CN115925918A - Antibody for specifically recognizing C5A and application thereof - Google Patents

Antibody for specifically recognizing C5A and application thereof Download PDF

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CN115925918A
CN115925918A CN202210791619.3A CN202210791619A CN115925918A CN 115925918 A CN115925918 A CN 115925918A CN 202210791619 A CN202210791619 A CN 202210791619A CN 115925918 A CN115925918 A CN 115925918A
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amino acid
acid sequence
seq
variant
sequence seq
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李忠
朱萍霞
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Staidson Beijing Biopharmaceutical Co Ltd
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Staidson Beijing Biopharmaceutical Co Ltd
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Abstract

The invention relates to an antibody specifically recognizing complement component 5a (C5 a), which has high C5a binding activity and weak C5 binding activity, and can avoid high concentration and/or frequent administration of anti-C5 a antibody. Also relates to a nucleic acid sequence for coding the antibody, a vector and a cell containing the nucleic acid sequence, a pharmaceutical composition containing the antibody and application of the anti-C5 a antibody in preparing medicines for treating autoimmune diseases, inflammation, cancer, pain, respiratory diseases and/or transplantation related diseases.

Description

Antibody for specifically recognizing C5A and application thereof
Cross Reference to Related Applications
The present application claims priority from chinese patent application having application number 202110762546.0, application date 2021.07.06 entitled "antibody specifically recognizing C5A and use thereof", and the entire contents of the application are incorporated herein by reference.
Submission sequence Listing in ASCII TEXT TEXT files
The contents of the ASCII TEXT file filed below are incorporated herein by reference in its entirety: sequence Listing in Computer Readable Form (CRF) (text name: CN _202106216389_, SEQ LIST. Txt, recording date: 2021.06.21, size: 79 KB).
Technical Field
The present application relates to antibodies that specifically recognize complement component 5a (C5 a), and methods of making and uses thereof, including use for treating autoimmune diseases, inflammation, cancer, pain, respiratory and/or transplantation-related diseases.
Background
C5a is an active peptide in allergic and inflammatory processes, which is formed by cleavage of complement component C5 by C5 convertase in the complement cascade. C5a stimulates mast cell degranulation, tumor necrosis factor-alpha (TNF- α) and histamine release, and also recruits phagocytes to the site of infection and inflammation by increasing the expression of endothelial cell surface adhesion molecules (Mollnes, t.e. et al. Blood 2002,100,1869-1877, riedemann, n.c. et al. Immunity 2003,19, 193-202. C5a also leads to increased vascular permeability in the presence of some pathological stimuli, such as allograft rejection and asthma after transplantation (Gueler, f.et al.j.am.soc.nephrol.2008,19,2302-2312, krug, n.et al.am.j.respir.crit.care med.2001,164,1841-1843, m.a.et al.proc.natl.acad.sci.usa 2013,110, 6061-6066). Several studies have discussed the level of C5a in serum. In one study by Lechner et al, the level of C5a in the control group was 8.34. + -. 2.05 (ng/mL) (Lechner, J.et al.Immun.Ageing 2016,13, 4). Additional studies have shown that under normal conditions, the levels of C5a in plasma are very low due to the rapid clearance of the anaphylatoxin (Oppermann, M.et al. Immunology 1994,82, 516-521). After treatment with C5a (25 nM), levels of transforming growth factor- β (TGF- β) are elevated in mouse cortical tubular cells, suggesting that C5a can lead to renal fibrosis and renal scarring (Boor, p.et al.j.am.soc.nephrol.2007,18, 1508-1515).
C5a is a potent pro-inflammatory molecule that binds to a classical G protein-coupled receptor (GPCR) C5aRI (CD 88) and triggers activation of pro-inflammatory signaling pathways (Li, r.et al. Fasebj.2013, 27, 855-864). C5aR is widely expressed on non-myeloid cells, such as umbilical vascular endothelial cells (HUVEC), murine dermis, liver, lung, and kidney proximal tubules (Monsinjon, T.et al. FASEB J.2003,17,1003-1014 Gerard, C.et al. Annu.Rev.Immunol.1994,12,775-808, haviland, D.L.et al. J.Immunol.1995,154, 1861-1869. Furthermore, studies demonstrated that C5aR is expressed in glomerular endothelial cells but not podocytes, suggesting that C5a may cause proteinuria primarily in renal endothelial cells (Tsai, i.j.et al.cell.mol.life sci.2015,72, 3157-3171).
Thus, blocking its binding to C5aR by neutralizing C5a is a method of treating C5a mediated diseases and conditions. The antibody INab308 against human C5a (InflaRx) is disclosed in patent application WO2011063980 A1, the C5a antibody MEDI-7814 (medimmunee) is disclosed in WO2012088247 A1, and the C5a antibody BNJ383 (Alexion) is disclosed in patent US 10450370B 2.
The disclosures of all publications, patents, patent applications and published patent applications mentioned herein are incorporated by reference in their entirety.
Summary of the application
In some embodiments, an isolated anti-C5 a antibody is provided comprising a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: heavy chain complementarity determining region (HC-CDR) 1, comprisingContaining X 1 LSX 2 H (SEQ ID NO: 70), wherein X 1 Is D or E, X 2 Is I or M; HC-CDR2 comprising GFX 1 PX 2 X 3 GX 4 TIYAQNFQG (SEQ ID NO: 71), wherein X 1 Is A, D, E, G, L, N, P, Q, S, V or Y, X 2 D, E, F, I, L, N, R, S, T or V, X 3 Is A, D, F, I, L, N, Q or S, X 4 Is D, G, T or V; and HC-CDR3 comprising GISX 1 X 2 X 3 NDAFDI (SEQ ID NO: 74), wherein X 1 Is D, E or S, X 2 Is A, G, I, V or W, X 3 Is H or W; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASQSVX 1 SX 2 YLA (SEQ ID NO: 77), wherein X 1 Is K or S, X 2 Is N, R or S; LC-CDR2 comprising DASX 1 RX 2 T (SEQ ID NO: 78), wherein X 1 Is A, D, E or S, X 2 Is A, D or S; and LC-CDR3 comprising QQYYYX 1 X 2 PX 3 T (SEQ ID NO: 79), wherein X 1 Is A, D or I, X 2 Is L, P or S, X 3 Is I, L or T.
In some embodiments, an isolated anti-C5 a antibody is provided comprising V H Said V is H Comprises the following steps: HC-CDR1 comprising an amino acid sequence set forth in any of SEQ ID NOs:1-3, or a variant thereof comprising up to about 3 amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:6-31 or a variant thereof comprising up to about 3 amino acid substitutions; and HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs:38-44 or a variant thereof comprising substitutions of up to about 3 amino acids; and V L Said V is L Comprises the following steps: LC-CDR1 comprising an amino acid sequence set forth in any one of SEQ ID NOs:48-50 or a variant thereof comprising up to about 3 amino acid substitutions; LC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:54-58 or a variant thereof comprising up to about 3 amino acid substitutions; and LC-CDR3 comprising a sequence as set forth in any one of SEQ ID NOs:62-66An amino acid sequence, or a variant thereof, comprising substitutions of up to about 3 amino acids.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: v H Said V is H Comprising a V as set forth in any one of the amino acid sequences of SEQ ID NOs:80-109 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3, and V L Said V is L Comprising a V as shown in any one of the amino acid sequences of SEQ ID NOs 118-124 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: (i) V H Comprising a V as shown in the amino acid sequence SEQ ID NO:80 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:118 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (ii) V H Comprising V as shown in amino acid sequence SEQ ID NO:81 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:118 L Comprises LC-CDR1, LC-CDR2 and LC-CDR3; (iii) V H Comprising V as shown in amino acid sequence SEQ ID NO:82 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:118 L Comprises LC-CDR1, LC-CDR2 and LC-CDR3; (iv) V H Comprising V as shown in the amino acid sequence SEQ ID NO 83 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:119 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (v) V H Comprising V as shown in the amino acid sequence SEQ ID NO:84 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:120 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (vi) V H Comprising V as shown in amino acid sequence SEQ ID NO:85 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:118 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3；(vii)V H Comprising V as shown in the amino acid sequence SEQ ID NO 86 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO. 121 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (viii) V H Comprising V as shown in the amino acid sequence SEQ ID NO:87 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO. 122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (ix) V H Comprising V as shown in amino acid sequence SEQ ID NO:88 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in amino acid sequence SEQ ID NO 123 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (x) V H Comprising V as shown in the amino acid sequence SEQ ID NO. 89 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in amino acid sequence SEQ ID NO:124 L Comprises LC-CDR1, LC-CDR2 and LC-CDR3; (xi) V H Comprising V as shown in the amino acid sequence SEQ ID NO. 90 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xii) V H Comprising a V as shown in the amino acid sequence SEQ ID NO:91 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xiii) V H Comprising V as shown in amino acid sequence SEQ ID NO:92 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xiv) V H Comprising V as shown in the amino acid sequence SEQ ID NO. 93 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xv) V H Comprising V as shown in the amino acid sequence SEQ ID NO 94 H Containing HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xvi) V H Comprising V as shown in the amino acid sequence SEQ ID NO:95 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xvii) V H Comprising V as shown in amino acid sequence SEQ ID NO:96 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xviii) V H Comprising V as shown in the amino acid sequence SEQ ID NO:97 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xix) V H Comprising V as shown in the amino acid sequence SEQ ID NO 98 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO. 122 L Comprises LC-CDR1, LC-CDR2 and LC-CDR3; (xx) V H Comprising V as shown in the amino acid sequence SEQ ID NO 99 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprises LC-CDR1, LC-CDR2 and LC-CDR3; (xxi) V H Comprising V as shown in the amino acid sequence SEQ ID NO 100 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO. 122 L Comprises LC-CDR1, LC-CDR2 and LC-CDR3; (xxii) V H Comprising a V as shown in the amino acid sequence SEQ ID NO 101 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO. 122 L Comprises LC-CDR1, LC-CDR2 and LC-CDR3; (xxiii) V H Comprising V as shown in the amino acid sequence SEQ ID NO. 102 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising the amino acid sequence SEQ ID NO 1V shown in 22 L Comprises LC-CDR1, LC-CDR2 and LC-CDR3; (xxiv) V H Comprising a V as shown in the amino acid sequence SEQ ID NO:103 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxv) V H Comprising a V as shown in the amino acid sequence SEQ ID NO:104 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprises LC-CDR1, LC-CDR2 and LC-CDR3; (xxvi) V H Comprising V as shown in amino acid sequence SEQ ID NO:105 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxvii) V H Comprising a V as shown in the amino acid sequence SEQ ID NO 106 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxviii) V H Comprising a V as shown in the amino acid sequence SEQ ID NO:107 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (xxix) V H Comprising V as shown in the amino acid sequence SEQ ID NO:108 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; or (xxx) V H Comprising V as shown in the amino acid sequence SEQ ID NO:109 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: (i) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 38, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (ii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (iii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 7, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (iv) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 8, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 40, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence63, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (v) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 64, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (vi) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 10 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 41, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (vii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 11 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 55, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (viii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (ix) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 13 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 49, LC-CDR2 comprising the amino acid sequence SEQ ID NO 57, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (x) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 14, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 50, LC-CDR2 comprising the amino acid sequence SEQ ID NO 58, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 66, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xi) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 15 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Variants of (5), LC thereof-substitutions in the CDRs comprising up to about 5 amino acids; (xii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 16, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xiii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 17, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xiv) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xv) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 19, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H Comprises up to about 5 of the HC-CDRsSubstitution of amino acids; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xvi) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 42, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xvii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 43, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xviii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 44, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;(xix)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xx) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xxi) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 22 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xxii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 23, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L The above-mentionedV L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xxiii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 24 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xxiv) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 25 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xxv) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xxvi) V H Said V is H Comprises the following steps:HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xxvii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xxviii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 29 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (xxix) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 30 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprisingAmino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; or (xxx) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 31, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the isolated anti-C5 a antibody as described above, the isolated anti-C5 a antibody comprising: v H (ii) comprising an amino acid sequence set forth in any one of SEQ ID NOs:80-109, or a variant thereof having at least about 90% sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 80-109; and V L Comprising an amino acid sequence set forth in any one of SEQ ID NOs:118-124 or a variant thereof having at least about 90% sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 118-124.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: (i) V H Comprising the amino acid sequence of SEQ ID NO:80 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 80; and V L Comprising the amino acid sequence of SEQ ID No. 118 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 118; (ii) V H (ii) comprising the amino acid sequence of SEQ ID NO:81 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 81; and V L Comprising the amino acid sequence SEQ ID NO 118 or a variant thereof having at least about 90% sequence to the amino acid sequence SEQ ID NO 118Identity; (iii) V H Comprising the amino acid sequence of SEQ ID No. 82 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 82; and V L Comprising the amino acid sequence of SEQ ID NO. 118 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 118; (iv) V H (ii) comprising the amino acid sequence of SEQ ID NO:83 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 83; and V L Comprising the amino acid sequence of SEQ ID NO 119 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 119; (v) V H Comprising the amino acid sequence of SEQ ID NO:84 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 84; and V L Comprising the amino acid sequence of SEQ ID No. 120 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 120; (vi) V H Comprising the amino acid sequence of SEQ ID NO. 85 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 85; and V L Comprising the amino acid sequence of SEQ ID NO. 118 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 118; (vii) V H (ii) comprising the amino acid sequence of SEQ ID NO:86 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 86; and V L Comprising the amino acid sequence of SEQ ID NO. 121 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 121; (viii) V H Comprising the amino acid sequence of SEQ ID No. 87 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 87; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (ix) V H Comprising the amino acid sequence of SEQ ID NO:88 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 88; and V L Comprising an amino acid sequence123 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 123; (x) V H Comprising the amino acid sequence of SEQ ID NO. 89 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 89; and V L Comprising the amino acid sequence of SEQ ID NO:124 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 124; (xi) V H Comprising the amino acid sequence of SEQ ID NO:90 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 90; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xii) V H Comprising the amino acid sequence of SEQ ID No. 91 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 91; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xiii) V H Comprising the amino acid sequence of SEQ ID No. 92 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 92; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xiv) V H Comprising the amino acid sequence of SEQ ID NO:93 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 93; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xv) V H Comprising the amino acid sequence SEQ ID NO 94 or a variant thereof having at least about 90% sequence identity to the amino acid sequence SEQ ID NO 94; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xvi) V H Comprising the amino acid sequence SEQ ID NO 95 or a variant thereof, said variant and amino acid sequence95 has at least about 90% sequence identity; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xvii) V H Comprising the amino acid sequence of SEQ ID NO:96 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 96; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xviii) V H Comprising the amino acid sequence of SEQ ID No. 97 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 97; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xix) V H Comprising the amino acid sequence of SEQ ID No. 98 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 98; and V L 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122; (xx) V H Comprising the amino acid sequence of SEQ ID NO 99 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 99; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xxi) V H Comprising the amino acid sequence of SEQ ID No. 100 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 100; and V L 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122; (xxii) V H (ii) comprising the amino acid sequence of SEQ ID No. 101 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 101; and V L Comprising the amino acid sequence SEQ ID NO. 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence SEQ ID NO. 122Sex; (xxiii) V H Comprising the amino acid sequence of SEQ ID No. 102 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 102; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xxiv) V H 103 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 103; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xxv) V H Comprising the amino acid sequence of SEQ ID No. 104 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 104; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xxvi) V H Comprising the amino acid sequence of SEQ ID No. 105 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 105; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xxvii) V H 106 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 106; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; (xxviii) V H Comprising the amino acid sequence of SEQ ID No. 107 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 107; and V L 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122; (xxix) V H Comprising the amino acid sequence of SEQ ID No. 108 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 108; and V L Therein is disclosedComprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; or (xxx) V H Comprising the amino acid sequence of SEQ ID No. 109 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 109; and V L Comprising the amino acid sequence of SEQ ID No. 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122.
In some embodiments, an isolated anti-C5 a antibody is provided comprising a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising ELSMH (SEQ ID NO: 3); HC-CDR2 comprising GFDPX 1 X 2 GETAYAQKFQG (SEQ ID NO: 72), where X 1 Is E or R, X 2 Is D or L; and HC-CDR3 comprising GISX 1 X 2 WNDAFDI (SEQ ID NO: 75), where X 1 Is D or S, X 2 Is G, I or W; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASQSVRNDLA (SEQ ID NO: 51); LC-CDR2 comprising DASDRAT (SEQ ID NO: 59); and LC-CDR3 comprising QQYMDSHPLT (SEQ ID NO: 67).
In some embodiments, an isolated anti-C5 a antibody is provided comprising V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 3 or a variant thereof comprising up to about 3 amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:32-34 or a variant thereof comprising up to about 3 amino acid substitutions; and HC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:38-39 and 42, or a variant thereof comprising substitutions of up to about 3 amino acids; and V L Said V is L Comprises the following steps: an LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 51 or a variant thereof comprising up to about 3 amino acid substitutions; an LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 59 or a variant thereof comprising up to about 3 amino acid substitutions; and LC-CDR3 comprising SEQ ID NO 6 7 or a variant thereof, said variant comprising substitutions of up to about 3 amino acids.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: v H Said V is H Comprising a V as set forth in any one of the amino acid sequences of SEQ ID NOs:110-114 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3, and V L Said V is L Comprising V as shown in amino acid sequence SEQ ID NO 125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: (i) V H Comprising V as shown in the amino acid sequence SEQ ID NO. 110 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (ii) V H Comprising V as shown in amino acid sequence SEQ ID NO:111 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (iii) V H Comprising a V as shown in the amino acid sequence SEQ ID NO:112 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (iv) V H Comprising V as shown in amino acid sequence SEQ ID NO 113 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; or (V) V H Comprising a V as shown in the amino acid sequence SEQ ID NO:114 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: (i) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequenceSEQ ID NO 32 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 38, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (ii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (iii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 33, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (iv) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 34, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; or (V) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 42, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the isolated anti-C5 a antibody as described above, the isolated anti-C5 a antibody comprising: v H Comprising an amino acid sequence set forth in any one of SEQ ID NOs:110-114, or a variant thereof having at least about 90% sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 110-114; and V L Comprising the amino acid sequence set forth in SEQ ID NO:125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 125.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: (i) V H Comprising the amino acid sequence of SEQ ID NO. 110 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 110; and V L 125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 125; (ii) V H Comprising the amino acid sequence of SEQ ID No. 111 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 111; and V L 125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 125; (iii) V H 112 or a variant thereof, said variant and amino acid112 has at least about 90% sequence identity; and V L 125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 125; (iv) V H (ii) comprising the amino acid sequence of SEQ ID No. 113 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 113; and V L Comprising the amino acid sequence of SEQ ID No. 125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 125; or (V) V H Comprising the amino acid sequence SEQ ID NO:114 or a variant thereof having at least about 90% sequence identity to the amino acid sequence SEQ ID NO: 114; and V L Comprising the amino acid sequence of SEQ ID No. 125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 125.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: v H Comprising V as shown in amino acid sequence SEQ ID NO:115 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:126 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO 35, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 45, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 52, LC-CDR2 comprising the amino acid sequence SEQ ID NO 60, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 68, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the isolated anti-C5 a antibody as described above, the isolated anti-C5 a antibody comprising: v H Comprising the sequence shown in SEQ ID NO. 115Or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID No. 115; and V L Comprising the amino acid sequence set forth in SEQ ID NO:126 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 126.
In some embodiments, an isolated anti-C5 a antibody is provided comprising a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: heavy chain complementarity determining region (HC-CDR) 1 comprising NYAIN (SEQ ID NO: 5); HC-CDR2 comprising GIX 1 PFFGX 2 EDYAQKFQG (SEQ ID NO: 73), where X 1 Is V or Y, X 2 Is T or W; and HC-CDR3 comprising DLLX 1 GFDI (SEQ ID NO: 76), wherein X 1 Is E or H; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASHIDIETWLA (SEQ ID NO: 53); LC-CDR2 comprising GASNLQS (SEQ ID NO: 61); and LC-CDR3, which contains QQANNELPYT (SEQ ID NO: 69).
In some embodiments, an isolated anti-C5 a antibody is provided comprising V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 5 or a variant thereof comprising up to about 3 amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:36-37 or a variant thereof comprising up to about 3 amino acid substitutions; and HC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:46-47, or a variant thereof comprising substitutions of up to about 3 amino acids; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 53 or a variant thereof comprising up to about 3 amino acid substitutions; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 61 or a variant thereof comprising up to about 3 amino acid substitutions; and an LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:69 or a variant thereof comprising up to about 3 amino acid substitutions.
In some embodiments, there is provided an isolated anti-C5 a antibody, comprisingComprises the following components: v H Said V is H Comprising a V as shown in any one of SEQ ID NOs:116-117 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3, and V L Said V is L Comprising V as shown in amino acid sequence SEQ ID NO:127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: (i) V H Comprising V as shown in the amino acid sequence SEQ ID NO:116 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in amino acid sequence SEQ ID NO:127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3; (ii) V H Comprising V as shown in amino acid sequence SEQ ID NO:117 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in amino acid sequence SEQ ID NO:127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: (i) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 36 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 46, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 69, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; (ii) V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 37, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 47, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:69, or the V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the isolated anti-C5 a antibody as described above, the isolated anti-C5 a antibody comprising: v H (ii) comprising the amino acid sequence set forth in any one of SEQ ID NOs:116-117 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 116-117; and V L Comprising the amino acid sequence set forth in SEQ ID NO:127 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 127.
In some embodiments, there is provided an isolated anti-C5 a antibody comprising: (i) V H Comprising the amino acid sequence of SEQ ID No. 116 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 116; and V L Comprising the amino acid sequence of SEQ ID No. 127 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 127; (ii) V H Comprising the amino acid sequence SEQ ID NO:117 or a variant thereof having at least about 90% sequence identity to the amino acid sequence SEQ ID NO: 117; and V L Comprising the amino acid sequence of SEQ ID No. 127 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 127.
In some embodiments, the Kd value for binding of an isolated anti-C5 a antibody to human C5a is from 0.1pM to 1nM.
In some embodiments, an isolated anti-C5 a antibody is provided that competitively binds C5a with any of the isolated anti-C5 a antibodies described above. In some embodiments, an isolated anti-C5 a antibody is provided that specifically binds to the same epitope as any one of the isolated anti-C5 a antibodies described above.
In some embodiments, the isolated anti-C5 a antibody as described above, wherein the isolated anti-C5 a antibody comprises an Fc fragment. In some embodiments, the isolated anti-C5 a antibody is a full-length IgG antibody. In some embodiments, the isolated anti-C5 a antibody is a full-length IgG1,An IgG2, igG3, or IgG4 antibody. In some embodiments, the isolated anti-C5 a antibody is chimeric, fully human, or humanized. In some embodiments, the isolated anti-C5 a antibody is an antigen binding fragment selected from Fab, fab ', F (ab)' 2 Fab' -SH, single chain antibodies (scFv), fv fragments, dAbs, fd, nanobodies (nanobodies), diabodies (diabodies) and linear antibodies.
In some embodiments, there is provided an isolated nucleic acid molecule encoding any one of the anti-C5 a antibodies described above. In some embodiments, there is provided a vector comprising any one of the nucleic acid molecules described above. In some embodiments, there is provided a host cell comprising any one of the anti-C5 a antibodies described above, any one of the nucleic acid molecules described above, or any one of the vectors described above. In some embodiments, there is provided a method of making an anti-C5 a antibody, comprising: a) Culturing any one of the above host cells under conditions effective to express the anti-C5 a antibody; and b) obtaining the expressed anti-C5 a antibody from the host cell.
In some embodiments, there is provided a method of treating a disease or disorder in an individual in need thereof, comprising administering to the individual an effective amount of any one of the anti-C5 a antibodies described above. In some embodiments, there is provided the use of any one of the anti-C5 a antibodies described above in the manufacture of a pharmaceutical composition for treating a disease or disorder in a subject in need thereof. In some embodiments, there is provided the use of any one of the anti-C5 a antibodies described above, or a pharmaceutical composition comprising an anti-C5 a antibody, in the manufacture of a medicament for the treatment of a disease or disorder. In some embodiments, the disease or disorder is associated with the C5a signaling pathway, including autoimmune diseases, inflammation, cancer, pain, respiratory and/or transplantation-related diseases or disorders. In some embodiments, the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion-related injury, acute lung injury, pneumonia, acute and chronic transplant rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, solid renal failure, rheumatoid arthritis, autoimmune disease, bechterew's disease, lupus-like diseases, inflammatory bowel disease, crohn's disease, tumor growth, and solid organ cancer.
Also provided are pharmaceutical compositions, kits and articles of manufacture comprising any of the anti-C5 a antibodies described above.
Drawings
The results shown in FIGS. 1A-1G are the binding affinities of an exemplary full-length anti-C5 a antibody (reconstituted into the human IgG4 format) to human recombinant C5a as analyzed by ELISA.
The results shown in FIGS. 2A-2B are analyzed by ELISA for the binding affinity of the full-length anti-C5 a antibody H1701, H1712, 1714, H4 or H401 (reconstituted adult IgG4 format) to cynomolgus monkey C5 a. The results shown in fig. 2C-2E are the binding affinities of an exemplary full-length anti-C5 a antibody to human native C5 analyzed by ELISA. The results shown in figure 2C are binding curves of the full-length anti-C5 a antibody H1701, H1712, 1714 (reconstituted to the adult IgG4 format) or the control antibody INab308 with human native C5. The results are shown in FIG. 2D as binding curves for H3 (reconstituted human IgG4 format) or the control antibody INab308 to human native C5. The results shown in FIG. 2E are binding curves of the full-length anti-C5 a antibodies H4, H401 (reconstituted into an adult IgG4 format) or the control antibody INab308 with human native C5. The results shown in FIGS. 2F-2G are the binding affinities of exemplary full-length anti-C5 a antibodies to recombinant C5a-des Arg analyzed by ELISA.
The results shown in fig. 3 are the binding specificities of the optimized anti-C5 a antibodies H106, H107, H108, H109, H1712 or H1714 (reconstituted human IgG4 format) to BV particles.
FIGS. 4A-4G show results of optimized full-length anti-C5 a antibodies H101-H114, H1701-H1715, H201-H204, H401, and the parent C5a antibody H1-H4 (reconstituted adult IgG4 form) inhibiting the release of Reactive Oxygen Species (ROS) in a ROS release assay.
Fig. 5 shows the results of calcium influx experiments, which indicate that the optimized full-length anti-C5 a antibodies H101, H103, H104, H105, H106, H1701, or H1712 (reconstituted to the adult IgG4 form) can block the binding of C5a to its receptor C5aR 1.
