Monospecific and bispecific antibodies and antigen-binding fragments thereof

Abstract

Isolated monospecific and bispecific anti-properdin antibodies or antigen-binding fragments thereof for use in the treatment of complement-mediated disorders.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Patent Application No. 17 / 462,795, filed August 31, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application contains a sequence listing submitted electronically in XML format, the entire contents of which are incorporated herein by reference. The XML file, created on August 29, 2022, has the filename NMT-028649WO-ORD st.26 and is 400,995 bytes in size.

[0003] The present disclosure relates to monospecific and bispecific antibodies and antigen-binding fragments thereof capable of binding to properdin and selectively inhibiting the alternative complement pathway in conditions in which the alternative complement pathway contributes to a disease pathology. [Background technology]

[0004] The complement system is important for pathogen clearance and host defense against pathogens. The complement system is activated through three different complement pathways: the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway is activated by antigen-antibody complexes. The lectin pathway is a variant of the classical pathway. The alternative pathway (AP) is activated by foreign substances, artificial surfaces, dead tissues, bacteria, and dead yeast cells. In several pathological conditions, AP activation leads to the formation of C3a, C5a, and C5b-9 (also known as the MAC complex). Elevated levels of C3a, C5a, and C5b-9 have been found to be associated with several acute and chronic pathological conditions. These inflammatory molecules activate leukocytes, neutrophils, monocytes, platelets, mast cells, and endothelial cells, and also induce vascular permeability, cell lysis, and tissue injury. Activated cells release inflammatory mediators, such as TNF-α, IL-1β, IL-6, IL-8, VEGF, neutrophil elastase, and superoxide, and thus inhibition of disease-induced AP activation may be of important clinical benefit in diseases in which complement activation plays a role in the disease pathology.

[0005] Initiation of the alternative complement pathway requires high affinity binding of properdin to C3b. Properdin-bound C3b (PC3b) associates with factor B to form the PC3bB complex, which is then cleaved by factor D to PC3bBb and Ba, releasing Ba. Properdin-depleted serum completely lacks AP-activating activity, indicating that properdin is essential for this initiation process to occur. The concentration of properdin in blood is approximately 5 μg / ml, and thus it is the only non-protease molecule present at a much lower concentration than other non-protease molecules.

[0006] Inhibiting AP activation is an important therapeutic strategy for alleviating symptoms and slowing or preventing disease progression. By depleting, neutralizing, or inactivating properdin, AP activation can be blocked without inhibiting the classical complement pathway, and therefore this is a viable and promising therapeutic strategy. The advantage of leaving the classical pathway uninhibited is enhanced protection against infection. Summary of the Invention

[0007] The embodiments described herein relate to isolated monospecific or bispecific antibodies or antigen-binding fragments thereof. The isolated monospecific or bispecific antibodies or antigen-binding fragments thereof can specifically bind to properdin and selectively inhibit the alternative complement pathway. The isolated monospecific or bispecific antibodies or antigen-binding fragments thereof described herein can neutralize the functional activity of properdin and prevent AP-induced production of C3a, C5a, C3b, and Mac complexes (C5b-9). As a result, cell activation, inflammation, and release of inflammatory mediators can also be prevented. Since AP activation is associated with a variety of acute and chronic human diseases, inhibition of AP activation by isolated monospecific or bispecific antibodies or antigen-binding fragments thereof can also inhibit inflammation, providing humans with the clinical benefit of treatment with isolated monospecific or bispecific antibodies or antigen-binding fragments thereof.

[0008] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment may comprise at least one of the following: (a) CDR-H1 comprising the amino acid sequence of GYIFTX1YPIH (SEQ ID NO:201), where X1 is N, Q, S, A, or D; CDR-H2 comprising the amino acid sequence of FIX1PGGGX2DEX3X4X5X6X7X8X9 (SEQ ID NO:202), where X1 is D, E, S, or A; X2 is H or Y; X3 is P, S, or Y; X4 is A or D; X5 is D, R, or Q; X6 is K, R, or S; X7 is F or V; X8 is E, K, Q, or R; and X9 is D or G; and CDR-H3 comprising the amino acid sequence of RGGGYYLDY (SEQ ID NO: 203); (b) CDR-L1 comprising the amino acid sequence of RASQDISFFLN (SEQ ID NO: 206); CDR-L2 comprising an amino acid sequence of X1X2SX3YHS (SEQ ID NO:207), where X1 is G or Y; X2 is A or T; and X3 is R or S; and CDR-L3 comprising the amino acid sequence of QHGX1TLPX2T (SEQ ID NO:208), where X1 is A, D, N, Q, or S; and X2 is F, H, R, W, or Y; (c) CDR-H1 comprising the amino acid sequence of GFSLSTSGX1GVG (SEQ ID NO:211), where X1 is I, K, M, or V; CDR-H2 comprising the amino acid sequence of HIX1X1DDVKSYX2PALKS (SEQ ID NO:212), where X1 is F, H, W, or Y; and X2 is A, N, Q, or S; and CDR-H3 comprising the amino acid sequence of IGX1GYYSFDY (SEQ ID NO:213), where X1 is A, D, E, or S; (d) CDR-L1 comprising the amino acid sequence of X1ASQDVSDAVA (SEQ ID NO:216), where X1 is K or R; CDR-L2 comprising the amino acid sequence of SPSYRYT (SEQ ID NO: 217); and A CDR-L3 comprising the amino acid sequence of QQHYSTPX1TF (SEQ ID NO:218), where X1 is F, H, W, or Y; (e) CDR-H1 comprising the amino acid sequence of GFSFSSGYX1IF (SEQ ID NO:221), where X1 is F, H, W, or Y; CDR-H2 comprising the amino acid sequence of GIYSGSSGTTY (SEQ ID NO: 222); and CDR-H3 comprising the amino acid sequence of SVX1GIX1SYX1AAFX2L (SEQ ID NO:223), where X1 is A, D, E, or S; and X2 is A, N, Q, or S; (f) CDR-L1 comprising the amino acid sequence of X1ASDX2IYSLLA (SEQ ID NO:229), where X1 is Q or R; and X2 is A, N, Q, or S; CDR-L2 comprising the amino acid sequence of RASTLAS (SEQ ID NO: 230); and CDR-L3 comprising the amino acid sequence of QQHYDYX1YLDVA (SEQ ID NO:231), where X1 is A, N, Q, or S; (g) CDR-H1 comprising the amino acid sequence of GFSFSSSYX1IF (SEQ ID NO:225), where X1 is F, H, W, or Y; CDR-H2 comprising the amino acid sequence of GIYSSSGRX1Y (SEQ ID NO: 226), where X1 is I, K, L, or M; and a CDR-H3 comprising the amino acid sequence of SAX1GSX1SYX1AYFTL (SEQ ID NO:227); (wherein X1 is A, D, E, or S); (h) CDR-L1 comprising the amino acid sequence of X1ASDX2IYSX2LA (SEQ ID NO:233), where X1 is Q or R; and X2 is A, N, Q, or S; CDR-L2 comprising the amino acid sequence of RASTLAS (SEQ ID NO: 234); and CDR-L3 comprising the amino acid sequence of QQHX1DYDYIDVA (SEQ ID NO:235), where X1 is F, H, W, or Y; (i) CDR-H1 comprising the amino acid sequence of GRISSIIHMA (SEQ ID NO:237), where X1 is F, H, W, or Y; CDR-H2 comprising the amino acid sequence of RX1GTTX1YAX2SX1X3G (SEQ ID NO:238), where X1 is I or V; X2 is A, D, E, or S; and X3 is A or K; and CDR-H3 comprising the amino acid sequence of LQYEX1HGGAX2Y (SEQ ID NO: 239), where X1 is A or K; and X2 is A, D, E, or S; (j) CDR-H1 comprising the amino acid sequence of GRIFEX1X2MMA (SEQ ID NO:241), where X1 is I or V; and X2 is A, D, N, Q, or S; CDR-H2 comprising the amino acid sequence of RX1GTTTYAX2SX1X3G (SEQ ID NO: 242), where X1 is I or V; X2 is A, D, E, or S; and X3 is A or K; and CDR-H3 comprising the amino acid sequence of LQYX1RYGGAEY (SEQ ID NO:243), where X1 is A, D, E, or S; or (k) or An isolated monospecific or bispecific antibody comprising at least one of (a), (b), (c), (d), (e), (f), (g), (h), (i), or (j), and a heavy chain variable region and / or a light chain variable region that competitively inhibits the binding of the antigen-binding fragment thereof to monomeric properdin.

[0009] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment may comprise: CDR-H1 comprising the amino acid sequence of GYIFTX1YPIH (SEQ ID NO:201), where X1 is N, Q, S, A, or D; CDR-H2 comprising the amino acid sequence of FIX1PGGGX2DEX3X4X5X6X7X8X9 (SEQ ID NO:202), where X1 is D, E, S, or A; X2 is H or Y; X3 is P, S, or Y; X4 is A or D; X5 is D, R, or Q; X6 is K, R, or S; X7 is F or V; X8 is E, K, Q, or R; and X9 is D or G; and CDR-H3 comprising the amino acid sequence of RGGGYYLDY (SEQ ID NO: 203); CDR-L1 comprising the amino acid sequence of RASQDISFFLN (SEQ ID NO: 206); CDR-L2 comprising an amino acid sequence of X1X2SX3YHS (SEQ ID NO:207), where X1 is G or Y; X2 is A or T; and X3 is R or S; and CDR-L3 comprising the amino acid sequence of QHGX1TLPX2T (SEQ ID NO:208), where X1 is A, D, N, Q, or S; and X2 is F, H, R, W, or Y.

[0010] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment may comprise: CDR-H1 comprising the amino acid sequence of GFSLSTSGX1GVG (SEQ ID NO:211), where X1 is I, K, M, or V; CDR-H2 comprising the amino acid sequence of HIX1X1DDVKSYX2PALKS (SEQ ID NO:212), where X1 is F, H, W, or Y; and X2 is A, N, Q, or S; CDR-H3 comprising the amino acid sequence of IGX1GYYSFDY (SEQ ID NO:213), where X1 is A, D, E, or S; CDR-L1 comprising the amino acid sequence of X1ASQDVSDAVA (SEQ ID NO:216), where X1 is K or R; CDR-L2 comprising the amino acid sequence of SPSYRYT (SEQ ID NO: 217); and CDR-L3 comprising the amino acid sequence of QQHYSTPX1TF (sequence number: 218), where X1 is F, H, W, or Y.

[0011] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise: CDR-H1 comprising the amino acid sequence of GFSFSSGYX1IF (SEQ ID NO:221), where X1 is F, H, W, or Y; CDR-H2 comprising the amino acid sequence of GIYSGSSGTTY (SEQ ID NO: 222); CDR-H3 comprising the amino acid sequence of SVX1GIX1SYX1AAFX2L (SEQ ID NO:223), where X1 is A, D, E, or S; and X2 is A, N, Q, or S; CDR-L1 comprising the amino acid sequence of X1ASDX2IYSLLA (SEQ ID NO:229), where X1 is Q or R; and X2 is A, N, Q, or S; CDR-L2 comprising the amino acid sequence of RASTLAS (SEQ ID NO: 230); and CDR-L3 comprising the amino acid sequence of QQHYDYX1YLDVA (SEQ ID NO: 231), where X1 is A, N, Q, or S.

[0012] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise: CDR-H1 comprising the amino acid sequence of GFSFSSSYX1IF (SEQ ID NO:225), where X1 is F, H, W, or Y; CDR-H2 comprising the amino acid sequence of GIYSSSGRX1Y (SEQ ID NO: 226), where X1 is I, K, L, or M; CDR-H3 comprising the amino acid sequence of SAX1GSX1SYX1AYFTL (SEQ ID NO:227), where X1 is A, D, E, or S; CDR-L1 comprising the amino acid sequence of X1ASDX2IYSX2LA (SEQ ID NO:233), where X1 is Q or R; and X2 is A, N, Q, or S; CDR-L2 comprising the amino acid sequence of RASTLAS (SEQ ID NO: 234); and CDR-L3 comprising the amino acid sequence of QQHX1DYDYIDVA (SEQ ID NO: 235), where X1 is F, H, W, or Y.

[0013] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise a heavy chain variable region comprising the three CDRs of one of the following SEQ ID NOs: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, No. 71, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, or SEQ ID NO: 107; or, The heavy chain variable region may competitively inhibit the binding of an isolated antibody or antigen-binding fragment comprising at least one of a heavy chain variable region comprising the three CDRs of one of the following SEQ ID NOs: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, No.:71, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, or SEQ ID NO:107.

[0014] In other embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise a heavy chain variable region comprising an amino acid sequence at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of one of the following SEQ ID NOs: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, No.:71, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, or SEQ ID NO:107.

[0015] In yet other embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising the three CDRs of one of the following SEQ ID NOs: SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:72; or, The antibody or antigen-binding fragment may comprise a light chain variable region that competitively inhibits binding of an isolated antibody or antigen-binding fragment comprising at least one of a light chain variable region comprising the three CDRs of one of the following SEQ ID NOs: SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:72.

[0016] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of one of the following SEQ ID NOs: SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:72.

[0017] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise at least one of the following: (a) a heavy chain variable region comprising the three CDRs of SEQ ID NO:1 and a light chain variable region comprising the three CDRs of SEQ ID NO:24; (b) a heavy chain variable region comprising the three CDRs of SEQ ID NO:2 and a light chain variable region comprising the three CDRs of SEQ ID NO:25; (c) a heavy chain variable region comprising the three CDRs of SEQ ID NO:3 and a light chain variable region comprising the three CDRs of SEQ ID NO:26; (d) a heavy chain variable region comprising the three CDRs of SEQ ID NO:4 and a light chain variable region comprising the three CDRs of SEQ ID NO:27; (e) a heavy chain variable region comprising the three CDRs of SEQ ID NO:5 and a light chain variable region comprising the three CDRs of SEQ ID NO:28; (f) a heavy chain variable region comprising the three CDRs of SEQ ID NO:6 and a light chain variable region comprising the three CDRs of SEQ ID NO:29; (g) a heavy chain variable region comprising the three CDRs of SEQ ID NO:7 and a light chain variable region comprising the three CDRs of SEQ ID NO:30; (h) a heavy chain variable region comprising the three CDRs of SEQ ID NO:8 and a light chain variable region comprising the three CDRs of SEQ ID NO:31; (i) a heavy chain variable region comprising the three CDRs of SEQ ID NO:9 and a light chain variable region comprising the three CDRs of SEQ ID NO:32; (j) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 10 and a light chain variable region comprising the three CDRs of SEQ ID NO: 33; (k) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 11 and a light chain variable region comprising the three CDRs of SEQ ID NO: 34; (l) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 12 and a light chain variable region comprising the three CDRs of SEQ ID NO: 35; (m) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 13 and a light chain variable region comprising the three CDRs of SEQ ID NO: 36; (n) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 14 and a light chain variable region comprising the three CDRs of SEQ ID NO: 37; (o) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 15 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (p) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 16 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (q) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 17 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (r) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 18 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (s) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 19 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (t) a heavy chain variable region comprising the three CDRs of SEQ ID NO:20 and a light chain variable region comprising the three CDRs of SEQ ID NO:38 or SEQ ID NO:39; (u) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 21 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (v) a heavy chain variable region comprising the three CDRs of SEQ ID NO:22 and a light chain variable region comprising the three CDRs of SEQ ID NO:38 or SEQ ID NO:39; (w) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 23 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (x) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 40 and a light chain variable region comprising the three CDRs of SEQ ID NO: 45; (y) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 41 and a light chain variable region comprising the three CDRs of SEQ ID NO: 46; (z) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 42 and a light chain variable region comprising the three CDRs of SEQ ID NO: 47; (aa) a heavy chain variable region comprising the three CDRs of SEQ ID NO:43 and a light chain variable region comprising the three CDRs of SEQ ID NO:48, SEQ ID NO:49, or SEQ ID NO:50; (bb) a heavy chain variable region comprising the three CDRs of SEQ ID NO:44 and a light chain variable region comprising the three CDRs of SEQ ID NO:48, SEQ ID NO:49, or SEQ ID NO:50; (cc) a heavy chain variable region comprising the three CDRs of SEQ ID NO:51 and a light chain variable region comprising the three CDRs of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (dd) a heavy chain variable region comprising the three CDRs of SEQ ID NO:52 and a light chain variable region comprising the three CDRs of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (ee) a heavy chain variable region comprising the three CDRs of SEQ ID NO:53 and a light chain variable region comprising the three CDRs of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (ff) a heavy chain variable region comprising the three CDRs of SEQ ID NO:54 and a light chain variable region comprising the three CDRs of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (gg) a heavy chain variable region comprising the three CDRs of SEQ ID NO:55 and a light chain variable region comprising the three CDRs of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (hh) a heavy chain variable region comprising the three CDRs of SEQ ID NO:56 and a light chain variable region comprising the three CDRs of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (ii) a heavy chain variable region comprising the three CDRs of SEQ ID NO:57 and a light chain variable region comprising the three CDRs of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (jj) a heavy chain variable region comprising the three CDRs of SEQ ID NO:58 and a light chain variable region comprising the three CDRs of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (kk) a heavy chain variable region comprising the three CDRs of SEQ ID NO:59 and a light chain variable region comprising the three CDRs of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; or (ll) a heavy chain variable region comprising the three CDRs of SEQ ID NO:60 and a light chain variable region comprising the three CDRs of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70.

[0018] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise at least one of the following: (a) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:1, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:24; (b) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:2, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:25; (c) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:3, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:26; (d) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:4, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:27; (e) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:5, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:28; (f) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:6, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:29; (g) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:7, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:30; (h) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:8, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:31; (i) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:9, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:32; (j) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:10, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:33; (k) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:11, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:34; (l) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:12, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:35; (m) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:13, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:36; (n) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO: 14, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO: 37; (o) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:15, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (p) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:16, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (q) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:17, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (r) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:18, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (s) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:19, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (t) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:20, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (u) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:21, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (v) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:22 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (w) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:23, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (x) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:40, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:45; (y) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:41, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:46; (z) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:42, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:47; (aa) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:43, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:48, SEQ ID NO:49, or SEQ ID NO:50; (bb) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:44, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:48, SEQ ID NO:49, or SEQ ID NO:50; (cc) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:51, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (dd) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:52, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (ee) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:53, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (ff) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:54, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (gg) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:55, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (hh) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:56, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (ii) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:57, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (jj) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:58, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (kk) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:59, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; or (ll) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:60, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70.

[0019] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise a constant chain region, wherein the antibody or antigen-binding fragment thereof comprising said constant chain region has an increased in vivo half-life and / or reduced immunogenicity compared to the antibody or antigen-binding fragment thereof lacking said constant chain region.

[0020] In some embodiments, the constant chain region comprises an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, or SEQ ID NO:139.

[0021] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise at least one of the following: a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:156, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:157; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:166 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:167; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:170 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:171; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:178 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:179; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:182; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:184 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:185; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:187 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:188; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:191; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:193 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:194; or A heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:197, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:198.

[0022] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise a peptide linker. The peptide linker may comprise the amino acid sequence of SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:245, or SEQ ID NO:246.

[0023] In some embodiments, the antibody or antigen-binding fragment thereof is humanized.

[0024] In other embodiments, the antibody or antigen-binding fragment thereof binds to human properdin.

[0025] In some embodiments, the antibody or antigen-binding fragment thereof inhibits alternative complement pathway activation in a mammal without inhibiting classical complement pathway activation.

