cones), loss of neuroretin, and loss of choriocapillaries. Loss of one or more of these cells and/or tissues results in permanent loss of central vision. Despite some progress in the development of new therapeutic agents for wet AMD, in particular the use of VEGF inhibitors, there are no approved treatments for dry AMD and/or GA. Thus, new therapeutic agents and methods of using these agents for the treatment of AMD are needed.

SUMMARY OF THE INVENTION

[0008] This invention provides agents that bind the C3 component of complement (eg, SEQ ID NO:1). Agents include, but are not limited to, polypeptides such as antibodies that specifically bind C3. The agents may be referred to herein as "C3 binding agents". The present invention provides methods for making and using a C3 binding agent. In some embodiments, the C3 binding agent inhibits C3 activity. In some embodiments, the C3 binding agent inhibits complement activation. In some embodiments, the C3 binding agent inhibits activation of the classical complement pathway, the alternative complement pathway, or both the classical and the alternative complement pathway. In some embodiments, a C3 binding agent is used in combination therapy. In some embodiments, a C3 binding agent is used in combination with at least one additional therapeutic agent.

[0009] This invention also provides compositions containing the C3 binding agents described herein. In some embodiments, this invention also provides pharmaceutical compositions containing the C3 binding agents described herein. Also provided are polynucleotides and/or vectors encoding C3 binding agents and methods for producing the agents. Proposed cells containing or producing C3-binding agents described in this document. Also provided are cells containing the polynucleotides and/or vectors described herein.

[0010] In one aspect, the present invention provides C3 binding agents (eg, SEQ ID NO:1). In some embodiments, the agent binds human C3 (eg, SEQ ID NO:1). In some embodiments, the agent binds C3 of the cynomolgus monkey ("macaque") (eg, SEQ ID NO:32). In some embodiments, the agent binds human C3 and macaque C3. In some embodiments, the agent is an antibody. In some embodiments, the agent is an antibody that binds human C3. In some embodiments, the agent is an antibody that binds to macaque C3. In some embodiments, the agent is an antibody that binds human C3 and macaque C3. In some embodiments, the agent is an antibody that binds human C3 and does not bind mouse C3. In some embodiments, the agent does not bind mouse C3 at a detectable level. In some embodiments, the agent is an antibody that binds human C3 and does not bind rat C3. In some embodiments, the agent does not bind rat C3 at a detectable level. In some embodiments, the agent is an antibody that binds human C3 and does not bind human C3b. In some embodiments, the agent does not bind human C3b at a detectable level. In some embodiments, the agent is an antibody that binds human C3 with an affinity that is at least 50 times greater than the affinity of an antibody for human C3b. In some embodiments, the agent is an antibody that binds human C3 with an affinity that is at least 100 times greater than the affinity of an antibody for human C3b. In some embodiments, affinity is measured using Surface Plasmon Resonance (SPR) technology on the Biacore system, as described herein or as known to those skilled in the art.

[0011] In one aspect, the invention provides an agent (e.g., an antibody) that specifically binds human C3 (e.g., SEQ ID NO:1) and has at least one or more (e.g., 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12) of the following properties: (a) binds to macaque C3 (e.g., SEQ ID NO:32), (b) inhibits C3 cleavage, (c) inhibits C3 cleavage, and C3a release, (d) inhibits alternative complement pathway activation (eg, as measured by hemolytic plaque assays), (e) inhibits classical complement pathway activation (eg, as measured by hemolytic plaque assays), (f) inhibits alternative complement pathway activation, and classical complement pathway (e.g., by assessing hemolytic plaque assays), (g) does not bind at a detectable level to factor Bb, (h) does not bind at a detectable level to C3d, (i) does not bind at a detectable level to C3a, (j ) does not bind at a detectable level to C3b, (k) does not bind at a detectable level to iC3b, (l) does not bind at a detectable level to Factor Bb and C3d, (m) does not bind at a detectable level to Factor Bb, C3d, and C3a , (n) does not bind at a detectable level to factor Bb, C3d, C3a, C3b, and iC3b, (o) binds to human C3 (e.g., SEQ ID NO:1) with greater affinity than compstatin, and (p) has a period half-life is about 4-5 days in the human vitreous body. In certain embodiments, the C3 binding agent inhibits activation of the classical complement pathway (eg, as assessed by tests for hemolytic plaques). In some embodiments, the C3 binding agent inhibits the activation of the alternative complement pathway and the classical complement pathway (eg, as assessed by hemolytic plaque assays). In certain embodiments, the C3 binding agent comprises: (a) a heavy chain CDR1 comprising SEQ ID NO:7, a heavy chain CDR2 comprising SEQ ID NO:8, a heavy chain CDR3 comprising SEQ ID NO:9, a light chain CDR1, containing SEQ ID NO:10, a light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (b) Heavy chain CDR1 containing SEQ ID NO:7, heavy chain CDR2 containing SEQ ID NO:13, heavy chain CDR3 containing SEQ ID NO:9, light chain CDR1 containing SEQ ID NO:10, light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (c) Heavy chain CDR1 containing SEQ ID NO:7, heavy chain CDR2 containing SEQ ID NO:14, heavy chain CDR3 containing SEQ ID NO:9, light chain CDR1 containing SEQ ID NO:10, light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (d) Heavy chain CDR1 comprising SEQ ID NO:7, Heavy chain CDR2 comprising SEQ ID NO:15, Heavy chain CDR3 comprising SEQ ID NO:9, Light chain CDR1 comprising SEQ ID NO:10, Light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (e) Heavy chain CDR1 containing SEQ ID NO:7, heavy chain CDR2 containing SEQ ID NO:16, heavy chain CDR3 containing SEQ ID NO:9, light chain CDR1 containing SEQ ID NO:10, light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; or (f) a heavy chain CDR1 comprising SEQ ID NO:7, a heavy chain CDR2 comprising SEQ ID NO:17, a heavy chain CDR3 comprising SEQ ID NO:9, a light chain CDR1 comprising SEQ ID NO:10, a light chain CDR2 chain containing SEQ ID NO:11 and light chain CDR3 containing SEQ ID NO:12. In certain embodiments, the C3 binding agent comprises a heavy chain CDR1 comprising SEQ ID NO:7, a heavy chain CDR2 comprising SEQ ID NO:14, a heavy chain CDR3 comprising SEQ ID NO:9, a light chain CDR1 comprising SEQ ID NO: :10, a light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12. In certain embodiments, the C3 binding agent comprises: (a) a heavy chain variable region comprising SEQ ID NO:20 and a light chain variable region comprising SEQ ID NO:25; (b) a heavy chain variable region comprising SEQ ID NO:21 and a light chain variable region comprising SEQ ID NO:25; (c) a heavy chain variable region comprising SEQ ID NO:22 and a light chain variable region comprising SEQ ID NO:25; (d) a heavy chain variable region comprising SEQ ID NO:23 and a light chain variable region comprising SEQ ID NO:25; or (e) a heavy chain variable region comprising SEQ ID NO:24 and a light chain variable region comprising SEQ ID NO:25. In certain embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 21 and a light chain variable region comprising SEQ ID NO: 25.

[0012] In another aspect, the invention provides an agent (e.g., an antibody) that specifically binds human C3 and has at least one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) of the following properties: (a) binds to macaque C3 (e.g., SEQ ID NO:32), (b) inhibits C3 cleavage, (c) inhibits C3 cleavage and release of C3a, (d) inhibits activation of alternative complement pathway (eg, as assessed by hemolytic plaque assays), (e) inhibits activation of the classical complement pathway (eg, as assessed by hemolytic plaque assays), (f) inhibits activation of the alternative complement pathway and the classical complement pathway (eg, as assessed by on hemolytic plaques), (g) does not bind at a detectable level to factor Bb, (h) does not bind at a detectable level to C3d, (i) does not bind at a detectable level to C3a, (j) does not bind at a detectable level to C3b, (k) does not bind at a detectable level to iC3b, (l) does not bind at a detectable level to factor Bb and C3d, (m) does not bind at a detectable level to factor Bb, C3d and C3a, (n) does not bind at a detectable level to factor Bb, C3d and C3a, (n) does not bind at a detectable level to factor Bb, C3d, C3a, C3b and iC3b, (o) binds to human C3 (e.g., SEQ ID NO:1) with greater affinity than compstatin, and (p) has a half-life of about 4-5 days in the human vitreous wherein the antibody or antigen-binding fragment is for use in the prevention or treatment of a disease selected from AMD, macular degeneration, diabetic retinopathy, retinopathy of prematurity, macular degeneration, retinal dystrophy, uveitis, keratitis, scleritis, retinitis pigmentosa, choroidal neovascularization, retinal neovascularization, and inflammation eyes. In certain embodiments, the disease is AMD. In certain embodiments, the agent (eg, an antibody or antigen-binding fragment thereof) inhibits the activation of the alternative complement pathway and the classical complement pathway (eg, as measured by tests for hemolytic plaques).

[0013] In some embodiments, an agent (eg, antibody) that specifically binds C3 comprises: (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7); A heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8), YIYPHNGGTTYNQQFTG (SEQ ID NO:13), YIYPHNAGTTYNQQFTG (SEQ ID NO:14), YIYPHNTGTTYNQQFTG (SEQ ID NO:15), YIYPHEGGTTYNQQFTG (SEQ ID NO:16), or YIYPHQGGTTYNQQFTG (SEQ ID NO:17), and a heavy chain CDR3 containing RGGFDFDY (SEQ ID NO:9); and/or (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, an agent (eg, antibody) that specifically binds C3 comprises: a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); A heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8), YIYPHNGGTTYNQQFTG (SEQ ID NO:13), YIYPHNAGTTYNQQFTG (SEQ ID NO:14), YIYPHNTGTTYNQQFTG (SEQ ID NO:15), YIYPHEGGTTYNQQFTG (SEQ ID NO:16) or YIYPHQGGTTYNQQFTG (SEQ ID NO:17), and a heavy chain CDR3 containing RGGFDFDY (SEQ ID NO:9). In some embodiments, an agent (eg, antibody) that specifically binds C3 comprises a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); A light chain CDR2 containing GASNRYT (SEQ ID NO:11) and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, an agent (eg, antibody) that specifically binds C3 comprises: (a) a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, an agent (eg, antibody) that specifically binds C3 comprises: (a) a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNGGTTYNQQFTG (SEQ ID NO:13) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, an agent (eg, antibody) that specifically binds C3 comprises: (a) a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNAGTTYNQQFTG (SEQ ID NO:14) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, an agent (eg, antibody) that specifically binds C3 comprises: (a) a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNTGTTYNQQFTG (SEQ ID NO:15) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, an agent (eg, antibody) that specifically binds C3 comprises: (a) a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHEGGTTYNQQFTG (SEQ ID NO:16) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, an agent (eg, antibody) that specifically binds C3 comprises: (a) a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHQGGTTYNQQFTG (SEQ ID NO:17) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the agent is an antibody.

[0014] In certain embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHNGGTTYNQNFTG (SEQ ID NO:8), the heavy chain CDR3 contains RGGDFFDY (SEQ ID NO:9), the light chain CDR1 contains KASENVDTYVS (SEQ ID NO: 10), the light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12). In certain embodiments, an agent (e.g., antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYTFTDFYMD (SEQ ID NO:7), heavy chain CDR2 contains YIYPHNGGTTYNQQFTG (SEQ ID NO:13), heavy chain CDR3 contains RGGFDFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), The light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12). In certain embodiments, an agent (e.g., antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYTFTDFYMD (SEQ ID NO:7), heavy chain CDR2 contains YIYPHNAGTTYNQQFTG (SEQ ID NO:14), heavy chain CDR3 contains RGGFDFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), The light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12). In certain embodiments, an agent (e.g., antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYTFTDFYMD (SEQ ID NO:7), heavy chain CDR2 contains YIYPHNTGTTYNQQFTG (SEQ ID NO:15), heavy chain CDR3 contains RGGFDFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), The light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12). In certain embodiments, an agent (e.g., antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYTFTDFYMD (SEQ ID NO:7), heavy chain CDR2 contains YIYPHEGGTTYNQQFTG (SEQ ID NO:16), heavy chain CDR3 contains RGGFDFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), The light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12). In certain embodiments, an agent (e.g., antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYTFTDFYMD (SEQ ID NO:7), heavy chain CDR2 contains YIYPHQGGTTYNQQFTG (SEQ ID NO:17), heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), The light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12).

[0015] In some embodiments, an agent (eg, antibody) that specifically binds C3 further comprises (a) a heavy chain framework region (FR) 1, heavy chain FR2, heavy chain FR3, and heavy chain FR4; and/or (b) light chain FR1, light chain FR2, light chain FR3, and light chain FR4. In some embodiments, the agent (eg, antibody) that specifically binds C3 comprises heavy chain FR1, heavy chain FR2, heavy chain FR3, and heavy chain FR4. In some embodiments, the agent comprises light chain FR1, light chain FR2, light chain FR3, and light chain FR4. In some embodiments, the agent (eg, antibody) that specifically binds C3 comprises (a) heavy chain FR1, heavy chain FR2, heavy chain FR3, and heavy chain FR4; and (b) light chain FR1, light chain FR2, light chain FR3, and light chain FR4.

[0016] In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: (a) a heavy chain variable region having at least 90% sequence identity with SEQ ID NO:18, SEQ ID NO:20 , SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23 or SEQ ID NO:24; and/or (b) a light chain variable region having at least 90% sequence identity with SEQ ID NO:19 or SEQ ID NO:25. In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises a heavy chain variable region having at least 95% sequence identity with SEQ ID NO: 18 and a light chain variable region having at least 95% sequence identity to SEQ ID NO: 19. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region having at least 95% sequence identity to SEQ ID NO: 20 and the variable region light chain having at least 95% sequence identity with SEQ ID NO: 25. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region having at least 95% sequence identity with SEQ ID NO: 21, and a light chain variable region having at least 95% sequence identity with SEQ ID NO: 25. In some embodiments, an agent (e.g., antibody) that specifically binds C3 contains a heavy chain variable region, having at least 95% sequence identity with SEQ ID NO: 22, and a light chain variable region having at least 95% sequence identity with SEQ ID NO: 25. In some embodiments, an agent (e.g., an antibody) that specifically binds C3, contains a heavy chain variable region having at least 95% sequence identity to SEQ ID NO: 23 and a light chain variable region having at least 95% sequence identity to SEQ ID NO: 25. In some embodiments, the agent (e.g., an antibody) that specifically binds C3 contains a heavy chain variable region having at least 95% sequence identity to SEQ ID NO: 24 and a light chain variable region having at least 95% sequence identity to SEQ ID NO: 25. In some embodiments, an agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising SEQ ID NO: 18 and a light chain variable region comprising SEQ ID NO: 19. In some embodiments, An agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising SEQ ID NO: 20 and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising SEQ ID NO: 21 and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, an agent (e.g., an antibody) that specifically binds C3, comprises a heavy chain variable region comprising SEQ ID NO: 22 and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises a heavy chain variable region comprising SEQ ID NO: 23, and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, an agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising SEQ ID NO: 24, and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, the agent is an antibody.

[0017] In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises a heavy chain CDR1, CDR2, and CDR3 and/or a light chain CDR1, CDR2, and CDR3 from: (a) an antibody designated 38G10, which contains a heavy chain variable region comprising SEQ ID NO:18 and a light chain variable region comprising SEQ ID NO:19; (b) an antibody designated Hz38G10 which contains a heavy chain variable region comprising SEQ ID NO:20 and a light chain variable region comprising SEQ ID NO:25; (c) an antibody designated Hz38G10(G56A) which contains a heavy chain variable region comprising SEQ ID NO:21 and a light chain variable region comprising SEQ ID NO:25; (d) an antibody designated Hz38G10(G56T) which contains a heavy chain variable region comprising SEQ ID NO:22 and a light chain variable region comprising SEQ ID NO:25; (e) an antibody designated Hz38G10(N55E) which contains a heavy chain variable region comprising SEQ ID NO:23 and a light chain variable region comprising SEQ ID NO:25 or (f) an antibody designated Hz38G10(N55Q) which contains a heavy chain variable region containing SEQ ID NO:24, and a light chain variable region containing SEQ ID NO:25.

[0018] In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises CDR1, CDR2, and CDR3 from the heavy chain variable region and CDR1, CDR2, and CDR3 from the light chain variable region, each CDR being defined according to By exemplary definition, Chothia definition, AbM definition, Kabat definition, or contact definition. Thus, in some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises CDR1, CDR2, and CDR3 from the heavy chain variable region comprising SEQ ID NO: 18, and CDR1, CDR2, and CDR3 from the light chain variable region. containing SEQ ID NO: 19. In some embodiments, the agent (e.g., antibody) that specifically binds C3 contains CDR1, CDR2, and CDR3 from the heavy chain variable region containing SEQ ID NO: 20, and CDR1, CDR2, and CDR3 from a light chain variable region comprising SEQ ID NO: 25. In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises CDR1, CDR2, and CDR3 from a heavy chain variable region comprising SEQ ID NO: 21, and CDR1, CDR2, and CDR3 from a light chain variable region containing SEQ ID NO: 25. In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises CDR1, CDR2, and CDR3 from a heavy chain variable region containing SEQ ID NO: 22, and CDR1, CDR2, and CDR3 from the light chain variable region comprising SEQ ID NO: 25. In some embodiments, an agent (e.g., antibody) that specifically binds C3 contains CDR1, CDR2, and CDR3 from the heavy chain variable region. chain containing SEQ ID NO: 23, and CDR1, CDR2, and CDR3 from the light chain variable region containing SEQ ID NO: 25. In some embodiments, an agent (e.g., antibody) that specifically binds C3 contains CDR1, CDR2, and CDR3 from the heavy chain variable region containing SEQ ID NO: 24, and CDR1, CDR2 and CDR3 from the light chain variable region containing SEQ ID NO: 25.

[0019] In some embodiments, the C3 binding agent is an antibody that contains the heavy chain of SEQ ID NO: 27 and/or the light chain of SEQ ID NO: 31. In some embodiments, the C3 binding agent is an antibody that contains a heavy chain chain of SEQ ID NO: 27; and light chain of SEQ ID NO: 31. In some embodiments, the C3 binding agent is an antibody that contains the heavy chain of SEQ ID NO: 29 and/or the light chain of SEQ ID NO: 31. In some embodiments, The C3 binding agent is an antibody that contains the heavy chain of SEQ ID NO: 29 and the light chain of SEQ ID NO: 31.

[0020] In certain embodiments, an agent (e.g., an antibody) that specifically binds C3 contains heavy chain CDRs 1, 2, and 3 from a heavy chain variable region containing the amino acid sequence set forth in SEQ ID NO: 91. In certain embodiments, embodiment, the agent (e.g., antibody) that specifically binds C3 contains light chain CDRs 1, 2, and 3 from the light chain variable region containing the amino acid sequence shown in SEQ ID NO: 92. In certain embodiments, the agent (e.g., antibody ) that specifically binds C3 contains heavy chain CDRs 1, 2 and 3 from the heavy chain variable region containing the amino acid sequence set forth in SEQ ID NO: 91 and light chain CDRs 1, 2 and 3 from the light chain variable region, containing the amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYSFTGYNMN (SEQ ID NO: 38), the heavy chain CDR2 contains NINPYYGSTNYNQKFKG (SEQ ID NO: 39), and the heavy chain CDR3 contains GYYGGNYPFAY (SEQ ID NO: 40). In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a light chain variable region comprising light chain CDRs 1, 2, and 3, wherein the light chain CDR1 contains RASENIYSYLA (SEQ ID NO: 41), the light chain CDR2 contains NAKTLAE (SEQ ID NO: 42) and light chain CDR3 contains QHYYGTPYT (SEQ ID NO: 43). In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYSFTGYNMN (SEQ ID NO:38), heavy chain CDR2 contains NINPYYGSTNYNQKFKG (SEQ ID NO:39), heavy chain CDR3 contains GYYGGNYPFAY (SEQ ID NO:40), light chain CDR1 contains RASENIYSYLA (SEQ ID NO:41), The light chain CDR2 contains NAKTLAE (SEQ ID NO:42) and the light chain CDR3 contains QHYYGTPYT (SEQ ID NO:43).

[0021] In certain embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises heavy chain CDRs 1, 2, and 3 from a heavy chain variable region containing the amino acid sequence set forth in SEQ ID NO: 93. In certain embodiments, The agent (e.g., antibody) that specifically binds C3 contains light chain CDRs 1, 2, and 3 from the light chain variable region containing the amino acid sequence shown in SEQ ID NO: 94. In certain embodiments, the agent (e.g., antibody ), which specifically binds C3, contains heavy chain CDRs 1, 2 and 3 from the heavy chain variable region containing the amino acid sequence shown in SEQ ID NO: 93, and light chain CDRs 1, 2 and 3 from the light chain variable region, containing the amino acid sequence set forth in SEQ ID NO: 94. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYSFTGYNMN (SEQ ID NO: 38), the heavy chain CDR2 contains NINPYYDSTSYNQKFKG (SEQ ID NO: 44), and the heavy chain CDR3 contains ENYDFVGFAY (SEQ ID NO: 45). In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a light chain variable region comprising light chain CDRs 1, 2, and 3, wherein the light chain CDR1 contains RASSSVSYMH (SEQ ID NO: 46), the light chain CDR2 contains VTSNLAS (SEQ ID NO: 47) and light chain CDR3 contains QQWSTNPLT (SEQ ID NO: 48). In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYSFTGYNMN (SEQ ID NO:38), heavy chain CDR2 contains NINPYYDSTSYNQKFKG (SEQ ID NO:44), heavy chain CDR3 contains ENYDFVGFAY (SEQ ID NO:45), light chain CDR1 contains RASSSSVSYMH (SEQ ID NO:46), The light chain CDR2 contains VTSNLAS (SEQ ID NO:47) and the light chain CDR3 contains QQWSTNPLT (SEQ ID NO:48).

[0022] In certain embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises heavy chain CDRs 1, 2, and 3 from a heavy chain variable region containing the amino acid sequence set forth in SEQ ID NO: 95. In certain embodiments, embodiment, the agent (e.g., antibody) that specifically binds C3 contains light chain CDRs 1, 2, and 3 from the light chain variable region containing the amino acid sequence shown in SEQ ID NO: 96. In certain embodiments, the agent (e.g., antibody ), which specifically binds C3, contains heavy chain CDRs 1, 2 and 3 from the heavy chain variable region containing the amino acid sequence shown in SEQ ID NO: 95, and light chain CDRs 1, 2 and 3 from the light chain variable region, containing the amino acid sequence set forth in SEQ ID NO: 96. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYSFTGYNMH (SEQ ID NO: 49), the heavy chain CDR2 contains NINPYYGTTNSNQKFED (SEQ ID NO: 50) and the heavy chain CDR3 contains GIYYYGTGYPYFDF (SEQ ID NO: 51). In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a light chain variable region comprising light chain CDRs 1, 2, and 3, wherein the light chain CDR1 contains RASQDINNYLN (SEQ ID NO: 52), the light chain CDR2 contains YTSRLHS (SEQ ID NO: 53) and light chain CDR3 contains QQGITLPWT (SEQ ID NO: 54). In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYSFTGYNMH (SEQ ID NO:49), heavy chain CDR2 contains NINPYYGTTNSNQKFED (SEQ ID NO:50), heavy chain CDR3 contains GIYYYGTGYPYFDF (SEQ ID NO:51), light chain CDR1 contains RASQDINNYLN (SEQ ID NO:52), The light chain CDR2 contains YTSRLHS (SEQ ID NO:53) and the light chain CDR3 contains QQGITLPWT (SEQ ID NO:54).

[0023] In certain embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises heavy chain CDRs 1, 2, and 3 from a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 97. In certain embodiments, The agent (e.g., antibody) that specifically binds C3 contains light chain CDRs 1, 2, and 3 from the light chain variable region containing the amino acid sequence shown in SEQ ID NO: 98. In certain embodiments, the agent (e.g., antibody ), which specifically binds C3, contains heavy chain CDRs 1, 2 and 3 from the heavy chain variable region containing the amino acid sequence shown in SEQ ID NO: 97, and light chain CDRs 1, 2 and 3 from the light chain variable region, containing the amino acid sequence set forth in SEQ ID NO: 98. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 contains GYTFTDYWIN (SEQ ID NO: 55), the heavy chain CDR2 contains NIYPGSTSANYNEKFKS (SEQ ID NO: 56) and the heavy chain CDR3 contains YGYDSWFAY (SEQ ID NO: 57). In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a light chain variable region comprising light chain CDRs 1, 2, and 3, wherein the light chain CDR1 comprises KSTKSLLNSDGFTYLD (SEQ ID NO: 58), the light chain CDR2 comprises LVSNRFS (SEQ ID NO: 59) and light chain CDR3 contains FQSNYLPLT (SEQ ID NO: 60). In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYTFTDYWIN (SEQ ID NO:55), heavy chain CDR2 contains NIYPGSTSANYNEKFKS (SEQ ID NO:56), heavy chain CDR3 contains YGYDSWFAY (SEQ ID NO:57), light chain CDR1 contains KSTKSLLNSDGFTYLD (SEQ ID NO:58), The light chain CDR2 contains LVSNRFS (SEQ ID NO:59) and the light chain CDR3 contains FQSNYLPLT (SEQ ID NO:60).

[0024] In certain embodiments, an agent (e.g., an antibody) that specifically binds C3 contains heavy chain CDRs 1, 2, and 3 from a heavy chain variable region containing the amino acid sequence set forth in SEQ ID NO: 99. In certain embodiments, The agent (e.g., antibody) that specifically binds C3 contains light chain CDRs 1, 2, and 3 from the light chain variable region containing the amino acid sequence shown in SEQ ID NO: 100. In certain embodiments, the agent (e.g., antibody ), which specifically binds C3, contains heavy chain CDRs 1, 2 and 3 from the heavy chain variable region containing the amino acid sequence shown in SEQ ID NO: 99, and light chain CDRs 1, 2 and 3 from the light chain variable region, containing the amino acid sequence set forth in SEQ ID NO: 100. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYAFNSCWMN (SEQ ID NO: 61), the heavy chain CDR2 contains RIYPGDGDTNYNGKFKG (SEQ ID NO: 62), and the heavy chain CDR3 contains EGRNYGYEDY (SEQ ID NO: 63). In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a light chain variable region comprising light chain CDRs 1, 2, and 3, wherein the light chain CDR1 contains KASQSVDYDGDSYMN (SEQ ID NO: 64), the light chain CDR2 contains AASDLES (SEQ ID NO: 65) and the light chain CDR3 contains QQANEDPRT (SEQ ID NO: 66). In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYAFNSCWMN (SEQ ID NO:61), heavy chain CDR2 contains RIYPGDGDTNYNGKFKG (SEQ ID NO:62), heavy chain CDR3 contains EGRNYGYEDY (SEQ ID NO:63), light chain CDR1 contains KASQSVDYDGDSYMN (SEQ ID NO:64), The light chain CDR2 contains AASDLES (SEQ ID NO:65) and the light chain CDR3 contains QQANEDPRT (SEQ ID NO:66).

[0025] In certain embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises heavy chain CDRs 1, 2, and 3 from a heavy chain variable region containing the amino acid sequence set forth in SEQ ID NO: 101. In certain embodiments, The agent (e.g., antibody) that specifically binds C3 contains light chain CDRs 1, 2, and 3 from the light chain variable region containing the amino acid sequence shown in SEQ ID NO: 102. In certain embodiments, the agent (e.g., antibody ), which specifically binds C3, contains heavy chain CDRs 1, 2 and 3 from the heavy chain variable region containing the amino acid sequence shown in SEQ ID NO: 101, and light chain CDRs 1, 2 and 3 from the light chain variable region, containing the amino acid sequence set forth in SEQ ID NO: 102. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GFTFSNYAMS (SEQ ID NO: 67), the heavy chain CDR2 contains QTISSGGRYTYYPDSVKG (SEQ ID NO: 68), and the heavy chain CDR3 contains RYYGNSYWYFDV (SEQ ID NO: 69). In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a light chain variable region comprising light chain CDRs 1, 2, and 3, wherein the light chain CDR1 comprises KSSQSLLNSGNQKHYLT (SEQ ID NO: 70), the light chain CDR2 comprises GASTRGS (SEQ ID NO: 71) and light chain CDR3 contains QNDHSYPYT (SEQ ID NO: 72). In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GFTFSNYAMS (SEQ ID NO:67), heavy chain CDR2 contains QTISSGGRYTYYPDSVKG (SEQ ID NO:68), heavy chain CDR3 contains RYYGNSYWYFDV (SEQ ID NO:69), light chain CDR1 contains KSSQSLLNSGNQKHYLT (SEQ ID NO:70), The light chain CDR2 contains GASTRGS (SEQ ID NO:71) and the light chain CDR3 contains QNDHSYPYT (SEQ ID NO:72).

[0026] In certain embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises heavy chain CDRs 1, 2, and 3 from a heavy chain variable region containing the amino acid sequence set forth in SEQ ID NO: 103. In certain embodiments, The agent (e.g., antibody) that specifically binds C3 contains light chain CDRs 1, 2, and 3 from the light chain variable region containing the amino acid sequence shown in SEQ ID NO: 104. In certain embodiments, the agent (e.g., antibody ), which specifically binds C3, contains heavy chain CDRs 1, 2 and 3 from the heavy chain variable region containing the amino acid sequence shown in SEQ ID NO: 103, and light chain CDRs 1, 2 and 3 from the light chain variable region, containing the amino acid sequence set forth in SEQ ID NO: 104. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GFTFSSYTMS (SEQ ID NO: 73), the heavy chain CDR2 contains YISSGGGTTYYPDTVKG (SEQ ID NO: 74) and the heavy chain CDR3 contains RYYRGSSLWYFDV (SEQ ID NO: 75). In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a light chain variable region comprising light chain CDRs 1, 2, and 3, wherein the light chain CDR1 comprises KSSQSLFNSGSQKNFLT (SEQ ID NO: 76), the light chain CDR2 comprises WASTRES (SEQ ID NO: 77) and light chain CDR3 contains QNDYSYPLT (SEQ ID NO: 78). In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GFTFSSYTMS (SEQ ID NO:73), heavy chain CDR2 contains YISSGGGTTYYPDTVKG (SEQ ID NO:74), heavy chain CDR3 contains RYYRGSSLWYFDV (SEQ ID NO:75), light chain CDR1 contains KSSQSLFNSGSQKNFLT (SEQ ID NO:76), The light chain CDR2 contains WASTRES (SEQ ID NO:77) and the light chain CDR3 contains QNDYSYPLT (SEQ ID NO:78).

[0027] In certain embodiments, an agent (e.g., an antibody) that specifically binds C3 contains heavy chain CDRs 1, 2, and 3 from a heavy chain variable region containing the amino acid sequence set forth in SEQ ID NO: 105. In certain embodiments, The agent (e.g., antibody) that specifically binds C3 contains light chain CDRs 1, 2, and 3 from the light chain variable region containing the amino acid sequence shown in SEQ ID NO: 106. In certain embodiments, the agent (e.g., antibody ), which specifically binds C3, contains heavy chain CDRs 1, 2 and 3 from the heavy chain variable region containing the amino acid sequence shown in SEQ ID NO: 105, and light chain CDRs 1, 2 and 3 from the light chain variable region, containing the amino acid sequence set forth in SEQ ID NO: 106. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYSITSGYSLH (SEQ ID NO: 79), the heavy chain CDR2 contains YIHYSGSTNYNPSLKS (SEQ ID NO: 80) and the heavy chain CDR3 contains AWDYLDY (SEQ ID NO: 81). In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a light chain variable region comprising light chain CDRs 1, 2, and 3, wherein the light chain CDR1 contains RASENIYSQLA (SEQ ID NO: 82), the light chain CDR2 contains DAKTLAE (SEQ ID NO: 83) and light chain CDR3 contains HHHFGILYT (SEQ ID NO: 84). In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYSITSGYSLH (SEQ ID NO:79), heavy chain CDR2 contains YIHYSGSTNYNPSLKS (SEQ ID NO:80), heavy chain CDR3 contains AWDYLDY (SEQ ID NO:81), light chain CDR1 contains RASENIYSQLA (SEQ ID NO:82), The light chain CDR2 contains DAKTLAE (SEQ ID NO:83) and the light chain CDR3 contains HHHFGILYT (SEQ ID NO:84).

[0028] In certain embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises heavy chain CDRs 1, 2, and 3 from a heavy chain variable region containing the amino acid sequence set forth in SEQ ID NO: 107. In certain embodiments, The agent (e.g., antibody) that specifically binds C3 contains light chain CDRs 1, 2, and 3 from the light chain variable region containing the amino acid sequence shown in SEQ ID NO: 108. In certain embodiments, the agent (e.g., antibody ), which specifically binds C3, contains heavy chain CDRs 1, 2 and 3 from the heavy chain variable region containing the amino acid sequence shown in SEQ ID NO: 107, and light chain CDRs 1, 2 and 3 from the light chain variable region, containing the amino acid sequence set forth in SEQ ID NO: 108. In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 contains GYSITSGYYWN (SEQ ID NO: 85), the heavy chain CDR2 contains YIRYDGSNNYNPSLKN (SEQ ID NO: 86) and the heavy chain CDR3 contains HYGYDGGAFDF (SEQ ID NO: 87). In some embodiments, the agent (e.g., antibody) that specifically binds C3 comprises a light chain variable region comprising light chain CDRs 1, 2, and 3, wherein the light chain CDR1 contains RTSENIYNYLV (SEQ ID NO: 88), the light chain CDR2 contains NAKTLEE (SEQ ID NO: 89) and light chain CDR3 contains QHHYGTPFT (SEQ ID NO: 90). In some embodiments, an agent (e.g., an antibody) that specifically binds C3 comprises: a heavy chain variable region containing heavy chain CDRs 1, 2, and 3, and a light chain variable region containing CDRs 1, 2, and 3, wherein the heavy chain CDR1 chain contains GYSITSGYYWN (SEQ ID NO:85), heavy chain CDR2 contains YIRYDGSNNYNPSLKN (SEQ ID NO:86), heavy chain CDR3 contains HYGYDGGAFDF (SEQ ID NO:87), light chain CDR1 contains RTSENIYNYLV (SEQ ID NO:88), The light chain CDR2 contains NAKTLEE (SEQ ID NO:89) and the light chain CDR3 contains QHHYGTPFT (SEQ ID NO:90).

[0029] In another aspect of the invention, provided herein is an antibody that competes for C3 binding with any of the C3 binding agents described herein. In some embodiments, provided herein is an antibody that competes for binding to C3 with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, provided herein is an antibody that competes for binding to C3 with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNGGTTYNQQFTG (SEQ ID NO:13) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, provided herein is an antibody that competes for binding to C3 with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNAGTTYNQQFTG (SEQ ID NO:14) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, provided herein is an antibody that competes for binding to C3 with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNTGTTYNQQFTG (SEQ ID NO:15) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, provided herein is an antibody that competes for binding to C3 with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHEGGTTYNQQFTG (SEQ ID NO:16) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, provided herein is an antibody that competes for binding to C3 with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHQGGTTYNQQFTG (SEQ ID NO:17) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12).

[0030] In some embodiments, provided herein is an antibody that competes for binding to C3 with a reference antibody, wherein the reference antibody comprises a heavy chain variable region comprising SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO: 21, SEQ ID NO:22, SEQ ID NO:23 or SEQ ID NO:24, and a light chain variable region containing SEQ ID NO:19 or SEQ ID NO:25. In some embodiments, the reference antibody comprises a heavy chain variable region comprising SEQ ID NO: 18 and a light chain variable region comprising SEQ ID NO: 19. In some embodiments, the reference antibody comprises a heavy chain variable region comprising SEQ ID NO: 20 , and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, the reference antibody comprises a heavy chain variable region comprising SEQ ID NO: 21 and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, the implementation of the reference antibody comprises a heavy chain variable region comprising SEQ ID NO: 22 and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, the reference antibody comprises a heavy chain variable region comprising SEQ ID NO: 23 and the variable region light chain comprising SEQ ID NO: 25. In some embodiments, the reference antibody comprises a heavy chain variable region comprising SEQ ID NO: 24 and a light chain variable region comprising SEQ ID NO: 25.

[0031] In some embodiments, provided herein is a C3 binding agent that binds the same epitope on C3 as the antibody described herein. In some embodiments, provided herein is a C3 binding agent that binds an epitope on C3 that overlaps with an epitope on C3 bound by an antibody described herein. In some embodiments, provided herein is a C3 binding agent that binds the same epitope as an antibody comprising a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody selected from the group consisting of: 38G10, Hz38G10, Hz38G10(N55E), Hz38G10(N55Q), Hz38G10(G56A) or Hz38G10(G56T). In some embodiments, provided herein is a C3 binding agent that binds an epitope that overlaps with an epitope bound by an antibody comprising a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 of an antibody selected from the group consisting of: 38G10, Hz38G10, Hz38G10(N55E), Hz38G10(N55Q), Hz38G10(G56A) or Hz38G10(G56T). In some embodiments, provided herein is a C3 binding agent that binds the same epitope as an antibody comprising a heavy chain variable region and a light chain variable region of an antibody selected from the group consisting of: 38G10, Hz38G10, Hz38G10(N55E) , Hz38G10(N55Q), Hz38G10(G56A) or Hz38G10(G56T). In some embodiments, provided herein is a C3 binding agent that binds an epitope that overlaps with an epitope bound by an antibody comprising a heavy chain variable region and a light chain variable region of an antibody selected from the group consisting of: 38G10, Hz38G10, Hz38G10( N55E), Hz38G10(N55Q), Hz38G10(G56A) or Hz38G10(G56T).

[0032] In some embodiments, provided herein is a C3 binding agent that competes for binding to human C3 with an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 27 and a light chain having the amino acid sequence of SEQ ID NO: 31. In some embodiments, provided herein is a C3 binding agent that competes for binding to human C3 with an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 29 and a light chain having the amino acid sequence of SEQ ID NO: 31 .

[0033] In some embodiments of each of the above aspects and embodiments, as well as in other aspects and embodiments described herein, the C3 binding agent is an antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a complete antibody or an intact antibody. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments, the antibody is a bispecific antibody or a multispecific antibody. In some embodiments, the antibody is an antibody fragment (eg, a C3 binding fragment). In some embodiments, the antibody or antibody fragment is Fab, Fab', F(ab') ₂ , Fv, scFv, (scFv) ₂ , single chain antibody, dual variable region antibody, single variable region antibody, linear antibody, nanobody or an antibody with a V region. In some embodiments, the antibody is an scFv-CH3 fusion, scFv-Fc fusion, scFv-HSA fusion, scFv-PEG fusion, or scFv-XTEN fusion.

[0034] In some embodiments, the antibody is an scFv antibody comprising a heavy chain variable region and a light chain variable region. In some embodiments, the antibody is a disulfide-linked scFv (dsscFv) containing a heavy chain variable region and a light chain variable region. In some embodiments, the dsscFv heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110. In some embodiments, the dsscFv dsscFv heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 111. In some embodiments, the dsscFv light chain variable region comprises the amino acid sequence of SEQ ID NO: 112. In some embodiments, the dsscFv heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 112. In some embodiments, the dsscFv heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 111 and the light chain variable region contains the amino acid sequence of SEQ ID NO: 112. In some embodiments, dsscFv, dsscFv contains the amino acid sequence of SEQ ID NO: 113. In some embodiments, dsscFv, dsscFv contains the amino acid sequence of SEQ ID NO: 114 In some embodiments, the dsscFv, dsscFv comprises the amino acid sequence of SEQ ID NO: 119. In some embodiments, the dsscFv, dsscFv comprises the amino acid sequence of SEQ ID NO: 229.

[0035] In some embodiments of each of the above aspects and embodiments, as well as in other aspects and embodiments described herein, the C3 binding agent (e.g., antibody) described herein is a C3 antagonist. In some embodiments, the C3 binding agent is an antagonistic antibody. In some embodiments, the C3 binding agent (eg, antibody) inhibits C3 activity. In some embodiments, the C3 binding agent (eg, antibody) inhibits activation of the complement system. In some embodiments, the C3 binding agent (eg, antibody) inhibits activation of the classical complement pathway. In some embodiments, the C3 binding agent (eg, antibody) inhibits the activation of the alternative complement pathway. In some embodiments, the C3 binding agent (eg, antibody) inhibits the activation of the classical complement pathway and the alternative complement pathway.

[0036] In another aspect, the invention provides compositions containing the C3 binding agent (eg, antibody) described herein.

[0037] In another aspect, the invention provides pharmaceutical compositions comprising a C3 binding agent (eg, an antibody) described herein and a pharmaceutically acceptable carrier.

[0038] In some embodiments of each of the above aspects, as well as in other aspects and/or embodiments described elsewhere herein, the C3 binding agent (eg, antibody) is isolated. In some embodiments, the C3 binding agent (eg, antibody) is substantially pure.

[0039] In another aspect, the invention provides polynucleotides comprising a polynucleotide that encodes a C3 binding agent as described herein. In some embodiments, the polynucleotide is isolated. In some embodiments, the implementation of the vector contains a polynucleotide that encodes a C3-binding agent described in this document. In some embodiments, the isolated cell contains a polynucleotide that encodes a C3 binding agent described herein. In some embodiments, the isolated cell contains a vector containing a polynucleotide that encodes a C3 binding agent described herein. In some embodiments, the present invention provides a cell containing the C3 binding agent described herein. In some embodiments, the present invention provides a cell that produces the C3 binding agent described herein. In some embodiments, the cell produces an anti-C3 antibody described herein. In some embodiments, the cell is a monoclonal cell line. In some embodiments, the cell is a hybridoma.

[0040] In another aspect, the invention provides methods for using the C3 binding agents (eg, antibodies) described herein. In some embodiments, the implementation of the method includes the use of compositions containing C3-binding agent (eg, antibody)described in this document. In some embodiments, the implementation of the method includes the use of a pharmaceutical composition containing a C3-binding agent (eg, antibody)described in this document.

[0041] In some embodiments, a method of treating an ocular disorder or disease in a subject (eg, human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent (eg, antibody) described herein. In some embodiments, the ocular disorder is selected from the group consisting of macular degeneration (maculopathy), diabetic retinopathy, retinopathy of prematurity, macular degeneration, retinal dystrophy, uveitis, keratitis, scleritis, retinitis pigmentosa, choroidal neovascularization, retinal neovascularization, and ocular inflammation. In some embodiments, the ocular disorder is macular degeneration. In some embodiments, the ocular disorder is age-related macular degeneration (AMD). In some embodiments, a method for treating AMD in a subject (eg, a human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent (eg, an antibody) described herein. In some embodiments, AMD is dry AMD. In some embodiments, AMD is geographic atrophy. In some embodiments, a method for treating geographic atrophy in a subject (eg, human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent (eg, antibody) described herein.

[0042] In some embodiments, a method for inhibiting or suppressing drusen formation in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent (eg, antibody) described herein.

[0043] In some embodiments, a method for inhibiting or suppressing retinal pigment epithelium atrophy of a subject (e.g., human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent (e.g., an antibody) described herein.

[0044] In some embodiments, a method for inhibiting complement activation in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent (eg, antibody) described herein.

[0045] In some embodiments of the methods described herein, a C3 binding agent (eg, antibody) is administered to the eye of a subject (eg, human) via ocular injection, intraocular injection, or intravitreal injection. In some embodiments, a C3 binding agent (eg, an antibody) is administered to the patient's eye by intravitreal injection. In some embodiments of the methods described herein, a C3 binding agent (eg, an antibody) is administered to the eye of a subject by local delivery. In some embodiments, the C3 binding agent is administered to the subject's eye in the form of eye drops.

[0046] In some embodiments of the methods described herein, a C3 binding agent is administered to a subject (eg, human) as part of a combination therapy. In some embodiments, the combination therapy includes photodynamic therapy. In some embodiments, the combination therapy includes photodynamic therapy with verteporfin. In some embodiments, the C3 binding agent is administered to a subject (eg, a human), wherein the subject is administered one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is compstatin or a compstatin analog or derivative (eg, POT-4; APL-2). In some embodiments, the additional therapeutic agent is a C5 inhibitor. In some embodiments, the C5 inhibitor is selected from the group including, but not limited to, eculizumab, LFG316, or Zimura (an anti-C5 aptamer). In some embodiments, the additional therapeutic agent is a properdin inhibitor (eg, an anti-properdin antibody). In some embodiments, the additional therapeutic agent is a factor D inhibitor. In some embodiments, the factor D inhibitor is an anti-factor D antibody (eg, lampalizumab). In some embodiments, the additional therapeutic agent is a VEGF inhibitor. In some embodiments, the VEGF inhibitor is selected from the group including, but not limited to, pegaptanib (MACUGEN), ranibizumab (LUCENTIS), bevacizumab (AVASTIN), aflibercept (EYLEA), bralucizumab, and OPT-302. In some embodiments, the additional therapeutic agent is a PDGF inhibitor. In some embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the additional therapeutic agent is a neuroprotective agent. In some embodiments, the implementation of the neuroprotective agent is selected from the group including, without limitation, ciliary neurotrophic factor (CNTF), tandospirone and brimonidine.

[0047] Also disclosed is the use of a C3 binding agent (eg, antibody) described herein in the manufacture of a medicament for the treatment of an ocular disorder. Also disclosed is the use of a C3 binding agent (eg, an antibody) described herein in the manufacture of a medicament for the treatment of a C3 associated disease or disorder associated with complement activation.

[0048] In some embodiments of each of the above aspects and embodiments, as well as in other aspects and embodiments described herein, the subject is a human.

[0049] When aspects or embodiments of this invention are described in terms of the Markush group or other grouping of alternatives, this invention covers not only the entire group listed as a whole, but also each member of the group individually and all possible subgroups of the main groups, as well as the main group A that lacks one or more members of the group. The present invention also proposes an explicit exclusion of one or more members of the group in the claimed invention.

BRIEF DESCRIPTION OF GRAPHICS

[0050] FIG. 1. C3a release assay.

[0051] FIG. 2. Alternate pathway and classical pathway hemolysis assays. Antibodies 38G10, 3D8 and 15C12 were tested for their ability to inhibit complement activation.

[0052] FIG. 3. Alternate pathway and classical pathway hemolysis assays. The Hz38G10 antibody and compstatin derivative (COMP) were tested for their ability to inhibit complement activation.

[0053] FIG. 4. Alternate pathway and classical pathway hemolysis assays. The Hz38G10 antibody and a pegylated compstatin derivative (COMP-PEG) were tested for their ability to inhibit complement activation.

[0054] FIG. 5. Analysis of the binding site. Hz38G10 and the compstatin derivative were tested in a competitive binding assay to assess whether the molecules bind to the same or different epitopes.

[0055] FIG. 6. Inhibition of complement activation. The Hz38G10 antibody was tested for its ability to inhibit complement activation in the eye.

DETAILED DESCRIPTION OF THE INVENTION

[0056] The present invention provides novel agents, including, without limitation, polypeptides, such as antibodies, that bind the C3 component of complement. C3 binding agents include, without limitation, polypeptides, antibodies (including their antigen-binding fragments), scaffold proteins, and heterodimeric molecules. C3 binding agents include, without limitation, antagonists of C3 activity, inhibitors of C3 activity, and/or agents that modulate C3 activity. Also proposed are related polypeptides, polynucleotides, vectors, compositions containing agents, cells containing related polynucleotides or vectors, and methods for producing agents. Methods for using the novel C3 binding agents are also provided.

I. Definitions

[0057] Unless otherwise defined herein, the technical and scientific terms used in this specification have the meanings that are commonly understood by those skilled in the art. For the purposes of interpreting this description, the following description of terms applies and, whenever appropriate, terms used in the singular also include the plural and vice versa. In the event that any of the following descriptions of a term conflict with any document incorporated herein by reference, the description of the term below takes precedence.

[0058] As used herein, the term "binding agent" refers to a molecule that binds a particular antigen or target (eg, the C3 component of complement). The binding agent may include a protein, peptide, nucleic acid, carbohydrate, lipid, or low molecular weight compound. In some embodiments, the implementation of the binding agent includes an antibody or antigennegative fragment. In some embodiments, the binding agent is an antibody or an antigen-binding fragment thereof. In some embodiments, the binding agent comprises an alternative protein scaffold or an artificial scaffold (eg, a non-immunoglobulin scaffold). In some embodiments, the binding agent is a fusion protein containing an antigen binding site. In some embodiments, the binding agent is a bispecific or multispecific molecule containing at least one antigen-binding site.

[0059] As used herein, the term "antibody" refers to an immunoglobulin molecule, or antigen-binding fragment thereof, that recognizes and binds a target through at least one antigen-binding site. "Antibody" is used herein in its broadest sense and encompasses various antibody structures, including, without limitation, polyclonal antibodies, recombinant antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, bispecific antibodies, multispecific antibodies, diabodies, tribodies, tetrabodies, Fv single chain antibodies (scFv), and antibody fragments, if they exhibit the desired antigen-binding activity.

[0060] The term "intact antibody" or "full-length antibody" refers to an antibody having a structure substantially similar to that of a native antibody. It includes, for example, an antibody containing two light chains, each containing a variable region and a light chain constant region (CL), and two heavy chains, each containing a variable region and at least the heavy chain constant regions CH1, CH2 and CH3.

[0061] As used herein, the term "antibody fragment" refers to a molecule, other than an intact antibody, that contains an antibody portion and usually an antigen-binding site. Examples of antibody fragments include, without limitation, Fab, Fab', F(ab')2, Fv, single chain antibody molecules (e.g. scFv), disulfide-linked scFv (dsscFv), nanobodies, diabodies, triabodies, tetrabodies, minibodies , dual variable domain (DVD) antibodies, single variable domain antibodies (eg, camelid antibodies), and multispecific antibodies formed from antibody fragments.

[0062] The term "monoclonal antibody" in the context of this invention refers to an essentially homogeneous population of antibodies involved in the highly specific recognition and binding of a single antigenic determinant or epitope. The term "monoclonal antibody" or its antigen-binding fragment includes intact and full-length monoclonal antibodies, as well as antibody fragments (for example, Fab, Fab', F(ab')2, Fv), single-chain antibodies (for example, scFv), fusion proteins containing an antibody fragment; and any other modified immunoglobulin molecule containing at least one antigen-binding site. In addition, "monoclonal antibody" refers to such antibodies produced by any number of methods, including, without limitation, hybridoma production, phage library display, recombinant expression, and transgenic animals.

[0063] The term "chimeric antibody" refers to an antibody in which the heavy and/or light chain fragment is derived from a first source or species, while the heavy and/or light chain portion is derived from a different source or species.

[0064] The term "humanized antibody" in the context of this invention refers to an antibody that contains a human heavy chain variable region and a light chain variable region, wherein the native CDR residues are replaced by residues from the corresponding CDRs from a non-human antibody (e.g., mouse, rat, rabbit, or non-human primate), wherein the non-human antibody has the desired specificity, affinity, and/or activity. In some embodiments, one or more human heavy or light chain variable region framework residues are replaced with corresponding non-human antibody residues. In addition, humanized antibodies may contain residues that are not present in a human or non-human antibody. In some embodiments, these modifications are made to further refine and/or optimize antibody performance. In some embodiments, the humanized antibody comprises at least a portion of an immunoglobulin constant region (eg, CH1, CH2, CH3, Fc), typically a human immunoglobulin.

[0065] As used herein, the term "human antibody" refers to an antibody that has an amino acid sequence corresponding to an antibody produced by a human and/or an antibody produced using any of the methods known to those skilled in the art to generate human antibodies. These methods include, without limitation, phage display libraries, yeast display libraries, transgenic animals, recombinant protein production, and B-cell hybridoma technology.

[0066] The terms "epitope" and "antigenic determinant" are used interchangeably herein and refer to that portion of an antigen or target that can be recognized and bound by a particular antibody. When the antigen or target is a polypeptide, "epitopes" can be formed by either contiguous amino acids or non-contiguous amino acids formed by folding the protein's tertiary structure. Epitopes derived from contiguous amino acids (also referred to as linear epitopes) are generally retained upon protein denaturation, while epitopes derived from tertiary structure (also referred to as conformational epitopes) are generally lost upon protein denaturation. An epitope typically includes at least 3 or more, typically at least 5, 6, 7, or 8-10 amino acids in a unique spatial conformation. Epitopes can be predicted using any of the large number of bioinformatics software tools available on the internet. X-ray crystallography can be used to characterize an epitope on a target protein by analyzing the interactions of amino acid residues of the antigen/antibody complex.

[0067] The term "specifically binds" in the context of this invention refers to an agent (for example, an antibody) that interacts more often, faster, for a longer duration, with greater affinity, or with some combination of the above with a particular antigen, epitope, protein or target molecule than with alternative substances. A binding agent (eg, an antibody) that specifically binds an antigen can be identified, for example, by immunoassays, ELISA, PPR (eg, Biacore), or other methods known to those skilled in the art. In some embodiments, an agent (eg, antibody) that specifically binds an antigen (eg, human C3) can bind related antigens (eg, macaque C3). A binding agent that specifically binds an antigen may bind a target antigen with a higher affinity than its affinity for another antigen. The other antigen may be a related antigen. In some embodiments, a binding agent that specifically binds an antigen can bind a target antigen with an affinity that is at least 20 times greater, at least 30 times greater, at least 40 times greater, at least 50 times greater. times greater, at least 60 times greater, at least 70 times greater, at least 80 times greater, at least 90 times greater, or at least 100 times greater than its affinity for another antigen. In some embodiments, a binding agent that specifically binds a particular antigen binds another antigen with such low affinity that binding cannot be detected using the assay described herein or otherwise known in the art. In some embodiments, affinity is measured using SPR technology in the Biacore system, as described herein or as known to those skilled in the art.

[0068] The terms "polypeptide" and "peptide" and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be separated by non-amino acids. In addition, these terms include an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included in the definition are, for example, polypeptides containing one or more analogs of an amino acid, including, without limitation, unnatural amino acids, as well as other modifications known in the art. It is understood that, since the polypeptides of this invention may be based on antibodies, the term "polypeptide" includes polypeptides in the form of a single chain and polypeptides of two or more linked chains.

[0069] The terms "polynucleotide" and "nucleic acid" and "nucleic acid molecule" are used interchangeably herein and refer to polymers of nucleotides of any length and include DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or analogs thereof, or any substrate that can be incorporated into a DNA or RNA polymerase polymer.

[0070] The terms "identical" or percent "identity" in the context of two or more nucleic acids or polypeptides refers to two or more sequences or subsequences that are identical or have a certain percentage of the same nucleotides or amino acid residues, when compared and aligned (introduction of gaps, if necessary) for maximum match, without considering any conservative amino acid substitutions as part of sequence identity. Percent identity can be measured using software or sequence comparison algorithms or by visual inspection. Various algorithms and software are well known in the art that can be used to align amino acid or nucleotide sequences. These include, without limitation, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variations thereof. In some embodiments, two nucleic acids or polypeptides of the invention are substantially identical, meaning that they contain at least 70%, at least 75%, at least 80%, at least 85%, at least 90% and in some embodiments, at least 95%, 96%, 97%, 98%, 99% nucleotide or amino acid residue identity when compared and aligned for maximum match as measured using a sequence comparison algorithm or by visual inspection. In some embodiments, identity exists in a sequence range that is at least about 10, at least about 20, at least about 20-40, at least about 40-60 nucleotides or amino acid residues, at least about 60- 80 nucleotides or amino acid residues in length, or any whole number in between. In some embodiments, identity exists over a longer region than 60-80 nucleotides or amino acid residues, e.g., at least about 80-100 nucleotides or amino acid residues, and in some embodiments, sequences that are substantially identical across the length of the sequences are compared, for example, (i) the coding region of a nucleotide sequence or (ii) an amino acid sequence.

[0071] As used herein, the term "conservative amino acid substitution" is a substitution in which an amino acid residue is replaced by an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are commonly defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g. alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g. threonine, valine, isoleucine) and aromatic side chains (eg tyrosine, phenylalanine, tryptophan, histidine). For example, substitution of phenylalanine for tyrosine is considered a conservative substitution. In general, conservative substitutions in the sequences of the polypeptides and/or antibodies do not abolish the binding of the polypeptide or antibody to the target binding site. Methods for identifying conservative nucleotide and amino acid substitutions that do not abolish binding are well known in the art.

[0072] As used herein, the term "vector" means a construct that is capable of delivering and typically expressing one or more genes or sequences of interest in a host cell. Examples of vectors include, without limitation, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors coupled with cationic condensing agents, and DNA or RNA expression vectors encapsulated in liposomes.

[0073] As used herein, the term "isolated" refers to a polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition that is in a form not found in nature. An "isolated" antibody contains virtually no material from the cellular source from which it was derived. In some embodiments, the isolated polypeptides, soluble proteins, antibodies, polynucleotides, vectors, cells, or compositions are those that have been purified to the extent that they are no longer present in their natural form. In some embodiments, the polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition that is isolated is substantially pure. The polypeptide, soluble protein, antibody, polynucleotide, vector, cell or composition may be isolated from a natural source (eg tissue) or from a source such as an engineered cell line.

[0074] As used herein, the term "substantially pure" refers to material that is at least 50% pure (i.e., free of contaminants), at least 90% pure, at least 95% pure, at least 98% pure or at least 99% pure.

[0075] The term "subject" refers to any animal (eg, mammal), including, without limitation, humans, non-human primates, dogs, felines, rabbits, rodents, and the like.

[0076] As used herein, the term "pharmaceutically acceptable" refers to a substance approved or subject to regulatory approval or listed in the USP, European Pharmacopoeia, or other generally accepted pharmacopoeia for use in animals, including humans.

[0077] The terms "pharmaceutically acceptable excipient, carrier, or adjuvant" or "acceptable pharmaceutical carrier" as used herein refers to an excipient, carrier, or adjuvant that can be administered to a subject (e.g., a human), together with at least one therapeutic an agent (eg, an antibody), and which is generally safe, non-toxic, and does not interfere with the pharmacological activity of the therapeutic agent. Generally, those skilled in the art and the US FDA consider a pharmaceutically acceptable excipient, carrier, or adjuvant to be the inactive ingredient of any formulation.

[0078] The term "pharmaceutical composition" or "pharmaceutical composition" in the context of this invention refers to a composition that is in such a form as to allow the biological activity of the agent (eg, antibodies) to be effective. The pharmaceutical composition or composition usually contains additional components such as a pharmaceutically acceptable excipient, carrier, adjuvant, buffers, etc.

[0079] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an agent (e.g., antibody) that is sufficient to reduce and/or alleviate the severity and/or duration of (i) a disease, disorder, or condition in a subject (eg, a human) and/or (ii) a symptom in a subject (eg, a human). The term also includes the amount of an agent necessary to (i) reduce or improve the development or progression of a given disease, disorder or condition, (ii) reduce or improve the recurrence, development or onset of a given disease, disorder or condition, and/or (iii) improve or enhancing the prophylactic or therapeutic effect(s) of another agent or therapy (eg, an agent other than the binding agents provided herein).

[0080] The term "therapeutic effect" as used herein refers to the effect and/or ability of an agent (e.g., antibody) to reduce and/or alleviate the severity and/or duration of (i) a disease, disorder, or condition in a subject (e.g., human) and/or (ii) a symptom in a subject (eg, human). The term also includes the ability of an agent to (i) reduce or alleviate the development or progression of a given disease, disorder, or condition, (ii) reduce or alleviate the recurrence, development, or onset of a given disease, disorder, or condition, and/or (iii) to improve or enhance the prophylactic or therapeutic effect(s) of another agent or therapy (eg, an agent other than the binding agents provided herein).

[0081] The term "treat" or "treatment" or "process of treatment" or "cure" or "alleviate" or "alleviate" or "alleviate" or "process of alleviation" in the context of this invention refers to both (1) therapeutic measures that aim to cure, retard, relieve symptoms, and/or stop the progression of the condition or disorder; and (2) prophylactic or prophylactic measures that aim to prevent or slow the development of the target condition or disorder. Thus, patients in need of treatment include those who already have the disease, those who are at risk for the onset/development of the disorder, and those in whom the disorder is to be prevented.

[0082] The term "prevent" or "prevention" or "prevention process" as used herein refers to the partial or complete suppression of the development, recurrence, onset or spread of a disease, disorder or condition or symptom thereof in a subject (e.g. human) .

[0083] As used herein, reference to "about" or "approximately" a value or parameter includes (and describes) embodiments that address that value or parameter. For example, a description referring to "about X" includes a description of "X".

[0084] As used in this specification and claims, singular forms include plural forms unless the context clearly dictates otherwise.

[0085] It should be understood that in cases where embodiments are described herein with the wording "comprising", similar embodiments described in terms of "consisting of" and/or "consisting essentially of" are also provided. It should be understood that in cases where embodiments are described herein with the wording "consisting essentially of", similar embodiments described in terms of "consisting of" are also provided.

[0086] The term "and/or" used in a phrase such as "A and/or B" is intended to include both A and B; A or B; A (separate) and B (separate). Likewise, the term "and/or" used in a phrase such as "A, B and/or C" is intended to cover each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (separately); B (separately); and C (separately).