Fig. 6 shows the results of migration chemotaxis experiments, which indicate that the optimized full-length anti-C5 a antibodies H101, H103, H105, H107, H108, H1701 and H1712 (reconstituted to adult IgG4 form) can significantly block chemotaxis induced by C5a with better effect than the control antibody INab308.
Fig. 7A-7B show the results of CD11B blocking experiments, which indicate that optimized anti-C5 a antibodies H101, H107, H1701, H1712, and H1714 (reconstituted adult IgG4 format) can block CD11B upregulation induced by human recombinant C5a (fig. 7A) or endogenous C5a (fig. 7B) in human neutrophils. Figure 7C shows the results of CD11b blocking experiments, which indicate that the optimized anti-C5 a antibodies H1702, H1703, H1706, H1710, H201, H202 (reconstituted adult IgG4 format) block C5a activity globally in a dose-dependent manner.
The results shown in FIGS. 8A-8D are plasma hemolytic activity of anti-C5 a antibody. In the classical activation pathway, anti-C5 a antibodies H106, H108, H111, H112, H113, H114 (reconstituted adult IgG4 form) (fig. 8A) or anti-C5 a antibodies H1701, H1712, H1714, H4, H401 (reconstituted adult IgG4 form) (fig. 8B) did not inhibit plasma hemolytic activity compared to the control antibody Eculizumab. In the bypass activation pathway, anti-C5 a antibodies H101, H103, H105, H1701, H1702 (reconstituted adult IgG4 form) (fig. 8C) or anti-C5 a antibodies H106, H107, H108, H109, H110, H111, H112, H113, H114, H1701, H1706, H1710, H1712, H1714 (reconstituted adult IgG4 form) (fig. 8D) did not inhibit plasma hemolytic activity compared to the control antibody Eculizumab.
FIG. 9 shows the results of the inhibition of the optimized anti-C5 a antibodies H101 or H1712 (reconstituted to the human IgG4 format) in the C5 a-induced chemotaxis assay in mouse neutrophils.
FIGS. 10A-10B show the results of pharmacokinetic analysis in rats. The half-life of the anti-C5 a antibodies H1701, H1712, H1714 (reconstituted adult IgG4 form) in rats after subcutaneous injection (fig. 10A) or intravenous injection (fig. 10B) was measured by ELISA.
Detailed description of the present application
One aspect of the invention relates to anti-C5 a antibody molecules. Through a combination of natural scFv phage library screening, affinity maturation, and appropriately designed biochemical and biological experiments, we have identified highly potent antibody molecules that are capable of binding to human C5a and inhibiting the action of C5a. In some embodiments, the isolated anti-C5 a antibody or antigen-binding fragment binds to human C5 and C5a. C5a is known to be an essential part of the pathogenesis of complement-associated disorders, including but not limited to sepsis, rheumatoid arthritis, and asthma. Since the concentration of C5 in human serum is much higher than C5a, high concentrations and/or frequent administration of anti-C5 a antibodies are required if the antibodies bind to C5 and C5a with equal binding capacity. The advantage of the antibodies or antigen-binding fragments described herein is that our antibodies bind C5a with an affinity comparable to or better than the control antibody INab308, while binding C5 with an affinity lower than the control antibody INab308, and surprisingly, our antibodies proved even more effective than INab308 in various biological experiments.
anti-C5 a antibodies provided herein include, for example, full-length anti-C5 a antibodies, anti-C5 a single chain antibodies (scFvs), anti-C5 a Fc fusion proteins, multispecific (e.g., bispecific) anti-C5 a antibodies, anti-C5 a immunoconjugates, and the like.
In another aspect, the present application provides anti-C5 a antibodies, wherein the anti-C5 a antibodies comprise a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: heavy chain complementarity determining region (HC-CDR) 1 comprising X 1 LSX 2 H (SEQ ID NO: 70), wherein X 1 Is D or E, X 2 Is I or M; HC-CDR2 comprising GFX 1 PX 2 X 3 GX 4 TIYAQNFQG (SEQ ID NO: 71), wherein X 1 Is A, D, E, G, L, N, P, Q, S, V or Y, X 2 D, E, F, I, L, N, R, S, T or V, X 3 Is A, D, F, I, L, N, Q or S, X 4 Is D, G, T or V; and HC-CDR3 comprising GISX 1 X 2 X 3 NDAFDI (SEQ ID NO: 74), wherein X 1 Is D, E or S, X 2 Is A, G, I, V or W, X 3 Is H or W; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASQSVX 1 SX 2 YLA (SEQ ID NO: 77) wherein X 1 Is K or S, X 2 Is N, R or S; LC-CDR2Which comprises DASX 1 RX 2 T (SEQ ID NO: 78), wherein X 1 Is A, D, E or S, X 2 Is A, D or S; and LC-CDR3 comprising QQYYYX 1 X 2 PX 3 T (SEQ ID NO: 79), wherein X 1 Is A, D or I, X 2 Is L, P or S, X 3 Is I, L or T.
In another aspect, the present application provides anti-C5 a antibodies, wherein the anti-C5 a antibodies comprise a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: heavy chain complementarity determining region (HC-CDR) 1 comprising ELSMH (SEQ ID NO: 3); HC-CDR2 comprising GFDPX 1 X 2 GETAYAQKFQG (SEQ ID NO: 72), where X 1 Is E or R, X 2 Is D or L; and HC-CDR3 comprising GISX 1 X 2 WNDAFDI (SEQ ID NO: 75), where X 1 Is D or S, X 2 Is G, I or W; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASQSVRNDLA (SEQ ID NO: 51); LC-CDR2 comprising DASDRAT (SEQ ID NO: 59); and LC-CDR3 comprising QQYMDSHPLT (SEQ ID NO: 67).
In another aspect, the present application provides an anti-C5 a antibody, wherein the anti-C5 a antibody comprises: heavy chain variable domain (V) H ) Said V is H Comprises the following steps: heavy chain complementarity determining region (HC-CDR) 1 comprising SYWIG (SEQ ID NO: 4); HC-CDR2 comprising IIYPGDSDTRYSPSFQG (SEQ ID NO: 35); and HC-CDR3 comprising RAYGPVSSVAFDI (SEQ ID NO: 45); and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementary determining region (LC-CDR) 1 comprising RASQGIRNDLG (SEQ ID NO: 52); LC-CDR2 comprising AASSLQS (SEQ ID NO: 60); and LC-CDR3 comprising LQDYYPLT (SEQ ID NO: 68).
In another aspect, the present application provides anti-C5 a antibodies, wherein the anti-C5 a antibodies comprise a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: heavy chain complementarity determining region (HC-CDR) 1 comprising NYAIN (SEQ ID NO: 5); HC-CDR2 comprising GIX 1 PFFGX 2 EDYAQKFQG (SEQ ID NO: 73), where X 1 Is V or Y, X 2 Is T or W; and HC-CDR3 comprising DLLX 1 GFDI (SEQ ID NO: 76), wherein X 1 Is E or H; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASHIDIETWLA (SEQ ID NO: 53); LC-CDR2 comprising GASNLQS (SEQ ID NO: 61); and LC-CDR3, which contains QQANNELPYT (SEQ ID NO: 69).
Also provided are nucleic acids encoding anti-C5 a antibodies, compositions comprising anti-C5 a antibodies, and methods of making and using anti-C5 a antibodies.
Definition of
As used herein, "treatment" or "treating" is a method of achieving a beneficial or desired result, including a clinical result. For the purposes of this application, the beneficial or desired clinical results include, but are not limited to, one or more of the following: relieving one or more symptoms caused by the disease, lessening the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease (e.g., metastasis), preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, relieving the disease (partially or completely), reducing the dose of one or more other drugs required to treat the disease, delaying the progression of the disease, improving or enhancing the quality of life, increasing body weight, and/or prolonging survival. Also, "treatment" includes a reduction in the pathological consequences of the disease (e.g., tumor volume in the case of cancer). The methods of the present application contemplate any one or more aspects of these treatments.
The term "antibody" includes full-length antibodies and antigen-binding fragments thereof. Full-length antibodies comprise two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable regions in both chains typically comprise 3 hypervariable loops, referred to as Complementarity Determining Regions (CDRs) (the Light Chain (LC) CDRs comprise LC-CDR1, LC-CDR2 and LC-CDR3, and the Heavy Chain (HC) CDRs comprise HC-CDR1, HC-CDR2 and HC-CDR 3). The CDR boundaries of the antibodies or antigen-binding fragments disclosed herein can be defined or identified by the convention Kabat, chothia or Al-Lazikani (Al-Lazikani 1997, chothia 1985. The 3 CDR regions of the heavy or light chain are inserted between flanking segments called Framework Regions (FRs) which are more conserved than the CDR regions and form a scaffold supporting hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit multiple effector functions. Antibodies are classified based on the amino acid sequence of their heavy chain constant region. The five major classes or isotypes of antibodies are IgA, igD, igE, igG and IgM, which are characterized by heavy chains of the alpha, delta, epsilon, gamma and mu type, respectively. Several major antibody classes are divided into subclasses, such as IgG1 (γ 1 heavy chain), igG2 (γ 2 heavy chain), igG3 (γ 3 heavy chain), igG4 (γ 4 heavy chain), igA1 (α 1 heavy chain), or IgA2 (α 2 heavy chain).
As used herein, the term "antigen-binding fragment" includes antibody fragments, e.g., diabodies (diabodies), fab ', F (ab') 2 Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv) 2 Bispecific dsFv (dsFv-dsFv'), disulfide stabilized diabodies (ds diabodies), single chain antibodies (scFv), scFv dimers (diabodies), multispecific antibodies consisting of antibody fragments comprising one or more CDRs, single domain antibodies, nanobodies (nanobodies), domain antibodies, bivalent domain antibodies, or any other antibody fragment capable of binding to an antigen but which does not comprise a complete antibody structure. The antigen binding fragment is capable of binding the same antigen as the parent antibody or parent antibody fragment (e.g., parent scFv). In some embodiments, an antigen-binding fragment may include one or more CDRs from a particular human antibody grafted into a framework region from one or more different human antibodies.
As used herein, the term "epitope" refers to a particular group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. Two antibodies or antibody portions may bind to the same epitope on an antigen if they exhibit competitive binding to the antigen.
As used herein, a first antibody "competes" with a second antibody for binding to a C5a target when the first antibody inhibits binding of the second antibody to the C5a target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) at equimolar concentrations, and vice versa. PCT publication WO 03/48731 describes a cross-competition based method of high-throughput antibody "epitope categorization".
As used herein, the terms "specifically binds," specifically recognizes, "or" specific for.. Refer to a measurable and reproducible interaction, e.g., binding of an antibody to a target can determine the presence of the target in a heterogeneous population of molecules, including biomolecules. For example, an antibody that is capable of specifically recognizing a target (which may be an epitope) means that the antibody binds to the target with higher affinity, avidity, more readily, and/or more permanently than to other targets. In some embodiments, an antibody that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen with a binding affinity that is at least 10-fold greater than its binding affinity to other targets.
As used herein, an "isolated" anti-C5 a antibody refers to an anti-C5 a antibody that (1) is unrelated to naturally occurring proteins, (2) does not contain other proteins of the same origin, (3) is expressed by a cell of a different species, or (4) does not occur in nature.
The term "isolated nucleic acid," as described herein, refers to nucleic acid of genomic, cDNA, or synthetic origin, or a combination thereof. Depending on its source, the "isolated nucleic acid" means (1) unrelated to all or part of a polynucleotide in the "isolated nucleic acid" found in nature, (2) operably linked to a polynucleotide to which it is not naturally associated, or (3) not occurring in nature as part of a longer sequence.
As used herein, the term "CDR" or "complementarity determining region" means a non-continuous antigen binding site found within the variable domains of heavy and light chain polypeptides. In the literature Kabat et al, J.biol.chem.252:6609-6616 (1977); kabat et al, u.s.dept.of Health and Human Services, "Sequences of proteins of immunological interest" (1991); chothia et al, J.mol.biol.196:901-917 (1987); al-Lazikani b.et Al, j.mol.biol., 273; macCallum et al, J.mol.biol.262:732-745 (1996); abhinandan and Martin, mol.immunol., 45; lefranc m.p.et al, dev.comp.immunol., 27; and honeyger and Pl ü ckthun, j. Mol. Biol.,309, 657-670 (2001), wherein these definitions include the coincidence or subset of amino acid residues when compared to one another. However, any manner of definition to refer to the CDRs of an antibody or grafted antibody or variant thereof is intended to be included within the scope of the terms as defined and used herein. The positions of the amino acid residues comprised by the CDRs defined by the various references cited above are listed in table 1 for comparison. Algorithms and binding interfaces for CDR prediction are known in the art, including, for example, abhindandan and Martin, mol.immunol., 45; ehrenmann f.et al, nucleic Acids res, 38; and Adolf-Bryfogle J.et al, nucleic Acids Res.,43, D432-D438 (2015). The contents of the references cited in this paragraph are incorporated herein by reference in their entirety for purposes of this application and for possible inclusion in one or more claims herein.
Table 1 cdr definitions
Kabat 1 Chothia 2 MacCallum 3 IMGT 4 AHo 5
V H CDR1 31-35 26-32 30-35 27-38 25-40
V H CDR2 50-65 53-55 47-58 56-65 58-77
V H CDR3 95-102 96-101 93-101 105-117 109-137
V L CDR1 24-34 26-32 30-36 27-38 25-40
V L CDR2 50-56 50-52 46-55 56-65 58-77
V L CDR3 89-97 91-96 89-96 105-117 109-137
1 Numbering of amino acid residues is by reference to the nomenclature in Kabat et al, supra
2 Amino acid residue numbering reference the nomenclature used in Chothia et al, supra
3 Amino acid residue numbering is referred to the nomenclature in MacCallum et al, supra
4 Amino acid residue numbering reference to the nomenclature given in Lefranc et al, supra
5 Amino acid residue numbering is done by reference to the nomenclature in Honegger and Pluckthun, supra
The term "chimeric antibody" refers to an antibody in which a portion of the heavy and/or light chain is identical or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they have the biological activity of the present application (see U.S. patent No.4,816,567; and Morrison et al, proc. Natl. Acad. Sci. Usa, 81.
"Fv" is the smallest antibody fragment that contains the entire antigen recognition and binding site. The fragment is a dimer formed by the tight non-covalent linkage of a heavy chain variable domain and a light chain variable domain. By folding of these two domains 6 hypervariable loops (3 loops each in the light and heavy chains) are derived which provide the antibody with amino acid residues for binding to the antigen and confer the antibody with specificity for antigen binding. However, even a single variable domain (or half of an Fv fragment, which contains only 3 CDRs specific for an antigen) has the ability to recognize and bind antigen, although with a lower affinity than the entire binding site.
' Single chainFv ", which may also be abbreviated as" sFv "or" scFv ", is a polypeptide comprising V connected as a single polypeptide chain H And V L An antibody fragment of an antibody domain. In some embodiments, the scFv polypeptide further comprises V H And V L A linker polypeptide between the domains that allows the scFv to form the desired structure for antigen binding. For a summary of scFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol.113, rosenburg and Moore eds, springer-Verlag, new York, pp.269-315 (1994).
The term "diabodies" is used in V H And V L Small antibody fragments prepared from scFv fragments (see above) are constructed using short linkers (e.g.residues 5-10) between the domains, so that the variable domains pair between the chains rather than within the chains, resulting in a bivalent fragment, i.e.a fragment with two antigen binding sites. Bispecific diabodies are heterodimers of two "cross" scFv fragments, where the V of both antibodies H And V L Domains are located on different polypeptide chains. In EP 404,097; WO93/11161; diabodies are fully described in Hollinger et al, proc.Natl.Acad.Sci.USA, 90.
"humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies, which comprise minimal sequence derived from the non-human antibody. In most cases, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (HVR) of the recipient antibody are replaced by residues from a hypervariable region of a non-human species, such as mouse, rat, rabbit or non-human mammal, which residues have the desired antibody specificity, affinity and performance (donor antibody). In some cases, residues in the framework regions of an immunoglobulin of human origin are replaced by corresponding residues that are not human. In addition, humanized antibodies may include residues that are not present in either the recipient antibody or the donor antibody. These modifications can further improve the performance of the antibody. Typically, a humanized antibody will comprise substantially all, at least one, and typically two variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are human immunoglobulin sequences. The human antibody optionally also includes at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For specific details, reference may be made to Jones et al, nature 321; riechmann et al, nature 332; and Presta, curr, op, structure, biol.2:593-596 (1992).
The "percent (%) amino acid sequence identity" or "homology" of the polypeptide and antibody sequences identified herein is defined as: sequence alignments are performed with conservative substitutions considered as part of the sequence identity, the percentage of identical amino acid residues in the candidate sequence and the polypeptide sequence to be compared. Percent amino acid sequence identity can be determined by a variety of alignment means within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, megalign (DNASTAR), or MUSCLE software. One skilled in the art can determine suitable parameters for measuring alignment, including any algorithms required to achieve maximum alignment over the full length of the sequences being compared. For purposes herein, however, percent amino acid sequence identity values are generated using the sequence alignment computer program MUSCLE (Edgar, R.C., nucleic Acids Research 32 (5): 1792-1797,2004 Edgar, R.C., BMC Bioinformatics 5 (1): 113, 2004).
The term "Fc receptor" or "FcR" is used to describe a receptor that binds the Fc region of an antibody. In some embodiments, an FcR described herein is an FcR that binds an IgG antibody (a gamma receptor), including receptors of the Fc γ RI, fc γ RII, and Fc γ RIII subclasses, including allelic variants and alternatively spliced forms of these receptors. Fc γ RII receptors include Fc γ RIIA ("activating receptor") and Fc γ RIIB ("inhibiting receptor"), which have similar amino acid sequences, differing primarily in the cytoplasmic domain. The activating receptor Fc γ RIIA contains an Immunoreceptor Tyrosine Activation Motif (ITAM) in the cytoplasmic domain. The inhibitory receptor Fc γ RIIB contains an Immunoreceptor Tyrosine Inhibitory Motif (ITIM) in the cytoplasmic domain (see m.in)
Figure SMS_1
Annu. Rev. Immunol.15:203-234 (1997)). The termAlso included are allotypes, such as the Fc γ RIIIA allotype: fc gamma RIIIA-Phe158, fc gamma RIIIA-Val158, fc gamma RIIA-R131 and/or Fc gamma RIIA-H131. In ravech and Kinet, annu.rev.immunol.9 (1991) and Capel et al, immunology 4-34 (1994); and de Haas et al, J.Lab.Clin.Med.126:330-41 (1995). The term FcR in this application encompasses other types of FcRs, including those identified in the future. The term FcR also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgGs to the neonate (Guyer et al, j. Immunol.117:587 (1976) and Kim et al, j. Immunol.24:249 (1994)).
The term "FcRn" refers to the neonatal Fc receptor (FcRn). FcRn is structurally similar to the Major Histocompatibility Complex (MHC), and consists of an alpha chain non-covalently bound to beta 2 microglobulin. The multiple functions of the neonatal Fc receptor FcRn are reviewed in Ghetie and Ward (2000) Annu.Rev.Immunol.18,739-766. FcRn plays an important role in the passive transport of immunoglobulin IgGs from mother to newborn and in the regulation of serum IgG levels. FcRn, a salvage receptor, can bind and transport endocytosed IgG in an intact form both intracellularly and intercellularly and protect them from the default degradation pathways.
The "CH1 domain" of the human IgG Fc region typically extends from amino acid 118 to amino acid 215 (EU numbering system).
A "hinge region" is generally defined as extending from Glu at position 216 to Pro at position 230 of human IgG1 (Burton, mol. Immunol.22:161-206 (1985)). The hinge region of other IgG isotypes can be aligned to the IgG1 sequence by placing the first and last cysteine residues that form the inter-heavy chain disulfide bond in place of IgG 1.
The "CH2 domain" of the human IgG Fc region typically extends from amino acid 231 to amino acid 340. The CH2 domain is unique in that it does not pair tightly with another region, but rather inserts two N-terminally attached branched sugar chains between the two CH2 domains of the intact native IgG molecule. It is speculated that carbohydrates may help to keep the CH2 domain stable as a replacement for the pairing of domains with interdomains. Burton, mol. Immunol.22:161-206 (1985).
The "CH3" domain includes domains extending from the C-terminal residue to the CH2 domain (from amino acid 341 to the C-terminus of the antibody sequence, typically amino acid residues 446 or 447 of IgG) within the Fc region.
A "functional Fc fragment" has the "effector functions" possessed by the native Fc region sequences. Exemplary "effector functions" include C1q binding; complement Dependent Cytotoxicity (CDC); fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor; BCR), and the like. Such effector functions typically require binding of the Fc region to a binding domain (e.g., an antibody variable region) and can be assessed using a variety of experimental methods well known in the art.
An antibody having an IgG Fc variant with "altered" FcR binding affinity or ADCC activity which has increased or decreased FcR binding activity and/or ADCC activity as compared to the parent polypeptide or a polypeptide comprising a native Fc sequence. Fc variants exhibiting "enhanced binding" to an FcR have a higher binding affinity (e.g., lower apparent Kd or IC) to at least one FcR as compared to the parent polypeptide or polypeptide comprising a native IgG Fc sequence 50 Value). In some embodiments, the binding capacity is enhanced by 3 fold, e.g., 5, 10, 25, 50, 60, 100, 150, 200, even up to 500 fold or an increase in binding capacity of 25% to 1000% compared to the parent polypeptide. Fc variants exhibiting "reduced binding" to an FcR, having lower affinity (e.g., higher apparent Kd or IC) for at least one FcR than the parent polypeptide 50 Value). The binding capacity is reduced by 40% or more compared to the parent polypeptide.
"antibody-dependent cell-mediated cytotoxicity" or "ADCC" is a form of cytotoxicity in which secreted Ig binds Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural Killer (NK) cells, neutrophils, and macrophages) enabling these cytotoxic effector cells to specifically bind antigen-bearing target cells, followed by the use of cytotoxins to kill the target cells. The antibody "arms" the cytotoxic cells and is necessary for such killing. Among the major cell types mediating ADCC, NK cells express only Fc γ RIII, whereas monocytes express Fc γ RI, fc γ RII and Fc γ RIII. FcR expression on hematopoietic cells is summarized in Table 3 at page 464 of ravatch and Kinet, annu. ADCC activity of a molecule of interest can be assessed by performing in vitro ADCC assays as described in U.S. patent No.5,500,362 or 5,821,337. Effector cells suitable for such experiments include Peripheral Blood Mononuclear Cells (PBMC) and natural killer cells (NK). Alternatively, or in addition, ADCC activity of the target molecule may also be assessed in vivo, for example as described in animal models as disclosed in Clynes et al pnas (USA) 95.
A polypeptide comprising a variant Fc region that when tested in substantially the same amount as a polypeptide comprising a wild-type IgG Fc polypeptide (or parent polypeptide) is capable of more effectively mediating ADCC in vitro or in vivo, exhibits "enhanced ADCC activity" or is capable of more effectively mediating ADCC effects in the presence of human effector cells as compared to a polypeptide comprising a wild-type IgG Fc polypeptide or parent polypeptide. Such variants are typically identified using any in vitro ADCC assay known in the art, e.g. assays or methods for identifying ADCC activity, e.g. in animal models etc. In some embodiments, such variants have an increase in the efficiency of mediating ADCC of 5-fold to 100-fold, e.g., 25-fold to 50-fold, as compared to the wild-type Fc (or parent polypeptide).
"complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the association of the first component of the complement system (C1 q) with antibodies (of a suitable structural subclass) that bind to the cognate antigen. To assess complement activation, CDC experiments can be performed as described in Gazzano-Santoro et al, j.immunol.methods 202 (1996). Polypeptide variants having altered Fc region amino acid sequences and increased or decreased C1q binding ability are described in U.S. Pat. No.6,194,551b1 and WO 99/51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogene et al.J.Immunol.164:4178-4184 (2000).
Unless otherwise indicated, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The nucleotide sequence encoding the protein or RNA may also include introns, for example the nucleotide sequence encoding the protein may in some forms include introns.
The term "operably linked" refers to a functional linkage between a regulatory sequence and a heterologous nucleotide sequence, thereby allowing expression of the latter. For example, a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence. For example, a promoter is operably linked to a coding sequence if it affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are contiguous and, where necessary, may join two protein coding regions in the same reading frame.
"homologous" refers to sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. Two DNA molecules are homologous at the same position if the position in the two compared sequences is the same base or amino acid monomer subunit, e.g., adenine in both positions. The percent homology between two sequences is a function of the number of matching or homologous positions in common in both sequences, multiplied by 100. For example, if 6 of 10 positions in two sequences are matched or homologous, the homology between the two sequences is 60%. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. Generally, when aligning two sequences, the comparison is made with the aim of obtaining maximum homology.
An "effective amount" of an anti-C5 a antibody or composition disclosed herein refers to an amount sufficient to achieve a particular purpose. An "effective amount" can be determined empirically and by known methods associated with the stated purpose.
The term "therapeutically effective amount" refers to an amount of an anti-C5 a antibody or composition thereof disclosed herein effective to treat a disease or condition in an individual. In the case of cancer, for example, a therapeutically effective amount of an anti-C5 a antibody or composition thereof refers to an amount that is capable of reducing the number of cancer cells; reducing the size or weight of the tumor; inhibit (i.e., slow or preferably stop to some extent) tumor cell infiltration into peripheral organs; inhibit (i.e., slow or preferably stop to some extent) tumor metastasis; inhibit the growth of tumors to some extent, and/or alleviate one or more symptoms associated with cancer to some extent. The anti-C5 a antibodies or compositions thereof disclosed herein are capable of blocking and/or killing existing tumor cells to some extent, which may be cytostatic or cytotoxic. In some embodiments, a therapeutically effective amount refers to an amount that is capable of extending the survival of a patient. In some embodiments, a therapeutically effective amount refers to an amount that is capable of improving progression-free survival in a patient.
As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" refers to a material that is biologically inactive or otherwise undesirable, e.g., that is capable of being added to a pharmaceutical composition administered to a patient without causing a significant adverse biological response or interacting in a deleterious manner with any of the other components included in the composition. The pharmaceutically acceptable carrier or excipient preferably meets the required standards for toxicological or manufacturing testing and/or is included in the inactive ingredient guidelines as set forth by the U.S. food and drug administration.
Embodiments of the present application described herein should be understood to include embodiments "consisting of 8230; \8230;" consisting of 8230and/or "consisting essentially of 8230; \8230;" consisting of ".
Reference herein to "about" is a value or parameter that includes (and describes) variations that are directed to that value or parameter itself. For example, a description referring to "about X" includes a description of "X".