[0026] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise a first heavy chain variable region that binds properdin and a second heavy chain variable region that binds to a different epitope than the first heavy chain variable region.

[0027] In some embodiments, the second heavy chain variable region extends the in vivo half-life of the antibody or antigen-binding fragment thereof to about 3 weeks to about 8 weeks.

[0028] In other embodiments, the second heavy chain variable region binds to either albumin, TNF, or VEGF.

[0029] In some embodiments, the second antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:150, or SEQ ID NO:152.

[0030] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof is capable of inhibiting the in vivo formation of C3b and Mac complexes (C5b-9).

[0031] Other embodiments described herein relate to isolated monospecific or bispecific anti-properdin antibodies or antigen-binding fragments comprising: an anti-properdin heavy chain variable region comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:2; and an anti-properdin light chain variable region comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:25; and wherein the heavy chain variable region is CDR-H1 comprising the amino acid sequence of GYIFTX1YPIH (SEQ ID NO:201), where X1 is N, Q, S, A, or D (e.g., X1 is Q, S, A, or D); CDR-H2 comprising the amino acid sequence of FIX1PGGGX2DEX3X4X5X6X7X8X9 (SEQ ID NO:202), where X1 is D, E, S (e.g., E or S), or A; X2 is H or Y; X3 is P, S, or Y; X4 is A or D; X5 is D, R, or Q; X6 is K, R, or S; X7 is F or V; X8 is E, K, Q, or R; and X9 is D or G); and CDR-H3 comprising the amino acid sequence of RGGGYYLDY (SEQ ID NO: 203); Includes; The light chain variable region comprises: CDR-L1 comprising the amino acid sequence of RASQDISFFLN (SEQ ID NO: 206); CDR-L2 comprising an amino acid sequence of X1X2SX3YHS (SEQ ID NO:207), where X1 is G or Y; X2 is A or T; and X3 is R or S; and a CDR-L3 comprising the amino acid sequence of QHGX1TLPX2T (SEQ ID NO:208), where X1 is N, A, D, Q, or S (e.g., A, D, Q, or S); and X2 is F, H, R, W, or Y (e.g., F, H, R, or Y); Includes.

[0032] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof can comprise at least one constant chain region or a second heavy chain variable region that binds to a distinct epitope from the anti-properdin heavy chain region, wherein the antibody or antigen-binding fragment comprising the constant chain region or second heavy chain variable region has an increased in vivo half-life and / or reduced immunogenicity compared to the antibody or antigen-binding fragment having neither the constant chain region nor the second heavy chain variable region.

[0033] In some embodiments, the constant chain region comprises an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, or SEQ ID NO:139: The second heavy chain variable region also comprises an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:150, or SEQ ID NO:152.

[0034] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise a heavy chain having an amino acid sequence that is at least 90% identical to SEQ ID NO:247, and a light chain having an amino acid sequence that is at least 90% identical to SEQ ID NO:248.

[0035] Other embodiments described herein relate to methods of treating a complement-mediated disease or disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof, as described herein.

[0036] In some embodiments, the subject has a disease or disorder in which activation of the alternative complement pathway plays a role, and the disease or disorder is treated by administering the antibody or antigen-binding fragment thereof.

[0037] In another aspect, the method comprises treating a disease or disorder in which activation of the alternative complement pathway plays a role, comprising administering an antibody or antigen-binding fragment thereof described herein to an individual having the disease or disorder or at risk of developing the disease or disorder.

[0038] In a further aspect, the method includes treating a disease or disorder selected from the group consisting of inflammatory diseases and inflammatory disorders.

[0039] In another aspect, the method includes treating a disease or disorder selected from the group consisting of an autoimmune disease and an autoimmune disorder.

[0040] In a further aspect, the method includes treating an autoimmune disease or disorder selected from the group consisting of systemic lupus erythematosus, myasthenia gravis, arthritic conditions, Alzheimer's disease, and multiple sclerosis.

[0041] In another aspect, the method includes treating an arthritic condition, which may be selected from the group consisting of rheumatoid arthritis, osteoarthritis, and juvenile arthritis.

[0042] In a further aspect, the method includes treating a complement-related disease or disorder selected from the group consisting of ocular diseases and disorders. The ocular disease or disorder may be selected from the group consisting of diabetic retinopathy, ocular histoplasmosis, age-related macular degeneration, diabetic retinopathy, choroidal neovascularization (CNV), uveitis, diabetic macular edema, pathological myopia, von Hippel-Lindau disease, ocular histoplasmosis, central retinal vein occlusion (CRVO), corneal neovascularization, and retinal neovascularization. The age-related macular degeneration may be selected from the group consisting of intermediate atrophic age-related macular degeneration (AMD) and geographic atrophy.

[0043] In another aspect, the complement-associated disorder being treated is selected from the group consisting of asthma disorders and airway inflammatory disorders. The airway inflammatory disorder may be selected from the group consisting of: Asthma, Chronic Obstructive Pulmonary Disease ("COPD"), Allergic Bronchopulmonary Aspergillosis, Hypersensitivity Pneumonitis, Eosinophilic Pneumonia, Emphysema, Bronchitis, Allergic Bronchitis Bronchiectasis, Cystic Fibrosis, Tuberculosis, Hypersensitivity Pneumonitis, Occupational Asthma, Sarcoidosis, Reactive Airways Disease Syndrome, Interstitial Lung Disease, Hypereosinophilic Syndrome, Rhinitis, Sinusitis, Exercise-Induced Asthma, Pollution-Induced Asthma, Cough Varicose Vein Asthma, Parasitic Lung Disease, Respiratory Syncytial Virus ("RSV") Infection, Parainfluenza Virus ("PIV") Infection, Rhinovirus ("RV") Infection, and Adenovirus Infection.

[0044] In another aspect, treating a complement-associated disorder is selected from central and peripheral nervous system / neurological diseases and disorders, including: Multiple sclerosis (MS), myasthenia gravis (MG), myasthenia gravis, multiple sclerosis, Guillain-Barré syndrome, Miller Fisher syndrome, stroke, post-stroke reperfusion, Alzheimer's disease, multifocal motor neuropathy (MMN), demyelination, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, degenerative disc disease (DDD), meningitis, cranial nerve damage due to meningitis, variant Creutzfeldt-Jakob disease (vCJD), idiopathic polyneuropathy, brain / cerebral trauma (including but not limited to bleeding, inflammation, and edema), neuromyelitis optica (NMO) (including those serologically positive for aquaporin 4 (AQP4)-IgG autoantibody), and neuropathic pain. [Brief description of the drawings]

[0045] [Figure 1] 1 shows a schematic diagram of the structure of a monospecific anti-properdin antibody according to one embodiment and a listing of the amino acid sequences of the VH region (SEQ ID NOs: 204 and 205) and the VL region (SEQ ID NOs: 209 and 210) of the monospecific anti-properdin antibody. [Diagram 2] FIG. 1 shows a schematic diagram of the structure of a monospecific anti-properdin antibody according to another embodiment and a listing of the amino acid sequences of the VH region (SEQ ID NOs: 214 and 215) and the VL region (SEQ ID NOs: 219 and 220) of the monospecific anti-properdin antibody. [Diagram 3] FIG. 1 shows a schematic diagram of the structure of a monospecific anti-properdin antibody according to another embodiment and a listing of the amino acid sequences of the VH region (SEQ ID NOs: 224 and 228) and the VL region (SEQ ID NOs: 232 and 236) of the monospecific anti-properdin antibody. [Figure 4] 1 shows a table showing variable and constant chain linkers (SEQ ID NOs: 140-149). [Diagram 5]FIG. 1 shows a schematic diagram of the structure of a bispecific anti-properdin / anti-albumin antibody according to another embodiment and amino acid sequence listings of the camelid anti-properdin portion (SEQ ID NOs: 240 and 244) and the anti-albumin portion (SEQ ID NOs: 108 and 119) of the bispecific anti-properdin / anti-albumin antibody. [Figure 6] Schematic diagram of the structure of camelid single-chain anti-properdin / anti-albumin antibodies (NMT1001 and NMT1002) and amino acid sequence listing of the camelid anti-properdin VHH domain (SEQ ID NO: 108), linker (SEQ ID NO: 143), and anti-albumin domain (SEQ ID NO: 75) of NMT1001 (SEQ ID NO: 108, 143, and 75) and the camelid anti-properdin VHH domain (SEQ ID NO: 110), linker (SEQ ID NO: 143), and anti-albumin domain (SEQ ID NO: 75) of NMT1002. [Figure 7] FIG. 1 shows a schematic diagram of the structure of monospecific anti-properdin (Fab) 2 (NMT1003) and the amino acid sequences of the VH and VL regions (SEQ ID NO: 1 and 24), Fc-CH1 (SEQ ID NO: 138), and Fc-LC (SEQ ID NO: 139) of NMT1003. [Figure 8] Schematic diagram of the structure of bispecific anti-albumin / anti-properdin Fab (NMT1004 and NMT1005) and amino acid sequence listing of anti-properdin VH (SEQ ID NO:1), Fc-CH1 (SEQ ID NO:138), VL (SEQ ID NO:24), and Fc-LC (SEQ ID NO:139), linker (SEQ ID NO:143), and anti-albumin region (SEQ ID NO:110) of NMT1004, and anti-properdin VH (SEQ ID NO:1), Fc-CH1 (SEQ ID NO:138), VL (SEQ ID NO:24), and Fc-LC (SEQ ID NO:139), linker (SEQ ID NO:143), and anti-albumin region (SEQ ID NO:108) of NMT1005. [Figure 9]Figure 1 shows a schematic diagram of the structure of a monospecific camelid anti-properdin antibody according to another embodiment and the amino acid sequence listing of the IgG4 Fc with camelid anti-properdin VHH (SEQ ID NO: 74), linker (SEQ ID NO: 143), and hinge region (SEQ ID NO: 137) of the monospecific camelid anti-properdin antibody (SEQ ID NO: 162). [Figure 10] FIG. 1 shows a schematic diagram of the structure of a bispecific anti-properdin / anti-albumin antibody according to another embodiment and amino acid sequence listings of the anti-properdin VH (SEQ ID NO:2), IG1 Fc (SEQ ID NO:129), VL (SEQ ID NO:25), and Fc-LC (SEQ ID NO:139) of the bispecific anti-properdin / anti-albumin antibody, as well as the anti-albumin VH (SEQ ID NO:71), IG1 Fc (SEQ ID NO:129), VL (SEQ ID NO:72), and Fc-LC (SEQ ID NO:139). [Figure 11] FIG. 1 shows a schematic diagram of the structure of a bispecific anti-properdin / anti-albumin antibody according to another embodiment and amino acid sequence listings of the anti-properdin VH (SEQ ID NO:52), IG1 Fc (SEQ ID NO:131), VL (SEQ ID NO:62), and Fc-LC (SEQ ID NO:139) of the bispecific anti-properdin / anti-albumin antibody, as well as the anti-albumin VH (SEQ ID NO:71), IG1 Fc (SEQ ID NO:131), VL (SEQ ID NO:72), and Fc-LC (SEQ ID NO:139). [Figure 12] FIG. 1 shows a schematic diagram of the structure of a bispecific anti-properdin / anti-TNF antibody according to another embodiment and a listing of the amino acid sequences of the anti-properdin VH (SEQ ID NO:2), IG1 Fc (SEQ ID NO:129), VL (SEQ ID NO:25), and Fc-LC (SEQ ID NO:139) of the bispecific anti-properdin / anti-TNF antibody, as well as the anti-TNF VH (SEQ ID NO:150), IG1 Fc (SEQ ID NO:129), VL (SEQ ID NO:151), and Fc-LC (SEQ ID NO:139). [Figure 13]FIG. 1 shows a schematic diagram of the structure of a bispecific anti-properdin / anti-VEGF antibody according to another embodiment and amino acid sequence listings of the anti-properdin VH (SEQ ID NO:2), IG1 Fc (SEQ ID NO:130), VL (SEQ ID NO:25), and Fc-LC (SEQ ID NO:139) of the bispecific anti-properdin / anti-VEGF antibody, as well as the anti-VEGF VH (SEQ ID NO:152), IG1 Fc (SEQ ID NO:130), VL (SEQ ID NO:153), and Fc-LC (SEQ ID NO:139). [Figure 14] Figure 1 shows a schematic diagram of the structure of a bispecific camelid anti-properdin / anti-albumin antibody according to another embodiment and the amino acid sequence listing of the IgG1 Fc with camelid anti-properdin VHH (SEQ ID NO: 74), linker (SEQ ID NO: 143), and hinge region (SEQ ID NO: 130) of the bispecific camelid anti-properdin / anti-albumin antibody, as well as the anti-albumin VH (SEQ ID NO: 108), linker (SEQ ID NO: 143), and IgG1 Fc (SEQ ID NO: 143). [Figure 15] FIG. 1 shows a schematic diagram of the structure of a bispecific anti-properdin / anti-albumin antibody according to another embodiment and a listing of the amino acid sequences of the anti-properdin VH (SEQ ID NO:2), IG1 Fc (SEQ ID NO:131), VL (SEQ ID NO:25), and Fc-LC (SEQ ID NO:139) of the bispecific anti-properdin / anti-albumin antibody, as well as the anti-albumin VH (SEQ ID NO:110), linker (SEQ ID NO:143), and IgG1 Fc (SEQ ID NO:131). [Figure 16] FIG. 1 shows a schematic diagram of the structure of a bispecific anti-properdin / anti-albumin antibody according to another embodiment and a listing of the amino acid sequences of the anti-properdin VH (SEQ ID NO:2), IG1 Fc (SEQ ID NO:130), VL (SEQ ID NO:25), and Fc-LC (SEQ ID NO:139) of the bispecific anti-properdin / anti-albumin antibody, as well as the anti-albumin VH (SEQ ID NO:71), IG1 Fc (SEQ ID NO:130), VL (SEQ ID NO:72), and Fc-LC (SEQ ID NO:139). [Figure 17]Figure 1 shows a schematic diagram of the structure of a bispecific camelid anti-properdin / anti-albumin antibody according to another embodiment and the amino acid sequence listing of the IgG4 Fc with camelid anti-properdin VHH (SEQ ID NO: 75), linker (SEQ ID NO: 143), and hinge region (SEQ ID NO: 137) of the bispecific camelid anti-properdin / anti-albumin antibody, as well as the anti-albumin VH (SEQ ID NO: 108), linker (SEQ ID NO: 143), and IgG4 Fc (SEQ ID NO: 137). [Figure 18] FIG. 1 shows a schematic diagram of the structure of a bispecific anti-properdin / anti-TNF antibody according to another embodiment and a listing of the amino acid sequences of the anti-properdin VH (SEQ ID NO:2), IG1 Fc (SEQ ID NO:131), VL (SEQ ID NO:25), and Fc-LC (SEQ ID NO:139) of the bispecific anti-properdin / anti-TNF antibody, as well as the anti-TNF VH (SEQ ID NO:150), IG1 Fc (SEQ ID NO:131), VL (SEQ ID NO:151), and Fc-LC (SEQ ID NO:139). [Figure 19] FIG. 1 shows a schematic diagram of the structure of a bispecific anti-properdin / anti-VEGF antibody according to another embodiment and amino acid sequence listings of the anti-properdin VH (SEQ ID NO:2), IG1 Fc (SEQ ID NO:131), VL (SEQ ID NO:25), and Fc-LC (SEQ ID NO:139) of the bispecific anti-properdin / anti-VEGF antibody, as well as the anti-VEGF VH (SEQ ID NO:152), IG1 Fc (SEQ ID NO:131), VL (SEQ ID NO:153), and Fc-LC (SEQ ID NO:139). [Figure 20] 1 is a plot showing the binding affinity of NMT15, NMT16, NMT17, and NMT18 to properdin. [Figure 21] 1 is a plot showing the binding affinity of NMT19, NMT20, NMT21, and NMT22 to properdin. [Figure 22] 1 is a plot showing inhibition of AP hemolysis by NMT15, NMT16, NMT17, and NMT18. [Figure 23] 1 is a plot showing inhibition of AP hemolysis by NMT19, NMT20, NMT21, and NMT22. [Figure 24] 1 is a plot showing inhibition of MAC formation by NMT15, NMT16, NMT17, and NMT18. [Diagram 25] 1 is a plot showing inhibition of MAC formation by NMT19, NMT20, NMT21, and NMT22. [Figure 26] 1 is a plot showing inhibition of properdin C3b binding by NMT15, NMT16, NMT17, and NMT18. [Figure 27] 1 is a plot showing inhibition of properdin C3b binding by NMT19, NMT20, NMT21, and NMT22. [Figure 28] 1 is a plot showing inhibition of AP-mediated C3b formation and deposition by NMT15, NMT17, NMT18, NMT20, and NMT21. [Figure 29] 1 is a plot showing CP-mediated MAC formation and deposition by NMT15, NMT17, NMT18, NMT20, and NMT21. [Diagram 30] 1 is a plot showing CP-mediated C3b formation and deposition by NMT15, NMT17, NMT18, NMT20, and NMT21. [Diagram 31] 1 is a plot showing the binding affinity of NMT23, NMT24, NMT25, NMT26, NMT27, and NMT28 to properdin. [Diagram 32] 1 is a plot showing inhibition of MAC formation and deposition by NMT23, NMT24, NMT25, NMT26, NMT27, and NMT28. [Diagram 33] 1 is a plot showing inhibition of AP hemolysis by NMT23, NMT24, NMT26, and NMT27. [Diagram 34] 1 is a plot showing inhibition of AP-mediated C3 convertase formation and deposition by NMT28. [Diagram 35] 1 is a plot showing CP-mediated C3b formation and deposition by NMT28. [Diagram 36]1 is a plot showing the binding affinity of NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101 to properdin. [Figure 37] 1 is a plot showing inhibition of AP hemolysis by NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. [Figure 38] 1 is a plot showing inhibition of Mac formation by NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. [Figure 39] 1 is a plot showing inhibition of AP-mediated C3b formation and deposition by NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. [Diagram 40] 1 is a plot showing binding affinity to properdin. Comparison of the Fc regions of N297 and Xtend--NMT17, NMT18, NMT28, NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. [Diagram 41] 1 is a plot showing binding affinity to properdin. Comparison of the Fc regions of N297 and Xtend--NMT17, NMT18, NMT28, NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. [Diagram 42] 1 is a plot showing AP hemolysis inhibition. Comparison of the Fc region of N297 and Xtend - NMT17, NMT18, NMT28, NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. [Diagram 43]1 is a plot showing inhibition of C3b formation and deposition. Comparison of the Fc region of N297 and Xtend - NMT17, NMT18, NMT28, NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. [Diagram 44] 1 is a plot showing binding avidity to properdin. Comparison of the Fc regions of N297 and Xtend--NMT29, NMT30, NMT31. [Diagram 45] 1 is a plot showing AP-mediated MAC formation. Comparison of the Fc regions of N297 and Xtend--NMT29, NMT30, NMT31. [Diagram 46] 1 is a plot showing inhibition of AP-mediated hemolysis. Comparison of the Fc region of N297 and Xtend--NMT29, NMT30, NMT31. [Figure 47] 1 is a plot showing inhibition of AP-mediated C3b formation and deposition.Comparison of the Fc region of N297 and Xtend-NMT29, NMT30, NMT31. [Figure 48] 1 is a plot showing binding avidity to properdin. Comparison of the Fc regions of N297 and Xtend--NMT30-100, NMT30-101, NMT31-100, and NMT31-101. [Figure 49] 1 is a plot showing inhibition of AP hemolysis. Comparison of the Fc region of N297 and Xtend--NMT30-100, NMT30-101, NMT31-100, and NMT31-101. [Figure 50] 1 is a plot showing inhibition of AP-mediated MAC formation. Comparison of the Fc regions of N297 and Xtend--NMT30-100, NMT30-101, NMT31-100, and NMT31-101. [Figure 51] 1 is a plot showing inhibition of AP-mediated C3b formation and deposition. Comparison of the Fc regions of N297 and Xtend--NMT30-100, NMT30-101, NMT31-100, and NMT31-101. [Figure 52]1 is a plot showing binding avidity to properdin. Comparison of the Fc regions of N297 and Xtend--NMT30, NMT31, NMT30-100, NMT30-101, NMT31-100, and NMT31-101. [Figure 53] 1 is a plot showing inhibition of AP hemolysis. Comparison of the Fc region of N297 and Xtend - NMT30, NMT31, NMT30-100, NMT30-101, NMT31-100, and NMT31-101. [Figure 54] 1 is a plot showing inhibition of MAC formation. Comparison of the Fc region of N297 and Xtend--NMT30, NMT31, NMT30-100, NMT30-101, NMT31-100, and NMT31-101. [Figure 55] 1 is a plot showing inhibition of C3b formation and deposition. Comparison of the Fc region of N297 and Xtend--NMT30, NMT31, NMT30-100, NMT30-101, NMT31-100, and NMT31-101. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0046] The term "acceptor human framework" herein refers to a framework that comprises the amino acid sequence of a VL or VH framework derived from a human immunoglobulin framework or derived from a human consensus framework.