II. C3 binding agents

[0087] The amino acid (aa) sequences for human C3 (UniProtKB No. P01024), cynomolgus monkey (NCBI Ref No. XP_005587776.1), and C3 rat (UniProtKB No. P01026) are shown herein as SEQ ID NO: 1, SEQ ID NO: 32 and SEQ ID NO: 37, respectively. As used herein, reference to C3 amino acid positions refers to the numbering of amino acid sequences, including the signal sequence.

[0088] The present invention provides C3 binding agents. In some embodiments, the C3 binding agent binds the C3 moiety. In some embodiments, the implementation of the C3-binding agent binds to a specific region of C3. In some embodiments, the C3 binding agent binds an epitope on C3. In some embodiments, the C3 binding agent binds a linear epitope on C3. In some embodiments, the C3 binding agent binds a conformational epitope on C3. In some embodiments, the C3 binding agent binds human C3 (eg, SEQ ID NO:1). In some embodiments, the C3 binding agent binds macaque C3 (eg, SEQ ID NO:32). In some embodiments, the C3 binding agent binds human C3 and macaque C3. In some embodiments, the C3 binding agent binds C3 and does not bind C3b. In some embodiments, the C3 binding agent binds C3 and does not bind C3b at a detectable level. In some embodiments, the C3 binding agent binds C3 with an affinity that is at least 50 times its affinity for C3b. In some embodiments, the C3 binding agent binds C3 with an affinity that is at least 100 times its affinity. to C3b. In some embodiments, the affinity of the C3 binding agent is measured using SPR technology in the Biacore system.

[0089] In some embodiments, the C3 binding agent binds to human C3 (e.g., SEQ ID NO: 1) and has at least one or more of the following properties: (a) binds to macaque C3 (e.g., SEQ ID NO: 32), (b) inhibits C3 cleavage and C3a release, (c) inhibits alternative complement pathway activation, (d) inhibits classical complement pathway activation, (e) inhibits alternative complement pathway activation and inhibits classical complement pathway activation, (f) does not binds to factor Bb at a detectable level, (g) does not bind to C3d at a detectable level, and (h) does not bind to C3a at a detectable level. In certain embodiments, the C3 binding agent inhibits activation of the classical complement pathway (eg, as assessed by tests for hemolytic plaques). In some embodiments, the C3 binding agent inhibits the activation of the alternative complement pathway and the classical complement pathway (eg, as measured by hemolytic plaque assays).

[0090] Assays for determining inhibition of C3 cleavage and C3a release are known in the art. In certain embodiments, the assay is the assay described herein (see, for example, Example 2). In certain embodiments, the C3 binding agent inhibits C3 cleavage and C3a release at a concentration of 0.1 to 1000 nM. In certain embodiments, the C3 binding agent inhibits C3 cleavage and C3a release if there is a decrease of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, by at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the amount of C3 cleavage and C3a release compared to C3 cleavage and C3a release in the absence of a C3 binding agent.

[0091] Assays for determining whether a C3 binding agent inhibits the activation of the alternative complement pathway or the classical complement pathway are known in the art. In certain embodiments, the assay is as described herein (eg, hemolysis assays; see, for example, Example 3).

[0092] Assays for determining the binding of a C3 binding agent to factor Bb, C3d, or C3a are known in the art. In certain embodiments, the assay is the assay described herein (eg, BiaCore; see, eg, Example 5). In certain embodiments, the C3 binding agent does not bind to factor Bb, C3d, or C3a unless the C3 binding agent binds to factor Bb, C3d, or C3a, respectively, at a concentration of up to 1 μM, according to the assay described herein (e.g. , BiaCore; see, for example, example 5).

[0093] In some embodiments, the C3 binding agent is an antibody. In some embodiments, the antibody is a recombinant antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is an IgA, IgD, IgE, IgG, or IgM antibody. In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG4 antibody. In some embodiments, the antibody is an antibody fragment containing an antigen-binding site. In some embodiments, the antibody is a scFv. In some embodiments, the antibody is a disulfide-linked scFv. In some embodiments, the antibody is a bispecific antibody or a multispecific antibody. In some embodiments, the antibody is a monovalent antibody. In some embodiments, the antibody is a monospecific antibody. In some embodiments, the antibody is a bivalent antibody.

[0094] In some embodiments, the antibody is isolated. In some embodiments, the antibody is substantially pure.

[0095] In some embodiments, the C3 binding agent is a polyclonal antibody. Polyclonal antibodies can be obtained by any method known to those skilled in the art. In some embodiments, polyclonal antibodies are produced by immunizing an animal (e.g., rabbit, rat, mouse, goat, donkey) with an antigen of interest (e.g., a purified peptide fragment, recombinant protein, or fusion protein) using multiple subcutaneous or intraperitoneal injections. In some embodiments, the antigen is conjugated to a carrier such as keyhole limpet hemocyanin (KLH), serum albumin, bovine thyroglobulin, or soy trypsin inhibitor. The antigen (with or without carrier protein) is reconstituted in sterile saline and usually combined with an adjuvant (eg complete or incomplete Freund's adjuvant) to form a stable emulsion. After some time, polyclonal antibodies are isolated from the immunized animal (for example, from blood or ascites). In some embodiments, polyclonal antibodies are purified from serum or ascites according to standard methods in the art, including, without limitation, affinity chromatography, ion exchange chromatography, gel electrophoresis, and/or dialysis.

[0096] In some embodiments, the C3 binding agent is a monoclonal antibody. Monoclonal antibodies can be obtained by any method known to those skilled in the art. In some embodiments, monoclonal antibodies are generated using hybridoma techniques known to one of skill in the art. For example, using the hybridoma method, a mouse, rat, rabbit, hamster, or other suitable host animal is immunized as described above. In some embodiments, lymphocytes are immunized in vitro. In some embodiments, the immunizing antigen is a human protein or a fragment thereof. In some embodiments, the immunizing antigen is a mouse protein or a fragment thereof.

[0097] After immunization, the lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol. Hybridoma cells are selected using specialized media known in the art, and non-fused lymphocytes and myeloma cells do not survive the selection process. Hybridomas that produce monoclonal antibodies directed specifically against a selected antigen can be identified by various methods, including, but not limited to, immunoprecipitation, immunoblotting, and in vitro binding assays (e.g., flow cytometry, FACS, ELISA, SPR (e.g., Biacore) and radioimmunoassay ). Once hybridoma cells have been identified that produce antibodies with the desired specificity, affinity, and/or activity, clones can be subcloned using limiting dilution techniques. Hybridomas can be propagated either in culture in vitro using standard methods, or in vivo as ascitic tumors in animals. Monoclonal antibodies can be purified from the culture medium or ascitic fluid by standard methods in the art, including, without limitation, affinity chromatography, ion exchange chromatography, gel electrophoresis, and dialysis.

[0098] In some embodiments, monoclonal antibodies are produced using recombinant DNA techniques known to those skilled in the art. For example, antibody-encoding polynucleotides are isolated from mature B cells or hybridoma cells, for example, by RT-PCR using oligonucleotide primers that specifically amplify antibody heavy and light chain-encoding genes and sequenced using standard techniques. The isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors that produce monoclonal antibodies when transfected into host cells such as E. coli , monkey COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells, which otherwise do not produce immunoglobulin proteins.

[0099] In some embodiments, recombinant monoclonal antibodies are isolated from phage display libraries expressing variable domains or CDRs of the desired species. Screening of phage libraries can be carried out in various ways known in the art.

[00100] In some embodiments, a monoclonal antibody is modified using recombinant DNA technology to create alternative antibodies. In some embodiments, the light chain and heavy chain constant regions of a mouse monoclonal antibody are replaced with human antibody constant regions to form a chimeric antibody. In some embodiments, the constant regions are truncated or removed to obtain the desired monoclonal antibody fragment. In some embodiments, site-directed mutagenesis or high density mutagenesis of the variable region(s) is used to optimize the specificity and affinity of a monoclonal antibody.

[00101] In some embodiments, the C3 binding agent is a humanized antibody. Various methods for producing humanized antibodies are known in the art. In some embodiments, the humanized antibody contains one or more amino acid residues that have been introduced into it from a non-human source. In some embodiments, humanization is performed by replacing one or more non-human CDR sequences with corresponding human antibody CDR sequences. In some embodiments, humanized antibodies are constructed by replacing all six CDRs of a non-human antibody (eg, a mouse antibody) with the corresponding CDRs of a human antibody.

[00102] The choice of which human heavy chain variable region and/or human light chain variable region to use to generate humanized antibodies can be made based on a variety of factors and a variety of methods known in the art. In some embodiments, a "best fit" method is used where the variable region sequence of a non-human (eg, rodent) antibody is screened against the entire library of known human variable region sequences. The human sequence that most closely resembles a non-human sequence (eg, a rodent) is selected as the human variable region framework for the humanized antibody. In some embodiments, a particular variable region framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains is selected as the variable region framework. In some embodiments, the variable region framework sequence is derived from consensus sequences of the most common human subclasses. In some embodiments, human germline genes are used as a source of variable region framework sequences.

[00103] Other humanization methods include, without limitation, a method called "overhumanization", which is described as direct transfer of CDRs into a human germline scaffold, a method called "human string content" (HSC), which is based on an "antibody humanity" metric , methods based on the creation of large libraries of humanized variants (including libraries of phage, ribosome and yeast displays), and methods based on frame shuffling.

[00104] In some embodiments, the C3 binding agent is a human antibody. Human antibodies can be obtained using various techniques known in the art. In some embodiments, human antibodies are generated from immortalized human B lymphocytes immunized in vitro . In some embodiments, human antibodies are generated from lymphocytes isolated from an immunized individual. In either case, cells that produce an antibody directed against the target antigen can be generated and isolated. In some embodiments, the human antibody is selected from a phage library, where the phage library expresses human antibodies. Alternatively, phage display technology can be used to generate human antibodies and antibody fragments in vitro from immunoglobulin variable region gene repertoires from unimmunized donors. Methods for creating and using antibody phage libraries are well known in the art. Once antibodies have been identified, affinity maturation strategies known in the art, including but not limited to strand shuffling and site-directed mutagenesis, can be used to generate higher affinity human antibodies. In some embodiments, human antibodies are produced in transgenic mice that contain human immunoglobulin loci. After immunization, these mice are able to produce the full repertoire of human antibodies in the absence of endogenous immunoglobulin production.

[00105] In some embodiments, the C3 binding agent is an scFv antibody. ScFvs are molecules that contain a heavy chain variable region and a light chain variable region associated to form a single polypeptide. ScFv can be obtained using recombinant technologies known in the art. In some embodiments, the scFv comprises a polypeptide linker between the heavy chain variable region and the light chain variable region. In some embodiments, the scFv comprises (N- to C-terminal) (i) a heavy chain variable region, (ii) a linker, and (iii) a light chain variable region. In some embodiments, the scFv comprises (N- to C-terminal) (i) a light chain variable region, (ii) a linker, and (iii) a heavy chain variable region. In some embodiments, the scFv is a disulfide-linked scFv (dsscFv), which is a scFv containing an engineered disulfide bond between the light chain variable region and the heavy chain variable region of the scFv. In some embodiments, the dsscFv heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110. In some embodiments, the dsscFv heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 111. In some embodiments, the dsscFv light chain variable region comprises the amino acid sequence of SEQ ID NO: 112. In some embodiments, the dsscFv heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 110 and the dsscFv light chain variable region comprises the amino acid sequence of SEQ ID NO: 112. In some embodiments, the dsscFv heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 111 and the dsscFv light chain variable region comprises the amino acid sequence of SEQ ID NO: 112. In some embodiments, the dsscFv comprises the amino acid sequence of SEQ ID NO: 113. In some embodiments, the dsscFv comprises the amino acid sequence of SEQ ID NO: 114. embodiments, the dsscFv comprises the amino acid sequence of SEQ ID NO: 119. In some embodiments, the dsscFv comprises the amino acid sequence of SEQ ID NO: 229. such as an Fc molecule, an immunoglobulin CH3 domain (eg IgG1 CH3), polyethylene glycol (PEG) or a PEG mimetic, XTEN, serum albumin (eg human serum albumin), polysicalic acid, N-(2-hydroxypropyl)methacrylamide or dextran , or modified, eg, by hyperglycosylation, to increase the half-life of the scFv (eg, dsscFv).

[00106] A number of suitable linkers are known to those skilled in the art and are not limited to any specific sequences disclosed herein. In some embodiments, the implementation of the polypeptide linker consists of naturally occurring or non-naturally occurring amino acids. In some embodiments, the implementation of the linker contains amino acids that provide flexibility. In some embodiments, the implementation of the linker contains amino acids that provide suitable solubility. In some embodiments, the implementation of the linker contains the amino acids of glycine. In some embodiments, the implementation of the linker contains the amino acids glycine and serine. In certain embodiments, the linker contains one or more glycine/serine repeat sets. In some embodiments, the polypeptide linker is selected from the group consisting of: (GGGGS) _n where n=1-4 (SEQ ID NO:232), GGGGS (SEQ ID NO:115), GGGGSGGGGS (SEQ ID NO:116), GGGGSGGGGSGGGGS (SEQ ID NO:117), GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:118) and (GGGGA) _n where n=1-4 (SEQ ID NO:230). In some embodiments, the implementation of the linker contains GGGGSGGGGSGGGGS (SEQ ID NO:117).

[00107] In some embodiments, the implementation of the scFv contains a disulfide bond formed between the variable region of the heavy chain and the variable region of the light chain. In some embodiments, the scFv contains a disulfide bond that enhances the stability of the scFv molecule. In some embodiments, the implementation of the scFv contains a disulfide bond, which increases the thermal stability of the scFv molecule.

[00108] In some embodiments, the C3 binding agent is Fv. Fv contains a heavy chain variable region and a light chain variable region. In some embodiments, the Fv attaches (directly or indirectly) to a half-life-prolonging moiety, such as, for example, an Fc molecule, an IgG CH3 domain (e.g., IgG1 CH3), PEG, or a PEG mimetic, XTEN, serum albumin (e.g., human serum albumin), polysicalic acid, N-(2-hydroxypropyl)methacrylamide or dextran, or modified, for example, by hyperglycosylation to increase the half-life of Fv.

[00109] In some embodiments, the C3 binding agent is a Fab. Fab is one of the molecules that results from the enzymatic cleavage of an immunoglobulin antibody with papain. Fabs are monovalent molecules that contain a light chain, a heavy chain variable region, a CH1 region, and optionally a heavy chain constant region hinge region or a portion thereof. Fab can be obtained using recombinant technologies known in the art. In some embodiments, the Fab contains a polypeptide linker between the light chain constant region and the heavy chain variable region. In some embodiments, the Fab contains a polypeptide linker between the heavy chain constant region and the light chain variable region. A number of suitable linkers are known to those skilled in the art and are not limited to any particular sequences disclosed herein. In certain embodiments, the implementation of the linker is a linker described in this document. In some embodiments, a Fab is attached (directly or indirectly) to a half-life-prolonging moiety, such as, for example, an Fc molecule, an IgG CH3 domain (e.g., IgG1 CH3), PEG, or a PEG mimic, XTEN, serum albumin (e.g., human serum albumin), polysicalic acid, N-(2-hydroxypropyl)methacrylamide or dextran, or modified, for example, by hyperglycosylation to increase the half-life of the Fab.

[00110] In some embodiments, the implementation of the Fab contains a disulfide bond formed between the variable region of the heavy chain and the variable region of the light chain. In some embodiments, the Fab contains a disulfide bond that enhances the stability of the Fab molecule. In some embodiments, the Fab contains a disulfide bond that increases the thermal stability of the Fab molecule.

[00111] In some embodiments, the C3 binding agent is F(ab') ₂ . AF(ab') ₂ is one of the molecules that result from the enzymatic cleavage of an immunoglobulin antibody with pepsin. F(ab') ₂ is a divalent molecule that contains a first light chain in combination with a first polypeptide containing a first heavy chain variable region, a first CH1 and a first hinge region, and a second light chain in combination with a second polypeptide containing a second variable region a heavy chain region, a second CH1, and a second hinge region, wherein the first hinge region is linked to the second hinge region by at least one disulfide bond. F(ab') ₂ can be obtained using recombinant technologies known in the art. In some embodiments, F(ab') ₂ attaches (directly or indirectly) to a half-life increasing moiety, such as, for example, an IgG CH3 domain (e.g., IgG1 CH3), PEG, or a PEG mimetic, XTEN, serum albumin (e.g., human serum albumin), polysicalic acid, N-(2-hydroxypropyl) methacrylamide or dextran, or modified, for example, by hyperglycosylation to increase the half-life of F(ab') ₂ .

[00112] In some embodiments, the implementation of F(ab') ₂ contains a disulfide bond formed between the variable region of the heavy chain and the variable region of the light chain. In some embodiments, F(ab') ₂ contains a disulfide bond that enhances the stability of the F(ab') ₂ molecule. In some embodiments, F(ab') ₂ contains a disulfide bond that increases the thermal stability of the F(ab') ₂ molecule.

[00113] In some embodiments, the C3 binding agent is F(ab'). F(ab') is a molecule that results from treatment of F(ab') ₂ with beta-mercaptoethanol. F(ab') is a monovalent molecule that contains a light chain in combination with a polypeptide containing a heavy chain variable region, CH1 and a hinge region. In some embodiments, F(ab') is attached (directly or indirectly) to a half-life increasing moiety, such as, for example, an Fc molecule, an IgG CH3 domain (eg, IgG1 CH3), PEG, or a PEG mimetic, XTEN, serum albumin ( eg human serum albumin), polysicalic acid, N-(2-hydroxypropyl) methacrylamide or dextran, or modified, eg by hyperglycosylation, to increase the F(ab') half-life.

[00114] In some embodiments, F(ab') contains a disulfide bond formed between the heavy chain variable region and the light chain variable region. In some embodiments, F(ab') contains a disulfide bond that enhances the stability of the F(ab') molecule. In some embodiments, F(ab') contains a disulfide bond that increases the thermal stability of the F(ab') molecule.

[00115] In some embodiments, the C3 binding agent is a bispecific antibody. Bispecific antibodies are capable of recognizing and binding at least two different antigens or epitopes. Different epitopes can be on the same molecule (eg two epitopes on C3) or on different molecules (eg one epitope on C3 and one epitope on a different target). In some embodiments, the implementation of the bispecific antibody has increased efficiency compared to a single antibody or a combination of more than one antibody. In some embodiments, the bispecific antibody has reduced toxicity compared to an individual antibody or a combination of more than one antibody. Those skilled in the art will recognize that any therapeutic agent may have a unique pharmacokinetic (PK) (eg, circulating half-life). In some embodiments, the bispecific antibody has the ability to synchronize the PK of two active binding agents, where the two individual binding agents have different PK profiles. In some embodiments, the bispecific antibody has the ability to concentrate the actions of two agents in a common area (eg, tissue) in a subject (eg, human). In some embodiments, the bispecific antibody has the ability to focus the actions of the two agents on a common target (eg, on a particular cell type). In some embodiments, the bispecific antibody has the ability to target the actions of two agents to more than one biological pathway or function. In some embodiments, the bispecific antibody has the ability to target and bring two different cells closer together.

[00116] In some embodiments, the bispecific antibody has reduced toxicity and/or side effects. In some embodiments, the bispecific antibody has reduced toxicity and/or side effects compared to a mixture of two separate antibodies or antibodies as separate agents. In some embodiments, the bispecific antibody has an increased therapeutic index. In some embodiments, the bispecific antibody has an increased therapeutic index compared to a mixture of two separate antibodies or antibodies as separate agents.

[00117] Specialists in the art are aware of several methods for obtaining bispecific antibodies. In some embodiments, the bispecific antibodies comprise heavy chain constant regions with amino acid modifications that are part of the interface between two heavy chains. These modifications are made to enhance the formation of heterodimers and generally reduce or eliminate the formation of homodimers. In some embodiments, the implementation of bispecific antibodies are created using the strategy "protrusions in holes" (KIH). In some embodiments, the bispecific antibodies contain variant hinge regions that are unable to form disulfide bonds between identical heavy chains (eg, reduce the formation of homodimers). In some embodiments, the bispecific antibodies comprise heavy chains with amino acid changes that result in altered electrostatic interactions. In some embodiments, the bispecific antibodies comprise heavy chains with amino acid changes that result in altered hydrophobic/hydrophilic interactions.

[00118] Bispecific antibodies can be intact antibodies or antibody fragments containing antigen-binding sites.

[00119] C3 binding agents with more than two valences are also contemplated. In some embodiments, trispecific or tetraspecific antibodies are generated.

[00120] In some embodiments, the C3 binding agent is an antibody that binds C3. In some embodiments, the anti-C3 antibody binds human C3. In some embodiments, the anti-C3 antibody binds macaque C3. In some embodiments, the anti-C3 antibody binds human C3 and macaque C3. In some embodiments, the anti-C3 antibody does not bind rat C3. In some embodiments, an anti-C3 antibody binds a C3 epitope. In some embodiments, the anti-C3 antibody does not bind C3a, C3b, C3c, C3d, or iC3b. In some embodiments, the anti-C3 antibody does not bind C3a, C3b, C3c, C3d, and iC3b. In some embodiments, the anti-C3 antibody does not bind C3a. In some embodiments, the anti-C3 antibody does not bind C3c. In some embodiments, the anti-C3 antibody does not bind C3d. In some embodiments, the anti-C3 antibody does not bind iC3b. In some embodiments, the anti-C3 antibody does not bind C3b. In some embodiments, the anti-C3 antibody does not bind C3a, C3b, C3c, C3d, or iC3b at a detectable level. In some embodiments, the anti-C3 antibody binds human C3 with an affinity that is at least 20 times greater than the affinity of the antibody for C3a, C3c, C3d, iC3b, or C3b. In some embodiments, the anti-C3 antibody binds human C3 with an affinity that is at least 50 times greater than the affinity of the antibody for C3a, C3c, C3d, iC3b, or C3b. In some embodiments, the anti-C3 antibody binds human C3 with an affinity that is at least 100 times greater than the affinity of the antibody for C3a, C3c, C3d, iC3b, or C3b. In some embodiments, the anti-C3 antibody binds C3 and does not bind C3b at a detectable level. In some embodiments, the anti-C3 antibody binds human C3 with an affinity that is at least 50 times greater than the affinity of the anti-C3b antibody. In some embodiments, the anti-C3 antibody binds human C3 with an affinity that is at least 100 times greater than the affinity of the anti-C3b antibody.

[00121] In some embodiments, the C3 binding agent is an anti-C3 antibody that contains one, two, three, four, five, and/or six CDRs of any of the antibodies described herein. In some embodiments, the anti-C3 antibody comprises (i) one, two and/or three heavy chain CDRs from Table 1A and/or (ii) one, two and/or three light chain CDRs from Table 1A. In some embodiments, the anti-C3 antibody comprises (i) three heavy chain CDRs from Table 1A (ie, CDR1, CDR2, and CDR3) and (ii) three light chain CDRs from Table 1A. In some embodiments, the anti-C3 antibody comprises (i) one, two and/or three heavy chain CDRs from Table 1B and/or (ii) one, two and/or three light chain CDRs from Table 1B. In some embodiments, the anti-C3 antibody comprises (i) three heavy chain CDRs from Table 1B (ie, CDR1, CDR2, and CDR3) and (ii) three light chain CDRs from Table 1B. In some embodiments, the anti-C3 antibody comprises (i) one, two and/or three heavy chain CDRs from Table 1C and/or (ii) one, two and/or three light chain CDRs from Table 1C. In some embodiments, the anti-C3 antibody comprises (i) three heavy chain CDRs from Table 1C (ie, CDR1, CDR2, and CDR3) and (ii) three light chain CDRs from Table 1C. In some embodiments, the anti-C3 antibody comprises (i) one, two, and/or three heavy chain CDRs from Table 2, and/or (ii) one, two, and/or three light chain CDRs from Table 2. In some embodiments, the antibody anti-C3 contains (i) three heavy chain CDRs from Table 2, and (ii) three light chain CDRs from Table 2. In some embodiments, an anti-C3 antibody contains (i) one, two, and/or three heavy chain CDRs from Table 3 , and/or (ii) one, two, and/or three light chain CDRs from Table 3. In some embodiments, the anti-C3 antibody comprises (i) three heavy chain CDRs from Table 3, and (ii) three light chain CDRs from Table 3. 3. In some embodiments, the anti-C3 antibody comprises (i) one, two, and/or three heavy chain CDRs from Table 4, and/or (ii) one, two, and/or three light chain CDRs from Table 4. In some embodiments, An anti-C3 antibody comprises (i) three heavy chain CDRs from Table 4, and (ii) three light chain CDRs from Table 4. In some embodiments, an anti-C3 antibody comprises (i) one, two, and/or three heavy chain CDRs from Table 5, and/or (ii) one, two, and/or three light chain CDRs from Table 5. In some embodiments, the anti-C3 antibody comprises (i) three heavy chain CDRs from Table 5, and (ii) three light chain CDRs from Table 5. In some embodiments, the anti-C3 antibody comprises (i) one, two, and/or three heavy chain CDRs from Table 6, and/or (ii) one, two, and/or three light chain CDRs from Table 6. B in some embodiments, the anti-C3 antibody comprises (i) three heavy chain CDRs from Table 6, and (ii) three light chain CDRs from Table 6. In some embodiments, the anti-C3 antibody contains (i) one, two, and/or three heavy chain CDRs. chains from Table 7, and/or (ii) one, two, and/or three light chain CDRs from Table 7. In some embodiments, the anti-C3 antibody comprises (i) three heavy chain CDRs from Table 7, and (ii) three CDRs light chain from Table 7. In some embodiments, the anti-C3 antibody comprises (i) one, two, and/or three heavy chain CDRs from Table 8, and/or (ii) one, two, and/or three light chain CDRs from Table 8 In some embodiments, the anti-C3 antibody comprises (i) three heavy chain CDRs from Table 8, and (ii) three light chain CDRs from Table 8. In some embodiments, the anti-C3 antibody comprises (i) one, two, and/or three Heavy chain CDRs from Table 9, and/or (ii) one, two, and/or three light chain CDRs from Table 9. In some embodiments, the anti-C3 antibody comprises (i) three heavy chain CDRs from Table 9, and (ii) three light chain CDRs from Table 9. In some embodiments, the anti-C3 antibody comprises (i) one, two and/or three heavy chain CDRs from Table 10, and/or (ii) one, two and/or three light chain CDRs from Table 10. In some embodiments, the anti-C3 antibody comprises (i) three heavy chain CDRs from Table 10 and (ii) three light chain CDRs from Table 10. In some embodiments, the C3 binding agent is a humanized anti-C3 antibody that contains (i) one, two and/or three heavy chain CDRs and/or (ii) one, two and/or three light chain CDRs from any of Tables 1-10.

Table 1A: Sequences of the 38G10 antibody

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GYTFDFYMD
(SEQ ID NO:7) GYTFDF
(SEQ ID NO:120) GYTFDFYMD
(SEQ ID NO:7) DFYMD
(SEQ ID NO:121) TDFYMD
(SEQ ID NO:122) heavy chain CDR2 YIYPHNGGTTYN
QNFTG
(SEQ ID NO:8) YPHNGG
(SEQ ID NO:123) YIYPHNGGTT
(SEQ ID NO:124) YIYPHNGGTTYN
QNFTG
(SEQ ID NO:8) WIGYIYPHNGGTT
(SEQ ID NO:125) heavy chain
CDR3 RGGFFDY
(SEQ ID NO:9) RGGFFDY
(SEQ ID NO:9) RGGFFDY
(SEQ ID NO:9) RGGFFDY
(SEQ ID NO:9) ARRGGFFD
(SEQ ID NO:126) light chain
CDR1 KASENVDTYVS (SEQ ID NO:10) KASENVDTYVS (SEQ ID NO:10) KASENVDTYVS (SEQ ID NO:10) KASENVDTYVS (SEQ ID NO:10) DTYVSWY
(SEQ ID NO:127) light chain
CDR2 GASNRYT
(SEQ ID NO:11) GASNRYT
(SEQ ID NO:11) GASNRYT
(SEQ ID NO:11) GASNRYT
(SEQ ID NO:11) LLIYGASNRY
(SEQ ID NO:128) light chain
CDR3 GQSHSYPLT
(SEQ ID NO:12) GQSHSYPLT
(SEQ ID NO:12) GQSHSYPLT
(SEQ ID NO:12) GQSHSYPLT
(SEQ ID NO:12) GQSHSYPL
(SEQ ID NO:129) Heavy chain variable region 38G10 (SEQ ID NO: 18)
EVQLQQSGPELVKPGDSVKMSCKASGYTFDFYMDWVKQSHGKSLEWIGYIYPHNGGTTY
NQNFTGKATLTVDKSSNTAYMELHSLTSEDSAVYYCARRGGFFDYWGQGTTLTVSS Light chain variable region 38G10 (SEQ ID NO: 19)
NIVMTQSPKSMSLSVGERVTLRCKASENVDTYVSWYQQKPEQSPKLLIYGASNRYTGVPD
RFTGSGSATEFTLTISSVQAEDLVGYHCGQSHSYPLTFGAGTKLELK

[00122]

Table 1B: Sequences of the Hz38G10 antibody

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GYTFDFYMD
(SEQ ID NO:7) GYTFDF
(SEQ ID NO:120) GYTFDFYMD
(SEQ ID NO:7) DFYMD
(SEQ ID NO:121) TDFYMD
(SEQ ID NO:122) heavy chain CDR2 YIYPHNGGTTYN
QQFTG
(SEQ ID NO:13) YPHNGG
(SEQ ID NO:123) YIYPHNGGTT
(SEQ ID NO:124) YIYPHNGGTTYN
QQFTG
(SEQ ID NO:13) WMGYIYPHN
GGTT
(SEQ ID NO:130) heavy chain
CDR3 RGGFFDY
(SEQ ID NO:9) RGGFFDY
(SEQ ID NO:9) RGGFFDY
(SEQ ID NO:9) RGGFFDY
(SEQ ID NO:9) ARRGGFFD
(SEQ ID NO:126) light chain
CDR1 KASENVDTYVS (SEQ ID NO:10) KASENVDTYVS (SEQ ID NO:10) KASENVDTYVS (SEQ ID NO:10) KASENVDTYVS (SEQ ID NO:10) DTYVSWY
(SEQ ID NO:127) light chain
CDR2 GASNRYT
(SEQ ID NO:11) GASNRYT
(SEQ ID NO:11) GASNRYT
(SEQ ID NO:11) GASNRYT
(SEQ ID NO:11) LLIYGASNRY
(SEQ ID NO:128) light chain
CDR3 GQSHSYPLT
(SEQ ID NO:12) GQSHSYPLT
(SEQ ID NO:12) GQSHSYPLT
(SEQ ID NO:12) GQSHSYPLT
(SEQ ID NO:12) GQSHSYPL
(SEQ ID NO:129) Heavy chain variable region Hz38G10 (SEQ ID NO: 20)
QVQLVQSGAEVKKPGASVKVSCKASGYTFDFYMDWVRQAPGQRLEWMGYIYPHNGGTTY
nqqftgrvtitvdksastaymelsslrsedtavyycarrggFDFDYWGQGTLVTVSS Light chain variable region Hz38G10 (SEQ ID NO: 25)
DIQMTQSPSSLSASVGDRVTITCKASENVDTYVSWYQQKPGKAPKLLIYGASNRYTGVPS
RFSGSGSGTDFTFTISSLQPEDIATYHCGQSHSYPLTFGQGTKLEIK

[00123]

Table 1C: HZ38G10 antibody variant sequences

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GYTFDFYMD
(SEQ ID NO:7) GYTFDF
(SEQ ID NO:120) GYTFDFYMD
(SEQ ID NO:7) DFYMD
(SEQ ID NO:121) TDFYMD
(SEQ ID NO:122) Option
heavy chain CDR2 YIYPHNAGTTYN
QQFTG
(SEQ ID NO:14) YPHNAG
(SEQ ID NO:131) YIYPHNAGTT
(SEQ ID NO:132) YIYPHNAGTTYN
QQFTG
(SEQ ID NO:14) WMGYIYPHN
AGTT
(SEQ ID NO:133) Option
heavy chain CDR2 YIYPHNTGTTYN
QQFTG
(SEQ ID NO:15) YPHNTG
(SEQ ID NO:134) YIYPHNTGTT
(SEQ ID NO:135) YIYPHNTGTTYN
QQFTG
(SEQ ID NO:15) WMGYIYPHN
TGTT
(SEQ ID NO:136) Option
heavy chain CDR2 YIYPHEGGTTYN
QQFTG
(SEQ ID NO:16) YPHEGG
(SEQ ID NO:137) YIYPHEGGTT
(SEQ ID NO:138) YIYPHEGGTTYN
QQFTG
(SEQ ID NO:16) WMGYIYPHE
GGTT
(SEQ ID NO:139) Option
heavy chain CDR2 YIYPHQGGTTYN
QQFTG
(SEQ ID NO:17) YPHQGG
(SEQ ID NO:140) YIYPHQGGTT
(SEQ ID NO:141) YIYPHQGGTTYN
QQFTG
(SEQ ID NO:17) WMGYIYPHQ
GGTT
(SEQ ID NO:142) heavy chain
CDR3 RGGFFDY
(SEQ ID NO:9) RGGFFDY
(SEQ ID NO:9) RGGFFDY
(SEQ ID NO:9) RGGFFDY
(SEQ ID NO:9) ARRGGFFD
(SEQ ID NO:126) light chain
CDR1 KASENVDTYVS (SEQ ID NO:10) KASENVDTYVS (SEQ ID NO:10) KASENVDTYVS (SEQ ID NO:10) KASENVDTYVS (SEQ ID NO:10) DTYVSWY
(SEQ ID NO:127) light chain
CDR2 GASNRYT
(SEQ ID NO:11) GASNRYT
(SEQ ID NO:11) GASNRYT
(SEQ ID NO:11) GASNRYT
(SEQ ID NO:11) LLIYGASNRY
(SEQ ID NO:128) light chain
CDR3 GQSHSYPLT
(SEQ ID NO:12) GQSHSYPLT
(SEQ ID NO:12) GQSHSYPLT
(SEQ ID NO:12) GQSHSYPLT
(SEQ ID NO:12) GQSHSYPL
(SEQ ID NO:129)

[00124]

Table 2: 3D8 antibody sequences

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GYSFTGYNMN
(SEQ ID NO:38) GYSFTGY
(SEQ ID NO:143) GYSFTGYNMN
(SEQ ID NO:38) GYNMN
(SEQ ID NO:144) TGYNMN
(SEQ ID NO:145) heavy chain CDR2 NINPYYGSTNYN
QKFKG
(SEQ ID NO:39) NPYYGS
(SEQ ID NO:146) NINPYYGSTN
(SEQ ID NO:147) NINPYYGSTNYN
QKFKG
(SEQ ID NO:39) WIGNINPYYGSTN (SEQ ID NO:149) heavy chain
CDR3 GYYGGNYPFAY (SEQ ID NO:40) GYYGGNYPFAY (SEQ ID NO:40) GYYGGNYPFAY (SEQ ID NO:40) GYYGGNYPFAY (SEQ ID NO:40) ARGYYGGNYPFA (SEQ ID NO:150) light chain
CDR1 RASENIYSYLA
(SEQ ID NO:41) RASENIYSYLA
(SEQ ID NO:41) RASENIYSYLA
(SEQ ID NO:41) RASENIYSYLA
(SEQ ID NO:41) YSYLAWY
(SEQ ID NO:151) light chain
CDR2 NAKTLAE
(SEQ ID NO:42) NAKTLAE
(SEQ ID NO:42) NAKTLAE
(SEQ ID NO:42) NAKTLAE
(SEQ ID NO:42) LLVYNAKTLA
(SEQ ID NO:152) light chain
CDR3 QHYYGTPYT
(SEQ ID NO:43) QHYYGTPYT
(SEQ ID NO:43) QHYYGTPYT
(SEQ ID NO:43) QHYYGTPYT
(SEQ ID NO:43) QHYYGTPY
(SEQ ID NO:153) Heavy chain variable region 3D8 (SEQ ID NO: 91)
EIQLQQSGAELVKPGASVKISCKASGYSFTGYNMNWVKQSHGKSLEWIGNINPYYGSTNY
NQKFKGKATLTVDKSSTTAYMQLDSLTSEDSAVYYCARGYYGGNYPFAYWGQGTLVTVSA Light chain variable region 3D8 (SEQ ID NO: 92)
DIQMTQSPASLSASVGETVTITCRASENIYSYLAWYQQKQGKSPQLLVYNAKTLAEGVPS
RFSGSGSGTQFSLKINSLQPEDFGSYYCQHYYGTPYTFGGGSKVEIK

[00125]

Table 3: 3G8 antibody sequences

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GYSFTGYNMN
(SEQ ID NO:38) GYSFTGY
(SEQ ID NO:143) GYSFTGYNMN
(SEQ ID NO:38) GYNMN
(SEQ ID NO:144) TGYNMN
(SEQ ID NO:145) heavy chain CDR2 NINPYYDSTSYN
QKFKG
(SEQ ID NO:44) NPYYDS
(SEQ ID NO:154) NINPYYDSTS
(SEQ ID NO:155) NINPYYDSTSYN
QKFKG
(SEQ ID NO:44) WIGNINPYYDSTS
(SEQ ID NO:156) heavy chain
CDR3 ENYDFVGFAY
(SEQ ID NO:45) ENYDFVGFAY
(SEQ ID NO:45) ENYDFVGFAY
(SEQ ID NO:45) ENYDFVGFAY
(SEQ ID NO:45) ARENYDFVGFA (SEQ ID NO:157) light chain
CDR1 RASSSVSYMH
(SEQ ID NO:46) RASSSVSYMH
(SEQ ID NO:46) RASSSVSYMH
(SEQ ID NO:46) RASSSVSYMH
(SEQ ID NO:46) SYMHWF
(SEQ ID NO:158) light chain
CDR2 VTSNLAS
(SEQ ID NO:47) VTSNLAS
(SEQ ID NO:47) VTSNLAS
(SEQ ID NO:47) VTSNLAS
(SEQ ID NO:47) PWIYVTSNLA
(SEQ ID NO:159) light chain
CDR3 QQWSTNPLT
(SEQ ID NO:48) QQWSTNPLT
(SEQ ID NO:48) QQWSTNPLT
(SEQ ID NO:48) QQWSTNPLT
(SEQ ID NO:48) QQWSTNPL
(SEQ ID NO:160) 3G8 heavy chain variable region (SEQ ID NO: 93)
EIQLQQSGAELVKPGASVKISCMASGYSFTGYNMNWVKQSHGKGLEWIGNINPYYDSTSY
NQKFKGKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARENYDFVGFAYWGQGTLVTVSA 3G8 light chain variable region (SEQ ID NO: 94)
QIVLSQSPAILSASPGEKVTMTCRASSSVSYMHWFQQKPGSSPKPWIYVTSNLASGVPPR
FSGSGSGTSYSLTISRVEEAEDAATYYCQQWSTNPLTFGAGTKLELK

[00126]

Table 4: Sequences of the 15C12 antibody

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GYSFTGYNMH
(SEQ ID NO:49) GYSFTGY
(SEQ ID NO:143) GYSFTGYNMH
(SEQ ID NO:49) GYNMH
(SEQ ID NO:161) TGYNMH
(SEQ ID NO:162) heavy chain CDR2 NINPYYGTTNSN
QKFED
(SEQ ID NO:50) NPYYGT
(SEQ ID NO:163) NINPYYGTTN
(SEQ ID NO:164) NINPYYGTTNSN
QKFED
(SEQ ID NO:50) WIGNINPYYGTTN
(SEQ ID NO:165) heavy chain
CDR3 GIYYYGTGYP
YFDF
(SEQ ID NO:51) GIYYYGTGYP
YFDF
(SEQ ID NO:51) GIYYYGTGYP
YFDF
(SEQ ID NO:51) GIYYYGTGYP
YFDF
(SEQ ID NO:51) ARGIYYYGTGYP
YFD
(SEQ ID NO:166) light chain
CDR1 RASQDINNYLN (SEQ ID NO:52) RASQDINNYLN (SEQ ID NO:52) RASQDINNYLN (SEQ ID NO:52) RASQDINNYLN (SEQ ID NO:52) NNYLNWY
(SEQ ID NO:167) light chain
CDR2 YTSRLHS
(SEQ ID NO:53) YTSRLHS
(SEQ ID NO:53) YTSRLHS
(SEQ ID NO:53) YTSRLHS
(SEQ ID NO:53) LLIYYTSRLH
(SEQ ID NO:168) light chain
CDR3 QQGITLPWT
(SEQ ID NO:54) QQGITLPWT
(SEQ ID NO:54) QQGITLPWT
(SEQ ID NO:54) QQGITLPWT
(SEQ ID NO:54) QQGITLPW
(SEQ ID NO:169) Heavy chain variable region 15C12 (SEQ ID NO: 95)
EIQLQQSGAELEKPGASVKISCKASGYSFTGYNMHWVKQSHGKSLEWIGNINPYYGTTNS
NQKFEDKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARGIYYYGTGYPYFDFWGQGTTLT
VSS Light chain variable region 15C12 (SEQ ID NO: 96)
DIQMTQTTSSLSASLGDRVTISCRASQDINNYLNWYLQKPDGTVKLLIYYTSRLHSGVPS
RFSGSGSGTDYSLTISNLEQEDLATYFCQQGITLPWTFGGGTKLEIK

[00127]

Table 5: Sequences of the 27A8 antibody

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GYTFTDYWIN
(SEQ ID NO:55) GYTFTDY
(SEQ ID NO:170) GYTFTDYWIN
(SEQ ID NO:55) DYWIN
(SEQ ID NO:171) TDYWIN
(SEQ ID NO:172) heavy chain CDR2 NIYPGSTSANYN
EKFKS
(SEQ ID NO:56) YPGTSTS
(SEQ ID NO:173) NIYPGSTSAN
(SEQ ID NO:174) NIYPGSTSANYN
EKFKS
(SEQ ID NO:56) WIGNIYPGSTSAN
(SEQ ID NO:175) heavy chain
CDR3 YGYDSWFAY
(SEQ ID NO:57) YGYDSWFAY
(SEQ ID NO:57) YGYDSWFAY
(SEQ ID NO:57) YGYDSWFAY
(SEQ ID NO:57) ARYGYDSWFA (SEQ ID NO:176) light chain
CDR1 KSTKSLLNSDG
FTYLD
(SEQ ID NO:58) KSTKSLLNSDG
FTYLD
(SEQ ID NO:58) KSTKSLLNSDG
FTYLD
(SEQ ID NO:58) KSTKSLLNSDG
FTYLD
(SEQ ID NO:58) LNSDGFTYLDWF
(SEQ ID NO:177) light chain
CDR2 LVSNRFS
(SEQ ID NO:59) LVSNRFS
(SEQ ID NO:59) LVSNRFS
(SEQ ID NO:59) LVSNRFS
(SEQ ID NO:59) LLIYLVSNRF
(SEQ ID NO:178) light chain
CDR3 FQSNYLPLT
(SEQ ID NO:60) FQSNYLPLT
(SEQ ID NO:60) FQSNYLPLT
(SEQ ID NO:60) FQSNYLPLT
(SEQ ID NO:60) FQSNYLPL
(SEQ ID NO:179) Heavy chain variable region 27A8 (SEQ ID NO: 97)
QVQLLQPGAEFVKPGASVKLSCKASGYTFTDYWINWVKQRPGQGLEWIGNIYPGSTSANY
NEKFKSKATLTIDTSSITAYMQLSSLTSDDSAVYYCARYGYDSWFAYWGQGTLVTVSA Light chain variable region 27A8 (SEQ ID NO: 98)
DVVLTQTPLSLPVNIGDQASISCKSTKSLLNSDGFTYLDWFLQKPGQSPHLLIYLVSNRF
SGIPDRFSGSGSETDFTLKISRVEAEDLGVYYCFQSNYLPLTFGSGTKLEIK

[00128]

Table 6: Sequences of the 28C3 antibody

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GYAFNSCWMN
(SEQ ID NO:61) GYAFNSC
(SEQ ID NO:180) GYAFNSCWMN (SEQ ID NO:61) SCWMN
(SEQ ID NO:181) NSCWMN
(SEQ ID NO:182) heavy chain CDR2 RIYPGDGDTNYN
GKFKG
(SEQ ID NO:62) YPGDGD
(SEQ ID NO:183) RIYPGDGDTN
(SEQ ID NO:184) RIYPGDGDTNYN
GKFKG
(SEQ ID NO:62) WIGRIYPGDGDTN
(SEQ ID NO:185) heavy chain
CDR3 EGRNYGYEDY
(SEQ ID NO:63) EGRNYGYEDY
(SEQ ID NO:63) EGRNYGYEDY
(SEQ ID NO:63) EGRNYGYEDY
(SEQ ID NO:63) AREGRNYGYED (SEQ ID NO:186) light chain
CDR1 KASQSVDYDG
DSYMN
(SEQ ID NO:64) KASQSVDYDG
DSYMN
(SEQ ID NO:64) KASQSVDYDG
DSYMN
(SEQ ID NO:64) KASQSVDYDG
DSYMN
(SEQ ID NO:64) DYDGDSYMNWY
(SEQ ID NO:187) light chain
CDR2 AASDLES
(SEQ ID NO:65) AASDLES
(SEQ ID NO:65) AASDLES
(SEQ ID NO:65) AASDLES
(SEQ ID NO:65) LLIYAASDLE
(SEQ ID NO:188) light chain
CDR3 QQANEDPRT
(SEQ ID NO:66) QQANEDPRT
(SEQ ID NO:66) QQANEDPRT
(SEQ ID NO:66) QQANEDPRT
(SEQ ID NO:66) QQANEDPR
(SEQ ID NO:189) Heavy chain variable region 28C3 (SEQ ID NO: 99)
QVQLQQSGPELVKPGASVKISCKASGYAFNSCWMNWVKQRPGKGLEWIGRIYPGDGDTNY
NGKFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFCAREGRNYGYEDYWGQGTTLTVSS Light chain variable region 28C3 (SEQ ID NO: 100)
DIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASDLES
GIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQANEDPRTFGGGTKLEIK

[00129]

Table 7: 38F5 antibody sequences

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GFTFSNYAMS
(SEQ ID NO:67) GFTFSNY
(SEQ ID NO:190) GFTFSNYAMS
(SEQ ID NO:67) NYAMS
(SEQ ID NO:191) SNYAMS
(SEQ ID NO:192) heavy chain CDR2 QTISSGGRYTYYP
DSVKG
(SEQ ID NO:68) ISSGGRY
(SEQ ID NO:193) QTISSGGRYTY
(SEQ ID NO:194) QTISSGGRYTYYP
DSVKG
(SEQ ID NO:68) WVQTISSGGRYTY (SEQ ID NO:195) heavy chain
CDR3 RYYGNSYWY
FDV
(SEQ ID NO:69) RYYGNSYWY
FDV
(SEQ ID NO:69) RYYGNSYWY
FDV
(SEQ ID NO:69) RYYGNSYWY
FDV
(SEQ ID NO:69) VRRYYGNSYW
YFD
(SEQ ID NO:196) light chain
CDR1 KSSQSLLNSGNQ
KHYLT
(SEQ ID NO:70) KSSQSLLNSGNQ
KHYLT
(SEQ ID NO:70) KSSQSLLNSGNQ
KHYLT
(SEQ ID NO:70) KSSQSLLNSGNQ
KHYLT
(SEQ ID NO:70) LNSGNQKHYL
TWY
(SEQ ID NO:197) light chain
CDR2 GASTRGS
(SEQ ID NO:71) GASTRGS
(SEQ ID NO:71) GASTRGS
(SEQ ID NO:71) GASTRGS
(SEQ ID NO:71) LLIYGASTRG
(SEQ ID NO:198) light chain
CDR3 QNDHSYPYT
(SEQ ID NO:72) QNDHSYPYT
(SEQ ID NO:72) QNDHSYPYT
(SEQ ID NO:72) QNDHSYPYT
(SEQ ID NO:72) QNDHSYPY
(SEQ ID NO:199) Heavy chain variable region 38F5 (SEQ ID NO: 101)
EVMLVESGGALVKPGGSLKLSCTASGFTFSNYAMSWVRQTPEKRLEWVAQTISSGGRYTY
YPDSVKGRFTISRDNARNTLYLQMSSLRSEDTAMYYCVRRYYGNSYWYFDVWGAGTTVTV
SS Light chain variable region 38F5 (SEQ ID NO: 102)
DIVMTQSPSSLSVSAGEKVTMNCKSSQSLLNSGNQKHYLTWYQQKPGQPPKLLIYGASTR
GSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDHSYPYTFGGGTKLEIK

[00130]

Table 8: Sequences of the 62B11 antibody

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GFTFSSYTMS
(SEQ ID NO:73) GFTFSSY
(SEQ ID NO:200) GFTFSSYTMS
(SEQ ID NO:73) SYTMS
(SEQ ID NO:201) SSYTMS
(SEQ ID NO:202) heavy chain CDR2 YISSGGGTTYYP
DTVKG
(SEQ ID NO:74) SSGGGT
(SEQ ID NO:203) YISSGGGTTY
(SEQ ID NO:204) YISSGGGTTYYP
DTVKG
(SEQ ID NO:74) WVAYISSGGGTTY
(SEQ ID NO:205) heavy chain
CDR3 RYYRGSSLWY
FDV
(SEQ ID NO:75) RYYRGSSLWY
FDV
(SEQ ID NO:75) RYYRGSSLWY
FDV
(SEQ ID NO:75) RYYRGSSLWY
FDV
(SEQ ID NO:75) ARRYYRGSSLW
YFD
(SEQ ID NO:206) light chain
CDR1 KSSQSLFNSGSQ
KNFLT
(SEQ ID NO:76) KSSQSLFNSGSQ
KNFLT
(SEQ ID NO:76) KSSQSLFNSGSQ
KNFLT
(SEQ ID NO:76) KSSQSLFNSGSQ
KNFLT
(SEQ ID NO:76) FNSGSQKNFLTWY
(SEQ ID NO:207) light chain
CDR2 WASTRES
(SEQ ID NO:77) WASTRES
(SEQ ID NO:77) WASTRES
(SEQ ID NO:77) WASTRES
(SEQ ID NO:77) LLIYWASTRE
(SEQ ID NO:208) light chain
CDR3 QNDYSYPLT
(SEQ ID NO:78) QNDYSYPLT
(SEQ ID NO:78) QNDYSYPLT
(SEQ ID NO:78) QNDYSYPLT
(SEQ ID NO:78) QNDYSYPL
(SEQ ID NO:209) Heavy chain variable region 62B11 (SEQ ID NO: 103)
EVKLVESGGGLVQPGGSLKLSCAASGFTFSSYTMSWVRQTPEKRLEWVAYISSGGGTTYY
PDTVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYSCARRYYRGSSLWYFDVWGAGTTVTV
SS Light chain variable region 62B11 (SEQ ID NO: 104)
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLFNSGSQKNFLTWYQQRPGQPPKLLIYWASTR
ESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLELK

[00131]

Table 9: 62F2 antibody sequences

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GYSITSGYSLH
(SEQ ID NO:79) GYSITSGY
(SEQ ID NO:210) GYSITSGYSLH
(SEQ ID NO:79) SGYSLH
(SEQ ID NO:211) TSGYSLH
(SEQ ID NO:212) heavy chain CDR2 YIHYSGSTNYNP
SLKS
(SEQ ID NO:80) HYSGS
(SEQ ID NO:213) YIHYSGSTN
(SEQ ID NO:214) YIHYSGSTNYNP
SLKS
(SEQ ID NO:80) WMGYIHYSGSTN (SEQ ID NO:215) heavy chain
CDR3 AWDYLDY
(SEQ ID NO:81) AWDYLDY
(SEQ ID NO:81) AWDYLDY
(SEQ ID NO:81) AWDYLDY
(SEQ ID NO:81) ARAWDYLD
(SEQ ID NO:216) light chain
CDR1 RASENIYSQLA
(SEQ ID NO:82) RASENIYSQLA
(SEQ ID NO:82) RASENIYSQLA
(SEQ ID NO:82) RASENIYSQLA
(SEQ ID NO:82) YSQLAWY
(SEQ ID NO:217) light chain
CDR2 DAKTLAE
(SEQ ID NO:83) DAKTLAE
(SEQ ID NO:83) DAKTLAE
(SEQ ID NO:83) DAKTLAE
(SEQ ID NO:83) LLVYDAKTLA
(SEQ ID NO:218) light chain
CDR3 HHHFGILYT
(SEQ ID NO:84) HHHFGILYT
(SEQ ID NO:84) HHHFGILYT
(SEQ ID NO:84) HHHFGILYT
(SEQ ID NO:84) HHHFGILY
(SEQ ID NO:219) Heavy chain variable region 62F2 (SEQ ID NO: 105)
DVQLQESGPDLVKPSQSLSLTCTVTGYSITSGYSLHWIRQFPGNKLEWMGYIHYSGSTNY
NPSLKSRISITRDTSKNQFFLKLNSVTSEDTATYHCARAWDYLDYWGQGTTLTVSS Light chain variable region 62F2 (SEQ ID NO: 106)
DIQMTQSPASLSASVGETVTITCRASENIYSQLAWYQQKQGKSPQLLVYDAKTLAEGVPS
RFSGGSDTQFSLKIISLQPEDFGRYYCHHHFGILYTFGGGTKLEMK

[00132]

Table 10: Sequences of the 63A3 antibody

Illustrative Chothia AbM Kabat Contact heavy chain CDR1 GYSITSGYYWN (SEQ ID NO:85) GYSITSGY
(SEQ ID NO:210) GYSITSGYYWN (SEQ ID NO:85) SGYYWN
(SEQ ID NO:220) TSGYYWN
(SEQ ID NO:221) heavy chain CDR2 YIRYDGSNNYN
PSLKN
(SEQ ID NO:86) RYDGS
(SEQ ID NO:222) YIRYDGSNN
(SEQ ID NO:223) YIRYDGSNNYN
PSLKN
(SEQ ID NO:86) WMGYIRYDGSNN
(SEQ ID NO:224) heavy chain
CDR3 HYGYDGGAFFDF (SEQ ID NO:87) HYGYDGGAFFDF (SEQ ID NO:87) HYGYDGGAFFDF (SEQ ID NO:87) HYGYDGGAFFDF (SEQ ID NO:87) ARHYGYDGGAFD (SEQ ID NO:225) light chain
CDR1 RTSENIYNYLV
(SEQ ID NO:88) RTSENIYNYLV
(SEQ ID NO:88) RTSENIYNYLV
(SEQ ID NO:88) RTSENIYNYLV
(SEQ ID NO:88) YNYLVWY
(SEQ ID NO:226) light chain
CDR2 NAKTLEE
(SEQ ID NO:89) NAKTLEE
(SEQ ID NO:89) NAKTLEE
(SEQ ID NO:89) NAKTLEE
(SEQ ID NO:89) LLVYNAKTLE
(SEQ ID NO:227) light chain
CDR3 QHHYGTPFT
(SEQ ID NO:90) QHHYGTPFT
(SEQ ID NO:90) QHHYGTPFT
(SEQ ID NO:90) QHHYGTPFT
(SEQ ID NO:90) QHHYGTPF
(SEQ ID NO:228) Heavy chain variable region 63A3 (SEQ ID NO: 107)
DVQLQESGPGLVKPSQSLSLTCSVTGYSITSGYYWNWIRQFPGNKLEWMGYIRYDGSNNY
NPSLKNRISITRDTSKNQVFLKLNSVTPEDTATYYCARHYGYDGGAFDFWGQGTTLTVSS Light chain variable region 63A3 (SEQ ID NO: 108)
DIQMTQSPASLSASVGETVTITCRTSENIYNYLVWYQQKQGKSPQLLVYNAKTLEEGVPS
RFSGSGSGTQFSLKVNSLQPEDFGSYYCQHHYGTPFTFGSGTKLEIK

[00122] In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 and/or a light chain CDR1, CDR2, CDR3 from an antibody described herein. In some embodiments, the C3 binding agent comprises a humanized version or a humanized variant of an antibody described herein. In some embodiments, the C3 binding agent comprises heavy chain CDR1, CDR2 and CDR3 and/or light chain CDR1, CDR2, CDR3 from the 38G10 antibody or a humanized version thereof. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, CDR3 from the 38G10 antibody or a humanized version thereof. In some embodiments, the C3 binding agent comprises heavy chain CDR1, CDR2 and CDR3 and/or light chain CDR1, CDR2, CDR3 from the Hz38G10 antibody or variants thereof. In some embodiments, the C3 binding agent comprises heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2, CDR3 from the Hz38G10 antibody or variants thereof. In some embodiments, the C3 binding agent comprises heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, CDR3 from a 38G10 antibody, a Hz38G10 antibody, or Hz38G10 variants.

[00123] In some embodiments, the C3 binding agent comprises heavy chain CDR1, CDR2, and CDR3 and/or light chain CDR1, CDR2, and CDR3 from the 3D8 antibody, a humanized version thereof, or variants thereof. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 from the 3D8 antibody. In other embodiments, the C3 binding agent comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 3D8 antibody. In certain embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 3D8 antibody. In some embodiments, the 3D8 antibody is a humanized version of the 3D8 antibody. In some embodiments, the 3D8 antibody is a variant of the 3D8 antibody.

[00124] In some embodiments, the C3 binding agent comprises heavy chain CDR1, CDR2, and CDR3 and/or light chain CDR1, CDR2, and CDR3 from the 3G8 antibody, a humanized version thereof, or variants thereof. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 from the 3G8 antibody. In other embodiments, the C3 binding agent comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 3G8 antibody. In certain embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 3G8 antibody. In some embodiments, the 3G8 antibody is a humanized version of the 3G8 antibody. In some embodiments, the 3G8 antibody is a variant of the 3G8 antibody.

[00125] In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 and/or a light chain CDR1, CDR2, CDR3 from the 15C12 antibody, a humanized version thereof, or variants thereof. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 from the 15C12 antibody. In other embodiments, the C3 binding agent comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 15C12 antibody. In certain embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 15C12 antibody. In some embodiments, the 15C12 antibody is a humanized version of the 15C12 antibody. In some embodiments, the 15C12 antibody is a variant of the 15C12 antibody.

[00126] In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 and/or a light chain CDR1, CDR2, CDR3 from the 27A8 antibody, a humanized version thereof, or variants thereof. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 from the 27A8 antibody. In other embodiments, the C3 binding agent comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 27A8 antibody. In certain embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 27A8 antibody. In some embodiments, the 27A8 antibody is a humanized version of the 27A8 antibody. In some embodiments, the implementation of the antibody 27A8 is a variant of the antibody 27A8.

[00127] In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 and/or a light chain CDR1, CDR2, CDR3 from the 28C3 antibody, a humanized version thereof, or variants thereof. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 from the 28C3 antibody. In other embodiments, the C3 binding agent comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 28C3 antibody. In certain embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 28C3 antibody. In some embodiments, the 28C3 antibody is a humanized version of the 28C3 antibody. In some embodiments, the 28C3 antibody is a variant of the 28C3 antibody.

[00128] In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 and/or a light chain CDR1, CDR2, CDR3 from the 38F5 antibody, a humanized version thereof, or variants thereof. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 from the 38F5 antibody. In other embodiments, the C3 binding agent comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 38F5 antibody. In certain embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 38F5 antibody. In some embodiments, the 38F5 antibody is a humanized version of the 38F5 antibody. In some embodiments, the 38F5 antibody is a variant of the 38F5 antibody.

[00129] In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 and/or a light chain CDR1, CDR2, CDR3 from the 62B11 antibody, a humanized version thereof, or variants thereof. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 from the 62B11 antibody. In other embodiments, the C3 binding agent comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 62B11 antibody. In certain embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 62B11 antibody. In some embodiments, the 62B11 antibody is a humanized version of the 62B11 antibody. In some embodiments, the 62B11 antibody is a variant of the 62B11 antibody.

[00130] In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 and/or a light chain CDR1, CDR2, CDR3 from the 62F2 antibody, a humanized version thereof, or variants thereof. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 from the 62F2 antibody. In other embodiments, the C3 binding agent comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 62F2 antibody. In certain embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 62F2 antibody. In some embodiments, the 62F2 antibody is a humanized version of the 62F2 antibody. In some embodiments, the 62F2 antibody is a variant of the 62F2 antibody.

[00131] In some embodiments, the C3 binding agent comprises heavy chain CDR1, CDR2, and CDR3 and/or light chain CDR1, CDR2, CDR3 from the 63A3 antibody, a humanized version thereof, or variants thereof. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 from the 63A3 antibody. In other embodiments, the C3 binding agent comprises a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 63A3 antibody. In certain embodiments, the C3 binding agent comprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3, a light chain CDR1, a light chain CDR2, and a light chain CDR3 from the 63A3 antibody. In some embodiments, the 63A3 antibody is a humanized version of the 63A3 antibody. In some embodiments, the implementation of the antibody 63A3 is a variant of the antibody 63A3.