As used herein, reference to "not" a value or parameter generally means and describes "in addition to" an "value or parameter. For example, the method cannot be used to treat type X cancer, meaning that the method is generally used to treat other types of cancer in addition to type X cancer.
As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
anti-C5 a antibodies
In one aspect, the application provides anti-C5 a antibodies that specifically bind C5a. Such anti-C5 a antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibody molecules comprising heavy and/or light chain CDRs as described herein. In one aspect, the present application provides an isolated antibody that binds to C5a. Contemplated anti-C5 a antibodies include, for example, full-length anti-C5 a antibodies (e.g., full-length IgG1 or IgG 4), anti-C5 a single chain antibodies, anti-C5 a Fc fusion proteins, multispecific (e.g., bispecific) anti-C5 a antibodies, anti-C5 a immunoconjugates, and the like. In some embodiments, the anti-C5 a antibody is a full-length antibody (e.g., full-length IgG1 or IgG 4) or antigen-binding fragment thereof that specifically binds C5a. In some embodiments, the anti-C5 a antibody is Fab, fab ', F (ab)' 2 Fab' -SH, single-chain antibodies (scFv), fv fragments, dAbs, fds, nanobodies (nanobodies), diabodies (diabodies) or linear antibodies. In some embodiments, an antibody that specifically binds C5a means that the antibody binds C5a with at least 10-fold or greater affinity (including, e.g., 10) than the binding affinity to non-target 2 、10 3 、10 4 、10 5 、10 6 Or 10 7 Multiple). In some embodiments, non-target refers to an antigen that is not C5 a. Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence Activated Cell Sorting (FACS) analysis or radioimmunoprecipitation analysis (RIA). Kd values may be determined by methods known in the art, such as Surface Plasmon Resonance (SPR) techniques or biolayer interferometry (BLI).
Although anti-C5 a antibodies comprising human sequences (e.g., human heavy and light chain variable domains comprising human CDR sequences) are discussed extensively herein, non-human anti-C5 a antibodies are also contemplated. In some embodiments, the non-human anti-C5 a antibody comprises the human CDR sequences and non-human framework region sequences of the anti-C5 a antibodies described herein, and in some embodiments, the non-human framework region sequences comprise any sequence useful for producing heavy and/or light chain variable domains using one or more human CDR sequences as described herein, including, for example, mammals, e.g., mice, rats, rabbits, pigs, cattle (e.g., cows, bulls, buffalos), deer, sheep, goats, chickens, cats, dogs, ferrets, primates (e.g., apes, macaques), and the like. In some embodiments, a non-human anti-C5 a antibody comprises an anti-C5 a antibody produced by grafting one or more human CDR sequences described herein into a non-human framework region (e.g., a murine or chicken framework region sequence).
The complete amino acid sequence of exemplary human C5a comprises SEQ ID NO:132 or the amino acid sequence set forth by SEQ ID NO: 132.
In some embodiments, the anti-C5 a antibodies described herein specifically recognize an epitope in human C5 a. In some embodiments, the anti-C5 a antibody cross-reacts with C5a of a species other than human. In some embodiments, the anti-C5 a antibody is fully specific for human C5a and does not cross-react with other non-human species.
In some embodiments, the anti-C5 a antibody cross-reacts with at least one allelic variant of a C5a protein (or fragment thereof). In some embodiments, an allelic variant has up to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, or 30) amino acid substitutions (e.g., conservative substitutions) compared to a naturally occurring C5a protein (or fragment thereof). In some embodiments, the anti-C5 a antibody does not cross-react with any allelic variant of the C5a protein (or fragment thereof).
In some embodiments, the anti-C5 a antibody cross-reacts with at least one interspecific variant of C5a protein. In some embodiments, for example, the C5a protein (or fragment thereof) is human C5a and the inter-species variant of the C5a protein (or fragment thereof) is a variant in cynomolgus monkeys. In some embodiments, the anti-C5 a antibody does not cross-react with any intervarietal variant of C5a protein.
In some embodiments, any of the anti-C5 a antibodies as described herein, the anti-C5 a antibody comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the anti-C5 a antibody comprises an IgG 1-type heavy chain constant region. In some embodiments, the anti-C5 a antibody comprises an IgG 2-type heavy chain constant region. In some embodiments, the anti-C5 a antibody comprises an IgG 3-type heavy chain constant region. In some embodiments, the anti-C5 a antibody comprises an IgG 4-type heavy chain constant region. In some embodiments, the heavy chain constant region comprises (comprises, consists of, or consists essentially of \8230; and/or consists of) the amino acid sequence of SEQ ID NO:128. In some embodiments, the heavy chain constant region comprises (comprises, consists of, or consists essentially of \8230; and/or consists of) the amino acid sequence of SEQ ID NO:129. In some embodiments, the anti-C5 a antibody comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises (consists of or consists essentially of …) the amino acid sequence SEQ ID NO:130. In some embodiments, the anti-C5 a antibody comprises a lambda light chain constant region. In some embodiments, the light chain constant region comprises (comprises, consists of, or consists essentially of \8230; and/or consists of) the amino acid sequence of SEQ ID NO:131. In some embodiments, the anti-C5 a antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.
In some embodiments, the anti-C5 a antibody comprises a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: heavy chain complementarity determining region (HC-CDR) 1 comprising X 1 LSX 2 H (SEQ ID NO: 70), wherein X 1 Is D or E, X 2 Is I or M; HC-CDR2 comprising GFX 1 PX 2 X 3 GX 4 TIYAQNFQG (SEQ ID NO: 71), wherein X 1 Is A, D, E, G, L, N, P, Q, S, V or Y, X 2 D, E, F, I, L, N, R, S, T or V, X 3 Is A, D, F, I, L, N, Q or S, X 4 Is D, G, T or V; and HC-CDR3 comprising GISX 1 X 2 X 3 NDAFDI (SEQ ID NO: 74), wherein X 1 Is D, E or S, X 2 Is A, G, I, V or W, X 3 Is H or W; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASQSVX 1 SX 2 YLA (SEQ ID NO: 77) wherein X 1 Is K or S, X 2 Is N, R or S; LC-CDR2 comprising DASX 1 RX 2 T (SEQ ID NO: 78), wherein X 1 Is A, D, E or S, X 2 Is A, D or S; and LC-CDR3 comprising QQYYYX 1 X 2 PX 3 T (SEQ ID NO: 79), wherein X 1 Is A, D or I, X 2 Is L, P or S, X 3 Is I, L or T.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising an amino acid sequence set forth in any of SEQ ID NOs:1-3, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:6-31 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs:38-44, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence depicted in any one of SEQ ID NOs:1-3, HC-CDR2 comprising the amino acid sequence depicted in any one of SEQ ID NOs:6-31, HC-CDR3 comprising the amino acid sequence depicted in any one of SEQ ID NOs: 38-44.
In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprises the following steps: LC-CDR1 comprising an amino acid sequence set forth in any one of SEQ ID NOs:48-50, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; LC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:54-58 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an LC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs:62-66, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions.
In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs:48-50, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:54-58, LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 62-66.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising an amino acid sequence set forth in any of SEQ ID NOs:1-3, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:6-31 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs:38-44, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and V L Said V is L Comprises the following steps: LC-CDR1 comprising an amino acid sequence set forth in any one of SEQ ID NOs:48-50, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; LC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:54-58 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an LC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs:62-66, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence set forth in any of SEQ ID NOs:1-3, HC-CDR2 comprising the amino acid sequence set forth in any of SEQ ID NOs:6-31, and HC-CDR3 comprising the amino acid sequence set forth in any of SEQ ID NOs: 38-44; and V L Said V is L Comprises the following steps: LC-CDR1 comprising an amino acid sequence set forth in any one of SEQ ID NOs:48-50, LC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:54-58, and LC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs: 62-66.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, HC-CDR3 comprising the amino acid sequence SEQ ID NO 38, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; andV L said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 1, HC-CDR2, comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 38; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO 7, HC-CDR3, which comprises the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 1, HC-CDR2, comprising the amino acid sequence SEQ ID NO 7, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 8, HC-CDR3 comprising the amino acid sequence SEQ ID NO 40, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, LC-CDR3 comprising the amino acid sequence SEQ ID NO 63, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 8, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 40; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3,it comprises the amino acid sequence SEQ ID NO 63.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 9, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, LC-CDR3 comprising the amino acid sequence SEQ ID NO 64, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 1, HC-CDR2, comprising the amino acid sequence SEQ ID NO 9, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 64.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 10, HC-CDR3 comprising the amino acid sequence SEQ ID NO 41, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 10, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 41; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 11, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 55, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 11, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 55, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65 or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 13, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 49, LC-CDR2 comprising the amino acid sequence SEQ ID NO 57, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 13, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 49, LC-CDR2 comprising the amino acid sequence SEQ ID NO 57, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 14, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 50DR2 comprising the amino acid sequence SEQ ID NO 58, LC-CDR3 comprising the amino acid sequence SEQ ID NO 66, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 14, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 50, LC-CDR2 comprising the amino acid sequence SEQ ID NO 58, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 66.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 15, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65 or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 15, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 16, HC-CDR3 comprising the amino acid sequence 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 16, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 17, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65 or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 17, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some implementationsIn one embodiment, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 18, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 18, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 19, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65 or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 19, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, HC-CDR3 comprising the amino acid sequence SEQ ID NO 42, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 42; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, HC-CDR3 comprising the amino acid sequence SEQ ID NO 43, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65 or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 43; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, HC-CDR3 comprising the amino acid sequence SEQ ID NO 44, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 44; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO65, or the V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 20, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 22, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (5) comprising up to about 5 amino groups in the HC-CDRsSubstitution of an acid; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 23, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 23, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, whichComprises the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 24, HC-CDR3, comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 25, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence 56, and LC-CDR3, comprising the amino acid sequence SEQ ID NO:65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 27, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acidsThe sequences SEQ ID NO 27, and HC-CDR3, comprising the amino acid sequences SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 28, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 29, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65 or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs of (A)。
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 29, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 30, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, LC-CDR3 comprising the amino acid sequence SEQ ID NO 65 or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 30, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 31, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising amino acidsThe sequence SEQ ID NO 48, LC-CDR2, comprising the amino acid sequence SEQ ID NO 56, LC-CDR3, comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 31, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H 1-3, 6-31, 38-44 or a variant thereof comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequence of any one of SEQ ID NOs:48-50, 54-58, 62-66 or a variant thereof comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises any one of SEQ ID NOs 1-3, 6-31 and 38-44; and V L Said V is L Comprises any one of SEQ ID NOs 48-50, 54-58 and 62-66.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 1, 6 and 38, or V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequence SEQ ID NOs 48, 54 and 62, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:1, 6 and 38; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 54 and 62.
In some casesIn embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequences SEQ ID NOs:2, 6 and 39, or said V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequence SEQ ID NOs 48, 54 and 62, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 6 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 54 and 62.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 1, 7 and 39, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequence SEQ ID NOs 48, 54 and 62, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:1, 7 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 54 and 62.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 8 and 40, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequence SEQ ID NOs 48, 54 and 63, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 8 and 40; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 54 and 63.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs:1,9 and 39, or said V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 54 and 64, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:1, 9 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 54 and 64.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequences SEQ ID NOs:3, 10 and 41, or said V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequence SEQ ID NOs 48, 54 and 62, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:3, 10 and 41; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 54 and 62.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 11 and 39, or V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 55 and 65, or said V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 11 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 55 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 12 and 39, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising a substitution of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 12 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 13 and 39, or V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequence SEQ ID NOs 49, 57 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 13 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 49, 57 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 14 and 39, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 50, 58 and 66, or said V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 14 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:50, 58 and 66.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 15 and 39, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 15 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequences SEQ ID NOs:2, 16 and 39, or said V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 16 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 17 and 39, or V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 17 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 18 and 39, or the V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or said V L The variant of (a), said variant comprising a substitution of up to about 5 amino acids. In some embodiments, the anti-C5 aThe antibody includes V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 18 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequences SEQ ID NOs:2, 19 and 39, or said V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising a substitution of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 19 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs:2, 12 and 42, or said V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 12 and 42; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs:2, 12 and 43, or said V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 12 and 43; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequences SEQ ID NOs:2, 12 and 44, or said V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 12 and 44; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequences SEQ ID NOs:2, 20 and 39, or said V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 20 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 21 and 39, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or said V L The variant of (a), said variant comprising a substitution of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 21 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs:2, 22 and 39, or said V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 22 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 23 and 39, or V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 23 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 24 and 39, or V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 24 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Containing ammoniaAmino acid sequences SEQ ID NOs 2, 25 and 39, or said V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 25 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 26 and 39, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 26 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 27 and 39, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 27 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequences SEQ ID NOs:2, 28 and 39, or said V H The variant of (a), said variant comprising up to about 5Substitution of amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or said V L The variant of (a), said variant comprising a substitution of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 28 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 29 and 39, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or said V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 29 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 2, 30 and 39, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and 65, or said V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 30 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs:2, 31 and 39, or said V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 48, 56 and65, or said V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:2, 31 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:48, 56 and 65.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises a V shown as any one of SEQ ID NOs:80-109 in amino acid sequence H Comprising HC-CDR1, HC-CDR2 and HC-CDR3, and V L Said V is L Comprising a V as shown in any one of the amino acid sequences of SEQ ID NOs 118-124 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 80. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 81. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 82. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 83. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs of the amino acid sequence SEQ ID NO: 84. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 85. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 86. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 87. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 81, 2 or 3 HC-CDRs in 8. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO. 89. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO 90. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO. 91. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs of the amino acid sequence SEQ ID NO 92. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 93. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO 94. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO 95. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO. 96. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 97. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO 98. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO 99. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 100. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO. 101. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO. 102. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO 103. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs of the amino acid sequence SEQ ID NO 104. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO 105. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs of the amino acid sequence SEQ ID NO 106. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 107. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 108. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 109.
In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprises 1, 2 or 3 LC-CDRs in the amino acid sequence SEQ ID NO: 118. In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprising 1, 2 or 3 LC-CDRs in the amino acid sequence SEQ ID NO 119. In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprising 1, 2 or 3 LC-CDRs in the amino acid sequence SEQ ID NO 120. In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprising 1, 2 or 3 LC-CDRs in the amino acid sequence SEQ ID NO. 121. In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprising 1, 2 or 3 LC-CDRs in the amino acid sequence SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprising the amino acid sequence SEQ ID1, 2 or 3 LC-CDRs in NO 123. In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprising 1, 2 or 3 LC-CDRs in the amino acid sequence SEQ ID NO: 124.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:80 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:118 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:81 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:118 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO:82 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:118 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:83 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in amino acid sequence SEQ ID NO:119 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO:84 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:120 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:85 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Which comprise, for example, amino acids V shown in SEQ ID NO 118 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO 86 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO. 121 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:87 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO. 88 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in amino acid sequence SEQ ID NO 123 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO. 89 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:124 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:90 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:91 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:92 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:93 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO 94 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO. 122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO:95 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:96 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO:97 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising the amino acid sequence SEQ ID NO 98V of the show H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO. 122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO 99 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO 100 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO. 122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO 101 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO. 102 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:103 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:104 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising, for example, an amino acid sequenceV shown in SEQ ID NO. 122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:105 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO 106 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:107 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:108 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:109 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO:122 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs:80-109 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V L Said V is L Comprising an amino acid sequence set forth in any one of SEQ ID NOs:118-124 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 118-124. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence shown in any one of SEQ ID NOs:80-109, and V L Said V is L Comprises the amino acid sequence shown in any one of SEQ ID NOs: 118-124.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence SEQ ID NO:80 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO: 80; and V L Said V is L Comprising the amino acid sequence of SEQ ID No. 118 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 118. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 80, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 118.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO:81 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 81; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 118 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 118. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ IDNO 81 and V L Said V is L Comprises the amino acid sequence SEQ ID NO:118.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO. 82 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 82; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 118 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 118. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequence SEQ ID NO 82, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 118.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO 83 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 83; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 119 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 119. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequence SEQ ID NO 83, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 119.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO:84 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 84; and V L Said V is L Comprising an amino acid sequence120 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 120. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 84, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 120.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO. 85 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 85; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 118 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 118. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 85, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 118.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO 86 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 86; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 121 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 121. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 86, and V L Said V is L Comprises the amino acid sequence SEQ ID NO. 121.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID No. 87 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 87; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 87, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID No. 88 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 88; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO 123 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 123. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 88, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 123.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID No. 89 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 89; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 124 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence SEQ ID NO 124Sequence identity. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequence SEQ ID NO 89, and V L Said V is L Comprising the amino acid sequence SEQ ID NO:124.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID NO:90 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 90; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 90, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO 91 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 91; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 91, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID NO 92 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%) of the amino acid sequence of SEQ ID NO 9294%, 95%, 96%, 97%, 98% or 99%) sequence identity; and V L Said V is L Comprising the amino acid sequence of SEQ ID No. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 92, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO:93 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 93; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequence SEQ ID NO 93, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID No. 94 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 94; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 94, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID No. 95 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 95; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 95, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO 96 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 96; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 96, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO 97 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 97; and V L Said V is L 122 or a variant thereof comprising the amino acid sequence SEQ ID NO, said variant and amino groupThe sequence of SEQ ID No. 122 has at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 97, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID No. 98 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 98; and V L Said V is L Comprising the amino acid sequence of SEQ ID No. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 98, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID NO 99 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 99; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 99, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising an amino acid sequence100 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 100; and V L Said V is L Comprising the amino acid sequence of SEQ ID No. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 100, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO 101 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 101; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 101, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID No. 102 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 102; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, theThe anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 102, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO. 103 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 103; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 103, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID NO 104 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 104; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 104, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence SEQ ID NO 105 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%) amino acid sequence SEQ ID NO 105,98% or 99%) sequence identity; and V L Said V is L Comprising the amino acid sequence of SEQ ID No. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 105, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID NO 106 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 106; and V L Said V is L Comprising the amino acid sequence of SEQ ID No. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 106, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID No. 107 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 107; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 107, and V L Said V is L Comprising the amino acid sequence SEQ ID NO:122。
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID No. 108 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 108; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 108, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO:109 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 109; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO. 122 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 122. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 109, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122.
In some embodiments, the anti-C5 a antibody comprises a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising ELSMH (SEQ ID NO: 3); HC-CDR2 comprising GFDPX 1 X 2 GETIYAQKFQG (SEQ ID NO: 72), where X 1 Is E or R, X 2 Is D or L; and HC-CDR3 comprising GISX 1 X 2 WNDAFDI (SEQ ID NO: 75), where X 1 Is D or S, X 2 Is G, I or W; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASQSVRNDLA (SEQ ID NO: 51); LC-CDR2 comprising DASDRAT (SEQ ID NO: 59); and LC-CDR3 comprising QQYMDSHPLT (SEQ ID NO: 67).
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 3 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:32-34, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:38-39, and 42, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 3, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:32-34, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs:38-39, and 42.
In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 51 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 59 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:67 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions.
In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 51, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 59, and LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO. 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 3 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:32-34 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:38-39, and 42, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and V L Said V is L Comprises the following steps: an LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:51, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 59 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:67 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 3, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:32-34, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs:38-39, and 42; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 51, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 59, and LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO. 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, HC-CDR3 comprising the amino acid sequence SEQ ID NO 38, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: the LC-CDR1 is a non-linear molecule,comprising the amino acid sequence SEQ ID NO 51, LC-CDR2, comprising the amino acid sequence SEQ ID NO 59, LC-CDR3, comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 38; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, comprising the amino acid sequence SEQ ID33, HC-CDR3 comprising the amino acid sequence SEQ ID NO:39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, comprising the amino acid sequence SEQ ID NO 33, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 34, HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 34, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, HC-CDR3 comprising the amino acid sequence SEQ ID NO 42, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 42; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H 3,32-34,38-39,42 or a variant thereof, said variant, or comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequence of any one of SEQ ID NOs:51,59,67, or a variant thereof, said variant, or comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises any one of the amino acid sequences of SEQ ID NOs 3,32-34,38-39, 42; and V L Said V is L Comprises any one of the amino acid sequences of SEQ ID NOs:51,59, 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 3,32 and 38, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 51,59 and 67, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:3, 32 and 38; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:51, 59 and 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequences SEQ ID NOs 3, 32 and 39, or said V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 51, 59 and 67, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:3, 32 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:51, 59 and 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 3, 33 and 39, or said V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 51, 59 and 67, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:3, 33 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:51, 59 and 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 3, 34 and 39, or V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 51, 59 and 67, or the V L In a variant of (a) the first and second,the variants comprise substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:3, 34 and 39; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:51, 59 and 67.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 3, 32 and 42, or the V H A variant of (a), said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 51, 59 and 67, or the V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:3, 32 and 42; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:51, 59 and 67.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising a V as shown in any one of the amino acid sequences of SEQ ID NOs 110-114 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3, and V L Said V is L Comprising V as shown in amino acid sequence SEQ ID NO 125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO. 110. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO 111. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs of the amino acid sequence SEQ ID NO: 112. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO 113. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 1141, 2 or 3 HC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprises 1, 2 or 3 LC-CDRs in the amino acid sequence SEQ ID NO 125.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:110 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO:111 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO 125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO:112 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO 125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in amino acid sequence SEQ ID NO 113 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:114 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in the amino acid sequence SEQ ID NO 125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence shown in any one of SEQ ID NOs:110-114 or a variant thereof, said variant and S110-114 has at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of EQ ID NOs; and V L Said V is L Comprising the amino acid sequence set forth in SEQ ID NO:125 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 125. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence shown in any one of SEQ ID NOs:110-114, and V L Said V is L Comprises an amino acid sequence shown as SEQ ID NO. 125.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID NO. 110 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO. 110; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO 125 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 125. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 110, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 125.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence of SEQ ID No. 111 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 111; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO 125 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 125.In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 111, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 125.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID No. 112 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 112; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO 125 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 125. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 112, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 125.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID NO 113 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 113; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO 125 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 125. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 113, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 125.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising the amino acid sequence SEQ ID NO:114 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%)95%, 96%, 97%, 98% or 99%) sequence identity; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO 125 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 125. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 114, and V L Said V is L Comprises the amino acid sequence SEQ ID NO 125.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO 35, HC-CDR3 comprising the amino acid sequence SEQ ID NO 45, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 52, LC-CDR2 comprising the amino acid sequence SEQ ID NO 60, LC-CDR3 comprising the amino acid sequence SEQ ID NO 68, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO 35, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 45; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 52, LC-CDR2 comprising the amino acid sequence SEQ ID NO 60, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 68.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NOs 4, 35 and 45, or V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs 52, 60 and 68, or the V L The variant of (a), said variant comprising up to about 5And (3) amino acid substitution. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:4, 35 and 45; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:52, 60 and 68.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO. 115.
In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprising 1, 2 or 3 LC-CDRs in the amino acid sequence SEQ ID NO 126.
In some embodiments, the anti-C5 a antibody comprises V as set forth in amino acid sequence SEQ ID NO:115 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:126 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises the amino acid sequence of SEQ ID No. 115 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID No. 115; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO:126 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO: 126. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 115, and V L Said V is L Comprising the amino acid sequence SEQ ID NO 126.
In some embodiments, the anti-C5 a antibody comprises a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: heavy chain complementarity determining region (HC-CDR) 1 comprising NYAIN (SEQ ID NO: 5); HC-CDR2 comprising GIX 1 PFFGX 2 EDYAQKFQG (SEQ ID NO: 73), where X 1 Is V or Y, X 2 Is T or W; andHC-CDR3 comprising DLLX 1 GFDI (SEQ ID NO: 76), wherein X 1 Is E or H; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASHIDIETWLA (SEQ ID NO: 53); LC-CDR2 comprising GASNLQS (SEQ ID NO: 61); and LC-CDR3, which contains QQANNELPYT (SEQ ID NO: 69).
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 5 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:36-37 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:46-47, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence shown in SEQ ID NO. 5, HC-CDR2, comprising the amino acid sequence shown in any one of SEQ ID NOs:36-37, HC-CDR3, comprising the amino acid sequence shown in any one of SEQ ID NOs: 46-47.
In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO:53 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:61 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:69 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions.
In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence depicted in SEQ ID NO. 53, LC-CDR2 comprising the amino acid sequence depicted in SEQ ID NO. 61, LC-CDR3 comprisingThe amino acid sequence shown in SEQ ID NO. 69.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 5 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:36-37, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and HC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:46-47, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and V L Said V is L Comprises the following steps: an LC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO:53, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO:61 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an LC-CDR3 comprising the amino acid sequence set forth in SEQ ID NO:69 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 5, HC-CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs:36-37, and HC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 46-47; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 53, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 61, and LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO. 69.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 36, HC-CDR3 comprising the amino acid sequence SEQ ID NO 46, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L SaidV L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, LC-CDR3 comprising the amino acid sequence SEQ ID NO 69, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 36, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 46; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 69.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 37, HC-CDR3 comprising the amino acid sequence SEQ ID NO 47, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, LC-CDR3 comprising the amino acid sequence SEQ ID NO 69, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 37, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 47; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 69.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence of any one of SEQ ID NOs 5,36-37,46-47 or a variant thereof Said variant comprising substitutions of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequence of any one of SEQ ID NOs:53,61,69 or a variant thereof comprising up to about 5 amino acid substitutions. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequence of any one of SEQ ID NOs 5,36-37, 46-47; and V L Said V is L Comprises any one of SEQ ID NOs:53,61, 69.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequences SEQ ID NOs:5,36 and 46, or said V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequence SEQ ID NOs:53,61 and 69, or said V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:5,36 and 46; and V L Said V is L Comprises the amino acid sequences SEQ ID NOs:53,61 and 69.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequences SEQ ID NOs:5, 37 and 47, or said V H The variant of (a), said variant comprising a substitution of up to about 5 amino acids; and V L Said V is L Comprising the amino acid sequences SEQ ID NOs:53, 61 and 69, or said V L The variant of (a), said variant comprising substitutions of up to about 5 amino acids. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises the amino acid sequences SEQ ID NOs:5, 37 and 47; and V L Said V is L Comprises the amino acid sequences SEQ ID NOs:53, 61 and 69.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising a V as shown in any one of SEQ ID NOs:116-117 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3, and V L Said V is L Comprises the amino acid sequence SEQ ID NV is O127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO 116. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprises 1, 2 or 3 HC-CDRs in the amino acid sequence SEQ ID NO: 117.
In some embodiments, the anti-C5 a antibody comprises V L Said V is L Comprises 1, 2 or 3 LC-CDRs in the amino acid sequence SEQ ID NO: 127.