[0047] The term "antibody" as used herein includes full-length monoclonal antibodies, polyclonal antibodies, nanobodies, and multispecific antibodies. Biological antibodies are typically heterotetrameric glycoproteins of about 150,000 daltons composed of two identical light chains (L) and two identical heavy chains (H). The two heavy chains are linked by disulfide bonds, and each heavy chain is linked to a light chain by a disulfide bond. Each full-length IgG molecule contains at least two binding sites for a specific target or antigen. The light chains are either kappa or lambda. Both light chains contain a variable region ("V L ", "V カッパ " or "Vラムダ Each heavy chain contains a domain of variable amino acid sequence called the constant region ("CL-region"), as well as a relatively conserved domain of amino acid sequence called the variable region ("V-region"). H -region") and three constant domains ("C H1 -Area", "C H2 -Area" and "C H3 -region") and the hinge region.

[0048] The term "antibody fragment" herein refers to a segment of a full-length antibody, generally referred to as the target binding region or variable region. Other antibodies include bispecific antibodies, linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments. Examples include Fab, Fab', F(ab')2, Fv, or scFv fragments. An "Fv" fragment is the smallest antibody fragment that contains a complete target recognition and binding site.

[0049] As used herein, the term "antigen-binding fragment" refers to a fragment or fragments of an antibody molecule that contain the antibody variable region that functions in antigen binding.

[0050] Antigen-binding fragments can be prepared from full-length antibodies by protease digestion. Antigen-binding fragments may also be generated by one of skill in the art using standard recombinant DNA techniques. Examples of antigen-binding fragments include: "Fab" fragment (single chain variable region having VH and VL); "Monovalent fragment" (antibody fragment consisting of the VL, VH, CL and CH1 domains) "F(ab')2" fragment (a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region); "Fd" fragment (consisting of the VH and CH1 domains of an antibody); "Fv" fragment (consisting of the VL and VH domains of a single arm of an antibody); Single domain antibodies ("dAbs") (consisting of a VH or VL domain); and Isolated complementarity determining regions ("CDRs").

[0051] "Complementarity determining regions" ("CDRs") herein are the primary binding regions of antibodies. CDRs refer to specific regions within the variable regions of the heavy and light chains. Generally, the variable region consists of four framework regions (FR1, FR2, FR3, FR4) and three CDRs arranged in the following manner: NH2-FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4-COOH. The term "framework region" refers to the variable domain residues other than the CDR residues as defined herein.

[0052] The CDRs as antigen-binding fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, bispecific antibodies, triabodies, tetrabodies, v-NARs and bispecific single chain Fvs (bis-scFvs). Antigen-binding fragments of antibodies can also be linked to polypeptide-based scaffolds. Antigen-binding fragments can be incorporated into single chain molecules that contain tandem Fv segment (VH-CH1-VH-CH1) pairs, thereby forming antigen-binding region pairs with complementary light chain polypeptides.

[0053] "Single-chain Fv" or "scFv" antibody fragments herein comprise the VH and VL domains of antibody, however, these domains are present in a single polypeptide chain.

[0054] "Effector function" in this specification refers to the biological activity of the natural Fc region of antibody, which varies depending on antibody isotype.Examples of antibody effector function include C1q binding and complement-dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor); lack of activation of platelets expressing Fc receptors; and B cell activation.In order to minimize or eliminate the side effects of therapeutic antibodies, it may be preferable to minimize or eliminate effector function.

[0055] In the present application, "undesirable effector functions" include ADCC, CDC, classical pathway activation, cellular activation, and antibody-mediated inflammation.

[0056] An "engineered antibody" is an antibody that is not produced in nature and that has been altered or created to achieve a particular purpose or have particular properties. For example, an antibody obtained by deliberately modifying the wild-type form to reduce effector function is an engineered antibody.

[0057] As used herein, the term "Fc region" refers to the region of an antibody that provides protection against a given antigen.

[0058] The term "first portion of the antibody" as used herein refers to a portion of a complete antibody, which is a smaller portion than the whole, that includes the antigen-binding region of the antibody. The term "second portion of the antibody" refers to a portion of a complete antibody, which is a smaller portion than the whole, that consists of the portion of the antibody that is not included in the first portion.

[0059] The term "Fc receptor" or "FcγR" refers to a receptor that binds to the Fc region of IgG. "FcγRI", "FcγRII" and "FcγRIII" are subclasses of FcγRs.

[0060] The term "reduced Fc effector function" as used herein refers to an antibody function that does not act on an antigen but recognizes the Fc region of an antibody. Examples of reduced Fc effector function include, but are not limited to, reduced Fc binding to an antigen, lack of Fc activation to an antigen, an Fc region containing a mutation that inhibits normal Fc effector function, or inhibited activation of platelets and other cells that have Fc receptors.

[0061] A "modification" to an antibody, antibody fragment, and / or Fc region of an antibody refers to the substitution, insertion, or deletion of one or more amino acids in the wild-type polypeptide sequence of the protein. Modified antibodies, antibody fragments, and / or Fc regions are those that have been modified artificially.

[0062] As used herein, "competitively inhibit" refers to the competitive inhibition by any other molecule of the binding of an isolated antibody, or antigen-binding portion thereof, to properdin.

[0063] The term "epitope" as used herein refers to a site on properdin to which antibodies and fragments thereof bind and exert functional activity. The term "epitope" is synonymous with "antigenic site" and "antibody binding site." One skilled in the art can align the human properdin sequence with the properdin sequence of another animal species to determine the location of the epitope.

[0064] "Fab fragment" herein refers to the constant domain of the light chain and the first constant domain of the heavy chain. Fab' fragments differ from Fab fragments in the presence of a few extra residues at the carboxyl terminus of the heavy chain CH1 domain including one or more cysteines of the antibody hinge region. F(ab') fragments are produced by cleavage of the disulfide bonds at the hinge cysteines of a F(ab')2 pepsin digest.

[0065] As used herein, the term "antigen-binding fragment thereof" of an antibody refers to an antibody fragment having a qualitative biological activity in common with the full-length antibody, for example, an antigen-binding fragment thereof is a fragment capable of binding to properdin such that secondary complement activation is prevented or substantially reduced.

[0066] The term "human consensus framework" as used herein refers to a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Typically, the human immunoglobulin VL or VH sequences are selected from a subgroup of variable domain sequences.

[0067] "Humanized antibody" herein refers to an antibody that consists mostly of human sequences, except for CDR1, CDR2, and CDR3. Also, all framework regions are humanized. Chimeric antibodies contain mouse CDRs, mouse framework regions, and human constant regions. In summary, chimeric antibodies contain two mouse variable regions and a human constant region.

[0068] As used herein, the term "monovalent antibody or antigen-binding fragment thereof" refers to an antibody or antigen-binding fragment thereof that comprises a single binding domain (e.g., a V H or V HH ) In one embodiment, the bound antigen molecule is part of a multimer (e.g., a trimer or higher multimer of properdin monomers). Antibodies, including monovalent antibodies or antibody fragments thereof, generally bind with high specificity to a particular antigen.

[0069] The term "single domain antibody" is defined herein as a molecule in which an antigen-binding site exists and which is formed by a single immunoglobulin domain. In general, the antigen-binding site of an immunoglobulin single variable domain is formed by three or less CDRs. The single variable domain may, for example, be any light chain variable domain sequence (VL) that is capable of forming a single antigen-binding unit (i.e., a functional antigen-binding unit that is essentially a single variable domain and does not require the single antigen-binding domain to interact with another variable domain to form a functional antigen-binding unit). L sequence) or a suitable fragment thereof; or a heavy chain variable domain sequence (e.g., H Array or V HH sequence) or a suitable fragment thereof.

[0070] The term "camelid antibody" herein refers to an antibody derived from a camelid species (e.g., camel, dromedary, llama, alpaca, or guanaco). Camelid antibodies differ from most other mammalian antibodies in that they lack light chains and contain only heavy chains with various intact antigen-binding capacities (Hamers-Casterman, C. et al., Nature, 363:446-8, 1993).

[0071] As used herein, the term "V HH " refers to a single heavy chain variable domain antibody that is devoid of light chains. HH The chains may be of a type that may be present, for example, in camelids or cartilaginous fish, which normally lack light chains, or may be synthetic and non-immune V HH , i.e., the V that can be constructed HH Each heavy chain can include a variable region encoded by a V exon, a D exon, and a J exon. HH is a natural V HH It may be an antibody (eg a camelid antibody) or it may be a recombinant protein comprising the heavy chain variable domain.

[0072] As used herein, the term "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that binds properdin is substantially free of contaminants, such as antibodies that do not bind properdin). Moreover, an "isolated" antibody is one that has been identified, separated and / or recovered from a component of its natural environment, which are substances that may interfere with diagnostic or therapeutic uses for the antibody, and which may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes.

[0073] As used herein, the term "specific binding" of an antibody or fragment thereof, polypeptide, or peptidomimetic refers to binding to a target molecule that is measurably different from binding to a non-target molecule. As used herein, specific binding refers to specific antigen binding that is greater than 95% selective over background ("non-specific") binding. "Substantially specific" binding refers to specific antigen binding that is greater than about 80% selective over background binding. Binding can be measured using a variety of methods, including, but not limited to, Western blot, immunoblot, enzyme-linked immunosorbent assay ("ELISA"), radioimmunoassay ("RIA"), immunoprecipitation, surface plasmon resonance, biolayer interferometry, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemistry, matrix-assisted laser desorption / ionization time-of-flight mass spectrometry ("MALDI-TOF"), microcytometry, microarrays, microscopy, fluorescence-activated cell sorting ("FACS"), and flow cytometry.

[0074] As used herein, the term "human properdin" refers to a soluble glycoprotein of 469 amino acids present in plasma that has an N-terminal domain, TSR0 (which is a truncated domain), along with seven thrombospondin type I repeats (TSR). Human properdin is a 53 kilodalton protein that contains a signal peptide (amino acids 1-28), six non-identical TSR repeats (each of approximately 60 amino acids); the repeats are: Amino acids 80-134 (TSR1); amino acids 139-191 (TSR2); amino acids 196-255 (TSR3); amino acids 260-313 (TSR4); amino acids 318-377 (TSR5); and amino acids 382-462 (TSR6). Properdin is formed by oligomerization of rod-shaped monomers into cyclic dimers, trimers, and tetramers. The amino acid sequence of human properdin is listed in the GenBank database under the following human properdin accession numbers: See, for example, GenBank Accession Nos. AAA36489, NP_002612, AAH15756, AAP43692, S29126 and CAA40914. Properdin is a positive regulator of the alternative complement activation cascade. Known binding ligands for properdin include C3b, C3bB and C3bBb (Blatt, A. et al., Immunol.Rev., 274:172-90, 2016).

[0075] As used herein, the term "mouse properdin" refers to a soluble glycoprotein of 457 amino acids present in plasma that has an N-terminal domain, TSR0 (truncated), as well as seven TSRs. Mouse properdin is a 50 kilodalton protein with a signal peptide (amino acids 1-24) and six non-identical TSRs (each of approximately 60 amino acids); the TSRs are: Amino acids 73-130 (TSR1), amino acids 132-187 (TSR2), amino acids 189-251 (TSR3), amino acids 253-309 (TSR4), amino acids 311-372 (TSR5), and amino acids 374-457 (TSR6). Mouse properdin is formed by oligomerization of rod-shaped monomers into cyclic dimers, trimers, and tetramers. The amino acid sequence of mouse properdin is listed, for example, in the GenBank database (Gen Bank accession numbers: P11680 and S05478).

[0076] As used herein, the term "TSR0 domain" refers to a truncated domain of properdin that precedes the TSR1 domain of properdin. For example, the TSR0 domain of human properdin includes amino acids 28-76.

[0077] As used herein, the term "TSR1 domain" refers to a domain of properdin adjacent to the TSR0 domain of properdin. For example, the TSR0 domain of human properdin includes amino acids 77-134.

[0078] The term "activity of properdin" as used herein refers to the biological activities of properdin, including but not limited to binding interactions that stabilize the C3 / C5 convertase. Properdin binds most avidly to C3b,Bb (the C3 / C5 convertase of the alternative pathway), but also binds to C3b;C3b,B and C3b,Bb. One function is to stabilize the C3b,Bb complex, which allows for enhanced activation of the alternative pathway (Pangburn, M., Methods Enzymol., 162:639-53, 1988; Nolan, K. and Reid, K., Methods Enzymol., 223:35-46, 1993). Properdin promotes the formation of the C3 convertase of the alternative pathway by enhancing the binding of factor B to the P,C3b complex. Thus, properdin is a promoter (positive regulator) of complement activation. Properdin also plays a role in initiating alternative pathway activation by binding to target surfaces and initiating C3 / C5 convertase formation (Kemper C. and Hourcade, D., Mol. Immunol., 45:4048-56, 2008).

[0079] The term "alternative complement pathway" as used herein refers to one of three pathways of complement activation (the others being the classical pathway and the lectin pathway). The alternative complement pathway is typically activated by bacteria, parasites, viruses or fungi, although IgA antibodies and certain Ig light chains have also been reported to activate this pathway.

[0080] As used herein, the term "dysregulation of the alternative complement pathway" refers to any abnormality in the ability of the alternative complement pathway to provide host defense against pathogens, to clear immune complexes and damaged cells, and to regulate immunity. Dysregulation of the alternative complement pathway can occur both in the fluid phase as well as on the cell surface and can result in excessive complement activation or insufficient regulation, both of which can result in tissue damage.

[0081] The term "disease mediated by dysregulation of the alternative complement pathway" herein refers to the interference, arrest or damage to bodily functions, systems or organs caused by dysregulation of the alternative complement pathway. Such diseases may benefit from treatment with the compositions or formulations described herein. In some embodiments, the disease is caused by any abnormality in the ability of the alternative complement pathway to provide host defense against pathogens, to remove immune complexes and damaged cells, and to regulate immunity. Diseases directly or indirectly mediated by dysregulation of one or more components of the alternative complement pathway or products generated by the alternative complement pathway are also included in the disease herein.

[0082] The term "alternative complement pathway-dependent membrane attack complex assembly" as used herein refers to the terminal complex formed as a result of activation of the alternative complement pathway, which includes complement components C5, C6, C7, C8, and C9. The formation of the membrane attack complex (MAC) leads to cell lysis.

[0083] As used herein, the term "alternative complement pathway-dependent hemolysis" refers to the lysis of red blood cells mediated by the increase and / or deposition of alternative complement pathway-dependent MAC assembly on red blood cells.

[0084] The term "linker" herein refers to a bond between two elements (e.g., protein domains). A linker can be a covalent bond or a spacer. The term "bond" refers to any type of bond formed by chemical bonding, such as an amide bond or a disulfide bond, or a chemical reaction (e.g., chemical conjugation). A linker can refer to a moiety (e.g., a polyethylene glycol (PEG) polymer) or an amino acid sequence (e.g., a sequence of 3-200 amino acids, 3-150 amino acids, or 3-100 amino acids) between two polypeptides or polypeptide domains to provide space and / or flexibility between the two polypeptides or polypeptide domains. An amino acid spacer can refer to a portion of the primary sequence of a polypeptide (e.g., attached to a polypeptide or polypeptide domain spaced apart in the polypeptide backbone). A linker can include one or more glycine and serine residues.

[0085] The terms "identical" or "substantially identical" herein with respect to antibody chain polypeptide sequences may also refer to antibody chains that exhibit at least 65%, 70%, 80%, 90% or 95% sequence identity to a reference polypeptide sequence present in the variable region of an antigen-binding fragment. With respect to nucleic acid sequences, the terms may also refer to a sequence of nucleotides that exhibits at least about 65%, 75%, 85%, 90%, 95% or 97% sequence identity to a reference nucleic acid sequence.

[0086] The term "individual" herein refers to a vertebrate, preferably a mammal, and more preferably a human. Treatable individuals include those who are currently asymptomatic but at risk of developing a symptomatic disorder in which the alternative complement pathway plays a role or in which activation of the alternative complement pathway plays a role.

[0087] As used herein, the term "mammal" refers to any animal classified as a mammal, including humans, higher primates, pet and farm animals, horses, pigs, cows, dogs, cats, ferrets, etc. In one embodiment of the invention, the mammal is a human.

[0088] "Monoclonal antibody" herein refers to a homogeneous population of antibodies. Such antibodies are highly specific and directed to a single target antigen. These monoclonal antibodies are homogeneously produced by hybridoma culture and are free of contaminating other immunoglobulins. Monoclonal antibodies can also be prepared by other means, such as phase display, by well-known methods.

[0089] The term "selectively inhibiting the alternative complement pathway" as used herein refers to selectively inhibiting only the alternative complement pathway, but not inhibiting other complement activation pathways, including the classical complement pathway. For example, humanized and chimerized antibodies and their antigen-binding fragments selectively inhibit the alternative complement pathway. This definition also applies to other methods described herein in which the alternative complement pathway is selectively inhibited.

[0090] As used herein, the term "therapeutically effective amount" refers to the amount of a "properdin antagonist" required to achieve a measurable improvement in the condition (e.g., pathology) of a target disease or condition (such as, for example, a complement-associated eye condition).

[0091] As used herein, the term "treatment" refers to both therapeutic treatment and prophylactic or preventative measures.

[0092] Described herein are novel anti-properdin antibodies and antigen-binding fragments thereof useful for the prevention and treatment of complement-mediated and / or related pathologies. These anti-properdin antibodies and antigen-binding fragments may include, but are not limited to, anti-properdin antibodies and antibody variants thereof, antigen-binding fragments thereof, other binding polypeptides and / or peptides. These anti-properdin antibodies and antigen-binding fragments are capable of binding to properdin and may neutralize, block, partially or completely inhibit, eliminate, reduce, or interfere with the functional activity of properdin (e.g., the ability of properdin to participate in the pathology of any complement-related inflammatory disease or disorder).