[00132] In some embodiments, the C3 binding agent is an antibody. In some embodiments, a variant of an anti-C3 antibody described herein contains from one to thirty conservative amino acid substitutions. In some embodiments, the anti-C3 antibody variant contains from one to twenty-five conservative amino acid substitutions. In some embodiments, the anti-C3 antibody variant contains from one to twenty conservative amino acid substitutions. In some embodiments, the anti-C3 antibody variant contains one to fifteen conservative amino acid substitutions. In some embodiments, the anti-C3 antibody variant contains one to ten conservative amino acid substitutions. In some embodiments, the anti-C3 antibody variant contains one to five conservative amino acid substitutions. In some embodiments, the anti-C3 antibody variant contains one to three conservative amino acid substitutions. In some embodiments, the conservative(s) amino acid(s) substitution(s) is in the CDR of the antibody. In some embodiments, the conservative(s) amino acid(s) substitution(s) is not in the CDR of the antibody. In some embodiments, the conservative(s) amino acid(s) substitution(s) is in the framework region of the antibody.

[00133] CDRs are determined using a variety of methods/systems by those skilled in the art. These systems and/or definitions have been developed and refined over a number of years and include Kabat, Chothia, IMGT, AbM and contact. The Kabat definition is based on sequence variability and is generally the most commonly used. The Chothia definition is based on the location of the structural loop regions. The IMGT system is based on sequence variability and location within the variable domain structure. The AbM definition is a compromise between Kabat and Chothia. The definition of Contact is based on the analysis of available crystal structures of antibodies. An exemplary system is a combination of Kabat and Chothia. Software (eg abYsis (www.bioinf.org.uk/abysis/sequence_input/key_annotation/key_annotation.cgi)) is available and known to those skilled in the art for analyzing antibody sequences and determining CDRs.

[00134] The specific CDR sequences defined herein are typically based on a combination of the Kabat and Chothia definitions (illustrative system). However, it will be understood that reference to a heavy chain CDR or multiple CDRs and/or a light chain CDR or multiple CDRs of a particular antibody will encompass all definitions of CDRs known to those skilled in the art.

[00135] In some embodiments, the C3 binding agent (eg, antibody) comprises heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3 from an antibody designated 38G10. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 from an antibody designated 38G10. In some embodiments, the C3 binding agent comprises a light chain CDR1, CDR2, and CDR3 from an antibody designated 38G10. In some embodiments, the C3 binding agent (eg, antibody) comprises heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 from an antibody designated Hz38G10. In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 from an antibody designated Hz38G10. In some embodiments, the C3 binding agent (eg, antibody) comprises heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 from an antibody designated Hz38G10 (G56A). In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 from an antibody designated Hz38G10 (G56A). In some embodiments, the C3 binding agent (eg, antibody) comprises heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 from an antibody designated Hz38G10 (G56T). In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 from an antibody designated Hz38G10 (G56T). In some embodiments, the C3 binding agent (eg, antibody) comprises heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 from an antibody designated Hz38G10 (N55E). In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 from an antibody designated Hz38G10 (N55E). In some embodiments, the C3 binding agent (eg, antibody) comprises heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 from an antibody designated Hz38G10 (N55Q). In some embodiments, the C3 binding agent comprises a heavy chain CDR1, CDR2, and CDR3 from an antibody designated Hz38G10 (N55Q). In some embodiments, the C3 binding agent (e.g., antibody) comprises a light chain CDR1, CDR2, and CDR3 from an antibody designated Hz38G10, Hz38G10 (G56A), Hz38G10 (G56T), Hz38G10 (N55E), or Hz38G10 (N55Q).

[00136] In some embodiments, the C3 binding agent (eg, antibody) comprises heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3 from Table 1A, Table 1B, or Table 1C.

[00137] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO: 7, a heavy chain CDR2 comprising SEQ ID NO: 8, a heavy chain CDR3 comprising SEQ ID NO: :9, a light chain CDR1 containing SEQ ID NO:10, a light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (b) Heavy chain CDR1 containing SEQ ID NO:120, heavy chain CDR2 containing SEQ ID NO:123, heavy chain CDR3 containing SEQ ID NO:9, light chain CDR1 containing SEQ ID NO:10, light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (c) Heavy chain CDR1 containing SEQ ID NO:7, heavy chain CDR2 containing SEQ ID NO:124, heavy chain CDR3 containing SEQ ID NO:9, light chain CDR1 containing SEQ ID NO:10, light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (d) Heavy chain CDR1 containing SEQ ID NO:121, heavy chain CDR2 containing SEQ ID NO:8, heavy chain CDR3 containing SEQ ID NO:9, light chain CDR1 containing SEQ ID NO:10, light chain CDR2 containing SEQ ID NO:11 and a light chain CDR3 containing SEQ ID NO:12, or (e) a heavy chain CDR1 containing SEQ ID NO:122, a heavy chain CDR2 containing SEQ ID NO:125, a heavy chain CDR3, containing SEQ ID NO:126, a light chain CDR1 containing SEQ ID NO:127, a light chain CDR2 containing SEQ ID NO:128, and a light chain CDR3 containing SEQ ID NO:129. In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:7, a heavy chain CDR2 comprising SEQ ID NO:13, a heavy chain CDR3 comprising SEQ ID NO:9, A light chain CDR1 containing SEQ ID NO:10, a light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (b) Heavy chain CDR1 containing SEQ ID NO:120, heavy chain CDR2 containing SEQ ID NO:123, heavy chain CDR3 containing SEQ ID NO:9, light chain CDR1 containing SEQ ID NO:10, light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (c) Heavy chain CDR1 containing SEQ ID NO:7, heavy chain CDR2 containing SEQ ID NO:124, heavy chain CDR3 containing SEQ ID NO:9, light chain CDR1 containing SEQ ID NO:10, light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (d) Heavy chain CDR1 comprising SEQ ID NO:121, Heavy chain CDR2 comprising SEQ ID NO:13, Heavy chain CDR3 comprising SEQ ID NO:9, Light chain CDR1 comprising SEQ ID NO:10, Light chain CDR2 containing SEQ ID NO:11 and a light chain CDR3 containing SEQ ID NO:12, or (e) a heavy chain CDR1 containing SEQ ID NO:122, a heavy chain CDR2 containing SEQ ID NO:130, a heavy chain CDR3, containing SEQ ID NO:126, a light chain CDR1 containing SEQ ID NO:127, a light chain CDR2 containing SEQ ID NO:128, and a light chain CDR3 containing SEQ ID NO:129.

[00138] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:7, a heavy chain CDR2 comprising SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16 or SEQ ID NO:17, a heavy chain CDR3 containing SEQ ID NO:9, a light chain CDR1 containing SEQ ID NO:10, a light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (b) A heavy chain CDR1 containing SEQ ID NO:120, a heavy chain CDR2 containing SEQ ID NO:131, SEQ ID NO:134, SEQ ID NO:137 or SEQ ID NO:140, a heavy chain CDR3 containing SEQ ID NO:9, a light chain CDR1 containing SEQ ID NO:10, a light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (c) A heavy chain CDR1 containing SEQ ID NO:7, a heavy chain CDR2 containing SEQ ID NO:132, SEQ ID NO:135, SEQ ID NO:138 or SEQ ID NO:141, a heavy chain CDR3 containing SEQ ID NO:9, a light chain CDR1 containing SEQ ID NO:10, a light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12; (d) A heavy chain CDR1 containing SEQ ID NO:121, a heavy chain CDR2 containing SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16 or SEQ ID NO:17, a heavy chain CDR3 containing SEQ ID NO:9, a light chain CDR1 containing SEQ ID NO:10, a light chain CDR2 containing SEQ ID NO:11, and a light chain CDR3 containing SEQ ID NO:12, or (e) a heavy chain CDR1 containing SEQ ID NO: :122, heavy chain CDR2 containing SEQ ID NO:133, SEQ ID NO:136, SEQ ID NO:139 or SEQ ID NO:142, heavy chain CDR3 containing SEQ ID NO:126, light chain CDR1 containing SEQ ID NO:127, a light chain CDR2 containing SEQ ID NO:128, and a light chain CDR3 containing SEQ ID NO:129.

[00139] In some embodiments, the C3 binding agent (eg, antibody) comprises: (a) a heavy chain variable region containing a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); A heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8), YIYPHNGGTTYNQQFTG (SEQ ID NO:13), YIYPHNAGTTYNQQFTG (SEQ ID NO:14), YIYPHNTGTTYNQQFTG (SEQ ID NO:15), YIYPHEGGTTYNQQFTG (SEQ ID NO:16), or YIYPHQGGTTYNQQFTG (SEQ ID NO:17), and a heavy chain CDR3 containing RGGFDFDY (SEQ ID NO:9); and/or (b) a light chain variable region containing a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12).

[00140] In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7), a heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8) and a heavy chain CDR3 containing RGGFDFDY ( SEQ ID NO:9), and/or (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); A light chain CDR2 containing GASNRYT (SEQ ID NO:11) and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the C3 binding agent comprises a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7), a heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO:9 ). In some embodiments, the C3 binding agent comprises a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10), a light chain CDR2 containing GASNRYT (SEQ ID NO:11), and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12 ). In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO: 7), a heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO: 8), and a heavy chain CDR3 containing RGGFDFDY (SEQ ID NO: :9), and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); A light chain CDR2 containing GASNRYT (SEQ ID NO:11) and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12).

[00141] In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7), a heavy chain CDR2 containing YIYPHNGGTTYNQQFTG (SEQ ID NO:13) and a heavy chain CDR3 containing RGGFDFDY ( SEQ ID NO:9), and/or (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); A light chain CDR2 containing GASNRYT (SEQ ID NO:11) and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7), a heavy chain CDR2 containing YIYPHNGGTTYNQQFTG (SEQ ID NO:13), and a heavy chain CDR3 containing RGGFDFFDY ( SEQ ID NO:9). In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO: 7), a heavy chain CDR2 containing YIYPHNGGTTYNQQFTG (SEQ ID NO: 13), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO: :9), and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); A light chain CDR2 containing GASNRYT (SEQ ID NO:11) and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12).

[00142] In some embodiments, the C3 binding agent is a variant of the agent described herein. In some embodiments, the C3 binding agent (eg, antibody) comprises (a) a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7) or a variant thereof containing 1, 2, 3, or 4 amino acid substitutions; a heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8) or YIYPHNGGTTYNQQFTG (SEQ ID NO:13), or a variant thereof containing 1, 2, 3 or 4 amino acid substitutions; a heavy chain CDR3 containing RGGDFFDY (SEQ ID NO:9) or a variant thereof containing 1, 2, 3 or 4 amino acid substitutions; a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10), or a variant thereof containing 1, 2, 3 or 4 amino acid substitutions; A light chain CDR2 containing GASNRYT (SEQ ID NO:11), or a variant thereof containing 1, 2, 3, or 4 amino acid substitutions, and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12), or a variant thereof containing 1 , 2, 3 or 4 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative conservative substitutions. In some embodiments, the implementation of the CDR contains one conservative amino acid substitution. In some embodiments, the implementation of the CDR contains two conservative amino acid substitutions. In some embodiments, the implementation of the CDR contains three conservative amino acid substitutions. In some embodiments, the implementation of the CDR contains four conservative amino acid substitutions. In some embodiments, the CDR is a heavy chain CDR1. In some embodiments, the CDR is a heavy chain CDR2. In some embodiments, the CDR is a heavy chain CDR3. In some embodiments, the CDR is a light chain CDR1. In some embodiments, the CDR is a light chain CDR2. In some embodiments, the CDR is a light chain CDR3. In some embodiments, the substitutions are made as part of the humanization process. In some embodiments, substitutions are made as part of the germline humanization process. In some embodiments, the substitutions are made as part of the affinity maturation process. In some embodiments, replacements are made as part of the optimization process.

[00143] In some embodiments, the C3 binding agent (eg, antibody) contains one or more heavy or light chain CDRs that have been modified to reduce deamidation in the CDR sequence. Deamidation is a chemical reaction in which the amide functional group in the side chain of the amino acids asparagine (N) or glutamine (Q) is removed or converted to another functional group. Typically, asparagine is converted to aspartic acid or isoaspartic acid, and glutamine is converted to glutamic acid or polyglutamic acid. In some situations, deamidation may alter the structure, function, and/or stability of a polypeptide, potentially leading to a reduction in biological activity.

[00144] In some embodiments, the C3 binding agent (eg, antibody) comprises (a) a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); A heavy chain CDR2 containing YIYPHNAGTTYNQQFTG (SEQ ID NO:14), YIYPHNTGTTYNQQFTG (SEQ ID NO:15), YIYPHEGGTTYNQQFTG (SEQ ID NO:16) or YIYPHQGGTTYNQQFTG (SEQ ID NO:17), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO:9); and/or (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7), a heavy chain CDR2 containing YIYPHNAGTTYNQQFTG (SEQ ID NO:14), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO:9). In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO: 7), a heavy chain CDR2 containing YIYPHNAGTTYNQQFTG (SEQ ID NO: 14), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO: :9), and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); A light chain CDR2 containing GASNRYT (SEQ ID NO:11) and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7), a heavy chain CDR2 containing YIYPHNTGTTYNQQFTG (SEQ ID NO:15), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO:9). In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7), a heavy chain CDR2 containing YIYPHNTGTTYNQQFTG (SEQ ID NO:15), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO: :9), and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); A light chain CDR2 containing GASNRYT (SEQ ID NO:11) and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7), a heavy chain CDR2 containing YIYPHEGGTTYNQQFTG (SEQ ID NO:16), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO:9). In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7), a heavy chain CDR2 containing YIYPHEGGTTYNQQFTG (SEQ ID NO:16), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO: :9), and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); A light chain CDR2 containing GASNRYT (SEQ ID NO:11) and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7), a heavy chain CDR2 containing YIYPHQGGTTYNQQFTG (SEQ ID NO:17), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO:9). In some embodiments, the C3 binding agent comprises (a) a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO: 7), a heavy chain CDR2 containing YIYPHQGGTTYNQQFTG (SEQ ID NO: 17), and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO: :9), and (b) a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); A light chain CDR2 containing GASNRYT (SEQ ID NO:11) and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12).

[00145] In certain embodiments, the C3 binding agent comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 and a light chain variable region comprising CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYTFTDFYMD (SEQ ID NO:7), heavy chain CDR2 contains YIYPHNGGTTYNQNFTG (SEQ ID NO:8), heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), light chain CDR2 contains GASNRYT ( SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12). In certain embodiments, the C3 binding agent comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 and a light chain variable region comprising CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYTFDDFYMD (SEQ ID NO:7 ), heavy chain CDR2 contains YIYPHNGGTTYNQQFTG (SEQ ID NO:13), heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), light chain CDR2 contains GASNRYT (SEQ ID NO:10 :11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12). In certain embodiments, the C3 binding agent comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 and a light chain variable region comprising CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYTFDDFYMD (SEQ ID NO:7 ), heavy chain CDR2 contains YIYPHNAGTTYNQQFTG (SEQ ID NO:14), heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), light chain CDR2 contains GASNRYT (SEQ ID NO:10). :11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12). In certain embodiments, the C3 binding agent comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 and a light chain variable region comprising CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYTFDDFYMD (SEQ ID NO:7 ), heavy chain CDR2 contains YIYPHNTGTTYNQQFTG (SEQ ID NO:15), heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), light chain CDR2 contains GASNRYT (SEQ ID NO:10 :11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12). In certain embodiments, the C3 binding agent comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 and a light chain variable region comprising CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYTFDDFYMD (SEQ ID NO:7 ), heavy chain CDR2 contains YIYPHEGGTTYNQQFTG (SEQ ID NO:16), heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), light chain CDR2 contains GASNRYT (SEQ ID NO:10 :11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12). In certain embodiments, the C3 binding agent comprises a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 and a light chain variable region comprising CDRs 1, 2, and 3, wherein the heavy chain CDR1 comprises GYTFDDFYMD (SEQ ID NO:7 ), heavy chain CDR2 contains YIYPHQGGTTYNQQFTG (SEQ ID NO:17), heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), light chain CDR2 contains GASNRYT (SEQ ID NO:10 :11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12).

[00146] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80% sequence identity with SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:21 , SEQ ID NO:22, SEQ ID NO:23 or SEQ ID NO:24; and/or a light chain variable region having at least 80% sequence identity with SEQ ID NO:19 or SEQ ID NO:25. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least at least about 99% sequence identity with SEQ ID NO: 18. In some embodiments, the C3 binding agent (e.g., antibody) comprises a light chain variable region having at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% sequence identity with SEQ ID NO: 19. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% sequence identity with SEQ ID NO: 20. In some embodiments, a C3 binding agent (e.g., antibody) contains a heavy chain variable region having at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% sequence identity with SEQ ID NO: 21. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% sequence identity with SEQ ID NO: 22. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% sequence identity with SEQ ID NO: 23. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% sequence identity with SEQ ID NO: 24. In some embodiments, a C3 binding agent ( e.g., an antibody) comprises a light chain variable region having at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% sequence identity with SEQ ID NO: 25.

[00147] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80% sequence identity with SEQ ID NO: 18 and/or a light chain variable region having at least at least about 80% sequence identity to SEQ ID NO: 19. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80% sequence identity to SEQ ID NO: 18, and a light chain variable region having at least about 80% sequence identity with SEQ ID NO: 19. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 90% sequence identity with SEQ ID NO: 18, and/or a light chain variable region having at least about 90% sequence identity with SEQ ID NO: 19. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region , having at least about 90% sequence identity to SEQ ID NO: 18, and a light chain variable region having at least about 90% sequence identity to SEQ ID NO: 19. In some embodiments, a C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 95% sequence identity to SEQ ID NO: 18 and/or a light chain variable region having at least about 95% sequence identity to SEQ ID NO: 19. B in some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 95% sequence identity with SEQ ID NO: 18 and a light chain variable region having at least about 95% sequence identity with SEQ ID NO: 19.

[00148] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 90% sequence identity with SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22 , SEQ ID NO:23 or SEQ ID NO:24; and/or a light chain variable region having at least about 90% sequence identity with SEQ ID NO:25. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 90% sequence identity with SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23 or SEQ ID NO:24; and a light chain variable region having at least about 90% sequence identity with SEQ ID NO:25. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 95% sequence identity with SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23 or SEQ ID NO:24; and/or a light chain variable region having at least about 95% sequence identity with SEQ ID NO:25. In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 95% sequence identity with SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23 or SEQ ID NO:24; and a light chain variable region having at least about 95% sequence identity with SEQ ID NO:25. In some embodiments, the C3 binding agent comprises a heavy chain variable region having at least about 95% sequence identity to SEQ ID NO: 20 and a light chain variable region having at least about 95% sequence identity to SEQ ID NO: 25. In some embodiments, the C3 binding agent comprises a heavy chain variable region having at least about 95% sequence identity with SEQ ID NO: 21 and a light chain variable region having at least about 95% sequence identity with SEQ ID NO: 21. NO: 25. In some embodiments, the C3 binding agent comprises a heavy chain variable region having at least about 95% sequence identity with SEQ ID NO: 22 and a light chain variable region having at least about 95% sequence identity with SEQ ID NO: 25. In some embodiments, the C3 binding agent comprises a heavy chain variable region having at least about 95% sequence identity with SEQ ID NO: 23 and a light chain variable region having at least about 95% sequence identity. sequences of SEQ ID NO: 25. In some embodiments, the C3 binding agent comprises a heavy chain variable region having at least about 95% sequence identity to SEQ ID NO: 24 and a light chain variable region having at least about 95 % sequence identity to SEQ ID NO: 25.

[00149] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region comprising SEQ ID NO: 18. In some embodiments, the C3 binding agent comprises a light chain variable region comprising SEQ ID NO: 19. In some embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 18 and a light chain variable region comprising SEQ ID NO: 19.

[00150] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region comprising SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, or SEQ ID NO:24, and/or a light chain variable region comprising SEQ ID NO:25. In some embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 20. In some embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 21. In some embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 22. In some embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 23. In some embodiments, the C3 binding agent (e.g., antibody) comprises the variable region heavy chain comprising SEQ ID NO: 24. In some embodiments, the C3 binding agent comprises a light chain variable region comprising SEQ ID NO: 25. In some embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 20 and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 21 and a light chain variable region comprising SEQ ID NO: 25. B in some embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 22 and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 23, and a light chain variable region comprising SEQ ID NO: 25. In some embodiments, the C3 binding agent comprises a heavy chain variable region comprising SEQ ID NO: 24 and a light chain variable region comprising SEQ ID NO: 25 .

[00151] In some embodiments, a C3 binding agent (e.g., an antibody) comprises a heavy chain variable region CDR1, CDR2, and CDR3 having the amino acid sequence of SEQ ID NO: 18, and a light chain variable region CDR1, CDR2, and CDR3 having the amino acid sequence of SEQ ID NO: 19. In some embodiments, the C3 binding agent (e.g., antibody) comprises the CDR1, CDR2, and CDR3 of the heavy chain variable region having the amino acid sequence of SEQ ID NO: 20, and the CDR1, CDR2, and CDR3 of the heavy chain variable region. light chain region having the amino acid sequence of SEQ ID NO: 25. In some embodiments, the C3 binding agent (e.g., antibody) comprises CDR1, CDR2, and CDR3 of the heavy chain variable region having the amino acid sequence of SEQ ID NO: 21, and CDR1 , CDR2, and CDR3 of the light chain variable region having the amino acid sequence of SEQ ID NO: 25. In some embodiments, the C3 binding agent (e.g., antibody) comprises the CDR1, CDR2, and CDR3 of the heavy chain variable region having the amino acid sequence of SEQ ID NO: : 22, and CDR1, CDR2, and CDR3 of a light chain variable region having the amino acid sequence of SEQ ID NO: 25. In some embodiments, a C3 binding agent (e.g., an antibody) comprises the amino acid sequence of SEQ ID NO: 23, and the CDR1, CDR2, and CDR3 of the light chain variable region having the amino acid sequence of SEQ ID NO: 25. heavy chain region having the amino acid sequence of SEQ ID NO: 24; and CDR1, CDR2 and CDR3 of the light chain variable region having the amino acid sequence of SEQ ID NO: 25.

[00152] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:38, a heavy chain CDR2 comprising SEQ ID NO:39, a heavy chain CDR3 comprising SEQ ID NO: :40, a light chain CDR1 containing SEQ ID NO:41, a light chain CDR2 containing SEQ ID NO:42, and a light chain CDR3 containing SEQ ID NO:43; (b) Heavy chain CDR1 containing SEQ ID NO:143, heavy chain CDR2 containing SEQ ID NO:146, heavy chain CDR3 containing SEQ ID NO:40, light chain CDR1 containing SEQ ID NO:41, light chain CDR2 containing SEQ ID NO:42, and a light chain CDR3 containing SEQ ID NO:43; (c) Heavy chain CDR1 containing SEQ ID NO:38, heavy chain CDR2 containing SEQ ID NO:147, heavy chain CDR3 containing SEQ ID NO:40, light chain CDR1 containing SEQ ID NO:41, light chain CDR2 containing SEQ ID NO:42, and a light chain CDR3 containing SEQ ID NO:43; (d) Heavy chain CDR1 comprising SEQ ID NO:144, Heavy chain CDR2 comprising SEQ ID NO:39, Heavy chain CDR3 comprising SEQ ID NO:40, Light chain CDR1 comprising SEQ ID NO:41, Light chain CDR2 containing SEQ ID NO:42 and a light chain CDR3 containing SEQ ID NO:43, or (e) a heavy chain CDR1 containing SEQ ID NO:145, a heavy chain CDR2 containing SEQ ID NO:149, a heavy chain CDR3, containing SEQ ID NO:150, a light chain CDR1 containing SEQ ID NO:151, a light chain CDR2 containing SEQ ID NO:152, and a light chain CDR3 containing SEQ ID NO:153.

[00153] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYSFTGYNMN (SEQ ID NO:38), a heavy chain CDR2 containing NINPYYGSTNYNQKFKG (SEQ ID NO:39), and A heavy chain CDR3 containing GYYGGNYPFAY (SEQ ID NO:40) and/or (b) a light chain CDR1 containing RASENIYSYLA (SEQ ID NO:41), a light chain CDR2 containing NAKTLAE (SEQ ID NO:42) and a CDR3 a light chain containing QHYYGTPYT (SEQ ID NO:43). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYSFTGYNMN (SEQ ID NO:38), a heavy chain CDR2 containing NINPYYGSTNYNQKFKG (SEQ ID NO:39), and a heavy chain CDR3 containing GYYGGNYPFAY (SEQ ID NO:40), and (b) a light chain CDR1 containing RASENIYSYLA (SEQ ID NO:41), a light chain CDR2 containing NAKTLAE (SEQ ID NO:42), and a light chain CDR3 containing QHYYGTPYT (SEQ ID NO:43).

[00154] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 containing GYSFTGYNMN (SEQ ID NO:38), a heavy chain CDR2 containing NINPYYGSTNYNQKFKG (SEQ ID NO:39), and a heavy chain CDR3 containing GYYGGNYPFAY (SEQ ID NO:40), and/or (b) a light chain variable region containing a light chain CDR1 containing RASENIYSYLA (SEQ ID NO:41), a light chain CDR2, containing NAKTLAE (SEQ ID NO:42), and a light chain CDR3 containing QHYYGTPYT (SEQ ID NO:43). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 comprising GYSFTGYNMN (SEQ ID NO:38), a heavy chain CDR2 comprising NINPYYGSTNYNQKFKG (SEQ ID NO:39 ), and a heavy chain CDR3 containing GYYGGNYPFAY (SEQ ID NO:40), and (b) a light chain variable region containing a light chain CDR1 containing RASENIYSYLA (SEQ ID NO:41), a light chain CDR2 containing NAKTLAE (SEQ ID NO:42), and a light chain CDR3 containing QHYYGTPYT (SEQ ID NO:43).

[00155] In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2, and 3 from the heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 91. In certain embodiments, the C3 binding agent comprises CDRs of 1, 2 and 3 of a light chain from a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 92. In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2 and 3 from a heavy chain variable region comprising the amino acid sequence, specified in SEQ ID NO: 91, and light chain CDRs 1, 2 and 3 from the variable region of the light chain containing the amino acid sequence specified in SEQ ID NO: 92.

[00156] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 91 and/or a light chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 92. In some embodiments, a C3 binding agent (e.g., an antibody ) comprises a heavy chain variable region comprising SEQ ID NO: 91 and/or a light chain variable region comprising SEQ ID NO: 92. In some embodiments, a C3 binding agent (e.g., an antibody) comprises a heavy chain variable region of SEQ ID NO: : 91 and the light chain variable region of SEQ ID NO: 92.

[00157] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:38, a heavy chain CDR2 comprising SEQ ID NO:44, a heavy chain CDR3 comprising SEQ ID NO: :45, a light chain CDR1 containing SEQ ID NO:46, a light chain CDR2 containing SEQ ID NO:47, and a light chain CDR3 containing SEQ ID NO:48; (b) Heavy chain CDR1 containing SEQ ID NO:143, heavy chain CDR2 containing SEQ ID NO:154, heavy chain CDR3 containing SEQ ID NO:45, light chain CDR1 containing SEQ ID NO:46, light chain CDR2 containing SEQ ID NO:47, and a light chain CDR3 containing SEQ ID NO:48; (c) Heavy chain CDR1 containing SEQ ID NO:38, heavy chain CDR2 containing SEQ ID NO:155, heavy chain CDR3 containing SEQ ID NO:45, light chain CDR1 containing SEQ ID NO:46, light chain CDR2 containing SEQ ID NO:47, and a light chain CDR3 containing SEQ ID NO:48; (d) Heavy chain CDR1 comprising SEQ ID NO:144, Heavy chain CDR2 comprising SEQ ID NO:44, Heavy chain CDR3 comprising SEQ ID NO:45, Light chain CDR1 comprising SEQ ID NO:46, Light chain CDR2 containing SEQ ID NO:47 and a light chain CDR3 containing SEQ ID NO:48, or (e) a heavy chain CDR1 containing SEQ ID NO:145, a heavy chain CDR2 containing SEQ ID NO:156, a heavy chain CDR3, containing SEQ ID NO:157, a light chain CDR1 containing SEQ ID NO:158, a light chain CDR2 containing SEQ ID NO:159, and a light chain CDR3 containing SEQ ID NO:160.

[00158] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYSFTGYNMN (SEQ ID NO:38), a heavy chain CDR2 containing NINPYYDSTSYNQKFKG (SEQ ID NO:44), and A heavy chain CDR3 containing ENYDFVGFAY (SEQ ID NO:45) and/or (b) a light chain CDR1 containing RASSSVSYMH (SEQ ID NO:46), a light chain CDR2 containing VTSNLAS (SEQ ID NO:47) and a CDR3 light chain containing QQWSTNPLT (SEQ ID NO:48). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYSFTGYNMN (SEQ ID NO:38), a heavy chain CDR2 containing NINPYYDSTSYNQKFKG (SEQ ID NO:44), and a heavy chain CDR3 containing ENYDFVGFAY (SEQ ID NO:45), and (b) a light chain CDR1 containing RASSSVSYMH (SEQ ID NO:46), a light chain CDR2 containing VTSNLAS (SEQ ID NO:47), and a light chain CDR3 containing QQWSTNPLT (SEQ ID NO:48).

[00159] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 comprising GYSFTGYNMN (SEQ ID NO:38), a heavy chain CDR2 comprising NINPYYDSTSYNQKFKG (SEQ ID NO:44), and a heavy chain CDR3 containing ENYDFVGFAY (SEQ ID NO:45), and/or (b) a light chain variable region containing a light chain CDR1 containing RASSSVSYMH (SEQ ID NO:46), a light chain CDR2, containing VTSNLAS (SEQ ID NO:47), and a light chain CDR3 containing QQWSTNPLT (SEQ ID NO:48). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 comprising GYSFTGYNMN (SEQ ID NO:38), a heavy chain CDR2 comprising NINPYYDSTSYNQKFKG (SEQ ID NO:44 ), and a heavy chain CDR3 containing ENYDFVGFAY (SEQ ID NO:45), and (b) a light chain variable region containing a light chain CDR1 containing RASSSVSYMH (SEQ ID NO:46), a light chain CDR2 containing VTSNLAS (SEQ ID NO:47), and a light chain CDR3 containing QQWSTNPLT (SEQ ID NO:48).

[00160] In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2, and 3 from the heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 93. In certain embodiments, the C3 binding agent comprises CDRs of 1, 2 and 3 of a light chain from a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 94. In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2 and 3 from a heavy chain variable region comprising the amino acid sequence, specified in SEQ ID NO: 93, and light chain CDRs 1, 2 and 3 from the variable region of the light chain containing the amino acid sequence specified in SEQ ID NO: 94.

[00161] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 93 and/or a light chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 94. In some embodiments, a C3 binding agent (e.g., an antibody ) comprises a heavy chain variable region comprising SEQ ID NO: 93 and/or a light chain variable region comprising SEQ ID NO: 94. In some embodiments, a C3 binding agent (e.g., an antibody) comprises a heavy chain variable region of SEQ ID NO: : 93 and the light chain variable region of SEQ ID NO: 94.

[00162] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:49, a heavy chain CDR2 comprising SEQ ID NO:50, a heavy chain CDR3 comprising SEQ ID NO: :51, a light chain CDR1 containing SEQ ID NO:52, a light chain CDR2 containing SEQ ID NO:53, and a light chain CDR3 containing SEQ ID NO:54; (b) Heavy chain CDR1 containing SEQ ID NO:143, heavy chain CDR2 containing SEQ ID NO:163, heavy chain CDR3 containing SEQ ID NO:51, light chain CDR1 containing SEQ ID NO:52, light chain CDR2 containing SEQ ID NO:53, and a light chain CDR3 containing SEQ ID NO:54; (c) Heavy chain CDR1 containing SEQ ID NO:49, heavy chain CDR2 containing SEQ ID NO:164, heavy chain CDR3 containing SEQ ID NO:51, light chain CDR1 containing SEQ ID NO:52, light chain CDR2 containing SEQ ID NO:53, and a light chain CDR3 containing SEQ ID NO:54; (d) Heavy chain CDR1 containing SEQ ID NO:161, heavy chain CDR2 containing SEQ ID NO:50, heavy chain CDR3 containing SEQ ID NO:51, light chain CDR1 containing SEQ ID NO:52, light chain CDR2 containing SEQ ID NO:53 and a light chain CDR3 containing SEQ ID NO:54, or (e) a heavy chain CDR1 containing SEQ ID NO:162, a heavy chain CDR2 containing SEQ ID NO:165, a heavy chain CDR3, containing SEQ ID NO:166, a light chain CDR1 containing SEQ ID NO:167, a light chain CDR2 containing SEQ ID NO:168, and a light chain CDR3 containing SEQ ID NO:169.

[00163] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYSFTGYNMH (SEQ ID NO:49), a heavy chain CDR2 containing NINPYYGTTNSNQKFED (SEQ ID NO:50), and A heavy chain CDR3 containing GIYYYGTGYPYFDF (SEQ ID NO:51) and/or (b) a light chain CDR1 containing RASQDINNYLN (SEQ ID NO:52), a light chain CDR2 containing YTSRLHS (SEQ ID NO:53) and a CDR3 a light chain containing QQGITLPWT (SEQ ID NO:54). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYSFTGYNMH (SEQ ID NO:49), a heavy chain CDR2 containing NINPYYGTTNSNQKFED (SEQ ID NO:50), and a heavy chain CDR3 containing GIYYYGTGYPYFDF (SEQ ID NO:51), and (b) a light chain CDR1 containing RASQDINNYLN (SEQ ID NO:52), a light chain CDR2 containing YTSRLHS (SEQ ID NO:53), and a light chain CDR3 containing QQGITLPWT (SEQ ID NO:54).

[00164] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region containing a heavy chain CDR1 containing GYSFTGYNMH (SEQ ID NO:49), a heavy chain CDR2 containing NINPYYGTTNSNQKFED (SEQ ID NO:50), and a heavy chain CDR3 containing GIYYYGTGYPYFDF (SEQ ID NO:51), and/or (b) a light chain variable region containing a light chain CDR1 containing RASQDINNYLN (SEQ ID NO:52), a light chain CDR2, containing YTSRLHS (SEQ ID NO:53), and a light chain CDR3 containing QQGITLPWT (SEQ ID NO:54). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 comprising GYSFTGYNMH (SEQ ID NO:49), a heavy chain CDR2 comprising NINPYYGTTNSNQKFED (SEQ ID NO:50 ), and a heavy chain CDR3 containing GIYYYGTGYPYFDF (SEQ ID NO:51), and (b) a light chain variable region containing a light chain CDR1 containing RASQDINNYLN (SEQ ID NO:52), a light chain CDR2 containing YTSRLHS (SEQ ID NO:53), and a light chain CDR3 containing QQGITLPWT (SEQ ID NO:54).

[00165] In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2, and 3 from the heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 95. In certain embodiments, the C3 binding agent comprises CDRs of 1, 2 and 3 of a light chain from a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 96. In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2 and 3 from a heavy chain variable region comprising the amino acid sequence, specified in SEQ ID NO: 95, and light chain CDRs 1, 2 and 3 from the variable region of the light chain containing the amino acid sequence specified in SEQ ID NO: 96.

[00166] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 95 and/or a light chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 96. In some embodiments, a C3 binding agent (e.g., an antibody ) comprises a heavy chain variable region comprising SEQ ID NO: 95 and/or a light chain variable region comprising SEQ ID NO: 96. In some embodiments, a C3 binding agent (e.g., an antibody) comprises a heavy chain variable region of SEQ ID NO: : 95 and the light chain variable region of SEQ ID NO: 96.

[00167] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:55, a heavy chain CDR2 comprising SEQ ID NO:56, a heavy chain CDR3 comprising SEQ ID NO: :57, a light chain CDR1 containing SEQ ID NO:58, a light chain CDR2 containing SEQ ID NO:59, and a light chain CDR3 containing SEQ ID NO:60; (b) Heavy chain CDR1 containing SEQ ID NO:170, heavy chain CDR2 containing SEQ ID NO:173, heavy chain CDR3 containing SEQ ID NO:57, light chain CDR1 containing SEQ ID NO:58, light chain CDR2 containing SEQ ID NO:59, and a light chain CDR3 containing SEQ ID NO:60; (c) Heavy chain CDR1 containing SEQ ID NO:55, heavy chain CDR2 containing SEQ ID NO:174, heavy chain CDR3 containing SEQ ID NO:57, light chain CDR1 containing SEQ ID NO:58, light chain CDR2 containing SEQ ID NO:59, and a light chain CDR3 containing SEQ ID NO:60; (d) Heavy chain CDR1 comprising SEQ ID NO:171, Heavy chain CDR2 comprising SEQ ID NO:56, Heavy chain CDR3 comprising SEQ ID NO:57, Light chain CDR1 comprising SEQ ID NO:58, Light chain CDR2 containing SEQ ID NO:59 and a light chain CDR3 containing SEQ ID NO:60, or (e) a heavy chain CDR1 containing SEQ ID NO:172, a heavy chain CDR2 containing SEQ ID NO:175, a heavy chain CDR3, containing SEQ ID NO:176, a light chain CDR1 containing SEQ ID NO:177, a light chain CDR2 containing SEQ ID NO:178, and a light chain CDR3 containing SEQ ID NO:179.

[00168] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYTFTDYWIN (SEQ ID NO:55), a heavy chain CDR2 containing NIYPGSTSANYNEKFKS (SEQ ID NO:56), and A heavy chain CDR3 containing YGYDSWFAY (SEQ ID NO:57) and/or (b) a light chain CDR1 containing KSTKSLLNSDGFTYLD (SEQ ID NO:58), a light chain CDR2 containing LVSNRFS (SEQ ID NO:59), and a CDR3 light chain containing FQSNYLPLT (SEQ ID NO:60). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYTFTDYWIN (SEQ ID NO:55), a heavy chain CDR2 containing NIYPGSTSANYNEKFKS (SEQ ID NO:56), and a heavy chain CDR3 containing YGYDSWFAY (SEQ ID NO:57), and (b) a light chain CDR1 containing KSTKSLLNSDGFTYLD (SEQ ID NO:58), a light chain CDR2 containing LVSNRFS (SEQ ID NO:59), and a light chain CDR3 containing FQSNYLPLT (SEQ ID NO:60).

[00169] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region containing a heavy chain CDR1 containing GYTFTDYWIN (SEQ ID NO:55), a heavy chain CDR2 containing NIYPGSTSANYNEKFKS (SEQ ID NO:56), and a heavy chain CDR3 containing YGYDSWFAY (SEQ ID NO:57), and/or (b) a light chain variable region containing a light chain CDR1 containing KSTKSLLNSDGFTYLD (SEQ ID NO:58), a light chain CDR2, containing LVSNRFS (SEQ ID NO:59), and a light chain CDR3 containing FQSNYLPLT (SEQ ID NO:60). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 containing GYTFTDYWIN (SEQ ID NO:55), a heavy chain CDR2 containing NIYPGSTSANYNEKFKS (SEQ ID NO:56 ), and a heavy chain CDR3 containing YGYDSWFAY (SEQ ID NO:57), and (b) a light chain variable region containing a light chain CDR1 containing KSTKSLLNSDGFTYLD (SEQ ID NO:58), a light chain CDR2 containing LVSNRFS (SEQ ID NO:59), and a light chain CDR3 containing FQSNYLPLT (SEQ ID NO:60).

[00170] In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2, and 3 from the heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 97. In certain embodiments, the C3 binding agent comprises CDRs of 1, 2 and 3 of the light chain from a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 98. In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2 and 3 from a heavy chain variable region comprising the amino acid sequence, specified in SEQ ID NO: 97, and light chain CDRs 1, 2 and 3 from the variable region of the light chain containing the amino acid sequence specified in SEQ ID NO: 98.

[00171] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 97 and/or a light chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 98. In some embodiments, a C3 binding agent (e.g., an antibody ) contains a heavy chain variable region comprising SEQ ID NO: 97 and/or a light chain variable region comprising SEQ ID NO: 98. In some embodiments, a C3 binding agent (e.g., an antibody) comprises a heavy chain variable region of SEQ ID NO: : 97 and the light chain variable region of SEQ ID NO: 98.

[00172] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:61, a heavy chain CDR2 comprising SEQ ID NO:62, a heavy chain CDR3 comprising SEQ ID NO: :63, a light chain CDR1 containing SEQ ID NO:64, a light chain CDR2 containing SEQ ID NO:65, and a light chain CDR3 containing SEQ ID NO:66; (b) Heavy chain CDR1 containing SEQ ID NO:180, heavy chain CDR2 containing SEQ ID NO:183, heavy chain CDR3 containing SEQ ID NO:63, light chain CDR1 containing SEQ ID NO:64, light chain CDR2 containing SEQ ID NO:65, and a light chain CDR3 containing SEQ ID NO:66; (c) Heavy chain CDR1 comprising SEQ ID NO:61, Heavy chain CDR2 comprising SEQ ID NO:184, Heavy chain CDR3 comprising SEQ ID NO:63, Light chain CDR1 comprising SEQ ID NO:64, Light chain CDR2 containing SEQ ID NO:65, and a light chain CDR3 containing SEQ ID NO:66; (d) Heavy chain CDR1 comprising SEQ ID NO:181, Heavy chain CDR2 comprising SEQ ID NO:62, Heavy chain CDR3 comprising SEQ ID NO:63, Light chain CDR1 comprising SEQ ID NO:64, Light chain CDR2 containing SEQ ID NO:65 and a light chain CDR3 containing SEQ ID NO:66, or (e) a heavy chain CDR1 containing SEQ ID NO:182, a heavy chain CDR2 containing SEQ ID NO:185, a heavy chain CDR3, containing SEQ ID NO:186, a light chain CDR1 containing SEQ ID NO:187, a light chain CDR2 containing SEQ ID NO:188, and a light chain CDR3 containing SEQ ID NO:189.

[00173] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYAFNSCWMN (SEQ ID NO:61), a heavy chain CDR2 containing RIYPGDGDTNYNGKFKG (SEQ ID NO:62), and A heavy chain CDR3 containing EGRNYGYEDY (SEQ ID NO:63) and/or (b) a light chain CDR1 containing KASQSVDYDGDSYMN (SEQ ID NO:64), a light chain CDR2 containing AASDLES (SEQ ID NO:65) and a CDR3 a light chain containing QQANEDPRT (SEQ ID NO:66). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYAFNSCWMN (SEQ ID NO:61), a heavy chain CDR2 containing RIYPGDGDTNYNGKFKG (SEQ ID NO:62), and a heavy chain CDR3 containing EGRNYGYEDY (SEQ ID NO:63), and (b) a light chain CDR1 containing KASQSVDYDGDSYMN (SEQ ID NO:64), a light chain CDR2 containing AASDLES (SEQ ID NO:65), and a light chain CDR3 containing QQANEDPRT (SEQ ID NO:66).

[00174] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 containing GYAFNSCWMN (SEQ ID NO:61), a heavy chain CDR2 containing RIYPGDGDTNYNGKFKG (SEQ ID NO:62), and a heavy chain CDR3 containing EGRNYGYEDY (SEQ ID NO:63), and/or (b) a light chain variable region containing a light chain CDR1 containing KASQSVDYDGDSYMN (SEQ ID NO:64), a light chain CDR2, containing AASDLES (SEQ ID NO:65), and a light chain CDR3 containing QQANEDPRT (SEQ ID NO:66). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 comprising GYAFNSCWMN (SEQ ID NO:61), a heavy chain CDR2 comprising RIYPGDGDTNYNGKFKG (SEQ ID NO:62 ), and a heavy chain CDR3 containing EGRNYGYEDY (SEQ ID NO:63), and (b) a light chain variable region containing a light chain CDR1 containing KASQSVDYDGDSYMN (SEQ ID NO:64), a light chain CDR2 containing AASDLES (SEQ ID NO:65), and a light chain CDR3 containing QQANEDPRT (SEQ ID NO:66).

[00175] In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2, and 3 from the heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 99. In certain embodiments, the C3 binding agent comprises CDRs of 1, 2 and 3 of the light chain from a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 100. In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2 and 3 from a heavy chain variable region comprising the amino acid sequence, specified in SEQ ID NO: 99, and light chain CDRs 1, 2 and 3 from the variable region of the light chain containing the amino acid sequence specified in SEQ ID NO: 100.

[00176] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 99 and/or a light chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 100. In some embodiments, a C3 binding agent (e.g., an antibody ) comprises a heavy chain variable region comprising SEQ ID NO: 99 and/or a light chain variable region comprising SEQ ID NO: 100. In some embodiments, the C3 binding agent (e.g., antibody) comprises the heavy chain variable region of SEQ ID NO: : 99 and the light chain variable region of SEQ ID NO: 100.

[00177] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:67, a heavy chain CDR2 comprising SEQ ID NO:68, a heavy chain CDR3 comprising SEQ ID NO: :69, a light chain CDR1 containing SEQ ID NO:70, a light chain CDR2 containing SEQ ID NO:71, and a light chain CDR3 containing SEQ ID NO:72; (b) Heavy chain CDR1 containing SEQ ID NO:190, heavy chain CDR2 containing SEQ ID NO:193, heavy chain CDR3 containing SEQ ID NO:69, light chain CDR1 containing SEQ ID NO:70, light chain CDR2 containing SEQ ID NO:71, and a light chain CDR3 containing SEQ ID NO:72; (c) Heavy chain CDR1 comprising SEQ ID NO:67, Heavy chain CDR2 comprising SEQ ID NO:194, Heavy chain CDR3 comprising SEQ ID NO:69, Light chain CDR1 comprising SEQ ID NO:70, Light chain CDR2 containing SEQ ID NO:71, and a light chain CDR3 containing SEQ ID NO:72; (d) Heavy chain CDR1 comprising SEQ ID NO:191, Heavy chain CDR2 comprising SEQ ID NO:68, Heavy chain CDR3 comprising SEQ ID NO:69, Light chain CDR1 comprising SEQ ID NO:70, Light chain CDR2 containing SEQ ID NO:71 and a light chain CDR3 containing SEQ ID NO:72, or (e) a heavy chain CDR1 containing SEQ ID NO:192, a heavy chain CDR2 containing SEQ ID NO:195, a heavy chain CDR3, containing SEQ ID NO:196, a light chain CDR1 containing SEQ ID NO:197, a light chain CDR2 containing SEQ ID NO:198, and a light chain CDR3 containing SEQ ID NO:199.

[00178] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GFTFSNYAMS (SEQ ID NO:67), a heavy chain CDR2 containing QTISSGGRYTYYPDSVKG (SEQ ID NO:68), and A heavy chain CDR3 containing RYYGNSYWYFDV (SEQ ID NO:69) and/or (b) a light chain CDR1 containing KSSQSLLNSGNQKHYLT (SEQ ID NO:70), a light chain CDR2 containing GASTRGS (SEQ ID NO:71) and a CDR3 a light chain containing QNDHSYPYT (SEQ ID NO:72). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GFTFSNYAMS (SEQ ID NO:67), a heavy chain CDR2 containing QTISSGGRYTYYPDSVKG (SEQ ID NO:68), and a heavy chain CDR3 containing RYYGNSYWYFDV (SEQ ID NO:69), and (b) a light chain CDR1 containing KSSQSLLNSGNQKHYLT (SEQ ID NO:70), a light chain CDR2 containing GASTRGS (SEQ ID NO:71), and a light chain CDR3 containing QNDHSYPYT (SEQ ID NO:72).

[00179] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 containing GFTFSNYAMS (SEQ ID NO:67), a heavy chain CDR2 containing QTISSGGRYTYYPDSVKG (SEQ ID NO:68), and a heavy chain CDR3 containing RYYGNSYWYFDV (SEQ ID NO:69), and/or (b) a light chain variable region containing a light chain CDR1 containing KSSQSLLNSGNQKHYLT (SEQ ID NO:70), a light chain CDR2, containing GASTRGS (SEQ ID NO:71), and a light chain CDR3 containing QNDHSYPYT (SEQ ID NO:72). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 comprising GFTFSNYAMS (SEQ ID NO:67), a heavy chain CDR2 comprising QTISSGGRYTYYPDSVKG (SEQ ID NO:68 ), and a heavy chain CDR3 containing RYYGNSYWYFDV (SEQ ID NO:69), and (b) a light chain variable region containing a light chain CDR1 containing KSSQSLLNSGNQKHYLT (SEQ ID NO:70), a light chain CDR2 containing GASTRGS (SEQ ID NO:71), and a light chain CDR3 containing QNDHSYPYT (SEQ ID NO:72).

[00180] In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2, and 3 from a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 101. In certain embodiments, the C3 binding agent comprises CDRs of 1, 2 and 3 of a light chain from a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 102. In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2 and 3 from a heavy chain variable region comprising the amino acid sequence, set forth in SEQ ID NO: 101, and light chain CDRs 1, 2, and 3 from a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 102.

[00181] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 101 and/or a light chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 102. In some embodiments, a C3 binding agent (e.g., an antibody ) contains a heavy chain variable region comprising SEQ ID NO: 101 and/or a light chain variable region comprising SEQ ID NO: 102. In some embodiments, a C3 binding agent (e.g., an antibody) comprises a heavy chain variable region of SEQ ID NO: : 101 and the light chain variable region of SEQ ID NO: 102.

[00182] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:73, a heavy chain CDR2 comprising SEQ ID NO:74, a heavy chain CDR3 comprising SEQ ID NO: :75, a light chain CDR1 containing SEQ ID NO:76, a light chain CDR2 containing SEQ ID NO:77, and a light chain CDR3 containing SEQ ID NO:78; (b) Heavy chain CDR1 containing SEQ ID NO:200, heavy chain CDR2 containing SEQ ID NO:203, heavy chain CDR3 containing SEQ ID NO:75, light chain CDR1 containing SEQ ID NO:76, light chain CDR2 containing SEQ ID NO:77, and a light chain CDR3 containing SEQ ID NO:78; (c) Heavy chain CDR1 containing SEQ ID NO:73, heavy chain CDR2 containing SEQ ID NO:204, heavy chain CDR3 containing SEQ ID NO:75, light chain CDR1 containing SEQ ID NO:76, light chain CDR2 containing SEQ ID NO:77, and a light chain CDR3 containing SEQ ID NO:78; (d) Heavy chain CDR1 comprising SEQ ID NO:201, heavy chain CDR2 comprising SEQ ID NO:74, heavy chain CDR3 comprising SEQ ID NO:75, light chain CDR1 comprising SEQ ID NO:76, light chain CDR2 containing SEQ ID NO:77 and a light chain CDR3 containing SEQ ID NO:78, or (e) a heavy chain CDR1 containing SEQ ID NO:202, a heavy chain CDR2 containing SEQ ID NO:205, a heavy chain CDR3, containing SEQ ID NO:206, a light chain CDR1 containing SEQ ID NO:207, a light chain CDR2 containing SEQ ID NO:208, and a light chain CDR3 containing SEQ ID NO:209.

[00183] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GFTFSSYTMS (SEQ ID NO:73), a heavy chain CDR2 containing YISSGGGTTYYPDTVKG (SEQ ID NO:74), and A heavy chain CDR3 containing RYYRGSSLWYFDV (SEQ ID NO:75) and/or (b) a light chain CDR1 containing KSSQSLFNSGSQKNFLT (SEQ ID NO:76), a light chain CDR2 containing WASTRES (SEQ ID NO:77) and a CDR3 light chain containing QNDYSYPLT (SEQ ID NO:78). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GFTFSSYTMS (SEQ ID NO:73), a heavy chain CDR2 containing YISSGGGTTYYPDTVKG (SEQ ID NO:74), and a heavy chain CDR3 containing RYYRGSSLWYFDV (SEQ ID NO:75), and (b) a light chain CDR1 containing KSSQSLFNSGSQKNFLT (SEQ ID NO:76), a light chain CDR2 containing WASTRES (SEQ ID NO:77), and a light chain CDR3 containing QNDYSYPLT (SEQ ID NO:78).

[00184] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 containing GFTFSSYTMS (SEQ ID NO:73), a heavy chain CDR2 containing YISSGGGTTYYPDTVKG (SEQ ID NO:74), and a heavy chain CDR3 containing RYYRGSSLWYFDV (SEQ ID NO:75), and/or (b) a light chain variable region containing a light chain CDR1 containing KSSQSLFNSGSQKNFLT (SEQ ID NO:76), a light chain CDR2, containing WASTRES (SEQ ID NO:77), and a light chain CDR3 containing QNDYSYPLT (SEQ ID NO:78). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 comprising GFTFSSYTMS (SEQ ID NO:73), a heavy chain CDR2 comprising YISSGGGTTYYPDTVKG (SEQ ID NO:74 ), and a heavy chain CDR3 containing RYYRGSSLWYFDV (SEQ ID NO:75), and (b) a light chain variable region containing a light chain CDR1 containing KSSQSLFNSGSQKNFLT (SEQ ID NO:76), a light chain CDR2 containing WASTRES (SEQ ID NO:77), and a light chain CDR3 containing QNDYSYPLT (SEQ ID NO:78).

[00185] In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2, and 3 from a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 103. In certain embodiments, the C3 binding agent comprises CDRs of 1, 2 and 3 of a light chain from a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 104. In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2 and 3 from a heavy chain variable region comprising the amino acid sequence, set forth in SEQ ID NO: 103, and light chain CDRs 1, 2, and 3 from a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 104.

[00186] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 103 and/or a light chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 104. In some embodiments, a C3 binding agent (e.g., an antibody ) contains a heavy chain variable region comprising SEQ ID NO: 103 and/or a light chain variable region comprising SEQ ID NO: 104. In some embodiments, a C3 binding agent (e.g., an antibody) comprises a heavy chain variable region of SEQ ID NO: : 103 and the light chain variable region of SEQ ID NO: 104.

[00187] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:79, a heavy chain CDR2 comprising SEQ ID NO:80, a heavy chain CDR3 comprising SEQ ID NO: :81, a light chain CDR1 containing SEQ ID NO:82, a light chain CDR2 containing SEQ ID NO:83, and a light chain CDR3 containing SEQ ID NO:84; (b) Heavy chain CDR1 containing SEQ ID NO:210, heavy chain CDR2 containing SEQ ID NO:213, heavy chain CDR3 containing SEQ ID NO:81, light chain CDR1 containing SEQ ID NO:82, light chain CDR2 containing SEQ ID NO:83, and a light chain CDR3 containing SEQ ID NO:84; (c) Heavy chain CDR1 containing SEQ ID NO:79, heavy chain CDR2 containing SEQ ID NO:214, heavy chain CDR3 containing SEQ ID NO:81, light chain CDR1 containing SEQ ID NO:82, light chain CDR2 containing SEQ ID NO:83, and a light chain CDR3 containing SEQ ID NO:84; (d) Heavy chain CDR1 comprising SEQ ID NO:211, Heavy chain CDR2 comprising SEQ ID NO:80, Heavy chain CDR3 comprising SEQ ID NO:81, Light chain CDR1 comprising SEQ ID NO:82, Light chain CDR2 containing SEQ ID NO:83 and a light chain CDR3 containing SEQ ID NO:84, or (e) a heavy chain CDR1 containing SEQ ID NO:212, a heavy chain CDR2 containing SEQ ID NO:215, a heavy chain CDR3, containing SEQ ID NO:216, a light chain CDR1 containing SEQ ID NO:217, a light chain CDR2 containing SEQ ID NO:218, and a light chain CDR3 containing SEQ ID NO:219.

[00188] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYSITSGYSLH (SEQ ID NO:79), a heavy chain CDR2 containing YIHYSGSTNYNPSLKS (SEQ ID NO:80), and A heavy chain CDR3 containing AWDYLDY (SEQ ID NO:81) and/or (b) a light chain CDR1 containing RASENIYSQLA (SEQ ID NO:82), a light chain CDR2 containing DAKTLAE (SEQ ID NO:83) and a CDR3 light chain containing HHHFGILYT (SEQ ID NO:84). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYSITSGYSLH (SEQ ID NO:79), a heavy chain CDR2 containing YIHYSGSTNYNPSLKS (SEQ ID NO:80), and a heavy chain CDR3 containing AWDYLDY (SEQ ID NO:81), and (b) a light chain CDR1 containing RASENIYSQLA (SEQ ID NO:82), a light chain CDR2 containing DAKTLAE (SEQ ID NO:83), and a light chain CDR3 containing HHHFGILYT (SEQ ID NO:84).

[00189] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 containing GYSITSGYSLH (SEQ ID NO:79), a heavy chain CDR2 containing YIHYSGSTNYNPSLKS (SEQ ID NO:80), and a heavy chain CDR3 containing AWDYLDY (SEQ ID NO:81), and/or (b) a light chain variable region containing a light chain CDR1 containing RASENIYSQLA (SEQ ID NO:82), a light chain CDR2, containing DAKTLAE (SEQ ID NO:83), and a light chain CDR3 containing HHHFGILYT (SEQ ID NO:84). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 comprising GYSITSGYSLH (SEQ ID NO:79), a heavy chain CDR2 comprising YIHYSGSTNYNPSLKS (SEQ ID NO:80 ), and a heavy chain CDR3 containing AWDYLDY (SEQ ID NO:81), and (b) a light chain variable region containing a light chain CDR1 containing RASENIYSQLA (SEQ ID NO:82), a light chain CDR2 containing DAKTLAE (SEQ ID NO:83), and a light chain CDR3 containing HHHFGILYT (SEQ ID NO:84).

[00190] In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2, and 3 from the heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 105. In certain embodiments, the C3 binding agent comprises CDRs of 1, 2 and 3 of the light chain from a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 106. In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2 and 3 from a heavy chain variable region comprising the amino acid sequence, set forth in SEQ ID NO: 105, and light chain CDRs 1, 2, and 3 from a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 106.

[00191] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 105 and/or a light chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 106. In some embodiments, a C3 binding agent (e.g., an antibody ) comprises a heavy chain variable region comprising SEQ ID NO: 105 and/or a light chain variable region comprising SEQ ID NO: 106. In some embodiments, the C3 binding agent (e.g., antibody) comprises the heavy chain variable region of SEQ ID NO: : 105 and the light chain variable region of SEQ ID NO: 106.

[00192] In certain embodiments, the C3 binding agent (e.g., antibody) comprises (a) a heavy chain CDR1 comprising SEQ ID NO:85, a heavy chain CDR2 comprising SEQ ID NO:86, a heavy chain CDR3 comprising SEQ ID NO: :87, a light chain CDR1 containing SEQ ID NO:88, a light chain CDR2 containing SEQ ID NO:89, and a light chain CDR3 containing SEQ ID NO:90; (b) Heavy chain CDR1 containing SEQ ID NO:210, heavy chain CDR2 containing SEQ ID NO:222, heavy chain CDR3 containing SEQ ID NO:87, light chain CDR1 containing SEQ ID NO:88, light chain CDR2 containing SEQ ID NO:89, and a light chain CDR3 containing SEQ ID NO:90; (c) Heavy chain CDR1 containing SEQ ID NO:85, heavy chain CDR2 containing SEQ ID NO:223, heavy chain CDR3 containing SEQ ID NO:87, light chain CDR1 containing SEQ ID NO:88, light chain CDR2 containing SEQ ID NO:89, and a light chain CDR3 containing SEQ ID NO:90; (d) Heavy chain CDR1 comprising SEQ ID NO:220, Heavy chain CDR2 comprising SEQ ID NO:86, Heavy chain CDR3 comprising SEQ ID NO:87, Light chain CDR1 comprising SEQ ID NO:88, Light chain CDR2 containing SEQ ID NO:89 and a light chain CDR3 containing SEQ ID NO:90, or (e) a heavy chain CDR1 containing SEQ ID NO:221, a heavy chain CDR2 containing SEQ ID NO:224, a heavy chain CDR3, containing SEQ ID NO:225, a light chain CDR1 containing SEQ ID NO:226, a light chain CDR2 containing SEQ ID NO:227, and a light chain CDR3 containing SEQ ID NO:228.

[00193] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYSITSGYYWN (SEQ ID NO:85), a heavy chain CDR2 containing YIRYDGSNNYNPSLKN (SEQ ID NO:86), and A heavy chain CDR3 containing HYGYDGGAFDF (SEQ ID NO:87) and/or (b) a light chain CDR1 containing RTSENIYNYLV (SEQ ID NO:88), a light chain CDR2 containing NAKTLEE (SEQ ID NO:89) and a CDR3 a light chain containing QHHYGTPFT (SEQ ID NO:90). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain CDR1 containing GYSITSGYYWN (SEQ ID NO:85), a heavy chain CDR2 containing YIRYDGSNNYNPSLKN (SEQ ID NO:86), and a heavy chain CDR3 containing HYGYDGGAFDF (SEQ ID NO:87), and (b) a light chain CDR1 containing RTSENIYNYLV (SEQ ID NO:88), a light chain CDR2 containing NAKTLEE (SEQ ID NO:89), and a light chain CDR3 containing QHHYGTPFT (SEQ ID NO:90).

[00194] In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 containing GYSITSGYYWN (SEQ ID NO:85), a heavy chain CDR2 containing YIRYDGSNNYNPSLKN (SEQ ID NO:86), and a heavy chain CDR3 containing HYGYDGGAFDF (SEQ ID NO:87), and/or (b) a light chain variable region containing a light chain CDR1 containing RTSENIYNYLV (SEQ ID NO:88), a light chain CDR2, containing NAKTLEE (SEQ ID NO:89), and a light chain CDR3 containing QHHYGTPFT (SEQ ID NO:90). In some embodiments, the C3 binding agent (e.g., antibody) comprises: (a) a heavy chain variable region comprising a heavy chain CDR1 containing GYSITSGYYWN (SEQ ID NO:85), a heavy chain CDR2 containing YIRYDGSNNYNPSLKN (SEQ ID NO:86 ), and a heavy chain CDR3 containing HYGYDGGAFDF (SEQ ID NO:87), and (b) a light chain variable region containing a light chain CDR1 containing RTSENIYNYLV (SEQ ID NO:88), a light chain CDR2 containing NAKTLEE (SEQ ID NO:89), and a light chain CDR3 containing QHHYGTPFT (SEQ ID NO:90).