In some embodiments, the anti-C5 a antibody comprises V H Comprising a V as shown in the amino acid sequence SEQ ID NO:116 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in amino acid sequence SEQ ID NO:127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises V H Comprising V as shown in the amino acid sequence SEQ ID NO:117 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising V as shown in amino acid sequence SEQ ID NO:127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs:116-117 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 116-117; and V L Said V is L Comprising the amino acid sequence set forth in SEQ ID NO:127 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 127. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence shown in any one of SEQ ID NOs:116-117, and V L Said V is L Comprises an amino acid sequence shown as SEQ ID NO. 127.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises amino acid sequence SEQ ID NO:116 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO: 116; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO:127 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO:127. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 116, and V L Said V is L Comprises the amino acid sequence SEQ ID NO:127.
In some embodiments, the anti-C5 a antibody comprises: v H Said V is H Comprises amino acid sequence SEQ ID NO 117 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to amino acid sequence SEQ ID NO 117; and V L Said V is L Comprising the amino acid sequence of SEQ ID NO 127 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence of SEQ ID NO 127. In some embodiments, the anti-C5 a antibody comprises V H Said V is H Comprising the amino acid sequence SEQ ID NO 117, and V L Said V is L Comprises the amino acid sequence SEQ ID NO:127.
In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in table 4 herein. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in table 4 herein.
In some embodiments, functional epitopes can be resolved by combining alanine scanning methods. In this process, a combination alanine scanning technique can be used to identify the amino acids in the C5a protein that are essential for interaction with anti-C5 a antibodies. In some embodiments, the epitope is conformational, and the crystal structure of an anti-C5 a antibody that binds to C5a protein can be used to identify the epitope.
In some embodiments, the present application provides antibodies that compete for binding to C5a with any one of the anti-C5 a antibodies described herein. In some embodiments, an antibody is provided that is capable of competitively binding to an epitope on C5a with any one of the anti-C5 a antibodies described herein. In some embodiments, anti-C5 a antibodies are provided that bind to antibodies comprising V H And V L Binds to the same epitope as the anti-C5 a antibody molecule of (1), wherein the V H Comprising the amino acid sequence shown in any one of SEQ ID NOs:80-117, and the V L Comprises the amino acid sequence shown in any one of SEQ ID NOs: 118-127. In some embodiments, anti-C5 a antibodies are provided that bind to antibodies comprising V H And V L The anti-C5 a antibody of (a) competitively binds to C5a, wherein said V H Comprising the amino acid sequence shown in any one of SEQ ID NOs:80-117, and the V L Comprising the amino acid sequence shown in any one of SEQ ID NOs: 118-127.
In some embodiments, a competition experiment can be used to identify monoclonal antibodies that compete for binding to C5a with the anti-C5 a antibodies described herein. Competition experiments can determine whether two antibodies bind to the same epitope by recognizing the same or spatially overlapping epitopes or by competitively inhibiting the binding of one antibody to the antigen by the other antibody. In certain embodiments, such a competing antibody binds to the same epitope as an antibody described herein. Some exemplary competition experiments include, but are not limited to, conventional experiments as mentioned in Harlow and Lane (1988) Antibodies, A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, cold Spring Harbor, N.Y.). A detailed exemplary method for resolving epitopes bound by antibodies is described in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology vol.66 (Humana Press, totowa, N.J.). In some embodiments, each antibody is said to bind the same epitope if it blocks 50% or more of the binding of the other antibody. In some embodiments, the antibody that competes with the anti-C5 a antibody described herein is a chimeric, humanized, or fully human antibody.
Exemplary anti-C5 a antibody sequences are shown in tables 2, 3, wherein CDR numbering is according to the Kabat definition. Those skilled in the art will recognize that there are a variety of known algorithms (Kabat definitions) to predict the position of CDRs and to define antibody light and heavy chain variable regions. Comprising the CDRs, V of an antibody as described herein H And/or V L Sequences, but antibodies based on predictive algorithms rather than exemplified in the table below are also within the scope of the application.
TABLE 2 exemplary anti-C5 a antibody CDR sequences
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TABLE 3 exemplary sequences
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C5a
The complement system consists of over 30 proteins that are activated in response to tissue damage, invasion by pathogens or other foreign bodies. Complement component 5a (C5 a) was first described as a cleavage product of complement factor 5 (C5) with chemotactic and anaphylatoxin properties (Shin et al, 1968). The precursor C5 protein of C5a contains 1676 amino acids, has a molecular weight of 188kDa, and is located in 9q33-9q34 (Wetsel et al, 1988). Human C5a is an approximately 11kDa glycoprotein containing 74 amino acids produced by C5 convertase cleavage of the C5 alpha chain, but N-linked glycosylation is not essential for its function. The nature of C5a suggests that it is an important component of the innate immune response, but there is evidence that C5a may also play a role in adaptive immunity (Kohl, 2006). Although C5a is not necessarily a trigger for inflammatory diseases, excessive or uncontrolled C5a is produced in many inflammatory diseases, suggesting that C5a can promote and maintain inflammatory responses (Guo and Ward, 2005). C5a has four antiparallel alpha helices joined with peptide loops and is made more stable by three key disulfide bonds (Monk et al, 2007). Mutagenesis and antibody studies have identified several fundamental residues that provide for interaction with receptors (Monk et al, reviewed in 2007).
The complement cascade can be activated by four pathways: the classical pathway, the alternative pathway, the mannan-binding lectin pathway (MBL) or the exoprotease pathway (Ricklin and Lambris, 2007). The classical pathway and the lectin pathway are activated by recognizing an antibody complex formed on the surface of a pathogen and mannose on the surface of bacteria, respectively. Both pathways result in the cleavage of C4 by serine proteases to form C4a and C4b. After C4b binds to C2, resulting in the production of C2a by the action of a protease, C4b and C2a form the C3 convertase (C4 b2 a) in the classical pathway. The alternative pathway, which can be activated by foreign body surface or "slow transport", causes spontaneous hydrolysis of C3, which subsequently binds to factor B and forms the C3 convertase (C3 bBb) in the alternative pathway, maintains a continuously low level of complement cascade activation, thus ensuring a rapid response to invading pathogens (Ricklin and Lambris, 2007). All three pathways lead to the formation of C3 convertase, which further cleaves C3 protein to form C3a and C3b. C3b promotes recognition of pathogen surface by cells and clearance of pathogens, and can also form C5 convertase (C4 b2aC3b or C3 bbc3 b) with C3 convertase (C4 b2a or C3 bBb), and then C5 convertase further cleaves C5 to generate C5a and C5b. C5b continues to initiate assembly of the tapping membrane complex (MAC; C5 b-9). The complement cascade is tightly regulated by a series of soluble membrane-bound regulatory proteins that prevent the targeting of complement activation products to host tissues (Ricklin and Lambris, 2007). However, this control can be circumvented by several exogenous routes, such as thrombin which directly cleaves C3 and C5, resulting in activation of the complement system (Amara et al, 2008). In addition, activated neutrophils and alveolar macrophages can cleave C5 by secreted serine proteases to produce C5a (Amara et al, 2008). Plasma and cell surface carboxypeptidases remove arginine from the C-terminus of proteins, and thus the C5a produced by C5 cleavage is rapidly metabolized by it to form C5adesArg (Bokisch and Muller-Eberhard, 1970). C5adesArg has reduced potency compared to C5a, resulting in reduced binding affinity to the classical C5a receptor, CD88 (Higginbottom et al, 2005). C5a and C5adesArg are rapidly cleared in vivo, with about 50% of C5a and C5adesArg being cleared from circulation within 2-3 minutes, and with some C5a being mediated by binding to CD88 on leukocytes and other cells (Oppermann and Gotze, 1994). However, the second receptor, C5 a-like receptor 2 (C5L 2), removes complement fragments more efficiently by rapidly internalizing C5a/C5adesArg, particularly C5adesArg, and allowing it to remain therein and be degraded in certain cell types (Scola et al (2009). Conversely, after internalization of C5a by CD 88-expressing cells, C5a is released in a higher proportion and in an undegraded, possibly still active form. Plasma C5a can also be cleared by the liver (Chenoweth and Goodman, 1983).
CD88
C5a binds CD88 and C5L2 with similar high affinity. In contrast, the affinity of C5adesArg for C5L2 is similar to that of C5a
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But has a much lower affinity for CD88>
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(Monk et al, 2007). CD88 and C5L2 have 35% sequence homology and are located in the same region on chromosome 19 (19q13.3-19q13.4). They cluster with other chemokine receptor (e.g., formyl peptide receptor family and bradykinin receptor) genes. Both are glycosylated seven transmembrane proteins with a molecular weight of approximately 45kDa. CD88 is a G-protein coupled receptor and is also a member of the rhodopsin gene family (Monk et al, 2007). It is believed that the binding of C5a to CD88 occurs at two distinct and physically separate sites. The first "recognition" site is located at the extracellular amino-terminus (N-terminus) of the receptor, which binds to the C5a N-terminus and the disulfide-linked core. The second "activation" site is formed by the transmembrane domain of the receptor, which binds to the C-terminus of C5a and results in the generation of a specific signal transduction pathway mediated by the receptor-coupled G protein (Monk et al, 2007).
C5L2
The cell types expressing C5L2 are about the same as those expressing CD88, such as neutrophils, monocytes, lymphocytes, macrophages, and non-myeloid cells (e.g., vascular smooth muscle cells) and tissue-derived cells (e.g., adrenal gland, heart, liver, lung spleen, and brain), but the expression level of C5L2 is significantly lower than that of CD88 under non-inflammatory conditions (Gao et al, 2005). The function of C5L2 is not clear. Some experimental data indicate that C5L2 can act as a decoy receptor without signaling function. It was found that knocking out or blocking C5L2 exacerbates the inflammatory response in mice (Gao et al, 2005. This suggests that C5L2 has an anti-inflammatory function, which may act by reducing the amount of C5a that can bind to CD 88. Furthermore, C5L2 may act as a positive modulator, which is critical for C5a and C3a signaling, at least in mice (Chen et al, 2007). In vitro, C5L2 was found to be critical for promoting C5a signaling in neutrophils, macrophages and fibroblasts, while in vivo deficiency of C5L2 can lead to ovalbumin-induced airway hyperreactivity and inflammation (Chen et al, 2007). Furthermore, in the mouse "late" sepsis (100% mortality) model, protection is only afforded by blocking both C5L2 and CD88 (ritttirsch et al, 2008).
Full-length anti-C5 a antibodies
In some embodiments, the anti-C5 a antibody is a full-length anti-C5 a antibody. In some embodiments, the full-length anti-C5 a antibody is IgA, igD, igE, igG, or IgM. In some embodiments, the full-length anti-C5 a antibody comprises an IgG constant region, e.g., a constant region of IgG1, igG2, igG3, igG4, or a variant thereof. In some embodiments, the full-length anti-C5 a antibody comprises a lambda light chain constant region. In some embodiments, the full-length anti-C5 a antibody comprises a kappa light chain constant region. In some embodiments, the full-length anti-C5 a antibody is a full-length human anti-C5 a antibody. In some embodiments, the full-length anti-C5 a antibody comprises a mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-C5 a antibody comprises an Fc sequence that has been altered or otherwise altered such that it has the effector functions of enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Thus, for example, in some embodiments, a full-length anti-C5 a antibody comprising an IgG1 constant region is provided, which anti-C5 a antibody specifically binds to C5 a. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, a full-length anti-C5 a antibody comprising an IgG2 constant region is provided, which anti-C5 a antibody specifically binds to C5 a. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, a full-length anti-C5 a antibody comprising an IgG3 constant region is provided, wherein the anti-C5 a antibody specifically binds to C5 a. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, a full-length anti-C5 a antibody comprising an IgG4 constant region is provided, which anti-C5 a antibody specifically binds to C5 a. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence set forth in any one of SEQ ID NOs:1-5, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; HC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:6-37, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and HC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:38-47, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and b) a light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence set forth in any one of SEQ ID NOs:48-53, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids, LC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:54-61, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and an LC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:62-69, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG2 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence set forth in any of SEQ ID NOs:1-5, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:6-37 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs:38-47, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and b) a light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence set forth in any one of SEQ ID NOs:48-53, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; LC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:54-61 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an LC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:62-69, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG3 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence set forth in any one of SEQ ID NOs:1-5 or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids, HC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:6-37 or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs:38-47, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and b) a light chain variable domain comprising: LC-CDR1 comprising an amino acid sequence set forth in any one of SEQ ID NOs:48-53, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; LC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:54-61 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and an LC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:62-69, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence set forth in any of SEQ ID NOs:1-5, or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:6-37 or a variant thereof comprising up to about 3 (e.g., 1, 2, or 3) amino acid substitutions; and HC-CDR3 comprising an amino acid sequence set forth in any one of SEQ ID NOs:38-47, or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2, or 3) amino acids; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence set forth in any of SEQ ID NOs:48-53 or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids, an LC-CDR2 comprising the amino acid sequence set forth in any of SEQ ID NOs:54-61 or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids, and an LC-CDR3 comprising the amino acid sequence set forth in any of SEQ ID NOs:62-69 or a variant thereof comprising substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence set forth in any of SEQ ID NOs:1-5, HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:6-37, and HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs:38-47, or a variant of said heavy chain variable domain comprising up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acid substitutions in its HC-CDR sequence; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs:48-53, an LC-CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs:54-61, and an LC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs:62-69, or a variant of said light chain variable domain comprising up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acid substitutions in its LC-CDR sequence. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises a) a heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence set forth in any of SEQ ID NOs:1-5, HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:6-37, and HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs:38-47, or a variant of said heavy chain variable domain comprising up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acid substitutions in its HC-CDR sequence; and b) a light chain variable domain comprising: an LC-CDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs:48-53, an LC-CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs:54-61, and an LC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs:62-69, or a variant of said light chain variable domain comprising up to about 5 (e.g., 1, 2, 3, 4, or 5) amino acid substitutions in its LC-CDR sequence. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence set forth in any of SEQ ID NOs:1-5, HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:6-37, and HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs: 38-47; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs:48-53, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:54-61, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 62-69. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising an amino acid sequence set forth in any of SEQ ID NOs:1-5, HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:6-37, and HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs: 38-47; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs:48-53, LC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:54-61, and LC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs: 62-69. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 1, HC-CDR2, comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 7, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 8, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 40; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 63. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 1, HC-CDR2, comprising the amino acid sequence SEQ ID NO 9, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 64. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO 3, HC-CDR2, which comprises the amino acid sequence SEQ ID NO 10, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO 41; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 11, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 55, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 13, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 49, LC-CDR2 comprising the amino acid sequence SEQ ID NO 57, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 14, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 50, LC-CDR2 comprising the amino acid sequence SEQ ID NO 58, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 66. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 15, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 16, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 17, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 18, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 19, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 42; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 43; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 44; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 23, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 29, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 30, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 31, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, comprising the amino acid sequence SEQ ID NO 33, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 34, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 42; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 4, HC-CDR2, comprising the amino acid sequence SEQ ID NO 35, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 45; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 52, LC-CDR2 comprising the amino acid sequence SEQ ID NO 60, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 68. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 36, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 46; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 69. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 37, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 47; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 69. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 1, HC-CDR2, comprising the amino acid sequence SEQ ID NO 7, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 8, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 40; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 63. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 1, HC-CDR2, comprising the amino acid sequence SEQ ID NO 9, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 64. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO 3, HC-CDR2, which comprises the amino acid sequence SEQ ID NO 10, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO 41; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 11, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 55, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 13, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 49, LC-CDR2 comprising the amino acid sequence SEQ ID NO 57, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 14, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 50, LC-CDR2 comprising the amino acid sequence SEQ ID NO 58, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 66. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 15, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 16, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 17, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 19, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 42; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 43; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 44; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 20, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 22, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 23, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 25, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 29, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 30, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 31, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 38; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59 and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, comprising the amino acid sequence SEQ ID NO 33, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 34, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1, comprising the amino acid sequence SEQ ID NO 3, HC-CDR2, comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 42; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO 35, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 45; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 52, LC-CDR2 comprising the amino acid sequence SEQ ID NO 60, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 68. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 36, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 46; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 69. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a) A heavy chain variable domain comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 37, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 47; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 69. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: heavy chain variable domain (V) H ) Said V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs:80-117 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 80-117; and a light chain variable domain (V) L ) Said V is L Comprising an amino acid sequence set forth in any one of SEQ ID NOs:118-127 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 118-127. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG2 constant region, wherein the anti-C5 a antibody comprises: heavy chain variable domain (V) H ) Said V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs:80-117 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 80-117; and a light chain variable domain (V) L ) Said V is L Comprising any one of SEQ ID NOs 118-127An amino acid sequence set forth as, or a variant thereof, having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 118-127. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG3 constant region, wherein the anti-C5 a antibody comprises: heavy chain variable domain (V) H ) Said V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs:80-117 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 80-117; and a light chain variable domain (V) L ) Said V is L Comprising an amino acid sequence set forth in any one of SEQ ID NOs:118-127, or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 118-127. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: heavy chain variable domain (V) H ) Said V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs:80-117 or a variant thereof having at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 80-117; and a light chain variable domain (V) L ) Said V is L Comprising the amino acid sequence shown in any one of SEQ ID NOs:118-127 or a variant thereofSuch variants have at least about 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 118-127. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: heavy chain variable domain (V) H ) Said V is H Comprising the amino acid sequence set forth in any one of SEQ ID NOs:80-117, and a light chain variable domain (V) L ) Said V is L Comprises the amino acid sequence shown in any one of SEQ ID NOs: 118-127. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: heavy chain variable domain (V) H ) Said V is H Comprises any one of SEQ ID NOs:80-117And a light chain variable domain (V) L ) Said V is L Comprises the amino acid sequence shown in any one of SEQ ID NOs: 118-127. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:80, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:118. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:81, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:118. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:82, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:118. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 83 and a light chain variable domain comprising the amino acid sequence SEQ ID NO 119. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:84, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:120. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 85 and a light chain variable domain comprising the amino acid sequence SEQ ID NO 118. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 86 and a light chain variable domain comprising the amino acid sequence SEQ ID NO 121. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:87 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:88, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:123. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO. 89, and a light chain variable domain comprising the amino acid sequence SEQ ID NO. 124. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:90, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 91, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:92, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 93, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:94, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:95, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:96, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:97, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:98, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 99, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:100, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 101, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:102, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO. 103, and a light chain variable domain comprising the amino acid sequence SEQ ID NO. 122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 104, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 105, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 106, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 107, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:108, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:109, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 110 and a light chain variable domain comprising the amino acid sequence SEQ ID NO 125. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 111 and a light chain variable domain comprising the amino acid sequence SEQ ID NO 125. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:112, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:125. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 113, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 125. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:114, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:125. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:115, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:126. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:116, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:127. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG1 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 117 and a light chain variable domain comprising the amino acid sequence SEQ ID NO 127. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:128 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:80, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:118. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:81, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:118. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:82, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:118. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 83 and a light chain variable domain comprising the amino acid sequence SEQ ID NO 119. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:84, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:120. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:85, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:118. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 86 and a light chain variable domain comprising the amino acid sequence SEQ ID NO 121. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:87 and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:88, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:123. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO. 89, and a light chain variable domain comprising the amino acid sequence SEQ ID NO. 124. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:90, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 91, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:92, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:93, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:94, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:95, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:96, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:97, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:98, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 99, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:100, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 101, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 102, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 103 and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 104, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 105, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 106, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 107, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:108, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:109, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:122. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:110, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:125. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 111 and a light chain variable domain comprising the amino acid sequence SEQ ID NO 125. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:112, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:125. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO 113, and a light chain variable domain comprising the amino acid sequence SEQ ID NO 125. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:114, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:125. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:115, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:126. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:116, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:127. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
In some embodiments, there is provided a full-length anti-C5 a antibody comprising an IgG4 constant region, wherein the anti-C5 a antibody comprises: a heavy chain variable domain comprising the amino acid sequence SEQ ID NO:117, and a light chain variable domain comprising the amino acid sequence SEQ ID NO:127. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO 129 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 131.
Binding affinity
Binding affinity is expressed as Kd, koff, kon or Ka. As used herein, the term Koff refers to the rate constant for dissociation of an antibody from an antigen/antibody complex, as determined by a kinetic selection device. The term Kon refers to the rate constant of binding of an antibody to an antigen to form an antigen/antibody complex. As used herein, the equilibrium dissociation constant Kd refers to the dissociation constant for a particular antibody-antigen interaction, and refers to the concentration of antigen required to reach equilibrium, equal to Koff/Kon, where the antigen occupies half of all antibody binding sites in the antibody molecule solution. Determination of Kd assumes that all binding molecules are in solution. Where the antibody is attached to the cell wall, e.g.in a yeast expression system, the corresponding equilibrium dissociation rate constant is given by EC 50 It is a good approximation of Kd. The affinity binding constant Ka is the inverse of the dissociation constant Kd.
The dissociation constant (Kd) may be used as an indicator of the affinity of the reactive antibody moiety for the antigen. For example, simple analysis can be performed by the Scatchard method using antibodies labeled with various labels and a Biacore instrument (manufactured by Amersham Biosciences), and the interaction between biomolecules is analyzed by surface plasmon resonance according to the user's manual or an attached kit. The Kd values obtained using these methods are expressed in units of M. Antibodies that specifically bind to a target may have, for example ≦ 10 -7 M、≤10 -8 M、≤10 -9 M、≤10 -10 M、≤10 -11 M、≤10 -12 M is equal to or less than 10 -13 Kd value of M.
The binding specificity of an antibody can be determined experimentally by methods known in the art. These methods include, but are not limited to, western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore testing, peptide scanning, and the like.
In some embodiments, the anti-C5 a antibody specifically binds to a C5a target with a Kd value of 10 -7 M to 10 -13 M (e.g. 10) -7 M to 10 -13 M、10 -8 M to 10 -13 M、10 -9 M to 10 -13 M or 10 -10 M to 10 -12 M). Thus, in some embodiments, the Kd value for the binding between an anti-C5 a antibody and C5a is 10 -7 M to 10 -13 M、1×10 -7 M to 5X 10 -13 M、10 -7 M to 10 -12 M、10 -7 M to 10 -11 M、10 -7 M to 10 -10 M、10 -7 M to 10 -9 M、10 -8 M to 10 -13 M、1×10 -8 M to 5X 10 -13 M、10 -8 M to 10 -12 M、10 -8 M to 10 -11 M、10 -8 M to 10 -10 M、10 -8 M to 10 -9 M、5×10 -9 M to 1X 10 -13 M、5×10 -9 M to 1X 10 -12 M、5×10 -9 M to 1X 10 -11 M、5×10 -9 M to 1X 10 -10 M、10 -9 M to 10 -13 M、10 -9 M to 10 -12 M、10 -9 M to 10 -11 M、10 -9 M to 10 - 10 M、5×10 -10 M to 1X 10 -13 M、5×10 -10 M to 1X 10 -12 M、5×10 -10 M to 1X 10 -11 M、10 -10 M to 10 -13 M、1×10 -10 M to 5X 10 -13 M、1×10 -10 M to 1X 10 -12 M、1×10 -10 M to 5X 10 -12 M、1×10 -10 M to 1X 10 -11 M、10 - 11 M to 10 -13 M、1×10 -11 M to 5X 10 -13 M、10 -11 M to 10 -12 M、10 -12 M to 10 -13 And M. In some embodiments, the Kd value for the binding between an anti-C5 a antibody and C5a is 10 -7 M to 10 -13 M。
In some embodiments, the Kd value for binding between the anti-C5 a antibody and the non-target is higher than the Kd value for the anti-C5 a antibody and the target, and in some embodiments cited herein, the binding affinity of the anti-C5 a antibody to the target (e.g., C5 a) is higher than the binding affinity of the anti-C5 a antibody to the non-target. In some embodiments, the non-target refers to an antigen other than C5 a. In some embodiments, the Kd values for the binding of an anti-C5 a antibody (to C5 a) to a non-C5 a target differ by at least 10-fold, e.g., 10-100 fold, 100-1000 fold, 10-fold 3 -10 4 10 times of 4 -10 5 10 times of the Chinese traditional medicine 5 -10 6 10 times of 6 -10 7 10 times of 7 -10 8 10 times of the Chinese traditional medicine 8 -10 9 10 times of the Chinese traditional medicine 9 -10 10 10 times of the Chinese traditional medicine 10 -10 11 10 times of 11 -10 12 And (4) multiplying.
In some embodiments, the anti-C5 a antibody binds to a non-target with a Kd value of 10 -1 M to 10 -6 M (e.g. 10) -1 M to 10 -6 M、10 -1 M to 10 -5 M、10 -2 M to 10 -4 M). In some embodiments, the non-target refers to an antigen other than C5 a. Thus, in some embodiments, the Kd value for the binding between an anti-C5 a antibody and a non-C5 a target is 10 -1 M to 10 -6 M、1×10 -1 M to 5X 10 -6 M、10 -1 M to 10 -5 M、1×10 -1 M to 5X 10 -5 M、10 -1 M to 10 -4 M、1×10 -1 M to 5X 10 -4 M、10 -1 M to 10 - 3 M、1×10 -1 M to 5X 10 -3 M、10 -1 M to 10 -2 M、10 -2 M to 10 -6 M、1×10 -2 M to 5X 10 -6 M、10 -2 M to 10 -5 M、1×10 -2 M to 5X 10 -5 M、10 -2 M to 10 -4 M、1×10 -2 M to 5X 10 -4 M、10 -2 M to 10 -3 M、10 -3 M to 10 -6 M、1×10 -3 M to 5X 10 -6 M、10 -3 M to 10 -5 M、1×10 -3 M to 5X 10 -5 M、10 -3 M to 10 -4 M、10 -4 M to 10 -6 M、1×10 -4 M to 5X 10 - 6 M、10 -4 M to 10 -5 M、10 -5 M to 10 -6 M。
In some embodiments, when referring to an anti-C5 a antibody specifically recognizing a C5a target with high binding affinity and binding a non-target with low binding affinity, the anti-C5 a antibody binds to the C5a target with a Kd value of 10 -7 M to 10 -13 M (e.g. 10) -7 M to 10 -13 M、10 -8 M to 10 -13 M、10 -9 M to 10 -13 M、10 -10 M to 10 -12 M) and a Kd value for binding to non-target of 10 -1 M to 10 -6 M (e.g. 10) -1 M to 10 -6 M、10 -1 M to 10 -5 M、10 -2 M to 10 -4 M)。
In some embodiments, when referring to an anti-C5 a antibody specifically recognizing C5a, the binding affinity of the anti-C5 a antibody is compared to the binding affinity of a control anti-C5 a antibody (e.g., INab 308). In some embodiments, the Kd value for the binding between a control anti-C5 a antibody and C5a may be at least 2-fold, e.g., 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-100-fold, greater than the Kd value for the binding between an anti-C5 a antibody and C5a described herein100-1000 times, 10 3 -10 4 And (4) multiplying.