[0093] Anti-properdin antibodies and antigen-binding fragments thereof The anti-properdin antibodies and their antigen-binding fragments prevent properdin from binding to C3b to form the PC3b complex through selective properdin binding. As a result, the formation of PC3b and PC3bBb complexes does not occur. The PC3bBb complex cleaves C5 and converts it to C5a and C5b, so the formation of the MAC complex (C5b-9) does not occur. That is, the anti-properdin antibodies and their antigen-binding fragments inhibit the formation of the MAC complex by inhibiting the binding of properdin to C3b. It has been shown that elevated levels of the MAC complex are associated with multiple acute and chronic pathologies. Therefore, MAC complex inhibition by anti-properdin antibodies and their antigen-binding fragments is important for clinical benefit in diseases in which complement activation plays a role in the disease pathology.

[0094] The PC3b complex, the PC3bB complex, and the PC3bBb complex may all multimerize. The anti-properdin antibodies and antigen-binding fragments thereof described herein can inhibit the polymerization of each of these complexes, which may have a molar ratio of properdin to each of C3b, factor B, or factor Bb of 1:1. The anti-properdin antibodies and antigen-binding fragments thereof can inhibit the polymerization of each of the above complexes, each of which includes at least one or more moles of properdin to each of C3b, factor B, and factor Bb in each complex. In one example, for the PC3b complex, the molar ratio between properdin and C3b is (P) X (C3b) y In another example, for the PC3bB complex, the molar ratio between properdin, C, C3b, and factor B can be expressed as (P) X (C3b) y (B) z where X=Y+Z. This example can also be expressed as the molar ratio of properdin to C3b and factor Bb in the PC3bBb complex.

[0095] Anti-properdin antibodies and antigen-binding fragments thereof may have the ability to inhibit any biological activity of properdin. Such activity may result in measurable improvement in the pathological condition of properdin-related disease or pathology (e.g., complement-related inflammatory disease or disorder). The activity may be evaluated in in vitro or in vivo tests, including but not limited to binding assays, alternative pathway hemolytic assays using relevant animal models, or human clinical trials.

[0096] In another embodiment, the anti-properdin antibodies and antigen-binding fragments thereof can bind to a specific epitope located on properdin and inhibit AP activation. In one example, the anti-properdin agent can bind to the N-terminal domain of properdin and inhibit binding of properdin to C3b.

[0097] The anti-properdin antibodies or antigen-binding fragments thereof described herein can be generated using full-length properdin, properdin polypeptides, and / or using antigenic properdin epitope-containing peptides (e.g., fragments of properdin polypeptides). Properdin peptides and polypeptides can be isolated and used to generate antibodies as natural polypeptides, recombinant, or synthetic recombinant polypeptides. All of the antigens useful for generating anti-properdin antibodies can be used to generate monospecific and bispecific antibodies.

[0098] The anti-properdin antibody may be or may be derived from a monoclonal antibody. Suitable monoclonal antibodies against a selected antigen may be prepared by known techniques (Monoclonal Antibodies: A manual of techniques, Zola (CRC Press, 1988); Monoclonal Hybridoma Antibodies: Techniques and Applications, Hurrell (CRC Press, 1982); the entire contents of the above references are incorporated herein by reference.

[0099] The anti-properdin antibodies and antigen-binding fragments thereof include humanized monoclonal anti-properdin antibodies or antigen-binding fragments thereof that selectively bind to properdin and selectively inhibit activation of the alternative complement pathway. The anti-properdin antibodies and antigen-binding fragments thereof can be used to treat any inflammatory disease or disorder associated with the alternative pathway in humans or other mammals.

[0100] Methods for making humanized non-human antibodies are well known in the art. Humanization is essentially performed by replacing the sequence of the corresponding human antibody with rodent CDRs or a single CDR sequence. The selection of both light and heavy human variable domains used to make a humanized antibody may be important in some cases to reduce antigenicity and / or human anti-mouse antibody (HAMA) response. In some embodiments, the anti-properdin antibody and its antigen-binding fragments are humanized to reduce or eliminate HAMA response.

[0101] Originally, properdin can have an amino acid sequence identity (%) in the range of at least about 60% to at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% amino acid sequence identity with the mature human amino acid sequence.

[0102] The variable domain of an antibody refers to a specific portion of the variable domain that differs in sequence between antibodies. The variability in anti-properdin antibodies and antigen-binding fragments thereof may be concentrated in three CDR segments located in both the light and heavy chain variable domains. The highly conserved portions of the variable domain are called framework (FR) regions. In the anti-properdin antibodies described herein, there are four FR regions linked by three CDRs, which may comprise the variable chain. The CDRs in each of the light and heavy chains are held in close proximity to each other by the FR regions, together with the CDRs of the other chain, and may contribute to the formation of the target binding site of the antibody.

[0103] Antibody humanization is a process that can generate engineered human antibodies with variable region ("V-region") sequences that are substantially similar to actual human germline sequences while retaining the binding specificity and affinity of the reference antibody. This process can, for example, graft the CDR1, CDR2, and CDR3 regions of heavy and light chain sequences that have been both optimized and pre-identified before starting the grafting process onto a humanized human framework. Fab, Fab', Fab2, or single-chain antigen-binding fragments thereof can be generated from the variable regions that contain the humanized framework. The resulting engineered humanized antibody fragments can retain the binding specificity of the parent (original) mouse antibody for the antigen properdin, and can have the same or even stronger binding affinity as the parent antibody for a particular antigen. The engineered antigen-binding fragments can have heavy and light chain V regions with high amino acid sequence identity compared to the closest human germline antibody gene. For example, further maturational changes can be introduced into the CDR3 region of each chain under construction in order to identify antibodies with optimal binding kinetics.

[0104] In some embodiments, the antibody is HH The antibody may be a single domain antibody such as V. Such antibodies naturally occur in camelids and sharks (Saerens, D. et al., Curr. Opin. Pharmacol., 8:600-8, 2008). Camelid antibodies are described, for example, in U.S. Patent Nos. 5,759,808; 5,800,988; 5,840,526; 5,874,541; 6,005,079; and 6,015,695; each of which is incorporated herein by reference in its entirety. Cloned and isolated V HH The V domains are stable polypeptides that are characterized by the complete antigen-binding capacity of the original heavy chain antibody. HHThe domains combine the advantages of traditional antibodies (high target specificity, high target affinity, and low inherent toxicity) with important features of small molecule drugs (the ability to inhibit enzymes and access receptor clefts), and are stable, potentially administrable by means other than injection, and easier to manufacture.

[0105] In some embodiments, the anti-properdin antibodies and antigen-binding fragments thereof are capable of binding to the same epitope on properdin recognized by the antibodies recited herein. Such antibodies can be identified based on their ability to compete with or competitively inhibit the anti-properdin antibodies and their antigen-binding fragments in standard properdin binding assays. Thus, all anti-properdin antibodies and antigen-binding fragments thereof that competitively inhibit the binding of the anti-properdin antibodies and their antigen-binding fragments are intended to be included in the present disclosure.

[0106] Antigen-binding fragments of antibodies can be identified after protease digestion. Such fragments include, for example, "Fab fragments", "Fab' fragments" (Fab with heavy chain hinge regions), and "F(ab')2 fragments" (dimers of Fab' fragments linked at the heavy chain hinge regions). Such fragments can be generated, and even smaller antibody fragments (e.g., V fragments linked by synthetic peptide linkers) can be generated. L and V H (V L -Linker-V H Recombinant techniques have been used to generate "single-chain Fv" (fragment variable) or "scFv") fragments that consist of one V. H / V L Since they contain a single antigen-binding domain that comprises a dimer, they are monovalent or monospecific with respect to antigen binding. Even smaller monovalent antibody fragments are dAbs, which contain only a single immunoglobulin variable domain (e.g., V H or V L (only this specifically binds to the antigen); i.e., the complementary V L Domain is also V H(Abs do not require any V domains, either.) dAbs bind antigens independently of other V domains, but dAbs bind antigens independently of other V domains. H Domain or V L The dAb can exist as a heteromultimer with the additional V domain (where the other domain is not required for antigen binding by the dAb, i.e., the ... H Domain or V L (binding to antigens independent of domain).

[0107] In some embodiments, the anti-properdin antibody or antigen-binding fragment thereof can be a monospecific antibody or antigen-binding fragment thereof that comprises at least one of the following: (a) CDR-H1 comprising the amino acid sequence of GYIFTX1YPIH (SEQ ID NO:201), where X1 is N, Q, S, A, or D; CDR-H2 comprising the amino acid sequence of FIX1PGGGX2DEX3X4X5X6X7X8X9 (SEQ ID NO:202), where X1 is D, E, S, or A; X2 is H or Y; X3 is P, S, or Y; X4 is A or D; X5 is D, R, or Q; X6 is K, R, or S; X7 is F or V; X8 is E, K, Q, or R; and X9 is D or G; and CDR-H3 comprising the amino acid sequence of RGGGYYLDY (SEQ ID NO: 203); (b) CDR-L1 comprising the amino acid sequence of RASQDISFFLN (SEQ ID NO: 206); CDR-L2 comprising an amino acid sequence of X1X2SX3YHS (SEQ ID NO:207), where X1 is G or Y; X2 is A or T; and X3 is R or S; and CDR-L3 comprising the amino acid sequence of QHGX1TLPX2T (SEQ ID NO:208), where X1 is A, D, N, Q, or S; and X2 is F, H, R, W, or Y; (c) CDR-H1 comprising the amino acid sequence of GFSLSTSGX1GVG (SEQ ID NO:211), where X1 is I, K, M, or V; CDR-H2 comprising the amino acid sequence of HIX1X1DDVKSYX2PALKS (SEQ ID NO:212), where X1 is F, H, W, or Y; and X2 is A, N, Q, or S; and CDR-H3 comprising the amino acid sequence of IGX1GYYSFDY (SEQ ID NO:213), where X1 is A, D, E, or S; (d) CDR-L1 comprising the amino acid sequence of X1ASQDVSDAVA (SEQ ID NO:216), where X1 is K or R; CDR-L2 comprising the amino acid sequence of SPSYRYT (SEQ ID NO: 217); and A CDR-L3 comprising the amino acid sequence of QQHYSTPX1TF (SEQ ID NO:218), where X1 is F, H, W, or Y; (e) CDR-H1 comprising the amino acid sequence of GFSFSSGYX1IF (SEQ ID NO:221), where X1 is F, H, W, or Y; CDR-H2 comprising the amino acid sequence of GIYSGSSGTTY (SEQ ID NO: 222); and CDR-H3 comprising the amino acid sequence of SVX1GIX1SYX1AAFX2L (SEQ ID NO:223), where X1 is A, D, E, or S; and X2 is A, N, Q, or S; (f) CDR-L1 comprising the amino acid sequence of X1ASDX2IYSLLA (SEQ ID NO: 229), where X1 is Q or R; and X2 is A, N, Q, or S; CDR-L2 comprising the amino acid sequence of RASTLAS (SEQ ID NO: 230); and CDR-L3 comprising the amino acid sequence of QQHYDYX1YLDVA (SEQ ID NO:231), where X1 is A, N, Q, or S; (g) CDR-H1 comprising the amino acid sequence of GFSFSSSYX1IF (SEQ ID NO:225), where X1 is F, H, W, or Y; CDR-H2 comprising the amino acid sequence of GIYSSSGRX1Y (SEQ ID NO: 226), where X1 is I, K, L, or M; and CDR-H3 comprising the amino acid sequence of SAX1GSX1SYX1AYFTL (SEQ ID NO:227), where X1 is A, D, E, or S; (h) CDR-L1 comprising the amino acid sequence of X1ASDX2IYSX2LA (SEQ ID NO:233), where X1 is Q or R; and X2 is A, N, Q, or S; CDR-L2 comprising the amino acid sequence of RASTLAS (SEQ ID NO: 234); and CDR-L3 comprising the amino acid sequence of QQHX1DYDYIDVA (SEQ ID NO:235), where X1 is F, H, W, or Y; (i) CDR-H1 comprising the amino acid sequence of GRISSIIHMA (SEQ ID NO:237), where X1 is F, H, W, or Y; CDR-H2 comprising the amino acid sequence of RX1GTTX1YAX2SX1X3G (SEQ ID NO:238), where X1 is I or V; X2 is A, D, E, or S; and X3 is A or K; and CDR-H3 comprising the amino acid sequence of LQYEX1HGGAX2Y (SEQ ID NO: 239), where X1 is A or K; and X2 is A, D, E, or S; (j) CDR-H1 comprising the amino acid sequence of GRIFEX1X2MMA (SEQ ID NO:241), where X1 is I or V; and X2 is A, D, N, Q, or S; CDR-H2 comprising the amino acid sequence of RX1GTTTYAX2SX1X3G (SEQ ID NO: 242), where X1 is I or V; X2 is A, D, E, or S; and X3 is A or K; and CDR-H3 comprising the amino acid sequence of LQYX1RYGGAEY (SEQ ID NO:243), where X1 is A, D, E, or S; or (k) or A heavy chain variable region and / or a light chain variable region that competitively inhibits the binding of an isolated monospecific or bispecific antibody or an antigen-binding fragment thereof, comprising at least one of (a), (b), (c), (d), (e), (f), (g), (h), (i), or (j), to monomeric properdin.

[0108] In other embodiments, the anti-properdin antibody or antigen-binding fragment thereof may include: CDR-H1 comprising the amino acid sequence of GYIFTX1YPIH (SEQ ID NO:201), where X1 is N, Q, S, A, or D; CDR-H2 comprising the amino acid sequence of FIX1PGGGX2DEX3X4X5X6X7X8X9 (SEQ ID NO:202), where X1 is D, E, S, or A; X2 is H or Y; X3 is P, S, or Y; X4 is A or D; X5 is D, R, or Q; X6 is K, R, or S; X7 is F or V; X8 is E, K, Q, or R; and X9 is D or G; and CDR-H3 comprising the amino acid sequence of RGGGYYLDY (SEQ ID NO: 203); CDR-L1 comprising the amino acid sequence of RASQDISFFLN (SEQ ID NO: 206); CDR-L2 comprising an amino acid sequence of X1X2SX3YHS (SEQ ID NO:207), where X1 is G or Y; X2 is A or T; and X3 is R or S; and CDR-L3 comprising the amino acid sequence of QHGX1TLPX2T (SEQ ID NO:208), where X1 is A, D, N, Q, or S; and X2 is F, H, R, W, or Y.

[0109] In some embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise: CDR-H1 comprising the amino acid sequence of GFSLSTSGX1GVG (SEQ ID NO:211), where X1 is I, K, M, or V; CDR-H2 comprising the amino acid sequence of HIX1X1DDVKSYX2PALKS (SEQ ID NO:212), where X1 is F, H, W, or Y; and X2 is A, N, Q, or S; CDR-H3 comprising the amino acid sequence of IGX1GYYSFDY (SEQ ID NO:213), where X1 is A, D, E, or S; CDR-L1 comprising the amino acid sequence of X1ASQDVSDAVA (SEQ ID NO:216), where X1 is K or R; CDR-L2 comprising the amino acid sequence of SPSYRYT (SEQ ID NO: 217); and CDR-L3 comprising the amino acid sequence of QQHYSTPX1TF (sequence number: 218), where X1 is F, H, W, or Y.

[0110] In some embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise: CDR-H1 comprising the amino acid sequence of GFSFSSGYX1IF (SEQ ID NO:221), where X1 is F, H, W, or Y; CDR-H2 comprising the amino acid sequence of GIYSGSSGTTY (SEQ ID NO: 222); CDR-H3 comprising the amino acid sequence of SVX1GIX1SYX1AAFX2L (SEQ ID NO:223), where X1 is A, D, E, or S; and X2 is A, N, Q, or S; CDR-L1 comprising the amino acid sequence of X1ASDX2IYSLLA (SEQ ID NO:229), where X1 is Q or R; and X2 is A, N, Q, or S; CDR-L2 comprising the amino acid sequence of RASTLAS (SEQ ID NO: 230); and CDR-L3 comprising the amino acid sequence of QQHYDYX1YLDVA (SEQ ID NO: 231), where X1 is A, N, Q, or S.

[0111] In some embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise: CDR-H1 comprising the amino acid sequence of GFSFSSSYX1IF (SEQ ID NO:225), where X1 is F, H, W, or Y; CDR-H2 comprising the amino acid sequence of GIYSSSGRX1Y (SEQ ID NO: 226), where X1 is I, K, L, or M; CDR-H3 comprising the amino acid sequence of SAX1GSX1SYX1AYFTL (SEQ ID NO:227), where X1 is A, D, E, or S; CDR-L1 comprising the amino acid sequence of X1ASDX2IYSX2LA (SEQ ID NO:233), where X1 is Q or R; and X2 is A, N, Q, or S; CDR-L2 comprising the amino acid sequence of RASTLAS (SEQ ID NO: 234); and CDR-L3 comprising the amino acid sequence of QQHX1DYDYIDVA (SEQ ID NO: 235), where X1 is F, H, W, or Y.

[0112] In some embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise a heavy chain variable region comprising the three CDRs of one of the following SEQ ID NOs: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, No. 71, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, or SEQ ID NO: 107; or, The heavy chain variable region may competitively inhibit the binding of an isolated antibody or antigen-binding fragment comprising at least one of a heavy chain variable region comprising the three CDRs of one of the following SEQ ID NOs: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, No.:71, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, or SEQ ID NO:107.

[0113] In other embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise a heavy chain variable region comprising an amino acid sequence at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of one of the following SEQ ID NOs: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, No.:71, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:83, SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, or SEQ ID NO:107.

[0114] In yet other embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising the three CDRs of one of the following SEQ ID NOs: SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:72; or, The light chain variable region may comprise a light chain variable region that competitively inhibits binding of an isolated antibody or antigen-binding fragment comprising at least one of the light chain variable regions comprising the three CDRs of one of the following SEQ ID NOs: SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:72.

[0115] In some embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising an amino acid sequence at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of one of the following SEQ ID NOs: SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, or SEQ ID NO:72.