[00195] In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2, and 3 from the heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 107. In certain embodiments, the C3 binding agent comprises CDRs of 1, 2 and 3 of a light chain from a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 108. In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2 and 3 from a heavy chain variable region comprising the amino acid sequence, set forth in SEQ ID NO: 107, and light chain CDRs 1, 2, and 3 from a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 108.

[00196] In some embodiments, the C3 binding agent (e.g., antibody) comprises a heavy chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 107 and/or a light chain variable region having at least about 80%, about 85%, about 90%, or about 95% sequence identity with SEQ ID NO: 108. In some embodiments, a C3 binding agent (e.g., an antibody ) comprises a heavy chain variable region comprising SEQ ID NO: 107 and/or a light chain variable region comprising SEQ ID NO: 108. In some embodiments, the C3 binding agent (e.g., antibody) comprises the heavy chain variable region of SEQ ID NO: : 107 and the light chain variable region of SEQ ID NO: 108.

[00197] In some embodiments, the C3 binding agent (eg, antibody) is a scFv. In some embodiments, the scFv comprises a heavy chain variable region comprising SEQ ID NO: 110 or SEQ ID NO: 111. In some embodiments, the scFv comprises a light chain variable region comprising SEQ ID NO: 112. In some embodiments, the scFv comprises the variable region heavy chain comprising SEQ ID NO: 110 and a light chain variable region comprising SEQ ID NO: 112. In some embodiments, the scFv comprises a heavy chain variable region comprising SEQ ID NO: 111 and a light chain variable region comprising SEQ ID NO: 111 NO: 112. In some embodiments, the scFv comprises SEQ ID NO: 113. In some embodiments, the implementation of the scFv contains SEQ ID NO:114. In some embodiments, the implementation of the scFv contains SEQ ID NO:119. In some embodiments, the implementation of the scFv contains SEQ ID NO:229.

[00198] This invention provides antibodies that compete for C3 binding with one or more of the binding agents described herein. In some embodiments, the antibodies provided herein compete for binding to human C3 with one or more of the C3 binding agents described herein. In some embodiments, an antibody provided herein binds the same epitope as one of the antibodies described herein. In some embodiments, an antibody provided herein binds an epitope that overlaps with an epitope bound by one of the antibodies described herein. It is expected that antibodies and antigen-binding fragments that compete with or bind to the same epitope as the antibodies described herein will exhibit similar functional properties.

[00199] In some embodiments, an antibody competes for C3 binding with a C3 binding agent (eg, antibody) described herein. In some embodiments, the antibody competes for binding to human C3 with a C3 binding agent (eg, antibody) described herein. In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region containing a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); A heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8), YIYPHNGGTTYNQQFTG (SEQ ID NO:13), YIYPHNAGTTYNQQFTG (SEQ ID NO:14), YIYPHNTGTTYNQQFTG (SEQ ID NO:15), YIYPHEGGTTYNQQFTG (SEQ ID NO:16), or YIYPHQGGTTYNQQFTG (SEQ ID NO:17), and a heavy chain CDR3 containing RGGFDFDY (SEQ ID NO:9); and/or (b) a light chain variable region containing a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain variable region containing a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain variable region containing a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain variable region containing a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNGGTTYNQQFTG (SEQ ID NO:13) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain variable region containing a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain variable region containing a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNAGTTYNQQFTG (SEQ ID NO:14) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain variable region containing a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain variable region containing a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNTGTTYNQQFTG (SEQ ID NO:15) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain variable region containing a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain variable region containing a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHEGGTTYNQQFTG (SEQ ID NO:16) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain variable region containing a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain variable region containing a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHQGGTTYNQQFTG (SEQ ID NO:17) and a heavy chain CDR3 containing RGGFFDY (SEQ ID NO:9); and (b) a light chain variable region containing a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12).

[00200] In some embodiments, the antibody competes for binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region comprising SEQ ID NO: 18, and (b) a light chain variable region chain containing SEQ ID NO: 19. In some embodiments, the antibody competes for binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody contains: (a) a heavy chain variable region containing SEQ ID NO: 20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, or SEQ ID NO:24, and (b) a light chain variable region comprising SEQ ID NO:25. In some embodiments, the antibody competes for specific binding to C3 ( e.g. human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region comprising SEQ ID NO: 20, and (b) a light chain variable region comprising SEQ ID NO: 25. In some embodiments, implementation the antibody competes for specific binding to C3 ( e.g. human C3) with a reference antibody, wherein the reference antibody contains: (a) a heavy chain variable region containing SEQ ID NO: 21, and (b) a light chain variable region containing SEQ ID NO: : 25. In some embodiments, the antibody competes for specific binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region comprising SEQ ID NO: 22, and (b) a heavy chain variable region a light chain comprising SEQ ID NO: 25. In some embodiments, an antibody competes for specific binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region comprising SEQ ID NO: 23 , and (b) a light chain variable region comprising SEQ ID NO: 25. In some embodiments, an antibody competes for specific binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region containing SEQ ID NO: 24, and (b) a light chain variable region containing SEQ ID NO: 25.

[00201] In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain containing a heavy chain CDR1 containing GYSFTGYNMN (SEQ ID NO:38); a heavy chain CDR2 containing NINPYYGSTNYNQKFKG (SEQ ID NO:39) and a heavy chain CDR3 containing GYYGGNYPFAY (SEQ ID NO:40); and/or (b) a light chain containing a light chain CDR1 containing RASENIYSYLA (SEQ ID NO:41); Light chain CDR2 containing NAKTLAE (SEQ ID NO:42); and a light chain CDR3 containing QHYYGTPYT (SEQ ID NO:43). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain containing a heavy chain CDR1 containing GYSFTGYNMN (SEQ ID NO:38); a heavy chain CDR2 containing NINPYYDSTSYNQKFKG (SEQ ID NO:44) and a heavy chain CDR3 containing ENYDFVGFAY (SEQ ID NO:45); and/or (b) a light chain containing a light chain CDR1 containing RASSSVSYMH (SEQ ID NO:46); Light chain CDR2 containing VTSNLAS (SEQ ID NO:47); and a light chain CDR3 containing QQWSTNPLT (SEQ ID NO:48). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain containing a heavy chain CDR1 containing GYSFTGYNMH (SEQ ID NO:49); a heavy chain CDR2 containing NINPYYGTTNSNQKFED (SEQ ID NO:50) and a heavy chain CDR3 containing GIYYYGTGYPYFDF (SEQ ID NO:51); and/or (b) a light chain containing a light chain CDR1 containing RASQDINNYLN (SEQ ID NO:52); a light chain CDR2 containing YTSRLHS (SEQ ID NO:53); and a light chain CDR3 containing QQGITLPWT (SEQ ID NO:54). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain containing a heavy chain CDR1 containing GYTFTDYWIN (SEQ ID NO:55); a heavy chain CDR2 containing NIYPGSTSANYNEKFKS (SEQ ID NO:56) and a heavy chain CDR3 containing YGYDSWFAY (SEQ ID NO:57); and/or (b) a light chain containing a light chain CDR1 containing KSTKSLLNSDGFTYLD (SEQ ID NO:58); Light chain CDR2 containing LVSNRFS (SEQ ID NO:59); and a light chain CDR3 containing FQSNYLPLT (SEQ ID NO:60). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain containing a heavy chain CDR1 containing GYAFNSCWMN (SEQ ID NO:61); a heavy chain CDR2 containing RIYPGDGDTNYNGKFKG (SEQ ID NO:62) and a heavy chain CDR3 containing EGRNYGYEDY (SEQ ID NO:63); and/or (b) a light chain containing a light chain CDR1 containing KASQSVDYDGDSYMN (SEQ ID NO:64); A light chain CDR2 containing AASDLES (SEQ ID NO:65); and a light chain CDR3 containing QQANEDPRT (SEQ ID NO:66). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain containing a heavy chain CDR1 containing GFTFSNYAMS (SEQ ID NO:67); a heavy chain CDR2 containing QTISSGGRYTYYPDSVKG (SEQ ID NO:68) and a heavy chain CDR3 containing RYYGNSYWYFDV (SEQ ID NO:69); and/or (b) a light chain containing a light chain CDR1 containing KSSQSLLNSGNQKHYLT (SEQ ID NO:70); a light chain CDR2 containing GASTRGS (SEQ ID NO:71); and a light chain CDR3 containing QNDHSYPYT (SEQ ID NO:72). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain containing a heavy chain CDR1 containing GFTFSSYTMS (SEQ ID NO:73); a heavy chain CDR2 containing YISSGGGTTYYPDTVKG (SEQ ID NO:74) and a heavy chain CDR3 containing RYYRGSSLWYFDV (SEQ ID NO:75); and/or (b) a light chain containing a light chain CDR1 containing KSSQSLFNSGSQKNFLT (SEQ ID NO:76); a light chain CDR2 containing WASTRES (SEQ ID NO:77); and a light chain CDR3 containing QNDYSYPLT (SEQ ID NO:78). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain containing a heavy chain CDR1 containing GYSITSGYSLH (SEQ ID NO:79); a heavy chain CDR2 containing YIHYSGSTNYNPSLKS (SEQ ID NO:80) and a heavy chain CDR3 containing AWDYLDY (SEQ ID NO:81); and/or (b) a light chain containing a light chain CDR1 containing RASENIYSQLA (SEQ ID NO:82); a light chain CDR2 containing DAKTLAE (SEQ ID NO:83); and a light chain CDR3 containing HHHFGILYT (SEQ ID NO:84). In some embodiments, the antibody competes for binding to C3 (eg, human C3) with a reference antibody, wherein the reference antibody comprises (a) a heavy chain containing a heavy chain CDR1 containing GYSITSGYYWN (SEQ ID NO:85); a heavy chain CDR2 containing YIRYDGSNNYNPSLKN (SEQ ID NO:86) and a heavy chain CDR3 containing HYGYDGGAFDF (SEQ ID NO:87); and/or (b) a light chain containing a light chain CDR1 containing RTSENIYNYLV (SEQ ID NO:88); Light chain CDR2 containing NAKTLEE (SEQ ID NO:89); and a light chain CDR3 containing QHHYGTPFT (SEQ ID NO:90).

[00202] In some embodiments, the antibody competes for binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region comprising SEQ ID NO: 91, and (b) a light chain variable region chain containing SEQ ID NO: 92. In some embodiments, the antibody competes for binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody contains: (a) a heavy chain variable region comprising SEQ ID NO: 93, and (b) a light chain variable region comprising SEQ ID NO: 94. In some embodiments, an antibody competes for binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region comprising SEQ ID NO: 95, and (b) a light chain variable region comprising SEQ ID NO: 96. In some embodiments, an antibody competes for binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody contains: (a) the variable a heavy chain region comprising SEQ ID NO: 97; and (b) a light chain variable region comprising SEQ ID NO: 98. In some embodiments, an antibody competes for binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody contains: (a) a heavy chain variable region containing SEQ ID NO: 99, and (b) a light chain variable region containing SEQ ID NO: 100. In some embodiments, the antibody competes for binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region comprising SEQ ID NO: 101, and (b) a light chain variable region comprising SEQ ID NO: 102. In some embodiments, the antibody competes for binding to C3( e.g. , human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region comprising SEQ ID NO: 103, and (b) a light chain variable region comprising SEQ ID NO: 104. In some embodiments, the antibody competes for binding to C3 ( e.g. human C3) with a reference antibody, wherein the reference antibody contains: (a) a heavy chain variable region containing SEQ ID NO: 105 and (b) a light chain variable region containing SEQ ID NO: 106 In some embodiments, an antibody competes for binding to C3 (e.g. , human C3) with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region comprising SEQ ID NO: 107, and (b) a light chain variable region, containing SEQ ID NO: 108.

[00203] In some embodiments, the C3 binding agent described herein includes an antibody in which at least one or more constant regions have been modified or removed. In some embodiments, the antibodies may contain modifications to one or more of the three heavy chain constant regions (CH1, CH2, or CH3) and/or the light chain constant region (CL). In some embodiments, the modified antibody heavy chain constant region comprises at least one human constant region. In some embodiments, the heavy chain constant region of the modified antibody comprises more than one human constant region. In some embodiments, constant region modifications include additions, deletions, or substitutions of one or more amino acids in one or more regions. In some embodiments, one or more regions are partially or completely removed from the constant regions of the modified antibodies. In some embodiments, the entire CH2 domain has been removed from the antibody (ΔCH2 construct). In some embodiments, the deleted constant region is replaced with a short amino acid spacer that provides some of the molecular flexibility normally associated with the missing constant region. In some embodiments, the modified antibody comprises a CH3 domain directly fused to the antibody hinge region. In some embodiments, the modified antibody comprises a peptide spacer inserted between the hinge region and the modified CH2 and/or CH3 domains.

[00204] It is known in the art that the constant region(s) of an antibody mediate several effector functions, and these effector functions may vary depending on the isotype of the antibody. For example, binding of the C1 component of complement to the Fc region of an IgG or IgM antibody (antigen bound) activates the complement system. Complement activation is important in opsonization and lysis of cellular pathogens. Complement activation also stimulates the inflammatory response and may be involved in autoimmune hypersensitivity. In addition, the Fc region of an antibody can bind to a cell expressing an Fc receptor (FcR). There are a number of Fc receptors that are specific for different classes of antibodies, including IgG (gamma receptors), IgE (epsilon receptors), IgA (alpha receptors), and IgM (mu receptors). Binding of an antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological reactions, including uptake and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (called antibody-dependent cellular cytotoxicity or ADCC), release of inflammatory mediators , placental transfer and control of immunoglobulin production.

[00205] In some embodiments, the antibody comprises a variant Fc region. The amino acid sequences of the Fc region of human IgG1, IgG2, IgG3, and IgG4 are known to those of ordinary skill in the art (eg, a representative human IgG1 is SEQ ID NO: 34). In some cases, Fc regions with amino acid variations have been identified in native antibodies. In some embodiments, a variant Fc region is constructed with substitutions at certain amino acid positions compared to the native Fc region (eg, SEQ ID NO:35, SEQ ID NO:36, and SEQ ID NO:109).

[00206] In some embodiments, the modified antibodies (eg, a modified Fc region) provide altered effector functions, which in turn affect the biological profile of the antibody. For example, in some embodiments, deletion or inactivation (through point mutations or other means) of the constant region reduces the binding of the modified antibody to the Fc receptor as it circulates. In some embodiments, constant region modifications increase the serum half-life of the antibody. In some embodiments, the modification of the constant region reduces the serum half-life of the antibody. In some embodiments, constant region modifications reduce or eliminate ADCC and/or complement dependent cytotoxicity (CDC) of an antibody. In some embodiments, specific amino acid substitutions in the Fc region of human IgG1 with the corresponding IgG2 or IgG4 residues reduce effector functions (eg, ADCC and CDC) in the modified antibody. In some embodiments, the antibody does not perform one or more effector functions (eg, "effectorless" antibodies). In some embodiments, the antibody does not have ADCC activity and/or CDC activity. In some embodiments, the antibody does not bind the Fc receptor and/or complement factor. In some embodiments, the antibody has no effector function(s). In some embodiments, constant region modifications increase or enhance the ADCC and/or CDC of the antibody. In some embodiments, the constant region is modified to remove disulfide bonds or oligosaccharide moieties. In some embodiments, the constant region is modified to add/replace one or more amino acids to provide one or more cytotoxin, oligosaccharide, or carbohydrate binding sites.

[00207] In certain embodiments, the C3 binding agent comprises a heavy chain containing heavy chain CDRs 1, 2, and 3 and a light chain containing light chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 contains GYTFDDFYMD (SEQ ID NO: 7), heavy chain CDR2 contains YIYPHNGGTTYNQNFTG (SEQ ID NO:8), heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12) wherein the heavy chain is at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or 100% identity with the sequence shown in SEQ ID NO:27, and where the light chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 97 % or 100% identity with the sequence indicated in SEQ ID NO:31. In certain embodiments, the C3 binding agent comprises a heavy chain containing heavy chain CDRs 1, 2, and 3 and a light chain containing light chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), Heavy chain CDR2 contains YIYPHNGGTTYNQQFTG (SEQ ID NO:13), Heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9), Light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), Light chain CDR2 contains GASNRYT (SEQ ID NO:11 ), and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12) wherein the heavy chain is at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or 100% identity to the sequence shown in SEQ ID NO:27, and where the light chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or 100 % identity with the sequence indicated in SEQ ID NO:31. In certain embodiments, the C3 binding agent comprises heavy chain CDRs 1, 2, and 3, and a light chain containing light chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHNAGTTYNQQFTG (SEQ ID NO:14), heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9), light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), light chain CDR2 contains GASNRYT (SEQ ID NO:11), and CDR3 light chain contains GQSHSYPLT (SEQ ID NO:12), where the heavy chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or 100% identity with the sequence shown in SEQ ID NO:29, and where the light chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or 100% identity with the sequence specified in SEQ ID NO:31. In certain embodiments, the C3 binding agent comprises a heavy chain containing heavy chain CDRs 1, 2, and 3 and a light chain containing light chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), Heavy chain CDR2 contains YIYPHNTGTTYNQQFTG (SEQ ID NO:15), Heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9), Light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), Light chain CDR2 contains GASNRYT (SEQ ID NO:11 ), and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12), where the heavy chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% identity with the sequence shown in SEQ ID NO:27, and where the light chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or 100% identity with the sequence shown in SEQ ID NO:31. In certain embodiments, the C3 binding agent comprises a heavy chain containing heavy chain CDRs 1, 2, and 3 and a light chain containing light chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), Heavy chain CDR2 contains YIYPHEGGTTYNQQFTG (SEQ ID NO:16), Heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9), Light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), Light chain CDR2 contains GASNRYT (SEQ ID NO:11 ), and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12), where the heavy chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% identity with the sequence shown in SEQ ID NO:27, and where the light chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or 100% identity with the sequence shown in SEQ ID NO:31. In certain embodiments, the C3 binding agent comprises a heavy chain containing heavy chain CDRs 1, 2, and 3 and a light chain containing light chain CDRs 1, 2, and 3, wherein the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), Heavy chain CDR2 contains YIYPHQGGTTYNQQFTG (SEQ ID NO:17), Heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9), Light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), Light chain CDR2 contains GASNRYT (SEQ ID NO:11 ), and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12) wherein the heavy chain is at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or 100% identity to the sequence shown in SEQ ID NO:27, and where the light chain has at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or 100 % identity with the sequence indicated in SEQ ID NO:31.

[00208] In some embodiments, the C3 binding agent is an antibody that contains the heavy chain of SEQ ID NO: 27 and/or the light chain of SEQ ID NO: 31. In some embodiments, the C3 binding agent is an antibody that contains a heavy chain chain of SEQ ID NO: 27. In some embodiments, the C3 binding agent is an antibody that contains the light chain of SEQ ID NO: 31. In some embodiments, the C3 binding agent is an antibody that contains the heavy chain of SEQ ID NO: 27 and the light chain of SEQ ID NO: 31. In some embodiments, the C3 binding agent is an antibody that comprises the heavy chain of SEQ ID NO: 29 and/or the light chain of SEQ ID NO: 31. In some embodiments, the C3 binding agent is is an antibody that contains the heavy chain of SEQ ID NO: 29. In some embodiments, the C3 binding agent is an antibody that contains the light chain of SEQ ID NO: 31. In some embodiments, the C3 binding agent is an antibody that contains a heavy a chain of SEQ ID NO: 29; and a light chain of SEQ ID NO: 31.

[00209] Modifications to the constant region of the antibodies described herein can be made using well known biochemical or molecular engineering techniques. In some embodiments, antibody variants are obtained by making appropriate nucleotide changes to the coding DNA and/or by synthesizing the desired antibody or polypeptide. Using these antibody variants, it is possible to disrupt the activity or effector function provided by a particular sequence or region while substantially maintaining the structure, binding activity, and other desired characteristics of the modified antibody.

[00210] The invention further encompasses additional variants and equivalents that are substantially homologous to the recombinant, monoclonal, chimeric, humanized, and human antibodies or antibody fragments thereof described herein. In some embodiments, it is desirable to improve the binding affinity of an antibody. In some embodiments, it is desirable to modulate the biological properties of an antibody, including, but not limited to, specificity, thermostability, expression level, effector function(s), glycosylation, immunogenicity, or solubility. Those skilled in the art will recognize that amino acid changes can alter the post-translational processes of an antibody, such as changing the number or position of glycosylation sites, or changing membrane anchoring characteristics.

[00211] Variations can be represented by a substitution, deletion, or insertion of one or more nucleotides encoding an antibody or polypeptide that results in a change in amino acid sequence from the native sequence of the antibody or polypeptide. In some embodiments, amino acid substitutions result from the substitution of one amino acid for another amino acid having similar structural and/or chemical properties, such as substituting serine for leucine, eg, conservative amino acid substitutions. The size of the insertions or deletions may optionally range from about 1 to 5 amino acids. In some embodiments, the substitution, deletion, or insertion comprises less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions according to compared to the parent molecule. In some embodiments, amino acid sequence variations that are biologically useful and/or relevant are determined by systematically making insertions, deletions, or substitutions in the sequence and testing the resulting variant proteins for activity relative to the parent antibody.

[00212] In some embodiments, options may include the addition of amino acid residues at the amino and/or carboxyl terminus of an antibody or polypeptide. Additional amino acid residues can be from one residue to one hundred or more residues in length. In some embodiments, the variant contains an N-terminal methionyl residue. In some embodiments, the variant contains an additional polypeptide/protein, i. fused protein. In some embodiments, the variant is designed to be detectable and may contain a detectable label and/or protein (eg, an enzyme).

[00213] In some embodiments, a cysteine residue not involved in maintaining the proper conformation of the antibody may be replaced or removed to modulate the characteristics of the antibody, for example, to improve oxidative stability and/or prevent aberrant disulfide crosslinking. On the contrary, in some embodiments, one or more cysteine residues can be added to create a disulfide bond(s) to improve stability.

[00214] In some embodiments, the implementation of the antibody according to this invention is "deimmunized". Deimmunization of antibodies typically consists of introducing specific amino acid mutations (eg, substitutions, deletions, insertions) that result in the removal of T cell epitopes without significantly reducing binding affinity or other desired activities of the antibody.

[00215] Antibody or polypeptide variants described herein can be generated using methods known in the art, including, without limitation, site-directed mutagenesis, alanine scan mutagenesis, and PCR mutagenesis.

[00216] In some embodiments, the C3 binding agents described herein are chemically modified. In some embodiments, C3 binding agents are anti-C3 antibodies that have been chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting/blocking groups, proteolytic cleavage, and/or binding to a cellular ligand or other protein. Any of the numerous chemical modifications can be carried out by known methods.

[00217] This invention encompasses C3 binding agents built on non-immunoglobulin scaffolds, wherein the agents bind to the same epitope, or substantially the same epitope, as the anti-C3 antibody disclosed herein. In some embodiments, a non-immunoglobulin binding agent is an agent that competes with an anti-C3 antibody described herein in a competitive binding assay. In some embodiments, alternative C3 binding agents comprise a scaffold protein. In general, scaffold proteins can be assigned to one of three groups based on the architecture of their scaffold (1) scaffolds consisting of α-helices; (2) small scaffolds with few secondary structures or irregular architecture of α-helices and β-sheets; and (3) frameworks consisting predominantly of β-sheets. Scaffold proteins include, without limitation, anticalins, which are based on a lipocalin scaffold; adnectins, which are based on the ^10th domain of human fibronectin type 3; affiliations that are based on the B domain in the Ig-binding region of the Staphylococcus aureus A protein; darpins, which are based on ankyrin repeat domain proteins; finomers based on the SH3 domain of the human protein kinase Fyn; affitins based on Sac7d from Sulfolobus acidocaldarius ; affilins based on human γ-B-crystallin or human ubiquitin; avimers based on A-domains of membrane receptor proteins; knottins (cysteine knot miniproteins), which are based on a stable 30-amino acid antiparallel β-chain of the protein fold; and frameworks of Kunitz domain inhibitors, which are based on a structure containing three disulfide bonds and three loops. In some embodiments, the C3 binding agent comprises an engineered scaffold protein comprising the heavy chain CDR1, CDR2, and CDR3 and the light chain CDR1, CDR2, and CDR3 shown in Table 1. In some embodiments, the C3 binding agent comprises an engineered scaffold protein comprising CDR1 a heavy chain containing GYTFTDFYMD (SEQ ID NO:7); A heavy chain CDR2 containing YIYPHNGGTTYNQNFTG (SEQ ID NO:8), YIYPHNGGTTYNQQFTG (SEQ ID NO:13), YIYPHNAGTTYNQQFTG (SEQ ID NO:14), YIYPHNTGTTYNQQFTG (SEQ ID NO:15), YIYPHEGGTTYNQQFTG (SEQ ID NO:16), or YIYPHQGGTTYNQQFTG (SEQ ID NO:17), and a heavy chain CDR3 containing RGGFDFDY (SEQ ID NO:9); and/or (b) a light chain variable region containing a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12).

[00218] In some embodiments, the C3 binding agent comprises an engineered scaffold protein comprising the heavy chain CDR1, CDR2 and CDR3 and the light chain CDR1, CDR2 and CDR3 from the 3D8 antibody. In some embodiments, the C3 binding agent comprises an engineered scaffold protein comprising the heavy chain CDR1, CDR2 and CDR3 and the light chain CDR1, CDR2 and CDR3 from the 3G8 antibody. In some embodiments, the C3 binding agent comprises an engineered scaffold protein comprising the heavy chain CDR1, CDR2 and CDR3 and the light chain CDR1, CDR2 and CDR3 from the 15C12 antibody. In some embodiments, the C3 binding agent comprises an engineered scaffold protein containing heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 from antibody 27A8. In some embodiments, the C3 binding agent comprises an engineered scaffold protein comprising heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3 from the 28C3 antibody. In some embodiments, the C3 binding agent comprises an engineered scaffold protein comprising the heavy chain CDR1, CDR2 and CDR3 and the light chain CDR1, CDR2 and CDR3 from the 38F5 antibody. In some embodiments, the C3 binding agent comprises an engineered scaffold protein comprising the heavy chain CDR1, CDR2, and CDR3 and the light chain CDR1, CDR2, and CDR3 from the 62B11 antibody. In some embodiments, the C3 binding agent comprises an engineered scaffold protein comprising the heavy chain CDR1, CDR2, and CDR3 and the light chain CDR1, CDR2, and CDR3 from the 62F2 antibody. In some embodiments, the C3 binding agent comprises an engineered scaffold protein containing heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 from antibody 63A3.

[00219] Generally speaking, antigen-antibody interactions are non-covalent and reversible, they are formed by a combination of hydrogen bonds, hydrophobic interactions, electrostatic forces and van der Waals forces. When describing the strength of an antigen-antibody complex, the terms affinity and/or avidity are commonly used. The binding of an antibody to its antigen is a reversible process, and the binding affinity is usually reported as the equilibrium dissociation constant (K _D ). K _D is the ratio of the rate of dissociation of an antibody (k _off ) (how quickly it dissociates from its antigen) to the rate of association of an antibody (k _on ) (how quickly it binds to its antigen). In some embodiments, K _D values are determined by measuring the k _on and k _off ratios of a specific antibody/antigen interaction and then using the ratio of these values to calculate the K _D value. The K _D values can be used to evaluate and rank the strength of individual antibody/antigen interactions. The lower the K _D of an antibody, the higher the affinity of the antibody for its target. In some embodiments, affinity is measured using SPR technology in the Biacore system. Avidity gives a measure of the overall strength of the antibody-antigen complex. This depends on three main parameters: (i) the affinity of the antibody for the target, (ii) the valency of both the antibody and the antigen, and (iii) the structural arrangement of the parts that interact.

[00220] In some embodiments, a C3 binding agent (e.g., an antibody) binds C3 (e.g., human C3) with a dissociation constant (K _D ) of about 1 μM or less, about 100 nM or less, about 40 nM or less, about 20 nM or less, about 10 nM or less, about 1 nM or less, about 0.1 nM or less, 50 pM or less, 10 pM or less, or 1 pM or less. In some embodiments, the C3 binding agent binds C3 (eg, human C3) to a K _D of about 20 nM or less. In some embodiments, the C3 binding agent binds C3 (eg, human C3) to a K _D of about 10 nM or less. In some embodiments, the C3 binding agent binds C3 (eg, human C3) to a K _D of about 1 nM or less. In some embodiments, the C3 binding agent binds C3 (eg, human C3) to a K _D of about 0.5 nM or less. In some embodiments, the C3 binding agent binds C3 (eg, human C3) to a K _D of about 0.1 nM or less. In some embodiments, the C3 binding agent binds C3 (eg, human C3) to a K _D of about 50 pM or less. In some embodiments, the C3 binding agent binds C3 (eg, human C3) to a K _D of about 25 pM or less. In some embodiments, the C3 binding agent binds C3 (eg, human C3) to a K _D of about 10 pM or less. In some embodiments, the C3 binding agent binds C3 (eg, human C3) to a K _D of about 1 pM or less. In some embodiments, the dissociation constant of the binding agent (eg, antibody) for C3 is the dissociation constant determined using the C3 protein immobilized on the Biacore chip and passing the binding agent through the chip. In some embodiments, the dissociation constant of the binding agent (eg, antibody) for C3 is the dissociation constant determined using the binding agent captured by the anti-human IgG antibody on the Biacore chip and passing soluble C3 through the chip.

[00221] In some embodiments, a C3 binding agent (e.g., an antibody) binds C3 (e.g., human C3) at a half maximum effective concentration (EC50) of about 1 μM or less, about 100 nM or less, about 40 nM or less, about 20 nM or less, about 10 nM or less, about 1 nM or less, or about 0.1 nM or less. In some embodiments, the C3 binding agent binds to human C3 with an EC50 of about 1 μM or less, about 100 nM or less, about 40 nM or less, about 20 nM or less, about 10 nM or less, about 1 nM or less, or about 0.1 nM or less. In some embodiments, the C3 binding agent binds macaque and/or human C3 to an EC50 of about 40 nM or less, about 20 nM or less, about 10 nM or less, about 1 nM or less, or about 0.1 nM or less .

[00222] The C3 binding agents (eg, antibodies) described herein may be prepared by any suitable method known in the art. Such methods range from direct protein synthesis methods to the construction of a DNA sequence encoding polypeptide sequences and the expression of these sequences in a suitable host. In some embodiments, a DNA sequence is constructed using recombinant technology by isolating or synthesizing a DNA sequence encoding a wild-type protein of interest. Optionally, the sequence may be mutagenized by site-directed mutagenesis to obtain functional variants thereof. In some embodiments, a DNA sequence encoding a polypeptide of interest is constructed by chemical synthesis using an oligonucleotide synthesizer. Oligonucleotides can be designed based on the amino acid sequence of the desired polypeptide and the selection of those codons that are preferred in the host cell in which the recombinant polypeptide of interest will be produced. Standard methods can be used to synthesize a polynucleotide sequence encoding an isolated polypeptide of interest. For example, the complete amino acid sequence can be used to construct a reverse-translated gene. In addition, a DNA oligomer containing a nucleotide sequence encoding a particular isolated polypeptide can be synthesized. For example, several small oligonucleotides encoding portions of the desired polypeptide can be synthesized and then ligated. Individual oligonucleotides typically contain 5' or 3' sticky ends for complementary assembly.

[00223] Once assembled (by synthesis, site-directed mutagenesis, or other method), polynucleotide sequences encoding a particular polypeptide of interest can be inserted into an expression vector and operably linked to an expression control sequence suitable for protein expression in the desired host. Correct assembly can be confirmed by nucleotide sequencing, restriction enzyme mapping, and/or expression of a biologically active polypeptide in a suitable host. As is well known in the art, to obtain high levels of expression of a transfected gene in a host, the gene must be operably linked to transcriptional and translational expression control sequences that are functional in the chosen expression host.

[00224] In some embodiments, recombinant expression vectors are used to amplify and express DNA-encoding anti-human C3 antibodies or fragments thereof. For example, recombinant expression vectors can be replicable DNA constructs that have synthetic or cDNA-derived DNA fragments encoding the polypeptide chain of a C3 binding agent, such as an anti-C3 antibody or antigen-binding fragment thereof, operably linked to suitable transcriptional and/or translational regulatory elements. derived from the genes of mammals, microorganisms, viruses or insects. A transcription unit typically contains a collection of (1) a genetic element or elements that play a regulatory role in gene expression, such as transcriptional promoters or enhancers, (2) a structural or coding sequence that is transcribed into mRNA and translated into a protein, and (3) the corresponding initiation sequences and termination of transcription and translation. Regulatory elements may include an operator sequence to control transcription. Additionally, the ability to replicate in the host, usually provided by the origin of replication, and a selectable gene to facilitate recognition of transformants can be included. Regions of DNA are "operably linked" when they are operably linked to each other. For example, signal peptide DNA (secretory leader) is operably linked to polypeptide DNA if it is expressed as a precursor that is involved in the secretion of the polypeptide; a promoter is operably linked to a coding sequence if it controls the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is located to allow translation. In some embodiments, structural elements for use in yeast expression systems include a leader sequence that allows extracellular secretion of the translated protein by the host cell. In some embodiments, in situations where the recombinant protein is expressed without a leader or transport sequence, the polypeptide may contain an N-terminal methionine residue. This residue may optionally be subsequently cleaved from the expressed recombinant protein to obtain the final product.

[00225] The choice of expression control sequence and expression vector usually depends on the choice of the host. A wide range of host/expression vector combinations can be used. Suitable expression vectors for eukaryotic hosts include, for example, vectors containing expression control sequences from SV40, bovine papillomavirus, adenovirus, and cytomegalovirus. Suitable expression vectors for bacterial hosts include known bacterial plasmids such as plasmids from E. coli including pCR1, pBR322, pMB9 and their derivatives, and wider host range plasmids such as M13 and other filamentous single stranded DNA phages.

[00226] The C3 binding agents (eg, antibodies) of the invention may be expressed from one or more vectors. For example, in some embodiments, the heavy chain polypeptide is expressed by one vector and the light chain polypeptide is expressed by a second vector. In some embodiments, the heavy chain polypeptide and the light chain polypeptide are expressed on the same vector.

[00227] Suitable host cells for expressing a C3 binding agent (e.g., antibody) or C3 protein or fragment thereof for use as an antigen or immunogen include prokaryotes, yeast cells, insect cells, or higher eukaryotic cells under the control of appropriate promoters. Prokaryotes include Gram-negative or Gram-positive organisms such as E. coli or Bacillus . Higher eukaryotic cells include established mammalian cell lines as described herein. Cell-free translation systems can also be used. Suitable cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian hosts, as well as methods for protein production, including antibody production, are well known in the art.

[00228] Various mammalian culture systems can be used to express recombinant polypeptides. Expression of recombinant proteins in mammalian cells may be desirable because these proteins are usually correctly folded, appropriately modified, and biologically functional. Examples of suitable mammalian host cell lines include, without limitation, COS-7 (derived from monkey kidney), L-929 (derived from mouse fibroblast), C127 (derived from mouse mammary tumor), 3T3 (derived from mouse fibroblast), CHO (derived from Chinese hamster ovary), HeLa (derived from human cervical cancer), BHK (derived from hamster kidney fibroblasts), HEK-293 (derived from human embryonic kidney), and variants thereof. Mammalian expression vectors may contain non-transcribed elements such as an origin of replication, an appropriate promoter and enhancer associated with the gene to be expressed, and other 5'- or 3'-flanking non-transcribed sequences, as well as 5'- or 3'- non-transcribed sequences, translated sequences such as essential ribosome binding sites, polyadenylation site, splicing donor and acceptor sites, and transcription termination sequences.

[00229] Expression of recombinant proteins in insect cell culture systems (eg, baculovirus) also offers a reliable method for obtaining properly folded and biologically functional proteins. Baculovirus systems for the production of heterologous proteins in insect cells are well known to those skilled in the art.

[00230] Thus, provided herein are cells containing the C3 binding agents described herein. In some embodiments, the cells produce the C3 binding agents described herein. In some embodiments, the cells produce an antibody. In some embodiments, the cells produce an antibody that binds human C3. In some embodiments, the cells produce an antibody that binds macaque C3. In some embodiments, the cells produce an antibody that binds human C3 and macaque C3. In some embodiments, the cells produce an antibody designated 38G10. In some embodiments, the cells produce a humanized version of the 38G10 antibody, referred to as Hz38G10. In some embodiments, cells produce a Hz38G10 variant, such as Hz38G10(G56A), Hz38G10(G56T), Hz38G10(N55E), or Hz38G10(N55Q). In some embodiments, the cells produce the Hz38G10 (G56A) antibody. In some embodiments, cells produce a scFv version of the Hz38G10 antibody, referred to as dsscFv Hz38G10. In some embodiments, cells produce a scFv version of the Hz38G10 (G56A) antibody, referred to as dsscFv Hz38G10 (G56A). In some embodiments, the cells produce an antibody, designated 3D8. In some embodiments, the cells produce a humanized version of the 3D8 antibody. In some embodiments, the cells produce an antibody designated 3G8. In some embodiments, the cells produce a humanized version of the 3G8 antibody. In some embodiments, the cells produce an antibody designated 15C12. In some embodiments, the cells produce a humanized version of the 15C12 antibody. In some embodiments, the cells produce an antibody designated 27A8. In some embodiments, the cells produce a humanized version of the 27A8 antibody. In some embodiments, the cells produce an antibody designated 28C3. In some embodiments, the cells produce a humanized version of the 28C3 antibody. In some embodiments, the cells produce an antibody designated 38F5. In some embodiments, the cells produce a humanized version of the 38F5 antibody. In some embodiments, the cells produce an antibody designated 62B11. In some embodiments, the cells produce a humanized version of the 62B11 antibody. In some embodiments, the cells produce an antibody designated 62F2. In some embodiments, the cells produce a humanized version of the 62F2 antibody. In some embodiments, the cells produce an antibody designated 63A3. In some embodiments, the cells produce a humanized version of the 63A3 antibody. In some embodiments, the cell is a prokaryotic cell (eg, E. coli ). In some embodiments, the implementation of the cell is a eukaryotic cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a hybridoma cell.

[00231] The proteins produced by the host cell can be purified by any suitable method. Standard methods include chromatography (eg, ion exchange, affinity, and calibration column chromatography), centrifugation, differential solubility, or any other standard protein purification methods. Affinity tags such as hexa-histidine (SEQ ID NO: 231), maltose-binding domain, influenza envelope sequence, and glutathione S-transferase can be attached to the protein to facilitate purification by passing through an appropriate affinity column. Affinity chromatography used to purify immunoglobulins may include protein A, protein G and protein L chromatography. Isolated proteins can be physically characterized using methods such as proteolysis, size exclusion chromatography (SEC), mass spectrometry (MS), nuclear magnetic resonance (NMR), isoelectric focusing (IEF), high performance liquid chromatography (HPLC) and X-ray crystallography. The purity of isolated proteins can be determined using methods known to those skilled in the art, including, without limitation, SDS-PAGE, SEC, capillary gel electrophoresis, IEF, and capillary isoelectric focusing (cIEF).

[00232] In some embodiments, supernatants from expression systems that secrete the recombinant protein into the culture medium are first concentrated using a commercially available protein concentration filter, such as an Amicon® or Millipore Pellicon® ultrafiltration device. After the concentration step, the concentrate can be applied to a suitable cleansing matrix. In some embodiments, an anion exchange resin is used, such as a matrix or substrate, having pendent diethylaminoethyl (DEAE) groups. The matrices may be acrylamide, agarose, dextran, cellulose, or other types commonly used in protein purification. In some embodiments, a cation exchange step is used. Suitable cation exchangers include various insoluble matrices containing sulfopropyl or carboxymethyl groups. In some embodiments, a hydroxyapatite medium is used, including, without limitation, ceramic hydroxyapatite (CHT). In some embodiments, one or more reverse phase HPLC steps using a hydrophobic RP-HPLC medium, such as silica gel having pendant methyl or other aliphatic groups, are used to further purify the recombinant protein. In some embodiments, hydrophobic interaction chromatography (CHC) is used to separate recombinant proteins based on their hydrophobicity. CHB is a useful separation technique for purifying proteins while maintaining biological activity through the use of conditions and matrices that operate under less denaturing conditions than some other methods. Some or all of the above purification steps in various combinations can be used to obtain a homogeneous recombinant protein.

[00233] The anti-C3 antibodies of this invention can be analyzed for their physical/chemical properties and/or biological activity using various assays known in the art. In some embodiments, an anti-C3 antibody is tested for its ability to bind C3 (eg, human C3 and/or macaque C3). Binding assays include, without limitation, SPR (eg, Biacore), ELISA, and FACS. In some embodiments, an anti-C3 antibody is tested for its ability to inhibit, reduce, or block complement and/or C3 activity. Assays include, without limitation, hemolysis assays and C3a release assays. Additionally, antibodies can be evaluated for solubility, stability, thermal stability, viscosity, expression levels, expression quality, and/or purification efficiency.

[00234] In some embodiments, monoclonal antibodies generated against C3 are clustered based on the epitope that each individual antibody recognizes, a process known as "epitope binding". Typically, antibodies are tested in pairs in a combinatorial manner, and antibodies that compete with each other are grouped into groups. For example, in a premix binding assay, the first antibody is immobilized on a surface and the premix solution of the second antibody and antigen is passed through the immobilized first antibody. In tandem, an antigen is immobilized on a surface and two antibodies flow through the immobilized antigen and compete for binding. Using these methods, it is possible to identify antibodies that block each other. A competitive blocking profile is generated for each antibody against other antibodies. The blocking results determine which group each antibody is placed in. High throughput epitope binding methods are known in the art that allow screening and characterization of large numbers of antibodies in a short period of time. Antibodies that bind similar epitopes often have similar functions and/or capabilities. Conversely, antibodies that bind different epitopes may have different functional activities.

[00235] Epitope mapping is the process of identifying a binding site or epitope on a target protein/antigen to which an antibody (or other binding agent) binds. Various methods for mapping epitopes on target proteins are known in the art. These methods include mutagenesis, including, but not limited to, shotgun mutagenesis, site-directed mutagenesis, and alanine scanning; domain or fragment scanning, peptide scanning (eg, Pepscan technology); display methods (eg, phage display, microbial display, and ribosomal/mRNA display); methods including proteolysis and mass spectroscopy; and structural determination (eg X-ray crystallography and NMR).

[00236] In some embodiments, purified anti-C3 antibodies are characterized by assays including, but not limited to, N-terminal sequencing, amino acid analysis, high pressure liquid chromatography (HPLC), mass spectrometry, ion exchange chromatography, and papain digestion.

[00237] In some embodiments, assays are provided to identify anti-C3 antibodies that interfere with C3 activity. In some embodiments, hemolysis assays are used to evaluate the functional activity of the complement system. Hemolysis methods have been modified over the years to assess the activity of different complement pathways and/or individual complement components in the cascade. In some embodiments, a hemolysis assay is used to evaluate alternative pathway activity. In some embodiments, a hemolysis assay is used to evaluate classical pathway activity.

[00238] In some embodiments, a C3 binding agent (eg, an antibody) binds C3 and inhibits activation of the C3 alternative complement pathway. In some embodiments, a C3 binding agent (eg, an antibody) binds C3 and inhibits alternative pathway activation, the inhibition being assessed by a hemolysis assay. In certain embodiments, the C3 binding agent (e.g., antibody) inhibits alternative pathway activation by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least at least about 75%, at least about 90%, or about 100%. In some embodiments, the implementation of the percentage of inhibition is used to calculate the IC ₅₀ (half the maximum inhibitory concentration) for C3-binding agent. In some embodiments, the C3 binding agent that inhibits alternative pathway activation is a 38G10 antibody, Hz38G10 antibody, Hz38G10 antibody (G56A), Hz38G10 antibody (G56T), Hz38G10 antibody (N55E), Hz38G10 antibody (N55Q), 3D8 antibody, 3G8 antibody, 15C12 antibody, 27A8 antibody, 28C3 antibody, 38F5 antibody, 62B11 antibody, 62F2 antibody, or 63A3 antibody. In some embodiments, the C3 binding agent that inhibits alternative pathway activation is a 38G10 antibody, a Hz38G10 antibody, or a Hz38G10(G56A) antibody. In some embodiments, the C3 binding agent that inhibits alternative pathway activation is dsscFv Hz38G10 or dsscFv Hz38G10 (G56A).

[00239] In some embodiments, the C3 binding agent (eg, antibody) described herein binds C3 and inhibits activation of the C3 classical pathway. In some embodiments, a C3 binding agent (eg, an antibody) binds C3 and inhibits classical pathway activation, the inhibition being assessed by a hemolysis assay. In certain embodiments, the C3 binding agent (e.g., antibody) inhibits classical pathway activation by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least at least about 75%, at least about 90%, or about 100%. In some embodiments, the C3 binding agent that inhibits classical pathway activation is a 38G10 antibody, Hz38G10 antibody, Hz38G10 antibody (G56A), Hz38G10 antibody (G56T), Hz38G10 antibody (N55E), Hz38G10 antibody (N55Q), 3D8 antibody, 3G8 antibody, 15C12 antibody, 27A8 antibody, 28C3 antibody, 38F5 antibody, 62B11 antibody, 62F2 antibody, or 63A3 antibody. In some embodiments, the C3 binding agent that inhibits classical pathway activation is a 38G10 antibody, a Hz38G10 antibody, or a Hz38G10(G56A) antibody. In some embodiments, the C3 binding agent that inhibits classical pathway activation is dsscFv Hz38G10 or dsscFv Hz38G10 (G56A).

[00240] In some embodiments, the C3 binding agent (eg, antibody) described herein binds C3 and inhibits the activation of C3 classical and alternative pathways. In some embodiments, a C3 binding agent (eg, an antibody) binds C3 and inhibits activation of the classical and alternative pathways, the inhibition being assessed using a hemolysis assay. In certain embodiments, the C3 binding agent (e.g., antibody) inhibits classical and alternative pathway activation by at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 75%, at least about 90%, or about 100%. In some embodiments, the C3 binding agent that inhibits classical and alternative pathway activation is a 38G10 antibody, a Hz38G10 antibody, a Hz38G10 antibody (G56A), a Hz38G10 antibody (G56T), a Hz38G10 antibody (N55E), a Hz38G10 antibody (N55Q), a 3D8, 3G8 antibody, 15C12 antibody, 27A8 antibody, 28C3 antibody, 38F5 antibody, 62B11 antibody, 62F2 antibody, or 63A3 antibody. In some embodiments, the C3 binding agent that inhibits classical and alternative pathway activation is a 38G10 antibody, a Hz38G10 antibody, or a Hz38G10(G56A) antibody. In some embodiments, the C3 binding agent that inhibits classical and alternative pathway activation is dsscFv Hz38G10 or dsscFv Hz38G10 (G56A).

[00241] In some embodiments, an immunoassay to determine the presence and/or amount of individual components (eg, C3a) is used to evaluate the complement cascade. In some embodiments, the C3 binding agent (eg, antibody) described herein binds C3 and inhibits the release of C3a.

[00242] Also provided herein are conjugates containing the anti-C3 antibody described herein. In some embodiments, the antibody is attached to a second molecule. In some embodiments, the antibody is conjugated to a cytotoxic agent or fragment. In some embodiments, the antibody is conjugated to a cytotoxic agent to form an ADC (Antibody Drug Conjugate). In some embodiments, the cytotoxic agent is a chemotherapeutic agent, including but not limited to methotrexate, adriamycin/doxorubicin, melphalan, mitomycin C, chlorambucil, duocarmycin, daunorubicin, pyrrolobenzodiazepines (PBDs), or other intercalating agents. In some embodiments, the cytotoxic agent is a microtubule inhibitor, including, but not limited to, auristatins, maytansinoids (eg, DM1 and DM4), and tubulins. In some embodiments, the cytotoxic agent is an enzymatically active toxin of bacterial, fungal, plant or animal origin, or fragments thereof, including, but not limited to, diphtheria A chain, non-binding diphtheria toxin active fragments, exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, diantine proteins, Phytolaca americana proteins (PAPI, PAPII and PAP-S), Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, fenomycin, enomycin and trichothecenes. In some embodiments, the antibody is conjugated to one or more small molecule toxins such as calicheamicins, maytansinoids, trichotenes, and CC1065. You can use a derivative of any of these toxins, as long as it retains the cytotoxic activity of the original molecule.

[00243] Conjugates containing the anti-C3 antibody described herein can be prepared using any suitable method known in the art. In some embodiments, the conjugates are prepared using various bifunctional protein binding agents such as N-succinimidyl-3-(2-pyrididithiol) propionate (SPDP), iminothiolane (IT), bifunctional imidoester derivatives (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)ethylenediamine), diisocyanates (such as 2 toluene ,6-diisocyanate) and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene).

[00244] In some embodiments, an anti-C3 antibody described herein is conjugated to a detectable substance or molecule that allows the antibody to be used for diagnosis and/or detection. The detectable substance may include, without limitation, enzymes such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and acetylcholinesterase; prosthetic groups such as biotin and flavin(s); fluorescent materials such as umbelliferone, fluorescein, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine isothiocyanate (TRITC), dichlorotriazinylamine fluorescein, dansyl chloride, cyanine (Cy3) and phycoerythrin; bioluminescent materials such as luciferase; radioactive materials such as ²¹² Bi, ¹⁴ C, ⁵⁷ Co, ⁵¹ Cr, ⁶⁷ Cu, ¹⁸ F, ⁶⁸ Ga, ⁶⁷ Ga, ¹⁵³ Gd, ¹⁵⁹ Gd, ⁶⁸ Ge, ³ H, ¹⁶⁶ Ho, ¹³¹ I, ¹²⁵ I, ¹²³ I, ¹²¹ I, ¹¹⁵ In, ¹¹³ In, 112 In, ¹¹¹ In, ¹⁴⁰ La, ^{177 Lu} , ⁵⁴ Mn, ⁹⁹ Mo, ³² P, ¹⁰³ Pd, ¹⁴⁹ Pm, ¹⁴² Pr, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁰⁵ Rh , ⁹⁷ Ru, ³⁵ S, ⁴⁷ Sc, ⁷⁵ Se, ¹⁵³ Sm, ¹¹³ Sn, ^{117 Sn, 85 Sr} , ^99m Tc, ²⁰¹ Ti, ¹³³ Xe, ⁹⁰ Y, ⁶⁹ Yb, ¹⁷⁵ Yb, ⁶⁵ Zn; positron-emitting metals and ions of magnetic metals.

[00245] An anti-C3 antibody described herein can also be conjugated to a second antibody to form an antibody heteroconjugate.

[00246] The anti-C3 antibody described herein can be attached to a solid support. Such solid substrates include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene. In some embodiments, immobilized anti-C3 antibodies are used in immunoassays. In some embodiments, immobilized anti-C3 antibodies are used to purify the target antigen.

III Polynucleotides

[00247] In some embodiments, the invention encompasses polynucleotides comprising polynucleotides that encode for a polypeptide (ie, a C3 binding agent) described herein. The term "polynucleotide encoding a polypeptide" encompasses a polynucleotide that contains only coding sequences for a polypeptide, as well as a polynucleotide that contains additional coding and/or non-coding sequences. The polynucleotides of this invention may be in the form of RNA or in the form of DNA. DNA includes cDNA, genomic DNA and synthetic DNA; and may be double-stranded or single-stranded, and, if single-stranded, may be a coding strand or a non-coding (antisense) strand.

[00248] In some embodiments, the implementation of the polynucleotide contains a polynucleotide (for example, a nucleotide sequence) encoding a polypeptide containing an amino acid sequence selected from the group consisting of: SEQ ID NO: 18-31, 91-108, 110-114, 119 and 229 In some embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 27. In some embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 30 In some embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 113. In some embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 114. In some embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 119. In some embodiments, the polynucleotide comprises a polynucleotide encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 229 In some embodiments, the polynucleotide comprises a polynucleotide (e.g., a nucleotide sequence) encoding a polypeptide comprising more than one amino acid sequence selected from the group consisting of: SEQ ID NOS: 18-31, 91-108, and 110-112. In some embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO: 27, and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO: 29; and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO: 110, and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO: 112. In some embodiments, the polynucleotide comprises a polynucleotide encoding (i) a polypeptide comprising the amino acid sequence of SEQ ID NO: 111 and (ii) a polypeptide comprising the amino acid sequence of SEQ ID NO: 112.

[00249] In some embodiments, the polynucleotide comprises a polynucleotide having a nucleotide sequence that is at least about 80% identical, at least about 85% identical, at least about 90% identical, at least about 95% identical , and in some embodiments at least about 96%, 97%, 98%, or 99% identical with a polynucleotide encoding an amino acid sequence selected from the group consisting of: SEQ ID NOs: 18-31, 91-108, 110 -114, 119 and 229. Also provided is a polynucleotide that contains a polynucleotide that hybridizes to a polynucleotide encoding an amino acid sequence selected from the group consisting of: SEQ ID NOs: 18-31, 91-108, 110-114, 119 and 229 In some embodiments, hybridization occurs under conditions of high stringency, which are known to those skilled in the art.

[00250] In some embodiments, the implementation of the polynucleotide contains a polynucleotide having a nucleotide sequence encoding an amino acid sequence selected from the group consisting of: SEQ ID NO: 26-31. In some embodiments, the polynucleotide comprises a polynucleotide having a nucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 26 or SEQ ID NO: 27. In some embodiments, the polynucleotide comprises a polynucleotide having a nucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 29. In some embodiments, the polynucleotide comprises a polynucleotide having a nucleotide sequence that encodes the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 31.

[00251] In certain embodiments, the polynucleotide encodes a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 of the amino acid sequence specified in SEQ ID NOs: 18, 20, 21, 22, 23, or 24. In certain embodiments, ( a) The heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHNGGTTYNQNFTG (SEQ ID NO:8) and the heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9); (b) the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHNGGTTYNQQFTG (SEQ ID NO:13), and the heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9); (c) Heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), heavy chain CDR2 contains YIYPHNAGTTYNQQFTG (SEQ ID NO:14), and heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9); (d) The heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHNTGTTYNQQFTG (SEQ ID NO:15), and the heavy chain CDR3 contains RGGFFDY (SEQ ID NO:9); (e) The heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHEGGTTYNQQFTG (SEQ ID NO:16), the heavy chain CDR3 contains RGGFDFFDY (SEQ ID NO:9), or (f) the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHQGGTTYNQQFTG (SEQ ID NO:17), and the heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9). In certain embodiments, the polynucleotide encodes a light chain variable region comprising light chain CDRs 1, 2, and 3 of the amino acid sequence specified in SEQ ID NO:19 or 25. In certain embodiments, the light chain CDR1 comprises KASENVDTYVS (SEQ ID NO: 10), The light chain CDR2 contains GASNRYT (SEQ ID NO: 11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO: 12).

[00252] In certain embodiments, the polynucleotide encodes a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:91. In certain embodiments, the heavy chain CDR1 contains GYSFTGYNMN (SEQ ID NO: 38), the heavy chain CDR2 contains NINPYYGSTNYNQKFKG (SEQ ID NO: 39), and the heavy chain CDR3 contains GYYGGNYPFAY (SEQ ID NO: 40). In certain embodiments, the polynucleotide encodes a light chain variable region comprising light chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:92. In certain embodiments, the light chain CDR1 contains RASENIYSYLA (SEQ ID NO: 41), the light chain CDR2 contains NAKTLAE (SEQ ID NO: 42), and the light chain CDR3 contains QHYYGTPYT (SEQ ID NO: 43).

[00253] In certain embodiments, the polynucleotide encodes a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:93. In certain embodiments, the heavy chain CDR1 contains GYSFTGYNMN (SEQ ID NO: 38), the heavy chain CDR2 contains NINPYYDSTSYNQKFKG (SEQ ID NO: 44), and the heavy chain CDR3 contains ENYDFVGFAY (SEQ ID NO: 45). In certain embodiments, the polynucleotide encodes a light chain variable region comprising light chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:94. In certain embodiments, the light chain CDR1 contains RASSSVSYMH (SEQ ID NO: 46), the light chain CDR2 contains VTSNLAS (SEQ ID NO: 47), and the light chain CDR3 contains QQWSTNPLT (SEQ ID NO: 48).

[00254] In certain embodiments, the implementation of the polynucleotide encodes a heavy chain variable region containing CDR 1, 2 and 3 of the heavy chain of the amino acid sequence specified in SEQ ID NO:95. In certain embodiments, the heavy chain CDR1 contains GYSFTGYNMH (SEQ ID NO: 49), the heavy chain CDR2 contains NINPYYGTTNSNQKFED (SEQ ID NO: 50), and the heavy chain CDR3 contains GIYYYGTGYPYFDF (SEQ ID NO: 51). In certain embodiments, the polynucleotide encodes a light chain variable region comprising light chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:96. In certain embodiments, the light chain CDR1 contains RASQDINNYLN (SEQ ID NO: 52), the light chain CDR2 contains YTSRLHS (SEQ ID NO: 53), and the light chain CDR3 contains QQGITLPWT (SEQ ID NO: 54).

[00255] In certain embodiments, the polynucleotide encodes a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:97. In certain embodiments, the heavy chain CDR1 contains GYTFTDYWIN (SEQ ID NO: 55), the heavy chain CDR2 contains NIYPGSTSANYNEKFKS (SEQ ID NO: 56), and the heavy chain CDR3 contains YGYDSWFAY (SEQ ID NO: 57). In certain embodiments, the polynucleotide encodes a light chain variable region comprising light chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:98. In certain embodiments, the light chain CDR1 contains KSTKSLLNSDGFTYLD (SEQ ID NO: 58), the light chain CDR2 contains LVSNRFS (SEQ ID NO: 59), and the light chain CDR3 contains FQSNYLPLT (SEQ ID NO: 60).

[00256] In certain embodiments, the polynucleotide encodes a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:99. In certain embodiments, the heavy chain CDR1 contains GYAFNSCWMN (SEQ ID NO: 61), the heavy chain CDR2 contains RIYPGDGDTNYNGKFKG (SEQ ID NO: 62), and the heavy chain CDR3 contains EGRNYGYEDY (SEQ ID NO: 63). In certain embodiments, the polynucleotide encodes a light chain variable region comprising light chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:100. In certain embodiments, the light chain CDR1 contains KASQSVDYDGDSYMN (SEQ ID NO: 64), the light chain CDR2 contains AASDLES (SEQ ID NO: 65), and the light chain CDR3 contains QQANEDPRT (SEQ ID NO: 66).

[00257] In certain embodiments, the polynucleotide encodes a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:101. In certain embodiments, the heavy chain CDR1 contains GFTFSNYAMS (SEQ ID NO: 67), the heavy chain CDR2 contains QTISSGGRYTYYPDSVKG (SEQ ID NO: 68), and the heavy chain CDR3 contains RYYGNSYWYFDV (SEQ ID NO: 69). In certain embodiments, the polynucleotide encodes a light chain variable region comprising light chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:102. In certain embodiments, the light chain CDR1 contains KSSQSLLNSGNQKHYLT (SEQ ID NO: 70), the light chain CDR2 contains GASTRGS (SEQ ID NO: 71), and the light chain CDR3 contains QNDHSYPYT (SEQ ID NO: 72).

[00258] In certain embodiments, the polynucleotide encodes a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:103. In certain embodiments, the heavy chain CDR1 contains GFTFSSYTMS (SEQ ID NO: 73), the heavy chain CDR2 contains YISSGGGTTYYPDTVKG (SEQ ID NO: 74), and the heavy chain CDR3 contains RYYRGSSLWYFDV (SEQ ID NO: 75). In certain embodiments, the polynucleotide encodes a light chain variable region comprising light chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:104. In certain embodiments, the light chain CDR1 contains KSSQSLFNSGSQKNFLT (SEQ ID NO: 76), the light chain CDR2 contains WASTRES (SEQ ID NO: 77), and the light chain CDR3 contains QNDYSYPLT (SEQ ID NO: 78).

[00259] In certain embodiments, the polynucleotide encodes a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:105. In certain embodiments, the heavy chain CDR1 contains GYSITSGYSLH (SEQ ID NO: 79), the heavy chain CDR2 contains YIHYSGSTNYNPSLKS (SEQ ID NO: 80), and the heavy chain CDR3 contains AWDYLDY (SEQ ID NO: 81). In certain embodiments, the polynucleotide encodes a light chain variable region comprising light chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:106. In certain embodiments, the light chain CDR1 contains RASENIYSQLA (SEQ ID NO: 82), the light chain CDR2 contains DAKTLAE (SEQ ID NO: 83), and the light chain CDR3 contains HHHFGILYT (SEQ ID NO: 84).