Nucleic acids
Nucleic acid molecules encoding anti-C5 a antibodies are also contemplated. In some embodiments, a (or a panel of) nucleic acids encoding full-length anti-C5 a antibodies is provided, including any of the full-length anti-C5 a antibodies described herein. In some embodiments, the nucleic acid (or set of nucleic acids) of an anti-C5 a antibody described herein can further comprise a nucleic acid sequence encoding a polypeptide tag (e.g., a protein purification tag, a His tag, an HA tag).
Also contemplated herein are isolated host cells comprising an anti-C5 a antibody, isolated nucleic acids encoding anti-C5 a antibody polypeptide components, or vectors comprising nucleic acids encoding anti-C5 a antibody polypeptide components described herein.
The present application also includes variants of these nucleic acid sequences. For example, a variant includes a nucleotide sequence that hybridizes to a nucleic acid sequence encoding an anti-C5 a antibody of the present application under at least moderately stringent hybridization conditions.
The present application also provides vectors into which the nucleic acid sequences of the present application may be inserted.
Briefly, a natural or synthetic nucleic acid encoding an anti-C5 a antibody is inserted into a suitable expression vector such that the nucleic acid is operably linked to 5' and 3' regulatory elements, e.g., including a promoter (e.g., a lymphocyte-specific promoter) and a 3' untranslated region (UTR), to express an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody). The vectors may be suitable for replication and integration in eukaryotic host cells. Typical cloning and expression vectors contain transcriptional and translational terminators, initiation sequences, and promoters that regulate the expression of the nucleic acid sequence of interest.
The nucleic acids described herein can also be used for nucleic acid immunization and gene therapy by using standard gene delivery protocols. Methods of nucleic acid delivery are known in the art. See, for example, U.S. Pat. nos.5,399,346, 5,580,859, 5,589,466, which are incorporated herein by reference in their entirety. In some embodiments, the present application also provides gene therapy vectors.
Nucleic acids can be cloned into many types of vectors. For example, the nucleic acid can be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses, and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.
In addition, the expression vector may be provided to the cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Green and Sambrook (2013, molecular cloning. Viruses that can be used as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. Generally, suitable vectors include an origin of replication functional in at least one organism, a promoter sequence, a convenient restriction endonuclease site, and one or more selectable markers (see, e.g., WO 01/96584, WO 01/29058; and U.S. Pat. No.6,326,193).
Many virus-based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. The selected gene can be inserted into a vector and packaged into a retroviral particle using techniques known in the art. The recombinant virus is then isolated and delivered to cells of a subject in vivo or in vitro. Many retroviral systems are known in the art. In some embodiments, an adenoviral vector is used. Many adenoviral vectors are known in the art. In some embodiments, a lentiviral vector is used. Retroviral-derived vectors, such as lentiviruses, are suitable tools for achieving long-term gene transfer, as they allow long-term stable integration of transgenes and propagation in progeny cells. Lentiviral vectors have an additional advantage over tumor-derived retroviruses, such as murine leukemia virus, in that they can transduce non-dividing cells, such as hepatocytes. At the same time, it also has the additional advantage of low immunogenicity.
Other promoter elements, such as enhancers, regulate the transcription initiation frequency. Typically they are located 30-110bp upstream of the start site, although many promoters have recently been found to contain functional elements downstream of the start site as well. The spacing between promoter elements is generally flexible, so that promoter function is maintained when the elements are interchanged or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements increases to 50bp before activity begins to decrease.
An example of a suitable promoter is the immediate early Cytomegalovirus (CMV) promoter sequence. The promoter sequence is a strong constitutive promoter sequence that can drive high level expression of any polynucleotide sequence to which it is operably linked. Another example of a suitable promoter is the elongation factor 1 alpha (EF-1 alpha) promoter. However, other constitutive promoters may also be used, including, but not limited to, simian virus 40 (SV 40) early promoter, mouse Mammary Tumor Virus (MMTV), human immunodeficiency virus long terminal repeat (HIV-LTR) promoter, moMuLV promoter, avian leukemia virus promoter, epstein-Barr virus immediate early promoter, rous sarcoma virus promoter, and human gene promoters, including, but not limited to, actin promoter, myosin promoter, hemoglobin promoter, and creatine kinase promoter, for example. Furthermore, the application should not be limited to the use of constitutive promoters only, inducible promoters are also contemplated as part of the present application. The use of an inducible promoter provides a molecular switch that can turn on expression of the polynucleotide sequence to which it is operably linked when such expression is desired and turn off expression when not desired. Inducible promoters include, but are not limited to, the metallothionein promoter, the glucocorticoid promoter, the progesterone promoter, and the tetracycline promoter.
In some embodiments, the expression of the anti-C5 a antibody is inducible. In some embodiments, the nucleic acid sequence encoding the anti-C5 a antibody is operably linked to an inducible promoter, including any of the inducible promoters described herein.
Inducible promoters
The use of an inducible promoter provides a molecular switch that can initiate expression of the polynucleotide sequence to which it is operably linked when expression is desired and shut down expression when expression is not desired. Exemplary inducible promoters useful in eukaryotic cells include, but are not limited to, hormone regulatory elements (see, e.g., mader, s.and White, j.h. (1993) proc.natl.acad.sci.usa90: 5603-5607), synthetic ligand regulatory elements (see Spencer, d.m.et al (1993) Science 262. Other exemplary inducible promoters suitable for use in mammalian systems, either in vivo or in vitro, are described in Gingrich et al (1998) Annual rev. Neurosci 21. In some embodiments, the inducible promoter system used to express the anti-C5 a antibody is the Tet system. In some embodiments, the inducible promoter system used to express the anti-C5 a antibody is the e.coli lac suppression system.
An exemplary inducible promoter system employed herein is the Tet system. The system is based on the Tet system described by Gossen et al (1993). In one exemplary embodiment, the polynucleotide of interest is controlled by a promoter comprising one or more Tet operator (TetO) sites. In the inactive state, the Tet repressor (TetR) binds to the TetO site and inhibits transcription from the promoter. In the activated state, for example, in the presence of an inducing agent such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox), or an active analog thereof, the inducing agent releases TetR from TetO, thereby causing transcription to occur. Doxycycline is a member of the tetracycline antibiotic family, and has the chemical name 1-dimethylamino-2,4a, 5, 7-pentahydroxy-11-methyl-4, 6-dioxy-1,4a, 11,11a,12, 12a-hexahydrotetraene-3-carboxamide.
In one embodiment, tetR is codon optimized for expression in a mammalian cell, such as a mouse or human cell. Due to the degeneracy of the genetic code, most amino acids are encoded by more than one codon, thus allowing a large number of variants of a given nucleic acid sequence without any change in the encoded amino acid sequence. However, many organisms differ in codon usage, also referred to as "codon bias" (i.e., the bias of a given amino acid to use a particular codon). Codon bias is often associated with the presence of a dominant tRNA species for a particular codon, which in turn increases the efficiency of translation of the mRNA. Coding sequences derived from a particular species (e.g., prokaryotes) can thus be tailored by codon optimization to enhance their expression in different species (e.g., eukaryotes).
Other specific variations of the Tet system include the following "Tet-Off" and "Tet-On" systems. In the Tet-off system, transcription is inactivated in the presence of Tc or Dox. In this system, a tetracycline-regulated transcriptional activator (tTA), consisting of a fusion of TetR to the strong transcriptional activation domain of herpes simplex virus VP16, regulates expression of the target nucleic acid under the transcriptional control of a tetracycline responsive promoter element (TRE). The TRE element consists of a TetO sequence in tandem fused to a promoter (usually the minimal promoter sequence from the human cytomegalovirus immediate early promoter). In the absence of Tc or Dox, tTA binds to TRE and activates transcription of the target gene. In the presence of Tc or Dox, tTA cannot bind to TRE and the target gene cannot be expressed.
In contrast, in the Tet-On system, transcription is activated in the presence of Tc or Dox. The Tet-On system is based On the reverse tetracycline regulated transcriptional activator rtTA. Like tTA, rtTA is a fusion protein consisting of the TetR repressor and the VP16 transcriptional activation domain. However, the 4 amino acid change in the DNA binding region of TetR altered the binding properties of rtTA such that it only recognized the tetO sequence on the target transgenic TRE in the presence of Dox. Therefore, in the Tet-On system, rtTA activates transcription of a TRE-regulated target gene only in the presence of Dox.
Another inducible promoter system is the lac repressor system of E.coli (see Brown et al, cell 49. The Lac repressor system functions by regulating transcription of a polynucleotide of interest operably linked to a promoter comprising a Lac operator (lacO). The Lac repressor (lacR) binds to LacO, thereby preventing transcription of the target polynucleotide. Expression of the target polynucleotide is induced by a suitable inducing agent, for example, isopropyl- β -D thiogalactopyranoside (IPTG).
To assess the expression of the polypeptide or portion thereof, the expression vector to be introduced into the cells may further comprise a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from a population of cells transfected or infected with the viral vector. In other aspects, the selectable marker may be carried on a separate DNA fragment and used in a co-transfection experiment. Either the selectable marker gene or the reporter gene can be flanked by appropriate regulatory sequences that enable expression in the host cell. Useful selectable markers include, for example, antibiotic resistance genes, such as neo and the like.
The reporter gene can be used to identify potential transfected cells and to evaluate the function of regulatory sequences. Typically, a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and that encodes a polypeptide whose expression exhibits some readily detectable property, such as enzymatic activity. After the DNA is introduced into the recipient cells, the expression of the reporter gene is detected at an appropriate time. Suitable reporter genes may include genes encoding luciferase, β -galactosidase, chloramphenicol acetyltransferase, secreted alkaline phosphatase, or green fluorescent protein (see, ui-Tel et al, 2000febs Letters 479. Suitable expression systems are well known and can be prepared by known techniques or obtained commercially. In general, the construct of the smallest 5' flanking region that can show the highest expression level of the reporter gene is considered to be the promoter. Such promoter regions may be linked to reporter genes and used to assess the ability of certain substances to regulate promoter-driven transcription.
In some embodiments, a nucleic acid encoding any of the full-length anti-C5 a antibodies described herein is provided. In some embodiments, the nucleic acid comprises one or more nucleic acid sequences encoding the heavy and light chains of a full-length anti-C5 a antibody. In some embodiments, each of the one or more nucleic acid sequences is contained in a separate vector. In some embodiments, at least some of the nucleic acid sequences are contained in the same vector. In some embodiments, all nucleic acid sequences are contained in the same vector. The vector may be selected, for example, from mammalian expression vectors and viral vectors (e.g., vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses).
Methods for introducing and expressing genes into cells are known in the art. In the context of expression vectors, the vectors can be readily introduced into host cells, such as mammalian cells, bacterial, yeast or insect cells, by any method known in the art. For example, the expression vector may be introduced into a host cell by physical, chemical or biological means.
Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, lipofection, particle gun methods, microinjection, electroporation, and the like. Methods for preparing cells comprising vectors and/or exogenous nucleic acids are well known in the art. See, for example, green and Sambrook (2013, molecular cloning. In some embodiments, the polynucleotide is introduced into the host cell by calcium phosphate transfection.
Biological methods for introducing polynucleotides of interest into host cells include the use of DNA and RNA vectors. Viral vectors, particularly retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells. Other viral vectors may be derived from lentiviruses, poxviruses, herpes simplex virus type 1, adenoviruses, adeno-associated viruses, and the like. See, e.g., U.S. Pat. nos.5,350,674 and 5,585,362.
Chemical methods for introducing polynucleotides into host cells include colloidally dispersed systems such as polymer complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. One exemplary colloidal system that is used as a delivery vehicle in vivo and in vitro is a liposome (e.g., an artificial membrane vesicle).
In the case of non-viral delivery systems, an exemplary delivery vehicle is a liposome. Introduction of nucleic acids into host cells (in vitro, ex vivo or in vivo) using lipid formulations is contemplated. In another aspect, the nucleic acid can be bound to a lipid. The nucleic acid associated with a lipid may be encapsulated within the aqueous interior of a liposome, dispersed within the lipid bilayer of a liposome, linked to the liposome by a linker molecule that binds to the liposome and an oligonucleotide, entrapped in the liposome, formed a complex with the liposome, dispersed in a solution containing the lipid, mixed with the lipid, associated with the lipid, suspended in the lipid, contained in or mixed with micelles, or otherwise associated with the lipid. The lipid, lipid/DNA or lipid/expression vector related composition is not limited to any particular structure in solution. For example, they may exist in a bilayer structure, in micelles, or in a "collapsed" structure. They may also be simply dispersed in solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances, either naturally occurring or synthetic. For example, lipids include fat droplets that naturally occur in the cytoplasm, and a class of compounds containing long-chain aliphatic hydrocarbons and derivatives thereof, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.
Regardless of the method used to introduce the exogenous nucleic acid into the host cell or otherwise expose the cell to the inhibitors of the present application, various experiments can be performed in order to confirm that the recombinant DNA sequence is present in the host cell. Such assays include, for example, "molecular biology" assays well known to those skilled in the art. Such as Southern and Northern blotting, RT-PCR and PCR; "biochemical" assays, such as detecting the presence or absence of a particular polypeptide, such as by immunological methods (ELISAs and Western blots) or by assays described herein, are within the scope of the present application.
Preparation of anti-C5 a antibodies
In some embodiments, the anti-C5 a antibody is a monoclonal antibody or derived from a monoclonal antibody. In some embodiments, the anti-C5 a antibody comprises V from a monoclonal antibody H And V L Or a variant thereof. In some embodiments, the anti-C5 a antibody further comprises CH1 and CL regions from a monoclonal antibody, or a variant thereof. Monoclonal antibodies can be prepared, for example, by methods known in the art, including hybridoma cell methods, phage display methods, or by using recombinant DNA methods. In addition, exemplary phage display methods are described herein and in the examples below.
In the hybridoma cell method, a hamster, mouse, or other suitable host animal is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that specifically bind to the immunizing agent. Alternatively, lymphocytes may be immunized in vitro. The immunizing agent may include a polypeptide or fusion protein of the protein of interest. Generally, peripheral Blood Lymphocytes (PBLs) are used if cells of human origin are desired, while spleen cells or lymph node cells are used if cells of non-human mammalian origin are desired. The lymphocytes are fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form hybridoma cells. Immortalized cell lines are generally transformed mammalian cells, in particular myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are used. The hybridoma cells may be cultured in a suitable medium, which preferably contains one or more substances that inhibit the growth or survival of the unfused immortalized cells. For example, if the parental cells lack hypoxanthine-guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridoma cells typically includes hypoxanthine, aminopterin, and thymidine (HAT medium), which prevents the growth of HGPRT-deficient cells.
In some embodiments, the immortalized cell lines fuse efficiently, ensure high level, steady expression of the antibody by the selected antibody producing cells, and are sensitive to certain media, such as HAT media. In some embodiments, the immortalized cell line is a mouse myeloma cell line, and can be obtained, for example, from the solvay cell collection of san diego, california and the american type culture collection of manassas, virginia. Human myeloma and murine-human hybrid myeloma cell lines are also described for use in the preparation of human monoclonal antibodies.
The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the polypeptide. The binding specificity of monoclonal antibodies produced by hybridoma cells can be determined by immunoprecipitation or in vitro binding assays, such as Radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art. The binding affinity of monoclonal antibodies can be determined by Scatchard (Scatchard) analysis, for example, as described in Munson and polard, anal. Biochem.,107 (1980).
After the desired hybridoma cells have been identified, the desired clones can be subcloned by limiting dilution methods and cultured by standard methods. Suitable media for this purpose include, for example, modified Eagle Medium (DMEM) and RPMI-1640 medium. Alternatively, the hybridoma cells may be grown in ascites in a mammal.
Monoclonal antibodies secreted by subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification methods, such as protein a-sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
In some embodiments, the anti-C5 a antibody comprises the sequence of a clone selected from an antibody library (e.g., a phage library displaying scFv or Fab fragments), according to any one of the anti-C5 a antibodies described herein. Such clones may be identified by screening combinatorial libraries of antibody fragments having the desired activity. For example, various methods are known in the art for generating phage display libraries and screening these libraries for antibodies with desired binding properties. These Methods are reviewed, for example, in Hoogenboom et al, methods in Molecular Biology 178, 1-37 (O' Brien et al, ed., human Press, totowa, N.J., 2001), and in, for example, mcCafferty et al, nature 348; clackson et al, nature 352; marks et al, J.mol.biol.222:581-597 (1992); marks and Bradbury, methods in Molecular Biology 248 161-175 (Lo, ed., human Press, totowa, N.J., 2003); sidhu et al, j.mol.biol.338 (2): 299-310 (2004); lee et al, J.mol.biol.340 (5): 1073-1093 (2004); fellouse, proc. Natl. Acad. Sci. USA 101 (34): 12467-12472 (2004); and Lee et al, J.Immunol.methods 284 (1-2): 119-132 (2004).
In some phage display methods, V is cloned separately by Polymerase Chain Reaction (PCR) H And V L All components of the gene, randomly recombined in the phage library, and screenedPhage capable of binding antigen, as described in Winter et al, ann. The phage typically display the antibody fragment as an scFv fragment or as an Fab fragment. The immune-derived library phages provide high affinity antibodies to the immunogen without the need to construct hybridoma cells. Alternatively, natural libraries (e.g., from humans) can be cloned to provide a single source of antibodies to multiple non-self antigens and self antigens without any immunization, as described in Griffiths et al, EMBO J,12, 725-734 (1993). Finally, natural libraries can also be prepared by cloning non-rearranged V-gene fragments from stem cells and using PCR primers containing random sequences to encode the CDR3 hypervariable regions and to accomplish rearrangement in vitro as described in Hoogenboom and Winter, j.mol.biol., 227. Patent publications describing human antibody phage libraries include, for example, U.S. Pat. No.5,750,373 and US Patent Publication nos.2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.
The anti-C5 a antibody is prepared by phage display screening of the library for the portion of the anti-C5 a antibody that specifically binds to the target C5 a. The library may be a human scFv phage display library, having at least 1X 10 9 (e.g., at least 1X 10) 9 、2.5×10 9 、5×10 9 、7.5×10 9 、1×10 10 、2.5×10 10 、5×10 10 、7.5×10 10 Or 1X 10 11 ) A unique human antibody fragment of diverse species. In some embodiments, the library is a human natural library, constructed from DNA extracted from PMBCs and spleens of healthy subjects, comprising all human heavy and light chain subfamilies. In some embodiments, the library is a human natural library constructed from DNA extracted from PMBCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients, and patients with infectious diseases. In some embodiments, the library is a semi-synthetic human library in which the heavy chain CDR3 is completely random, with all amino acids (except cysteine) present at any given position with the same probability. (see, e.g., hoet, r.m.et al, nat.biotechnol.23 (3): 344-348, 2005). In some embodiments, the heavy chain CDR3 of the semi-synthetic human library is between 5 and 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24) amino acids in length. In some embodiments, the library is a fully synthetic phage display library. In some embodiments, the library is a non-human phage display library.
Phage clones with high affinity for target C5a can be screened by iterative binding of phage to target C5a, which target C5a is bound to a solid support (e.g., beads for solution panning or mammalian cells for cell panning), followed by removal of unbound phage and elution of specifically bound phage. Subsequently, the bound phage clones are eluted and used to infect appropriate host cells, e.g., e.coli XL1-Blue, for expression and purification. Phage clones that specifically bind C5a can be enriched by multiple rounds of panning (e.g., 2, 3, 4, 5, 6, or more rounds), such as solution panning, cell panning, or both. Specific binding of the enriched phage clones to the target C5a can be detected by any method known in the art, including, for example, ELISA and FACS.
Another method of screening antibody libraries is to display the proteins on the surface of yeast cells. Wittrup et al (U.S. Pat. Nos. 6,699,658 and 6,696,251) developed a method for displaying libraries in yeast cells. In this yeast display system, one component comprises the yeast lectin protein (Aga 1) anchored to the yeast cell wall, and the other component comprises a second subunit of the lectin protein Aga2, which can be displayed on the yeast cell surface by binding to the Aga1 protein via a disulfide bond. The Aga1 protein is expressed by integrating the Aga1 gene into the yeast chromosome. A single-chain variable fragment (scFv) library is fused to the Aga2 gene in a yeast display plasmid, and after transformation, the library remains in yeast due to the presence of additional nutritional markers. Both Aga1 and Aga2 proteins are expressed under the control of a galactose-inducible promoter.
Human antibody V Gene library (V) H And V K Fragments) were obtained by PCR method using a degenerate set of primers(Sbarlato, D.and Bradbury, A.Immunotechnology 3,271-278 1998). PCR templates were obtained from commercially available RNA or cDNA including PBMC, spleen, lymph nodes, bone marrow and tonsils. Will be independent of V H And V K After pooling of the PCR libraries, they were assembled into scFv format by overlap extension PCR (Sheets, M.D.et al, proc.Natl.Acad.Sci.USA 95,6157-6162 1998). To construct a yeast scFv display library, the resulting scFv PCR products were cloned into yeast display plasmids in yeast by homologous recombination. (Chao, G, et al, nat protocols.2006; 1 (2): 755-68.Miller KD, et al. Current Protocols in Cytometry 4.7.1-4.7.30, 2008).
anti-C5 a antibodies can be screened using a mammalian cell display system in which the antibody moiety is displayed on the cell surface and antibodies specifically targeting C5a are isolated by antigen-directed screening methods (as described in U.S. patent No.7,732,195b 2). Libraries of Chinese Hamster Ovary (CHO) cells displaying large amounts of human IgG antibody genes can be established and used to find clones expressing high affinity antibody genes. Another display system has been developed that allows the same protein to be displayed and secreted simultaneously on the cell surface by alternative splicing, wherein the displayed protein phenotype remains genotypically associated, allowing the secreted soluble antibody to be characterized in both biophysical and cell function-based assays. This approach overcomes many of the limitations of previous mammalian cell displays, and enables direct screening and maturation of antibodies in the form of full-length, glycosylated IgGs (Peter m. Bowers, et al, methods 2014, 65. Transient expression systems are suitable for a single round of antigen selection prior to antibody gene recovery and are therefore most useful for selecting antibodies from smaller libraries. Stable exosomal vectors offer an attractive option. Exosomal vectors can be efficiently transfected and stably maintained at low copy numbers, allowing for multiple rounds of panning and resolution of more complex antibody libraries.
IgG libraries were constructed based on the linkage of germline sequence V gene segments isolated from a population of human donors to a rearranged (D) J region. RNA collected from 2000 human blood samples was reverse transcribed into cDNA using V H And V K Specific primer amplification of V H And V K Fragments and purified by gel extraction. Will V H And V K The fragments were subcloned into display vectors containing IgG1 or K constant regions, respectively, and then 293T was electroporated or transduced into cells, thereby preparing an IgG library. To prepare scFv antibody display libraries, V was ligated H And V K To produce scFv, which are then subcloned into a display vector, which is then electroporated or transduced into 293T cells. It is well known that IgG libraries are constructed based on germline sequence V gene segments and rearranged (D) J regions isolated from a population of donors, which may be mice, rats, rabbits or monkeys.
Monoclonal antibodies can also be prepared by recombinant DNA methods, for example, as described in U.S. patent No.4,816,567. DNA encoding the monoclonal antibodies described herein can be readily isolated and sequenced by conventional methods (e.g., by oligonucleotide probes that specifically bind to genes encoding the light and heavy chains of murine antibodies). Hybridoma cells as described above or a C5 a-specific phage clone of the present application may be used as a source of such DNA. After isolation, the DNA may be placed in an expression vector, which is then transfected into a host cell, such as simian COS cells, chinese hamster ovary Cancer (CHO) cells, or myeloma cells that do not produce immunoglobulin, to obtain monoclonal antibodies synthesized in the recombinant host cells. The DNA may also be modified, for example, by replacing the human heavy and light chain constant regions with coding sequences and/or the homologous non-human sequences with framework regions (U.S. Pat. No.4,816,567; morrison et al, supra), or by covalently linking all or part of the coding sequence for an immunoglobulin polypeptide. Such non-immunoglobulin polypeptides may replace the constant region of an antibody herein, or may replace an antigen binding site in an antibody variable domain herein, forming a chimeric bivalent antibody.
The antibody may be a monovalent antibody. Methods of making monovalent antibodies are known in the art. For example, a recombinant expression method involving an immunoglobulin light chain and a modified heavy chain. The heavy chains are generally truncated at any position in the Fc region to prevent cross-linking of the heavy chains to each other. Alternatively, the relevant cysteine residues are substituted with other amino acid residues or deleted to prevent cross-linking.
In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, can be accomplished using any method known in the art.
Antibody variable domains with the desired binding specificity (antibody-antigen binding site) can be fused to immunoglobulin constant regions. Preferably to an immunoglobulin heavy chain constant region, which comprises at least part of the hinge, CH2 and CH3 regions. In some embodiments, the first heavy chain constant region (CH 1) comprising the site necessary for light chain binding is present in at least one fusion. The DNA encoding the immunoglobulin heavy chain fusion, and if desired the immunoglobulin light chain, is inserted into a separate expression vector and co-transfected into a suitable host organism.
Fully human and humanized antibodies
The anti-C5 a antibody (e.g., a full-length anti-C5 a antibody) can be a fully human antibody or a humanized antibody. Humanized forms of non-human (e.g., mouse) antibody portions are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (e.g., fv, fab ', F (ab') 2 scFv, or other antigen-binding subsequences of antibodies) that typically include minimal sequences derived from non-human immunoglobulins. Humanized antibodies include human immunoglobulins, immunoglobulin chains or fragments thereof (recipient antibody) in which residues from a CDR of the recipient are replaced by residues from a CDR of a non-human origin (donor antibody) having the desired specificity, affinity and performance, e.g., a mouse, rat or rabbit CDR. In some embodiments, the Fv framework region residues of the human immunoglobulin are substituted with corresponding residues of non-human origin. Humanized antibodies may also comprise amino acid residues that are neither within the recipient antibody nor within the introduced CDR or framework region sequences. Typically, a humanized antibody comprises at least one, and typically two, variable domains in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are human immunoglobulin consensus sequences.
Typically, humanized antibodies contain one or more amino acid residues introduced from a non-human source. Those amino acid residues of non-human origin are commonly referred to as "import" residues, typically from an "import" variable domain. According to some embodiments, humanization can be performed essentially as follows by Winter and co-workers (Jones et al, nature, 321-525 (1986); riechmann et al, nature,332, 323-327 (1988); verhoeyen et al, science,239, 1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Thus, the portion of such "humanized" antibodies (U.S. patent No.4,816,567), which is substantially less than a fully human antibody, has its variable domains replaced by corresponding sequences from non-human origin. In practice, humanized antibody portions are typically human antibody portions in which some CDR residues and possibly some framework region residues are substituted by residues from analogous sites in rodent antibodies.