[0116] In some embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise at least one of the following: (a) a heavy chain variable region comprising the three CDRs of SEQ ID NO:1 and a light chain variable region comprising the three CDRs of SEQ ID NO:24; (b) a heavy chain variable region comprising the three CDRs of SEQ ID NO:2 and a light chain variable region comprising the three CDRs of SEQ ID NO:25; (c) a heavy chain variable region comprising the three CDRs of SEQ ID NO:3 and a light chain variable region comprising the three CDRs of SEQ ID NO:26; (d) a heavy chain variable region comprising the three CDRs of SEQ ID NO:4 and a light chain variable region comprising the three CDRs of SEQ ID NO:27; (e) a heavy chain variable region comprising the three CDRs of SEQ ID NO:5 and a light chain variable region comprising the three CDRs of SEQ ID NO:28; (f) a heavy chain variable region comprising the three CDRs of SEQ ID NO:6 and a light chain variable region comprising the three CDRs of SEQ ID NO:29; (g) a heavy chain variable region comprising the three CDRs of SEQ ID NO:7 and a light chain variable region comprising the three CDRs of SEQ ID NO:30; (h) a heavy chain variable region comprising the three CDRs of SEQ ID NO:8 and a light chain variable region comprising the three CDRs of SEQ ID NO:31; (i) a heavy chain variable region comprising the three CDRs of SEQ ID NO:9 and a light chain variable region comprising the three CDRs of SEQ ID NO:32; (j) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 10 and a light chain variable region comprising the three CDRs of SEQ ID NO: 33; (k) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 11 and a light chain variable region comprising the three CDRs of SEQ ID NO: 34; (l) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 12 and a light chain variable region comprising the three CDRs of SEQ ID NO: 35; (m) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 13 and a light chain variable region comprising the three CDRs of SEQ ID NO: 36; (n) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 14 and a light chain variable region comprising the three CDRs of SEQ ID NO: 37; (o) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 15 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (p) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 16 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (q) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 17 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (r) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 18 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (s) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 19 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (t) a heavy chain variable region comprising the three CDRs of SEQ ID NO:20 and a light chain variable region comprising the three CDRs of SEQ ID NO:38 or SEQ ID NO:39; (u) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 21 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (v) a heavy chain variable region comprising the three CDRs of SEQ ID NO:22 and a light chain variable region comprising the three CDRs of SEQ ID NO:38 or SEQ ID NO:39; (w) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 23 and a light chain variable region comprising the three CDRs of SEQ ID NO: 38 or SEQ ID NO: 39; (x) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 40 and a light chain variable region comprising the three CDRs of SEQ ID NO: 45; (y) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 41 and a light chain variable region comprising the three CDRs of SEQ ID NO: 46; (z) a heavy chain variable region comprising the three CDRs of SEQ ID NO: 42 and a light chain variable region comprising the three CDRs of SEQ ID NO: 47; (aa) a heavy chain variable region comprising the three CDRs of SEQ ID NO:43 and a light chain variable region comprising the three CDRs of SEQ ID NO:48, SEQ ID NO:49, or SEQ ID NO:50; (bb) a heavy chain variable region comprising the three CDRs of SEQ ID NO:44 and a light chain variable region comprising the three CDRs of SEQ ID NO:48, SEQ ID NO:49, or SEQ ID NO:50; (cc) a heavy chain variable region comprising the three CDRs of SEQ ID NO:51 and a light chain variable region comprising the three CDRs of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (dd) a heavy chain variable region comprising the three CDRs of SEQ ID NO:52 and a light chain variable region comprising the three CDRs of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (ee) a heavy chain variable region comprising the three CDRs of SEQ ID NO:53 and a light chain variable region comprising the three CDRs of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (ff) a heavy chain variable region comprising the three CDRs of SEQ ID NO:54 and a light chain variable region comprising the three CDRs of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (gg) a heavy chain variable region comprising the three CDRs of SEQ ID NO:55 and a light chain variable region comprising the three CDRs of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (hh) a heavy chain variable region comprising the three CDRs of SEQ ID NO:56 and a light chain variable region comprising the three CDRs of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (ii) a heavy chain variable region comprising the three CDRs of SEQ ID NO:57 and a light chain variable region comprising the three CDRs of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (jj) a heavy chain variable region comprising the three CDRs of SEQ ID NO:58 and a light chain variable region comprising the three CDRs of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (kk) a heavy chain variable region comprising the three CDRs of SEQ ID NO:59 and a light chain variable region comprising the three CDRs of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; or (ll) a heavy chain variable region comprising the three CDRs of SEQ ID NO:60 and a light chain variable region comprising the three CDRs of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70.

[0117] In some embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise at least one of the following: (a) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:1, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:24; (b) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:2, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:25; (c) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:3, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:26; (d) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:4, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:27; (e) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:5, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:28; (f) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:6, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:29; (g) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:7, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:30; (h) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:8, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:31; (i) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:9, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:32; (j) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:10, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:33; (k) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:11, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:34; (l) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:12, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:35; (m) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:13, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:36; (n) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO: 14, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO: 37; (o) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:15, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (p) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:16, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (q) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:17, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (r) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:18, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (s) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:19, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (t) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:20, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (u) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:21, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (v) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:22 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (w) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:23, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:38 or SEQ ID NO:39; (x) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:40, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:45; (y) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:41, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:46; (z) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:42, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:47; (aa) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:43, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:48, SEQ ID NO:49, or SEQ ID NO:50; (bb) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:44, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:48, SEQ ID NO:49, or SEQ ID NO:50; (cc) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:51, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (dd) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:52, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (ee) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:53, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (ff) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:54, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (gg) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:55, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, or SEQ ID NO:65; (hh) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:56, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (ii) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:57, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (jj) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:58, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; (kk) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:59, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70; or (ll) a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:60, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, or SEQ ID NO:70.

[0118] In some embodiments, the antibody or antigen-binding fragment thereof may comprise a constant chain region, wherein the antibody or antigen-binding fragment thereof comprising a constant chain region has an increased in vivo half-life and / or reduced immunogenicity compared to the antibody or antigen-binding fragment thereof that does not have a constant chain region.

[0119] In some embodiments, the constant chain region comprises an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, or SEQ ID NO:139.

[0120] In some embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise at least one of the following: a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:156 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:157; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:166 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:167; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:170 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:171; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:178 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:179; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:182; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:184 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:185; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:187 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:188; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:191; a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:193 and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:194; or A heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:197, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:198.

[0121] Linker In some embodiments, the anti-properdin antibody or antigen-binding fragment thereof may comprise a linker. The linker may be used as a bond or link between the polypeptide or protein domains and / or associated non-protein moieties of the anti-properdin antibody or antigen-binding fragment thereof. In some embodiments, the linker is a bond or link between at least two polypeptide constructs (e.g., such that the two polypeptide constructs are tandemly linked to one another (e.g., an antibody or antigen-binding fragment thereof linked to a second polypeptide or antibody)). The linker may link the N-terminus or C-terminus of one antibody construct to the N-terminus or C-terminus of a second polypeptide construct.

[0122] The linker can be any type of bond created by a simple covalent bond, such as a peptide bond, a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer), or a chemical reaction (e.g., chemical conjugation). When the linker is a peptide bond, a carboxylic acid group at the C-terminus of one protein domain can be reacted with an amino group at the N-terminus of the other protein domain in a condensation reaction to form a peptide bond. Specifically, the peptide bond can be created by synthetic means using conventional organic chemistry reactions well known in the art, or by natural production by a host cell in which a polynucleotide sequence encodes the DNA sequences of the two proteins; for example, the two antibody constructs in tandem can be directly transcribed and translated into a contiguous polypeptide encoding both proteins by the necessary molecular machinery (e.g., DNA polymerase and ribosomes in the host cell).

[0123] When the linker is a synthetic polymer (e.g., a PEG polymer), the polymer can be functionalized with reactive chemical groups at each end for reaction with the terminal amino acids at the linking ends of the two proteins.

[0124] When the linker (other than the peptide bond described above) is created by chemical reaction, a chemical functional group (e.g., an amine, a carboxylic acid, an ester, an azide, or other functional group commonly used in the art) can be synthetically linked to the C-terminus of one protein and the N-terminus of another protein. The two functional groups can then be reacted by synthetic chemistry to form a chemical bond, i.e., the two proteins can be linked together. Such chemical linking reaction methods are common to those skilled in the art.

[0125] The linker between the two types of peptide constructs can be an amino acid linker containing 1 to 200 amino acids (e.g., 1 to 4 amino acids, 1 to 10 amino acids, 1 to 20 amino acids, 1 to 30 amino acids, 1 to 40 amino acids, 2 to 10 amino acids, 2 to 12 amino acids, 2 to 16 amino acids, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200 amino acids). Suitable peptide linkers are known in the art, and include, for example, peptide linkers containing flexible amino acid residues (such as glycine and serine). In certain embodiments, the peptide linker may comprise the amino acid sequence of SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:245, or SEQ ID NO:246.

[0126] Bispecific, Stability-Enhanced, and Modified Antibodies or Antigen-Binding Fragments Thereof In some embodiments, the antibody or antigen-binding fragment thereof may comprise a first heavy chain variable region that binds to properdin and a second polypeptide (such as a second antibody or antigen-binding fragment thereof having a second heavy chain variable region) that binds to a different epitope than the first heavy chain variable region, such that a bispecific antibody or antigen-binding fragment thereof is formed.

[0127] In some embodiments, the second heavy chain variable region extends the in vivo half-life of the antibody or antigen-binding fragment thereof to about 3 weeks to about 8 weeks.

[0128] In other embodiments, the second heavy chain variable region binds to any one of albumin, TNF, or VEGF.

[0129] In some embodiments, the second polypeptide is an albumin binding molecule, an albumin binding peptide, or an anti-albumin antibody (e.g., a monovalent antibody), or a modified version thereof.Albumin binding peptides are known in the art, for example, as described in WO2007 / 106120 (see Tables 1-9) and Dennis et al., 2002, J Biol.Chem.277:35035-35043; the disclosures of these references are incorporated herein by reference.

[0130] In some embodiments, the second polypeptide is an Fc domain, which improves the in vivo stability of the construct.

[0131] In some embodiments, the second antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:150, or SEQ ID NO:152.

[0132] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof is capable of inhibiting the formation of C3b and Mac complexes (C5b-9) in vivo.

[0133] Other embodiments described herein relate to isolated monospecific or bispecific antibodies or antigen-binding fragments comprising: an anti-properdin heavy chain variable region comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:2, and an anti-properdin light chain variable region comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:25; wherein the heavy chain variable region includes: CDR-H1 comprising the amino acid sequence of GYIFTX1YPIH (SEQ ID NO: 201), where X1 is N, Q, S, A, or D (e.g., X1 is Q, S, A, or D); CDR-H2 comprising the amino acid sequence of FIX1PGGGX2DEX3X4X5X6X7X8X9 (SEQ ID NO:202), where X1 is D, E, S (e.g., E or S), or A; X2 is H or Y; X3 is P, S, or Y; X4 is A or D; X5 is D, R, or Q; X6 is K, R, or S; X7 is F or V; X8 is E, K, Q, or R; and X9 is D or G; and CDR-H3 comprising the amino acid sequence of RGGGYYLDY (SEQ ID NO: 203); and The light chain variable region includes: CDR-L1 comprising the amino acid sequence of RASQDISFFLN (SEQ ID NO: 206); CDR-L2 comprising an amino acid sequence of X1X2SX3YHS (SEQ ID NO:207), where X1 is G or Y; X2 is A or T; and X3 is R or S; and A CDR-L3 comprising the amino acid sequence of QHGX1TLPX2T (SEQ ID NO:208), where X1 is N, A, D, Q, or S (e.g., A, D, Q, or S); and X2 is F, H, R, W, or Y (e.g., F, H, R, or Y).

[0134] In some embodiments, the antibody or antigen-binding fragment thereof may comprise at least one of a constant chain region or a second heavy chain variable region that binds to a different epitope than the anti-properdin heavy chain region, wherein the antibody or antigen-binding fragment comprising the constant chain region or second heavy chain variable region has an increased in vivo half-life and / or reduced immunogenicity compared to the antibody or antigen-binding fragment thereof that does not have either the constant chain region or the second heavy chain variable region.

[0135] In some embodiments, the constant chain region comprises an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, or SEQ ID NO:139; and the second heavy chain variable region comprises an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111. , SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:150, or SEQ ID NO:152.

[0136] In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof may comprise a heavy chain having an amino acid sequence that is at least 90% identical to SEQ ID NO:247 and a light chain having an amino acid sequence that is at least 90% identical to SEQ ID NO:248.

[0137] Generation of single domain antibodies In some embodiments, the isolated monospecific or bispecific antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (V H , e.g., V HH ) or the light chain domain (V L Thus, one means of generating a single domain antibody specific for properdin is to use the V domain of heavy and light chain gene sequences isolated (e.g., from a hybridoma (e.g., a murine hybridoma) expressing an anti-properdin monoclonal antibody). H and V L The aim is to amplify and express the region. H and V L Domain boundaries are discussed, for example, by Kabat et al. (Sequences of Proteins of Immunological Interest [National Institutes of Health, Bethesda, Md., 1991]). To design PCR primers to amplify the V domains of heavy or light chain coding sequences encoding known antibodies that bind properdin, the V domains of the heavy and light chain genes were sequenced. H and V L The amplified V domains are inserted into a suitable expression vector (e.g., pHEN-1; Hoogenboom, H. et al., Nucleic Acids Res., 19:4133-7, 1991) and expressed as, for example, an scFv or other suitable monovalent V domain. H and V LThe polypeptides are then expressed as fusions with properdin. The resulting polypeptides can then be screened for high affinity monovalent binding to properdin. Binding screening can be performed by methods known in the art. Single domain antibodies can be made using methods known in the art (WO2005118642; Ward, E. et al., Nature, 341:544-6, 1989; Holt, L. et al., Trends Biotechnol., 21:484-90, 2003). Each light chain domain can be of the kappa or lambda subgroup. H and V L Methods for isolating domains have been described in the art (EP0368684).

[0138] In one embodiment, the antibody or antigen-binding fragment thereof may comprise a single domain antibody obtained from a human, a humanized rodent, a camelid or a shark. Any such single domain antibody may be optionally humanized. Humanization of camelid single domain antibodies requires the insertion and mutagenesis of a limited number of amino acids into a single polypeptide chain. This is in contrast to humanization of scFv, Fab, (Fab')2 and IgG, which requires the introduction of amino acid modifications in two chains (light and heavy) and the retention of assembly of both chains. In some embodiments, the single domain antibody may include V HH In some embodiments, the V HH The domain is the V of a natural heavy chain antibody directed against properdin. HH Such a V HH The sequences can be determined, for example, by suitably immunizing a camelid species with properdin (i.e., to mount an immune response directed against properdin and / or to produce heavy chain antibodies), obtaining a suitable biological sample from said camelid (such as a blood sample, serum sample or B cell sample), and starting from said sample, isolating V sequences directed against properdin using any suitable technique known in the art. HHThe single domain antibody may be produced by generating the sequence (e.g., by cloning the gene encoding the single domain antibody by single cell PCR, or by immortalizing B cells encoding the single domain antibody by EBV transformation, or fusion with an immortalizing cell line).

[0139] Alternatively, such naturally occurring V sequences against properdin can be identified by screening such libraries using, for example, properdin, or at least a portion, fragment, antigenic determinant, or epitope thereof, using one or more screening techniques known in the art (WO99 / 37681, WO01 / 90190, WO03 / 025020, and WO03 / 035694). HH Domain, Camelidae V HH The sequences can be obtained from a naive library of sequences. Alternatively, a naive V HH Improved synthetic or semi-synthetic libraries derived from libraries (naive V, V+ ... HH V taken from library HH In one particular embodiment, a library of V HH The library is constructed and expressed on phage after infection with helper phage, and after several rounds of biopanning, single domain antibodies against human properdin can be isolated and efficiently expressed.

[0140] To facilitate screening, V HH or V HH Libraries of fusion proteins containing the fragments can be displayed on phages, phagemids, ribosomes, or suitable microorganisms such as yeast. HH or V HHSuitable methods, techniques, and host organisms for displaying and screening (sets, collections, or libraries) of fusion proteins comprising fragments are known in the art (WO03 / 054016; Hoogenboom, H., Nat. Biotechnol., 23:1105-16, 2005).

[0141] In another embodiment, V HH or V HH The method for producing a fusion protein containing a fragment sequence comprises at least the following steps: (a) providing a collection or sample of cells from a camelid species that expresses immunoglobulin sequences; (b) (i) for cells expressing immunoglobulin sequences capable of binding to and / or having affinity for properdin; and (ii) for cells expressing heavy chain antibodies; screening the collection or sample of cells; where In order to provide at least one cell expressing a heavy chain antibody capable of binding to and / or having affinity for properdin, substeps (i) and (ii) can be carried out essentially as a single screening step or as two distinct screening steps in any suitable order; and (c) (i) a V present in the heavy chain antibody HH or (ii) isolating a V sequence present in the heavy chain antibody from the cell; HH A nucleic acid sequence encoding the sequence is isolated from the cell, and then V HH Expressing the domain.

[0142] The method for generating an amino acid sequence directed to properdin may comprise at least the following steps: (a) Heavy chain antibody or V HH providing a set, collection, or library of nucleic acid sequences encoding the sequences; (b) V capable of binding to and / or having affinity for properdin HHscreening the set, collection, or library of nucleic acid sequences for a nucleic acid sequence encoding a heavy chain antibody or fusion protein comprising the sequence; and (c) isolating the nucleic acid sequence and then determining whether the V HH Array or V HH expressing each of the fusion proteins containing the sequence.

[0143] Natural V H Array or V HH Other suitable methods and techniques for obtaining said single domain antibodies and / or nucleic acids encoding same, starting from a sequence, can be implemented by, for example, cloning one or more naturally occurring V sequences in a suitable manner to provide a nucleotide sequence or nucleic acid encoding a monovalent anti-properdin single domain antibody or the same. HH One or more portions of the sequence (such as one or more framework region (FR) sequences and / or CDR sequences), one or more naturally occurring V HH It may involve combining one or more portions of a sequence, such as one or more framework region sequences or CDR sequences, and / or one or more synthetic or semi-synthetic sequences. HH Alternatively, nucleotide sequences encoding the framework sequences of single domain antibodies are known in the art or may be obtained by polymerase chain reaction (PCR) starting from nucleotide sequences obtained using the methods described herein. Such compositions can be suitably combined with nucleotide sequences encoding the desired CDRs (e.g. by PCR assembly using overlapping primers) in order to provide a single domain antibody, or an antibody fragment, or fragment thereof, fused to a regulator of the alternative complement pathway.

[0144] Antigen-binding fragments of antibodies that recognize the same epitope as the parent antibody can be generated by known techniques. For example, antigen-binding fragments of antibodies can be prepared by proteolytic hydrolysis of the antibody or by E. coli expression of DNA encoding the fragment. Antigen-binding fragments of antibodies are the antigen-binding portions of antibodies (such as Fab, F(ab')2, and scFV) and can be obtained by conventional methods such as pepsin or papain digestion of whole antibodies or by genetic engineering techniques.

[0145] Antigen-binding fragments of antibodies can be produced by enzymatic cleavage of antibodies with pepsin to produce a 100 kDa fragment called F(ab')2. This fragment can be further cleaved to produce 50 kDa Fab' monovalent fragments using a thiol reducing agent, and optionally a blocking group for the sulfhydryl groups resulting from cleavage of disulfide bonds. Alternatively, enzymatic cleavage with papain produces two monovalent Fab fragments and one Fc fragment directly (U.S. Pat. Nos. 4,036,945 and 4,331,647; Nisonoff, A. et al., Arch. Biochem. Biophys., 89:230-44, 1960; Porter, R., Biochem. J., 73:119-26, 1959; Edelman et al., Methods in Enzymology, Vol. I, p. 422 (Academic Press 1967); and Coligan et al., Current Protocols in Immunology, Vol. 1, p. 2.8.1-2.8.10 and 2.10.-2.10.4 (John Wiley & Sons 1991).

[0146] Other methods of cleaving antibodies (such as separation of heavy chains to form monovalent light chain and heavy chain fragments, further cleavage of the fragments, or other enzymatic, chemical, or genetic techniques) may also be used, so long as the fragments bind to the antigen recognized by the intact antibody.