[00260] In certain embodiments, the polynucleotide encodes a heavy chain variable region comprising heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:107. In certain embodiments, the heavy chain CDR1 contains GYSITSGYYWN (SEQ ID NO: 85), the heavy chain CDR2 contains YIRYDGSNNYNPSLKN (SEQ ID NO: 86), and the heavy chain CDR3 contains HYGYDGGAFDF (SEQ ID NO: 87). In certain embodiments, the polynucleotide encodes a light chain variable region comprising light chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:108. In certain embodiments, the light chain CDR1 contains RTSENIYNYLV (SEQ ID NO: 88), the light chain CDR2 contains NAKTLEE (SEQ ID NO: 89), and the light chain CDR3 contains QHHYGTPFT (SEQ ID NO: 90).

[00261] In certain embodiments, the polynucleotide encodes a dsscFv comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 110 or SEQ ID NO: 111 and the light chain variable region contains the amino acid sequence shown in SEQ ID NO: 112. In certain embodiments, the dsscFv contains the amino acid sequence of SEQ ID NO: 113 or SEQ ID NO: 114.

[00262] In some embodiments, the polynucleotide comprises a coding sequence for a polypeptide (e.g., an antibody) fused in-frame to a polynucleotide that promotes expression and secretion of the polypeptide from a host cell (e.g., a leader sequence that functions as a secretory sequence for polypeptide transport control). The polypeptide may have the leader sequence cleaved by the host cell to form the "mature" form of the polypeptide.

[00263] In some embodiments, the implementation of the polynucleotide contains a coding sequence for a polypeptide (eg, antibodies), fused in the same reading frame with the sequence of the marker or label. For example, in some embodiments, the marker sequence is a hexahistidine tag (SEQ ID NO: 231) (HIS-tag) that allows efficient purification of the polypeptide fused to the marker. In some embodiments, the marker sequence is a hemagglutinin (HA) tag derived from the influenza hemagglutinin protein when a mammalian host (eg, COS-7 cells) is used. In some embodiments, the marker sequence is a FLAG™ tag. In some embodiments, the implementation of the marker can be used in conjunction with other markers or labels.

[00264] The invention also provides variants of the polynucleotides described herein, wherein the variant encodes, for example, fragments, analogs, and/or derivatives of a polypeptide. In some embodiments, the invention provides a polynucleotide comprising a polynucleotide having a nucleotide sequence that is at least about 80% identical, at least about 85% identical, at least about 90% identical, at least about 95%, and in some embodiments, at least about 96%, 97%, 98%, or 99% identical to a polynucleotide sequence encoding a polypeptide disclosed herein.

[00265] As used herein, the phrase "a polynucleotide having a nucleotide sequence that is at least 95% identical to a polynucleotide sequence" means that the nucleotide sequence of the polynucleotide is identical to the reference sequence, except that the polynucleotide sequence may contain up to five point mutations for every 100 nucleotides of the reference nucleotide sequence. In other words, to obtain a polynucleotide having a nucleotide sequence that is at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted or replaced with another nucleotide, or up to 5% of all nucleotides in the reference sequence may be inserted. into the reference sequence. These reference sequence mutations can occur at the 5' or 3' end positions of the reference nucleotide sequence, or anywhere between these terminal positions, interspersed either individually among the nucleotides in the reference sequence or in one or more contiguous groups in the reference sequence.

[00266] Polynucleotide variants may contain changes in coding regions, non-coding regions, or both. In some embodiments, a variant polynucleotide contains changes that cause silent substitutions, additions, or deletions, but do not change the properties or activities of the encoded polypeptide. In some embodiments, a variant polynucleotide contains silent substitutions that do not result in a change in the amino acid sequence of the polypeptide (due to the degeneracy of the genetic code). In some embodiments, a variant polynucleotide contains one or more mutated codons containing one or more (eg, 1, 2, or 3) codon substitutions that change the amino acid encoded by that codon. Methods for introducing one or more codon substitutions are known in the art, such as, for example, PCR mutagenesis and site-directed mutagenesis. Variant polynucleotides can be generated for a variety of reasons, such as to optimize codon expression for a particular host (eg, changing codons in human mRNA to those that are preferred by the bacterial host, such as E. coli ). In some embodiments, a variant polynucleotide contains at least one silent mutation in a non-coding or coding region of the sequence.

[00267] In some embodiments, a variant polynucleotide is produced to modulate or change the expression (or expression levels) of the encoded polypeptide. In some embodiments, a variant polynucleotide is produced to increase expression of the encoded polypeptide. In some embodiments, a variant polynucleotide is produced to reduce expression of the encoded polypeptide. In some embodiments, a variant polynucleotide has increased expression of the encoded polypeptide compared to the original polynucleotide sequence. In some embodiments, a variant polynucleotide has reduced expression of the encoded polypeptide compared to the original polynucleotide sequence.

[00268] In some embodiments, the polynucleotide is isolated. In some embodiments, the polynucleotide is substantially pure.

[00269] Also provided are vectors and cells containing each of the polynucleotides described herein. In some embodiments, the expression vector contains a polynucleotide molecule that encodes a C3 binding agent as described herein. In some embodiments, the expression vector contains a polynucleotide molecule that encodes a polypeptide that is part of the C3 binding agent described herein. In some embodiments, the host cell contains an expression vector containing a polynucleotide molecule that encodes a C3 binding agent described herein. In some embodiments, the host cell contains an expression vector containing a polynucleotide molecule that encodes a polypeptide that is part of the C3 binding agent described herein. In some embodiments, the host cell contains a polynucleotide molecule that encodes a C3 binding agent described herein.

IV. Methods for obtaining binding agents

[00270] The present invention provides a method for preparing the C3 binding agents (eg, antibodies) described herein. In certain embodiments, in which the C3 binding agent is an antibody, the method includes obtaining a cell containing the heavy chain and/or light chain of the C3 binding agent, incubating the cell under conditions that allow expression of the antibody, and isolating the antibody. In certain embodiments, the cell contains one or more vectors (eg, one or more of the vectors described herein) encoding a heavy chain and a light chain. For example, in certain embodiments, the cell contains a first vector encoding a heavy chain and a second vector encoding a light chain. In other embodiments, the cell contains a vector encoding a heavy chain and a light chain. In certain embodiments, the cell contains one or more polynucleotides (eg, one or more of the polynucleotides described herein) encoding a heavy chain and a light chain. For example, in certain embodiments, the cell comprises a first polynucleotide encoding a heavy chain and a second polynucleotide encoding a light chain. In other embodiments, the cell contains a polynucleotide encoding a heavy chain and a light chain. In some embodiments, the method includes purifying the antibody. In certain embodiments, the cell is a CHO cell. In other embodiments, the cell is a 293 cell. In certain embodiments, the cell is a bacterial cell (eg, E. coli ).

[00271] In certain embodiments, in which the C3 binding agent is a scFv (e.g., dsscFv), the method includes providing a cell containing the scFv (e.g., dsscFv) of the C3 binding agent, incubating the cell under conditions that allow expression of the scFv, and scFv isolation. In certain embodiments, the cell contains a vector (eg, the vector described herein) encoding an scFv. In certain embodiments, the cell contains a polynucleotide (eg, a polynucleotide described herein) encoding an scFv. In some embodiments, the method includes purifying the antibody. In certain embodiments, the cell is a bacterial cell (eg, E. coli ). In certain embodiments, the cell is a yeast cell (eg, Pichia pastoris ). In certain embodiments, the cell is a CHO cell. In other embodiments, the cell is a 293 cell.

V. Methods of administration and pharmaceutical compositions

[00272] The C3 binding agents (eg, antibodies) of the present invention are useful in a variety of fields including, but not limited to, therapeutic treatments such as the treatment of diseases or disorders associated with complement activation. In some embodiments, the C3 binding agent described herein is useful in methods for inhibiting complement activation. In some embodiments, the C3 binding agent described herein is useful in methods for inhibiting C3 activity. In some embodiments, the C3 binding agent described herein is useful in methods of treating an ocular disorder. In some embodiments, the C3 binding agent described herein is useful in methods of inhibiting or suppressing drusen formation in the eye. In some embodiments, the C3 binding agent described herein is useful in methods for treating macular degradation. In some embodiments, the C3 binding agent described herein is useful in methods of treating a disorder associated with macular degradation. In some embodiments, the C3 binding agent described herein is useful in methods of treating age-related macular degeneration (AMD). In some embodiments, the C3 binding agent described herein is useful in methods for treating dry AMD. In some embodiments, the C3 binding agent described herein is useful in methods of treating early AMD. In some embodiments, the C3 binding agent described herein is useful in methods for treating intermediate AMD. In some embodiments, the C3 binding agent described herein is useful in methods of treating advanced dry AMD/geographic atrophy. The terms "triggered dry AMD" and "geographic atrophy" are used interchangeably in this document.

[00273] In some embodiments, a method for inhibiting complement activation in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent described herein. In some embodiments, a method for inhibiting complement activation in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of an anti-C3 antibody described herein. In some embodiments, a method for inhibiting C3 activity in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent described herein. In some embodiments, a method for inhibiting C3 activity in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of an anti-C3 antibody described herein. In some embodiments of the methods described herein, a C3 binding agent is administered to the eye of a subject. In some embodiments of the methods described herein, an anti-C3 antibody is administered to the eye of a subject.

[00274] In some embodiments, a method of treating an ocular disorder in a subject (eg, a human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent described herein. In some embodiments, a method for treating an ocular disorder in a subject (eg, a human) comprises administering to the subject a therapeutically effective amount of an anti-C3 antibody described herein. In some embodiments, the ocular disorder is selected from the group consisting of macular degeneration (maculopathy), age-related macular degeneration (AMD), diabetic retinopathy, retinopathy of prematurity, macular degeneration, retinal dystrophy, uveitis, keratitis, scleritis, retinitis pigmentosa, choroidal neovascularization, retinal neovascularization and inflammation of the eye. In some embodiments, the ocular disorder is macular degeneration. In some embodiments, the ocular disorder is AMD. In some embodiments, the ocular disorder is wet AMD. In some embodiments, the ocular disorder is dry AMD. In some embodiments, the ocular disorder is early AMD. In some embodiments, the ocular disorder is intermediate AMD. In some embodiments, the ocular disorder is geographic atrophy.

[00275] In the early stages of AMD, the disease is characterized by the presence of drusen, which may present with or without retinal pigment epithelium (RPE) disorders. In the early stages, when the drusen are small and/or few in number, vision is usually not impaired. As the drusen enlarge and multiply, patients report that their central vision becomes less sharp. Geographic atrophy (GA) is an advanced form of dry AMD. HA is characterized by RPE degeneration, while RPE degeneration leads to the death of photoreceptor cells (rods and cones). The patient thus has a point or area (a "continent") of atrophy surrounded by a "sea" of healthy or healthier retinas. Physicians can measure the area of atrophy (often referred to as the "HA lesion") and assess the loss of visual function. Changes in the area of GA involvement can be used to track disease progression over time.

[00276] In some embodiments, a method for treating AMD in a subject (eg, a human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent described herein. In some embodiments, a method of treating AMD in a subject (eg, human) comprises administering to the subject a therapeutically effective amount of an antibody that specifically binds C3 (eg, human C3) described herein. In some embodiments, AMD is dry AMD. In some embodiments, AMD is early AMD. In some embodiments, AMD is intermediate AMD. In some embodiments, AMD is HA. In some embodiments, a method for treating geographic atrophy in a subject (eg, a human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent described herein. In some embodiments, a method for treating geographic atrophy in a subject (eg, a human) comprises administering to the subject a therapeutically effective amount of an antibody that specifically binds human C3 described herein.

[00277] In some embodiments, a method for inhibiting or suppressing drusen formation in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent described herein. In some embodiments, a method for inhibiting or suppressing drusen formation in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of an anti-C3 antibody described herein.

[00278] In some embodiments, a method for inhibiting or suppressing retinal pigment epithelium atrophy in a subject (eg, human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent described herein. In some embodiments, a method for inhibiting or suppressing retinal pigment epithelium atrophy in a subject (eg, human) comprises administering to the subject a therapeutically effective amount of an anti-C3 antibody described herein.

[00279] In some embodiments, a method of treating a subject (eg, human) at risk of developing AMD comprises administering to the subject a therapeutically effective amount of a C3 binding agent described herein. In some embodiments, a method of treating a subject (eg, a human) at risk of developing AMD comprises administering to the subject a therapeutically effective amount of an anti-C3 antibody described herein. In some embodiments, a method of treating a subject (eg, human) at risk of developing geographic atrophy comprises administering to the subject a therapeutically effective amount of a C3 binding agent described herein. In some embodiments, a method of treating a subject (eg, a human) at risk of developing geographic atrophy comprises administering to the subject a therapeutically effective amount of an anti-C3 antibody described herein.

[00280] In some embodiments, a method for slowing or reducing the progression of AMD in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of a C3 binding agent described herein. In some embodiments, a method for slowing or reducing the progression of AMD in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of an anti-C3 antibody described herein. In some embodiments, the method slows down or reduces the progression from early AMD to intermediate AMD. In some embodiments, the implementation of the method slows down or reduces the progression from intermediate AMD to geographic atrophy. In some embodiments, a method for slowing or reducing the progression of geographic atrophy in the eye of a subject (eg, human) comprises administering to the subject a C3 binding agent described herein. In some embodiments, a method for slowing or reducing the progression of geographic atrophy in the eye of a subject (eg, human) comprises administering to the subject a therapeutically effective amount of an anti-C3 antibody described herein.

[00281] In some embodiments of the methods described herein, the subject (eg, human) has AMD or GA. In some embodiments of the methods described herein, the subject (eg, human) is diagnosed with AMD or HA. Criteria for diagnosing AMD and GA vary by scoring system and may depend on the imaging modalities used. In some embodiments, the criteria for AMD include: (1) no AMD - no or few small (<63 µm in diameter) drusen; (2) Early AMD - medium-sized drusen (63-124 µm in diameter); (3) Intermediate AMD - medium-sized drusen and pigmentary changes or at least 1 large (> 125 µm) drusen; (4) Late AMD (dry) - geographic atrophy or late AMD (wet) - CNV with features such as subretinal hemorrhage, serous retinal or retinal pigment epithelium detachments, lipid exudate or fibrovascular scarring. In some embodiments, the criteria for GA include an area of pallor in the fundus with visible underlying choroidal blood vessels and well-defined borders, occupying (1) a diameter >175 µm; (2) diameter > 250 µm; or (3) at least 433 microns in diameter. Currently, there is no consensus on the minimum diameter for diagnosing GA.

[00282] There are a number of imaging techniques used by practitioners skilled in the art, including, without limitation, color fundus photography (CFP), fundus autofluorescence (FAF) )), optical coherence tomography (eng. - coherence tomography (OCT)), fluorescein angiography (eng. - fluorescein angiography (FA)) and indocyanine. green angiography (English - indocyanine green angiography (ICGA)). Imaging techniques allow direct measurement and quantification of the HA lesion area.

[00283] Thus, in some embodiments, a method of treating geographic atrophy in a subject (e.g., a human) comprises administering to the subject a therapeutically effective amount of an antibody that specifically binds human C3, described herein, wherein the treatment reduces the growth of the HA lesion. In some embodiments, the GA lesion area is measured using color fundus photography, fluorescein angiography, and/or optical coherence tomography. In some embodiments, GA lesion is measured prior to anti-C3 antibody treatment and measured again after treatment. In some embodiments, GA lesion growth is reduced by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80% or more. In some embodiments, the growth of the HA lesion is reduced by at least 25%. In some embodiments, the growth of the HA lesion is reduced by at least 40%. In some embodiments, the growth of the HA lesion is reduced by at least 50%. In some embodiments, the area of HA lesion is measured at about 6 months post-treatment, about 1 year post-treatment, about 18 months post-treatment, and/or about 2 years post-treatment. In some embodiments, the HA lesion area is measured each time a C3 binding agent is administered. In some embodiments, the HA lesion area is measured at time points selected by the practitioner.

[00284] In some embodiments of the methods disclosed herein, a C3 binding agent (e.g., an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated 38G10. In some embodiments of the methods disclosed herein, the C3 binding agent (eg, an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated Hz38G10. In some embodiments of the methods disclosed herein, the C3 binding agent (e.g., an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated Hz38G10 (G56A). In some embodiments of the methods disclosed herein, the C3 binding agent (e.g., an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated Hz38G10 (G56T). In some embodiments of the methods disclosed herein, the C3 binding agent (e.g., an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated Hz38G10 (N55E). In some embodiments of the methods disclosed herein, a C3 binding agent (e.g., an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated Hz38G10 (N55Q). In some embodiments of the methods disclosed herein, the C3 binding agent (eg, an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated 3D8. In some embodiments of the methods disclosed herein, the C3 binding agent (eg, an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated 3G8. In some embodiments of the methods disclosed herein, the C3 binding agent (eg, an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated 15C12. In some embodiments of the methods disclosed herein, the C3 binding agent (eg, an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated 27A8. In some embodiments of the methods disclosed herein, the C3 binding agent (eg, an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated 28C3. In some embodiments of the methods disclosed herein, the C3 binding agent (eg, an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated 38F5. In some embodiments of the methods disclosed herein, the C3 binding agent (eg, an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated 62B11. In some embodiments of the methods disclosed herein, the C3 binding agent (eg, an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated 62F2. In some embodiments of the methods disclosed herein, the C3 binding agent (eg, an anti-C3 antibody) comprises a heavy chain CDR1, CDR2 and CDR3 and a light chain CDR1, CDR2 and CDR3 of an antibody designated 63A3.

[00285] In some embodiments of the methods described herein, the C3 binding agent is a humanized anti-C3 antibody having the above CDRs.

[00286] In some embodiments of the methods disclosed herein, the anti-C3 antibody comprises a heavy chain CDR1 containing GYTFDDFYMD (SEQ ID NO:7); A heavy chain CDR2 containing YIYPHNGGTTYNQQFTG (SEQ ID NO:13), YIYPHNAGTTYNQQFTG (SEQ ID NO:14), YIYPHNTGTTYNQQFTG (SEQ ID NO:15), YIYPHEGGTTYNQQFTG (SEQ ID NO:16), or YIYPHQGGTTYNQQFTG (SEQ ID NO:17) , and a heavy chain CDR3 containing RGGFDFDY (SEQ ID NO:9) and a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments of the methods disclosed herein, the anti-C3 antibody comprises a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNGGTTYNQQFTG (SEQ ID NO:13) and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO:9), a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments of the methods disclosed herein, the anti-C3 antibody comprises a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNAGTTYNQQFTG (SEQ ID NO:14) and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO:9), a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12). In some embodiments of the methods disclosed herein, the anti-C3 antibody comprises a heavy chain CDR1 containing GYTFTDFYMD (SEQ ID NO:7); a heavy chain CDR2 containing YIYPHNTGTTYNQQFTG (SEQ ID NO:15) and a heavy chain CDR3 containing RGGFDFFDY (SEQ ID NO:9), a light chain CDR1 containing KASENVDTYVS (SEQ ID NO:10); a light chain CDR2 containing GASNRYT (SEQ ID NO:11); and a light chain CDR3 containing GQSHSYPLT (SEQ ID NO:12).

[00287] In some embodiments of the methods described herein, the anti-C3 antibody comprises: (a) the heavy chain variable region of SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24; and (b) the light chain variable region of SEQ ID NO: 25. In some embodiments of the methods described herein, the anti-C3 antibody comprises: (a) the heavy chain variable region of SEQ ID NO: 20, and (b ) a light chain variable region of SEQ ID NO: 25. In some embodiments of the methods described herein, an anti-C3 antibody comprises: (a) a heavy chain variable region of SEQ ID NO: 21 and (b) a light chain variable region of SEQ ID NO: : 25. In some embodiments of the methods described herein, the anti-C3 antibody comprises: (a) the heavy chain variable region of SEQ ID NO: 22, and (b) the light chain variable region of SEQ ID NO: 25. In some embodiments of the methods, described herein, the anti-C3 antibody comprises: (a) the heavy chain variable region of SEQ ID NO: 23 and (b) the light chain variable region of SEQ ID NO: 25. In some embodiments of the methods described herein, the anti-C3 antibody C3 contains: (a) the heavy chain variable region of SEQ ID NO: 24; and (b) the light chain variable region of SEQ ID NO: 25. In some embodiments of the methods described herein, the C3 antibody is Hz38G10. In some embodiments of the methods described herein, the anti-C3 antibody is Hz38G10 (G56A). In some embodiments of the methods described herein, the anti-C3 antibody is Hz38G10 (G56T). In some embodiments of the methods described herein, the anti-C3 antibody is Hz38G10 (N55E). In some embodiments of the methods described herein, the anti-C3 antibody is Hz38G10 (N55Q).

[00288] In some embodiments of the methods described herein, the C3 antibody comprises a polypeptide of SEQ ID NO:27. In some embodiments of the methods described herein, the C3 antibody comprises a polypeptide of SEQ ID NO:29. In some embodiments of the methods described herein, the C3 antibody comprises a polypeptide of SEQ ID NO:31. In some embodiments of the methods described herein, the anti-C3 antibody comprises a polypeptide of SEQ ID NO:27 and a polypeptide of SEQ ID NO:31. In some embodiments of the methods described herein, the anti-C3 antibody comprises a polypeptide of SEQ ID NO:29 and a polypeptide of SEQ ID NO:31.

[00289] In some embodiments of the methods described herein, the anti-C3 antibody comprises a polypeptide of SEQ ID NO:110 and a polypeptide of SEQ ID NO:112. In some embodiments of the methods described herein, the anti-C3 antibody comprises a polypeptide of SEQ ID NO:111 and a polypeptide of SEQ ID NO:112. In some embodiments of the methods described herein, the anti-C3 antibody comprises a polypeptide of SEQ ID NO:113. In some embodiments of the methods described herein, the C3 antibody comprises a polypeptide of SEQ ID NO:114. In some embodiments of the methods described herein, the C3 antibody comprises a polypeptide of SEQ ID NO:119. In some embodiments of the methods described herein, the C3 antibody comprises a polypeptide of SEQ ID NO:229.

[00290] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:18 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:19. In certain embodiments, the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR1 contains YIYPHNGGTTYNQNFTG (SEQ ID NO:8), the heavy chain CDR3 contains RGGFDFFDY (SEQ ID NO:9), the light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), the light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12).

[00291] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:20 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:25. In certain embodiments, the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHNGGTTYNQQFTG (SEQ ID NO:13), the heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9), the light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), the light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12).

[00292] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:21 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:25. In certain embodiments, the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHNAGTTYNQQFTG (SEQ ID NO:14), the heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9), the light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), the light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12).

[00293] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:22 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:25. In certain embodiments, the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHNTGTTYNQQFTG (SEQ ID NO:15), the heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9), the light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), the light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12).

[00294] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:23 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:25. In certain embodiments, the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHEGGTTYNQQFTG (SEQ ID NO:16), the heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9), the light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), the light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12).

[00295] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:24 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:25. In certain embodiments, the heavy chain CDR1 contains GYTFTDFYMD (SEQ ID NO:7), the heavy chain CDR2 contains YIYPHQGGTTYNQQFTG (SEQ ID NO:17), the heavy chain CDR3 contains RGGFDFDY (SEQ ID NO:9), the light chain CDR1 contains KASENVDTYVS (SEQ ID NO:10), the light chain CDR2 contains GASNRYT (SEQ ID NO:11) and the light chain CDR3 contains GQSHSYPLT (SEQ ID NO:12).

[00296] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:91 and the light chain variable region contains light chain CDRs 1, 2 and 3 from the amino acid sequence shown in SEQ ID NO:92. In certain embodiments, the heavy chain CDR1 contains GYSFTGYNMN (SEQ ID NO:38), the heavy chain CDR2 contains NINPYYGSTNYNQKFKG (SEQ ID NO:39), the heavy chain CDR3 contains GYYGGNYPFAY (SEQ ID NO:40), the light chain CDR1 contains RASENIYSYLA (SEQ ID NO:41), the light chain CDR2 contains NAKTLAE (SEQ ID NO:42) and the light chain CDR3 contains QHYYGTPYT (SEQ ID NO:43).

[00297] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:93 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:94. In certain embodiments, the heavy chain CDR1 contains GYSFTGYNMN (SEQ ID NO:38), the heavy chain CDR2 contains NINPYYDSTSYNQKFKG (SEQ ID NO:44), the heavy chain CDR3 contains ENYDFVGFAY (SEQ ID NO:45), the light chain CDR1 contains RASSSSVSYMH (SEQ ID NO:46), the light chain CDR2 contains VTSNLAS (SEQ ID NO:47) and the light chain CDR3 contains QQWSTNPLT (SEQ ID NO:48).

[00298] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:95 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:96. In certain embodiments, the heavy chain CDR1 contains GYSFTGYNMH (SEQ ID NO:49), the heavy chain CDR2 contains NINPYYGTTNSNQKFED (SEQ ID NO:50), the heavy chain CDR3 contains GIYYYGTGYPYFDF (SEQ ID NO:51), the light chain CDR1 contains RASQDINNYLN (SEQ ID NO:52), the light chain CDR2 contains YTSRLHS (SEQ ID NO:53) and the light chain CDR3 contains QQGITLPWT (SEQ ID NO:54).

[00299] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:97 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:98. In certain embodiments, the heavy chain CDR1 contains GYTFTDYWIN (SEQ ID NO:55), the heavy chain CDR2 contains NIYPGSTSANYNEKFKS (SEQ ID NO:56), the heavy chain CDR3 contains YGYDSWFAY (SEQ ID NO:57), the light chain CDR1 contains KSTKSLLNSDGFTYLD (SEQ ID NO:58), the light chain CDR2 contains LVSNRFS (SEQ ID NO:59) and the light chain CDR3 contains FQSNYLPLT (SEQ ID NO:60).

[00300] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:99 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:100. In certain embodiments, the heavy chain CDR1 contains GYAFNSCWMN (SEQ ID NO:61), the heavy chain CDR2 contains RIYPGDGDTNYNGKFKG (SEQ ID NO:62), the heavy chain CDR3 contains EGRNYGYEDY (SEQ ID NO:63), the light chain CDR1 contains KASQSVDYDGDSYMN (SEQ ID NO:64), the light chain CDR2 contains AASDLES (SEQ ID NO:65) and the light chain CDR3 contains QQANEDPRT (SEQ ID NO:66).

[00301] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:101 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:102. In certain embodiments, the heavy chain CDR1 contains GFTFSNYAMS (SEQ ID NO:67), the heavy chain CDR2 contains QTISSGGRYTYYPDSVKG (SEQ ID NO:68), the heavy chain CDR3 contains RYYGNSYWYFDV (SEQ ID NO:69), the light chain CDR1 contains KSSQSLLNSGNQKHYLT (SEQ ID NO:70), the light chain CDR2 contains GASTRGS (SEQ ID NO:71) and the light chain CDR3 contains QNDHSYPYT (SEQ ID NO:72).

[00302] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:103 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:104. In certain embodiments, the heavy chain CDR1 contains GFTFSSYTMS (SEQ ID NO:73), the heavy chain CDR2 contains YISSGGGTTYYPDTVKG (SEQ ID NO:74), the heavy chain CDR3 contains RYYRGSSLWYFDV (SEQ ID NO:75), the light chain CDR1 contains KSSQSLFNSGSQKNFLT (SEQ ID NO:76), the light chain CDR2 contains WASTRES (SEQ ID NO:77) and the light chain CDR3 contains QNDYSYPLT (SEQ ID NO:78).

[00303] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:105 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:106. In certain embodiments, the heavy chain CDR1 contains GYSITSGYSLH (SEQ ID NO:79), the heavy chain CDR2 contains YIHYSGSTNYNPSLKS (SEQ ID NO:80), the heavy chain CDR3 contains AWDYLDY (SEQ ID NO:81), the light chain CDR1 contains RASENIYSQLA (SEQ ID NO:82), the light chain CDR2 contains DAKTLAE (SEQ ID NO:83) and the light chain CDR3 contains HHHFGILYT (SEQ ID NO:84).

[00304] In certain embodiments of the methods disclosed herein, the C3 binding agent comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises heavy chain CDRs 1, 2, and 3 of the amino acid sequence shown in SEQ ID NO:107 and the light chain variable region contains light chain CDRs 1, 2 and 3 of the amino acid sequence shown in SEQ ID NO:108. In certain embodiments, the heavy chain CDR1 contains GYSITSGYYWN (SEQ ID NO:85), the heavy chain CDR2 contains YIRYDGSNNYNPSLKN (SEQ ID NO:86), the heavy chain CDR3 contains HYGYDGGAFDF (SEQ ID NO:87), the light chain CDR1 contains RTSENIYNYLV (SEQ ID NO:88), the light chain CDR2 contains NAKTLEE (SEQ ID NO:89) and the light chain CDR3 contains QHHYGTPFT (SEQ ID NO:90).

[00305] In certain embodiments of the methods described herein, the C3 binding agent comprises a dsscFv comprising a heavy chain variable region and a light chain variable region. In certain embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:110 or SEQ ID NO:111 and the light chain variable region contains the amino acid sequence shown in SEQ ID NO:112. In certain embodiments, the dsscFv contains the amino acid sequence of SEQ ID NO: 113. In certain embodiments, the dsscFv contains the amino acid sequence of SEQ ID NO: 114. In certain embodiments, the dsscFv contains the amino acid sequence of SEQ ID NO: 119. In certain embodiments, the dsscFv contains the amino acid sequence SEQ ID NO: 229.

[00306] In some embodiments of the methods described herein, the method includes administering a C3 binding agent (eg, antibody) described herein in combination with at least one additional therapeutic agent or therapeutic therapy. When treating with two or more therapeutic agents, agents are often used that work through different mechanisms of action, although this is not required. Combination therapy using agents with different mechanisms of action may result in additive or synergistic effects. Combination therapy may allow a lower dose of each agent than is used in monotherapy, thereby reducing toxic side effects and/or increasing the therapeutic index of the agent(s). Combination therapy may reduce the likelihood of developing resistance to the agent.

[00307] In some embodiments, the combination of a C3 binding agent (eg, antibody) described herein and at least one additional therapeutic agent results in additional or synergistic results. In some embodiments, the combination therapy results in an increase in the therapeutic index of the C3 binding agent. In some embodiments, the combination therapy results in an increase in the therapeutic index of the additional therapeutic agent(s). In some embodiments, the combination therapy results in a reduction in toxicity and/or side effects of the C3 binding agent. In some embodiments, the combination therapy results in reduced toxicity and/or side effects of the additional therapeutic agent(s).

[00308] In some embodiments, the combination treatment comprises one additional therapeutic agent or two or more additional therapeutic agents. In some embodiments, treatment with a C3 binding agent may occur before, simultaneously with, or after administration of additional therapeutic agents. In some embodiments, combination administration includes co-administration either in the same pharmaceutical formulation, or using separate formulations, or sequential administration in any order, but usually over a period of time, so that all active agents can exert their biological activity. In some embodiments, the formulation of agents and/or dosing regimens for additional therapeutic agents are in accordance with the manufacturer's instructions or empirically determined by a qualified medical practitioner.

[00309] In some embodiments of the methods described herein, a C3 binding agent (eg, antibody) is administered to a subject (eg, human) as part of a combination therapy. In some embodiments, the combination therapy includes photodynamic therapy. In some embodiments, the combination therapy includes photodynamic therapy with verteporfin. In some embodiments, a C3 binding agent (eg, an antibody) is administered to a subject (eg, a human), wherein one or more additional therapeutic agents are administered to the subject. In some embodiments, the additional therapeutic agent is compstatin or a compstatin analog or derivative (eg, POT-4; APL-2). In some embodiments, the additional therapeutic agent is a C5 inhibitor. In some embodiments, the C5 inhibitor is selected from the group including, but not limited to, eculizumab, LFG316, or Zimura (an anti-C5 aptamer). In some embodiments, the additional therapeutic agent is a properdin inhibitor (eg, an anti-properdin antibody). In some embodiments, the additional therapeutic agent is a factor D inhibitor. In some embodiments, the factor D inhibitor is an anti-factor D antibody (eg, lampalizumab). In some embodiments, the additional therapeutic agent is a VEGF inhibitor. In some embodiments, the VEGF inhibitor is selected from the group including, but not limited to, pegaptanib (MACUGEN), ranibizumab (LUCENTIS), bevacizumab (AVASTIN), aflibercept (EYLEA), bralucizumab, and OPT-302. In some embodiments, the additional therapeutic agent is a PDGF inhibitor. In some embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the additional therapeutic agent is a neuroprotective agent. In some embodiments, the implementation of the neuroprotective agent is selected from the group including, without limitation, ciliary neurotrophic factor (CNTF), tandospirone and brimonidine.

[00310] It should be appreciated that the combination of the C3 binding agent (eg, antibody) described herein and at least one additional therapeutic agent may be administered in any order or simultaneously. In some embodiments, the C3 binding agent is administered to subjects (eg, humans) who have previously been treated with a therapeutic agent. In some embodiments, the C3 binding agent and the second therapeutic agent are administered substantially simultaneously or together. For example, a subject (eg, human) may be given a C3 binding agent while undergoing treatment with a second therapeutic agent (eg, an angiogenesis inhibitor). In some embodiments, the C3 binding agent is administered within 1 year of treatment with the second therapeutic agent. In some embodiments, the C3 binding agent is administered within 10, 8, 6, 4, or 2 months after any treatment with the second therapeutic agent. In some embodiments, the C3 binding agent is administered within 4, 3, 2, or 1 weeks after any treatment with the second therapeutic agent. In some embodiments, the C3 binding agent is administered within 5, 4, 3, 2, or 1 days after any treatment with the second therapeutic agent. In addition, it should be understood that two (or more) agents or treatments can be administered to a subject over several hours or minutes (ie, substantially simultaneously).

[00311] For the treatment of a disease, an appropriate dose of a C3 binding agent (e.g., an antibody) of this invention depends on the disorder or disease to be treated, the severity and course of the disorder or disease, the response of the disorder or disease, whether the agent is administered in therapeutic or prophylactic purposes, previous therapy, patient history, etc. The C3 binding agent can be administered once or over a series of treatments lasting from several days to several months, or until a cure is achieved or a reduction in the disease state is achieved.

[00312] The dose of the C3 binding agent (eg, antibody) described herein may vary depending on the nature and/or severity of the disease or disorder, as well as the condition of the subject. In some embodiments, the implementation of the dose of C3-binding agent depends on the site of administration (for example, in the vitreous cavity). In some embodiments, the implementation of the dose of C3-binding agent depends on the delivery system (eg, eye drops). In some embodiments, the dose of the C3 binding agent (eg, antibody) described herein is from about 0.1 mg to about 20 mg. In some embodiments, the dose of the C3 binding agent (eg, antibody) described herein is from about 0.1 mg to about 20 mg into the vitreous cavity. In some embodiments, the dose of the C3 binding agent (eg, antibody) described herein is from about 0.1 mg to about 20 mg, and is delivered by eye drops. In some embodiments, the dosage of the C3 binding agent described herein is from about 1.0 mg to about 10 mg. In some embodiments, the dosage of the C3 binding agent described herein is about 0.1, 0.25, 0.5, 1.0, 1.25, 2.0, 2.5, 3.0, 4 .0, 5.0, 6.0, 7.0, 7.5, 8.0, 9.0, 10.0, 11.0, 12.0, 12.5, 13.0, 14.0 or 15 mg into the vitreous cavity. In some embodiments, the dosage of the C3 binding agent described herein is about 0.1, 0.25, 0.5, 1.0, 1.25, 2.0, 2.5, 3.0, 4 .0, 5.0, 6.0, 7.0, 7.5, 8.0, 9.0, 10.0, 11.0, 12.0, 12.5, 13.0, 14.0 or 15 mg, and is delivered by eye drops.

[00313] In some embodiments, the C3 binding agent (eg, antibody) described herein is administered once a month, once every 2 months, or once every 3 months. In some embodiments, the implementation of the C3-binding agent is administered as a dose once a month. In some embodiments, the C3 binding agent is administered as a dose once every 6 weeks. In some embodiments, the C3 binding agent is administered as a dose once every 2 months. In some embodiments, the C3 binding agent is administered as a dose once every 10 weeks. In some embodiments, the C3 binding agent is administered as a dose once every 3 months.

[00314] In some embodiments, the C3 binding agent (eg, antibody) is administered as a dose using a 30 gauge needle. In some embodiments, the C3 binding agent is administered as a dose using a 30+ gauge needle. In some embodiments, the C3 binding agent is administered in about 25 to about 100 µl (per eye). In some embodiments, the C3 binding agent is administered in about 50 µl (per eye). In some embodiments, the C3 binding agent is administered in about 75 µl (per eye). In some embodiments, the C3 binding agent is administered in about 100 µl (per eye).

[00315] In some embodiments, the C3 binding agent (eg, antibody) is administered as eye drops. In some embodiments, the C3 binding agent is delivered in about 25 to about 100 µl (per eye). In some embodiments, the C3 binding agent is delivered in about 50 µl (per eye). In some embodiments, the C3 binding agent is delivered in about 75 µl (per eye). In some embodiments, the C3 binding agent is delivered in about 100 µl (per eye).

[00316] In some embodiments, the C3 binding agent (eg, antibody) is delivered topically. In certain topical embodiments, the C3 binding agent (eg, antibody) is administered in combination with a cell-penetrating peptide. In certain embodiments, the C3 binding agent (eg, antibody) and the cell-penetrating peptide are delivered as part of the same pharmaceutical composition. Cell-penetrating peptides are known in the art (see, for example, de Cogan et al ., 2017, Investigative Opthamology & Visual Science , 58(5):2578-2590). Non-limiting examples of cell penetrating peptides are described in US Patent Publication Nos. 2019/0015521, 2017/0355730, 2018/0346531, and 2012/0065124.

[00317] This invention provides compositions containing the C3 binding agent (eg, antibody) described herein. The invention also provides pharmaceutical compositions comprising a C3 binding agent as described herein and a pharmaceutically acceptable carrier.

[00318] Formulations are prepared for storage and use by combining the purified antibody or agent of this invention with a pharmaceutically acceptable carrier medium (eg, carrier or excipient). Those skilled in the art generally consider pharmaceutically acceptable carriers, excipients and/or stabilizers to be inactive ingredients of a formulation or pharmaceutical composition.

[00319] Suitable pharmaceutically acceptable carriers include, without limitation, non-toxic buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol; low molecular weight polypeptides (eg, less than 10 amino acid residues); proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; carbohydrates such as monosaccharides, disaccharides, glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes such as Zn-protein complexes; and non-ionic surfactants such as TWEEN or polyethylene glycol. ( Remington: The Science and Practice of Pharmacy, 22nd ^Edition , 2012, Pharmaceutical Press, London.). In some embodiments, the formulation is in the form of an aqueous solution. In some embodiments, the formulation is stored in a lyophilized or alternatively dried form.

[00320] The binding agents of this invention may be formulated in any suitable form for delivery to a cell/target tissue. In some embodiments, the C3 binding agent (eg, antibody) may be formulated as a liposome, microparticle, microcapsule, albumin microsphere, microemulsion, nanoparticle, nanocapsule, or macroemulsion. In some embodiments, the implementation of the pharmaceutical composition includes an agent of this invention in combination with liposomes. Methods for preparing liposomes are known to those skilled in the art. For example, some liposomes can be obtained by reverse phase evaporation with a lipid composition containing phosphatidylcholine, cholesterol and a PEG derivative phosphatidylethanolamine (PEG-PE).

[00321] In some embodiments, the C3 binding agent (eg, antibody) is formulated as a sustained release formulation. Suitable examples of sustained release formulations include semi-permeable matrices of solid hydrophobic polymers containing the agent, the matrices being in form (eg, films or microcapsules). Sustained release matrices include, but are not limited to, polyesters, hydrogels (such as poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene vinyl acetate, degradable copolymers lactic acid and glycolic acid such as LUPRON DEPOT™ (injectable microspheres consisting of a copolymer of lactic acid and glycolic acid and leuprolide acetate), sucrose acetate isobutyrate and poly-D-(-)-3-hydroxybutyric acid.

[00322] Pharmaceutical compositions or formulations of this invention may be administered by any number of routes for both topical and systemic treatment. The introduction can be local in the form of epidermal or transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders; through the pulmonary route of inhalation or inhalation of powders or aerosols, including using a nebulizer, intratracheal and intranasal; oral; or parenteral, including intravenous, intraarterial, intratumoral, subcutaneous, intraperitoneal, intramuscular (eg, injection or infusion), intracranial (eg, intrathecal or intraventricular), ophthalmic, intraocular, or intravitreal.

[00323] In some embodiments of the methods described herein, the C3 binding agent (eg, antibody) described herein is administered by ophthalmic injection. In some embodiments of the methods described herein, the C3 binding agent is administered via intraocular injection. In some embodiments of the methods described herein, the C3 binding agent is administered via intravitreal injection.

EXAMPLES

Example 1

Antibody generation

[00324] Antibodies to C3 were generated using human C3 as an immunogen. Single cell suspensions of lymphocytes were obtained from the spleen and lymph nodes of immunized mice after appropriate antibody titers had been determined in individual animals. Lymphocytes were fused with mouse myeloma cells by standard methods. Cells were dispersed in 96-well plates in selection medium containing HAT. Cell supernatants (approximately 10,000) were tested by ELISA for binding to human C3 and cynomolgus C3. Approximately 1600 cell clones were selected based on the results of the binding assay.

Example 2

Biochemical analysis of alternative C3 pathway

[00325] Anti-C3 antibodies identified in C3 binding assays were tested for their ability to inhibit C3a formation in vitro . C3a is produced by cleaving C3 with the C3 convertase complex. The C3a assay was based on a previously described method (Loyet et al., 2014, J Pharmacol and Exp Ther ; 351:527-537). Briefly, 20 µl of a solution of 50 nM human C3 (Complement Technologies) in GVB (bovine skin gelatin in veronal buffer) was mixed with 20 µl of test anti-C3 antibodies or controls diluted in GVB for 10 minutes. Included controls (i) no C3; (ii) without factor B and factor D; (iii) no inhibitor and (iv) compstatin as a positive control. 100 nM human factor B and 100 nM human factor D (Complement Technologies) in 0.05 M EGTA/0.1 M MgCl2/GVB were added to the C3/Ab samples and the mixtures were incubated for an additional 10 minutes. Added 20 μl of 50% rabbit serum (diluted 1:2 in GVB) and incubated for 10 minutes followed by the addition of 20 μl of 0.5 M EDTA to quench the reaction. The addition of rabbit serum cleaves C3a produced by C3 convertase in reaction mixtures to C3a des Arg (C3a des Arg has been found to be more stable than C3a). The concentrations of C3 des Arg were then measured by ELISA. Briefly, mouse antibody to C3a/C3a des Arg (ThermoFisher) was applied to ELISA plates at a concentration of 1.0 μg/ml and incubated overnight at 4°C. The next day, the plates were washed, 60 μl of SuperBlock blocking buffer (Pierce) was added and incubated for 60 minutes at room temperature. The blocking buffer was decanted from the wells before adding the samples. Samples from C3/Ab reactions were diluted, added to plates and incubated for 90 minutes. The plates were washed, biotinylated anti-human C3/C3a/C3a des Arg antibody (Biolegend) (0.5 μg/ml) was added to the wells and the plates were incubated for 60 minutes. The plates were washed, 20 μl of streptavidin poly-HRP (Pierce) was added to each well and the plates were incubated for 30 minutes. SuperSignal PICO ELISA chemiluminescent substrate (ThermoFisher Scientific) was added to each well for detection. The plates were read on a luminometer with a reading time of 0.2 seconds per well at 425 nm.

[00326] Under these assay conditions, anti-C3 antibodies tested were evaluated for their ability to inhibit the production of C3a des Arg. Several dozen exemplary antibodies have been found to strongly inhibit C3 cleavage and C3a release. The activities of three illustrative antibodies, 38G10, 3D8 and 15C12, at concentrations from 0.1 to 1000 nM are shown in FIG. 1.

Example 3

Hemolysis assays dependent on alternative and classical pathways

[00327] Hemolytic plaque assays have traditionally been used to assess the functional activity of the complement system. For alternative pathway (AP) analysis, rabbit erythrocytes were included with C3 depleted human serum and 50 nM human C3 in the presence of increasing concentrations of anti-C3 antibodies 38G10, 3D8 and 15C12. For classical pathway (CP) analysis, IgM-coated ram erythrocytes were incubated with C3-depleted human serum and increasing concentrations of anti-C3 antibodies 38G10, 3D8 and 15C12 in the presence of 10 nM human C3. Hemolysis was determined by the optical density of the supernatant at 412 nm. The results were expressed as the percentage of hemolysis observed in controls without any inhibitor and can be calculated in IC50. These assays were duplicated using cynomolgus monkey serum as the C3 source.

[00328] The results of AP and CP analyzes using human C3 and cynomolgus C3 for an exemplary antibody array are shown in Table 11 (IC ₅₀ ) and shown in FIG. 2 for 38G10, 3D8 and 15C12 antibodies (% hemolysis).

Table 11

Antibody Hemolytic plaque test, IC ₅₀ (nM) Human AP Human CP AP of the cynomolgus macaque CP cynomolgus monkey 3D8 4.2 3.6 5.5 BUT 3G8 6.8 10.4 20.9 102.5 15C12 3.7 3.8 8.8 BUT 27A8 8.5 7.6 9.6 BUT 28C3 8.0 6.5 7.8 3.4 38F5 9.2 6.7 12.9 2.3 38G10 1.9 1.7 3.5 BUT 62B11 6.6 4.2 ~11.0 ~1.0 62F2 5.7 5.0 8.7 5.3 63A3 6.5 4.1 3.4 1.6

BUT - not defined

[00329] These results demonstrate that anti-C3 antibodies inhibit the activation of both alternative and classical pathways as demonstrated by inhibition of hemolysis.

Example 4

Binding affinity

[00330] The binding affinity of exemplary anti-C3 antibodies to human C3 and cynomolgus monkey C3 was measured using the Biacore system (GE Healthcare LifeSciences). Briefly, an anti-Fc antibody (Sigma-Aldrich) was immobilized on all four flow cells of the CM5 chip using amine coupling reagents (GE Healthcare LifeSciences). Antibodies were captured on flow cells 2, 3 and 4 using flow cell 1 as a reference. Concentrations of 0.62 to 40 nM human C3 or cynomolgus C3 were injected at a flow rate of 50 μl/min at 37°C. Kinetic data were collected over time and fitted using a simultaneous global fit equation to obtain affinity constants (K _D values) for each antibody.

[00331] Table 12 shows the binding affinities for antibodies 38G10, 3D8 and 15C12.

Table 12

Binding affinity, K _D (nM) Antibody C3 human C3 cynomolgus macaque 38G10 0.19 0.16 3D8 1.90 1.40 15C12 0.13 0.13

Example 5

Binding Profile

[00332] Anti-C3 antibodies described herein were characterized by their ability to bind a number of other components of the complement cascade. Antibodies were tested for binding to C3, C3a, C3b, C3c, C3d, iC3b and factor Bb. An exemplary set of results is shown in Table 13. All C3 antibodies included in Table 13 were able to block complement activation. Data are presented in comparison to the binding of the mIgG2 antibody as a negative control.

Table 13

C3 C3a C3b C3c c3d iC3b Bb factor 3D8 0.47 -0.01 0.38 0.17 0.01 0.29 -0.01 3G8 0.37 -0.01 0.33 0.22 0.00 0.25 0.00 28C3 0.66 0.11 0.09 0.28 0.01 0.01 0.00 38F5 0.83 0.00 0.66 0.45 0.01 0.45 -0.01 38G10 0.53 0.02 0.06 0.13 0.00 0.06 0.01 62B11 0.83 -0.03 0.76 0.49 -0.02 0.54 -0.02 62F2 0.7 -0.04 0.61 0.43 0.01 0.49 0.00 63A3 0.95 -0.02 0.83 0.55 0.01 0.72 0.00 Control
mIgG2 0.00 0.00 0.00 0.00 0.00 0.00 0.00

[00333] These data indicate that the 38G10 antibody had a unique C3 binding profile in that it binds preferentially to C3 with no detectable or very limited binding to any of the fragments of the complement cascade.

Example 6

Anti-C3 antibody sequence analysis

[00334] Antibodies 3D8, 3G8, 15C12, 27A8, 28C3, 38F5, 38G10, 62B11, 62F2, and 63A3 were sequenced, and the amino acid sequences of the heavy chain variable region and the light chain variable region are disclosed herein and are presented in Table 14.

Table 14

Antibody Heavy chain variable region Light chain variable region 3D8 SEQ ID NO: 91 SEQ ID NO: 92 3G8 SEQ ID NO: 93 SEQ ID NO: 94 15C12 SEQ ID NO: 95 SEQ ID NO: 96 27A8 SEQ ID NO: 97 SEQ ID NO: 98 28C3 SEQ ID NO: 99 SEQ ID NO: 100 38F5 SEQ ID NO: 101 SEQ ID NO: 102 38G10 SEQ ID NO: 18 SEQ ID NO: 19 62B11 SEQ ID NO: 103 SEQ ID NO: 104 62F2 SEQ ID NO: 105 SEQ ID NO: 106 63A3 SEQ ID NO: 107 SEQ ID NO: 108

[00335] The heavy chain and light chain CDRs for individual antibodies are disclosed in Tables 1-10 and as SEQ ID NOs: 7-12, 38-90, and 120-228.

[00336] Based on antibody characterization data, as well as additional studies, the 38G10 antibody was selected for humanization (CDRs disclosed in Table 1A and the heavy chain variable region and light chain variable region amino acid sequences disclosed herein as SEQ ID NO: 18 and SEQ ID NO:19, respectively).

Example 7

Generation of Humanized Antibody

[00337] The 38G10 antibody has been humanized by methods known to those skilled in the art, and the humanized 38G10 is referred to herein as Hz38G10. The 38G10 antibody was found to have a potential glycosylation site in the heavy chain variable region CDR2, YIYPHNGGTTYNQ NFT G (SEQ ID NO:8). The consensus glycosylation site for N-linked glycans is NXS/T, where X can be any amino acid other than proline. During the humanization process, the heavy chain CDR2 was re-engineered to remove the glycosylation site, resulting in an antibody Hz38G10 containing a heavy chain CDR2 containing YIYPHNGGTTYNQQFTG (SEQ ID NO:13). The heavy chain variable region sequence of the Hz38G10 antibody is SEQ ID NO: 20 and the light chain variable region sequence is SEQ ID NO: 25; CDRs are disclosed in Table 1B.

Example 8

Characteristic Hz38G10

[00338] The binding affinity of Hz38G10 was determined using the Biacore system as described herein and compared to the binding affinity of the parent 38G10 antibody. The Hz38G10 antibody had a binding affinity for human C3 of 0.3 nM and for cynomolgus monkey C3 of 1.8 nM compared to a parent antibody binding affinity of approximately 0.1 nM for both human and cynomolgus C3. macaque (at 37°C). These results demonstrated that the humanization process of the 38G10 antibody, as well as the removal of the glycosylation site in the heavy chain CDR2, did not significantly affect the ability to bind to human C3 or cynomolgus C3.

[00339] Hz38G10 was formulated in two different buffers and evaluated for viscosity at high concentrations. The first buffer formulation was 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20 and 5% sucrose at pH 6.2. Hz38G10 was concentrated to 164 mg/ml with a viscosity of 15.2 mPa-s (RheoSense). The second buffer formulation was 10 mM histidine HCl, 10% α,α trehalose dihydrate, and 0.01% polysorbate 20 at pH 5.5. Hz38G10 was concentrated to 152 mg/ml with a viscosity of 17.6 mPa-s. These results demonstrate that Hz38G10 maintains acceptable viscosity at high compound concentrations.

[00340] Due to the lack of anti-C3 antibodies in the clinic or licensed by the FDA, the binding affinity of Hz38G10 to human C3 was compared to compstatin, a 13-residue cyclic peptide with potent C3 inhibitory activity that was identified several years ago (Morikis et al., 1998, Protein Science ; 7:619-627). More recently, a number of analogues and derivatives of compstatin have been generated and studied. The binding affinity of Hz38G10 to human C3 was compared to the binding affinity of the compstatin derivative (referred to herein as "COMP") and the pegylated version of the compstatin derivative (referred to herein as "COMP-PEG"). The Biacore system was used to evaluate the binding affinity of various molecules to human C3. The binding affinity of Hz38G10 to human C3 at 25°C and 37°C was performed as described in Example 4. The evaluation of COMP or COMP-PEG binding to human C3 was performed as follows. Human C3 was immobilized on flow cell 2 of the CM5 chip using amine binding reagents (GE Healthcare LifeSciences) and flow cell 1 (immobilized with the same amount of human IgG) was used as a reference. Concentrations ranging from 1.56 to 100 nM COMP were injected at a flow rate of 50 μl/min to assess binding affinity at 25°C and 37°C. Similar experiments were performed with COMP-PEG (concentration range 25-400 nM) for evaluation at 37°C. The binding of COMP-PEG to human C3 was also evaluated at 25° C. with modifications. Briefly, rat anti-PEG antibodies (Abcam Inc.) were immobilized on the surface of the CM5 chip using amine coupling reagents and COMP-PEG was captured in flow cell 2. Human C3 (concentration range 12-100 nM) was injected at a flow rate of 50 µl/ min. Kinetic data were collected over time and fitted using a simultaneous global fitting equation to obtain affinity constants (K _D values) for each antibody.

[00341] A set of illustrative results is presented in Table 15.

Table 15

Hz38G10 COMP COMP-PEG K _D (25°C), nM <0.1 7.1 55 K _D (37°C), nM 0.28 21 490

[00342] These results suggest that the Hz38G10 antibody binds to human C3 with significantly greater affinity than the compstatin derivative or the pegylated version (approximately 50-80 times more).

[00343] To confirm that the humanized version of the 38G10 antibody retained the ability to inhibit complement activation, Hz38G10 was evaluated in alternative and classical pathway dependent hemolysis assays as described herein and compared to COMP and COMP-PEG. Hz38G10 and COMP or Hz38G10 antibody and COMP-PEG were tested for their ability to inhibit hemolysis in assays.

[00344] As shown in FIG. 3 and 4 and in Table 16, the results of these experiments demonstrated that the Hz38G10 antibody was more effective at inhibiting complement activation than the compstatin derivative or the pegylated version of the compstatin derivative. The Hz38G10 antibody had similar inhibitory activity in both the classical and alternative pathways. In contrast, COMP and COMP-PEG appear to have more activity in the alternative pathway than in the classical pathway. The Hz38G10 antibody was approximately 10 times more effective than COMP or COMP-PEG in inhibiting the alternative pathway, and approximately 40-60 times more effective than compstatin derivatives in inhibiting the classical pathway.

Table 16

classic way
IC50 (nM) Alternative path
IC50 (nM) Hz38G10 2 2.5 COMP 90 23 Hz38G10 4.1 4.0 COMP-PEG 272 41.8

[00345] An additional experiment was performed to determine if the Hz38G10 antibody and the compstatin derivative (COMP) bind to the same or similar region on human C3. COMP was immobilized on the CM5 chip using amine coupling reagents (GE Healthcare LifeSciences) at high density (approximately 3000 RU). Individual reactions in a 96-well human C3 plate (5 nM) were titrated with increasing concentrations of Hz38G10 or COMP antibody (0.05-100 nM). After incubation for approximately 3 hours at room temperature, C3-COMP or C3-Hz38G10 reaction mixtures were applied to COMP-coated surfaces.

[00346] As shown in FIG. 5, increasing COMP concentration decreased C3 binding to the COMP surface due to self-blocking (positive control). However, an increase in the concentration of Hz38G10 did not prevent C3 from binding to the chip surface coated with COMP. The results of this experiment showed that the Hz38G10 antibody and COMP bind different epitopes on human C3.

Example 9

Generation and characterization of Hz38G10 variants

[00347] Sequence analysis of the heavy chain CDRs of the Hz38G10 antibody identified a potential site for deamidation within CDR2, YIYPH NG GTTYNQQFTG (SEQ ID NO:13). An elevated pH stress test was performed at pH 8.5 and the deamidation of asparagine (N55 SEQ ID NO: 20) was determined to be 29.75% on day 0 and 48.23% on day 7 (an increase of 18.5 %). A variant of the Hz38G10 antibody was generated with the N55D mutation in the heavy chain CDR2, a change that would mimic a fully deamidated molecule. This antibody, Hz38G10 (N55D), was tested for binding to human C3 using the Biacore system as described herein and was shown to have reduced binding compared to Hz38G10.

[00348] Four additional Hz38G10 variants were generated with amino acid substitutions in the heavy chain CDR2 at position N55 or G56 of SEQ ID NO: 20. The Hz38G10 variants contained (i) the N55E mutation, heavy chain CDR2 YIYPHEGGTTYNQQFTG (SEQ ID NO:16); (ii) mutation N55Q, heavy chain CDR2 YIYPHQGGTTYNQQFTG (SEQ ID NO:17); (iii) mutation G56A, heavy chain CDR2 YIYPHNAGTTYNQQFTG (SEQ ID NO:14), or (iv) mutation G56T heavy chain CDR2 YIYPHNTGTTYNQQFTG (SEQ ID NO:15). The heavy chain variable region sequence of the antibody Hz38G10(G56A) is SEQ ID NO:21, Hz38G10(G56T) is SEQ ID NO:22, Hz38G10(N55E) is SEQ ID NO:23, and Hz38G10(N55Q) is SEQ ID NO:24; the light chain variable region sequence for all variants is SEQ ID NO:25; CDRs are shown in Table 1C.

[00349] These antibodies, Hz38G10 (N55E), Hz38G10 (N55Q), Hz38G10 (G56A), and Hz38G10 (G56T), were assayed for binding to human C3 using the Biacore system as described herein and compared to the Hz38G10 antibody. The results are presented in table 17.

Table 17

Antibody KD binding (nM) Hz38G10 0.30 Hz38G10 (N55E) 6.20 Hz38G10 (N55Q) 0.82 Hz38G10 (G56A) 0.27 Hz38G10 (G56T) 0.23

[00350] These results demonstrate that a mutation at position G56 retains binding affinity to a greater extent than a mutation at position N55.

[00351] To determine if changing from glycine to alanine at position 56 of the heavy chain variable region (SEQ ID NO: 20) reduces deamidation at CDR2, a pH stress test was performed with the Hz38G10 antibody (G56A) as described above. For this variant, the N55 deamidation of Hz38G10 (G56A) (SEQ ID NO: 21) was determined to be 0.66% on day 0 and 1.0% on day 7. These results demonstrated that the Hz38G10 (G56A) antibody was very stable under deamidation stress conditions.

[00352] To determine if the Hz38G10 (G56A) antibody retains the ability to inhibit complement activation, the antibody was evaluated in the alternative and classical pathway hemolysis assay as described herein and compared to the Hz38G10 antibody. Hz38G10 and Hz38G10 (G56A) were tested for their ability to inhibit hemolysis in assays.

[00353] As shown in Table 18, the Hz38G10 (G56A) antibody showed almost identical inhibitory activity compared to the Hz38G10 antibody for human C3 and cynomolgus C3.

Table 18

Antibody classic way
IC50 (nM) Alternative path
IC50 (nM) C3 human Hz38G10 5.2 3.9 Hz38G10 (G56A) 5.4 3.9 C3 cynomolgus macaque Hz38G10 0.7 4.8 Hz38G10 (G56A) 0.6 4.8

Example 10

Pharmacokinetics of Hz38G10 antibody

[00354] The pharmacokinetics (PK) of the anti-C3 antibody Hz38G10 was evaluated in New Zealand white rabbits at a dose of 1 or 7.5 mg. The Hz38G10 antibody was administered by intravitreal injection (IVT) at a single dose of 50 μl/eye. Samples were taken at 1 and 8 hours, and on days 2, 4, 8, 15 and 22 (4 eyes/time point). The concentration of Hz38G10 was assessed in the vitreous body, intraocular fluid and retina.

[00355] As shown in Table 19, the vitreous half-life of Hz38G10 was approximately 4-5 days.

Table 19

Dose Hz38G10 Cmax
(µg/ml) AUC
(day mcg/ml) T _1/2
(day) 1.0 mg 541 3140 4.1 7.5 mg 5680 33049 5.3

[00356] The PK of Hz38G10 is similar to the registered PK of bevacizumab and aflibercept in the vitreous of rabbits. In addition, the distribution of Hz38G10 in the retina was approximately 20% of the vitreous for both Cmax and AUC.

Example 11

scFv generation Hz38G10

[00357] An scFv version of an exemplary anti-C3 antibody was generated. ScFv molecules based on the heavy chain variable region (VH) and the light chain variable region (VL) of Hz38G10 were designed in two orientations, with or without disulfide stabilization. Four molecules: (i) VL linker-VH scFv, (ii) VH linker-VL scFv, (iii) VL linker-VH dsscFv and (iv) VH linker-VL dsscFv, where dsscFv is scFv with an engineered disulfide connection between the VL and VH regions. These four molecules were tested in the E. coli expression system, and based on several parameters, such as expression titer and monomer percentage, the VL-linker-VH dsscFv molecule was selected for further study and characterization. The sequence of dsscFv Hz38G10 is disclosed herein as SEQ ID NO: 113.