Fully human antibodies are an alternative to humanization. For example, transgenic animals (e.g., mice) can now be prepared that are capable of producing a full human antibody library without producing endogenous immunoglobulins upon immunization. For example, it has been reported that homozygous deletion of the antibody heavy chain joining region (JH) gene in chimeric and germ-line mutant mice completely inhibits endogenous antibody production. Transfer of human germline immunoglobulin gene arrays into such germline mutant mice can produce human antibodies under antigen stimulation, see, e.g., akobovits et al, PNAS USA,90 2551 (1993); jakobovits et al, nature, 362; bruggemann et al, yeast in Immunol, 7 (1993); U.S. patent nos.5,545,806,5,569,825,5,591,669,5,545,807; and WO 97/17852. Alternatively, fully human antibodies can be prepared by introducing human immunoglobulin loci into transgenic animals (e.g., mice in which endogenous immunoglobulin genes have been partially or fully silenced). After antigen stimulation, it can be seen that the production of fully human antibodies is very similar in all respects to its production in humans, including gene rearrangement, assembly, and antibody libraries. Such processes are described, for example, in U.S. patent nos.5,545,807;5,545,806;5,569,825;5,625,126;5,633,425; and 5,661,016, and Marks et al, bio/Technology, 10; lonberg et al, nature, 368; morrison, nature, 368; fishwild et al, nature Biotechnology,14, 845-851 (1996); neuberger, nature Biotechnology,14 (1996); lonberg and Huszar, intern.Rev.Immunol.,13 (1995).
Fully human antibodies can also be generated by activating B cells in vitro (see U.S. patents 5,567,610and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, j.mol.biol.,227 (1991); techniques of Marks et al, j.mol.biol.,222 (1991). Cole et al, and Boerner et al, can also be used to prepare fully human monoclonal antibodies. See Cole et al, monoclonal Antibodies and Cancer Therapy, alan R.Liss, p.77 (1985) and Boerner et al, J.Immunol, 147 (1): 86-95 (1991).
anti-C5 a antibody variants
In some embodiments, the amino acid sequence of an anti-C5 a antibody variant provided herein (e.g., a full-length anti-C5 a antibody) is also under consideration. For example, it may be desirable to improve the binding affinity and/or other biological activity of an antibody. The amino acid sequence of an antibody variant may be prepared by introducing appropriate modifications in the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from and/or insertions into and/or substitutions of residues in the amino acid sequence of the antibody. The final construction can be accomplished by any combination of amino acid residue deletions, insertions, and substitutions that result in the desired characteristics. For example, antigen binding.
In some embodiments, anti-C5 a antibody variants are provided having one or more amino acid substitutions. The target sites for substitution mutations include hypervariable regions (HVRs) and Framework Regions (FRs). Amino acid substitutions may be introduced in the antibody of interest and the product screened for a desired activity, e.g., improved biological activity, retention/improvement of antigen binding capacity, reduced immunogenicity, or improved ADCC or CDC.
Conservative substitutions are shown in table 4 below.
TABLE 4 conservative substitutions
Figure SMS_12
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Figure SMS_13
Amino acids are classified into different classes according to their side chain properties:
a. hydrophobic amino acid: norleucine Norleucin, methionine Met, alanine Ala, valine Val, leucine Leu, isoleucine Ile;
b. neutral hydrophilic amino acids: cysteine Cys, serine Ser, threonine Thr, asparagine Asn, glutamine Gln;
c. acidic amino acids: aspartic acid Asp, glutamic acid Glu;
d. basic amino acids: histidine His, lysine Lys, arginine Arg;
e. contains chain orientation-affecting amino acids: glycine Gly, proline Pro;
f. aromatic amino acids: trp, tyr and Phe.
Substitutions of non-conservative amino acids include substitutions of one of the above classes into another.
An exemplary substitution variant is an affinity matured antibody, which can be conveniently generated using, for example, phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated, the variant antibody portion is displayed on a phage, and variants are screened for a particular biological activity (e.g., a biological activity or binding affinity based on a Reactive Oxygen Species (ROS) release assay). Alterations (e.g., substitutions) can be made in the HVRs regions to obtain improved biological activity or antibody affinity based on Reactive Oxygen Species (ROS) release assays. The resulting variant V may be detected at "hot spots" of the HVR, i.e., at residues encoded by codons that are frequently mutated during somatic maturation (see, e.g., chowdhury, methods mol. Biol.207:179-196 (2008)), and/or at Specific Determinant Residues (SDRs) H And V L Binding affinity of (4). Methods for constructing and reselecting affinity matures from secondary libraries have been described in some literature, e.g.，Hoogenboom et al.in Methods in Molecular Biology178:1-37(O'Brien et al.,ed.,Human Press,Totowa,NJ,(2001))。
In some embodiments of affinity maturation, diversity is introduced into the selected variable genes for affinity maturation by any of a variety of methods (e.g., error-prone PCR, strand shuffling, or oligonucleotide directed mutagenesis). A secondary library is then created. The library is screened to identify antibody variants with the desired affinity. Another method of introducing diversity includes HVR-mediated approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically recognized, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 regions are often particularly important targets.
In some embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, so long as such changes do not substantially reduce the ability of the antibody to bind antigen. For example, conservative changes that do not substantially reduce binding affinity (e.g., conservative substitutions as provided herein) may be made in HVRs. These changes may occur outside of the "hot spots" or SDRs regions of the HVRs. Variants V provided above in some embodiments H And V L The sequence, each HVR is either unaltered or contains no more than 1, 2 or 3 amino acid substitutions.
One useful method by which amino acid residues or regions of an antibody can be identified for targeted mutation is termed "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244. In this method, one or a group of target residues (e.g., charged residues such as arginine, aspartic acid, histidine, lysine and glutamic acid) are substituted with neutral or negatively charged amino acids (e.g., alanine or glutamic acid) to determine whether antibody-antigen interaction is affected. Substitutions may be further introduced at amino acid positions to demonstrate functional sensitivity of the position to the initial substitution. Alternatively, or in addition, the contact site between the antibody and the antigen is identified by the crystal structure of the antigen-antibody complex. These contact site residues and adjacent residues may be targeted or eliminated as candidates for substitution. The variants are screened to determine if they have the desired property.
Insertions of amino acid sequences, including fusions at the amino and/or carboxy terminus, ranging in length from 1 residue to polypeptides comprising 100 or more residues, also include insertions of 1 or more amino acid residues within the sequence. Examples of terminal insertions include antibodies with a methionyl residue at the N-terminus. Other insertional variants of the antibody molecule include the fusion of an enzyme (e.g., ADEPT) or polypeptide that increases the serum half-life of the antibody at the N-terminus or C-terminus of the antibody molecule.
Fc region variants
In some embodiments, one or more amino acid modifications are introduced into the Fc region of an antibody described herein (e.g., a full-length anti-C5 a antibody or an anti-C5 a antibody fusion protein), thereby generating an Fc region variant. In some embodiments, the Fc region variants have enhanced ADCC potency, typically associated with Fc-binding receptors (FcRs). In some embodiments, the Fc region variant has reduced ADCC potency. There are many examples of changes or mutations in the Fc sequence that affect its potency, for example, WO 00/42072 and Shields et al JBiol. Chem.9 (2): 6591-6604 (2001) describe antibody variants that have enhanced or reduced binding to FcRs. The contents of these publications are incorporated herein by reference.
Antibody-dependent cell-mediated cytotoxicity (ADCC) is the mechanism of action of therapeutic antibodies against tumor cells. ADCC is a cell-mediated immune defense in that when an antigen on the surface of the membrane of a target cell is bound by a specific antibody (e.g., an anti-C5 a antibody), effector cells of the immune system actively lyse the target cell (e.g., cancer cell). Typically the ADCC effect involves NK cells activated by the antibody. NK cells express the Fc receptor CD16. The receptor recognizes and binds the Fc portion of the antibody molecule bound to the surface of the target cell. The most common Fc receptors on NK cell surfaces are CD16 or Fc γ RIII. Binding of Fc receptors to the Fc region of antibodies results in activation of NK cells, release of cytolytic granules, followed by apoptosis of the target cell. Killing of tumor cells by ADCC can be determined by specific experiments with NK-92 cells transfected with high affinity FcR. The results were compared with wild-type NK-92 which does not express FcR.
In some embodiments, the present application also provides anti-C5 a antibody variants (e.g., full-length anti-C5 a antibody variants) comprising an Fc region having some, but not all, effector function such that it has an extended half-life in vivo, yet particular effector functions (e.g., CDC or ADCC) are not necessary or detrimental, such anti-C5 a antibodies being desirable candidates for the present application. The reduction/elimination of CDC and/or ADCC activity was confirmed by in vitro and/or in vivo cytotoxicity assays. For example, antibodies that lack fcyr binding capacity (and therefore may lack ADCC activity) but still retain FcRn binding capacity are confirmed by Fc receptor (FcR) binding assays. Among the major cells mediating ADCC, NK cells express only Fc γ RIII, whereas monocytes express Fc γ RI, fc γ RII and Fc γ RIII. Expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of ravech and Kinet Annu.Rev.Immunol.9:457-492 (1991). Non-limiting examples of assessing ADCC activity of a target molecule in vitro are described in u.s.pat. No.5,500,362 (see, e.g., hellstrom, i.et al, proc.nat' l acad.sci.sci.usa 83 nn Flow cytometry non-radioactive cytotoxicity assay (CellTechnology, inc. Mountain View, calif.) and CYTOTOX 96 nn Non-radioactive cytotoxicity assay (Promega, madison, wis.)). Effector cells used in such assays include Peripheral Blood Mononuclear Cells (PBMC) and natural killer cells (NK). Alternatively, additionally, ADCC activity of a target molecule is measured in vivo, for example, in animal models, as described by Clynes et al proc.nat' l acad.sci.usa 95. In addition, a C1q binding assay may be performed to confirm that the antibody is unable to bind to C1q and lacks CDC activity. See, e.g., WO2006/029879 and WO 2005/100402 for C1q and C3C binding ELISAs. To assess complement activation, CDC assays can be performed (see, e.g., gazzano-Santoro et al, J.Immunol.methods 202 (1996); cragg, M.S.et al, blood 101M.j. glennie, blood 103. FcRn binding and in vivo clearance/half-life are determined using methods known in the art (see, e.g., petkova, s.b.et al, int' l.immunol.18 (12): 1759-1769 (2006)).
An antibody with reduced effector function comprising substitution of one or more residues at residues 238, 265, 269, 270, 297, 327 and 329 of the Fc region (u.s.pat. No.6,737,056). These Fc variants include those substituted at two or more residues 265, 269, 270, 297 and 327, including those referred to as "DANA" with alanine substitutions at residues 265 and 297 (u.s.pat. No.7,332,581).
Such antibody variants with increased or decreased binding to FcRs have been described (see, e.g., U.S. Pat. No.6,737,056; WO2004/056312, and Shiels et al, J.biol. Chem.9 (2): 6591-6604 (2001)).
In some embodiments, an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody) variant is provided that comprises an Fc region variant having one or more amino acid substitutions capable of enhancing the ADCC effect. In some embodiments, the Fc region variant comprises one or more amino substitutions capable of enhancing ADCC effect at positions 298, 333, and/or 334 of the Fc region (EU residue numbering). In some embodiments, the anti-C5 a antibody (e.g., a full-length anti-C5 a antibody) variant comprises amino acid substitutions at positions S298A, E333A, and K334A of the Fc region.
In some embodiments, alterations in the Fc region result in altered (i.e., enhanced or diminished) C1q binding and/or Complement Dependent Cytotoxicity (CDC), as described in U.S. Pat.No.6,194,551, WO 99/51642, and Idusogene et al, J.Immunol.164:4178-4184 (2000).
In some embodiments, an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody) variant is provided that comprises an Fc region variant with one or more amino acid substitutions that are capable of increasing half-life or enhancing binding to an Fc receptor (FcRn). Antibodies with extended half-life and improved FcRn binding are described in US 2005/0014934A1 (Hinton et al). These antibody Fc regions comprise one or more amino acid substitutions that enhance binding of the Fc region to FcRn. These Fc variants comprise one or more substitutions in the Fc region at residue 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, for example at residue 434 of the Fc region (u.s.pat. No.7,371, 826).
See also Duncan & Winter, nature 322; U.S. Pat. No.5,648,260; other examples of Fc region variants are provided in u.s.pat.no.5,624,821 and WO 94/29351.
The present application contemplates anti-C5 a antibodies (e.g., full-length anti-C5 a antibodies) comprising any one of the Fc variants described herein, or a combination thereof.
Glycosylation variants
In some embodiments, an anti-C5 a antibody provided herein (e.g., a full-length anti-C5 a antibody) is altered to increase or decrease the degree of glycosylation of the anti-NGF antibody. Addition or deletion of glycosylation sites on the anti-C5 a antibody can be conveniently achieved by altering the amino acid sequence of the anti-NGF antibody or polypeptide portion thereof to add or remove one or more glycosylation sites.
Wherein the anti-C5 a antibody comprises an Fc region, to which the sugar can be altered. Natural antibodies produced by mammalian cells typically comprise branched biantennary oligosaccharides, which are typically linked to the CH2 domain Asn297 of the Fc region by N-linkage, see, e.g., wright et al, TIBTECH 15 (1997). The oligosaccharides may comprise a variety of sugars, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, as well as trehalose attached to the GlcNAc of the "stem" portion of the bi-antennary oligosaccharide structure. In some embodiments, anti-C5 a antibodies of the present application may be oligosaccharide modified, resulting in anti-C5 a antibody variants with certain improved properties.
The N-glycans attached to the CH2 domain of the Fc region are heterogeneous. Antibodies or Fc fusion proteins produced in CHO cells are fucosylated by fucosyltransferase activity, see Shoji-Hosaka et al, j.biochem.2006,140:777-83. Typically, a small fraction of naturally occurring nonfucosylated IgGs can be detected in human serum. N-glycosylation of the Fc region is important for its binding to Fc γ R; while the non-fucosylated N-glycans enhance the binding ability of Fc to Fc γ RIIIa. The enhanced binding to FcRIIIa results in an enhanced ADCC effect, which is advantageous in certain antibody therapeutic applications where cytotoxicity is required.
In some embodiments, when Fc-mediated cytotoxicity is not required, enhanced effector function may be detrimental. In some embodiments, the Fc fragment or CH2 domain is non-glycosylated. In some embodiments, glycosylation is prevented by mutating the N-glycosylation site in the CH2 domain.
In some embodiments, anti-C5 a antibody (e.g., full-length anti-C5 a antibody) variants are provided that comprise an Fc region, wherein the carbohydrate structures attached to the Fc region have reduced fucose or lack fucose, which may enhance ADCC function. In particular, provided herein are anti-C5 a antibodies having reduced fucose relative to the same anti-C5 a antibody produced by wild-type CHO cells. That is, they are characterized by having a lower amount of fucose than antibodies produced by native CHO cells (e.g., CHO cells producing the native glycosylated form, CHO cells containing the native FUT8 gene). In some embodiments, the N-linked glycans of the anti-C5 a antibody have less than 50%, 40%, 30%, 20%, 10%, or 5% fucose. For example, the fucose content of the anti-C5 a antibody may be 1% -80%, 1% -65%, 5% -65%, or 20% -40%. In some embodiments, the N-linked glycans of the anti-C5 a antibody do not comprise fucose, i.e., wherein the anti-C5 a antibody is completely free of fucose, or does not have fucose or is defucosylated. The content of fucose is determined by calculating the average content of fucose within the sugar chain attached to Asn297, relative to the total amount of all sugar structures (such as complexed, hybridized or mannose structures) attached to Asn297, measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546. Asn297 refers to the asparagine residue at position 297 of the Fc region (EU Fc region residue numbering system). However, due to minor sequence variations of the antibody, asn297 may also be located ± 3 amino acids upstream or downstream of position 297, i.e. between positions 294 and 300. These fucosylated variants may have enhanced ADCC function. See, for example, US Patent Publication nos. US2003/0157108 (Presta, l.), US 2004/0093621 (Kyowa Hakko Kogyo co., ltd). Examples of publications relating to antibody variants that are "defucosylated" or "fucose deficient" include, US 2003/0157108; WO 2000/61739; WO2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO2005/035586; WO 2005/035778; WO 2005/053742; WO 2002/031140; okazaki et al.J.mol.biol.336:1239-1249 (2004); yamane-Ohnuki et al Biotech.Bioeng.87:614 (2004). Cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking the protein fucosylation function (Ripka et al Arch. Biochem. Biophys.249:533-545 (1986); US Pat Appl No. US 2003/0157108A 1, presta, L; and WO 2004/056312A 1, adams et al, especially example 11), and gene knockout cell lines, such as the alpha-1, 6-fucosyltransferase gene, FUT8 gene knockout CHO cells (see Yamane-Ohnuki et al Biotech. Bioeng.87:614 (2004); kanda, Y.al., biotechnol. Bioeng.94 (4): 680-688 (2006); and WO 2003/085107).
anti-C5 a antibody (e.g., full-length anti-C5 a antibody) variants further provide bisected oligosaccharides, e.g., where the biantennary oligosaccharides attached to the Fc region of the anti-C5 a antibody are bisected by GlcNAc. Such anti-C5 a antibody (e.g., full-length anti-C5 a antibody) variants may have reduced fucosylation and/or enhanced ADCC function. Examples of such antibody variants are described in WO 2003/011878 (Jean-Mairet et al); pat. No.6,602,684 (Umana et al); US 2005/0123546 (Umana et al), and Ferrara et al, biotechnology and Bioengineering,93 (5): 851-861 (2006). Also provided are anti-C5 a antibody (e.g., full-length anti-C5 a antibody) variants having at least one galactose residue in an oligosaccharide linked to an Fc region. Such anti-C5 a antibody variants may have enhanced CDC function. Such variants are described, for example, in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).
In some embodiments, the anti-C5 a antibody (e.g., full-length anti-C5 a antibody) variant comprises an Fc region capable of binding to Fc γ RIII. In some embodiments, the anti-C5 a antibody (e.g., full-length anti-C5 a antibody) variant comprising an Fc region has ADCC activity in the presence of human effector cells (e.g., T cells) or enhanced ADCC activity in the presence of human effector cells as compared to an otherwise identical anti-C5 a antibody (e.g., full-length anti-C5 a antibody) having a human wild-type IgG1 Fc region.
Engineered variants of cysteine
In some embodiments, it is desirable to prepare cysteine engineered anti-C5 a antibodies (e.g., full length anti-C5 a antibodies) in which one or more amino acid residues are substituted with cysteine residues. In some embodiments, the substitution residue occurs at a accessible site of the anti-C5 a antibody. anti-C5 a immunoconjugates as further described herein can be prepared by substituting cysteine for those residues, with a reactive sulfhydryl group located at a accessible site of the anti-C5 a antibody, and can be used to conjugate the anti-C5 a antibody to other moieties, such as a drug moiety or a linker-drug moiety. Cysteine engineered anti-C5 a antibodies (e.g., full length anti-C5 a antibodies) can be prepared, for example, as described in u.s.pat. No.7,521,541.
Derivatives of the same
In some embodiments, the anti-C5 a antibodies provided herein (e.g., full-length anti-C5 a antibodies) can be further modified to include other non-protein portions known and readily available in the art. Suitable moieties for derivatizing the anti-C5 a antibody include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxolane, ethylene/maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers), dextran or poly (n-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, propylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde has advantages in manufacturing due to its stability in water. The polymer may have any molecular weight and may be branched or unbranched. The number of polymers attached to the anti-C5 a antibody may vary, and if more than one polymer is attached, they may be the same or different molecules. In general, the amount and/or type of polymer used for derivatization may be determined based on considerations including, but not limited to, the need to improve the properties or function of the anti-C5 a antibody, whether the anti-C5 a antibody derivative is used for therapy under particular conditions, and the like.
Pharmaceutical composition
Also provided herein are compositions (e.g., pharmaceutical compositions, also referred to herein as formulations) comprising any one of the anti-C5 a antibodies (e.g., full-length anti-C5 a antibodies), nucleic acids encoding the antibodies, vectors comprising nucleic acids encoding the antibodies, or host cells comprising the nucleic acids or vectors described herein. In some embodiments, there is provided a pharmaceutical composition comprising any one of the anti-C5 a antibodies described herein and a pharmaceutically acceptable carrier.
Suitable anti-C5 a antibody formulations can be obtained by mixing an anti-C5 a antibody of the desired purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences 1uth edition, osol, a.ed. (1980)), prepared in lyophilized or liquid formulation. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as: phosphates, citric acid and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (for example octadecyl dimethyl benzyl ammonium chloride; hexamethyl ammonium chloride; benzalkonium chloride; benzethonium chloride; phenol; butanol or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal composite (e.g., zinc-protein complex); and/or nonionic surfactants such as TWEEN TM ，PLURONICS TM Or polyethylene glycol (PEG); exemplary formulations are described in WO98/56418 and are expressly incorporated herein by reference. Lyophilized formulations suitable for subcutaneous administration are described in WO 97/04801. Such lyophilized formulations can be reconstituted with a suitable diluent to form a high protein concentration formulation, and the reconstituted formulation can be administered to the subject to be treated herein by subcutaneous administration. Cationic liposomes or liposomes can be used to deliver the anti-C5 a antibodies herein to cells.
The formulations described herein may comprise, in addition to an anti-C5 a antibody (e.g. a full-length anti-C5 a antibody), one or more other active substances necessary for the treatment of a particular condition, preferably substances having complementary activities and which do not adversely affect each other. For example, it may be desirable to further include an anti-tumor agent, a growth-inhibitory agent, a cytotoxic agent, or a chemotherapeutic agent in addition to the anti-C5 a antibody. These molecules are present in combination in amounts effective for the intended purpose. The effective amount of other substances will depend on the amount of anti-C5 a antibody in the formulation, the type of disease or disorder or treatment, and other factors as described above. These drugs are typically used at the same dosages and routes of administration as described herein, or at 1% to 99% of the currently used dosages.
The anti-C5 a antibody (e.g., full-length anti-C5 a antibody) can also be embedded in microcapsules prepared, for example, by coacervation techniques and interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in macroemulsions. Sustained release formulations can be prepared.
Sustained release formulations of anti-C5 a antibodies (e.g., full-length anti-C5 a antibodies) can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody (or fragment thereof), which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactic acid (U.S. Pat. No.3,773,919), L-glutamic acid and L-glutamic acid ethyl ester copolymers, nondegradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D (-) -3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid can release molecules for over 100 days, certain hydrogels can release proteins in a shorter time. When encapsulated antibodies are retained in vivo for extended periods of time, they may denature or aggregate upon exposure to moisture at 37 ℃, possibly resulting in loss of biological activity or altered immunogenicity. Rational strategies can be devised to stabilize anti-C5 a antibodies based on the corresponding mechanisms. For example, if the aggregation mechanism is found to be intermolecular S — S bond formation by thiodisulfide exchange, stabilization can be achieved by modifying sulfhydryl residues, lyophilizing in acidic solution, controlling water content, using appropriate additives, and developing specific polymer matrix compositions.
In some embodiments, the anti-C5 a antibody (e.g., a full-length anti-C5 a antibody) is formulated in a buffer comprising citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 (tween 80), or any combination thereof.
Formulations for in vivo administration must be sterile. This can be easily achieved by filtration, for example, using sterile filtration membranes.
Methods of treatment using anti-C5 a antibodies
anti-C5 a antibodies (e.g., full-length anti-C5 a antibodies) and/or compositions described herein can be administered to an individual (e.g., a mammal such as a human) to treat a disease and/or disorder (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) resulting from a deregulated C5a signaling pathway, including, but not limited to, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion-related injury, acute lung injury, pneumonia, acute and chronic transplant rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, solid kidney failure, rheumatoid arthritis, autoimmune disease, bechterew's disease, lupus-like disease, inflammatory bowel disease, crohn's disease, tumor growth, and solid organ cancer. Accordingly, the present application provides, in some embodiments, a method of treating a disease and/or disorder resulting from a dysregulation of the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to a subject an effective amount of a composition (e.g., a pharmaceutical composition) comprising an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody), such as any of the anti-C5 a antibodies described herein (e.g., a full-length anti-C5 a antibody), in some embodiments, the subject is a human.
For example, in some embodiments, a method is provided for treating an individual having a disease associated with a C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease), comprising administering to the individual an effective amount of a pharmaceutical composition comprising a C5a antibody (e.g., a full-length anti-C5 a antibody) that specifically binds to an epitope on human C5a, wherein the epitope comprises amino acid residues at position C5 a. In some embodiments, the anti-C5 a antibody is a full-length antibody. In some embodiments, the full-length anti-C5 a antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion-related injury, acute lung injury, pneumonia, acute and chronic transplant rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, solid renal failure, rheumatoid arthritis, autoimmune disease, bechterew's disease, lupus-like disease, inflammatory bowel disease, crohn's disease, tumor growth, and solid organ cancer. In some embodiments, the subject is a human.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with a C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody), whichThe anti-C5 a antibody of (1) comprises: heavy chain variable domain (V) H ) Said V is H Comprises the following steps: heavy chain complementarity determining region (HC-CDR) 1 comprising X 1 LSX 2 H (SEQ ID NO: 70), wherein X 1 Is D or E, X 2 Is I or M; HC-CDR2 comprising GFX 1 PX 2 X 3 GX 4 TIYAQNFQG (SEQ ID NO: 71), wherein X 1 Is A, D, E, G, L, N, P, Q, S, V or Y, X 2 D, E, F, I, L, N, R, S, T or V, X 3 Is A, D, F, I, L, N, Q or S, X 4 Is D, G, T or V; and HC-CDR3 comprising GISX 1 X 2 X 3 NDAFDI (SEQ ID NO: 74), wherein X 1 Is D, E or S, X 2 Is A, G, I, V or W, X 3 Is H or W; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASQSVX 1 SX 2 YLA (SEQ ID NO: 77) wherein X 1 Is K or S, X 2 Is N, R or S; LC-CDR2 comprising DASX 1 RX 2 T (SEQ ID NO: 78), wherein X 1 Is A, D, E or S, X 2 Is A, D or S; and LC-CDR3 comprising QQYYYX 1 X 2 PX 3 T (SEQ ID NO: 79), wherein X 1 Is A, D or I, X 2 Is L, P or S, X 3 Is I, L or T. In some embodiments, the anti-C5 a antibody is a full length antibody. In some embodiments, the full-length anti-C5 a antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion-related injury, acute lung injury, pneumonia, acute and chronic transplant rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, solid renal failure, rheumatoid arthritis, autoimmune disease, bechterew's disease, lupus-like disease, inflammatory bowel disease, crohn's disease, tumor growth, and solid organ cancer. In some embodiments, the subject is a human.