[0147] Another form of an antigen-binding fragment of an antibody is a peptide encoding a single complementarity-determining region (CDR). A CDR peptide can be obtained by constructing a gene encoding the CDR of the antibody of interest. Such genes are prepared, for example, using the polymerase chain reaction to synthesize the variable region from RNA of antibody-producing cells (Larrick, J & Fry, K., Methods--A Guide to Methods in Enzymology, Vol. 2:106-110, 1991; "Genetic Manipulation of Monoclonal Antibodies," in Monoclonal Antibodies: Production, Engineering and Clinical Application, edited by Ritter et al., Courtenay-Luck, pp. 166-179 (Cambridge University Press, 1995); and Ward et al., "Genetic Manipulation and Expression of Antibodies," in Monoclonal Antibodies: Principles And Applications, edited by Birch et al., pp. 137-185 (Wiley-Liss, 1995)).

[0148] Other antibody antigen-binding fragments, such as single domain antibody fragments, are known in the art and may be used in the claimed constructs (Muyldermans, S. et al., Trends Biochem. Sci., 26:230-5, 2001; Yau, K. et al., J. Immunol. Methods, 281:161-75, 2003; Maass, D. et al., J. Immunol. Methods, 324:13-25, 2007). HH has strong antigen-binding ability and is different from conventional V H -V L Camelids may be immunized with a known antigen (such as properdin) and Vs that bind and neutralize the target antigen are generated. HH can be isolated.

[0149] Screening of Antibodies or Antigen-Binding Fragments Thereof for Properdin Binding Library screening methods can be used to identify properdin-specific binding antibodies or their antigen-binding fragments. Phage display technology provides an approach to select antibodies that bind to desired targets (e.g., human properdin) from a diverse and large antibody repertoire (Smith, G., Science, 228:1315-7, 1985; Scott, J. & Smith, G., Science, 249:386-90, 1990; McCafferty, J. et al., Nature, 348:552-4, 1990). These phage-antibody libraries can be divided into two categories; natural libraries, which use rearranged V genes recovered from human B cells (Marks, J. et al., J. Mol. Biol., 222:581-97, 1991; Vaughan, T. et al., Nat. Biotechnol., 14:309-14, 1996) or synthetic libraries, whereby germline V gene segments or other antibody polypeptide coding sequences are "rearranged" in vitro (Hoogenboom, H. and Winter, G., J. Mol. Biol., 227:381-8, 1992; Nissim, A. et al., EMBO J., 13:692-8, 1994; Griffiths, A. et al., EMBO J., 13:3245-60, 1994; de Kruif, J. et al., J. Mol. Biol., 248:97-105, 1995), or synthetic CDRs are incorporated into a single rearranged V gene (Barbas, C. et al., Proc. Natl. Acad. Sci. USA, 89:4457-61, 1992). Methods involving genetic display packages (e.g., phage display, polysome display) are suitable for the selection of properdin-specific antibody constructs, since they generally express only fragments rather than the entire antibody in the display package. Methods for the preparation of phage display libraries displaying various antibody fragments are described in the prior art, and for example, in U.S. Patent No. 6,696,245; the entire contents of this reference are incorporated herein by reference.

[0150] After the antibody repertoire is expressed on the phage surface, selection is performed by contacting the phage repertoire with an immobilized target antigen (e.g., properdin), removing unbound phage by washing, and propagating bound phage; this overall process is often referred to as "panning." Display libraries (e.g., scFv, Fab, (Fab'), and V HH ; Harrison, J. et al., Meth. Enzymol., 267:83-109, 1996), this process can be used to screen for antibodies and their antigen-binding fragments that can be expressed on phage. Alternatively, phage are preselected for expression of variants of correctly folded members by panning against an immobilized generic ligand (e.g., protein A or protein L) to which only folded members bind (WO 99 / 20749). This has the advantage of reducing the proportion of non-functional members, thereby increasing the proportion of members likely to bind the target antigen. Screening of phage antibody libraries has been generally described, for example, in.

[0151] Screening is usually performed with purified immobilized antigen on a solid support (e.g., plastic tubes or wells) or on a chromatography matrix (e.g., Sepharose® (Pharmacia)). Screening or selection can also be performed on complex antigens, such as cell surfaces (Marks, J. et al., Biotechnology (NY), 11:1145-9, 1993; de Kruif, J. et al., Proc. Natl. Acad. Sci. USA, 92:3938-42, 1995). Yet another alternative is selection with bound biotinylated antigen in solution followed by capture on streptavidin-coated beads.

[0152] Pharmaceutical Compositions Other embodiments relate to formulations or compositions comprising inhibitors of the alternative complement pathway and selective inhibitors, including but not limited to murine, chimeric, or human antibodies that inhibit alternative pathway activation in a mammal. The formulations comprise (a) an inhibitor of the alternative complement pathway as described herein and (b) a pharma- ceutically acceptable carrier. In one embodiment, the formulation or composition may include one or more additional agents, such as an anti-inflammatory agent suitable for reducing inflammation in a mammal having or at risk of developing an inflammatory disorder. In another embodiment, the formulation or composition may include one or more additional agents, such as an additional agent suitable for preventing or reducing ischemia-reperfusion injury in a mammal. In yet another embodiment, the formulation or composition may include one or more additional agents, such as an additional agent suitable for treating another disease or condition associated with activation of the alternative complement pathway.

[0153] The monospecific or bispecific anti-properdin antibodies or antigen-binding fragments thereof described herein may be included with a pharma- ceutically acceptable carrier, including, but not limited to, a pharma- ceutically acceptable additive and / or a pharma- ceutically acceptable delivery vehicle suitable for use in administering the formulation or composition to a suitable in vivo site.

[0154] One type of pharma- ceutically acceptable carrier may include a controlled release formulation capable of slowly releasing the composition of the present invention in a mammal. The controlled release formulation described herein comprises a chemical entity of the present invention in a controlled release vehicle. Suitable controlled release vehicles may include, but are not limited to, biocompatible polymers, other polymeric matrices, capsules, microcapsules, microparticles, bolus formulations, osmotic pumps, diffusion devices, liposomes, lipospheres, and transdermal delivery systems. Other suitable carriers may include carriers that can bind to or incorporate the monospecific or bispecific anti-properdin antibodies or antigen-binding fragments thereof described herein, and that extend the half-life of the monospecific or bispecific anti-properdin antibodies or antigen-binding fragments thereof delivered herein. Such carriers may include any suitable protein carrier or fusion segment that extends the half-life of the protein when delivered in vivo. Suitable delivery vehicles may include, but are not limited to, liposomes, viral vectors, or other delivery vehicles, including ribozymes and natural lipid-containing delivery vehicles, such as cells and cell membranes.

[0155] Intravenous, intraperitoneal, intramuscular and intramuscular administration can be carried out using standard methods in the art. Aerosol delivery can be carried out using standard methods in the art. Aerosol formulation delivery devices can include, but are not limited to, pressurized metered dose inhalers ("MDI"), dry powder inhalers ("DPI"), and metered solution devices ("MSI"), as well as nebulizer and inhaler devices.

[0156] Other types of doses of monospecific or bispecific anti-properdin antibodies or antigen-binding fragments thereof described herein, or particularly when the antibody formulations are delivered by aerosol, include collections ranging from about 200 ng to about 600 μg, about 200 ng to about 500 μg, about 200 ng to about 400 μg, about 200 ng to about 300 μg, about 200 ng to 200 μg, about 200 ng to about 100 μg, and preferably about 200 ng to about 50 μg per kg of mammalian body weight.

[0157] The monospecific or bispecific anti-properdin antibodies or antigen-binding fragments thereof described herein can be linked to synthetic or biological substances at the -SH group positions or any other positions that do not interfere with the binding. Such conjugates are also included in the present invention.

[0158] Uses of anti-properdin antibodies or antigen-binding fragments In some embodiments, the anti-properdin antibodies or antigen-binding fragments can be used to inhibit complement activation via the alternative pathway in vivo in subjects (including humans) suffering from acute or chronic pathological injuries. For example, the anti-properdin antibodies or antigen-binding fragments can be used to treat complement-mediated or related diseases, disorders, or conditions, including, but not limited to, the following:

[0159] Extracorporeal Diseases and Disorders: Inflammation after cardiopulmonary bypass, postoperative pulmonary dysfunction, cardiopulmonary bypass, hemodialysis, leukocytepheresis, plasma exchange, plateletpheresis, heparin-induced extracorporeal LDL precipitation (HELP), postperfusion syndrome, extracorporeal membrane oxygenation (ECMO), cardiopulmonary bypass (CPB), postperfusion syndrome, systemic inflammatory response, and multiorgan dysfunction.

[0160] Cardiovascular Diseases and Disorders: Acute coronary syndromes, Kawasaki disease (arteritis), Takayasu's arteritis, Henoch-Schönlein purpura nephritis, vascular leak syndrome, percutaneous coronary intervention (PCI), myocardial infarction, ischemia-reperfusion injury after acute myocardial infarction, atherosclerosis, vasculitis, immune complex vasculitis, vasculitis associated with rheumatoid arthritis (also called malignant rheumatoid arthritis), systemic lupus erythematosus-associated vasculitis, sepsis, arteritis, aneurysm, cardiomyopathy, dilated cardiomyopathy, cardiac surgery, peripheral vascular pathology, renal vascular pathology, cardiovascular pathology, cerebrovascular pathology, mesenteric / intestinal vascular pathology, diabetic vasculopathy, venous gas embolism (VGE), Wegener's granulomatosis, heparin-induced extracorporeal membrane oxygenation, and Behcet's syndrome.

[0161] Bone / Musculoskeletal Diseases and Disorders: Arthritis, inflammatory arthritis, non-inflammatory arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, juvenile generalized rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus (SLE), Behcet's syndrome, and Sjogren's syndrome.

[0162] Transplant Diseases and Disorders: Transplant rejection, xenograft rejection, graft-versus-host disease, organ or graft xenotransplantation, organ or graft allotransplantation, and hyperacute rejection.

[0163] Eye / ocular Diseases and Disorders: Wet and dry age-related macular degeneration (AMD), choroidal neovascularization (CNV), retinal damage, diabetic retinopathy, diabetic retinal microangiopathy, ocular histoplasmosis, uveitis, diabetic macular edema, diabetic retinopathy, diabetic retinal microangiopathy, pathological myopia, central retinal vein occlusion (CRVO), corneal neovascularization, retinal neovascularization, retinal pigment epithelium (RPE), ocular histoplasmosis, and Purcher's retinopathy.

[0164] Hemolytic / Blood Diseases and Disorders: Sepsis, Systemic Inflammatory Response Syndrome (SIRS), Hemorrhagic Shock, Acute Respiratory Distress Syndrome (ARDS), Fulminant Antiphospholipid Syndrome (CAPS), Cold Agglutinin Disease (CAD), Autoimmune Thrombotic Thrombocytopenic Purpura (TTP), Endotoxemia, Hemolytic Uremic Syndrome (HUS), Atypical Hemolytic Uremic Syndrome (aHUS), Paroxysmal Nocturnal Hemoglobinuria (PNH), Sepsis, Septic Shock, Sickle Cell Anemia, Hemolytic Anemia, Hypereosinophilic Syndrome, and Antiphospholipid Syndrome (APLS).

[0165] Respiratory / Lung Diseases and Disorders: Asthma, Wegener's granulomatosis, Transfusion-associated acute lung injury (TRALI), Anti-glomerular basement membrane disease (Goodpasture's syndrome), Eosinophilic pneumonia, Hypersensitivity pneumonitis, Allergic bronchitis bronchiectasis, Reactive airway disease syndrome, Respiratory syncytial virus (RSV) infection, Parainfluenza virus infection, Rhinovirus infection, Adenovirus infection, Allergic bronchopulmonary aspergillosis (ABPA), Tuberculosis, Parasitic lung disease, Adult respiratory distress syndrome, Chronic obstructive pulmonary disease (COPD), Sarcoidosis, Emphysema, Bronchitis, Cystic fibrosis, Interstitial lung disease, Acute respiratory distress syndrome (ARDS), Transfusion-associated acute lung injury, Ischemia / reperfusion acute lung injury, Byssinosis, Heparin-induced extracorporeal membrane oxygenation, Anaphylactic shock, and Asbestos-induced inflammation.

[0166] Central and Peripheral Nervous System / Neurological Diseases and Disorders: Multiple sclerosis (MS), Myasthenia gravis (MG), Myasthenia gravis, Multiple sclerosis, Guillain-Barre syndrome, Miller Fisher syndrome, Stroke, Post-stroke reperfusion, Alzheimer's disease, Multifocal motor neuropathy (MMN), Demyelination, Huntington's disease, Amyotrophic lateral sclerosis (ALS), Parkinson's disease, Degenerative disc disease (DDD), Meningitis, Cranial nerve damage due to meningitis, Variant Creutzfeldt-Jakob disease (vCJD), Idiopathic polyneuropathy, Brain / cerebral trauma (including but not limited to bleeding, inflammation, and edema), Neuromyelitis optica (NMO) (including serologically positive for aquaporin 4 (AQP4)-IgG autoantibodies) and Neuropathic pain.

[0167] Trauma-induced injuries and disorders: hemorrhagic shock, hypovolemic shock, spinal cord injury, neurological injury, brain trauma, cerebral ischemia-reperfusion, crush injury, wound healing, severe burns, and frostbite.

[0168] Kidney Diseases and Disorders: Renal Reperfusion Injury, Poststreptococcal Glomerulonephritis (PSGN), Goodpasture's Syndrome, Membranous Nephritis, Buerger's Disease / IgA Nephropathy, Mesangial Proliferative Glomerulonephritis, Membranous Glomerulonephritis, Membranoproliferative Glomerulonephritis (Mesangial Capillary Glomerulonephritis), Acute Postinfectious Glomerulonephritis, Cryoglobulinemic Glomerulonephritis, Lupus Nephritis, Henoch-Schönlein Purpura Nephritis, and Renal Cortical Necrosis (RCN).

[0169] Reperfusion injury and damage to organs: including but not limited to the heart, brain, kidneys, and liver.

[0170] Reproductive and genitourinary diseases and disorders: painful bladder diseases and disorders, sensory bladder diseases and disorders, spontaneous abortion, diseases due to male and female infertility, diseases due to pregnancy, maternal-fetal immune tolerance, preeclampsia, inflammatory genitourinary diseases, diseases and disorders due to placental insufficiency, diseases and disorders due to miscarriage, chronic nonbacterial cystitis, and interstitial cystitis.

[0171] Skin / Dermatological Diseases and Disorders: Burns, psoriasis, atopic dermatitis (AD), eosinophilic spongiosis, urticaria, thermal burns, pemphigoid, epidermolysis bullosa acquisita, autoimmune bullous dermatoses, bullous pemphigoid, scleroderma, angioedema, hereditary vasomotor edema (HAE), erythema multiforme, herpes gestationis, Sjogren's syndrome, dermatomyositis, and dermatitis herpetiformis.

[0172] Gastrointestinal Diseases and Disorders: Crohn's disease, celiac disease / gluten-sensitive enteropathy, Whipple's disease, intestinal ischemia, inflammatory bowel disease, and ulcerative colitis.

[0173] Endocrine Diseases and Disorders: Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, stress anxiety and other diseases affecting prolactin, growth factors or insulin-like growth factors, adrenocorticotropic hormone release, pancreatitis, Addison's disease, diabetic conditions (including but not limited to types 1 and 2 diabetes), type I diabetes, sarcoidosis, diabetic retinal microangiopathy, non-obese diabetes mellitus (IDDM), vascular disorders, neuropathy or retinopathy complications of IDDM or type 2 diabetes, and insulin resistance.

[0174] Treatment of malignant tumors: diseases and disorders caused by chemotherapy and radiation therapy.

[0175] Working Example Properdin is an activator of the complement system. It is the only endogenous activator of the alternative pathway (AP). Moreover, properdin has no effect on the classical pathway (CP), so that inhibition of properdin formation leaves many essential mechanisms of the CP intact.

[0176] The following anti-properdin antibodies and antigen-binding fragments thereof were constructed using the variable chains, constant chains, and linkers: Substitutions were made in each of the above sequences and linkers to obtain multiple variants and embodiments of the anti-properdin antibodies.

[0177] Example 1 The structures and amino acid sequences of the anti-properdin antibodies NMT16 to NMT28 are described in Example 1. The CDR regions of the variable light and heavy chain sequences of NMT16 to NMT28 (SEQ ID NOs: 2 to 14 and 24 to 37) are shown in Figure 1 and Table 1. The framework regions are derived from the sequences of the heavy chain (SEQ ID NO: 2) and light chain (SEQ ID NO: 24) of NMT16. H Region (SEQ ID NO: 204) and V L The CDR regions of region (SEQ ID NO:209) contain multiple substitutions in variants of anti-properdin antibody NM5072, where substitutable amino acids in the CDR regions are marked with an X.

[0178] The same format is also shown for Presta humanized murine variable sequence anti-properdin antibody 9401 (SEQ ID NOs: 15-23 and 38-39). The CDR regions contain multiple substitutions across the entire humanized 9401 sequence, and the framework regions used are from Presta h9401-H1 heavy chain (SEQ ID NO: 15) and h9401-L1 light chain (SEQ ID NO: 38). H Region (SEQ ID NO: 205) and V L The CDR regions of region (SEQ ID NO:210) contain multiple substitutions, where substitutable amino acids in the CDR regions are marked with an X. A complete list of amino acid substitutions in NM5072 and Presta 9401 is provided in the table below.

[0179] [Table 1]

[0180] The antibody structures in Figure 1 are the V of NM5072 or Presta humanized mouse 9401. H and V L Different combinations of variable chain sequences can be utilized, with different amino acid CDR substitutions and framework variations. H Further combinations are possible when V is linked to the Fc region. The heavy chain can be linked to any Fc in Table 6 using any of the linkers in Table 7, with the ASTK linker (SEQ ID NO: 245) being the most common linker; L is linked to CL (SEQ ID NO:246) using a RTVAAP linker (SEQ ID NO:247). The heavy and light chain sequences are linked by a disulfide bond between the CH1 and CL chains at the site of the cystine residues. Similarly, disulfide bonds are formed between the hinge regions of the two fAbs, resulting in a complete monoclonal antibody. The antibody can be made bispecific by replacing one of the NM5072 or Presta fAbs with an anti-Alb sequence or fAb that binds to a different target.

[0181] The most important aspect for NM5072 was to identify substitutions in the CDR regions of the sequence, which allow the antibody to recognize its specific binding site (in this case, properdin) to inhibit the activation of the alternative pathway. Four major heavy chain substitutions were made. One was the substitution of amino acid V for I; another was the substitution of amino acid K for A; the third was the substitution of amino acid D for E, S, or A, also known as Asn / Pro fragmentation substitution; and the last was the substitution of amino acid N for Q, S, A, or D, also known as deamidation substitution.

[0182] The light chain had three major substitutions: one was a substitution of the amino acid A with T; another was a deamidation substitution; and the last was a substitution of the amino acid W with H, Y, or F, also known as a tryptophan oxidation substitution.

[0183] All other substitutions were due to minor changes in the CDR regions when all NM5072 sequences (NMT16-NMT28) were compared to each other. Differences in the framework regions are listed as different sequences.

[0184] Further CDR variants and differences in the framework regions are listed as different sequences in Table 1.

[0185] [Table 2] TIFF2024545741000003.tif201159TIFF2024545741000004.tif111159

[0186] Example 2 Example 2 describes the structures and amino acid sequences of anti-properdin antibodies NMT-29 to NMT-31. The CDR substitutions in the variable light and heavy chain regions of NMT29 to NMT31 (SEQ ID NOs: 40 to 42 and 45 to 47) are listed in FIG. 2. The framework regions are derived from the heavy chain (SEQ ID NO: 40) and light chain (SEQ ID NO: 45) sequences of NMT29. H Region (SEQ ID NO: 214) and V L The CDR regions of region (SEQ ID NO:219) contain multiple substitutions in variants of the anti-properdin antibody, where X represents amenable positions in the CDRs for substitution.