[00358] dsscFv Hz38G10 antibodies were produced by expression as inclusion bodies. E. coli BL21(DE3) was transformed with a plasmid encoding Hz38G10 VL-linker-VH dsscFv, hereinafter referred to as Hz38G10 dsscFv. Transformed E. coli BL21(DE3) were collected by low speed centrifugation. The bacteria pellet was resuspended by magnetic stirring in 50 mM Tris-HCl, pH 7.5 for 15 minutes at room temperature. To destroy the cells, the suspension was passed 3 times through a microfluidizer at 200 bar. Inclusion bodies were recovered from disrupted cells by centrifugation at 4° C. in a fixed angle rotor operating at 13,000 g for 45 minutes. The resultant inclusion body pellet was washed with Milli-Q® cold water until lipids and cell wall layers were removed. The sediment of the washed inclusion bodies was resuspended in 5 volumes of Milli-Q® water by stirring on a magnetic stirrer and collected by centrifugation at 13,000 xg for 30 minutes. The washed inclusion bodies were solubilized in 10 volumes of 8 M guanidine-HCl, 50 mM Tris-HCl, pH 7.5, 1 mM TCEP using a magnetic stirrer and incubated overnight at 4°C. The following day, a Downs homogenizer with free pestle was used to resuspend any remaining inclusion solids. Solubilized inclusion bodies were diluted dropwise 1:25 in refolding buffer (3 M urea, 50 mM Tris-HCl pH 8.0, 160 mM L-arginine, 1 mM cysteine, 3 mM cystamine) with gentle stirring with a magnetic stirrer at room temperature to a final concentration of 0.1 mg/ml. Refolding was performed for 48 hours at 4° C. and disulfide bond formation was monitored by SDS-PAGE under non-reducing conditions. The solution containing the refolded dsscFv was concentrated 5-fold by ultrafiltration/diafiltration (UF/DF) on a tangential NMWCO 0.22 m ² and 10,000 Da filter membrane. The concentrate was purified from misfolded dsscFv by rapid acidification to pH 2.8 with 4 volumes of 100 mM glycine, pH 2.5. The solution was maintained at pH 2.8 as the solution was further concentrated 5 times. After 15 minutes, the pH was quickly returned to neutral by adding a concentrated Tris-HCl solution. The resulting acid-treated solution was buffer exchanged with divolumes of protein-L affinity binding buffer (50 mM Tris-HCl pH 7.5, 50 mM NaCl). The recovered diafiltration product was purified from the precipitate by centrifugation at 13,000 g for 45 minutes at 4° C. and then filtered using a 0.2 μm membrane.

[00359] dsscFv Hz38G10 antibodies were purified in two chromatography steps: (i) protein L affinity column for capture and (ii) cation exchange column (CEX) for polishing. For protein L affinity chromatography, a suspension containing dsscFv Hz38G10 was applied to a 5 ml MiniChrom TOYOPEARL® AF-rProtein L-650F column (Tosoh Bioscience), washed thoroughly with Tris buffered saline, and eluted with a stepwise gradient of 100 mM glycine, pH 2.5 . The resulting elution pool (pool M) was dialyzed against CEX binding buffer (20 mM sodium acetate, pH 5.0). The dialyzed M pool was loaded onto a HiTrap® SP HP cation exchange column (GE Healthcare), washed with 20 mM sodium acetate, pH 5.0, and eluted with an isocratic gradient of 50 sodium chloride in 20 mM sodium acetate, pH 5.0. Fractions enriched in dsscFv Hz38G10 were pooled and evaluated by SDS-PAGE and SEC analytical methods. Subsequently, the dsscFv Hz38G10 (G56A) antibody (SEQ ID NO: 114) was generated using the same general methods.

Example 12

Specification dsscFv Hz38G10

[00360] The solubility parameters of dsscFv Hz38G10 were investigated. Purified antibodies were dialyzed into a buffer consisting of 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20 and 5% sucrose, pH 6.2. The solution was microconcentrated using a NMWCO 10000 Da centrifugal concentrator at 3000 g at room temperature. Protein concentration was measured on an Agilent Cary 60 UV-VIS Solo VPE spectrophotometer. The protein concentration reached 229 mg/ml without visible aggregation.

[00361] dsscFv Hz38G10 was compared with intact Hz38G10 antibody and Fab version of Hz38G10 in several assays. Binding affinity to human C3 was assessed using the Biacore system as described herein. In addition, inhibition of the alternative pathway and the classical pathway by three antibodies was assessed in hemolysis assays as described herein.

[00362] The results are shown in Table 20.

Table 20

Antibody Hz38G10 K _D (pM) AP C3 human
IC ₅₀ (nM) CP C3 human
IC ₅₀ (nM) Intact antibody 27 5.9 4.0 fab BUT 16 17.8 dsscFv 35 19.5 15.3

[00363] These results showed that dsscFv Hz38G10 had a similar K _D compared to intact antibody. In addition, dsscFv Hz38G10 had a similar level of inhibition of hemolytic activity in both the AP and CP pathways compared to the intact antibody or Fab version. It should be noted that the intact Hz38G10 antibody has two antigen-binding sites, while the Fab and dsscFv antibodies have only one antigen-binding site.

Example 13

Inhibition of C3 activation in vivo

[00364] To evaluate the ability of anti-C3 antibodies to block C3 activation in the eye, Hz38G10 was tested in an LPS-induced complement activation model in cynomolgus monkeys. In normal cynomolgus monkeys, C3 activation is minimal and therefore the inhibitory effects of an anti-C3 antibody on C3 activation cannot be reliably assessed under these conditions. It is known that LPS can activate the complement system, and a pilot study confirmed that complement C3 was activated by intravitreal injection (IVT) of LPS. Using this LPS-induced C3 activation model, the effects of Hz38G10 on C3 activation were evaluated.

[00365] Twelve normal female cynomolgus monkeys (8 to 17 years of age) were divided into 2 groups of 6 animals per group. The initial sample of the intraocular fluid was taken on day -3. On day 1, animals were injected into both eyes with a single IVT dose of either vehicle or Hz38G10 at a dose of 5 mg/eye at a dose volume of 67 μl/eye. On day 3, the animals were intravitreally injected with LPS at a dose of 30 ng/eye in a volume of 50 μl/eye. On the 5th, 8th, 13th, and 18th days, eye fluid samples were taken. Ocular fluid C3a concentrations were determined using a human complement C3a ELISA kit (Invitrogen) according to the manufacturer's instructions.

[00366] As shown in FIG. 6, LPS induced a significant increase in intraocular fluid C3a in both groups of animals compared to baseline (-3 days). Animals treated with Hz38G10 exhibited significantly lower levels of C3a compared to animals treated with vehicle.

[00367] These results demonstrate that an anti-C3 antibody is able to functionally inhibit complement activation in the eye.

[00368] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the present invention. The embodiments of the invention described herein are by way of example only, and those skilled in the art will recognize numerous equivalents to the specific procedures described herein. All such equivalents are considered to be within the scope of this invention and are covered by the embodiments.

[00369] All cited publications, patents, patent applications, Internet sites, and access numbers/database sequences, including both polynucleotide and polypeptide sequences, are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, website, or access number/database sequence were specifically and individually identified for inclusion as a reference.

[00370] The following are the sequences disclosed in the application. The CDR sequences are shown in Tables 1-10.

Human C3 amino acid sequence with predictive signal sequence underlined (SEQ ID NO:1)

MGPTSGPSLLLLLTHLPLALG SPMYSIITPNILRLESEETMVLEAHDAQGDVPVTVTVH

DFPGKKLVLSSEKTVLTPATNNHMGNVTFTIPANREFKSEKGRNKFVTVQATFGTQVVEKV

VLVSLQSGYLFIQTDKTIYTPGSTVLYRIFTVNHKLLPVGRTVMVNIENPEGIPVKQDSL

SSQNQLGVLPLSWDIPELVNMGQWKIRAYYENSPQQVFSTEFEVKEYVLPSFEVIVEPTE

KFYYIYNEKGLEVTITARFLYGKKVEGTAFVIFGIQDGEQRISLPESLKRIPIEDGSGEV

VLSRKVLLDGVQNPRAEDLVGKSLYVSATVILHSGSDMVQAERSGIPIVTSPYQIHFTKT

PKYFKPGMPFDLMVFVTNPDGSPAYRVPVAVQGEDTVQSLTQGDGVAKLSINTHPSQKPL

SITVRTKKQELSEAEQATRTMQALPYSTVGNSNNYLHLSVLRTELRPGETLNVNFLLRMD

RAHEAKIRYYTYLIMNKGRLLKAGRQVREPGQDLVVLPLSITTDDFIPSFRLVAYYTLIGA

SGQREVVADSVWVDVKDSCVGSLVVKSGQSEDRQPVPGQQMTLKIEGDHGARVVLVAVDK

GVFVLNKKNKLTQSKIWDVVEKADIGCTPGSGKDYAGVFSDAGLTFTSSSGQQTAQRAEL

QCPQPAARRRRSVQLTEKRMDKVGKYPKELRKCCEDGMRENPMRFSCQRRTRFISLGEAC

KKVFLDCCNYITELRRQHARASHLGLARSNLDEDIIAEENIVSRSEFPESWLWNVEDLKE

PPKNGISTKLMNIFLKDSITTWEILAVSMSDKKGICVADPFEVTVMQDFFIDLRLPYSVV

RNEQVEIRAVLYNYRQNQELKVRVELLHNPAFCSLATTKRRHQQTVTIPPKSSLSVPYVI

VPLKTGLQEVEVKAAVYHHFISDGVRKSLKVVPEGIRMNKTVAVRTLDPERLGREGVQKE

DIPPADLSDQVPDTESETRILLQGTPVAQMTEDAVDAERLKHLIVTPSGCGEQNMIGMTP

TVIAVHYLDETEQWEKFGLEKRQGALELIKKGYTQQLAFRQPSSAFAAFVKRAPSTWLTA

YVVKVFSLAVNLIAIDSQVLCGAVKWLILEKQKPDGVFQEDAPVIHQEMIGGLRNNNEKD

MALTAFVLISLQEAKDICEEQVNSLPGSITKAGDFLEANYMNLQRSYTVAIAGYALAQMG

RLKGPLLNKFLTTAKDKNRWEDPGKQLYNVEATSYALLALLQLKDFDFVPPVVRWLNEQR

YYGGGYGSTQATFMVFQALAQYQKDAPDHQELNLDVSLQLPSRSSKITHRIHWESASLLR

SEETKENEGFTVTAEGKGQGTLSVVTMYHAKAKDQLTCNKFDLKVTIKPAPETEKRPQDA

KNTMILEICTRYRGDQDATMSILDISMMTGFAPDTDDLKQLANGVDRYISKYELDKAAFSD

RNTLIIYLDKVSHSEDDCLAFKVHQYFNVELIQPGAVKVYAYYNLEESCTRFYHPEKEDG

KLNKLCRDELCRCAEENCFIQKSDDKVTLEERLDKACEPGVDYVYKTRLVKVQLSNDFDE

YIMAIEQTIKSGSDEVQVGQQRTFISPIKCREALKLEEKKHYLMWGLSSSDFWGEKPNLSY

IIGKDTWVEHWPEEDECQDEENQKQCQDLGAFTESMVVFGCPN

Human C3 amino acid sequence without predicted signal sequence (SEQ ID NO:2)

SPMYSIITPNILRLESEETMVLEAHDAQGDVPVTVTVHDFPGKKLVLSSEKTVLTPATNH

MGNVTFTIPANREFKSEKGRNKFVTVQATFGTQVVEKVVLVSLQSGYLFIQTDKTIYTPG

STVLYRIFTVNHKLLPVGRTVMVNIENPEGIPVKQDSLSSQNQLGVLPLSWDIPELVNMG

QWKIRAYYENSPQQVFSTEFEVKEYVLPSFEVIVEPTEKFYYIYNEKGLEVTITARFLYG

KKVEGTAFVIFGIQDGEQRISLPESLKRIPIEDGSGEVVLSRKVLLDGVQNPRAEDLVGK

SLYVSATVILHSGSDMVQAERSGIPIVTSPYQIHFTKTPKYFKPGMPFDLMVFVTNPDGS

PAYRVPVAVQGEDTVQSLTQGDGVAKLSINTHPSQKPLSITVRTKKQELSEAEQATRTMQ

ALPYSTVGNSNNYLHLSVLRTELRPGETLNVNFLLRMDRAHEAKIRYYTYLIMNKGRLLK

AGRQVREPGQDLVVLPLSITTDFIPSFRLVAYYTLIGASGQREVVADSVWVDVKDSCVGS

LVVKSGQSEDRQPVPGQQMTLKIEGDHGARVVLVAVDKGVFVLNKKNKLTQSKIWDVVEK

ADIGCTPGSGKDYAGVFSDAGLTFTSSSGQQTAQRAELQCPQPAARRRRSVQLTEKRMDK

VGKYPKELRKCCEDGMRENPMRFSCQRRTRFISLGEACKKVFLDCCNYITELRRQHARAS

HLGLARSNLDEDIIAEENIVSRSEFPESWLWNVEDLKEPPKNGISTKLMNIFLKDSITTW

EILAVSMSDKKGICVADPFEVTVMQDFFIDLRLPYSVVRNEQVEIRAVLYNYRQNQELKV

RVELLHNPAFCSLATTKRRHQQTVTIPPKSSLSVPYVIVPLKTGLQEVEVKAAVYHHFIS

DGVRKSLKVVPEGIRMNKTVAVRTLDPERLGREGVQKEDIPPADLSDQVPDTESETRILL

QGTPVAQMTEDAVDAERLKHLIVTPSGCGEQNMIGMTPTVIAVHYLDETEQWEKFGLEKR

QGALELIKKGYTQQLAFRQPSSAFAAFVKRAPSTWLTAYVVKVFSLAVNLIAIDSQVLCG

AVKWLILEKQKPDGVFQEDAPVIHQEMIGGLRNNNEKDMALTAFVLISLQEAKDICEEQV

NSLPGSITKAGDFLEANYMNLQRSYTVAIAGYALAQMGRLKGPLLNKFLTTAKDKNRWED

PGKQLYNVEATSYALLALLQLKDFDFVPPVVRWLNEQRYYGGGYGSTQATFMVFQALAQY

QKDAPDHQELNLDVSLQLPSRSSKITHRIHWESASLLRSEETKENEGFTVTAEGKGQGTL

SVVTMYHAKAKDQLTCNKFDLKVTIKPAPETEKRPQDAKNTMILEICTRYRGDQDATMSI

LDISMMTGFAPDTDDLKQLANGVDRYISKYELDKAFSDRNTLIIYLDKVSHSEDDCLAFK

VHQYFNVELIQPGAVKVYAYYNLEESCTRFYHPEKEDGKLNKLCRDELCRCAEENCFIQK

SDDKVTLEERLDKACEPGVDYVYKTRLVKVQLSNDFDEYIMAIEQTIKSGSDEVQVGQQR

TFISPIKCREALKLEEKKHYLMWGLSSSDFWGEKPNLSYIIGKDTWVEHWPEEDECQDEEN

QKQCQDLGAFTESMVVFGCPN

Human C3 and C3b Beta Chain (Amino Acids 23-667) (SEQ ID NO: 3)

SPMYSIITPNILRLESEETMVLEAHDAQGDVPVTVTVHDFPGKKLVLSSEKTVLTPATNH

MGNVTFTIPANREFKSEKGRNKFVTVQATFGTQVVEKVVLVSLQSGYLFIQTDKTIYTPG

STVLYRIFTVNHKLLPVGRTVMVNIENPEGIPVKQDSLSSQNQLGVLPLSWDIPELVNMG

QWKIRAYYENSPQQVFSTEFEVKEYVLPSFEVIVEPTEKFYYIYNEKGLEVTITARFLYG

KKVEGTAFVIFGIQDGEQRISLPESLKRIPIEDGSGEVVLSRKVLLDGVQNPRAEDLVGK

SLYVSATVILHSGSDMVQAERSGIPIVTSPYQIHFTKTPKYFKPGMPFDLMVFVTNPDGS

PAYRVPVAVQGEDTVQSLTQGDGVAKLSINTHPSQKPLSITVRTKKQELSEAEQATRTMQ

ALPYSTVGNSNNYLHLSVLRTELRPGETLNVNFLLRMDRAHEAKIRYYTYLIMNKGRLLK

AGRQVREPGQDLVVLPLSITTDFIPSFRLVAYYTLIGASGQREVVADSVWVDVKDSCVGS

LVVKSGQSEDRQPVPGQQMTLKIEGDHGARVVLVAVDKGVFVLNKKNKLTQSKIWDVVEK

ADIGCTPGSGKDYAGVFSDAGLTFTSSSGQQTAQRAELQCPQPAA

Human C3 alpha chain (amino acids 672-1663) (SEQ ID NO: 4)

SVQLTEKRMDKVGKYPKELRKCCEDGMRENPMRFSCQRRTRFISLGEACKKVFLDCCNYI

TELRRQHARASHLGLARSNLDEDIIAEENIVSRSEFPESWLWNVEDLKEPPKNGISTKLM

NIFLKDSITTWEILAVSMSDKKGICVADPFEVTVMQDFFIDLRLPYSVVRNEQVEIRAVL

YNYRQNQELKVRVELLHNPAFCSLATTKRRHQQTVTIPPKSSLSVPYVIVPLKTGLQEVE

VKAAVYHHFISDGVRKSLKVVPEGIRMNKTVAVRTLDPERLGREGVQKEDIPPADLSDQV

PDTESETRILLQGTPVAQMTEDAVDAERLKHLIVTPSGCGEQNMIGMTPTVIAVHYLDET

EQWEKFGLEKRQGALELIKKGYTQQLAFRQPSSAFAAFVKRAPSTWLTAYVVKVFSLAVN

LIAIDSQVLCGAVKWLILEKQKPDGVFQEDAPVIHQEMIGGLRNNNEKDMALTAFVLISL

QEAKDICEEQVNSLPGSITKAGDFLEANYMNLQRSYTVAIAGYALAQMGRLKGPLLNKFL

TTAKDKNRWEDPGKQLYNVEATSYALLALLQLKDFDFVPPVVRWLNEQRYYGGGYGSTQA

TFMVFQALAQYQKDAPDHQELNLDVSLQLPSRSSKITHRIHWESASLLRSEETKENEGFT

VTAEGKGQGTLSVVTMYHAKAKDQLTCNKFDLKVTIKPAPETEKRPQDAKNTMILEICTR

YRGDQDATMSILDISMMTGFAPDTDDLKQLANGVDRYISKYELDKAFSDRNTLIIYLDKV

SHSEDDCLAFKVHQYFNVELIQPGAVKVYAYYNLEESCTRFYHPEKEDGKLNKLCRDELC

RCAEENCFIQKSDDKVTLEERLDKACEPGVDYVYKTRLVKVQLSNDFDEYIMAIEQTIKS

GSDEVQVGQQRTFISPIKCREALKLEEKKHYLMWGLSSSDFWGEKPNLSYIIGKDTWVEHW

PEEDECQDEENQKQCQDLGAFTESMVVFGCPN

Human C3b alpha chain (amino acids 749-1663) (SEQ ID NO: 5)

SNLDEDIIAEENIVSRSEFPESWLWNVEDLKEPPKNGISTKLMNIFLKDSITTWEILAVS

MSDKKGICVADPFEVTVMQDFFIDLRLPYSVVRNEQVEIRAVLYNYRQNQELKVRVELLH

NPAFCSLATTKRRHQTVTIPPKSSLSVPYVIVPLKTGLQEVEVKAAVYHHFISDGVRKS

LKVVPEGIRMNKTVAVRTLDPERLGREGVQKEDIPPADLSDQVPDTESETRILLQGTPVA

QMTEDAVDAERLKHLIVTPSGCGEQNMIGMTPTVIAVHYLDETEQWEKFGLEKRQGALEL

IKKGYTQQLAFRQPSSAFAAFVKRAPSTWLTAYVVKVFSLAVNLIAIDSQVLCGAVKWLI

LEKQKPDGVFQEDAPVIHQEMIGGLRNNNEKDMALTAFVLISLQEAKDICEEQVNSLPGS

ITKAGDFLEANYMNLQRSYTVAIAGYALAQMGRLKGPLLNKFLTTAKDKNRWEDPGKQLY

NVEATSYALLALLQLKDFDFVPPVVRWLNEQRYYGGGYGSTQATFMVFQALAQYQKDAPD

HQELNLDVSLQLPSRSSKITHRIHWESASLLRSEETKENEGFTVTAEGKGQGTLSVVTMY

HAKAKDQLTCNKFDLKVTIKPAPETEKRPQDAKNTMILEICTRYRGDQDATMSILDISMM

TGFAPDTDDLKQLANGVDRYISKYELDKAFSDRNTLIIYLDKVSHSEDDCLAFKVHQYFN

VELIQPGAVKVYAYYNLEESCTRFYHPEKEDGKLNKLCRDELCRCAEENCFIQKSDDKVT

LEERLDKACEPGVDYVYKTRLVKVQLSNDFDEYIMAIEQTIKSGSDEVQVGQQRTFISPI

KCREALKLEEKKHYLMWGLSSSDFWGEKPNLSYIIGKDTWVEHWPEEDECQDEENQKQCQD

LGAFTESMVVFGCPN

Human C3a (amino acids 672-748) (SEQ ID NO: 6)

SVQLTEKRMDKVGKYPKELRKCCEDGMRENPMRFSCQRRTRFISLGEACKKVFLDCCNYI

TELRRQHARASHLGLAR

Heavy chain CDR1 38G10 (SEQ ID NO:7)

GYTFDFYMD

Heavy chain CDR2 38G10 (SEQ ID NO:8)

YIYPHNGGTTYNQNFTG

Heavy chain CDR3 38G10 (SEQ ID NO:9)

RGGFFDY

Light chain CDR1 38G10 (SEQ ID NO:10)

KASENVDTYVS

Light chain CDR2 38G10 (SEQ ID NO:11)

GASNRYT

Light chain CDR3 38G10 (SEQ ID NO:12)

GQSHSYPLT

Heavy chain CDR2 Hz38G10 (SEQ ID NO:13)

YIYPHNGGTTYNQQFTG

Heavy chain CDR2 G56A Hz38G10 (SEQ ID NO:14)

YIYPHNAGTTYNQQFTG

Heavy chain CDR2 G56T Hz38G10 (SEQ ID NO:15)

YIYPHNTGTTYNQQFTG

Heavy chain CDR2 N55E Hz38G10 (SEQ ID NO:16)

YIYPHEGGTTYNQQFTG

Heavy chain CDR2 N55Q Hz38G10 (SEQ ID NO:17)

YIYPHQGGTTYNQQFTG

38G10 Heavy Chain Variable Region Amino Acid Sequence (SEQ ID NO: 18)

EVQLQQSGPELVKPGDSVKMSCKASGYTFDFYMDWVKQSHGKSLEWIGYIYPHNGGTTY

NQNFTGKATLTVDKSSNTAYMELHSLTSEDSAVYYCARRGGFFDYWGQGTTLTVSS

38G10 Light Chain Variable Region Amino Acid Sequence (SEQ ID NO: 19)

NIVMTQSPKSMSLSVGERVTLRCKASENVDTYVSWYQQKPEQSPKLLIYGASNRYTGVPD

RFTGSGSATEFTLTISSVQAEDLVGYHCGQSHSYPLTFGAGTKLELK

Heavy chain variable region amino acid sequence of Hz38G10 (SEQ ID NO: 20)

QVQLVQSGAEVKKPGASVKVSCKASGYTFDFYMDWVRQAPGQRLEWMGYIYPHNGGTTY

nqqftgrvtitvdksastaymelsslrsedtavyycarrggFDFDYWGQGTLVTVSS

Heavy chain variable region amino acid sequence of Hz38G10 (G56A) (SEQ ID NO: 21)

QVQLVQSGAEVKKPGASVKVSCKASGYTFDFYMDWVRQAPGQRLEWMGYIYPHNAGTTY

nqqftgrvtitvdksastaymelsslrsedtavyycarrggFDFDYWGQGTLVTVSS

Heavy chain variable region amino acid sequence of Hz38G10 (G56T) (SEQ ID NO: 22)

QVQLVQSGAEVKKPGASVKVSCKASGYTFDFYMDWVRQAPGQRLEWMGYIYPHNTGTTY

nqqftgrvtitvdksastaymelsslrsedtavyycarrggFDFDYWGQGTLVTVSS

Heavy chain variable region amino acid sequence of Hz38G10 (N55E) (SEQ ID NO: 23)

QVQLVQSGAEVKKPGASVKVSCKASGYTFDFYMDWVRQAPGQRLEWMGYIYPHEGGTTY

nqqftgrvtitvdksastaymelsslrsedtavyycarrggFDFDYWGQGTLVTVSS

Heavy chain variable region amino acid sequence of Hz38G10 (N55Q) (SEQ ID NO: 24)

QVQLVQSGAEVKKPGASVKVSCKASGYTFDFYMDWVRQAPGQRLEWMGYIYPHQGGTTY

nqqftgrvtitvdksastaymelsslrsedtavyycarrggFDFDYWGQGTLVTVSS

Light chain variable region amino acid sequence of Hz38G10 (SEQ ID NO: 25)

DIQMTQSPSSLSASVGDRVTITCKASENVDTYVSWYQQKPGKAPKLLIYGASNRYTGVPS

RFSGSGSGTDFTFTISSLQPEDIATYHCGQSHSYPLTFGQGTKLEIK

Heavy chain amino acid sequence of Hz38G10 with underlined signal sequence (SEQ ID NO: 26)

mdmrvpaqllgllllwlrgarc QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFYMDWVR

QAPGQRLEWMGYIYPHNGGTTYnqqftgrvtitvdksastaymelsslrsedtavyycar

rggFDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW

NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK

SCDKTHTCPPCPAPALAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY

VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK

AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL

DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Heavy chain amino acid sequence of Hz38G10 without signal sequence (SEQ ID NO: 27)

QVQLVQSGAEVKKPGASVKVSCKASGYTFDFYMDWVRQAPGQRLEWMGYIYPHNGGTTY

nqqftgrvtitvdksastaymelsslrsedtavyycarrggFDFDYWGQGTLVTVSSAST

KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPALAGGPSV

FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG

NVFSCSVMHEALHNHYTQKSLSLSPGK

Heavy chain amino acid sequence of Hz38G10 (G56A) with underlined signal sequence (SEQ ID NO: 28)

mdmrvpaqllgllllwlrgarc QVQLVQSGAEVKKPGASVKVSCKASGYTFTDFYMDWVR

QAPGQRLEWMGYIYPHNAGTTYnqqftgrvtitvdksastaymelsslrsedtavyycar

rggFDFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW

NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK

SCDKTHTCPPCPAPALAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY

VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK

AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL

DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Heavy chain amino acid sequence of Hz38G10 (G56A) without signal sequence (SEQ ID NO: 29)

QVQLVQSGAEVKKPGASVKVSCKASGYTFDFYMDWVRQAPGQRLEWMGYIYPHNAGTTY

nqqftgrvtitvdksastaymelsslrsedtavyycarrggFDFDYWGQGTLVTVSSAST

KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY

SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPALAGGPSV

FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY

RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK

NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG

NVFSCSVMHEALHNHYTQKSLSLSPGK

Light chain amino acid sequence of Hz38G10 with underlined signal sequence (SEQ ID NO: 30)

mdmrvpaqllgllllwlrgarc DIQMTQSPSSLSASVGDRVTITCKASENVDTYVSWYQQ

KPGKAPKLLIYGASNRYTGVPSRFSGSGSGTDFTFTISSLQPEDIATYHCGQSHSYPLTF

GQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGN

SQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Light chain amino acid sequence of Hz38G10 without signal sequence (SEQ ID NO: 31)

DIQMTQSPSSLSASVGDRVTITCKASENVDTYVSWYQQKPGKAPKLLIYGASNRYTGVPS

RFSGSGSGTDFTFTISSLQPEDIATYHCGQSHSYPLTFGQGTKLEIKRTVAAPSVFIFPP

SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT

LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Cynomolgus monkey C3 amino acid sequence with predictive signal sequence underlined

(SEQ ID NO:32)

MGLTSGPSLLLLLIHLPLALG TPMYSMITPNVLRLESEETVVLEAHDANGDVPVTVTVH

DFPGKKLVLSSEKTVLTPATSHMGSVTIRIPANKEFKSEKGHNKFVTVQATFGAQVVEKV

VLVSLQSGYLFIQTDKTIYTPGSTVLCRIFTVNHKLLPVGRTVVVNIENPDGIPVKQDSL

SSQNQFGILPLSWDIPELVNMGQWKIRAYYENSPQQVFSTEFEVKEYVLPSFEVIVEPTE

KFYYIYNQKGLEVTITARFLYGKKVEGTAFVIFGIQDGEQRISLPESLKRIQIEDGSGDA

VLSRKVLLDGVQNPRPEDLVGKSLYVSVTVILHSGSDMVQAERSGIPIVTSPYQIHFTKT

PKYFKPGMPFDLMVFVTNPDGSPAYRVPVAVQGEDAVQSLTQGDGVAKLSINTHPSQKPL

SITVRTKKRELSEAEQATRTMEAQPYSTVGNSNNYLHLSVPRAELRPGETLNVNFLLRMD

RTQEAKIRYYTYLIMNKGKLLKVGRQVREPGQDLVVLPLSITTDFIPSFRLVAYYTLIGA

NGQREVVADSVWVDVKDSCVGSLVVKSGQSEDRQPLPGQQMTLKIEGDHGARVGLVAVDK

GVFVLNKKNKLTQSKIWDVVEKADIGCTPGSGKDYAGVFSDAGLTFASSSGQQTAQRAEL

QCPQPAARRRRSVQLAEKRMDKVGQYPKELRKCCEHGMRENPMRFSCQRRTRYITLDEAC

KKAFLDCCNYITELRRQHARASHLGLARSNLDEDIIAEENIVSRSEFPESWLWKIEELKE

APKNGISTKLMNIFLKDSITTWEILAVSLSDKKGICVADPFEVTVMQDFFIDLRLPYSVV

RNEQVEIRAVLYNYRQNQELKVRVELLHNPAFCSLATAKRRHQQTVTIPPKSSLSVPYVI

VPLKTGQQEVEVKAAVYHFFISDGVRKSLKVVPEGIRMNKTVAVRTLDPERLGQEGVQRE

DVPPADLSDQVPDTESETRILLQGTPVAQMTEDAIDAERLKHLIVTPSGCGEQNMITMTP

TVIAVHYLDETEQWEKFGPEKRQGALELIKKGYTQQLAFRQPSSAFAAAFLNRAPSTWLTA

YVVKVFSLAVNLIAIDSQVLCGAVKWLILEKQKPDGVFQEDAPVIHQEMTGGFRNTNEKD

MALTAFVLISLQEAKEICEEQVNSLPGSITKAGDFLEANYMNLQRSYTVAIAAYALAQMG

RLKGPLLNKFLTTAKDKNRWEEPGQQLYNVEATSYALLALLQLKDFDFVPPVVRWLNEQR

YYGGGYGSTQATFMVFQALAQYQKDVPDHKELNLDVSLQLPSRSSKIIHRIHWESASLLR

SEETKENEGFTVTAEGKGQGTLSVVTMYHAKAKGQLTCNKFDLKVTIKPAPETEKRPQDA

KNTMILEICTRYRGDQDATMSILDISMMTGFVPDTDDLKQLANGVDRYISKYELDKAAFSD

RNTLIIYLDKVSHSEDDCIAFKVHQYFNVELIQPGAVKVYAYYNLAESCTRFYHPEKEDG

KLNKLCRDELCRCAEENCFIQKLDDKVTLEERLDKACEPGVDYVYKTRLVKAQLSNDFDE

YIMAIEQIIKSGSDEVQVGQQRTFISPIKCREALKLEERKHYLMWGLSSSDFWGEKPNLSY

IIGKDTWVEHWPEEDECQDEENQKQCQDLGTFTENMVVFGCPN

Cynomolgus monkey C3 amino acid sequence without predicted signal sequence (SEQ ID NO:33)

TPMYSMITPNVLRLESEETVVLEAHDANGDVPVTVTVHDFPGKKLVLSSEKTVLTPATSH

MGSVTIRIPANKEFKSEKGHNKFVTVQATFGAQVVEKVVLVSLQSGYLFIQTDKTIYTPG

STVLCRIFTVNHKLLPVGRTVVVNIENPDGIPVKQDSLSSQNQFGILPLSWDIPELVNMG

QWKIRAYYENSPQQVFSTEFEVKEYVLPSFEVIVEPTEKFYYIYNQKGLEVTITARFLYG

KKVEGTAFVIFGIQDGEQRISLPESLKRIQIEDGSGDAVLSRKVLLDGVQNPRPEDLVGK

SLYVSVTVILHSGSDMVQAERSGIPIVTSPYQIHFTKTPKYFKPGMPFDLMVFVTNPDGS

PAYRVPVAVQGEDAVQSLTQGDGVAKLSINTHPSQKPLSITVRTKKRELSEAEQATRTME

AQPYSTVGNSNNYLHLSVPRAELRPGETLNVNFLLRMDRTQEAKIRYYTYLIMNKGKLLK

VGRQVREPGQDLVVLPLSITTDFIPSFRLVAYYTLIGANGQREVVADSVWVDVKDSCVGS

LVVKSGQSEDRQPLPGQQMTLKIEGDHGARVGLVAVDKGVFVLNKKNKLTQSKIWDVVEK

ADIGCTPGSGKDYAGVFSDAGLTFASSSGQQTAQRAELQCPQPAARRRRSVQLAEKRMDK

VGQYPKELRKCCEHGMRENPMRFSCQRRTRYITLDEACKKAFLDCCNYITELRRQHARAS

HLGLARSNLDEDIIAEENIVSRSEFPESWLWKIEELKEAPKNGISTKLMNIFLKDSITTW

EILAVSLSDKKGICVADPFEVTVMQDFFIDLRLPYSVVRNEQVEIRAVLYNYRQNQELKV

RVELLHNPAFCSLATAKRRHQQTVTIPPKSSLSVPYVIVPLKTGQQEVEVKAAVYHFFIS

DGVRKSLKVVPEGIRMNKTVAVRTLDPERLGQEGVQREDVPPADLSDQVPDTESETRILL

QGTPVAQMTEDAIDAERLKHLIVTPSGCGEQNMITMTPTVIAVHYLDETEQWEKFGPEKR

QGALELIKKGYTQQLAFRQPSSAFAAAFLNRAPSTWLTAYVVKVFSLAVNLIAIDSQVLCG

AVKWLILEKQKPDGVFQEDAPVIHQEMTGGFRNTNEKDMALTAFVLISLQEAKEICEEQV

NSLPGSITKAGDFLEANYMNLQRSYTVAIAAYALAQMGRLKGPLLNKFLTTAKDKNRWEE

PGQQLYNVEATSYALLALLQLKDFDFVPPVVRWLNEQRYYGGGYGSTQATFMVFQALAQY

QKDVPDHKELNLDVSLQLPSRSSKIIHRIHWESASLLRSEETKENEGFTVTAEGKGQGTL

SVVTMYHAKAKGQLTCNKFDLKVTIKPAPETEKRPQDAKNTMILEICTRYRGDQDATMSI

LDISMMTGFVPDTDDLKQLANGVDRYISKYELDKAFSDRNTLIIYLDKVSHSEDDCIAFK

VHQYFNVELIQPGAVKVYAYYNLAESCTRFYHPEKEDGKLNKLCRDELCRCAEENCFIQK

LDDKVTLEERLDKACEPGVDYVYKTRLVKAQLSNDFDEYIMAIEQIIKSGSDEVQVGQQR

TFISPIKCREALKLEERKHYLMWGLSSSDFWGEKPNLSYIIGKDTWVEHWPEEDECQDEEN

QKQCQDLGTFTENMVVFGCPN

Human IgG1 constant region (SEQ ID NO: 34)

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS

GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN

STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW

QQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Human IgG1 constant region E233A/L235A (SEQ ID NO:35)

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS

GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPALAGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN

STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW

QQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Human IgG1 constant region L234A/L235A (SEQ ID NO:36)

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS

GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN

STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW

QQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Rat C3 amino acid sequence with predictive signal sequence underlined

(SEQ ID NO:37)

MGPTSGSQLLVLLLLASSLLALG SPMYSIITPNVLRLESEETFILEAHDAQGDVPVTVT

VQDFLKKQVLTSEKTVLTGATGHLNRVFIKIPASKEFNADKGHKYVTVVANFGATVVEKA

VLVSFQSGYLFIQTDKTIYTPGSTVFYRIFTVDNNLLPVGKTVVIVIETPDGVPIKRDIL

SSHNQYGILPLSWNIPELVNMGQWKIRAFYEHAPKQTFSAEFEVKEYVLPSFEVLVEPTE

KFYYIHGPKGLEVSITARFLYGKNVDGTAFVIFGVQDEDKKISLALSLTRVLIEDGSGEA

VLSRKVLMDGVRPSSPEALVGKSLYVSVTVILHSGSDMVEAERSGIPIVTSPYQIHFTKT

PKFFKPAMPFDLMVFVTNPDGSPARRVPVVTQGSDAQALTQDDGVAKLSVNTPNNRQPLT

ITVSTKKEGIPDARQATRTMQAQPYSTMHNSNNYLHLSVSRVELKPGDNLNVNFHLRTDA

GQEAKIRYYTYLVMNKGKLLKAGRQVREPGQDLVVLSLPITPEFIPSFRLVAYYTLIGAN

GQREVVADSVWVDVKDSCVGTLVVKGDPRDNRQPAPGHQTTLRIEGNQGARVGLVAVDKG

VFVLNKKNKLTQSKIWDVVEKADIGCTPGSGKNYAGVFMDAGLTFKTNQGLQTDQREDPE

CAKPAARRRRSVQLMERRMDKAGQYTDKGLRKCCEDGMRDIPMPYSCQRRARLITQGESC

LKAFMDDCCNYITKLREQHRRDHVLGLARSDVDEDIIPEEDIISRSHFPESWLWTIEELKE

PEKNGISTKVMNIFLKDSITTWEILAVSLSDKKGICVADPYEITVMQDFFIDLRLPYSVV

RNEQVEIRAVLFNYREQEKLKVRVELLHNPAFCSMATAKKRYYQTIEIPPKSSVAVPYVI

VPLKIGLQEVEVKAAVFNHFISDGVKKILKVVPEGMRVNKTVAVRTLDPEHLNQGGVQRE

DVNAADLSDQVPDTDSETRILLQGTPVAQMAEDAVDGERLKHLIVTPSGCGEQNMIGMTP

TVIAVHYLDQTEQWEKFGLEKRQEALELIKKGYTQQLAFKQPISAYAAFNNRPPSTWLTA

MWSRSFSLAANLIAIDSQVLCGAVKWLILEKQKPDGVFQEDGPVIHQEMIGGFRNTKEAD

VSLTAFVLIALQEARDICEGQVNSLPGSINKAGEYLEASYLNLQRPYTVAIAGYALALMN

KLEEPYLTKFLNTAKDRNRWEEPGQQLYNVEATSYALLALLLLKDFDSVPPVVRWLNDER

YYGGGYGSTQATFMVFQALAQYRADVPDHKDLNMDVSLHLPSRSSPTVFRLLWESGSLLR

SEETKQNEGFSLTAKGKGQGTLSVVTVYHAKVKGKTTCKKFDLRVTIKPAPETAKKPQDA

KSSMILDICTRYLGDVDATMSILDISMMTGFIPDTNDLELLSSGVDRYISKYEMDKAFSN

KNTLIIYLEKISHSEEDCLSFKVHQFFNVGLIQPGSVKVYSYYNLEESCTRFYHPEKDDG

MLSKLCHNEMCRCAEENCFMHQSQDQVSLNERLDKACEPGVDYVYKTKLTTIELSDDFDE

YIMTIEQVIKSGSDEVQAGQERRFISHVKCRNALKLQKGKQYLMWGLSSSDLWGEKPNTSY

IIGKDTWVEHWPEAEERQDQKNQKQCEDLGAFTETMVVFGCPN

3D8 Heavy Chain Variable Region Amino Acid Sequence (SEQ ID NO: 91)

EIQLQQSGAELVKPGASVKISCKASGYSFTGYNMNWVKQSHGKSLEWIGNINPYYGSTNY

NQKFKGKATLTVDKSSTTAYMQLDSLTSEDSAVYYCARGYYGGNYPFAYWGQGTLVTVSA

3D8 Light Chain Variable Region Amino Acid Sequence (SEQ ID NO: 92)

DIQMTQSPASLSASVGETVTITCRASENIYSYLAWYQQKQGKSPQLLVYNAKTLAEGVPS

RFSGSGSGTQFSLKINSLQPEDFGSYYCQHYYGTPYTFGGGSKVEIK

3G8 Heavy Chain Variable Region Amino Acid Sequence (SEQ ID NO: 93)

EIQLQQSGAELVKPGASVKISCMASGYSFTGYNMNWVKQSHGKGLEWIGNINPYYDSTSY

NQKFKGKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARENYDFVGFAYWGQGTLVTVSA

3G8 Light Chain Variable Region Amino Acid Sequence (SEQ ID NO: 94)

QIVLSQSPAILSASPGEKVTMTCRASSSVSYMHWFQQKPGSSPKPWIYVTSNLASGVPPR

FSGSGSGTSYSLTISRVEEAEDAATYYCQQWSTNPLTFGAGTKLELK

15C12 Heavy Chain Variable Region Amino Acid Sequence (SEQ ID NO: 95)

EIQLQQSGAELEKPGASVKISCKASGYSFTGYNMHWVKQSHGKSLEWIGNINPYYGTTNS

NQKFEDKATLTVDKSSSTAYMQLNSLTSEDSAVYYCARGIYYYGTGYPYFDFWGQGTTLT

VSS

15C12 Light Chain Variable Region Amino Acid Sequence (SEQ ID NO: 96)

DIQMTQTTSSLSASLGDRVTISCRASQDINNYLNWYLQKPDGTVKLLIYYTSRLHSGVPS

RFSGSGSGTDYSLTISNLEQEDLATYFCQQGITLPWTFGGGTKLEIK

27A8 Heavy Chain Variable Region Amino Acid Sequence (SEQ ID NO: 97)

QVQLLQPGAEFVKPGASVKLSCKASGYTFTDYWINWVKQRPGQGLEWIGNIYPGSTSANY

NEKFKSKATLTIDTSSITAYMQLSSLTSDDSAVYYCARYGYDSWFAYWGQGTLVTVSA

27A8 Light Chain Variable Region Amino Acid Sequence (SEQ ID NO: 98)

DVVLTQTPLSLPVNIGDQASISCKSTKSLLNSDGFTYLDWFLQKPGQSPHLLIYLVSNRF

SGIPDRFSGSGSETDFTLKISRVEAEDLGVYYCFQSNYLPLTFGSGTKLEIK

28C3 Heavy Chain Variable Region Amino Acid Sequence (SEQ ID NO: 99)

QVQLQQSGPELVKPGASVKISCKASGYAFNSCWMNWVKQRPGKGLEWIGRIYPGDGDTNY

NGKFKGKATLTADKSSTTAYMQLSSLTSEDSAVYFCAREGRNYGYEDYWGQGTTLTVSS

28C3 Light Chain Variable Region Amino Acid Sequence (SEQ ID NO: 100)

DIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASDLES

GIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQANEDPRTFGGGTKLEIK

38F5 Heavy Chain Variable Region Amino Acid Sequence (SEQ ID NO: 101)

EVMLVESGGALVKPGGSLKLSCTASGFTFSNYAMSWVRQTPEKRLEWVAQTISSGGRYTY

YPDSVKGRFTISRDNARNTLYLQMSSLRSEDTAMYYCVRRYYGNSYWYFDVWGAGTTVTV

SS

38F5 Light Chain Variable Region Amino Acid Sequence (SEQ ID NO: 102)

DIVMTQSPSSLSVSAGEKVTMNCKSSQSLLNSGNQKHYLTWYQQKPGQPPKLLIYGASTR

GSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDHSYPYTFGGGTKLEIK

62B11 Heavy Chain Variable Region Amino Acid Sequence (SEQ ID NO: 103)

EVKLVESGGGLVQPGGSLKLSCAASGFTFSSYTMSWVRQTPEKRLEWVAYISSGGGTTYY

PDTVKGRFTVSRDNAKNTLYLQMSSLRSEDTAMYSCARRYYRGSSLWYFDVWGAGTTVTV

SS

62B11 Light Chain Variable Region Amino Acid Sequence (SEQ ID NO: 104)

DIVMTQSPSSLTVTAGEKVTMSCKSSQSLFNSGSQKNFLTWYQQRPGQPPKLLIYWASTR

ESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLELK

62F2 Heavy Chain Variable Region Amino Acid Sequence (SEQ ID NO: 105)

DVQLQESGPDLVKPSQSLSLTCTVTGYSITSGYSLHWIRQFPGNKLEWMGYIHYSGSTNY

NPSLKSRISITRDTSKNQFFLKLNSVTSEDTATYHCARAWDYLDYWGQGTTLTVSS

62F2 Light Chain Variable Region Amino Acid Sequence (SEQ ID NO: 106)

DIQMTQSPASLSASVGETVTITCRASENIYSQLAWYQQKQGKSPQLLVYDAKTLAEGVPS

RFSGGSDTQFSLKIISLQPEDFGRYYCHHHFGILYTFGGGTKLEMK

63A3 Heavy Chain Variable Region Amino Acid Sequence (SEQ ID NO: 107)

DVQLQESGPGLVKPSQSLSLTCSVTGYSITSGYYWNWIRQFPGNKLEWMGYIRYDGSNNY

NPSLKNRISITRDTSKNQVFLKLNSVTPEDTATYYCARHYGYDGGAFDFWGQGTTLTVSS

63A3 Light Chain Variable Region Amino Acid Sequence (SEQ ID NO: 108)

DIQMTQSPASLSASVGETVTITCRTSENIYNYLVWYQQKQGKSPQLLVYNAKTLEEGVPS

RFSGSGSGTQFSLKVNSLQPEDFGSYYCQHHYGTPFTFGSGTKLEIK

Human IgG1 constant region L234A/L235A/P329G (SEQ ID NO:109)

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS

GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGG

PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN

STYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSREE

MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW

QQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Heavy chain variable region dsscFv Hz38G10 (SEQ ID NO: 110)

QVQLVQSGAEVKKPGASVKVSCKASGYTFDFYMDWVRQAPGQCLEWMGYIYPHNGGTTY

NQQFTGRVTITVDKSASTAYMELSSLRSEDTAVYYCARRGGFFDYWGQGTLVTVSS

Heavy chain variable region dsscFv Hz38G10(G56A) (SEQ ID NO: 111)

QVQLVQSGAEVKKPGASVKVSCKASGYTFDFYMDWVRQAPGQCLEWMGYIYPHNAGTTY

NQQFTGRVTITVDKSASTAYMELSSLRSEDTAVYYCARRGGFFDYWGQGTLVTVSS

Light chain variable region dsscFv Hz38G10 (SEQ ID NO: 112)

DIQMTQSPSSLSASVGDRVTITCKASENVDTYVSWYQQKPGKAPKLLIYGASNRYTGVPS

RFSGSGSGTDFTFTISSLQPEDIATYHCGQSHSYPLTFGCGTKLEIK

dsscFv Hz38G10 (SEQ ID NO:113)

MDIQMTQSPSSLSASVGDRVTITCKASENVDTYVSWYQQKPGKAPKLLIYGASNRYTGVP

SRFSGSGSGTDFTFTISSLQPEDIATYHCGQSHSYPLTFGCGTKLEIKGGGGSGGGGSGG

GGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTDFYMDWVRQAPGQCLEWMGYIYPHNGG

TTYNQQFTGRVTITVDKSASTAYMELSSLRSEDTAVYYCARRGGFFDYWGQGTLVTVSS

dsscFv Hz38G10(G56A) (SEQ ID NO:114)

MDIQMTQSPSSLSASVGDRVTITCKASENVDTYVSWYQQKPGKAPKLLIYGASNRYTGVP

SRFSGSGSGTDFTFTISSLQPEDIATYHCGQSHSYPLTFGCGTKLEIKGGGGSGGGGSGG

GGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTDFYMDWVRQAPGQCLEWMGYIYPHNAG

TTYNQQFTGRVTITVDKSASTAYMELSSLRSEDTAVYYCARRGGFFDYWGQGTLVTVSS

Linker (SEQ ID NO:115)

GGGGS

Linker (SEQ ID NO:116)

GGGGSGGGGS

Linker (SEQ ID NO:117)

GGGGSGGGGSGGGGS

Linker (SEQ ID NO:118)

GGGGSGGGGSGGGGSGGGGS

dsscFv Hz38G10 (SEQ ID NO:119)

DIQMTQSPSSLSASVGDRVTITCKASENVDTYVSWYQQKPGKAPKLLIYGASNRYTGVPS

RFSGSGSGTDFTFTISSLQPEDIATYHCGQSHSYPLTFGCGTKLEIKGGGGSGGGGSGGG

GSQVQLVQSGAEVKKPGASVKVSCKASGYTFTDFYMDWVRQAPGQCLEWMGYIYPHNGGT

TYNQQFTGRVTITVDKSASTAYMELSSLRSEDTAVYYCARRGGFFDYWGQGTLVTVSS

dsscFv Hz38G10(G56A) (SEQ ID NO:229)

DIQMTQSPSSLSASVGDRVTITCKASENVDTYVSWYQQKPGKAPKLLIYGASNRYTGVPS

RFSGSGSGTDFTFTISSLQPEDIATYHCGQSHSYPLTFGCGTKLEIKGGGGSGGGGSGGG

GSQVQLVQSGAEVKKPGASVKVSCKASGYTFTDFYMDWVRQAPGQCLEWMGYIYPHNAGT

TYNQQFTGRVTITVDKSASTAYMELSSLRSEDTAVYYCARRGGFFDYWGQGTLVTVSS

--->

SEQUENCE LIST

<110> NGM BIOPHARMACEUTICALS, INC.