In some embodiments, a method for treating a disease associated with the C5a signaling pathway (e.g., self-treatment of disease) is providedImmune disease, inflammation, cancer, pain, respiratory and/or transplantation related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence shown in any of SEQ ID NOs:1-3, HC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs:6-31, and HC-CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs:38-44, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR comprising the amino acid sequence 1 shown in any of SEQ ID NOs:48-50, LC-CDR2 comprising the amino acid sequence shown in any of SEQ ID NOs:54-58, and LC-CDR3 comprising the amino acid sequence shown in any of SEQ ID NOs:62-66, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs:80-109, or a variant thereof having at least about 90% sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 80-109; and V L Said V is L Comprising the amino acid sequence set forth in any one of SEQ ID NOs:118-124 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 118-124.
In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 38, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise a polypeptide comprising: v H Said V is H Comprises the amino acid sequence SEQ ID NO:80; and V L Said V is L Comprises the amino acid sequence SEQ ID NO:118. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, a method is provided for treating a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer)Pain, respiratory and/or transplantation related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 81 or; and V L Said V is L Comprises the amino acid sequence SEQ ID NO:118. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 1, HC-CDR2, comprising the amino acid sequence SEQ ID NO 7, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 39,or the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO:82; and V L Said V is L Comprises the amino acid sequence SEQ ID NO:118. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 8, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 40, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 63, or said V L Comprises up to about 5 LC-CDRsAnd (4) amino acid substitution.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H 83 comprising the amino acid sequence SEQ ID NO; and V L Said V is L Comprises the amino acid sequence SEQ ID NO 119. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 64, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO:84; and V L Said V is L Comprises the amino acid sequence SEQ ID NO 120. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region And (3) a body. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 10 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 41, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO:85; and V L Said V is L Comprises the amino acid sequence SEQ ID NO:118. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130And (4) obtaining. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 11 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 55, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 86; and V L Said V is L Comprises the amino acid sequence SEQ ID NO. 121. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, a method is provided for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a compound of formula (i)An amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO:87; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 13, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 49, LC-CDR2 comprising the amino acid sequence SEQ ID NO 57, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 88; and V L Said V is L Comprises the amino acid sequence SEQ ID NO 123. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 14 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 50, LC-CDR2 comprising the amino acid sequence SEQ ID NO 58, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 66, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the antibodies described hereinThe C5a antibody comprises: v H Said V is H Comprises the amino acid sequence SEQ ID NO. 89; and V L Said V is L Comprising the amino acid sequence SEQ ID NO:124. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 15 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 90; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human I And gG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 16, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 91; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 17, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 92; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO:93; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 19, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48,LC-CDR2 comprising the amino acid sequence SEQ ID NO:56 and LC-CDR3 comprising the amino acid sequence SEQ ID NO:65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H 94 comprising the amino acid sequence SEQ ID NO; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 42, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 95; to be provided withAnd V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 43, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 96; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 44, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 97; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, a method for therapy and C5a messaging is providedA method of treating a subject having a pathway-related disease (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the subject an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 98; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acidsThe sequences SEQ ID NO 21 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 99; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 22 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56 and LC-CDR3 comprising the amino acid sequence SEQ ID N65 or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 100; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 23, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 101; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some implementationsIn an example, the anti-C5 a antibody described herein is a full-length anti-C5 a antibody comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 24 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 102; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 25 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 103; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, a method is provided for treating a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory tract, etc.)Inhalation and/or transplantation associated disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 104; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 105; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 28, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprises up to about 5 amino acids in the LC-CDRsSubstitution of (2).
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H 106 comprising the amino acid sequence SEQ ID NO; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 29 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO:107; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 30 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 108; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 31, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO:109; and V L Said V is L Comprising the amino acid sequence SEQ ID NO 122. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
For example, in some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individualAdministering an effective amount of a pharmaceutical composition comprising an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody), wherein the anti-C5 a antibody comprises a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: a heavy chain complementarity determining region (HC-CDR) 1 comprising ELSMH (SEQ ID NO: 3); HC-CDR2 comprising GFDPX 1 X 2 GETIYAQKFQG (SEQ ID NO: 72), where X 1 Is E or R, X 2 Is D or L; and HC-CDR3 comprising GISX 1 X 2 WNDAFDI (SEQ ID NO: 75), wherein X 1 Is D or S, X 2 Is G, I or W; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASQSVRNDLA (SEQ ID NO: 51); LC-CDR2 comprising DASDRAT (SEQ ID NO: 59); and LC-CDR3 comprising QQYMDSHPLT (SEQ ID NO: 67). In some embodiments, the anti-C5 a antibody is a full-length antibody. In some embodiments, the full-length anti-C5 a antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion-related injury, acute lung injury, pneumonia, acute and chronic transplant rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, solid renal failure, rheumatoid arthritis, autoimmune disease, bechterew's disease, lupus-like disease, inflammatory bowel disease, crohn's disease, tumor growth, and solid organ cancer. In some embodiments, the subject is a human.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 3, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:32-34, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs:38-39, and 42, or said V H Comprising up to about HC-CDRsSubstitution of 5 amino acids; and V L Said V is L Comprises the following steps: LC-CDR comprising the amino acid sequence 1 shown in SEQ ID NO. 51, LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 59, and LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO. 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprising an amino acid sequence set forth in any one of SEQ ID NOs:110-114 or a variant thereof having at least about 90% sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 110-114; and V L Said V is L Comprising the amino acid sequence set forth in SEQ ID NO:125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 125.
In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising ammoniaThe amino acid sequence SEQ ID NO 3, HC-CDR2, comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3, comprising the amino acid sequence SEQ ID NO 38, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 110; and V L Said V is L Comprises the amino acid sequence SEQ ID NO 125. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Of a variant of (1), whichThe LC-CDRs contain substitutions of up to about 5 amino acids.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 111; and V L Said V is L Comprises the amino acid sequence SEQ ID NO 125. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 33, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 112; and V L Said V is L Comprises the amino acid sequence SEQ ID NO 125. In some embodiments, the anti-C5 a antibodies described herein comprise IgG1 or Full-length anti-C5 a antibodies to IgG4 constant regions. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 34, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 113; and V L Said V is L Comprises the amino acid sequence SEQ ID NO 125. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises orConsists of amino acid sequence SEQ ID NO: 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 42, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO 114; and V L Said V is L Comprises the amino acid sequence SEQ ID NO 125. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
For example, in some embodiments, an individual is provided for treatment of a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases)Comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody), wherein the antibody comprises: heavy chain variable domain (V) H ) Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO 35, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 45, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 52, LC-CDR2 comprising the amino acid sequence SEQ ID NO 60, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 68, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs. In some embodiments, the anti-C5 a antibody is a full length antibody. In some embodiments, the full-length anti-C5 a antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion-related injury, acute lung injury, pneumonia, acute and chronic transplant rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, solid renal failure, rheumatoid arthritis, autoimmune disease, bechterew's disease, lupus-like disease, inflammatory bowel disease, crohn's disease, tumor growth, and solid organ cancer. In some embodiments, the subject is a human.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the amino acid sequence set forth in SEQ ID NO. 115 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO. 115; and V L Said V is L 126 or a variant thereof, and a polypeptide comprising the amino acid sequence shown in SEQ ID No. 126The variant has at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO 126.
In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
For example, in some embodiments, there is provided a method for treating an individual having a disease associated with a C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody), wherein the anti-C5 a antibody comprises a heavy chain variable domain (V) H ) Said V is H Comprises the following steps: heavy chain complementarity determining region (HC-CDR) 1 comprising NYAIN (SEQ ID NO: 5); HC-CDR2 comprising GIX 1 PFFGX 2 EDYAQKFQG (SEQ ID NO: 73), where X 1 Is V or Y, X 2 Is T or W; and HC-CDR3 comprising DLLX 1 GFDI (SEQ ID NO: 76), wherein X 1 Is E or H; and a light chain variable domain (V) L ) Said V is L Comprises the following steps: a light chain complementarity determining region (LC-CDR) 1 comprising RASHIDIETWLA (SEQ ID NO: 53); LC-CDR2 comprising GASNLQS (SEQ ID NO: 61); and LC-CDR3, which contains QQANNELPYT (SEQ ID NO: 69). In some embodiments, the anti-C5 a antibody is a full length antibody. In some embodiments, the full-length anti-C5 a antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion-related injury, acute lung injury, pneumonia, acute and chronic transplant rejection in transplant patients, graft-versus-host reaction, glomerular disease Glomerulonephritis, solid renal failure, rheumatoid arthritis, autoimmune diseases, bechterew's disease, lupus diseases, inflammatory bowel disease, crohn's disease, tumor growth and solid organ cancer. In some embodiments, the subject is a human.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 5, HC-CDR2 comprising the amino acid sequence shown in any one of SEQ ID NOs:36-37, and HC-CDR3 comprising the amino acid sequence shown in any one of SEQ ID NOs:46-47, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR comprising the amino acid sequence shown as SEQ ID NO. 53, LC-CDR2 comprising the amino acid sequence shown as SEQ ID NO. 61, and LC-CDR3 comprising the amino acid sequence shown as SEQ ID NO. 69, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprising the amino acid sequence set forth in any one of SEQ ID NOs:116-117 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 116-117; and V L Said V is L Comprising the amino acid sequence set forth in SEQ ID NO:127 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 127.
In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual for a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 36, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 46, or alternatively the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 69, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO:116; and V L Said V is L Comprises the amino acid sequence SEQ ID NO:127. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises Or consists of the amino acid sequence SEQ ID NO: 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, there is provided a method for treating an individual having a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease) comprising administering to the individual an effective amount of a composition comprising an anti-C5 a antibody, wherein the antibody comprises: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 37, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 47, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 69, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
In some embodiments, the anti-C5 a antibodies described herein comprise: v H Said V is H Comprises the amino acid sequence SEQ ID NO:117; and V L Said V is L Comprises the amino acid sequence SEQ ID NO:127. In some embodiments, the anti-C5 a antibodies described herein are full-length anti-C5 a antibodies comprising an IgG1 or IgG4 constant region. In some embodiments, the IgG1 is human IgG1. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 128. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 129. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO 130. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO 131.
In some embodiments, the subject is a mammal (e.g., human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.). In some embodiments, the subject is a human. In some embodiments, the subject is a clinical patient, a clinical trial volunteer, a laboratory animal, or the like. In some embodiments, the individual is less than 60 years of age (including, e.g., less than 50, 40, 30, 25, 20, 15, or 10 years of age). In some embodiments, the individual is older than 60 years (including, for example, older than 70, 80, 90, or 100 years). In some embodiments, the individual is diagnosed with or genetically predisposed to one or more diseases or disorders described herein (e.g., autoimmune diseases, inflammation, cancer, pain, respiratory and/or transplantation-related diseases). In some embodiments, the individual has one or more risk factors associated with one or more diseases or conditions described herein.
In some embodiments, the present application provides a method of delivering an anti-C5 a antibody (e.g., any of the anti-C5 a antibodies described herein, e.g., an isolated anti-C5 a antibody) to a cell expressing C5a on its surface in an individual, comprising administering to the individual a composition comprising the anti-C5 a antibody.
Many diagnostic methods and clinical descriptions of autoimmune diseases, inflammation, cancer, pain, respiratory and/or transplantation related diseases or any other disease exhibiting abnormal expression of C5a are known in the art. Such methods include, but are not limited to, e.g., immunohistochemistry, PCR, and Fluorescence In Situ Hybridization (FISH).
In some embodiments, the anti-C5 a antibodies (e.g., full-length anti-C5 a antibodies) and/or compositions described herein are used in combination with a second, third, or fourth agent (including, for example, an antineoplastic agent, a growth inhibitory agent, a cytotoxic agent, or a chemotherapeutic agent) to treat a disease associated with the C5a signaling pathway.
Cancer treatment is assessed using, for example, tumor regression, reduction in tumor weight or size, time to progression, survival, progression-free survival, overall response rate, duration of response, quality of survival, protein expression level, and/or activity. Methods of determining the effect of the treatment may be employed, including, for example, detecting a response by radiation imaging.
In some embodiments, the effect of treatment is evaluated as percent tumor growth inhibition (% TGI) calculated using the equation 100- (T/C × 100), where T is the relative average tumor volume for treated tumors and C is the relative average tumor volume for untreated tumors. In some embodiments, the% TGI is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, or more than 95%. In some embodiments, the therapeutic effect is assessed by changes in granulocyte morphology and/or an increase in the number of surviving granulocytes. In some embodiments, the therapeutic effect is assessed by an increase in cytokine secretion by monocytes.
Dosage and method of administration of anti-C5 a antibodies
The dosage of an anti-C5 a antibody (e.g., isolated anti-C5 a antibody) composition administered to an individual (e.g., human) may vary depending on the particular composition, mode of administration, and type of disease being treated. In some embodiments, the amount of the composition (e.g., a composition comprising an anti-C5 a antibody) is effective to produce an objective response (e.g., partial response or complete response) in the treatment of an autoimmune disease, inflammation, cancer, pain, respiration, and/or transplantation-related disease. In some embodiments, the amount of the anti-C5 a antibody composition is sufficient to produce a complete response in the individual. In some embodiments, the amount of the anti-C5 a antibody composition is sufficient to produce a partial response in the individual. In some embodiments, the anti-C5 a antibody composition is administered at a dose (e.g., when administered alone) sufficient to produce an overall response rate of greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90% in a population of individuals treated with the anti-C5 a antibody composition. The response of an individual to a treatment method described herein can be determined, for example, by the level of RECIST.
In some embodiments, the amount of the composition (e.g., a composition comprising an isolated anti-C5 a antibody) is sufficient to extend progression-free survival of the individual. In some embodiments, the amount of the composition is sufficient to extend the overall survival of the individual. In some embodiments, the amount of the composition (e.g., when administered alone) is sufficient to produce a clinical benefit of greater than 50%, 60%, 70%, or 77% in a population of individuals treated with the anti-C5 a antibody composition.
In some embodiments, the amount of a composition (e.g., a composition comprising an isolated anti-C5 a antibody), used alone or in combination with a second, third, and/or fourth agent, is sufficient to reduce the size of a tumor, the number of cancer cells, or the rate of tumor growth by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% as compared to the corresponding tumor size, number of cancer cells, or rate of tumor growth prior to treatment in the same subject or as compared to the corresponding activity in other subjects not receiving treatment. The magnitude of the therapeutic effect can be measured using standard methods, such as in vitro assays for purified enzymes, cell-based assays, animal models, or human assays.
In some embodiments, the amount of anti-C5 a antibody (e.g., a full-length anti-C5 a antibody) in the composition is below a level that causes a toxic effect (i.e., an effect above a clinically acceptable level of toxicity), or at a level where potential side effects can be controlled or tolerated, when the composition is administered to an individual.
In some embodiments, the amount of the composition approximates the Maximum Tolerated Dose (MTD) of the composition following the same dosing regimen. In some embodiments, the amount of the composition is greater than 80%, 90%, 95%, or 98% of the MTD.
In some embodiments, the amount of anti-C5 a antibody (e.g., full-length anti-C5 a antibody) in the composition is in the range of 0.001 μ g to 1000 μ g.
In any of the embodiments described above, the effective amount of anti-C5 a antibody (e.g., full-length anti-C5 a antibody) in the composition is in the range of 0.1 μ g/kg to 100mg/kg, calculated as body weight.
The anti-C5 a antibody composition can be administered to a subject (e.g., a human) by a variety of routes including, for example, intravenous injection, intraarterial administration, intraperitoneal injection, intrapulmonary administration, oral administration, inhalation administration, intravascular administration, intramuscular injection, intratracheal administration, subcutaneous injection, intraocular administration, intrathecal administration, mucosal administration, or transdermal administration. In some embodiments, a sustained release formulation of the composition is used. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered arterially. In some embodiments, the composition is administered intraperitoneally. In some embodiments, the composition is administered intrahepatically. In some embodiments, the composition is administered by hepatic arterial infusion. In some embodiments, the composition is administered to a site remote from the first lesion.
Article and kit
In some embodiments of the present application, an article of manufacture is provided that comprises a substance that can be used to treat a disease associated with a C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease), or to deliver an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody) to a cell that expresses C5a on its surface. The article may comprise a container and a label or package insert carried on or with the container. Suitable containers include, for example, bottles, vials, syringes, and the like. The container may be made of a variety of materials, such as glass or plastic. Typically, the container contains a composition effective to treat the disease or condition described herein and has a sterile port (e.g., the container can be an intravenous bag or a vial having a cap pierceable by a hypodermic injection needle). At least one active agent in the composition is an anti-C5 a antibody as described herein. The label or package insert indicates the particular condition for which the composition may be used to treat. The label or package insert further comprises instructions for administering the anti-C5 a antibody composition to a patient. Articles of manufacture and kits including combination therapies are contemplated herein.
Package insert refers to an insert typically contained within commercial packaging for therapeutic products that contains information regarding the indications, usage, dosages, administration, contraindications and/or warnings associated with the use of such therapeutic products. In some embodiments, the package insert indicates that the composition can be used to treat a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases). In some embodiments, the package insert indicates that the composition can be used to treat a disease or disorder selected from the group consisting of inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion-related injury, acute lung injury, pneumonia, acute and chronic transplant rejection in transplant patients, graft versus host reaction, glomerular disease, glomerulonephritis, solid renal failure, rheumatoid arthritis, autoimmune disease, bechterew's disease, lupus disease, inflammatory bowel disease, crohn's disease, tumor growth, and solid organ cancer.
In addition, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffer, gellin solution, or glucose solution. Other materials may also be included as desired from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
Also contemplated are kits that can be used for various purposes, such as for treating diseases associated with the C5a signaling pathway (e.g., autoimmune diseases, inflammation, cancer, pain, respiratory and/or transplantation related diseases), or for delivering an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody) to cells that express C5a on their surface, optionally in combination with an article of manufacture. The kits of the present application include one or more containers comprising an anti-C5 a antibody composition (or single dose form and/or article of manufacture), and in some embodiments, further comprising another agent (e.g., an agent described herein) and/or instructions for use consistent with any of the methods described herein. The kit may further include a description of selecting an appropriate subject for treatment. The instructions for use accompanying the kits of the present application are typically written instructions on a label or package insert (e.g., paper sheets contained within the kit), as well as machine-readable instructions (e.g., instructions on a magnetic or optical storage disk) that are also acceptable.
For example, in some embodiments, a kit includes a composition comprising an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody). In some embodiments, the kit comprises: a) A composition comprising any of the anti-C5 a antibodies described herein, and b) at least one other agent in an effective amount capable of enhancing the effect (e.g., therapeutic effect, detection effect) of the anti-C5 a antibody. In some embodiments, the kit comprises: a) A composition comprising any one of the anti-C5 a antibodies described herein, and b) instructions for administering the anti-C5 a antibody composition to a subject for treating a disease associated with a C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, a respiratory and/or transplantation-related disease). In some embodiments, the kit comprises: a) a composition comprising any of the anti-C5 a antibodies described herein, and b) at least one other agent in an effective amount capable of enhancing the effect of the anti-C5 a antibody (e.g., therapeutic effect, detection effect) and C) instructions for administering the anti-C5 a antibody composition and the other agent to an individual for treating a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease). The anti-C5 a antibody and the other substance may be present in separate containers or in the same container. For example, the kit may include one particular composition or two or more compositions, wherein one composition includes an anti-C5 a antibody and another composition includes another agent.
In some embodiments, the kit comprises one (or a set of) nucleic acids encoding an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody). In some embodiments, the kit comprises: a) A nucleic acid (or set) encoding an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody), and b) a host cell expressing the nucleic acid (or set of nucleic acids). In some embodiments, the kit comprises: a) A (or a set of) nucleic acids encoding an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody), and b) instructions for use, adapted for: i) Expressing an anti-C5 a antibody in a host cell, ii) preparing a composition comprising an anti-C5 a antibody, and iii) administering the composition comprising the anti-C5 a antibody to the subject to treat a disease associated with the C5a signaling pathway (e.g., an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related disease). In some embodiments, the kit comprises: a) a nucleic acid (or set) encoding an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody), b) a host cell expressing the nucleic acid (or set of nucleic acids), and C) instructions for use, adapted to: i) Expressing an anti-C5 a antibody in a host cell, ii) preparing a composition comprising an anti-C5 a antibody, and iii) administering the composition comprising the anti-C5 a antibody to the individual to treat a disease associated with the C5a signaling pathway (e.g., autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation-related diseases).
The kits described herein are packaged in a suitable form. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed mylar or plastic bags), and the like. The kit may optionally provide additional components, such as buffers and instructional information. Accordingly, the present application also provides articles of manufacture including vials, bottles, jars, flexible packaging (e.g., sealed mylar or plastic bags), and the like.
Instructions for use of the anti-C5 a antibody compositions will generally include information such as dosage, period of administration, and route of administration. The containers may be unit dose, bulk (e.g., multi-dose packages) or sub-unit dose. For example, a kit comprising a sufficient dose of an anti-C5 a antibody (e.g., a full-length anti-C5 a antibody) as described herein is provided to provide long-term effective treatment of an individual, e.g., one week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer. The kit may further comprise multiple unit doses of the anti-C5 a antibody, a pharmaceutical composition, and instructions for use, and packaged in sufficient quantities for storage and use in pharmacies, such as hospital pharmacies and compound pharmacies.
Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of the present application. The present application will now be described in more detail by reference to the following non-limiting examples. The following examples further illustrate the present application but should not be construed as in any way limiting its scope.
Detailed Description
In the examples disclosed below, the following abbreviations apply: complement components 5a (complement components 5a, c5a); avih-C5a (Avi-10 his-C5 a); bavih-C5a (Biotin-Avi-10 his-C5 a)
Example 1: preparation of recombinant human C5a and screening for Single chain antibodies (scFv) against C5a
Preparation of recombinant C5a antigen
Full-length human C5a (synthesized by shanghai agilent bioengineering, ltd.) was cloned by subcloning into prokaryotic and eukaryotic expression vectors pTWIN1 and pTT5, and His-tag and/or other tags commonly used by those skilled in the art were added to C5a. Construction of expression vectors producing pTWIN1-C5a and pTT5-Avi-10His-C5 a. Wherein "His or His represents a His tag and" Avi "represents an avidin tag. In addition, recombinant human C5a-desArg, cynomolgus monkey C5a (cynomolgus monkey C5a, cynoC5 a) expression vectors were constructed, respectively. Expression vectors pTWIN1-C5a-desArg and pTWIN1-cynoC5a were constructed to be generated as described above.
Recombinant human Avi-10His-C5a was expressed and purified according to the instrument manufacturer and kit instructions. Briefly, the eukaryotic expression vector was transfected into 293F cells and the cells were treated at 37 ℃ with 8% CO 2 And cultured at 120rpm for 5 days. And collecting the cell culture solution. The His-tag expressing protein was purified using a nickel column (Ni) according to the protocol. The specific operation is as follows: immobilized Metal Affinity Chromatography (IMAC) was performed using Ni-NTA from QIAGEN. Buffer A1 (50 mM Na) was first used 3 PO 4 0.15M NaCl, pH 7.2) equilibrated with a nickel column at a flow rate of 150cm/h. The pH of the culture supernatant was adjusted to 7.2, and the sample was applied at room temperature at a flow rate of 150cm/h. Subsequently, the column was again equilibrated with 6 column volumes of A1 buffer at a flow rate of 150cm/h. Finally, elution was performed using 10 column volumes of 50mM PB solution (containing 0.15M NaCl and 0.2M imidazole, pH 7.2) and the eluate was collected.
Recombinant human C5a, human C5a-desArg or cynomolgus monkey C5a were expressed and purified. Briefly, recombinant human C5a, human C5a-desArg, or cynomolgus monkey C5a prokaryotic expression vectors were transformed into E.coli and expanded. After collecting the cells, 300ml of 50mM Tris solution was added thereto, dissolved by stirring, and placed in a refrigerator at-40 ℃ overnight. The next day, the samples were thawed and the cells were disrupted using an ultrasonic disrupter. After centrifugation, the supernatant was collected and filtered through a 0.8um filter. The filtrate was diluted to 1L with water, adjusted to pH 6.5 with 10-fold diluted glacial acetic acid, and filtered through a 0.45um filter. After the sample is processed, the sample is purified by ion exchange chromatography (CM-sepharose FF), gel filtration chromatography (Superdex 75) and ion exchange column chromatography (SPHP) in sequence, and the concentration of the collected elution product is determined for later use after concentration.
Preparation of biotinylated C5a antigen
Avi-10His-C5a was biotinylated using biotinylated ligase B0101A (GeneCopoeia) according to the protocol. Briefly, bufferA/B and BirA ligase were added to Avi-10His-C5a followed by incubation at 30 ℃ for 2 hours. The biotinylated Avi-10His-C5a was named Bavih-C5a. The biotinylation efficiency was measured by ELISA. Briefly, bavih-C5a starting concentration was set at 500ng/ml, diluted at a ratio of 1. Signals were detected using SA-HRP, and biotinylated standards were used as controls. The efficiency of the Bavih-C5a biotinylation labeling was determined to be 70%.
Screening for anti-C5 a Single chain antibodies (scFv)
Construction of scFv antibody yeast display library: extracting RNA from 2000 human blood samples, reverse transcribing to obtain cDNA, and taking V H And V K Specific primer amplification of V H And V K Fragments, purified by gel recovery, ligated V H And V K scFv was constructed and cloned into yeast display plasmid PYD1, which was subsequently electroporated into yeast to obtain a scFv antibody yeast display library.
Screening for anti-C5 a single chain antibodies (scFv): after several rounds of panning, scFvs recognizing C5a were isolated from the yeast display library. Briefly, yeast cells expressing C5a scFv were enriched using MACS magnetic bead sorting. 1000OD yeast cells were centrifuged at 2500g for 5 minutes. The obtained cell pellet was resuspended in 1L SGCAA medium at an initial concentration of OD600=1, and induced to express at 20 ℃ under a culture condition of 250rpm for 40 to 48 hours. After centrifuging the cell culture fluid and washing the pellet with PBSM solution, the cell pellet was resuspended in 5-10 fold volume of PBSM solution containing 1. Mu.M Bavih-C5a and incubated at 4 ℃ for 1 hour. After centrifugation and PBSM washing, unbound antigen is washed away by the PBSM solution. After addition of the magnetic beads, the mixture was mixed well and then placed on a 4 ℃ rotator and incubated for 30 minutes. 2500g centrifugation for 5 minutes, discard the supernatant, 5-10 times volume of PBSM solution heavy suspension precipitation. 7ml of cell suspension was added to the column in one portion until all of the cell suspension flowed through the column. The cells bound to the column were collected, and further cultured and centrifuged to extract plasmids.