[0187] The CDRs of the variable light and heavy chain sequences of Presta humanized mouse 3196 are displayed in a similar format. The framework regions are Presta h3196-H2 heavy chain (SEQ ID NO: 43) and h3196-L3 light chain (SEQ ID NO: 48). H Region (SEQ ID NO: 215) and V L The CDR regions of region (SEQ ID NO:220) contain multiple substitutions in the variants of the anti-properdin antibody, where X represents a position in the CDR that is amenable to substitution. A complete list of substitutions in NM3196 and Presta3196 is provided below.

[0188] [Table 3]

[0189] The structure of the antibody is the same as that shown in Figure 1. In this case, the fAb region is derived from the variable chains of NM3196 and Presta3196. Multiple combinations of this antibody can be made by using the CDR substitutions listed above. H can be linked to any of the constant heavy chain Fc regions in Table 6 using any of the linkers shown in Table 7 (the most common linker is the ASTK linker (SEQ ID NO: 245)). Lis usually linked to CL (SEQ ID NO:246) by a RTVAAP (SEQ ID NO:247) linker. Bispecific antibodies can be made by replacing 3196 fAb with anti-Alb or fAb that binds to different targets.

[0190] For NM3196, the CDR substitutions were based on Presta's humanized mouse 3196. Five major substitutions were shown in the heavy chain sequence. One was the amino acid V to L substitution; another was the amino acid M to V, I, or K substitution, also known as methionine substitution; yet another was identical to the tryptophan substitution present in NM5072; the fourth was the N to Q, S, or A substitution, also known as Asn / Pro fragmentation substitution for NM3196; the last was the D to E, S, or A substitution, also known as isoaspartic acid substitution for NM3196.

[0191] For the light chain sequence, four major substitutions were noted: one was the amino acid L for M or V; another was the amino acid A for S or T; a third was the amino acid R for K; and the last was a tryptophan substitution.

[0192] Further CDR variants and differences in the framework regions are listed as different sequences in Table 2.

[0193] [Table 4]

[0194] Example 3 The structure and amino acid sequence of an anti-properdin antibody containing the CDRs of two different humanized rabbit variable light and heavy chain sequences are described in Example 3. The humanized rabbit variable light and heavy chain sequences are listed in Figure 3 (rabbit 27-03 and rabbit 86-06). For rabbit 27-03, the framework regions were derived from h2703-H1 heavy chain (SEQ ID NO: 51) and h2703-L1 light chain (SEQ ID NO: 61) of the Presta report. For rabbit 86-06, the framework regions were derived from h8606-H2 heavy chain (SEQ ID NO: 56) and h8606-L3 light chain (SEQ ID NO: 66) of the Presta report. V H Region (SEQ ID NO: 224 and 232) and V L The CDR regions of the regions (SEQ ID NOs:228 and 236) contain multiple substitutions in the variants of the anti-properdin antibody, where X represents a position in the CDR that is amenable to substitution. A complete list of CDR substitutions for both 27-03 and 86-06 is shown in the table below.

[0195] [Table 5]

[0196] The antibody structure is a monospecific antibody similar to NM5072 and NM3196. The CDR substitutions can be used to create different antibody sequence combinations. The V H can be linked. Linkers that can be used to link these two regions are shown in Table 7, with the most common linker being the ASTK (SEQ ID NO: 245) linker. L is usually linked to CL (SEQ ID NO:246) using a RTVAAP (SEQ ID NO:247) linker. The antibody can be made bispecific by replacing one of the fAbs with anti-albumin or with a different targeting fAb.

[0197] For rabbit 27-03, the heavy chain CDR had six major substitutions: one was a substitution of amino acid D for T; another was an N for T; yet another was a V for T; one was a tryptophan substitution; one was an isoaspartic acid forming substitution present in NM3196; and the final substitution was an N for Q, S, or A, also known as a deamidating substitution in rabbit 27-03.

[0198] For humanized rabbit 27-03, the light chain CDR had six major substitutions: one substitution was amino acid L to V; one substitution was R to Q; another substitution was A to P; one substitution was a deamidation substitution; one substitution was S to K; and the final substitution was I to V.

[0199] For rabbit 86-06, the heavy chain CDRs also had six major substitutions: one was a substitution of amino acid V for A or T; another was a tryptophan substitution; one was a substitution of M for L, I, or K, also known as the methionine substitution in rabbit 86-06; another was a substitution of D for T; yet another was a substitution of N for S or T; and the final substitution was an isoaspartic acid substitution present in NM3196.

[0200] For humanized rabbit 86-06, the light chain CDRs also contained six major substitutions: L can be substituted with V; R can be substituted with Q; one substitution was a deamidation substitution; A can be substituted with R; one substitution was a tryptophan substitution; and the final substitution was an I to V substitution.

[0201] Further CDR variants and differences in the framework regions are listed as different sequences in Table 3.

[0202] [Table 6] TIFF2024545741000009.tif96159

[0203] IgG Fc constant chain variations The variable chains of Figures 1, 2 and 3 can be combined into a complete fAb region and joined to create a complete IgG constant chain region. Complete constant chain regions (Fc') are listed in Table 6. CH regions contain variations in their sequence. IgG N298A Fc, as the name suggests, contains a point mutation at position 298 resulting in a substitution of amino acid N for A. This mutation does not always occur at position 298 in this sequence. It is possible that the V H and the length of the linker.

[0204] YTE Fc contains three point mutations: M253Y, S255T, and T257E. As with N298A Fc, it is not guaranteed that these mutations will always occur at the positions listed. H And the length of the linker will affect its location.

[0205] IgG2 is the commonly used Fc sequence for monospecific and bispecific complement-targeting antibodies.

[0206] There is no variation in the IgG constant light chain. L is almost always the same.

[0207] Table 7 lists the common linkers used to link variable chain regions to constant chain regions. The most commonly used variable heavy chain linker is the ASTK linker (SEQ ID NO: 245), and the most commonly used variable light chain linker is the RTVAAP linker (SEQ ID NO: 247). Any other linker is commonly used to link variable heavy chains to constant heavy chains. In some embodiments, the above linkers can be used when two variable heavy chains are directly linked to the CH1 region that separates them.

[0208] Example 4 Example 4 describes the structures and amino acid sequences of monospecific and bispecific camelid anti-properdin antibodies. The camelid sequences (LVP058 and VVP059) along with selected framework regions are shown. HH The CDR replacements of V are shown in Figure 4. The framework regions of the sequence are derived from SEQ ID NOs: 45-51, 59, and 61 of US Patent Application No. 20190352381A1; the entire contents of which are incorporated herein by reference. HH The CDR regions of the regions (SEQ ID NOs:240 and 244) contain multiple substitutions across variants of camelid anti-properdin antibodies, where X represents a position in the CDR that is amenable to substitution. The humanized anti-ALB sequences are also listed. A complete list of CDR substitutions for camelid anti-properdin sequences is provided in the table below.

[0209] [Table 7]

[0210] The structure in Figure 5 is a bispecific antibody that binds to both properdin and albumin. In this embodiment, it comprises an fAb ​​region directly linked to the CH2 region of the Fc. In camelid species, V L Since the Fc region does not require the A1b, there is no CH1 region. The addition of A1b helps to increase the half-life of the antibody in the body and decrease the clearance rate. The use of the Presta substitution allows different combinations of camelid heavy chain sequences to be linked to the Fc region.

[0211] Additionally, the above heavy chain regions can be linked to any of the heavy chain Fc shown in Table 6 with the CH1 region removed. For these embodiments, any linker in Table 7 can be used, although the most common linker is the (G4S)3 linker.

[0212] Regarding the camelid anti-properdin sequence, there is no light chain region. Camelid species have a heavy chain domain (V HH) in the CDR region. There were four major substitutions in the CDR regions. The substitutions were based on the Presta substitutions found in humanized mouse 9401 and 3196. One substitution was the substitution of amino acid V for I; another substitution was the substitution of amino acid K for A; one substitution was the presence of a deamidation substitution in Presta report 9401; and the last substitution was an isoaspartic acid forming substitution in Presta report 3196.

[0213] These substitutions do not encompass all the variations in the CDRs of the camelid heavy chain sequences. Further CDR variants and differences in the framework regions are listed as different sequences in Table 4 below.

[0214] [Table 8] TIFF2024545741000012.tif198159TIFF2024545741000013.tif64159

[0215] Example 5 Example 5 describes the structures and amino acid sequences of additional bispecific anti-properdin antibodies, including an anti-albumin chain, a camelid anti-properdin heavy chain, and variations of NovelMed's NMT15 light and heavy chains.

[0216] [Table 9]

[0217] The camelid anti-properdin heavy chain sequences of these antibodies were modified from US Patent Application No. 20190352381A1, as was the human anti-albumin sequence in constructs 1 and 4. The humanized anti-albumin sequence in constructs 2 and 5 was modified from US Patent Application No. 2007 / 0269422A1; this reference is incorporated herein by reference in its entirety. The light and heavy chains of NMT15 were created by humanizing the mouse anti-properdin Fab region of the original Presta sequence. The anti-albumin is used in the synthesis of these novel constructs to aid in the half-life extension and bioavailability enhancement of the drug. Examples of anti-albumin amino acid sequences are listed in Table 5. The complete sequence of each construct is shown in Figures 6-8.

[0218] For all sequences in the above table, the sequences were linked using a (G4S)3 linker (GGGSGGGSGGGS) (SEQ ID NO: 143). In FIG. 6, the anti-albumin is linked to camelid anti-properdin. Similarly, in FIG. 7, two identical Fab regions (NMT15HC / LC) are linked to generate a complete mAb. In FIG. 8, the anti-albumin sequence of FIG. 6 is linked to the Fab region of FIG. 7 to generate a complete mAb. Specifically, for sequences NMT1003-NMT1005, the heavy chain region was linked to an Fc containing only the CH1 region (SEQ ID NO: 138) and the light chain region was linked to a CL (SEQ ID NO: 139).

[0219] [Table 10] TIFF2024545741000016.tif69159

[0220] Example 6 Example 6 describes the structure and amino acid sequence of bispecific anti-properdin antibodies. The bispecific anti-properdin antibodies described in this example and in the table below were designed to be more stable and longer lasting in blood circulation. Linking an anti-albumin sequence to an anti-properdin antibody or its antigen-binding fragment allows the antibody to bind to serum albumin, thereby achieving a longer half-life and circulation time. Furthermore, the addition of an Fc region can extend the half-life of the antibody and improve the stability of the overall structure. A comprehensive description of several embodiments of bispecific anti-P antibodies constructed using different Fcs listed in Table 6, linkers listed in Table 7, and fAB binding regions listed in Table 8 is provided in the table and in the embodiments below.

[0221] [Table 11]

[0222] NM9625 is a monospecific antibody that binds to properdin. A camelid anti-P sequence is used to link it to various IgG4 Fc using a (G4S)3 linker. In this embodiment of IgG4 Fc, the CH1 region is absent and the camelid variable heavy domain is directly linked to the hinge region of the Fc. The complete sequence listing and antibody structure are shown in Figure 9.

[0223] NM9626 and NM9627 are bispecific antibodies that bind both properdin and serum albumin. The sequences and structures of these antibodies are shown in FIG. 4. They use various camelid anti-P sequences along with a humanized camelid anti-albumin sequence. These variable heavy chain sequences are linked to various IgG Fc with a (G4S)3 linker. In these embodiments of IgG Fc, the CH1 region is absent and both camelid anti-P and anti-Alb are linked directly to the hinge region of the IgG Fc. The main difference between these two antibodies is that NM9626 is made with the same IgG4 Fc as NM9625 (SEQ ID NO: 163 and 164) and NM9627 is made with an IgG1 Fc (SEQ ID NO: 165 and 166).

[0224] NM9628 is a bispecific antibody that binds to both properdin and serum albumin. Its full sequence listing and antibody structure are shown in Figure 10. NovelMed's NMT16 anti-P fAb region is combined with a humanized rabbit serum albumin fAb. The heavy chain regions of NMT16 and anti-Alb are linked to a full IgG1 Fc. The light chain regions of NMT16 and anti-ALB are linked to CL.

[0225] NM9629 is a bispecific antibody that binds to both properdin and serum albumin. Its full sequence listing and antibody structure are shown in FIG. 11. The humanized rabbit 27-03 anti-P sequence of Presta is combined with a humanized rabbit anti-albumin sequence. The heavy chain regions of Presta humanized rabbit and anti-albumin are linked to an IgG1 full Fc with a YTE mutation (SEQ ID NO: 131). The light chain regions of Presta humanized rabbit and anti-Alb are linked to CL.

[0226] NM9630 is a bispecific antibody that binds to both properdin and TNF. Its full sequence listing and antibody structure are shown in Figure 12. NovelMed's NMT16 fAb is combined with an anti-TNF fAb. The heavy chain is linked to an IgG1 Fc from an anti-TNF antibody (Humira (SEQ ID NO: 129)) and the light chain is linked to a CL.

[0227] NM9631 is a bispecific antibody that binds to both properdin and VEGF-A. The complete sequence listing and antibody structure are shown in FIG.

[0228] [Table 12] TIFF2024545741000019.tif81159

[0229] [Table 13]

[0230] [Table 14]

[0231] Example 7 Example 7 describes the structure and amino acid sequence of modified and reshaped antibodies from Examples 5 and 6. Specifically, it lists the (fAb)2 monospecific antibody NMT1003 from Example 5 along with several bispecific fAb regions from Example 6 (anti-P / anti-Alb, anti-P / anti-TNF, anti-P / anti-VEGF). The main difference is the variation of Fc used to link these heavy chain regions. By changing the Fc, it is possible to obtain monospecific and bispecific antibodies with better binding, half-life, and circulation time. The table below shows the list of antibodies obtained for Example 7.

[0232] [Table 15]

[0233] Figure 7 shows a monospecific antibody that binds only to properdin. The antibody contains the variable heavy and light chains (fAb) of NMT15. The variable heavy chain is linked only to the Fc CH1 region. The light chain is linked to the Fc CL. Two identical NMT15 fAb regions are linked via a (G4S)3 linker. The structure of the antibody is shown with two ovals representing the NMT15 fAb regions with the CH1 and CL regions. The green line connecting the two ovals represents the linker connecting them.

[0234] Figure 14 shows the sequence and structure of a bispecific antibody that binds both properdin and serum albumin. Both the anti-properdin and anti-albumin variable heavy chain sequences are derived from camelid species. Furthermore, both are linked to an IgG1 full Fc with a N297A mutation (asparagine at position 297 is replaced by alanine), although this position is subject to variation depending on the variable heavy chain linked to it. A (G4S)3 linker is used to link the variable chain to the constant chain.

[0235] Figure 15 shows the sequence and structure of a bispecific antibody that binds both properdin and serum albumin. The variable heavy and light chains of NMT16 are combined with a camelid anti-Alb single variable heavy chain. The variable heavy chain region of NMT16 is linked to an IgG1 Fc containing a YTE mutation for longer half-life. Ablynx camelid anti-alb is linked to the same Fc using a (G4S)3 linker. The light chain of NMT16 is linked to a CL Fc.

[0236] Figure 16 shows the sequence and structure of a bispecific antibody that binds both properdin and serum albumin. The NMT16 anti-P fAb region is combined with humanized rabbit serum albumin. It is similar to the NM9628 construct in Example 6. The difference is that the heavy chain region of NMT16 and anti-ALB is linked to IgG1 N297A Fc (the mutation does not always occur at position 297, depending on the VH it is linked to). The light chain region of NMT16 and anti-ALB is linked to CL.

[0237] Figure 17 shows the sequence and structure of a bispecific antibody that binds both properdin and serum albumin. A camelid anti-properdin single variable heavy chain is combined with a camelid anti-alb single heavy chain. These two variable heavy chain regions are linked to the IgG4 Fc (CH2 / CH3 regions only) of dulaglutide via a (G4S)3 linker.

[0238] Figure 18 shows the sequence and structure of a bispecific antibody that binds both properdin and TNF. It is similar to NM9630 in Example 6. NMT16 fAb is combined with an anti-TNF fAb. The difference is that the variable heavy chain sequence is linked to an IgG1 YTE Fc. The light chain is linked to a CL.

[0239] Figure 19 shows the sequence and structure of a bispecific antibody that binds both properdin and VEGF-A. It is similar to the NM9631 construct of Example 6. The NMT16 fAb is combined with an anti-VEGF-A fAb. The difference is that the heavy chain is linked to an IgG1 YTE Fc, just like the bispecific construct above. The light chain is linked to a CL.

[0240] Using Presta substitutions, several different combinations of variable chain sequences were created. These sequences can be used to describe and test how different substitutions affect the affinity, hemolysis, and potency of different antibody structures. Furthermore, the ability to create bispecific molecules using anti-Alb, anti-TNF, anti-VEGF, and IgG Fc mutations may help extend the half-life and circulation time of these antibodies in vivo.

[0241] The amino acid sequences of these and other monospecific and bispecific anti-properdin antibodies are shown in Tables 9, 10, and 11.

[0242] [Table 16] TIFF2024545741000024.tif61159

[0243] [Table 17] TIFF2024545741000026.tif186159TIFF2024545741000027.tif197159TIFF2024545741000028.tif194159TIFF2024545741000029.tif30159

[0244] [Table 18] TIFF2024545741000031.tif174159TIFF2024545741000032.tif202159TIFF2024545741000033.tif149159

[0245] Example 8: NMT15-NMT22 avidity and functional assays Binding affinity for properdin Polystyrene microtiter plates were coated overnight at 4°C with human properdin (2.0 μg / 50 μl / well) in phosphate-buffered saline (PBS). After aspirating the properdin solution, the wells were blocked with PBS containing 1% bovine serum albumin (BSA) (Sigma-Aldrich, St. Louis, MO) for 2 h at room temperature. Wells without peptide or properdin coating served as background controls. A portion of the blocking solution containing the test antibodies was added to the properdin-coated wells and incubated for 1 h to allow binding. After 1 h incubation at room temperature, the plates were rinsed five times with PBS and incubated with anti-properdin polyclonal antibody at a 1:2000 dilution.

[0246] As can be seen from Figure 20, NMT15, NMT16, NMT17, and NMT18 bind to properdin with high affinity. The affinity values ​​of NMT15, NMT16, NMT17, and NMT18 were comparable to that of NMT5072.

[0247] As can be seen from Figure 21, NMT19, NMT20, NMT21, and NMT22 bind to properdin with high affinity. The affinity values ​​of NMT19, NMT20, NMT21, and NMT22 were comparable to that of NMT5072.

[0248] Inhibition of AP hemolysis This cell assay is based on the formation of terminal complement complexes on the surface of rRBCs, which results in rRBC lysis. Evidence of lysed cells is a stepwise decrease in light scattering at 700 nm. rRBCs are incubated in AP buffer containing normal human serum. The surface of the rRBCs initiates AP activation in normal human serum. The AP cascade is initiated, leading to the formation of C5b-9 complexes on the surface of the rRBCs. Agents that inhibit this activation are expected to inhibit cell lysis.