<120> C3 BINDING AGENTS AND THEIR USE

<130> 47702-0011WO1

<140>

<141>

<150> 62/652253

<151> 04/03/2018

<160> 232

<170> PatentIn version 3.5

<210> 1

<211> 1663

<212> Protein

<213> Homo sapiens

<400> 1

Met Gly Pro Thr Ser Gly Pro Ser Leu Leu Leu Leu Leu Leu Thr His

1 5 10 15

Leu Pro Leu Ala Leu Gly Ser Pro Met Tyr Ser Ile Ile Thr Pro Asn

20 25 30

Ile Leu Arg Leu Glu Ser Glu Glu Thr Met Val Leu Glu Ala His Asp

35 40 45

Ala Gln Gly Asp Val Pro Val Thr Val Thr Val His Asp Phe Pro Gly

50 55 60

Lys Lys Leu Val Leu Ser Ser Glu Lys Thr Val Leu Thr Pro Ala Thr

65 70 75 80

Asn His Met Gly Asn Val Thr Phe Thr Ile Pro Ala Asn Arg Glu Phe

85 90 95

Lys Ser Glu Lys Gly Arg Asn Lys Phe Val Thr Val Gln Ala Thr Phe

100 105 110

Gly Thr Gln Val Val Glu Lys Val Val Leu Val Ser Leu Gln Ser Gly

115 120 125

Tyr Leu Phe Ile Gln Thr Asp Lys Thr Ile Tyr Thr Pro Gly Ser Thr

130 135 140

Val Leu Tyr Arg Ile Phe Thr Val Asn His Lys Leu Leu Pro Val Gly

145 150 155 160

Arg Thr Val Met Val Asn Ile Glu Asn Pro Glu Gly Ile Pro Val Lys

165 170 175

Gln Asp Ser Leu Ser Ser Gln Asn Gln Leu Gly Val Leu Pro Leu Ser

180 185 190

Trp Asp Ile Pro Glu Leu Val Asn Met Gly Gln Trp Lys Ile Arg Ala

195 200 205

Tyr Tyr Glu Asn Ser Pro Gln Gln Val Phe Ser Thr Glu Phe Glu Val

210 215 220

Lys Glu Tyr Val Leu Pro Ser Phe Glu Val Ile Val Glu Pro Thr Glu

225 230 235 240

Lys Phe Tyr Tyr Ile Tyr Asn Glu Lys Gly Leu Glu Val Thr Ile Thr

245 250 255

Ala Arg Phe Leu Tyr Gly Lys Lys Val Glu Gly Thr Ala Phe Val Ile

260 265 270

Phe Gly Ile Gln Asp Gly Glu Gln Arg Ile Ser Leu Pro Glu Ser Leu

275 280 285

Lys Arg Ile Pro Ile Glu Asp Gly Ser Gly Glu Val Val Leu Ser Arg

290 295 300

Lys Val Leu Leu Asp Gly Val Gln Asn Pro Arg Ala Glu Asp Leu Val

305 310 315 320

Gly Lys Ser Leu Tyr Val Ser Ala Thr Val Ile Leu His Ser Gly Ser

325 330 335

Asp Met Val Gln Ala Glu Arg Ser Gly Ile Pro Ile Val Thr Ser Pro

340 345 350

Tyr Gln Ile His Phe Thr Lys Thr Pro Lys Tyr Phe Lys Pro Gly Met

355 360 365

Pro Phe Asp Leu Met Val Phe Val Thr Asn Pro Asp Gly Ser Pro Ala

370 375 380

Tyr Arg Val Pro Val Ala Val Gln Gly Glu Asp Thr Val Gln Ser Leu

385 390 395 400

Thr Gln Gly Asp Gly Val Ala Lys Leu Ser Ile Asn Thr His Pro Ser

405 410 415

Gln Lys Pro Leu Ser Ile Thr Val Arg Thr Lys Lys Gln Glu Leu Ser

420 425 430

Glu Ala Glu Gln Ala Thr Arg Thr Met Gln Ala Leu Pro Tyr Ser Thr

435 440 445

Val Gly Asn Ser Asn Asn Tyr Leu His Leu Ser Val Leu Arg Thr Glu

450 455 460

Leu Arg Pro Gly Glu Thr Leu Asn Val Asn Phe Leu Leu Arg Met Asp

465 470 475 480

Arg Ala His Glu Ala Lys Ile Arg Tyr Tyr Thr Tyr Leu Ile Met Asn

485 490 495

Lys Gly Arg Leu Leu Lys Ala Gly Arg Gln Val Arg Glu Pro Gly Gln

500 505 510

Asp Leu Val Val Leu Pro Leu Ser Ile Thr Thr Asp Phe Ile Pro Ser

515 520 525

Phe Arg Leu Val Ala Tyr Tyr Thr Leu Ile Gly Ala Ser Gly Gln Arg

530 535 540

Glu Val Val Ala Asp Ser Val Trp Val Asp Val Lys Asp Ser Cys Val

545 550 555 560

Gly Ser Leu Val Val Lys Ser Gly Gln Ser Glu Asp Arg Gln Pro Val

565 570 575

Pro Gly Gln Gln Met Thr Leu Lys Ile Glu Gly Asp His Gly Ala Arg

580 585 590

Val Val Leu Val Ala Val Asp Lys Gly Val Phe Val Leu Asn Lys Lys

595 600 605

Asn Lys Leu Thr Gln Ser Lys Ile Trp Asp Val Val Glu Lys Ala Asp

610 615 620

Ile Gly Cys Thr Pro Gly Ser Gly Lys Asp Tyr Ala Gly Val Phe Ser

625 630 635 640

Asp Ala Gly Leu Thr Phe Thr Ser Ser Ser Gly Gln Gln Thr Ala Gln

645 650 655

Arg Ala Glu Leu Gln Cys Pro Gln Pro Ala Ala Arg Arg Arg Arg Ser

660 665 670

Val Gln Leu Thr Glu Lys Arg Met Asp Lys Val Gly Lys Tyr Pro Lys

675 680 685

Glu Leu Arg Lys Cys Cys Glu Asp Gly Met Arg Glu Asn Pro Met Arg

690 695 700

Phe Ser Cys Gln Arg Arg Thr Arg Phe Ile Ser Leu Gly Glu Ala Cys

705 710 715 720

Lys Lys Val Phe Leu Asp Cys Cys Asn Tyr Ile Thr Glu Leu Arg Arg

725 730 735

Gln His Ala Arg Ala Ser His Leu Gly Leu Ala Arg Ser Asn Leu Asp

740 745 750

Glu Asp Ile Ile Ala Glu Glu Asn Ile Val Ser Arg Ser Glu Phe Pro

755 760 765

Glu Ser Trp Leu Trp Asn Val Glu Asp Leu Lys Glu Pro Pro Lys Asn

770 775 780

Gly Ile Ser Thr Lys Leu Met Asn Ile Phe Leu Lys Asp Ser Ile Thr

785 790 795 800

Thr Trp Glu Ile Leu Ala Val Ser Met Ser Asp Lys Lys Gly Ile Cys

805 810 815

Val Ala Asp Pro Phe Glu Val Thr Val Met Gln Asp Phe Phe Ile Asp

820 825 830

Leu Arg Leu Pro Tyr Ser Val Val Arg Asn Glu Gln Val Glu Ile Arg

835 840 845

Ala Val Leu Tyr Asn Tyr Arg Gln Asn Gln Glu Leu Lys Val Arg Val

850 855 860

Glu Leu Leu His Asn Pro Ala Phe Cys Ser Leu Ala Thr Thr Lys Arg

865 870 875 880

Arg His Gln Gln Thr Val Thr Ile Pro Pro Lys Ser Ser Leu Ser Val

885 890 895

Pro Tyr Val Ile Val Pro Leu Lys Thr Gly Leu Gln Glu Val Glu Val

900 905 910

Lys Ala Ala Val Tyr His His Phe Ile Ser Asp Gly Val Arg Lys Ser

915 920 925

Leu Lys Val Val Pro Glu Gly Ile Arg Met Asn Lys Thr Val Ala Val

930 935 940

Arg Thr Leu Asp Pro Glu Arg Leu Gly Arg Glu Gly Val Gln Lys Glu

945 950 955 960

Asp Ile Pro Pro Ala Asp Leu Ser Asp Gln Val Pro Asp Thr Glu Ser

965 970 975

Glu Thr Arg Ile Leu Leu Gln Gly Thr Pro Val Ala Gln Met Thr Glu

980 985 990

Asp Ala Val Asp Ala Glu Arg Leu Lys His Leu Ile Val Thr Pro Ser

995 1000 1005

Gly Cys Gly Glu Gln Asn Met Ile Gly Met Thr Pro Thr Val Ile

1010 1015 1020

Ala Val His Tyr Leu Asp Glu Thr Glu Gln Trp Glu Lys Phe Gly

1025 1030 1035

Leu Glu Lys Arg Gln Gly Ala Leu Glu Leu Ile Lys Lys Gly Tyr

1040 1045 1050

Thr Gln Gln Leu Ala Phe Arg Gln Pro Ser Ser Ala Phe Ala Ala

1055 1060 1065

Phe Val Lys Arg Ala Pro Ser Thr Trp Leu Thr Ala Tyr Val Val

1070 1075 1080

Lys Val Phe Ser Leu Ala Val Asn Leu Ile Ala Ile Asp Ser Gln

1085 1090 1095

Val Leu Cys Gly Ala Val Lys Trp Leu Ile Leu Glu Lys Gln Lys

1100 1105 1110

Pro Asp Gly Val Phe Gln Glu Asp Ala Pro Val Ile His Gln Glu

1115 1120 1125

Met Ile Gly Gly Leu Arg Asn Asn Asn Glu Lys Asp Met Ala Leu

1130 1135 1140

Thr Ala Phe Val Leu Ile Ser Leu Gln Glu Ala Lys Asp Ile Cys

1145 1150 1155

Glu Glu Gln Val Asn Ser Leu Pro Gly Ser Ile Thr Lys Ala Gly

1160 1165 1170

Asp Phe Leu Glu Ala Asn Tyr Met Asn Leu Gln Arg Ser Tyr Thr

1175 1180 1185

Val Ala Ile Ala Gly Tyr Ala Leu Ala Gln Met Gly Arg Leu Lys

1190 1195 1200

Gly Pro Leu Leu Asn Lys Phe Leu Thr Thr Ala Lys Asp Lys Asn

1205 1210 1215

Arg Trp Glu Asp Pro Gly Lys Gln Leu Tyr Asn Val Glu Ala Thr

1220 1225 1230

Ser Tyr Ala Leu Leu Ala Leu Leu Gln Leu Lys Asp Phe Asp Phe

1235 1240 1245

Val Pro Pro Val Val Arg Trp Leu Asn Glu Gln Arg Tyr Tyr Gly

1250 1255 1260

Gly Gly Tyr Gly Ser Thr Gln Ala Thr Phe Met Val Phe Gln Ala

1265 1270 1275

Leu Ala Gln Tyr Gln Lys Asp Ala Pro Asp His Gln Glu Leu Asn

1280 1285 1290

Leu Asp Val Ser Leu Gln Leu Pro Ser Arg Ser Ser Lys Ile Thr

1295 1300 1305

His Arg Ile His Trp Glu Ser Ala Ser Leu Leu Arg Ser Glu Glu

1310 1315 1320

Thr Lys Glu Asn Glu Gly Phe Thr Val Thr Ala Glu Gly Lys Gly

1325 1330 1335

Gln Gly Thr Leu Ser Val Val Thr Met Tyr His Ala Lys Ala Lys

1340 1345 1350

Asp Gln Leu Thr Cys Asn Lys Phe Asp Leu Lys Val Thr Ile Lys

1355 1360 1365

Pro Ala Pro Glu Thr Glu Lys Arg Pro Gln Asp Ala Lys Asn Thr

1370 1375 1380

Met Ile Leu Glu Ile Cys Thr Arg Tyr Arg Gly Asp Gln Asp Ala

1385 1390 1395

Thr Met Ser Ile Leu Asp Ile Ser Met Met Thr Gly Phe Ala Pro

1400 1405 1410

Asp Thr Asp Asp Leu Lys Gln Leu Ala Asn Gly Val Asp Arg Tyr

1415 1420 1425

Ile Ser Lys Tyr Glu Leu Asp Lys Ala Phe Ser Asp Arg Asn Thr

1430 1435 1440

Leu Ile Ile Tyr Leu Asp Lys Val Ser His Ser Glu Asp Asp Cys

1445 1450 1455

Leu Ala Phe Lys Val His Gln Tyr Phe Asn Val Glu Leu Ile Gln

1460 1465 1470

Pro Gly Ala Val Lys Val Tyr Ala Tyr Tyr Asn Leu Glu Glu Ser

1475 1480 1485

Cys Thr Arg Phe Tyr His Pro Glu Lys Glu Asp Gly Lys Leu Asn

1490 1495 1500

Lys Leu Cys Arg Asp Glu Leu Cys Arg Cys Ala Glu Glu Asn Cys

1505 1510 1515

Phe Ile Gln Lys Ser Asp Asp Lys Val Thr Leu Glu Glu Arg Leu

1520 1525 1530

Asp Lys Ala Cys Glu Pro Gly Val Asp Tyr Val Tyr Lys Thr Arg

1535 1540 1545

Leu Val Lys Val Gln Leu Ser Asn Asp Phe Asp Glu Tyr Ile Met

1550 1555 1560

Ala Ile Glu Gln Thr Ile Lys Ser Gly Ser Asp Glu Val Gln Val

1565 1570 1575

Gly Gln Gln Arg Thr Phe Ile Ser Pro Ile Lys Cys Arg Glu Ala

1580 1585 1590

Leu Lys Leu Glu Glu Lys Lys His Tyr Leu Met Trp Gly Leu Ser

1595 1600 1605

Ser Asp Phe Trp Gly Glu Lys Pro Asn Leu Ser Tyr Ile Ile Gly

1610 1615 1620

Lys Asp Thr Trp Val Glu His Trp Pro Glu Glu Asp Glu Cys Gln

1625 1630 1635

Asp Glu Glu Asn Gln Lys Gln Cys Gln Asp Leu Gly Ala Phe Thr

1640 1645 1650

Glu Ser Met Val Val Phe Gly Cys Pro Asn

1655 1660

<210> 2

<211> 1641

<212> Protein

<213> Homo sapiens

<400> 2

Ser Pro Met Tyr Ser Ile Ile Thr Pro Asn Ile Leu Arg Leu Glu Ser

1 5 10 15

Glu Glu Thr Met Val Leu Glu Ala His Asp Ala Gln Gly Asp Val Pro

20 25 30

Val Thr Val Thr Val His Asp Phe Pro Gly Lys Lys Leu Val Leu Ser

35 40 45

Ser Glu Lys Thr Val Leu Thr Pro Ala Thr Asn His Met Gly Asn Val

50 55 60

Thr Phe Thr Ile Pro Ala Asn Arg Glu Phe Lys Ser Glu Lys Gly Arg

65 70 75 80

Asn Lys Phe Val Thr Val Gln Ala Thr Phe Gly Thr Gln Val Val Glu

85 90 95

Lys Val Val Leu Val Ser Leu Gln Ser Gly Tyr Leu Phe Ile Gln Thr

100 105 110

Asp Lys Thr Ile Tyr Thr Pro Gly Ser Thr Val Leu Tyr Arg Ile Phe

115 120 125

Thr Val Asn His Lys Leu Leu Pro Val Gly Arg Thr Val Met Val Asn

130 135 140

Ile Glu Asn Pro Glu Gly Ile Pro Val Lys Gln Asp Ser Leu Ser Ser

145 150 155 160

Gln Asn Gln Leu Gly Val Leu Pro Leu Ser Trp Asp Ile Pro Glu Leu

165 170 175

Val Asn Met Gly Gln Trp Lys Ile Arg Ala Tyr Tyr Glu Asn Ser Pro

180 185 190

Gln Gln Val Phe Ser Thr Glu Phe Glu Val Lys Glu Tyr Val Leu Pro

195 200 205

Ser Phe Glu Val Ile Val Glu Pro Thr Glu Lys Phe Tyr Tyr Ile Tyr

210 215 220

Asn Glu Lys Gly Leu Glu Val Thr Ile Thr Ala Arg Phe Leu Tyr Gly

225 230 235 240

Lys Lys Val Glu Gly Thr Ala Phe Val Ile Phe Gly Ile Gln Asp Gly

245 250 255

Glu Gln Arg Ile Ser Leu Pro Glu Ser Leu Lys Arg Ile Pro Ile Glu

260 265 270

Asp Gly Ser Gly Glu Val Val Leu Ser Arg Lys Val Leu Leu Asp Gly

275 280 285

Val Gln Asn Pro Arg Ala Glu Asp Leu Val Gly Lys Ser Leu Tyr Val

290 295 300

Ser Ala Thr Val Ile Leu His Ser Gly Ser Asp Met Val Gln Ala Glu

305 310 315 320

Arg Ser Gly Ile Pro Ile Val Thr Ser Pro Tyr Gln Ile His Phe Thr

325 330 335

Lys Thr Pro Lys Tyr Phe Lys Pro Gly Met Pro Phe Asp Leu Met Val

340 345 350

Phe Val Thr Asn Pro Asp Gly Ser Pro Ala Tyr Arg Val Pro Val Ala

355 360 365

Val Gln Gly Glu Asp Thr Val Gln Ser Leu Thr Gln Gly Asp Gly Val

370 375 380

Ala Lys Leu Ser Ile Asn Thr His Pro Ser Gln Lys Pro Leu Ser Ile

385 390 395 400

Thr Val Arg Thr Lys Lys Gln Glu Leu Ser Glu Ala Glu Gln Ala Thr

405 410 415

Arg Thr Met Gln Ala Leu Pro Tyr Ser Thr Val Gly Asn Ser Asn Asn

420 425 430

Tyr Leu His Leu Ser Val Leu Arg Thr Glu Leu Arg Pro Gly Glu Thr

435 440 445

Leu Asn Val Asn Phe Leu Leu Arg Met Asp Arg Ala His Glu Ala Lys

450 455 460

Ile Arg Tyr Tyr Thr Tyr Leu Ile Met Asn Lys Gly Arg Leu Leu Lys

465 470 475 480

Ala Gly Arg Gln Val Arg Glu Pro Gly Gln Asp Leu Val Val Leu Pro

485 490 495

Leu Ser Ile Thr Thr Asp Phe Ile Pro Ser Phe Arg Leu Val Ala Tyr

500 505 510

Tyr Thr Leu Ile Gly Ala Ser Gly Gln Arg Glu Val Val Ala Asp Ser

515 520 525

Val Trp Val Asp Val Lys Asp Ser Cys Val Gly Ser Leu Val Val Lys

530 535 540

Ser Gly Gln Ser Glu Asp Arg Gln Pro Val Pro Gly Gln Gln Met Thr

545 550 555 560

Leu Lys Ile Glu Gly Asp His Gly Ala Arg Val Val Leu Val Ala Val

565 570 575

Asp Lys Gly Val Phe Val Leu Asn Lys Lys Asn Lys Leu Thr Gln Ser

580 585 590

Lys Ile Trp Asp Val Val Glu Lys Ala Asp Ile Gly Cys Thr Pro Gly

595 600 605

Ser Gly Lys Asp Tyr Ala Gly Val Phe Ser Asp Ala Gly Leu Thr Phe

610 615 620

Thr Ser Ser Ser Gly Gln Gln Thr Ala Gln Arg Ala Glu Leu Gln Cys

625 630 635 640

Pro Gln Pro Ala Ala Arg Arg Arg Arg Ser Val Gln Leu Thr Glu Lys

645 650 655

Arg Met Asp Lys Val Gly Lys Tyr Pro Lys Glu Leu Arg Lys Cys Cys

660 665 670

Glu Asp Gly Met Arg Glu Asn Pro Met Arg Phe Ser Cys Gln Arg Arg

675 680 685

Thr Arg Phe Ile Ser Leu Gly Glu Ala Cys Lys Lys Val Phe Leu Asp

690 695 700

Cys Cys Asn Tyr Ile Thr Glu Leu Arg Arg Gln His Ala Arg Ala Ser

705 710 715 720

His Leu Gly Leu Ala Arg Ser Asn Leu Asp Glu Asp Ile Ile Ala Glu

725 730 735

Glu Asn Ile Val Ser Arg Ser Glu Phe Pro Glu Ser Trp Leu Trp Asn

740 745 750

Val Glu Asp Leu Lys Glu Pro Pro Lys Asn Gly Ile Ser Thr Lys Leu

755 760 765

Met Asn Ile Phe Leu Lys Asp Ser Ile Thr Thr Trp Glu Ile Leu Ala

770 775 780

Val Ser Met Ser Asp Lys Lys Gly Ile Cys Val Ala Asp Pro Phe Glu

785 790 795 800

Val Thr Val Met Gln Asp Phe Phe Ile Asp Leu Arg Leu Pro Tyr Ser

805 810 815

Val Val Arg Asn Glu Gln Val Glu Ile Arg Ala Val Leu Tyr Asn Tyr

820 825 830

Arg Gln Asn Gln Glu Leu Lys Val Arg Val Glu Leu Leu His Asn Pro

835 840 845

Ala Phe Cys Ser Leu Ala Thr Thr Lys Arg Arg His Gln Gln Thr Val

850 855 860

Thr Ile Pro Pro Lys Ser Ser Leu Ser Val Pro Tyr Val Ile Val Pro

865 870 875 880

Leu Lys Thr Gly Leu Gln Glu Val Glu Val Lys Ala Ala Val Tyr His

885 890 895

His Phe Ile Ser Asp Gly Val Arg Lys Ser Leu Lys Val Val Pro Glu

900 905 910

Gly Ile Arg Met Asn Lys Thr Val Ala Val Arg Thr Leu Asp Pro Glu

915 920 925

Arg Leu Gly Arg Glu Gly Val Gln Lys Glu Asp Ile Pro Pro Ala Asp

930 935 940

Leu Ser Asp Gln Val Pro Asp Thr Glu Ser Glu Thr Arg Ile Leu Leu

945 950 955 960

Gln Gly Thr Pro Val Ala Gln Met Thr Glu Asp Ala Val Asp Ala Glu

965 970 975

Arg Leu Lys His Leu Ile Val Thr Pro Ser Gly Cys Gly Glu Gln Asn

980 985 990

Met Ile Gly Met Thr Pro Thr Val Ile Ala Val His Tyr Leu Asp Glu

995 1000 1005

Thr Glu Gln Trp Glu Lys Phe Gly Leu Glu Lys Arg Gln Gly Ala

1010 1015 1020

Leu Glu Leu Ile Lys Lys Gly Tyr Thr Gln Gln Leu Ala Phe Arg

1025 1030 1035

Gln Pro Ser Ser Ala Phe Ala Ala Phe Val Lys Arg Ala Pro Ser

1040 1045 1050

Thr Trp Leu Thr Ala Tyr Val Val Lys Val Phe Ser Leu Ala Val

1055 1060 1065

Asn Leu Ile Ala Ile Asp Ser Gln Val Leu Cys Gly Ala Val Lys

1070 1075 1080

Trp Leu Ile Leu Glu Lys Gln Lys Pro Asp Gly Val Phe Gln Glu

1085 1090 1095

Asp Ala Pro Val Ile His Gln Glu Met Ile Gly Gly Leu Arg Asn

1100 1105 1110

Asn Asn Glu Lys Asp Met Ala Leu Thr Ala Phe Val Leu Ile Ser

1115 1120 1125

Leu Gln Glu Ala Lys Asp Ile Cys Glu Glu Gln Val Asn Ser Leu

1130 1135 1140

Pro Gly Ser Ile Thr Lys Ala Gly Asp Phe Leu Glu Ala Asn Tyr

1145 1150 1155

Met Asn Leu Gln Arg Ser Tyr Thr Val Ala Ile Ala Gly Tyr Ala

1160 1165 1170

Leu Ala Gln Met Gly Arg Leu Lys Gly Pro Leu Leu Asn Lys Phe

1175 1180 1185

Leu Thr Thr Ala Lys Asp Lys Asn Arg Trp Glu Asp Pro Gly Lys

1190 1195 1200

Gln Leu Tyr Asn Val Glu Ala Thr Ser Tyr Ala Leu Leu Ala Leu

1205 1210 1215

Leu Gln Leu Lys Asp Phe Asp Phe Val Pro Pro Val Val Arg Trp

1220 1225 1230

Leu Asn Glu Gln Arg Tyr Tyr Gly Gly Gly Tyr Gly Ser Thr Gln

1235 1240 1245

Ala Thr Phe Met Val Phe Gln Ala Leu Ala Gln Tyr Gln Lys Asp

1250 1255 1260

Ala Pro Asp His Gln Glu Leu Asn Leu Asp Val Ser Leu Gln Leu

1265 1270 1275

Pro Ser Arg Ser Ser Lys Ile Thr His Arg Ile His Trp Glu Ser

1280 1285 1290

Ala Ser Leu Leu Arg Ser Glu Glu Thr Lys Glu Asn Glu Gly Phe

1295 1300 1305

Thr Val Thr Ala Glu Gly Lys Gly Gln Gly Thr Leu Ser Val Val

1310 1315 1320

Thr Met Tyr His Ala Lys Ala Lys Asp Gln Leu Thr Cys Asn Lys

1325 1330 1335

Phe Asp Leu Lys Val Thr Ile Lys Pro Ala Pro Glu Thr Glu Lys

1340 1345 1350

Arg Pro Gln Asp Ala Lys Asn Thr Met Ile Leu Glu Ile Cys Thr

1355 1360 1365

Arg Tyr Arg Gly Asp Gln Asp Ala Thr Met Ser Ile Leu Asp Ile

1370 1375 1380

Ser Met Met Thr Gly Phe Ala Pro Asp Thr Asp Asp Leu Lys Gln

1385 1390 1395

Leu Ala Asn Gly Val Asp Arg Tyr Ile Ser Lys Tyr Glu Leu Asp

1400 1405 1410

Lys Ala Phe Ser Asp Arg Asn Thr Leu Ile Ile Tyr Leu Asp Lys

1415 1420 1425

Val Ser His Ser Glu Asp Asp Cys Leu Ala Phe Lys Val His Gln

1430 1435 1440

Tyr Phe Asn Val Glu Leu Ile Gln Pro Gly Ala Val Lys Val Tyr

1445 1450 1455

Ala Tyr Tyr Asn Leu Glu Glu Ser Cys Thr Arg Phe Tyr His Pro

1460 1465 1470

Glu Lys Glu Asp Gly Lys Leu Asn Lys Leu Cys Arg Asp Glu Leu

1475 1480 1485

Cys Arg Cys Ala Glu Glu Asn Cys Phe Ile Gln Lys Ser Asp Asp

1490 1495 1500

Lys Val Thr Leu Glu Glu Arg Leu Asp Lys Ala Cys Glu Pro Gly

1505 1510 1515

Val Asp Tyr Val Tyr Lys Thr Arg Leu Val Lys Val Gln Leu Ser

1520 1525 1530

Asn Asp Phe Asp Glu Tyr Ile Met Ala Ile Glu Gln Thr Ile Lys

1535 1540 1545

Ser Gly Ser Asp Glu Val Gln Val Gly Gln Gln Arg Thr Phe Ile

1550 1555 1560

Ser Pro Ile Lys Cys Arg Glu Ala Leu Lys Leu Glu Glu Glu Lys Lys

1565 1570 1575

His Tyr Leu Met Trp Gly Leu Ser Ser Asp Phe Trp Gly Glu Lys

1580 1585 1590

Pro Asn Leu Ser Tyr Ile Ile Gly Lys Asp Thr Trp Val Glu His

1595 1600 1605

Trp Pro Glu Glu Asp Glu Cys Gln Asp Glu Glu Asn Gln Lys Gln

1610 1615 1620

Cys Gln Asp Leu Gly Ala Phe Thr Glu Ser Met Val Val Phe Gly

1625 1630 1635

Cys Pro Asn

1640

<210> 3

<211> 645

<212> Protein

<213> Homo sapiens

<400> 3

Ser Pro Met Tyr Ser Ile Ile Thr Pro Asn Ile Leu Arg Leu Glu Ser

1 5 10 15

Glu Glu Thr Met Val Leu Glu Ala His Asp Ala Gln Gly Asp Val Pro

20 25 30

Val Thr Val Thr Val His Asp Phe Pro Gly Lys Lys Leu Val Leu Ser

35 40 45

Ser Glu Lys Thr Val Leu Thr Pro Ala Thr Asn His Met Gly Asn Val

50 55 60

Thr Phe Thr Ile Pro Ala Asn Arg Glu Phe Lys Ser Glu Lys Gly Arg

65 70 75 80

Asn Lys Phe Val Thr Val Gln Ala Thr Phe Gly Thr Gln Val Val Glu

85 90 95

Lys Val Val Leu Val Ser Leu Gln Ser Gly Tyr Leu Phe Ile Gln Thr

100 105 110

Asp Lys Thr Ile Tyr Thr Pro Gly Ser Thr Val Leu Tyr Arg Ile Phe

115 120 125

Thr Val Asn His Lys Leu Leu Pro Val Gly Arg Thr Val Met Val Asn

130 135 140

Ile Glu Asn Pro Glu Gly Ile Pro Val Lys Gln Asp Ser Leu Ser Ser

145 150 155 160

Gln Asn Gln Leu Gly Val Leu Pro Leu Ser Trp Asp Ile Pro Glu Leu

165 170 175

Val Asn Met Gly Gln Trp Lys Ile Arg Ala Tyr Tyr Glu Asn Ser Pro

180 185 190

Gln Gln Val Phe Ser Thr Glu Phe Glu Val Lys Glu Tyr Val Leu Pro

195 200 205

Ser Phe Glu Val Ile Val Glu Pro Thr Glu Lys Phe Tyr Tyr Ile Tyr

210 215 220

Asn Glu Lys Gly Leu Glu Val Thr Ile Thr Ala Arg Phe Leu Tyr Gly

225 230 235 240

Lys Lys Val Glu Gly Thr Ala Phe Val Ile Phe Gly Ile Gln Asp Gly

245 250 255

Glu Gln Arg Ile Ser Leu Pro Glu Ser Leu Lys Arg Ile Pro Ile Glu

260 265 270

Asp Gly Ser Gly Glu Val Val Leu Ser Arg Lys Val Leu Leu Asp Gly

275 280 285

Val Gln Asn Pro Arg Ala Glu Asp Leu Val Gly Lys Ser Leu Tyr Val

290 295 300

Ser Ala Thr Val Ile Leu His Ser Gly Ser Asp Met Val Gln Ala Glu

305 310 315 320

Arg Ser Gly Ile Pro Ile Val Thr Ser Pro Tyr Gln Ile His Phe Thr

325 330 335

Lys Thr Pro Lys Tyr Phe Lys Pro Gly Met Pro Phe Asp Leu Met Val

340 345 350

Phe Val Thr Asn Pro Asp Gly Ser Pro Ala Tyr Arg Val Pro Val Ala

355 360 365

Val Gln Gly Glu Asp Thr Val Gln Ser Leu Thr Gln Gly Asp Gly Val

370 375 380

Ala Lys Leu Ser Ile Asn Thr His Pro Ser Gln Lys Pro Leu Ser Ile

385 390 395 400

Thr Val Arg Thr Lys Lys Gln Glu Leu Ser Glu Ala Glu Gln Ala Thr

405 410 415

Arg Thr Met Gln Ala Leu Pro Tyr Ser Thr Val Gly Asn Ser Asn Asn

420 425 430

Tyr Leu His Leu Ser Val Leu Arg Thr Glu Leu Arg Pro Gly Glu Thr

435 440 445

Leu Asn Val Asn Phe Leu Leu Arg Met Asp Arg Ala His Glu Ala Lys

450 455 460

Ile Arg Tyr Tyr Thr Tyr Leu Ile Met Asn Lys Gly Arg Leu Leu Lys

465 470 475 480

Ala Gly Arg Gln Val Arg Glu Pro Gly Gln Asp Leu Val Val Leu Pro

485 490 495

Leu Ser Ile Thr Thr Asp Phe Ile Pro Ser Phe Arg Leu Val Ala Tyr

500 505 510

Tyr Thr Leu Ile Gly Ala Ser Gly Gln Arg Glu Val Val Ala Asp Ser

515 520 525

Val Trp Val Asp Val Lys Asp Ser Cys Val Gly Ser Leu Val Val Lys

530 535 540

Ser Gly Gln Ser Glu Asp Arg Gln Pro Val Pro Gly Gln Gln Met Thr

545 550 555 560

Leu Lys Ile Glu Gly Asp His Gly Ala Arg Val Val Leu Val Ala Val

565 570 575

Asp Lys Gly Val Phe Val Leu Asn Lys Lys Asn Lys Leu Thr Gln Ser

580 585 590

Lys Ile Trp Asp Val Val Glu Lys Ala Asp Ile Gly Cys Thr Pro Gly

595 600 605

Ser Gly Lys Asp Tyr Ala Gly Val Phe Ser Asp Ala Gly Leu Thr Phe

610 615 620

Thr Ser Ser Ser Gly Gln Gln Thr Ala Gln Arg Ala Glu Leu Gln Cys

625 630 635 640

Pro Gln Pro Ala Ala

645

<210> 4

<211> 992

<212> Protein

<213> Homo sapiens

<400> 4

Ser Val Gln Leu Thr Glu Lys Arg Met Asp Lys Val Gly Lys Tyr Pro

1 5 10 15

Lys Glu Leu Arg Lys Cys Cys Glu Asp Gly Met Arg Glu Asn Pro Met

20 25 30

Arg Phe Ser Cys Gln Arg Arg Thr Arg Phe Ile Ser Leu Gly Glu Ala

35 40 45

Cys Lys Lys Val Phe Leu Asp Cys Cys Asn Tyr Ile Thr Glu Leu Arg

50 55 60

Arg Gln His Ala Arg Ala Ser His Leu Gly Leu Ala Arg Ser Asn Leu

65 70 75 80

Asp Glu Asp Ile Ile Ala Glu Glu Asn Ile Val Ser Arg Ser Glu Phe

85 90 95

Pro Glu Ser Trp Leu Trp Asn Val Glu Asp Leu Lys Glu Pro Pro Lys

100 105 110

Asn Gly Ile Ser Thr Lys Leu Met Asn Ile Phe Leu Lys Asp Ser Ile

115 120 125

Thr Thr Trp Glu Ile Leu Ala Val Ser Met Ser Asp Lys Lys Gly Ile

130 135 140

Cys Val Ala Asp Pro Phe Glu Val Thr Val Met Gln Asp Phe Phe Ile

145 150 155 160

Asp Leu Arg Leu Pro Tyr Ser Val Val Arg Asn Glu Gln Val Glu Ile

165 170 175

Arg Ala Val Leu Tyr Asn Tyr Arg Gln Asn Gln Glu Leu Lys Val Arg

180 185 190

Val Glu Leu Leu His Asn Pro Ala Phe Cys Ser Leu Ala Thr Thr Lys

195 200 205

Arg Arg His Gln Gln Thr Val Thr Ile Pro Pro Lys Ser Ser Leu Ser

210 215 220

Val Pro Tyr Val Ile Val Pro Leu Lys Thr Gly Leu Gln Glu Val Glu

225 230 235 240

Val Lys Ala Ala Val Tyr His His Phe Ile Ser Asp Gly Val Arg Lys

245 250 255

Ser Leu Lys Val Val Pro Glu Gly Ile Arg Met Asn Lys Thr Val Ala

260 265 270

Val Arg Thr Leu Asp Pro Glu Arg Leu Gly Arg Glu Gly Val Gln Lys

275 280 285

Glu Asp Ile Pro Pro Ala Asp Leu Ser Asp Gln Val Pro Asp Thr Glu

290 295 300

Ser Glu Thr Arg Ile Leu Leu Gln Gly Thr Pro Val Ala Gln Met Thr

305 310 315 320

Glu Asp Ala Val Asp Ala Glu Arg Leu Lys His Leu Ile Val Thr Pro

325 330 335

Ser Gly Cys Gly Glu Gln Asn Met Ile Gly Met Thr Pro Thr Val Ile

340 345 350

Ala Val His Tyr Leu Asp Glu Thr Glu Gln Trp Glu Lys Phe Gly Leu

355 360 365

Glu Lys Arg Gln Gly Ala Leu Glu Leu Ile Lys Lys Gly Tyr Thr Gln

370 375 380

Gln Leu Ala Phe Arg Gln Pro Ser Ser Ala Phe Ala Ala Phe Val Lys

385 390 395 400

Arg Ala Pro Ser Thr Trp Leu Thr Ala Tyr Val Val Lys Val Phe Ser

405 410 415

Leu Ala Val Asn Leu Ile Ala Ile Asp Ser Gln Val Leu Cys Gly Ala

420 425 430

Val Lys Trp Leu Ile Leu Glu Lys Gln Lys Pro Asp Gly Val Phe Gln

435 440 445

Glu Asp Ala Pro Val Ile His Gln Glu Met Ile Gly Gly Leu Arg Asn

450 455 460

Asn Asn Glu Lys Asp Met Ala Leu Thr Ala Phe Val Leu Ile Ser Leu

465 470 475 480

Gln Glu Ala Lys Asp Ile Cys Glu Glu Gln Val Asn Ser Leu Pro Gly

485 490 495

Ser Ile Thr Lys Ala Gly Asp Phe Leu Glu Ala Asn Tyr Met Asn Leu

500 505 510

Gln Arg Ser Tyr Thr Val Ala Ile Ala Gly Tyr Ala Leu Ala Gln Met

515 520 525

Gly Arg Leu Lys Gly Pro Leu Leu Asn Lys Phe Leu Thr Thr Ala Lys

530 535 540

Asp Lys Asn Arg Trp Glu Asp Pro Gly Lys Gln Leu Tyr Asn Val Glu

545 550 555 560

Ala Thr Ser Tyr Ala Leu Leu Ala Leu Leu Gln Leu Lys Asp Phe Asp

565 570 575

Phe Val Pro Pro Val Val Arg Trp Leu Asn Glu Gln Arg Tyr Tyr Gly

580 585 590

Gly Gly Tyr Gly Ser Thr Gln Ala Thr Phe Met Val Phe Gln Ala Leu

595 600 605

Ala Gln Tyr Gln Lys Asp Ala Pro Asp His Gln Glu Leu Asn Leu Asp

610 615 620

Val Ser Leu Gln Leu Pro Ser Arg Ser Ser Lys Ile Thr His Arg Ile

625 630 635 640

His Trp Glu Ser Ala Ser Leu Leu Arg Ser Glu Glu Thr Lys Glu Asn

645 650 655

Glu Gly Phe Thr Val Thr Ala Glu Gly Lys Gly Gln Gly Thr Leu Ser

660 665 670

Val Val Thr Met Tyr His Ala Lys Ala Lys Asp Gln Leu Thr Cys Asn

675 680 685

Lys Phe Asp Leu Lys Val Thr Ile Lys Pro Ala Pro Glu Thr Glu Lys

690 695 700

Arg Pro Gln Asp Ala Lys Asn Thr Met Ile Leu Glu Ile Cys Thr Arg

705 710 715 720

Tyr Arg Gly Asp Gln Asp Ala Thr Met Ser Ile Leu Asp Ile Ser Met

725 730 735

Met Thr Gly Phe Ala Pro Asp Thr Asp Asp Leu Lys Gln Leu Ala Asn

740 745 750

Gly Val Asp Arg Tyr Ile Ser Lys Tyr Glu Leu Asp Lys Ala Phe Ser

755 760 765

Asp Arg Asn Thr Leu Ile Ile Tyr Leu Asp Lys Val Ser His Ser Glu

770 775 780

Asp Asp Cys Leu Ala Phe Lys Val His Gln Tyr Phe Asn Val Glu Leu

785 790 795 800

Ile Gln Pro Gly Ala Val Lys Val Tyr Ala Tyr Tyr Asn Leu Glu Glu

805 810 815

Ser Cys Thr Arg Phe Tyr His Pro Glu Lys Glu Asp Gly Lys Leu Asn

820 825 830

Lys Leu Cys Arg Asp Glu Leu Cys Arg Cys Ala Glu Glu Asn Cys Phe

835 840 845

Ile Gln Lys Ser Asp Asp Lys Val Thr Leu Glu Glu Arg Leu Asp Lys

850 855 860

Ala Cys Glu Pro Gly Val Asp Tyr Val Tyr Lys Thr Arg Leu Val Lys

865 870 875 880

Val Gln Leu Ser Asn Asp Phe Asp Glu Tyr Ile Met Ala Ile Glu Gln

885 890 895

Thr Ile Lys Ser Gly Ser Asp Glu Val Gln Val Gly Gln Gln Arg Thr

900 905 910

Phe Ile Ser Pro Ile Lys Cys Arg Glu Ala Leu Lys Leu Glu Glu Lys

915 920 925

Lys His Tyr Leu Met Trp Gly Leu Ser Ser Asp Phe Trp Gly Glu Lys

930 935 940

Pro Asn Leu Ser Tyr Ile Ile Gly Lys Asp Thr Trp Val Glu His Trp

945 950 955 960

Pro Glu Glu Asp Glu Cys Gln Asp Glu Glu Asn Gln Lys Gln Cys Gln

965 970 975

Asp Leu Gly Ala Phe Thr Glu Ser Met Val Val Phe Gly Cys Pro Asn

980 985 990

<210> 5

<211> 915

<212> Protein

<213> Homo sapiens

<400> 5

Ser Asn Leu Asp Glu Asp Ile Ile Ala Glu Glu Asn Ile Val Ser Arg

1 5 10 15

Ser Glu Phe Pro Glu Ser Trp Leu Trp Asn Val Glu Asp Leu Lys Glu

20 25 30

Pro Pro Lys Asn Gly Ile Ser Thr Lys Leu Met Asn Ile Phe Leu Lys

35 40 45

Asp Ser Ile Thr Thr Trp Glu Ile Leu Ala Val Ser Met Ser Asp Lys

50 55 60

Lys Gly Ile Cys Val Ala Asp Pro Phe Glu Val Thr Val Met Gln Asp

65 70 75 80

Phe Phe Ile Asp Leu Arg Leu Pro Tyr Ser Val Val Arg Asn Glu Gln

85 90 95

Val Glu Ile Arg Ala Val Leu Tyr Asn Tyr Arg Gln Asn Gln Glu Leu

100 105 110

Lys Val Arg Val Glu Leu Leu His Asn Pro Ala Phe Cys Ser Leu Ala

115 120 125

Thr Thr Lys Arg Arg His Gln Gln Thr Val Thr Ile Pro Pro Lys Ser

130 135 140

Ser Leu Ser Val Pro Tyr Val Ile Val Pro Leu Lys Thr Gly Leu Gln

145 150 155 160

Glu Val Glu Val Lys Ala Ala Val Tyr His His Phe Ile Ser Asp Gly

165 170 175

Val Arg Lys Ser Leu Lys Val Val Pro Glu Gly Ile Arg Met Asn Lys

180 185 190

Thr Val Ala Val Arg Thr Leu Asp Pro Glu Arg Leu Gly Arg Glu Gly

195 200 205

Val Gln Lys Glu Asp Ile Pro Pro Ala Asp Leu Ser Asp Gln Val Pro

210 215 220

Asp Thr Glu Ser Glu Thr Arg Ile Leu Leu Gln Gly Thr Pro Val Ala

225 230 235 240

Gln Met Thr Glu Asp Ala Val Asp Ala Glu Arg Leu Lys His Leu Ile

245 250 255

Val Thr Pro Ser Gly Cys Gly Glu Gln Asn Met Ile Gly Met Thr Pro

260 265 270

Thr Val Ile Ala Val His Tyr Leu Asp Glu Thr Glu Gln Trp Glu Lys

275 280 285

Phe Gly Leu Glu Lys Arg Gln Gly Ala Leu Glu Leu Ile Lys Lys Gly

290 295 300

Tyr Thr Gln Gln Leu Ala Phe Arg Gln Pro Ser Ser Ala Phe Ala Ala

305 310 315 320

Phe Val Lys Arg Ala Pro Ser Thr Trp Leu Thr Ala Tyr Val Val Lys

325 330 335

Val Phe Ser Leu Ala Val Asn Leu Ile Ala Ile Asp Ser Gln Val Leu

340 345 350

Cys Gly Ala Val Lys Trp Leu Ile Leu Glu Lys Gln Lys Pro Asp Gly

355 360 365

Val Phe Gln Glu Asp Ala Pro Val Ile His Gln Glu Met Ile Gly Gly

370 375 380

Leu Arg Asn Asn Asn Glu Lys Asp Met Ala Leu Thr Ala Phe Val Leu

385 390 395 400

Ile Ser Leu Gln Glu Ala Lys Asp Ile Cys Glu Glu Gln Val Asn Ser

405 410 415

Leu Pro Gly Ser Ile Thr Lys Ala Gly Asp Phe Leu Glu Ala Asn Tyr

420 425 430

Met Asn Leu Gln Arg Ser Tyr Thr Val Ala Ile Ala Gly Tyr Ala Leu

435 440 445

Ala Gln Met Gly Arg Leu Lys Gly Pro Leu Leu Asn Lys Phe Leu Thr

450 455 460

Thr Ala Lys Asp Lys Asn Arg Trp Glu Asp Pro Gly Lys Gln Leu Tyr

465 470 475 480

Asn Val Glu Ala Thr Ser Tyr Ala Leu Leu Ala Leu Leu Gln Leu Lys

485 490 495

Asp Phe Asp Phe Val Pro Pro Val Val Arg Trp Leu Asn Glu Gln Arg

500 505 510

Tyr Tyr Gly Gly Gly Tyr Gly Ser Thr Gln Ala Thr Phe Met Val Phe

515 520 525

Gln Ala Leu Ala Gln Tyr Gln Lys Asp Ala Pro Asp His Gln Glu Leu

530 535 540

Asn Leu Asp Val Ser Leu Gln Leu Pro Ser Arg Ser Ser Lys Ile Thr

545 550 555 560

His Arg Ile His Trp Glu Ser Ala Ser Leu Leu Arg Ser Glu Glu Thr

565 570 575

Lys Glu Asn Glu Gly Phe Thr Val Thr Ala Glu Gly Lys Gly Gln Gly

580 585 590

Thr Leu Ser Val Val Thr Met Tyr His Ala Lys Ala Lys Asp Gln Leu

595 600 605

Thr Cys Asn Lys Phe Asp Leu Lys Val Thr Ile Lys Pro Ala Pro Glu

610 615 620

Thr Glu Lys Arg Pro Gln Asp Ala Lys Asn Thr Met Ile Leu Glu Ile

625 630 635 640

Cys Thr Arg Tyr Arg Gly Asp Gln Asp Ala Thr Met Ser Ile Leu Asp

645 650 655

Ile Ser Met Met Thr Gly Phe Ala Pro Asp Thr Asp Asp Leu Lys Gln

660 665 670

Leu Ala Asn Gly Val Asp Arg Tyr Ile Ser Lys Tyr Glu Leu Asp Lys

675 680 685

Ala Phe Ser Asp Arg Asn Thr Leu Ile Ile Tyr Leu Asp Lys Val Ser

690 695 700

His Ser Glu Asp Asp Cys Leu Ala Phe Lys Val His Gln Tyr Phe Asn

705 710 715 720

Val Glu Leu Ile Gln Pro Gly Ala Val Lys Val Tyr Ala Tyr Tyr Asn

725 730 735

Leu Glu Glu Ser Cys Thr Arg Phe Tyr His Pro Glu Lys Glu Asp Gly

740 745 750

Lys Leu Asn Lys Leu Cys Arg Asp Glu Leu Cys Arg Cys Ala Glu Glu

755 760 765

Asn Cys Phe Ile Gln Lys Ser Asp Asp Lys Val Thr Leu Glu Glu Arg

770 775 780

Leu Asp Lys Ala Cys Glu Pro Gly Val Asp Tyr Val Tyr Lys Thr Arg

785 790 795 800

Leu Val Lys Val Gln Leu Ser Asn Asp Phe Asp Glu Tyr Ile Met Ala

805 810 815

Ile Glu Gln Thr Ile Lys Ser Gly Ser Asp Glu Val Gln Val Gly Gln

820 825 830

Gln Arg Thr Phe Ile Ser Pro Ile Lys Cys Arg Glu Ala Leu Lys Leu

835 840 845

Glu Glu Lys Lys His Tyr Leu Met Trp Gly Leu Ser Ser Asp Phe Trp

850 855 860

Gly Glu Lys Pro Asn Leu Ser Tyr Ile Ile Gly Lys Asp Thr Trp Val

865 870 875 880

Glu His Trp Pro Glu Glu Asp Glu Cys Gln Asp Glu Glu Asn Gln Lys

885 890 895

Gln Cys Gln Asp Leu Gly Ala Phe Thr Glu Ser Met Val Val Phe Gly

900 905 910

Cys Pro Asn

915

<210> 6

<211> 77

<212> Protein

<213> Homo sapiens

<400> 6

Ser Val Gln Leu Thr Glu Lys Arg Met Asp Lys Val Gly Lys Tyr Pro

1 5 10 15

Lys Glu Leu Arg Lys Cys Cys Glu Asp Gly Met Arg Glu Asn Pro Met

20 25 30

Arg Phe Ser Cys Gln Arg Arg Thr Arg Phe Ile Ser Leu Gly Glu Ala

35 40 45

Cys Lys Lys Val Phe Leu Asp Cys Cys Asn Tyr Ile Thr Glu Leu Arg

50 55 60

Arg Gln His Ala Arg Ala Ser His Leu Gly Leu Ala Arg

65 70 75

<210> 7

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 7

Gly Tyr Thr Phe Thr Asp Phe Tyr Met Asp

1 5 10

<210> 8

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 8

Tyr Ile Tyr Pro His Asn Gly Gly Thr Thr Tyr Asn Gln Asn Phe Thr

1 5 10 15

gly

<210> 9

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 9

Arg Gly Gly Phe Asp Phe Asp Tyr

15

<210> 10

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 10

Lys Ala Ser Glu Asn Val Asp Thr Tyr Val Ser

1 5 10

<210> 11

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 11

Gly Ala Ser Asn Arg Tyr Thr

15

<210> 12

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 12

Gly Gln Ser His Ser Tyr Pro Leu Thr

15

<210> 13

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 13

Tyr Ile Tyr Pro His Asn Gly Gly Thr Thr Tyr Asn Gln Gln Phe Thr

1 5 10 15

gly

<210> 14

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 14

Tyr Ile Tyr Pro His Asn Ala Gly Thr Thr Tyr Asn Gln Gln Phe Thr

1 5 10 15

gly

<210> 15

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 15

Tyr Ile Tyr Pro His Asn Thr Gly Thr Thr Tyr Asn Gln Gln Phe Thr

1 5 10 15

gly

<210> 16

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 16

Tyr Ile Tyr Pro His Glu Gly Gly Thr Thr Tyr Asn Gln Gln Phe Thr

1 5 10 15

gly

<210> 17

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 17

Tyr Ile Tyr Pro His Gln Gly Gly Thr Thr Tyr Asn Gln Gln Phe Thr

1 5 10 15

gly

<210> 18

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 18

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Asp

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe

20 25 30

Tyr Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Tyr Pro His Asn Gly Gly Thr Thr Tyr Asn Gln Asn Phe

50 55 60

Thr Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu His Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Leu Thr Val Ser Ser

115

<210> 19

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 19

Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Leu Ser Val Gly

1 5 10 15

Glu Arg Val Thr Leu Arg Cys Lys Ala Ser Glu Asn Val Asp Thr Tyr

20 25 30

Val Ser Trp Tyr Gln Gln Lys Pro Glu Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Ala Thr Glu Phe Thr Leu Thr Ile Ser Ser Val Gln Ala

65 70 75 80

Glu Asp Leu Val Gly Tyr His Cys Gly Gln Ser His Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 20

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 20

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe

20 25 30

Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Glu Trp Met

35 40 45

Gly Tyr Ile Tyr Pro His Asn Gly Gly Thr Thr Tyr Asn Gln Gln Phe

50 55 60

Thr Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 21

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 21

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe

20 25 30

Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Glu Trp Met

35 40 45

Gly Tyr Ile Tyr Pro His Asn Ala Gly Thr Thr Tyr Asn Gln Gln Phe

50 55 60

Thr Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 22

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 22

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe

20 25 30

Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Glu Trp Met

35 40 45

Gly Tyr Ile Tyr Pro His Asn Thr Gly Thr Thr Tyr Asn Gln Gln Phe

50 55 60

Thr Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 23

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 23

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe

20 25 30

Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Glu Trp Met

35 40 45

Gly Tyr Ile Tyr Pro His Glu Gly Gly Thr Thr Tyr Asn Gln Gln Phe

50 55 60

Thr Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 24

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 24

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe

20 25 30

Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Glu Trp Met

35 40 45

Gly Tyr Ile Tyr Pro His Gln Gly Gly Thr Thr Tyr Asn Gln Gln Phe

50 55 60

Thr Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 25

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 25

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Asp Thr Tyr

20 25 30

Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr His Cys Gly Gln Ser His Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 26

<211> 469

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 26

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu

20 25 30

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

35 40 45

Tyr Thr Phe Thr Asp Phe Tyr Met Asp Trp Val Arg Gln Ala Pro Gly

50 55 60

Gln Arg Leu Glu Trp Met Gly Tyr Ile Tyr Pro His Asn Gly Gly Thr

65 70 75 80

Thr Tyr Asn Gln Gln Phe Thr Gly Arg Val Thr Ile Thr Val Asp Lys

85 90 95

Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Ser Leu Arg Ser Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

130 135 140

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

145 150 155 160

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

165 170 175

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

180 185 190

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

195 200 205

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

210 215 220

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

225 230 235 240

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Ala Leu

245 250 255

Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

370 375 380

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro Gly Lys

465

<210> 27

<211> 447

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 27

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe

20 25 30

Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Glu Trp Met

35 40 45

Gly Tyr Ile Tyr Pro His Asn Gly Gly Thr Thr Tyr Asn Gln Gln Phe

50 55 60

Thr Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His

210 215 220

Thr Cys Pro Pro Cys Pro Ala Pro Ala Leu Ala Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

260 265 270

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 28

<211> 469

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 28

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Gln Ser Gly Ala Glu

20 25 30

Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly

35 40 45

Tyr Thr Phe Thr Asp Phe Tyr Met Asp Trp Val Arg Gln Ala Pro Gly

50 55 60

Gln Arg Leu Glu Trp Met Gly Tyr Ile Tyr Pro His Asn Ala Gly Thr

65 70 75 80

Thr Tyr Asn Gln Gln Phe Thr Gly Arg Val Thr Ile Thr Val Asp Lys

85 90 95

Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Ser Leu Arg Ser Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly

130 135 140

Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly

145 150 155 160

Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val

165 170 175

Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe

180 185 190

Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val

195 200 205

Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val

210 215 220

Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys

225 230 235 240

Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Ala Leu

245 250 255

Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser

305 310 315 320

Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala

340 345 350

Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

370 375 380

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro Gly Lys

465

<210> 29

<211> 447

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 29

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe

20 25 30

Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Glu Trp Met

35 40 45

Gly Tyr Ile Tyr Pro His Asn Ala Gly Thr Thr Tyr Asn Gln Gln Phe

50 55 60

Thr Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His

210 215 220

Thr Cys Pro Pro Cys Pro Ala Pro Ala Leu Ala Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

260 265 270

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 30

<211> 236

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 30

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

20 25 30

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser

35 40 45

Glu Asn Val Asp Thr Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys

50 55 60

Ala Pro Lys Leu Leu Ile Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val

65 70 75 80

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr

85 90 95

Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala Thr Tyr His Cys Gly Gln

100 105 110

Ser His Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile

115 120 125

Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp

130 135 140

Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn

145 150 155 160

Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu

165 170 175

Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp

180 185 190

Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr

195 200 205

Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser

210 215 220

Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

225 230 235

<210> 31

<211> 214

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 31

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Asp Thr Tyr

20 25 30

Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr His Cys Gly Gln Ser His Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 32