[0249] To assess the effect of test antibodies on AP activation, a given number of rabbit red blood cells (Covance) were incubated in AP buffer containing normal human serum (10% NHS) and various concentrations of test antibody at 37°C in a temperature-controlled ELISA plate reader capable of reading at 700 nm. The stepwise decrease in light scattering at 700 nm (due to lysis of intact cells) was measured as a function of time. Data were recorded and analyzed using a SpectraMax 190 plate reader and SoftMax Pro software. For calculations, the total inhibition at each concentration of antibody was calculated and the results were expressed as a percentage of the unlysed control. Sigmoidal plots of the data for each concentration were generated using MicroCal Origin software.

[0250] Figure 22 shows the strong hemolysis-inhibiting activity of NMT15, NMT16, NMT17, and NMT18. NMT15, NMT16, NMT17, and NMT18 were able to inhibit hemolysis at concentrations comparable to those of NM5072.

[0251] Figure 23 shows the strong hemolysis-inhibiting activity of NMT19, NMT20, NMT21, and NMT22. NMT21 was able to inhibit hemolysis at a concentration similar to that of NM5072.

[0252] Inhibition of MAC formation C5b-9 formation assay: Microtiter wells were coated overnight at 4°C with PBS containing LPS (2 μg / 50 top wells). Uncoated wells served as background controls. After aspirating the LPS solution, wells were treated with phosphate-buffered saline (PBS; pH 7.4) containing 1% BSA for 2 h. After 2 h incubation, wells were rinsed with PBS and incubated with AP buffer containing 10% normal human serum (NHS) and various concentrations of antibody. After 2 h incubation at 37°C to allow AP activation, detection of deposited MAC (C5b-9) was performed with mouse anti-human soluble neo-05b-9 monoclonal antibody diluted 1:2000. All antibody dilutions were prepared in blocking solution, and all antibody incubations were performed at room temperature for 1 h. Primary antibody was detected with goat anti-mouse monoclonal. After each incubation, plates were rinsed 5 times with PBS. The plate was developed with TMB, and the blue color reaction was stopped with 1 M phosphoric acid.

[0253] 24 is a plot showing inhibition of MAC formation by NMT15, NMT16, NMT17, and NMT18. NMT15, NMT16, NMT17, and NMT18 were able to inhibit MAC formation and deposition at concentrations comparable to those of NM5072.

[0254] 25 is a plot showing inhibition of MAC formation by NMT19, NMT20, NMT21, and NMT22. NMT20 and NMT21 were able to inhibit MAC formation and deposition at concentrations similar to those of NM5072.

[0255] Inhibition of properdin C3b binding Upon AP activation, C3a and C3b are generated as a result of cleavage of C3 by the C3 convertase of the alternative complement pathway. In normal human serum, under conditions that allow activation of the alternative complement pathway, activation of the alternative complement pathway occurs by lipopolysaccharide derived from Salmonella typhi. The present inventors utilized this assay to demonstrate whether the anti-properdin antibody of the present invention inhibits the formation and deposition of C3b. C3b deposition initiates the alternative complement pathway. The mechanistic mode is high affinity properdin binding by activated and deposited C3b. The properdin-C3b complex binds factor B, which is cleaved by factor D to generate PC3bBb (C3 convertase of the alternative pathway). Progression of the alternative complement pathway leads to the formation and deposition of the C5b-9 complex.

[0256] The formation and deposition of C3b is inhibited, and because the formation and deposition of C3b is inhibited, the deposition of other components (such as properdin) is also inhibited.

[0257] In a typical assay, wells of polystyrene microtiter plates were coated overnight with 2 μg / 50 μl LPS (lipopolysaccharide from Salmonella typhi) in PBS. To block the uncoated parts of the wells, the wells were incubated with BSA in PBS. After 2 h of blocking at room temperature and rinsing with PBS, AP buffer containing normal human serum (10%) was mixed with various concentrations of anti-properdin antibodies and its derived fragments. These mixtures were incubated in the LPS-coated wells. Plates were incubated for 2 h at 37°C to allow complement AP activation. After incubation, the plates were washed extensively with PBS and the components of C3 convertase were detected with appropriate antibodies. We detected C3b with rabbit anti-human C3c diluted 1:2000 in blocking solution; properdin with goat anti-human P; Bb with goat anti-human factor Bb diluted 1:500 in blocking solution; and C5b-9 with HRPO-conjugated neo anti-human C5b-9 diluted 1:2000 in blocking solution. Plates were incubated with their respective antibodies for 1 hour at room temperature. After incubation, the plates were rinsed with PBS and bound antibodies were detected for C3b with peroxidase-labeled goat anti-rabbit diluted 1:2000; P detection was performed with peroxidase-labeled rabbit anti-goat diluted 1:2000 in blocking solution. All plates were washed extensively with PBS and then developed with TMB. The blue reaction was stopped with 1M orthophosphoric acid. The presence of C3b, P, and Bb and MAC together suggests the formation of AP C3 convertase. It is shown that the antibodies of the present invention inhibit C3b formation and therefore deposition. This data provides direct evidence that anti-properdin monoclonal antibodies inhibit AP activation by inhibiting C3 convertase formation.

[0258] 26 is a plot showing inhibition of properdin deposition by NMT15, NMT16, NMT17, and NMT18. NMT15, NMT16, NMT17, and NMT18 were able to inhibit properdin binding to C3b and properdin deposition at concentrations comparable to those of NM5072.

[0259] 27 is a plot showing inhibition of properdin deposition by NMT15, NMT19, NMT20, NMT21, and NMT22. NMT20 and NMT21 were able to inhibit properdin binding to C3b and properdin deposition at concentrations similar to those of NM5072.

[0260] 28 is a plot showing the inhibition of AP-mediated C3b formation and deposition by NMT15, NMT17, NMT18, NMT20, and NMT21. NMT15, NMT17, NMT18, NMT20, and NMT21 were able to inhibit properdin binding to C3b and C3b deposition at similar concentrations.

[0261] Inhibition of classical pathway activation To test the activity of the antibodies in CP inhibition, antibody-sensitized sheep red blood cells (sRBCs) were incubated in CP buffer (Ca) containing 1% normal human serum. 2+ / Mg 2+ These sRBCs activate CP, which induces lysis of the cell membrane. As a result of the lysis of the cell membrane, light scattering by the cells gradually decreases. In the presence of 1% NHS, Ca 2+ and Mg 2+ When the alternative pathway-specific antibodies of the invention were incubated with sRBCs at 37° C. in a buffer containing 0.1% glycerol ("CP buffer"), no effect on hemolysis was observed within the time range from onset of hemolysis to maximum hemolysis, indicating that the antibodies have no effect on CP hemolytic activity in NHS and do not impair CP, which is expected to contribute to host defense against pathogens.

[0262] The antibodies described herein do not inhibit the classical pathway, regardless of the corresponding target antigen. In a typical assay, antibody-sensitized sheep red blood cells are incubated with normal human serum and CP buffer containing Ca2+. These conditions allow selective activation of the classical pathway. Mechanistically, the antigen-antibody complex on the surface of sheep cells activates the classical complement pathway, which causes hemolysis.

[0263] 29 is a plot showing CP-mediated MAC formation and deposition by NMT15, NMT17, NMT18, NMT20, and NMT21. NMT15, NMT17, NMT18, NMT20, and NMT21 did not inhibit CP-mediated MAC formation and deposition.

[0264] 30 is a plot showing CP-mediated C3b formation and deposition by NMT15, NMT17, NMT18, NMT20, and NMT21. NMT15, NMT17, NMT18, NMT20, and NMT21 did not inhibit CP-mediated C3b formation and deposition.

[0265] Table 12 shows a summary of the avidity and functional assays for NMT15-NMT22.

[0266] [Table 19]

[0267] Example 9: NMT23-NMT28 binding affinity and functional assays Binding affinity to properdin 31 is a plot showing the binding affinity of NMT23, NMT24, NMT25, NMT26, NMT27, and NMT28 to properdin. The properdin affinity values ​​of NMT23 and NMT28 were comparable to that of NMT1510.

[0268] Inhibition of MAC formation 32 is a plot showing inhibition of MAC formation and deposition by NMT23, NMT24, NMT25, NMT26, NMT27, and NMT28. NMT28 was able to inhibit MAC formation and deposition at concentrations similar to those of NMT1510.

[0269] Inhibition of AP hemolysis 33 is a plot showing the inhibition of AP hemolysis by NMT23, NMT24, NMT26, and NMT27. NMT15, NMT16, NMT17, and NMT28 were unable to inhibit hemolysis at concentrations comparable to NMT1510.

[0270] Inhibition of properdin C3b binding 34 is a plot showing the inhibition of AP-mediated C3 convertase formation and deposition of properdin and C3b by NMT28. NMT28 was able to inhibit properdin binding to C3b and deposition of properdin and C3b at concentrations comparable to NMT1510.

[0271] Inhibition of classical pathway activation 35 is a plot showing CP-mediated MAC formation and deposition by NMT28. NMT28 did not inhibit CP-mediated MAC formation and deposition.

[0272] Table 13 shows a summary of the avidity and functional assays for NMT23-NMT28.

[0273] [Table 20]

[0274] Binding and functional assays of NMT17, NMT18, and NMT28 with modified Fc regions Binding affinity to properdin 36 is a plot showing the binding affinity of NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101 to properdin. The properdin binding affinity values ​​of NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101 were comparable to that of NMT1510.

[0275] Inhibition of AP hemolysis 37 is a plot showing the inhibition of AP hemolysis by NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101 were able to inhibit hemolysis at concentrations comparable to those of NMT1510.

[0276] Inhibition of MAC formation 38 is a plot showing inhibition of MAC formation by NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101 were able to inhibit MAC formation and deposition at concentrations similar to NMT1510.

[0277] Inhibition of properdin C3b binding 39 is a plot showing the inhibition of AP-mediated C3b formation and deposition by NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101 were able to inhibit properdin binding to C3b and C3b deposition at concentrations comparable to those of NMT1510.

[0278] Table 14 shows a summary of the avidity and functional assays for NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101.

[0279] [Table 21]

[0280] Example 10: Avidity and Functional Assays of N297 and Xtend Fc Regions for NMT17, NMT18, NMT28 Binding affinity of properdin Figure 40 is a plot showing binding affinity to properdin. Comparison of the Fc region of N297 and Xtend-NMT17, NMT18, NMT28, NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. The properdin binding affinity values ​​of NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101 were comparable to NMT1510.

[0281] Inhibition of AP hemolysis Figure 41 is a plot showing inhibition of AP hemolysis. Comparison of the Fc region of N297 and Xtend - NMT17, NMT18, NMT28, NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101 were able to inhibit hemolysis at concentrations similar to NMT1510.

[0282] Inhibition of MAC formation Figure 42 is a plot showing inhibition of MAC formation. Comparison of the Fc region of N297 and Xtend - NMT17, NMT18, NMT28, NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101 were able to inhibit MAC formation and deposition at concentrations similar to NMT1510.

[0283] Inhibition of properdin C3b binding Figure 43 is a plot showing inhibition of C3b formation and deposition. Comparison of the Fc region of N297 and Xtend-NMT17, NMT18, NMT28, NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101. NMT17-100, NMT17-101, NMT18-100, NMT18-101, NMT28-100, and NMT28-101 were able to inhibit properdin binding to C3b and C3b deposition at concentrations similar to NMT1510.

[0284] Example 11: NMT29-NMT31 avidity and functional assays Binding affinity to properdin Figure 44 is a plot showing binding avidity to properdin. Comparison of the Fc regions of N297 and Xtend--NMT29, NMT30, NMT31. The properdin binding affinity values ​​of NMT29, NMT30, and NMT31 were comparable to that of NMT1510.

[0285] Inhibition of MAC formation Figure 45 is a plot showing AP-mediated MAC formation. Comparison of the Fc region of N297 and Xtend-NMT29, NMT30, NMT31. NMT29, NMT30, NMT31 were able to inhibit MAC formation and deposition at concentrations similar to NMT1510.

[0286] Inhibition of AP hemolysis Figure 46 is a plot showing inhibition of AP-mediated hemolysis. Comparison of the Fc region of N297 and Xtend-NMT29, NMT30, NMT31. NMT29, NMT30, NMT31 were able to inhibit hemolysis at concentrations similar to NMT1510.

[0287] Inhibition of properdin C3b binding Figure 47 is a plot showing inhibition of AP-mediated C3b formation and deposition. Comparison of the Fc regions of N297 and Xtend-NMT29, NMT30, NMT31. NMT29, NMT30, and NMT31 were able to inhibit properdin binding to C3b and deposition of C3b at concentrations comparable to NMT1510.

[0288] Example 12: Avidity and Functional Assays of NMT30 and NMT31 with Modified Fc Regions Binding affinity to properdin 48 is a plot showing the binding affinity of NMT30-100, NMT30-101, NMT31-100, and NMT31-101 to properdin. The properdin binding affinity values ​​of NMT30-100, NMT30-101, NMT31-100, and NMT31-101 were comparable to that of NMT1510.

[0289] Inhibition of AP hemolysis 49 is a plot showing the inhibition of AP hemolysis by NMT30-100, NMT30-101, NMT31-100, and NMT31-101. NMT30-100, NMT30-101, NMT31-100, and NMT31-101 were able to inhibit hemolysis at concentrations comparable to those of NMT1510.

[0290] Inhibition of MAC formation 50 is a plot showing inhibition of AP-mediated MAC formation by NMT30-100, NMT30-101, NMT31-100, and NMT31-101. NMT30-100, NMT30-101, NMT31-100, and NMT31-101 were able to inhibit MAC formation and deposition at concentrations comparable to NMT1510.

[0291] Inhibition of properdin C3b binding 51 is a plot showing the inhibition of AP-mediated C3b formation and deposition by NMT30-100, NMT30-101, NMT31-100, and NMT31-101. NMT30-100, NMT30-101, NMT31-100, and NMT31-101 were able to inhibit properdin binding to C3b and C3b deposition at concentrations comparable to those of NMT1510.

[0292] Example 13: Avidity and Functional Assays of NMT30 and NMT31 with N297 and Xtend Fc Regions Binding affinity to properdin Figure 52 is a plot showing binding affinity to properdin. Comparison of the Fc regions of N297 and Xtend-NMT30, NMT31, NMT30-100, NMT30-101, NMT31-100, and NMT31-101. The properdin binding affinity values ​​of NMT30-100, NMT30-101, NMT31-100, and NMT31-101 were comparable to NMT1510.

[0293] Inhibition of AP hemolysis Figure 53 is a plot showing inhibition of AP hemolysis. Comparison of the Fc region of N297 and Xtend - NMT30, NMT31, NMT30-100, NMT30-101, NMT31-100, and NMT31-101. NMT30-100, NMT30-101, NMT31-100, and NMT31-101 were able to inhibit hemolysis at concentrations similar to NMT1510.

[0294] Inhibition of MAC formation Figure 54 is a plot showing inhibition of MAC formation. Comparison of the Fc region of N297 and Xtend - NMT30, NMT31, NMT30-100, NMT30-101, NMT31-100, and NMT31-101. NMT30-100, NMT30-101, NMT31-100, and NMT31-101 were able to inhibit MAC formation and deposition at concentrations similar to NMT1510.

[0295] Inhibition of properdin C3b binding Figure 55 is a plot showing inhibition of C3b formation and deposition. Comparison of the Fc region of N297 and Xtend - NMT30, NMT31, NMT30-100, NMT30-101, NMT31-100, and NMT31-101. NMT30-100, NMT30-101, NMT31-100, and NMT31-101 were able to inhibit properdin binding to C3b and C3b deposition at concentrations similar to NMT1510.

[0296] From the above description of the invention, those skilled in the art will perceive improvements, modifications and variations. Such improvements, modifications and variations in the art are intended to be included within the scope of the appended claims. All references, publications and patents cited in this application are hereby incorporated by reference in their entirety.

Claims

1. 1. An isolated monospecific or bispecific antibody or antigen-binding fragment thereof, comprising: (a) GYIFTX １ CDR-H1 (wherein X １ is N), FIX １ PGGGX ２ DEX ３ X ４ X ５ X ６ X ７ X ８ X ９ CDR-H2 (wherein X １ is D; X ２ is H or Y; X ３ is P, S, or Y; X ４ is A or D; X ５ is D, E, or Q; X ６ is K, R, or S; X ７ is F or V; X ８ is E, K, Q, or R; and X ９ is D or G), and CDR-H3 comprising the amino acid sequence RGGGYYLDY (SEQ ID NO: 203); a heavy chain variable region having the formula: (b) CDR-L1 comprising the amino acid sequence of RASQDISFFLN (SEQ ID NO: 206); X １ X ２ SX ３ CDR-L2 (wherein X １ is G or Y; X ２ is A or T; and X ３ is R or S), and QHGX １ TLPX ２ CDR-L3 (wherein X is a CDR-L3 sequence) comprising the amino acid sequence of X (SEQ ID NO: 208). １ is Q or S; and X ２ is W or Y), a light chain variable region having the formula: wherein the antibody or antigen-binding fragment thereof binds to human properdin; or a heavy chain variable region and / or a light chain variable region that competitively inhibits the binding of an isolated monospecific or bispecific antibody or antigen-binding fragment thereof comprising (a) and (b) to monomeric properdin; An isolated monospecific or bispecific antibody or antigen-binding fragment thereof.

2. A heavy chain variable region comprising the three CDRs of SEQ ID NO: 4; or a heavy chain variable region that competitively inhibits the binding of an isolated antibody or antigen-binding fragment comprising a heavy chain variable region comprising the three CDRs of SEQ ID NO: 4 to monomeric properdin; 2. The isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1, comprising:

3. An isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 2, comprising a heavy chain variable region comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:

4. Claim 4: A light chain variable region comprising the three CDRs of SEQ ID NO: 27; or a light chain variable region that competitively inhibits the binding of an isolated antibody or antigen-binding fragment comprising a light chain variable region comprising the three CDRs of SEQ ID NO: 27 to monomeric properdin; 2. The isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1, comprising:

5. An isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 4, comprising a light chain variable region comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:

27.

6. An isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1, comprising a heavy chain variable region comprising the three CDRs of SEQ ID NO:4 and a light chain variable region comprising the three CDRs of SEQ ID NO:

27.

7. An isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 6, comprising a heavy chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:4, and a light chain comprising an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:

27.

8. The isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1, further comprising a constant chain region, The antibody or antigen-binding fragment comprising the constant chain region has an increased in vivo half-life and / or reduced immunogenicity compared to the antibody or antigen-binding fragment not comprising the constant chain region.

2. The isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1.

9. The isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 8, wherein the constant chain region comprises an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:129, SEQ ID NO:130, SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, or SEQ ID NO:

139.

10. The isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1, further comprising a peptide linker, Preferably, the peptide linker comprises the amino acid sequence of SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:245, or SEQ ID NO:246; 2. The isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1.

11. An isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1, which is humanized.

12. An isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1 that binds to human properdin.

13. An isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1, which inhibits alternative complement pathway activation in a mammal without inhibiting classical complement pathway activation.

14. A first heavy chain variable region that binds to properdin; and a second heavy chain variable region that binds to a different epitope than the first heavy chain variable region; 2. The isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 1, comprising:

15. The antibody of claim 1, wherein the second heavy chain variable region binds to one of albumin, TNF, or VEGF; Preferably, the second antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least about 70%, at least about 80%, or at least about 90% identical to the amino acid sequence of SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:122, SEQ ID NO:123, SEQ ID NO:124, SEQ ID NO:125, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, SEQ ID NO:150, or SEQ ID NO:

152.

15. The isolated monospecific or bispecific antibody or antigen-binding fragment thereof of claim 14.

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