<211> 1663

<212> Protein

<213> Macaca fascicularis

<400> 32

Met Gly Leu Thr Ser Gly Pro Ser Leu Leu Leu Leu Leu Leu Ile His

1 5 10 15

Leu Pro Leu Ala Leu Gly Thr Pro Met Tyr Ser Met Ile Thr Pro Asn

20 25 30

Val Leu Arg Leu Glu Ser Glu Ser Glu Thr Val Leu Glu Ala His Asp

35 40 45

Ala Asn Gly Asp Val Pro Val Thr Val Thr Val His Asp Phe Pro Gly

50 55 60

Lys Lys Leu Val Leu Ser Ser Glu Lys Thr Val Leu Thr Pro Ala Thr

65 70 75 80

Ser His Met Gly Ser Val Thr Ile Arg Ile Pro Ala Asn Lys Glu Phe

85 90 95

Lys Ser Glu Lys Gly His Asn Lys Phe Val Thr Val Gln Ala Thr Phe

100 105 110

Gly Ala Gln Val Val Glu Lys Val Val Leu Val Ser Leu Gln Ser Gly

115 120 125

Tyr Leu Phe Ile Gln Thr Asp Lys Thr Ile Tyr Thr Pro Gly Ser Thr

130 135 140

Val Leu Cys Arg Ile Phe Thr Val Asn His Lys Leu Leu Pro Val Gly

145 150 155 160

Arg Thr Val Val Val Asn Ile Glu Asn Pro Asp Gly Ile Pro Val Lys

165 170 175

Gln Asp Ser Leu Ser Ser Gln Asn Gln Phe Gly Ile Leu Pro Leu Ser

180 185 190

Trp Asp Ile Pro Glu Leu Val Asn Met Gly Gln Trp Lys Ile Arg Ala

195 200 205

Tyr Tyr Glu Asn Ser Pro Gln Gln Val Phe Ser Thr Glu Phe Glu Val

210 215 220

Lys Glu Tyr Val Leu Pro Ser Phe Glu Val Ile Val Glu Pro Thr Glu

225 230 235 240

Lys Phe Tyr Tyr Ile Tyr Asn Gln Lys Gly Leu Glu Val Thr Ile Thr

245 250 255

Ala Arg Phe Leu Tyr Gly Lys Lys Val Glu Gly Thr Ala Phe Val Ile

260 265 270

Phe Gly Ile Gln Asp Gly Glu Gln Arg Ile Ser Leu Pro Glu Ser Leu

275 280 285

Lys Arg Ile Gln Ile Glu Asp Gly Ser Gly Asp Ala Val Leu Ser Arg

290 295 300

Lys Val Leu Leu Asp Gly Val Gln Asn Pro Arg Pro Glu Asp Leu Val

305 310 315 320

Gly Lys Ser Leu Tyr Val Ser Val Thr Val Ile Leu His Ser Gly Ser

325 330 335

Asp Met Val Gln Ala Glu Arg Ser Gly Ile Pro Ile Val Thr Ser Pro

340 345 350

Tyr Gln Ile His Phe Thr Lys Thr Pro Lys Tyr Phe Lys Pro Gly Met

355 360 365

Pro Phe Asp Leu Met Val Phe Val Thr Asn Pro Asp Gly Ser Pro Ala

370 375 380

Tyr Arg Val Pro Val Ala Val Gln Gly Glu Asp Ala Val Gln Ser Leu

385 390 395 400

Thr Gln Gly Asp Gly Val Ala Lys Leu Ser Ile Asn Thr His Pro Ser

405 410 415

Gln Lys Pro Leu Ser Ile Thr Val Arg Thr Lys Lys Arg Glu Leu Ser

420 425 430

Glu Ala Glu Gln Ala Thr Arg Thr Met Glu Ala Gln Pro Tyr Ser Thr

435 440 445

Val Gly Asn Ser Asn Asn Tyr Leu His Leu Ser Val Pro Arg Ala Glu

450 455 460

Leu Arg Pro Gly Glu Thr Leu Asn Val Asn Phe Leu Leu Arg Met Asp

465 470 475 480

Arg Thr Gln Glu Ala Lys Ile Arg Tyr Tyr Thr Tyr Leu Ile Met Asn

485 490 495

Lys Gly Lys Leu Leu Lys Val Gly Arg Gln Val Arg Glu Pro Gly Gln

500 505 510

Asp Leu Val Val Leu Pro Leu Ser Ile Thr Thr Asp Phe Ile Pro Ser

515 520 525

Phe Arg Leu Val Ala Tyr Tyr Thr Leu Ile Gly Ala Asn Gly Gln Arg

530 535 540

Glu Val Val Ala Asp Ser Val Trp Val Asp Val Lys Asp Ser Cys Val

545 550 555 560

Gly Ser Leu Val Val Lys Ser Gly Gln Ser Glu Asp Arg Gln Pro Leu

565 570 575

Pro Gly Gln Gln Met Thr Leu Lys Ile Glu Gly Asp His Gly Ala Arg

580 585 590

Val Gly Leu Val Ala Val Asp Lys Gly Val Phe Val Leu Asn Lys Lys

595 600 605

Asn Lys Leu Thr Gln Ser Lys Ile Trp Asp Val Val Glu Lys Ala Asp

610 615 620

Ile Gly Cys Thr Pro Gly Ser Gly Lys Asp Tyr Ala Gly Val Phe Ser

625 630 635 640

Asp Ala Gly Leu Thr Phe Ala Ser Ser Ser Gly Gln Gln Thr Ala Gln

645 650 655

Arg Ala Glu Leu Gln Cys Pro Gln Pro Ala Ala Arg Arg Arg Arg Ser

660 665 670

Val Gln Leu Ala Glu Lys Arg Met Asp Lys Val Gly Gln Tyr Pro Lys

675 680 685

Glu Leu Arg Lys Cys Cys Glu His Gly Met Arg Glu Asn Pro Met Arg

690 695 700

Phe Ser Cys Gln Arg Arg Thr Arg Tyr Ile Thr Leu Asp Glu Ala Cys

705 710 715 720

Lys Lys Ala Phe Leu Asp Cys Cys Asn Tyr Ile Thr Glu Leu Arg Arg

725 730 735

Gln His Ala Arg Ala Ser His Leu Gly Leu Ala Arg Ser Asn Leu Asp

740 745 750

Glu Asp Ile Ile Ala Glu Glu Asn Ile Val Ser Arg Ser Glu Phe Pro

755 760 765

Glu Ser Trp Leu Trp Lys Ile Glu Glu Leu Lys Glu Ala Pro Lys Asn

770 775 780

Gly Ile Ser Thr Lys Leu Met Asn Ile Phe Leu Lys Asp Ser Ile Thr

785 790 795 800

Thr Trp Glu Ile Leu Ala Val Ser Leu Ser Asp Lys Lys Gly Ile Cys

805 810 815

Val Ala Asp Pro Phe Glu Val Thr Val Met Gln Asp Phe Phe Ile Asp

820 825 830

Leu Arg Leu Pro Tyr Ser Val Val Arg Asn Glu Gln Val Glu Ile Arg

835 840 845

Ala Val Leu Tyr Asn Tyr Arg Gln Asn Gln Glu Leu Lys Val Arg Val

850 855 860

Glu Leu Leu His Asn Pro Ala Phe Cys Ser Leu Ala Thr Ala Lys Arg

865 870 875 880

Arg His Gln Gln Thr Val Thr Ile Pro Pro Lys Ser Ser Leu Ser Val

885 890 895

Pro Tyr Val Ile Val Pro Leu Lys Thr Gly Gln Gln Glu Val Glu Val

900 905 910

Lys Ala Ala Val Tyr His Phe Phe Ile Ser Asp Gly Val Arg Lys Ser

915 920 925

Leu Lys Val Val Pro Glu Gly Ile Arg Met Asn Lys Thr Val Ala Val

930 935 940

Arg Thr Leu Asp Pro Glu Arg Leu Gly Gln Glu Gly Val Gln Arg Glu

945 950 955 960

Asp Val Pro Pro Ala Asp Leu Ser Asp Gln Val Pro Asp Thr Glu Ser

965 970 975

Glu Thr Arg Ile Leu Leu Gln Gly Thr Pro Val Ala Gln Met Thr Glu

980 985 990

Asp Ala Ile Asp Ala Glu Arg Leu Lys His Leu Ile Val Thr Pro Ser

995 1000 1005

Gly Cys Gly Glu Gln Asn Met Ile Thr Met Thr Pro Thr Val Ile

1010 1015 1020

Ala Val His Tyr Leu Asp Glu Thr Glu Gln Trp Glu Lys Phe Gly

1025 1030 1035

Pro Glu Lys Arg Gln Gly Ala Leu Glu Leu Ile Lys Lys Gly Tyr

1040 1045 1050

Thr Gln Gln Leu Ala Phe Arg Gln Pro Ser Ser Ala Phe Ala Ala

1055 1060 1065

Phe Leu Asn Arg Ala Pro Ser Thr Trp Leu Thr Ala Tyr Val Val

1070 1075 1080

Lys Val Phe Ser Leu Ala Val Asn Leu Ile Ala Ile Asp Ser Gln

1085 1090 1095

Val Leu Cys Gly Ala Val Lys Trp Leu Ile Leu Glu Lys Gln Lys

1100 1105 1110

Pro Asp Gly Val Phe Gln Glu Asp Ala Pro Val Ile His Gln Glu

1115 1120 1125

Met Thr Gly Gly Phe Arg Asn Thr Asn Glu Lys Asp Met Ala Leu

1130 1135 1140

Thr Ala Phe Val Leu Ile Ser Leu Gln Glu Ala Lys Glu Ile Cys

1145 1150 1155

Glu Glu Gln Val Asn Ser Leu Pro Gly Ser Ile Thr Lys Ala Gly

1160 1165 1170

Asp Phe Leu Glu Ala Asn Tyr Met Asn Leu Gln Arg Ser Tyr Thr

1175 1180 1185

Val Ala Ile Ala Ala Tyr Ala Leu Ala Gln Met Gly Arg Leu Lys

1190 1195 1200

Gly Pro Leu Leu Asn Lys Phe Leu Thr Thr Ala Lys Asp Lys Asn

1205 1210 1215

Arg Trp Glu Glu Pro Gly Gln Gln Leu Tyr Asn Val Glu Ala Thr

1220 1225 1230

Ser Tyr Ala Leu Leu Ala Leu Leu Gln Leu Lys Asp Phe Asp Phe

1235 1240 1245

Val Pro Pro Val Val Arg Trp Leu Asn Glu Gln Arg Tyr Tyr Gly

1250 1255 1260

Gly Gly Tyr Gly Ser Thr Gln Ala Thr Phe Met Val Phe Gln Ala

1265 1270 1275

Leu Ala Gln Tyr Gln Lys Asp Val Pro Asp His Lys Glu Leu Asn

1280 1285 1290

Leu Asp Val Ser Leu Gln Leu Pro Ser Arg Ser Ser Lys Ile Ile

1295 1300 1305

His Arg Ile His Trp Glu Ser Ala Ser Leu Leu Arg Ser Glu Glu

1310 1315 1320

Thr Lys Glu Asn Glu Gly Phe Thr Val Thr Ala Glu Gly Lys Gly

1325 1330 1335

Gln Gly Thr Leu Ser Val Val Thr Met Tyr His Ala Lys Ala Lys

1340 1345 1350

Gly Gln Leu Thr Cys Asn Lys Phe Asp Leu Lys Val Thr Ile Lys

1355 1360 1365

Pro Ala Pro Glu Thr Glu Lys Arg Pro Gln Asp Ala Lys Asn Thr

1370 1375 1380

Met Ile Leu Glu Ile Cys Thr Arg Tyr Arg Gly Asp Gln Asp Ala

1385 1390 1395

Thr Met Ser Ile Leu Asp Ile Ser Met Met Thr Gly Phe Val Pro

1400 1405 1410

Asp Thr Asp Asp Leu Lys Gln Leu Ala Asn Gly Val Asp Arg Tyr

1415 1420 1425

Ile Ser Lys Tyr Glu Leu Asp Lys Ala Phe Ser Asp Arg Asn Thr

1430 1435 1440

Leu Ile Ile Tyr Leu Asp Lys Val Ser His Ser Glu Asp Asp Cys

1445 1450 1455

Ile Ala Phe Lys Val His Gln Tyr Phe Asn Val Glu Leu Ile Gln

1460 1465 1470

Pro Gly Ala Val Lys Val Tyr Ala Tyr Tyr Asn Leu Ala Glu Ser

1475 1480 1485

Cys Thr Arg Phe Tyr His Pro Glu Lys Glu Asp Gly Lys Leu Asn

1490 1495 1500

Lys Leu Cys Arg Asp Glu Leu Cys Arg Cys Ala Glu Glu Asn Cys

1505 1510 1515

Phe Ile Gln Lys Leu Asp Asp Lys Val Thr Leu Glu Glu Arg Leu

1520 1525 1530

Asp Lys Ala Cys Glu Pro Gly Val Asp Tyr Val Tyr Lys Thr Arg

1535 1540 1545

Leu Val Lys Ala Gln Leu Ser Asn Asp Phe Asp Glu Tyr Ile Met

1550 1555 1560

Ala Ile Glu Gln Ile Ile Lys Ser Gly Ser Asp Glu Val Gln Val

1565 1570 1575

Gly Gln Gln Arg Thr Phe Ile Ser Pro Ile Lys Cys Arg Glu Ala

1580 1585 1590

Leu Lys Leu Glu Glu Arg Lys His Tyr Leu Met Trp Gly Leu Ser

1595 1600 1605

Ser Asp Phe Trp Gly Glu Lys Pro Asn Leu Ser Tyr Ile Ile Gly

1610 1615 1620

Lys Asp Thr Trp Val Glu His Trp Pro Glu Glu Asp Glu Cys Gln

1625 1630 1635

Asp Glu Glu Asn Gln Lys Gln Cys Gln Asp Leu Gly Thr Phe Thr

1640 1645 1650

Glu Asn Met Val Val Phe Gly Cys Pro Asn

1655 1660

<210> 33

<211> 1641

<212> Protein

<213> Macaca fascicularis

<400> 33

Thr Pro Met Tyr Ser Met Ile Thr Pro Asn Val Leu Arg Leu Glu Ser

1 5 10 15

Glu Glu Thr Val Val Leu Glu Ala His Asp Ala Asn Gly Asp Val Pro

20 25 30

Val Thr Val Thr Val His Asp Phe Pro Gly Lys Lys Leu Val Leu Ser

35 40 45

Ser Glu Lys Thr Val Leu Thr Pro Ala Thr Ser His Met Gly Ser Val

50 55 60

Thr Ile Arg Ile Pro Ala Asn Lys Glu Phe Lys Ser Glu Lys Gly His

65 70 75 80

Asn Lys Phe Val Thr Val Gln Ala Thr Phe Gly Ala Gln Val Val Glu

85 90 95

Lys Val Val Leu Val Ser Leu Gln Ser Gly Tyr Leu Phe Ile Gln Thr

100 105 110

Asp Lys Thr Ile Tyr Thr Pro Gly Ser Thr Val Leu Cys Arg Ile Phe

115 120 125

Thr Val Asn His Lys Leu Leu Pro Val Gly Arg Thr Val Val Val Asn

130 135 140

Ile Glu Asn Pro Asp Gly Ile Pro Val Lys Gln Asp Ser Leu Ser Ser

145 150 155 160

Gln Asn Gln Phe Gly Ile Leu Pro Leu Ser Trp Asp Ile Pro Glu Leu

165 170 175

Val Asn Met Gly Gln Trp Lys Ile Arg Ala Tyr Tyr Glu Asn Ser Pro

180 185 190

Gln Gln Val Phe Ser Thr Glu Phe Glu Val Lys Glu Tyr Val Leu Pro

195 200 205

Ser Phe Glu Val Ile Val Glu Pro Thr Glu Lys Phe Tyr Tyr Ile Tyr

210 215 220

Asn Gln Lys Gly Leu Glu Val Thr Ile Thr Ala Arg Phe Leu Tyr Gly

225 230 235 240

Lys Lys Val Glu Gly Thr Ala Phe Val Ile Phe Gly Ile Gln Asp Gly

245 250 255

Glu Gln Arg Ile Ser Leu Pro Glu Ser Leu Lys Arg Ile Gln Ile Glu

260 265 270

Asp Gly Ser Gly Asp Ala Val Leu Ser Arg Lys Val Leu Leu Asp Gly

275 280 285

Val Gln Asn Pro Arg Pro Glu Asp Leu Val Gly Lys Ser Leu Tyr Val

290 295 300

Ser Val Thr Val Ile Leu His Ser Gly Ser Asp Met Val Gln Ala Glu

305 310 315 320

Arg Ser Gly Ile Pro Ile Val Thr Ser Pro Tyr Gln Ile His Phe Thr

325 330 335

Lys Thr Pro Lys Tyr Phe Lys Pro Gly Met Pro Phe Asp Leu Met Val

340 345 350

Phe Val Thr Asn Pro Asp Gly Ser Pro Ala Tyr Arg Val Pro Val Ala

355 360 365

Val Gln Gly Glu Asp Ala Val Gln Ser Leu Thr Gln Gly Asp Gly Val

370 375 380

Ala Lys Leu Ser Ile Asn Thr His Pro Ser Gln Lys Pro Leu Ser Ile

385 390 395 400

Thr Val Arg Thr Lys Lys Arg Glu Leu Ser Glu Ala Glu Gln Ala Thr

405 410 415

Arg Thr Met Glu Ala Gln Pro Tyr Ser Thr Val Gly Asn Ser Asn Asn

420 425 430

Tyr Leu His Leu Ser Val Pro Arg Ala Glu Leu Arg Pro Gly Glu Thr

435 440 445

Leu Asn Val Asn Phe Leu Leu Arg Met Asp Arg Thr Gln Glu Ala Lys

450 455 460

Ile Arg Tyr Tyr Thr Tyr Leu Ile Met Asn Lys Gly Lys Leu Leu Lys

465 470 475 480

Val Gly Arg Gln Val Arg Glu Pro Gly Gln Asp Leu Val Val Leu Pro

485 490 495

Leu Ser Ile Thr Thr Asp Phe Ile Pro Ser Phe Arg Leu Val Ala Tyr

500 505 510

Tyr Thr Leu Ile Gly Ala Asn Gly Gln Arg Glu Val Val Ala Asp Ser

515 520 525

Val Trp Val Asp Val Lys Asp Ser Cys Val Gly Ser Leu Val Val Lys

530 535 540

Ser Gly Gln Ser Glu Asp Arg Gln Pro Leu Pro Gly Gln Gln Met Thr

545 550 555 560

Leu Lys Ile Glu Gly Asp His Gly Ala Arg Val Gly Leu Val Ala Val

565 570 575

Asp Lys Gly Val Phe Val Leu Asn Lys Lys Asn Lys Leu Thr Gln Ser

580 585 590

Lys Ile Trp Asp Val Val Glu Lys Ala Asp Ile Gly Cys Thr Pro Gly

595 600 605

Ser Gly Lys Asp Tyr Ala Gly Val Phe Ser Asp Ala Gly Leu Thr Phe

610 615 620

Ala Ser Ser Ser Gly Gln Gln Thr Ala Gln Arg Ala Glu Leu Gln Cys

625 630 635 640

Pro Gln Pro Ala Ala Arg Arg Arg Arg Ser Val Gln Leu Ala Glu Lys

645 650 655

Arg Met Asp Lys Val Gly Gln Tyr Pro Lys Glu Leu Arg Lys Cys Cys

660 665 670

Glu His Gly Met Arg Glu Asn Pro Met Arg Phe Ser Cys Gln Arg Arg

675 680 685

Thr Arg Tyr Ile Thr Leu Asp Glu Ala Cys Lys Lys Ala Phe Leu Asp

690 695 700

Cys Cys Asn Tyr Ile Thr Glu Leu Arg Arg Gln His Ala Arg Ala Ser

705 710 715 720

His Leu Gly Leu Ala Arg Ser Asn Leu Asp Glu Asp Ile Ile Ala Glu

725 730 735

Glu Asn Ile Val Ser Arg Ser Glu Phe Pro Glu Ser Trp Leu Trp Lys

740 745 750

Ile Glu Glu Leu Lys Glu Ala Pro Lys Asn Gly Ile Ser Thr Lys Leu

755 760 765

Met Asn Ile Phe Leu Lys Asp Ser Ile Thr Thr Trp Glu Ile Leu Ala

770 775 780

Val Ser Leu Ser Asp Lys Lys Gly Ile Cys Val Ala Asp Pro Phe Glu

785 790 795 800

Val Thr Val Met Gln Asp Phe Phe Ile Asp Leu Arg Leu Pro Tyr Ser

805 810 815

Val Val Arg Asn Glu Gln Val Glu Ile Arg Ala Val Leu Tyr Asn Tyr

820 825 830

Arg Gln Asn Gln Glu Leu Lys Val Arg Val Glu Leu Leu His Asn Pro

835 840 845

Ala Phe Cys Ser Leu Ala Thr Ala Lys Arg Arg His Gln Gln Thr Val

850 855 860

Thr Ile Pro Pro Lys Ser Ser Leu Ser Val Pro Tyr Val Ile Val Pro

865 870 875 880

Leu Lys Thr Gly Gln Gln Glu Val Glu Val Lys Ala Ala Val Tyr His

885 890 895

Phe Phe Ile Ser Asp Gly Val Arg Lys Ser Leu Lys Val Val Pro Glu

900 905 910

Gly Ile Arg Met Asn Lys Thr Val Ala Val Arg Thr Leu Asp Pro Glu

915 920 925

Arg Leu Gly Gln Glu Gly Val Gln Arg Glu Asp Val Pro Pro Ala Asp

930 935 940

Leu Ser Asp Gln Val Pro Asp Thr Glu Ser Glu Thr Arg Ile Leu Leu

945 950 955 960

Gln Gly Thr Pro Val Ala Gln Met Thr Glu Asp Ala Ile Asp Ala Glu

965 970 975

Arg Leu Lys His Leu Ile Val Thr Pro Ser Gly Cys Gly Glu Gln Asn

980 985 990

Met Ile Thr Met Thr Pro Thr Val Ile Ala Val His Tyr Leu Asp Glu

995 1000 1005

Thr Glu Gln Trp Glu Lys Phe Gly Pro Glu Lys Arg Gln Gly Ala

1010 1015 1020

Leu Glu Leu Ile Lys Lys Gly Tyr Thr Gln Gln Leu Ala Phe Arg

1025 1030 1035

Gln Pro Ser Ser Ala Phe Ala Ala Phe Leu Asn Arg Ala Pro Ser

1040 1045 1050

Thr Trp Leu Thr Ala Tyr Val Val Lys Val Phe Ser Leu Ala Val

1055 1060 1065

Asn Leu Ile Ala Ile Asp Ser Gln Val Leu Cys Gly Ala Val Lys

1070 1075 1080

Trp Leu Ile Leu Glu Lys Gln Lys Pro Asp Gly Val Phe Gln Glu

1085 1090 1095

Asp Ala Pro Val Ile His Gln Glu Met Thr Gly Gly Phe Arg Asn

1100 1105 1110

Thr Asn Glu Lys Asp Met Ala Leu Thr Ala Phe Val Leu Ile Ser

1115 1120 1125

Leu Gln Glu Ala Lys Glu Ile Cys Glu Glu Gln Val Asn Ser Leu

1130 1135 1140

Pro Gly Ser Ile Thr Lys Ala Gly Asp Phe Leu Glu Ala Asn Tyr

1145 1150 1155

Met Asn Leu Gln Arg Ser Tyr Thr Val Ala Ile Ala Ala Tyr Ala

1160 1165 1170

Leu Ala Gln Met Gly Arg Leu Lys Gly Pro Leu Leu Asn Lys Phe

1175 1180 1185

Leu Thr Thr Ala Lys Asp Lys Asn Arg Trp Glu Glu Pro Gly Gln

1190 1195 1200

Gln Leu Tyr Asn Val Glu Ala Thr Ser Tyr Ala Leu Leu Ala Leu

1205 1210 1215

Leu Gln Leu Lys Asp Phe Asp Phe Val Pro Pro Val Val Arg Trp

1220 1225 1230

Leu Asn Glu Gln Arg Tyr Tyr Gly Gly Gly Tyr Gly Ser Thr Gln

1235 1240 1245

Ala Thr Phe Met Val Phe Gln Ala Leu Ala Gln Tyr Gln Lys Asp

1250 1255 1260

Val Pro Asp His Lys Glu Leu Asn Leu Asp Val Ser Leu Gln Leu

1265 1270 1275

Pro Ser Arg Ser Ser Lys Ile Ile His Arg Ile His Trp Glu Ser

1280 1285 1290

Ala Ser Leu Leu Arg Ser Glu Glu Thr Lys Glu Asn Glu Gly Phe

1295 1300 1305

Thr Val Thr Ala Glu Gly Lys Gly Gln Gly Thr Leu Ser Val Val

1310 1315 1320

Thr Met Tyr His Ala Lys Ala Lys Gly Gln Leu Thr Cys Asn Lys

1325 1330 1335

Phe Asp Leu Lys Val Thr Ile Lys Pro Ala Pro Glu Thr Glu Lys

1340 1345 1350

Arg Pro Gln Asp Ala Lys Asn Thr Met Ile Leu Glu Ile Cys Thr

1355 1360 1365

Arg Tyr Arg Gly Asp Gln Asp Ala Thr Met Ser Ile Leu Asp Ile

1370 1375 1380

Ser Met Met Thr Gly Phe Val Pro Asp Thr Asp Asp Leu Lys Gln

1385 1390 1395

Leu Ala Asn Gly Val Asp Arg Tyr Ile Ser Lys Tyr Glu Leu Asp

1400 1405 1410

Lys Ala Phe Ser Asp Arg Asn Thr Leu Ile Ile Tyr Leu Asp Lys

1415 1420 1425

Val Ser His Ser Glu Asp Asp Cys Ile Ala Phe Lys Val His Gln

1430 1435 1440

Tyr Phe Asn Val Glu Leu Ile Gln Pro Gly Ala Val Lys Val Tyr

1445 1450 1455

Ala Tyr Tyr Asn Leu Ala Glu Ser Cys Thr Arg Phe Tyr His Pro

1460 1465 1470

Glu Lys Glu Asp Gly Lys Leu Asn Lys Leu Cys Arg Asp Glu Leu

1475 1480 1485

Cys Arg Cys Ala Glu Glu Asn Cys Phe Ile Gln Lys Leu Asp Asp

1490 1495 1500

Lys Val Thr Leu Glu Glu Arg Leu Asp Lys Ala Cys Glu Pro Gly

1505 1510 1515

Val Asp Tyr Val Tyr Lys Thr Arg Leu Val Lys Ala Gln Leu Ser

1520 1525 1530

Asn Asp Phe Asp Glu Tyr Ile Met Ala Ile Glu Gln Ile Ile Lys

1535 1540 1545

Ser Gly Ser Asp Glu Val Gln Val Gly Gln Gln Arg Thr Phe Ile

1550 1555 1560

Ser Pro Ile Lys Cys Arg Glu Ala Leu Lys Leu Glu Glu Glu Arg Lys

1565 1570 1575

His Tyr Leu Met Trp Gly Leu Ser Ser Asp Phe Trp Gly Glu Lys

1580 1585 1590

Pro Asn Leu Ser Tyr Ile Ile Gly Lys Asp Thr Trp Val Glu His

1595 1600 1605

Trp Pro Glu Glu Asp Glu Cys Gln Asp Glu Glu Asn Gln Lys Gln

1610 1615 1620

Cys Gln Asp Leu Gly Thr Phe Thr Glu Asn Met Val Val Phe Gly

1625 1630 1635

Cys Pro Asn

1640

<210> 34

<211> 330

<212> Protein

<213> Homo sapiens

<400> 34

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 35

<211> 330

<212> Protein

<213> Homo sapiens

<400> 35

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Ala Leu Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 36

<211> 330

<212> Protein

<213> Homo sapiens

<400> 36

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 37

<211> 1663

<212> Protein

<213> Rattus norvegicus

<400> 37

Met Gly Pro Thr Ser Gly Ser Gln Leu Leu Val Leu Leu Leu Leu Leu

1 5 10 15

Ala Ser Ser Leu Leu Ala Leu Gly Ser Pro Met Tyr Ser Ile Ile Thr

20 25 30

Pro Asn Val Leu Arg Leu Glu Ser Glu Glu Thr Phe Ile Leu Glu Ala

35 40 45

His Asp Ala Gln Gly Asp Val Pro Val Thr Val Thr Val Gln Asp Phe

50 55 60

Leu Lys Lys Gln Val Leu Thr Ser Glu Lys Thr Val Leu Thr Gly Ala

65 70 75 80

Thr Gly His Leu Asn Arg Val Phe Ile Lys Ile Pro Ala Ser Lys Glu

85 90 95

Phe Asn Ala Asp Lys Gly His Lys Tyr Val Thr Val Val Ala Asn Phe

100 105 110

Gly Ala Thr Val Val Glu Lys Ala Val Leu Val Ser Phe Gln Ser Gly

115 120 125

Tyr Leu Phe Ile Gln Thr Asp Lys Thr Ile Tyr Thr Pro Gly Ser Thr

130 135 140

Val Phe Tyr Arg Ile Phe Thr Val Asp Asn Asn Leu Leu Pro Val Gly

145 150 155 160

Lys Thr Val Val Ile Val Ile Glu Thr Pro Asp Gly Val Pro Ile Lys

165 170 175

Arg Asp Ile Leu Ser Ser His Asn Gln Tyr Gly Ile Leu Pro Leu Ser

180 185 190

Trp Asn Ile Pro Glu Leu Val Asn Met Gly Gln Trp Lys Ile Arg Ala

195 200 205

Phe Tyr Glu His Ala Pro Lys Gln Thr Phe Ser Ala Glu Phe Glu Val

210 215 220

Lys Glu Tyr Val Leu Pro Ser Phe Glu Val Leu Val Glu Pro Thr Glu

225 230 235 240

Lys Phe Tyr Tyr Ile His Gly Pro Lys Gly Leu Glu Val Ser Ile Thr

245 250 255

Ala Arg Phe Leu Tyr Gly Lys Asn Val Asp Gly Thr Ala Phe Val Ile

260 265 270

Phe Gly Val Gln Asp Glu Asp Lys Lys Ile Ser Leu Ala Leu Ser Leu

275 280 285

Thr Arg Val Leu Ile Glu Asp Gly Ser Gly Glu Ala Val Leu Ser Arg

290 295 300

Lys Val Leu Met Asp Gly Val Arg Pro Ser Ser Pro Glu Ala Leu Val

305 310 315 320

Gly Lys Ser Leu Tyr Val Ser Val Thr Val Ile Leu His Ser Gly Ser

325 330 335

Asp Met Val Glu Ala Glu Arg Ser Gly Ile Pro Ile Val Thr Ser Pro

340 345 350

Tyr Gln Ile His Phe Thr Lys Thr Pro Lys Phe Phe Lys Pro Ala Met

355 360 365

Pro Phe Asp Leu Met Val Phe Val Thr Asn Pro Asp Gly Ser Pro Ala

370 375 380

Arg Arg Val Pro Val Val Thr Gln Gly Ser Asp Ala Gln Ala Leu Thr

385 390 395 400

Gln Asp Asp Gly Val Ala Lys Leu Ser Val Asn Thr Pro Asn Asn Arg

405 410 415

Gln Pro Leu Thr Ile Thr Val Ser Thr Lys Lys Glu Gly Ile Pro Asp

420 425 430

Ala Arg Gln Ala Thr Arg Thr Met Gln Ala Gln Pro Tyr Ser Thr Met

435 440 445

His Asn Ser Asn Asn Tyr Leu His Leu Ser Val Ser Arg Val Glu Leu

450 455 460

Lys Pro Gly Asp Asn Leu Asn Val Asn Phe His Leu Arg Thr Asp Ala

465 470 475 480

Gly Gln Glu Ala Lys Ile Arg Tyr Tyr Thr Tyr Leu Val Met Asn Lys

485 490 495

Gly Lys Leu Leu Lys Ala Gly Arg Gln Val Arg Glu Pro Gly Gln Asp

500 505 510

Leu Val Val Leu Ser Leu Pro Ile Thr Pro Glu Phe Ile Pro Ser Phe

515 520 525

Arg Leu Val Ala Tyr Tyr Thr Leu Ile Gly Ala Asn Gly Gln Arg Glu

530 535 540

Val Val Ala Asp Ser Val Trp Val Asp Val Lys Asp Ser Cys Val Gly

545 550 555 560

Thr Leu Val Val Lys Gly Asp Pro Arg Asp Asn Arg Gln Pro Ala Pro

565 570 575

Gly His Gln Thr Thr Leu Arg Ile Glu Gly Asn Gln Gly Ala Arg Val

580 585 590

Gly Leu Val Ala Val Asp Lys Gly Val Phe Val Leu Asn Lys Lys Asn

595 600 605

Lys Leu Thr Gln Ser Lys Ile Trp Asp Val Val Glu Lys Ala Asp Ile

610 615 620

Gly Cys Thr Pro Gly Ser Gly Lys Asn Tyr Ala Gly Val Phe Met Asp

625 630 635 640

Ala Gly Leu Thr Phe Lys Thr Asn Gln Gly Leu Gln Thr Asp Gln Arg

645 650 655

Glu Asp Pro Glu Cys Ala Lys Pro Ala Ala Arg Arg Arg Arg Ser Val

660 665 670

Gln Leu Met Glu Arg Arg Met Asp Lys Ala Gly Gln Tyr Thr Asp Lys

675 680 685

Gly Leu Arg Lys Cys Cys Glu Asp Gly Met Arg Asp Ile Pro Met Pro

690 695 700

Tyr Ser Cys Gln Arg Arg Ala Arg Leu Ile Thr Gln Gly Glu Ser Cys

705 710 715 720

Leu Lys Ala Phe Met Asp Cys Cys Asn Tyr Ile Thr Lys Leu Arg Glu

725 730 735

Gln His Arg Arg Asp His Val Leu Gly Leu Ala Arg Ser Asp Val Asp

740 745 750

Glu Asp Ile Ile Pro Glu Glu Asp Ile Ile Ser Arg Ser His Phe Pro

755 760 765

Glu Ser Trp Leu Trp Thr Ile Glu Glu Leu Lys Glu Pro Glu Lys Asn

770 775 780

Gly Ile Ser Thr Lys Val Met Asn Ile Phe Leu Lys Asp Ser Ile Thr

785 790 795 800

Thr Trp Glu Ile Leu Ala Val Ser Leu Ser Asp Lys Lys Gly Ile Cys

805 810 815

Val Ala Asp Pro Tyr Glu Ile Thr Val Met Gln Asp Phe Phe Ile Asp

820 825 830

Leu Arg Leu Pro Tyr Ser Val Val Arg Asn Glu Gln Val Glu Ile Arg

835 840 845

Ala Val Leu Phe Asn Tyr Arg Glu Gln Glu Lys Leu Lys Val Arg Val

850 855 860

Glu Leu Leu His Asn Pro Ala Phe Cys Ser Met Ala Thr Ala Lys Lys

865 870 875 880

Arg Tyr Tyr Gln Thr Ile Glu Ile Pro Pro Lys Ser Ser Val Ala Val

885 890 895

Pro Tyr Val Ile Val Pro Leu Lys Ile Gly Leu Gln Glu Val Glu Val

900 905 910

Lys Ala Ala Val Phe Asn His Phe Ile Ser Asp Gly Val Lys Lys Ile

915 920 925

Leu Lys Val Val Pro Glu Gly Met Arg Val Asn Lys Thr Val Ala Val

930 935 940

Arg Thr Leu Asp Pro Glu His Leu Asn Gln Gly Gly Val Gln Arg Glu

945 950 955 960

Asp Val Asn Ala Ala Asp Leu Ser Asp Gln Val Pro Asp Thr Asp Ser

965 970 975

Glu Thr Arg Ile Leu Leu Gln Gly Thr Pro Val Ala Gln Met Ala Glu

980 985 990

Asp Ala Val Asp Gly Glu Arg Leu Lys His Leu Ile Val Thr Pro Ser

995 1000 1005

Gly Cys Gly Glu Gln Asn Met Ile Gly Met Thr Pro Thr Val Ile

1010 1015 1020

Ala Val His Tyr Leu Asp Gln Thr Glu Gln Trp Glu Lys Phe Gly

1025 1030 1035

Leu Glu Lys Arg Gln Glu Ala Leu Glu Leu Ile Lys Lys Gly Tyr

1040 1045 1050

Thr Gln Gln Leu Ala Phe Lys Gln Pro Ile Ser Ala Tyr Ala Ala

1055 1060 1065

Phe Asn Asn Arg Pro Ser Thr Trp Leu Thr Ala Met Trp Ser

1070 1075 1080

Arg Ser Phe Ser Leu Ala Ala Asn Leu Ile Ala Ile Asp Ser Gln

1085 1090 1095

Val Leu Cys Gly Ala Val Lys Trp Leu Ile Leu Glu Lys Gln Lys

1100 1105 1110

Pro Asp Gly Val Phe Gln Glu Asp Gly Pro Val Ile His Gln Glu

1115 1120 1125

Met Ile Gly Gly Phe Arg Asn Thr Lys Glu Ala Asp Val Ser Leu

1130 1135 1140

Thr Ala Phe Val Leu Ile Ala Leu Gln Glu Ala Arg Asp Ile Cys

1145 1150 1155

Glu Gly Gln Val Asn Ser Leu Pro Gly Ser Ile Asn Lys Ala Gly

1160 1165 1170

Glu Tyr Leu Glu Ala Ser Tyr Leu Asn Leu Gln Arg Pro Tyr Thr

1175 1180 1185

Val Ala Ile Ala Gly Tyr Ala Leu Ala Leu Met Asn Lys Leu Glu

1190 1195 1200

Glu Pro Tyr Leu Thr Lys Phe Leu Asn Thr Ala Lys Asp Arg Asn

1205 1210 1215

Arg Trp Glu Glu Pro Gly Gln Gln Leu Tyr Asn Val Glu Ala Thr

1220 1225 1230

Ser Tyr Ala Leu Leu Ala Leu Leu Leu Leu Lys Asp Phe Asp Ser

1235 1240 1245

Val Pro Pro Val Val Arg Trp Leu Asn Asp Glu Arg Tyr Tyr Gly

1250 1255 1260

Gly Gly Tyr Gly Ser Thr Gln Ala Thr Phe Met Val Phe Gln Ala

1265 1270 1275

Leu Ala Gln Tyr Arg Ala Asp Val Pro Asp His Lys Asp Leu Asn

1280 1285 1290

Met Asp Val Ser Leu His Leu Pro Ser Arg Ser Ser Pro Thr Val

1295 1300 1305

Phe Arg Leu Leu Trp Glu Ser Gly Ser Leu Leu Arg Ser Glu Glu

1310 1315 1320

Thr Lys Gln Asn Glu Gly Phe Ser Leu Thr Ala Lys Gly Lys Gly

1325 1330 1335

Gln Gly Thr Leu Ser Val Val Thr Val Tyr His Ala Lys Val Lys

1340 1345 1350

Gly Lys Thr Thr Cys Lys Lys Phe Asp Leu Arg Val Thr Ile Lys

1355 1360 1365

Pro Ala Pro Glu Thr Ala Lys Lys Pro Gln Asp Ala Lys Ser Ser

1370 1375 1380

Met Ile Leu Asp Ile Cys Thr Arg Tyr Leu Gly Asp Val Asp Ala

1385 1390 1395

Thr Met Ser Ile Leu Asp Ile Ser Met Met Thr Gly Phe Ile Pro

1400 1405 1410

Asp Thr Asn Asp Leu Glu Leu Leu Ser Ser Gly Val Asp Arg Tyr

1415 1420 1425

Ile Ser Lys Tyr Glu Met Asp Lys Ala Phe Ser Asn Lys Asn Thr

1430 1435 1440

Leu Ile Ile Tyr Leu Glu Lys Ile Ser His Ser Glu Glu Asp Cys

1445 1450 1455

Leu Ser Phe Lys Val His Gln Phe Phe Asn Val Gly Leu Ile Gln

1460 1465 1470

Pro Gly Ser Val Lys Val Tyr Ser Tyr Tyr Asn Leu Glu Glu Ser

1475 1480 1485

Cys Thr Arg Phe Tyr His Pro Glu Lys Asp Asp Gly Met Leu Ser

1490 1495 1500

Lys Leu Cys His Asn Glu Met Cys Arg Cys Ala Glu Glu Asn Cys

1505 1510 1515

Phe Met His Gln Ser Gln Asp Gln Val Ser Leu Asn Glu Arg Leu

1520 1525 1530

Asp Lys Ala Cys Glu Pro Gly Val Asp Tyr Val Tyr Lys Thr Lys

1535 1540 1545

Leu Thr Thr Ile Glu Leu Ser Asp Asp Phe Asp Glu Tyr Ile Met

1550 1555 1560

Thr Ile Glu Gln Val Ile Lys Ser Gly Ser Asp Glu Val Gln Ala

1565 1570 1575

Gly Gln Glu Arg Arg Phe Ile Ser His Val Lys Cys Arg Asn Ala

1580 1585 1590

Leu Lys Leu Gln Lys Gly Lys Gln Tyr Leu Met Trp Gly Leu Ser

1595 1600 1605

Ser Asp Leu Trp Gly Glu Lys Pro Asn Thr Ser Tyr Ile Ile Gly

1610 1615 1620

Lys Asp Thr Trp Val Glu His Trp Pro Glu Ala Glu Glu Glu Arg Gln

1625 1630 1635

Asp Gln Lys Asn Gln Lys Gln Cys Glu Asp Leu Gly Ala Phe Thr

1640 1645 1650

Glu Thr Met Val Val Phe Gly Cys Pro Asn

1655 1660

<210> 38

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 38

Gly Tyr Ser Phe Thr Gly Tyr Asn Met Asn

1 5 10

<210> 39

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 39

Asn Ile Asn Pro Tyr Tyr Gly Ser Thr Asn Tyr Asn Gln Lys Phe Lys

1 5 10 15

gly

<210> 40

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 40

Gly Tyr Tyr Gly Gly Asn Tyr Pro Phe Ala Tyr

1 5 10

<210> 41

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 41

Arg Ala Ser Glu Asn Ile Tyr Ser Tyr Leu Ala

1 5 10

<210> 42

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 42

Asn Ala Lys Thr Leu Ala Glu

15

<210> 43

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 43

Gln His Tyr Tyr Gly Thr Pro Tyr Thr

15

<210> 44

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 44

Asn Ile Asn Pro Tyr Tyr Asp Ser Thr Ser Tyr Asn Gln Lys Phe Lys

1 5 10 15

gly

<210> 45

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 45

Glu Asn Tyr Asp Phe Val Gly Phe Ala Tyr

1 5 10

<210> 46

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 46

Arg Ala Ser Ser Ser Val Ser Tyr Met His

1 5 10

<210> 47

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 47

Val Thr Ser Asn Leu Ala Ser

15

<210> 48

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 48

Gln Gln Trp Ser Thr Asn Pro Leu Thr

15

<210> 49

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 49

Gly Tyr Ser Phe Thr Gly Tyr Asn Met His

1 5 10

<210> 50

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 50

Asn Ile Asn Pro Tyr Tyr Gly Thr Thr Asn Ser Asn Gln Lys Phe Glu

1 5 10 15

asp

<210> 51

<211> 14

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 51

Gly Ile Tyr Tyr Tyr Gly Thr Gly Tyr Pro Tyr Phe Asp Phe

1 5 10

<210> 52

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 52

Arg Ala Ser Gln Asp Ile Asn Asn Tyr Leu Asn

1 5 10

<210> 53

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 53

Tyr Thr Ser Arg Leu His Ser

15

<210> 54

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 54

Gln Gln Gly Ile Thr Leu Pro Trp Thr

15

<210> 55

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 55

Gly Tyr Thr Phe Thr Asp Tyr Trp Ile Asn

1 5 10

<210> 56

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 56

Asn Ile Tyr Pro Gly Ser Thr Ser Ala Asn Tyr Asn Glu Lys Phe Lys

1 5 10 15

Ser

<210> 57

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 57

Tyr Gly Tyr Asp Ser Trp Phe Ala Tyr

15

<210> 58

<211> 16

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 58

Lys Ser Thr Lys Ser Leu Leu Asn Ser Asp Gly Phe Thr Tyr Leu Asp

1 5 10 15

<210> 59

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 59

Leu Val Ser Asn Arg Phe Ser

15

<210> 60

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 60

Phe Gln Ser Asn Tyr Leu Pro Leu Thr

15

<210> 61

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 61

Gly Tyr Ala Phe Asn Ser Cys Trp Met Asn

1 5 10

<210> 62

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 62

Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys

1 5 10 15

gly

<210> 63

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 63

Glu Gly Arg Asn Tyr Gly Tyr Glu Asp Tyr

1 5 10

<210> 64

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 64

Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn

1 5 10 15

<210> 65

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 65

Ala Ala Ser Asp Leu Glu Ser

15

<210> 66

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 66

Gln Gln Ala Asn Glu Asp Pro Arg Thr

15

<210> 67

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 67

Gly Phe Thr Phe Ser Asn Tyr Ala Met Ser

1 5 10

<210> 68

<211> 18

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 68

Gln Thr Ile Ser Ser Gly Gly Arg Tyr Thr Tyr Tyr Pro Asp Ser Val

1 5 10 15

Lys Gly

<210> 69

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 69

Arg Tyr Tyr Gly Asn Ser Tyr Trp Tyr Phe Asp Val

1 5 10

<210> 70

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 70

Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys His Tyr Leu

1 5 10 15

Thr

<210> 71

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 71

Gly Ala Ser Thr Arg Gly Ser

15

<210> 72

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 72

Gln Asn Asp His Ser Tyr Pro Tyr Thr

15

<210> 73

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 73

Gly Phe Thr Phe Ser Tyr Thr Met Ser

1 5 10

<210> 74

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 74

Tyr Ile Ser Ser Gly Gly Gly Thr Thr Tyr Tyr Pro Asp Thr Val Lys

1 5 10 15

gly

<210> 75

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 75

Arg Tyr Tyr Arg Gly Ser Ser Leu Trp Tyr Phe Asp Val

1 5 10

<210> 76

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 76

Lys Ser Ser Gln Ser Leu Phe Asn Ser Gly Ser Gln Lys Asn Phe Leu

1 5 10 15

Thr

<210> 77

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 77

Trp Ala Ser Thr Arg Glu Ser

15

<210> 78

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 78

Gln Asn Asp Tyr Ser Tyr Pro Leu Thr

15

<210> 79

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 79

Gly Tyr Ser Ile Thr Ser Gly Tyr Ser Leu His

1 5 10

<210> 80

<211> 16

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 80

Tyr Ile His Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser

1 5 10 15

<210> 81

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 81

Ala Trp Asp Tyr Leu Asp Tyr

15

<210> 82

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 82

Arg Ala Ser Glu Asn Ile Tyr Ser Gln Leu Ala

1 5 10

<210> 83

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 83

Asp Ala Lys Thr Leu Ala Glu

15

<210> 84

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 84

His His His Phe Gly Ile Leu Tyr Thr

15

<210> 85

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 85

Gly Tyr Ser Ile Thr Ser Gly Tyr Tyr Trp Asn

1 5 10

<210> 86

<211> 16

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 86

Tyr Ile Arg Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys Asn

1 5 10 15

<210> 87

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 87

His Tyr Gly Tyr Asp Gly Gly Ala Phe Asp Phe

1 5 10

<210> 88

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 88

Arg Thr Ser Glu Asn Ile Tyr Asn Tyr Leu Val

1 5 10

<210> 89

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 89

Asn Ala Lys Thr Leu Glu Glu

15

<210> 90

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 90

Gln His His Tyr Gly Thr Pro Phe Thr

15

<210> 91

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 91

Glu Ile Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Asn Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asn Ile Asn Pro Tyr Tyr Gly Ser Thr Asn Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr

65 70 75 80

Met Gln Leu Asp Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Tyr Tyr Gly Gly Asn Tyr Pro Phe Ala Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 92

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 92

Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val

35 40 45

Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His Tyr Tyr Gly Thr Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Ser Lys Val Glu Ile Lys

100 105

<210> 93

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 93

Glu Ile Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Met Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Asn Met Asn Trp Val Lys Gln Ser His Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Asn Pro Tyr Tyr Asp Ser Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Asn Tyr Asp Phe Val Gly Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ala

115

<210> 94

<211> 106

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 94

Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Met

20 25 30

His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr

35 40 45

Val Thr Ser Asn Leu Ala Ser Gly Val Pro Pro Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Thr Asn Pro Leu Thr

85 90 95

Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 95

<211> 123

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 95

Glu Ile Gln Leu Gln Gln Ser Gly Ala Glu Leu Glu Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asn Ile Asn Pro Tyr Tyr Gly Thr Thr Asn Ser Asn Gln Lys Phe

50 55 60

Glu Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Ile Tyr Tyr Tyr Gly Thr Gly Tyr Pro Tyr Phe Asp Phe

100 105 110

Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser

115 120

<210> 96

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 96

Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Asn Asn Tyr

20 25 30

Leu Asn Trp Tyr Leu Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile

35 40 45

Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln

65 70 75 80

Glu Asp Leu Ala Thr Tyr Phe Cys Gln Gln Gly Ile Thr Leu Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 97

<211> 118

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 97

Gln Val Gln Leu Leu Gln Pro Gly Ala Glu Phe Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Tyr Pro Gly Ser Thr Ser Ala Asn Tyr Asn Glu Lys Phe

50 55 60

Lys Ser Lys Ala Thr Leu Thr Ile Asp Thr Ser Ser Ile Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Gly Tyr Asp Ser Trp Phe Ala Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ala

115

<210> 98

<211> 112

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 98

Asp Val Val Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Asn Ile Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Lys Ser Thr Lys Ser Leu Leu Asn Ser

20 25 30

Asp Gly Phe Thr Tyr Leu Asp Trp Phe Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro His Leu Leu Ile Tyr Leu Val Ser Asn Arg Phe Ser Gly Ile Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Glu Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Ser

85 90 95

Asn Tyr Leu Pro Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 99

<211> 119

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 99

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Asn Ser Cys

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Glu Gly Arg Asn Tyr Gly Tyr Glu Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Leu Thr Val Ser Ser

115

<210> 100

<211> 111

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 100

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp

20 25 30

Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asp Leu Glu Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ala Asn

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 101

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 101

Glu Val Met Leu Val Glu Ser Gly Gly Ala Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Gln Thr Ile Ser Ser Gly Gly Arg Tyr Thr Tyr Tyr Pro Asp Ser

50 55 60

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu

65 70 75 80

Tyr Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr

85 90 95

Cys Val Arg Arg Tyr Tyr Gly Asn Ser Tyr Trp Tyr Phe Asp Val Trp

100 105 110

Gly Ala Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 102

<211> 113

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 102

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Ala Gly

1 5 10 15

Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Gly Asn Gln Lys His Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Gly Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn

85 90 95

Asp His Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 103

<211> 122

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 103

Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Thr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Tyr Ile Ser Ser Gly Gly Gly Thr Thr Tyr Tyr Pro Asp Thr Val

50 55 60

Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Ser Cys

85 90 95

Ala Arg Arg Tyr Tyr Arg Gly Ser Ser Leu Trp Tyr Phe Asp Val Trp

100 105 110

Gly Ala Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 104

<211> 113

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 104

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Phe Asn Ser

20 25 30

Gly Ser Gln Lys Asn Phe Leu Thr Trp Tyr Gln Gln Arg Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn

85 90 95

Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu

100 105 110

Lys

<210> 105

<211> 116

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 105

Asp Val Gln Leu Gln Glu Ser Gly Pro Asp Leu Val Lys Pro Ser Gln

1 5 10 15

Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Ser Leu His Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp

35 40 45

Met Gly Tyr Ile His Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe

65 70 75 80

Leu Lys Leu Asn Ser Val Thr Ser Glu Asp Thr Ala Thr Tyr His Cys

85 90 95

Ala Arg Ala Trp Asp Tyr Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu

100 105 110

Thr Val Ser Ser

115

<210> 106

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 106

Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Gln

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val

35 40 45

Tyr Asp Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Asp Thr Gln Phe Ser Leu Lys Ile Ile Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Gly Arg Tyr Tyr Cys His His His Phe Gly Ile Leu Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys

100 105

<210> 107

<211> 120

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 107

Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Ser Leu Ser Leu Thr Cys Ser Val Thr Gly Tyr Ser Ile Thr Ser Gly

20 25 30

Tyr Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp

35 40 45

Met Gly Tyr Ile Arg Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu

50 55 60

Lys Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Val Phe

65 70 75 80

Leu Lys Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Thr Tyr Tyr Cys

85 90 95

Ala Arg His Tyr Gly Tyr Asp Gly Gly Ala Phe Asp Phe Trp Gly Gln

100 105 110

Gly Thr Thr Leu Thr Val Ser Ser

115 120

<210> 108

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 108

Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Glu Thr Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Ile Tyr Asn Tyr

20 25 30

Leu Val Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val

35 40 45

Tyr Asn Ala Lys Thr Leu Glu Glu Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Val Asn Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 109

<211> 330

<212> Protein

<213> Homo sapiens

<400> 109

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 110

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 110

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe

20 25 30

Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met

35 40 45

Gly Tyr Ile Tyr Pro His Asn Gly Gly Thr Thr Tyr Asn Gln Gln Phe

50 55 60

Thr Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 111

<211> 117

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 111

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe

20 25 30

Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met

35 40 45

Gly Tyr Ile Tyr Pro His Asn Ala Gly Thr Thr Tyr Asn Gln Gln Phe

50 55 60

Thr Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Gly Gly Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 112

<211> 107

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 112

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Asp Thr Tyr

20 25 30

Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr His Cys Gly Gln Ser His Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 113

<211> 240

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 113

Met Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val

1 5 10 15

Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Asp Thr

20 25 30

Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln

65 70 75 80

Pro Glu Asp Ile Ala Thr Tyr His Cys Gly Gln Ser His Ser Tyr Pro

85 90 95

Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val

115 120 125

Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser

130 135 140

Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe Tyr Met Asp Trp Val

145 150 155 160

Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Tyr Pro

165 170 175

His Asn Gly Gly Thr Thr Tyr Asn Gln Gln Phe Thr Gly Arg Val Thr

180 185 190

Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser

195 200 205

Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Gly

210 215 220

Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

225 230 235 240

<210> 114

<211> 240

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 114

Met Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val

1 5 10 15

Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Asp Thr

20 25 30

Tyr Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln

65 70 75 80

Pro Glu Asp Ile Ala Thr Tyr His Cys Gly Gln Ser His Ser Tyr Pro

85 90 95

Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly

100 105 110

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val

115 120 125

Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser

130 135 140

Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe Tyr Met Asp Trp Val

145 150 155 160

Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Tyr Pro

165 170 175

His Asn Ala Gly Thr Thr Tyr Asn Gln Gln Phe Thr Gly Arg Val Thr

180 185 190

Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser

195 200 205

Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Gly

210 215 220

Phe Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

225 230 235 240

<210> 115

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 115

Gly Gly Gly Gly Ser

15

<210> 116

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 116

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10

<210> 117

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 117

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 118

<211> 20

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 118

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser

20

<210> 119

<211> 239

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 119

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Asp Thr Tyr

20 25 30

Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr His Cys Gly Gln Ser His Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln

115 120 125

Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys

130 135 140

Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe Tyr Met Asp Trp Val Arg

145 150 155 160

Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Tyr Pro His

165 170 175

Asn Gly Gly Thr Thr Tyr Asn Gln Gln Phe Thr Gly Arg Val Thr Ile

180 185 190

Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu

195 200 205

Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Gly Phe

210 215 220

Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

225 230 235

<210> 120

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 120

Gly Tyr Thr Phe Thr Asp Phe

15

<210> 121

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 121

Asp Phe Tyr Met Asp

15

<210> 122

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 122

Thr Asp Phe Tyr Met Asp

15

<210> 123

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 123

Tyr Pro His Asn Gly Gly

15

<210> 124

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 124

Tyr Ile Tyr Pro His Asn Gly Gly Thr Thr

1 5 10

<210> 125

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 125

Trp Ile Gly Tyr Ile Tyr Pro His Asn Gly Gly Thr Thr

1 5 10

<210> 126

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 126

Ala Arg Arg Gly Gly Phe Asp Phe Asp

15

<210> 127

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 127

Asp Thr Tyr Val Ser Trp Tyr

15

<210> 128

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 128

Leu Leu Ile Tyr Gly Ala Ser Asn Arg Tyr

1 5 10

<210> 129

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 129

Gly Gln Ser His Ser Tyr Pro Leu

15

<210> 130

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 130

Trp Met Gly Tyr Ile Tyr Pro His Asn Gly Gly Thr Thr

1 5 10

<210> 131

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 131

Tyr Pro His Asn Ala Gly

15

<210> 132

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 132

Tyr Ile Tyr Pro His Asn Ala Gly Thr Thr

1 5 10

<210> 133

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 133

Trp Met Gly Tyr Ile Tyr Pro His Asn Ala Gly Thr Thr

1 5 10

<210> 134

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 134

Tyr Pro His Asn Thr Gly

15

<210> 135

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 135

Tyr Ile Tyr Pro His Asn Thr Gly Thr Thr

1 5 10

<210> 136

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 136

Trp Met Gly Tyr Ile Tyr Pro His Asn Thr Gly Thr Thr

1 5 10

<210> 137

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 137

Tyr Pro His Glu Gly Gly

15

<210> 138

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 138

Tyr Ile Tyr Pro His Glu Gly Gly Thr Thr

1 5 10

<210> 139

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 139

Trp Met Gly Tyr Ile Tyr Pro His Glu Gly Gly Thr Thr

1 5 10

<210> 140

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 140

Tyr Pro His Glyn Gly Gly

15

<210> 141

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 141

Tyr Ile Tyr Pro His Gly Gly Gly Thr Thr

1 5 10

<210> 142

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 142

Trp Met Gly Tyr Ile Tyr Pro His Gln Gly Gly Thr Thr

1 5 10

<210> 143

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 143

Gly Tyr Ser Phe Thr Gly Tyr

15

<210> 144

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 144

Gly Tyr Asn Met Asn

15

<210> 145

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 145

Thr Gly Tyr Asn Met Asn

15

<210> 146

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 146

Asn Pro Tyr Tyr Gly Ser

15

<210> 147

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 147

Asn Ile Asn Pro Tyr Tyr Gly Ser Thr Asn

1 5 10

<210> 148

<211> 17

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 148

Asn Ile Asn Pro Tyr Tyr Gly Ser Thr Asn Tyr Asn Gln Lys Phe Lys

1 5 10 15

gly

<210> 149

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 149

Trp Ile Gly Asn Ile Asn Pro Tyr Tyr Gly Ser Thr Asn

1 5 10

<210> 150

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 150

Ala Arg Gly Tyr Tyr Gly Gly Asn Tyr Pro Phe Ala

1 5 10

<210> 151

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 151

Tyr Ser Tyr Leu Ala Trp Tyr

15

<210> 152

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 152

Leu Leu Val Tyr Asn Ala Lys Thr Leu Ala

1 5 10

<210> 153

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 153

Gln His Tyr Tyr Gly Thr Pro Tyr

15

<210> 154

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 154

Asn Pro Tyr Tyr Asp Ser

15

<210> 155

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 155

Asn Ile Asn Pro Tyr Tyr Asp Ser Thr Ser

1 5 10

<210> 156

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 156

Trp Ile Gly Asn Ile Asn Pro Tyr Tyr Asp Ser Thr Ser

1 5 10

<210> 157

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 157

Ala Arg Glu Asn Tyr Asp Phe Val Gly Phe Ala

1 5 10

<210> 158

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 158

Ser Tyr Met His Trp Phe

15

<210> 159

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 159

Pro Trp Ile Tyr Val Thr Ser Asn Leu Ala

1 5 10

<210> 160

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 160

Gln Gln Trp Ser Thr Asn Pro Leu

15

<210> 161

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 161

Gly Tyr Asn Met His

15

<210> 162

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 162

Thr Gly Tyr Asn Met His

15

<210> 163

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 163

Asn Pro Tyr Tyr Gly Thr

15

<210> 164

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 164

Asn Ile Asn Pro Tyr Tyr Gly Thr Thr Asn

1 5 10

<210> 165

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 165

Trp Ile Gly Asn Ile Asn Pro Tyr Tyr Gly Thr Thr Asn

1 5 10

<210> 166

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 166

Ala Arg Gly Ile Tyr Tyr Tyr Gly Thr Gly Tyr Pro Tyr Phe Asp

1 5 10 15

<210> 167

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 167

Asn Asn Tyr Leu Asn Trp Tyr

15

<210> 168

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 168

Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His

1 5 10

<210> 169

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 169

Gln Gln Gly Ile Thr Leu Pro Trp

15

<210> 170

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 170

Gly Tyr Thr Phe Thr Asp Tyr

15

<210> 171

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 171

Asp Tyr Trp Ile Asn

15

<210> 172

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 172

Thr Asp Tyr Trp Ile Asn

15

<210> 173

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 173

Tyr Pro Gly Ser Thr Ser

15

<210> 174

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 174

Asn Ile Tyr Pro Gly Ser Thr Ser Ala Asn

1 5 10

<210> 175

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 175

Trp Ile Gly Asn Ile Tyr Pro Gly Ser Thr Ser Ala Asn

1 5 10

<210> 176

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 176

Ala Arg Tyr Gly Tyr Asp Ser Trp Phe Ala

1 5 10

<210> 177

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 177

Leu Asn Ser Asp Gly Phe Thr Tyr Leu Asp Trp Phe

1 5 10

<210> 178

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 178

Leu Leu Ile Tyr Leu Val Ser Asn Arg Phe

1 5 10

<210> 179

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 179

Phe Gln Ser Asn Tyr Leu Pro Leu

15

<210> 180

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 180

Gly Tyr Ala Phe Asn Ser Cys

15

<210> 181

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 181

Ser Cys Trp Met Asn

15

<210> 182

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 182

Asn Ser Cys Trp Met Asn

15

<210> 183

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 183

Tyr Pro Gly Asp Gly Asp

15

<210> 184

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 184

Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn

1 5 10

<210> 185

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 185

Trp Ile Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn

1 5 10

<210> 186

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 186

Ala Arg Glu Gly Arg Asn Tyr Gly Tyr Glu Asp

1 5 10

<210> 187

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 187

Asp Tyr Asp Gly Asp Ser Tyr Met Asn Trp Tyr

1 5 10

<210> 188

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 188

Leu Leu Ile Tyr Ala Ala Ser Asp Leu Glu

1 5 10

<210> 189

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 189

Gln Gln Ala Asn Glu Asp Pro Arg

15

<210> 190

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 190

Gly Phe Thr Phe Ser Asn Tyr

15

<210> 191

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 191

Asn Tyr Ala Met Ser

15

<210> 192

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 192

Ser Asn Tyr Ala Met Ser

15

<210> 193

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 193

Ile Ser Ser Gly Gly Arg Tyr

15

<210> 194

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 194

Gln Thr Ile Ser Ser Gly Gly Arg Tyr Thr Tyr

1 5 10

<210> 195

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 195

Trp Val Gln Thr Ile Ser Ser Gly Gly Arg Tyr Thr Tyr

1 5 10

<210> 196

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 196

Val Arg Arg Tyr Tyr Gly Asn Ser Tyr Trp Tyr Phe Asp

1 5 10

<210> 197

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 197

Leu Asn Ser Gly Asn Gln Lys His Tyr Leu Thr Trp Tyr

1 5 10

<210> 198

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 198

Leu Leu Ile Tyr Gly Ala Ser Thr Arg Gly

1 5 10

<210> 199

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description:

synthetic

peptide"

<400> 199

Gln Asn Asp His Ser Tyr Pro Tyr

15

<210> 200

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 200

Gly Phe Thr Phe Ser Ser Tyr

15

<210> 201

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 201

Ser Tyr Thr Met Ser

15

<210> 202

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 202

Ser Ser Tyr Thr Met Ser

15

<210> 203

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 203

Ser Ser Gly Gly Gly Thr

15

<210> 204

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 204

Tyr Ile Ser Ser Gly Gly Gly Thr Thr Tyr

1 5 10

<210> 205

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 205

Trp Val Ala Tyr Ile Ser Ser Gly Gly Gly Thr Thr Tyr

1 5 10

<210> 206

<211> 14

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 206

Ala Arg Arg Tyr Tyr Arg Gly Ser Ser Leu Trp Tyr Phe Asp

1 5 10

<210> 207

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 207

Phe Asn Ser Gly Ser Gln Lys Asn Phe Leu Thr Trp Tyr

1 5 10

<210> 208

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 208

Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu

1 5 10

<210> 209

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 209

Gln Asn Asp Tyr Ser Tyr Pro Leu

15

<210> 210

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 210

Gly Tyr Ser Ile Thr Ser Gly Tyr

15

<210> 211

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 211

Ser Gly Tyr Ser Leu His

15

<210> 212

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 212

Thr Ser Gly Tyr Ser Leu His

15

<210> 213

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 213

His Tyr Ser Gly Ser

15

<210> 214

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 214

Tyr Ile His Tyr Ser Gly Ser Thr Asn

15

<210> 215

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 215

Trp Met Gly Tyr Ile His Tyr Ser Gly Ser Thr Asn

1 5 10

<210> 216

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 216

Ala Arg Ala Trp Asp Tyr Leu Asp

15

<210> 217

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 217

Tyr Ser Gln Leu Ala Trp Tyr

15

<210> 218

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 218

Leu Leu Val Tyr Asp Ala Lys Thr Leu Ala

1 5 10

<210> 219

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 219

His His His Phe Gly Ile Leu Tyr

15

<210> 220

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 220

Ser Gly Tyr Tyr Trp Asn

15

<210> 221

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 221

Thr Ser Gly Tyr Tyr Trp Asn

15

<210> 222

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 222

Arg Tyr Asp Gly Ser

15

<210> 223

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 223

Tyr Ile Arg Tyr Asp Gly Ser Asn Asn

15

<210> 224

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 224

Trp Met Gly Tyr Ile Arg Tyr Asp Gly Ser Asn Asn

1 5 10

<210> 225

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 225

Ala Arg His Tyr Gly Tyr Asp Gly Gly Ala Phe Asp

1 5 10

<210> 226

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 226

Tyr Asn Tyr Leu Val Trp Tyr

15

<210> 227

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 227

Leu Leu Val Tyr Asn Ala Lys Thr Leu Glu

1 5 10

<210> 228

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<400> 228

Gln His His Tyr Gly Thr Pro Phe

15

<210> 229

<211> 239

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

polypeptide"

<400> 229

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asn Val Asp Thr Tyr

20 25 30

Val Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr His Cys Gly Gln Ser His Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser

100 105 110

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln

115 120 125

Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys

130 135 140

Lys Ala Ser Gly Tyr Thr Phe Thr Asp Phe Tyr Met Asp Trp Val Arg

145 150 155 160

Gln Ala Pro Gly Gln Cys Leu Glu Trp Met Gly Tyr Ile Tyr Pro His

165 170 175

Asn Ala Gly Thr Thr Tyr Asn Gln Gln Phe Thr Gly Arg Val Thr Ile

180 185 190

Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu

195 200 205

Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Gly Gly Phe

210 215 220

Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

225 230 235

<210> 230

<211> 20

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

<220>

<221> Website

<222> (1)..(20)

<223> /note="This sequence can span 1-4

repeat units "Gly Gly Gly Gly Ala

»

peptide"

<400> 230

Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Gly

1 5 10 15

Gly Gly Gly Ala

20

<210> 231

<211> 6

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

label 6xHis"

<400> 231

His His His His His His His

15

<210> 232

<211> 20

<212> Protein

<213> Artificial sequence

<220>

<221> source

<223> /note = "Description of the artificial sequence:

synthetic

peptide"

<220>

<221> Website

<222> (1)..(20)

<223> /note="This sequence can span 1-4

repeat units "Gly Gly Gly Gly Ser

»

<400> 232

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser

20

<---

Claims (105)

1. An antibody that specifically binds the C3 component of human complement (SEQ ID NO: 2), wherein the antibody contains: (a) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 14, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (b) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 120, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 131, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (c) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 132, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (d) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 121, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 14, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; or (e) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 122, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 133, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 126; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 127, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 128, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 129. 2. The antibody of claim 1, wherein the antibody comprises (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 121, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 14, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12. 3. An antibody according to claim 1 or 2, where: (i) the VH sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 21; (ii) the VL sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 25; or (iii) VH has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 21 and VL has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 25. 4. An antibody that specifically binds the C3 component of human complement (SEQ ID NO: 2), wherein the antibody comprises a VH containing the amino acid sequence shown in SEQ ID NO: 21 and a VL containing the amino acid sequence shown in SEQ ID NO: 25 . 5. An antibody that specifically binds the C3 component of human complement (SEQ ID NO: 2), wherein the antibody contains: (a) (1) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 8, and a VH CDR3 containing the amino acid sequence, presented in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (2) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 120, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 123, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (3) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 124, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (4) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 121, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 8, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; or (5) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 122, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 125, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 126; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 127, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 128, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 129; (b) (1) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 13, and a VH CDR3 containing the amino acid sequence, presented in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (2) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 120, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 123, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (3) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 124, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (4) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 121, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 13, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; or (5) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 122, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 130, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 126; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 127, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 128, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 129; (c) (1) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 16, and a VH CDR3 containing the amino acid sequence, presented in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (2) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 120, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 137, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (3) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 138, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (4) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 121, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 16, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; or (5) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 122, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 139, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 126; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 127, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 128, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 129; (d) (1) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 17, and a VH CDR3 containing the amino acid sequence, presented in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (2) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 120, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 140, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (3) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 141, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (4) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 121, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 17, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; or (5) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 122, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 142, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 126; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 127, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 128, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 129; or (e) (1) VH containing CDR1 VH containing the amino acid sequence shown in SEQ ID NO: 7, CDR2 VH containing the amino acid sequence shown in SEQ ID NO: 15, and CDR3 VH containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (2) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 120, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 134, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (3) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 7, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 135, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; (4) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 121, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 15, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 9; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 10, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 11, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 12; or (5) (i) a VH containing a VH CDR1 containing the amino acid sequence shown in SEQ ID NO: 122, a VH CDR2 containing the amino acid sequence shown in SEQ ID NO: 136, and a VH CDR3 containing the amino acid sequence shown in SEQ ID NO: 126; and (ii) a VL containing a VL CDR1 containing the amino acid sequence shown in SEQ ID NO: 127, a VL CDR2 containing the amino acid sequence shown in SEQ ID NO: 128, and a VL CDR3 containing the amino acid sequence shown in SEQ ID NO: : 129. 6. An antibody according to claim 5, where: (i) the VH sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 18; (ii) the VH sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 20; (iii) the VH sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 23; (iv) the VH sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 24; (v) the VH sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 22; (vi) the VL sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 19; (vii) the VL sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 25; (viii) VH has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 18 and VL has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 19; (ix) VH has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 20 and VL has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 25; (x) VH has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 23 and VL has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 25; (xi) VH has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 24 and VL has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 25; or (xii) VH has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 22 and VL has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 25. 7. An antibody according to claim 5, where: (i) VH contains the amino acid sequence shown in SEQ ID NO: 18 and VL contains the amino acid sequence shown in SEQ ID NO: 19; (ii) VH contains the amino acid sequence shown in SEQ ID NO: 20 and VL contains the amino acid sequence shown in SEQ ID NO: 25; (iii) VH contains the amino acid sequence shown in SEQ ID NO: 23 and VL contains the amino acid sequence shown in SEQ ID NO: 25; (iv) VH contains the amino acid sequence shown in SEQ ID NO: 24 and VL contains the amino acid sequence shown in SEQ ID NO: 25; or (v) VH contains the amino acid sequence shown in SEQ ID NO: 22 and VL contains the amino acid sequence shown in SEQ ID NO: 25. 8. An antibody according to claim 1 or 2, which is a single-chain variable fragment (scFv), where: (a) VH has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 111 and VL has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 112; or (b) the scFv has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 114 or SEQ ID NO: 229. 9. An antibody according to claim 1 or 2, which is a scFv, where VH contains the amino acid sequence shown in SEQ ID NO: 111 and VL contains the amino acid sequence shown in SEQ ID NO: 112. 10. An antibody according to claim 5 or 6, which is a single-chain variable fragment (scFv), where: (a) VH has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 110 and VL has at least 80% sequence identity with the amino acid sequence shown in SEQ ID NO: 112; or (b) the scFv has at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 113 or SEQ ID NO: 119. 11. An antibody according to claim 5 or 6, which is a scFv, where: (a) VH contains the amino acid sequence shown in SEQ ID NO: 110 and VL contains the amino acid sequence shown in SEQ ID NO: 112; or (b) the scFv has the amino acid sequence of SEQ ID NO: 113 or SEQ ID NO: 119. 12. An antibody according to any one of paragraphs. 1-4, wherein the antibody comprises a heavy chain and a light chain, wherein the heavy chain sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 29 and the light chain sequence is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 31. 13. An antibody that specifically binds the C3 component of human complement (SEQ ID NO: 2), wherein the antibody comprises a heavy chain containing the amino acid sequence shown in SEQ ID NO: 29 and a light chain containing the amino acid sequence shown in SEQ ID NO: : 31. 14. An antibody that specifically binds the C3 component of human complement (SEQ ID NO: 2), where the antibody contains a heavy chain and a light chain, where: (a) the heavy chain comprises a VH containing the amino acid sequence shown in any of SEQ ID NOs: 20 and 22-24 and a heavy chain constant region containing the amino acid sequence shown in any of SEQ ID NOs: 34-36 and 109; And (b) the light chain contains the amino acid sequence of SEQ ID NO: 31. 15. An antibody according to any one of paragraphs. 1-7, which is: (a) a chimeric antibody; (b) a bispecific antibody or a multispecific antibody; (c) Fab, Fab', F(ab') ₂ , Fv, scFv, (scFv) ₂ , single chain antibody, dual variable region antibody, or diabody; (d) an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody; or (e) a humanized antibody. 16. An antibody according to any one of paragraphs. 1-12 and 15, which has at least one or more of the following properties: (i) does not bind C3b at a detectable level; (ii) binds C3 with an affinity of at least 50 times that of an antibody to C3b; (iii) binds C3 with an affinity of at least 100 times that of an antibody to C3b; (iv) is a C3 antagonist; (v) inhibits C3 activity; (vi) inhibits complement activation; (vii) inhibits activation of the classical complement pathway; (viii) inhibits the activation of the alternative complement pathway; And (ix) inhibits activation of the classical complement pathway and the alternative complement pathway. 17. scFv that specifically binds to the C3 component of human complement (SEQ ID NO: 2) containing the amino acid sequence shown in SEQ ID NO: 114 or shown in SEQ ID NO: 229. 18. A pharmaceutical composition for treating an eye disease in a subject, inhibiting or suppressing drusen formation in a subject's eye, inhibiting or suppressing retinal pigment epithelium atrophy in a subject's eye, or inhibiting complement activation in a subject's eye, comprising an antibody according to any one of paragraphs. 1-16 or scFv according to claim 17 and a pharmaceutically acceptable carrier. 19. Selected polynucleotide encoding an antibody according to any one of paragraphs. 1-16 or scFv according to claim 17. 20. Composition for producing antibodies according to any one of paragraphs. 1-16 or scFv according to claim 17, containing the first selected polynucleotide and the second selected polynucleotide, where the first selected polynucleotide encodes the VH of the antibody according to any one of paragraphs. 1-16 or scFv according to claim 17 and where the second selected polynucleotide encodes the VL of the antibody according to any one of paragraphs. 1-16 or scFv according to claim 17. 21. An expression vector containing a polynucleotide according to claim 19. 22. Composition for producing antibodies according to any one of paragraphs. 1-16 or scFv according to claim 17, containing the first expression vector and the second expression vector, where the first expression vector contains the first polynucleotide encoding the VH of the antibody according to any one of paragraphs. 1-16 or scFv according to claim 17, and where the second expression vector contains a second polynucleotide encoding the VL of the antibody according to any one of paragraphs. 1-16 or scFv according to claim 17. 23. Selected cell: (a) containing a polynucleotide according to paragraph 19, or an expression vector according to paragraph 21, or a composition according to paragraph 20 or 22; and (b) producing antibodies according to any one of paragraphs. 1-16 or scFv according to claim 17. 24. A method for producing an antibody or scFv that specifically binds to the C3 component of human complement (SEQ ID NO: 2), comprising culturing a cell according to claim 23 and isolating the antibody or scFv, the method optionally further comprising formulating the antibody or scFv in the form of a sterile pharmaceutical compositions. 25. A method of treating an ocular disease in a subject, comprising administering to the subject a therapeutically effective amount of an antibody according to any one of paragraphs. 1-16 or scFv according to claim 17, wherein the ocular disease is selected from the group consisting of macular degeneration, diabetic retinopathy, retinopathy of prematurity, macular degeneration, retinal dystrophy, uveitis, keratitis, scleritis, retinitis pigmentosa, choroidal neovascularization, retinal neovascularization, and inflammation eyes. 26. A method of treating dry age-related macular degeneration (AMD) in a subject, comprising administering to the subject a therapeutically effective amount of an antibody according to any one of paragraphs. 1-16 or scFv according to claim 17. 27. The method of claim 26 wherein dry AMD is geographic atrophy. 28. A method of inhibiting or suppressing the formation of drusen in the eye of a subject, comprising administering to the subject a therapeutically effective amount of an antibody according to any one of paragraphs. 1-16 or scFv according to claim 17. 29. A method of inhibiting or suppressing retinal pigment epithelium atrophy in the eye of a subject, comprising administering to the subject a therapeutically effective amount of an antibody according to any one of paragraphs. 1-16 or scFv according to claim 17. 30. A method of inhibiting complement activation in the eye of a subject, comprising administering to the subject a therapeutically effective amount of an antibody according to any one of paragraphs. 1-16 or scFv according to claim 17. 31. A method of treating wet age-related macular degeneration (AMD) in a subject, comprising administering to the subject a therapeutically effective amount of an antibody according to any one of paragraphs. 1-16 or scFv according to claim 17. 32. The method according to any one of paragraphs. 25-31, where the subject is a human.

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