Phage display libraries were prepared and screened for scFv antibodies: the scFv antibody fragment obtained from the yeast library was subjected to PCR amplification using scFv-F and scFv-R primers, the obtained scFvs antibody fragment was cloned into phage display vector pDA 5 via SfiI, and after ligation, the plasmid was electroporated into TG1 phage competent cells to obtain scFv antibody phage display library. After a series of repeated screening steps, scFv antibodies that specifically bind C5a are isolated from phage display libraries. Briefly, take 2 × 10 11 The phage scFv library of PFU was added to Bavih-C5a and incubated at 37 ℃ for 2 hours. Phage bound to C5a were captured by magnetic beads coated with streptavidin, while unbound phage were washed away. After washing 8-15 times with TBST solution (the number of washing times increases with the number of screening rounds), phages specifically binding to C5a were eluted with Glycine-HCl solution (pH 2.2). Ampicillin was added, and these phages were infected into TG1 cells in the exponential growth phase, and after 1 hour of culture, helper phages were added and cultured overnight at 28 ℃ and 200 rpm. The culture fluid is collected the next day, and after centrifugation, the supernatant is obtained and enters the next round of screening. After the screening was completed, a panel of positive scFv antibodies was obtained.
C5a ELISA binding assay
C5a binding experiments were performed and scFv monoclonal antibodies were screened. This experiment was designed to identify scFv antibodies that bind to human recombinant C5 a. Briefly, recombinant human C5a antigen was dissolved in PBS solution, and 96-well plates were coated at 0.1 μ g/well overnight at 4 ℃. Prior to addition of the scFv antibody, the 96-well plate was washed with TBST solution, blocked with 5% milk at 37 ℃ for 1-2 hours, and washed with TBST solution. Each scFv sample was first diluted to 40 μ g/mL, 150 μ L was added to the wells of the first row, and then the 40 μ g/mL scFv samples were mixed at a ratio of 1:3, and adding the diluted solution into the rest holes. After incubation for 1 hour at 37 ℃, wash 6 times with TBST solution. 100 μ L of primary antibody and secondary antibodyAnti-mixture (mouse anti-flag (1 2500) and anti-mouse F C AP (1). mu.L of pNPP was added to each well and incubated at 37 ℃ for 10-20 minutes. The reaction was stopped with 3M NaOH. The absorbance values at 410nm were read, ELISA results were analyzed, and binding curves were generated by PRISM.
Example 2: preparation and characterization of full-length human C5a antibodies
Preparation of full-Length anti-C5 a antibodies
The most potential scFv antibodies were reconstituted into human IgG1 or IgG4 antibody molecules with the heavy chain constant region of human IgG1 or IgG4 and the light chain constant region of human kappa or lambda. Amplification of V from prokaryotic expression vectors L And V H Respectively, into eukaryotic expression vectors pTT5-K (comprising a kappa constant region) or pTT5-L (comprising a lambda constant region) and pTT5-H1 (comprising an IgG1 heavy chain constant region) or pTT5-H4 (comprising an IgG4 heavy chain constant region). Plasmids expressing light or heavy chains were extracted and co-transfected into 293F cells. 37 ℃ C., 8% CO 2 After culturing at 120rpm for 5 days, the culture was purified by Protein A affinity column chromatography. Briefly, a protein A column was first equilibrated with 6 column volumes of PBS buffer (containing 50mM PBS and 0.15M NaCl, pH 7.2) at a flow rate of 150cm/h. The pH of the culture supernatant was adjusted to 7.2, and the sample was applied at room temperature at a flow rate of 150cm/h. After complete equilibration, 50mM sodium citrate buffer (pH 3.5) was added for elution, and the eluate was collected.
In order to improve the affinity and activity of the C5a antibody, H1, H2, H3 and H4 in the constructed full-length antibody are selected as leading parent antibodies. scFv phage display libraries containing mutations in the CDR regions were prepared with H1, H2, H3 and H4 scFv, respectively. ROS release experiments are adopted to evaluate the biological activity of the antibody which can block the human C5a efficiently. And selecting the scFv antibody with high biological activity to construct a full-length antibody. A new round of screening for full-length antibodies was performed using the ROS release assay. And further performing biochemical and biological activity analysis on the screened lead optimized antibody.
Affinity of anti-C5 a antibodies
C5a ELISA binding assay:
miningUsing ELISA-probesThe full-length anti-C5 a antibodies H101-H114, H1071-H1715, H201-H204, H3, H4, H401 or the control antibody INab308 were evaluated for affinity to human C5a in a combined experiment with INab308 as a control. Briefly, the recombinant human C5a protein prepared in example 1 was coated on ELISA plates overnight at 4 ℃. After each full-length anti-C5 a antibody is diluted in a multiple ratio, the diluted full-length anti-C5 a antibody is added into a 96-well plate for incubation, and after TBST washing, an anti-human IgG-HRP antibody is added. After incubation at room temperature and TBST washing, pNPP is added into the wells for color development, and incubation is carried out for 10-20 minutes at 37 ℃. The reaction was stopped with 3M NaOH and the absorbance at 410nm was read.
The results are shown in FIGS. 1A-1E, and compared with the control antibody INab308, the optimized full-length anti-C5 a antibodies H101-H114, H1071-H1715 and H201-H204 (reconstructed into an adult IgG4 form) can bind to human C5a with higher or equivalent affinity, and the affinity of the optimized antibodies is also significantly better than that of the parent lead antibody.
The results are shown in figure 1F, where the full-length anti-C5 a antibody H3 (reconstituted in the form of human IgG 4) binds human C5a with comparable affinity compared to the control antibody INab 308.
The results are shown in figure 1G, where both the full-length anti-C5 a antibody H4 (reconstituted adult IgG4 format) and the optimized antibody H401 (reconstituted adult IgG4 format) bound human C5a with higher affinity than the control antibody INab 308.
In addition, the affinity of the full-length anti-C5 a antibody to cynomolgus C5a was also tested. Briefly, the recombinant cynomolgus monkey C5a protein prepared in example 1 was coated on ELISA plates overnight at 4 ℃. After each full-length anti-C5 a antibody is diluted in a multiple ratio, the diluted full-length anti-C5 a antibody is added into a 96-well plate for incubation, and after TBST washing, an anti-human IgG-HRP antibody is added. After incubation at room temperature and TBST washing, pNPP is added into the wells for color development, and incubation is carried out for 10-20 minutes at 37 ℃. The reaction was stopped with 3M NaOH and the absorbance at 410nm was read.
As a result, as shown in FIGS. 2A-2B, the anti-C5 a antibodies H1701, H1712, H1714, H4 and H401 (reconstituted in an adult IgG4 form) all cross-reacted with cynomolgus monkey C5 a.
C5 ELISA binding experiments:
at the same time, the affinity of the full-length anti-C5 a antibodies H1701, H1712, H1714, H3, H4 to the native human full-length complement component C5 was determined by ELISA binding assay with INab308 as control. Briefly, recombinant human C5 protein (Merck, 20488) was coated on ELISA plates overnight at 4 ℃. After each full-length anti-C5 a antibody was diluted in multiple, the diluted antibodies were added to 96-well plates, incubated, washed with TBST, and then added with an anti-human IgG-HRP antibody. Incubation is carried out at room temperature, after TBST washing, pNPP is added into the hole for color development, and incubation is carried out for 10-20 minutes at 37 ℃. The reaction was stopped with 3M NaOH and the absorbance at 410nm was read. The results are shown in FIGS. 2C-2E, where the anti-C5 a antibodies H1701, H1712, H1714, H3, H4 (reconstituted adult IgG4 format) bind human C5 with lower or comparable affinity compared to the control antibody INab 308.
C5a-desArg ELISA binding assay:
full-length anti-C5 a antibodies H1701, H1712, H1714, H4, H401 were evaluated for affinity to human C5a-desArg using an ELISA binding assay with INab308 as control. Briefly, recombinant human C5-desArg protein prepared in example 1 was coated on ELISA plates overnight at 4 ℃. After each full-length anti-C5 a antibody was diluted in multiple, the diluted antibodies were added to 96-well plates, incubated, washed with TBST, and then added with an anti-human IgG-HRP antibody. Incubation is carried out at room temperature, after TBST washing, pNPP is added into the hole for color development, and incubation is carried out for 10-20 minutes at 37 ℃. The reaction was stopped with 3M NaOH and the absorbance at 410nm was read.
Results as shown in figures 2F-2G, the anti-C5 a antibodies H1701, H1712, H1714, H4, H401 (reconstituted adult IgG4 format) bind human C5a-desArg with higher or comparable affinity compared to the control antibody INab 308.
Non-specific binding of anti-C5 a antibodies
Cross-reactivity with BV: the cross-reactivity of the optimized full-length anti-C5 a antibodies H106, H107, H108, H109, H1712 or H1714 with BV particles was tested using ELISA binding experiments. The experiment was performed as described previously (see
Figure SMS_14
I, et al,2012, mabs 4, 6,753-760) to detect cross-reactivity of full-length anti-C5 a antibodies with BV particles. Briefly, purified baculoviruses were coated On ELISA plates, 4 ℃ overnight. anti-C5 a antibodies H106, H107, H108, H109, H1712, H1714, INab308, positive control antibody lenzilumab or negative control antibody Tildrakizumab, respectively, were co-incubated with baculovirus at room temperature, washed with PBS, and anti-human IgG-HRP antibody was added. After incubation at room temperature, PBS washes, TMB was added to the wells for color development, followed by reading the absorbance value at 450 nm. And simultaneously setting a blank hole (without adding the antibody), calculating the ratio of the absorbance value of the sample hole to the absorbance value of the blank hole, and reflecting the cross reactivity of the anti-C5 a antibody and BV. />
As shown in FIG. 3, the anti-C5 a antibodies H106, H107, H108, H109, H1712, H1714 (reconstituted to the adult IgG4 format) did not react specifically with the BV particles as compared to the positive control lentizilumab.
Characterization of antibody binding affinity and dissociation constant (Kd):
biacore T200 (GE) was used to detect the binding affinity of the anti-C5 a antibodies H1701-IgG4 and H1712-IgG4 to human C5a or human C5, respectively. The H1701-IgG4 and H1712-IgG4 antibodies were immobilized on the sensor chip CM5, respectively, and the affinity of the antibodies to human C5a or human C5 was measured at different concentrations, which ranged from 10, 5, 2.5, 1.25, 0.625, 0.3125, 0.15625, 0.078, 0.039, 0.0195, and 0nM, with 0.625 and 0nM being repeated once, respectively. The binding and dissociation rates of the antibodies were measured using SPR techniques and the binding affinities were determined. Table 5 lists the Kon, koff and Kd values for H1701-IgG4, H1712-IgG4 and human C5a or human C5 antigen.
The results in Table 5 show that the optimized anti-C5 a antibodies H1701-IgG4, H1712-IgG4 bind to human C5a with comparable affinity and to human C5 with lower affinity than the control antibody INab 308.
TABLE 5
Figure SMS_15
Reactive Oxygen Species (ROS) release assay
C5a stimulates neutrophils to release Reactive Oxygen Species (ROS), thereby promoting neutrophil participation in a wide range of inflammatory responses. Based on this mechanism, the blocking effect of the anti-C5 a antibody was examined using induced neutrophils. The HL-60 cell line was human promyelocytic leukemia cell, briefly, HL60 cells were treated with 1mM dibutyryl cAMP sodium salt (sigma, D0260) for 48h to induce their differentiation, the cells were narrowed down into spindle shapes, and differentiated into neutrophils. C5a stimulates differentiated HL-60 cells to produce ROS in a dose-dependent manner.
The C5a antibodies H101-H114, H1701-H1715, H201-H204, H401 or the parent C5a antibodies H1-H4, diluted in multiple ratios, respectively, were premixed with C5a (5 nM) and the differentiated cells were treated with the mixture for 30 minutes. DCFH-DA fluorescent probe (sigma, D6883) was added and incubated. And detecting the fluorescence intensity under the conditions of excitation wavelength of 480nm and emission wavelength of 525nm by using a microplate reader. The inhibition rate of the C5 a-only stimulation and that of the C5 a-free stimulation were calculated as 0% and 100%, respectively, and the inhibition effect of the C5a antibody was calculated by normalizing the experimental data.
The results are shown in FIGS. 4A-4G, and the optimized anti-C5 a antibodies H101-H114, H1701-H1715, H201-H204, H401 and the parent C5a antibodies H1-H4 all have higher ability to inhibit ROS release.
Example 3: calcium ion influx experiment
C5aR1 is one of the receptors for C5a and is also a typical GPCR family member. When C5a binds to its receptor, downstream second messenger Ca is rapidly triggered by G protein signal transduction 2+ The inner flow of (2). The second messenger can play a role in signal transduction again, activate a downstream signal path, induce the expression of a target gene and play the biological effect of C5 a. Based on this, the experiment employed a CHO K1 cell line stably transfected with C5a receptor by detecting C5 a-induced Ca 2+ The signal changes were evaluated for blocking of the anti-C5 a antibody.
The diluted C5a antibodies H101, H103, H104, H105, H106, H1701 or H1712 were premixed in multiple ratios with C5a (20 nM), respectively, and added to the well plate of CHO K1 cell line seeded with stably transfected C5a receptors using a fluorescent probe (Fluo-4 Direct) TM Calcium, thermo fisher, F10471) captures Calcium ions, which in turn initiates a fluorescent signal. And detecting the fluorescence intensity under the conditions of excitation wavelength of 480nm and emission wavelength of 525nm by using a microplate reader. Will only stimulate C5a and The inhibition rate without C5a stimulation was 0% and 100%, respectively, and the inhibition effect of the antibody was calculated by normalizing the experimental data.
The results are shown in fig. 5, and the optimized anti-C5 a antibodies H101, H103, H104, H105, H106, H1701, and H1712 exhibited good ligand blocking ability, inhibiting the binding of C5a to its receptor C5aR 1.
Example 4: migration chemotaxis assay
C5a induces chemotactic migration of neutrophils and mononuclear macrophages to an inflammatory site, and is one of important biological activities. Based on the mechanism, an experiment is designed to evaluate the blocking effect of the antibody to be detected on the chemotaxis of C5 a-induced neutrophils and mononuclear macrophages. HL-60 or U937 cells were induced to differentiate into monocytes using 1mM dibutyryl cAMP sodium salt (sigma, D0260), both differentiated cells were chemotropic for C5a and dose-dependent.
A dilution of the C5a antibodies H101, H103, H105, H107, H108, H1701, H1712 or the control antibody INab308 in fold ratios were premixed with C5a (0.5 nM), respectively. HL-60 cells were seeded on the upper layer of a 96-well Transwell plate (Corning CLS 3380), and a mixture of the above-mentioned antibody and C5a was added to the lower layer of the 96-well Transwell plate (Corning CLS 3380). After incubation for 0.5h, cell-titer-glo (Promega G9242) substrate was added to the lower wells of a 96-well Transwell plate and the spontaneous light intensity was measured using a microplate reader. Since the luminescence intensity is proportional to the number of cells, the number of cells can be evaluated by the luminescence intensity, and thus the inhibitory effect of the C5a antibody on C5 a-induced cell chemotaxis can be evaluated. The inhibition rates of C5 a-only stimulation and no C5a stimulation were 0% and 100%, respectively, and the inhibition effect of the C5a antibody was calculated by normalizing the experimental data.
As shown in fig. 6, the optimized anti-C5 a antibodies H101, H103, H105, H107, H108, H1701, and H1712 exhibited significant inhibitory effects, were able to inhibit C5 a-induced chemotaxis, and were superior to the control antibody INab308.
Example 5: CD11b blocking assay in Whole blood
Upregulation of CD11b expression is a hallmark and sensitive marker of neutrophil activation, and the level of CD11b expression in neutrophils was used to assess neutrophil activation. The blocking activity of anti-C5 a antibodies H101, H107, H1701, H1712, H1714 (reconstituted adult IgG4 format) against recombinant human C5a and endogenous C5a was evaluated using the human whole blood model with INab308 as a control.
Human whole blood was incubated with human C5a (including recombinant human C5a or endogenous C5a (complete Technology, a 144)) alone or in combination with human C5a and different concentrations of each antibody (H101, H107, H1701, H1712, H1714 or control antibody INab 308), respectively. After incubation was complete, the erythrocytes were lysed by staining with the detection antibody CD11b FITC and CD11b MFI was analyzed by flow cytometry to reflect the level of neutrophil activation in the blood. The inhibitory activity of the anti-C5 a antibody was calculated by normalizing the experimental data by taking the inhibition rates of C5a stimulation only and no C5a stimulation as 0% and 100%, respectively.
As shown in fig. 7A-7B, the optimized C5a antibodies H101, H107, H1701, H1712 and H1714 can inhibit the stimulatory activity of recombinant human C5a (fig. 7A) or endogenous C5a (fig. 7B) on neutrophils in whole blood, and the inhibitory effect is better than or equal to that of the control antibody INab 308. Results as shown in fig. 7C, the optimized C5a antibodies H1702, H1703, H1706, H1710, H201, H202 (reconstituted adult IgG4 format) blocked C5a activity globally in a dose-dependent manner, and the presence of anti-C5 a antibodies significantly reduced endogenous C5 a-induced expression of CD11b on human neutrophils, even at an Ab: ag molar ratio of 0.25.
Example 6: serum hemolytic activity of anti-C5 a antibody
The complement system can be independently activated by three activation pathways, all eventually forming the Membrane Attack Complex (MAC). The presence of complement indigenous components in serum leads to activation of different complement activation pathways under specific experimental conditions, eventually forming a membrane-attacking complex, leading to red blood cell lysis. And C5b is one of the components of the tapping membrane complex. Based on this, experiments were performed to assess whether the C5a antibody would affect the biological activity of C5 convertase cleavage of C5 to C5 b.
Detecting the role of C5a antibody in the classical pathway of complement activation CH50eq assay is a method for determining the total complement activity in the classical pathway of activation in serum. In the experiment, anti-erythrocyte antibodies are used as activators of a classical complement pathway to sensitize erythrocytes. Sensitized erythrocytes can activate the complement components of serum, leading to hemolysis of the erythrocytes. The human serum was diluted at different concentrations to determine the amount of serum required for 50% lysis (CHSO) of the erythrocytes, with the sample without serum added as a negative lysis control (0% lysis rate) and the sample of rabbit erythrocytes completely lysed with distilled water as a positive control (100% lysis rate). The CH50eq experiment provides a method to indirectly measure the formation of tapping membrane complex (MAC) as MAC itself has a direct effect on hemolysis. This experiment is well known and routine to those skilled in the art, e.g., as Limei Zhao et al front immunol.2017may 31;8, 636; zhao et al, parasites & vectors, 2014feb 24;7, the following formula (I).
Briefly, guinea pig fresh whole blood was centrifuged to prepare guinea pig erythrocytes. Adding precooled HBSS-Ca 2+ -Mg 2+ The buffer (containing 0.5mM Mgcl2.6H2O and 0.15mM CaCl2, pH 7.4) was resuspended and a erythroblast suspension (3X 10) was prepared 8 /mL), then sensitized with rabbit anti-guinea pig erythrocyte antibodies (Fitzgerald, 20R-RR 019). Human serum was added to 96 well plates at 50. Mu.L/well. The anti-C5 a antibodies H106, H108, H111, H112, H113, H114, H1701, H1712, H1714, H4 and H401 or the control antibody Eculizumab are respectively diluted in multiple, added into a 96-well plate containing serum, mixed at 50 mu L/well, and incubated for 10min at room temperature in a dark place. Sensitized guinea pig erythrocytes were added to the above 96-well plate at 50. Mu.L/well and incubated at 37 ℃ for 30min. The above procedure activates the classical complement pathway, causing lysis of erythrocytes. The lysis was stopped by adding pre-cooled HBSS (Hank's Balanced Salt Solution) buffer (containing 10mM EDTA, pH 7.4), 80. Mu.L/well. The plate was centrifuged at 1200g for 5 min at 4 ℃. 100 μ L of the supernatant was transferred to a new 96-well plate and the absorbance at OD405nm was read using a microplate reader. The inhibition rates of the sample without the addition of anti-C5 a antibody and the sample without the addition of serum were respectively calculated as 0% and 100%, and the experimental data were normalized.
Testing the role of C5a antibodies in the complement-mediated alternative activation pathway: hemolysis by classical routeAssay hemolytic assays for the alternative pathway were performed in a similar manner. After ethylene glycol bisaminotetraacetic acid (EGTA) is added into the reaction system, the substance can react with Ca in serum 2+ Chelated but with Mg 2+ The classical pathway is blocked because of its weak binding capacity. Briefly, rabbit red blood cells were prepared by centrifuging fresh whole rabbit blood. Addition of precooled HBSS-Mg 2+ EGTA buffer (5 mM Mgcl2.6H2O and 10mM EGTA, pH 7.4) for resuspension, and preparing into erythrocyte suspension for later use. Human blood was added to 96-well plates at 50. Mu.L/well. anti-C5 a antibodies H101, H103, H105, H106, H107, H108, H109, H110, H111, H112, H113, H114, H1701, H1702, H1706, H1710, H1712, H1714 or a control antibody Eculizumab are respectively diluted in a multiple ratio, added into a 96-well plate containing serum, mixed at 50 mu L/well, and incubated for 10min at room temperature in a dark place. Rabbit red blood cells were added to the above 96-well plate at 50. Mu.L/well and incubated at 37 ℃ for 30min. The above procedure activates the alternative complement pathway, causing lysis of erythrocytes. The lysis was stopped by adding pre-cooled HBSS buffer (containing 10mM EDTA, pH 7.4), 80. Mu.L/well. The plate was centrifuged at 1200g for 5 min at 4 ℃. 100 μ L of the supernatant was transferred to a new 96-well plate and the absorbance at OD405nm was read using a microplate reader. The inhibition rates of the samples without anti-C5 a antibody and the samples without serum were calculated as 0% and 100%, respectively, and the experimental data were normalized.
In the classical activation pathway, results are shown in FIGS. 8A-8B, with the addition of the C5 antibody Eculizumab inhibits hemolytic reaction in a dose-dependent manner, whereas the optimized anti-C5 a antibodies H106, H108, H111, H112, H113, H114 (reconstituted adult IgG4 format) (FIG. 8A) or anti-C5 a antibodies H1701, H1712, H1714, H4, H401 (reconstituted adult IgG4 format) (FIG. 8B) do not inhibit serum hemolytic activity.
In the bypass activation pathway, C5 antibody Eculizumab, which inhibits hemolytic reaction in a dose-dependent manner after addition, whereas the optimized anti-C5 a antibodies H101, H103, H105, H1701, H1702 (reconstituted adult IgG4 form) (fig. 8C) or anti-C5 a antibodies H106, H107, H108, H109, H110, H111, H112, H113, H114, H1701, H1706, H1710, H1712, H1714 (reconstituted adult IgG4 form) (fig. 8D) do not inhibit serum hemolytic activity.
In summary, the above anti-C5 a antibodies do not affect the function of C5b in the complement-mediated classical activation pathway, nor the function of C5b in the alternative activation pathway.
Example 7: in vivo bioactivity assay for anti-C5 a antibodies
C5a has a strong chemotactic effect on neutrophils. Intravenous injection of human C5a into mice rapidly caused neutrophil migration to peripheral tissues within a short time (3-5 minutes), resulting in a significant decrease in neutrophils in whole blood.
Briefly, mice were administered either test or control antibodies by intraperitoneal injection 24 hours prior to the experiment and 10 μ g of human C5a was injected into each mouse by intravenous injection on the day of the experiment. After 5 minutes, blood was collected for anticoagulation, and the number of neutrophils in the whole blood was measured. The effect of anti-C5 a antibodies was assessed by the reduction of C5 a-induced neutrophil chemotaxis.
The results are shown in fig. 9, where C5 a-induced neutrophil chemotaxis was evident, and the optimized anti-C5 a antibodies H1712-IgG4 and H101-IgG4 showed a great inhibitory effect (P < 0.0001) in C5 a-induced neutrophil chemotaxis, comparable to or better than that of the control antibody INab308.
Example 8: pharmacokinetics of anti-C5 a antibodies
PK study in rats: 40 rats (body weight about 0.25 kg/rat) were divided into two groups, one group was intravenously injected with the anti-C5 a antibody at a dose of 10mg/kg, and the other group was subcutaneously injected with the anti-C5 a antibody at a dose of 10 mg/kg. Rats in each large group were divided into four groups and injected with H1701, H1712, H1714 or the control antibody INab308, respectively. Blood was collected from each animal at 1 day before injection, 0.25h, 2h, 4h, 8h, 1 day, 3 days, 5 days, 7 days, 9 days, 11 days, 15 days, 18 days, 21 days, 27 days, 30 days, and 33 days after injection, respectively. Blood samples were collected at 1mL per time point, centrifuged at 5000g for 15 minutes to obtain plasma, and the plasma was aliquoted into 50 μ L and stored in a-80 ℃ freezer for evaluation of the pharmacokinetics of the antibodies in rats.
Plasma was analyzed for H1701, H1712, H1714 and INab308 concentrations using ELISA. Briefly, 96-well plates were coated with synthetic human C5a protein. After PBST washing, blocking with 200. Mu.L PBS-solubilized milk for 1 hour. After several PBST washes, plasma was added and incubated at 37 ℃ for 1 hour. After washing the 96-well plate 6 times with 0.1% TBST, 100. Mu.L of goat anti-human Fc antibody-AP (diluted 1: 3000 with PBS) was added to each well, and incubated for 1 hour. After washing 6 times with 0.1% TBST, 50. Mu.L pNPP was added to each well, and color development was carried out at 37 ℃ for 10 to 20 minutes. The absorbance value at 410nm was read using a microplate reader.
In the subcutaneous route, the results are shown in fig. 10A, with the optimized anti-C5 a antibodies H1701 and H1712 having a longer half-life than the control antibody INab 308. In contrast, in the intravenous route, the results are shown in fig. 10B, and the half-lives of the optimized anti-C5 a antibodies H1701 and H1712 are comparable to the half-life of the control antibody INab 308.

Claims (34)

1. An isolated anti-C5 a antibody, wherein the anti-C5 a antibody comprises:
heavy chain variable domain (V) H ) Said V is H Comprises the following steps:
heavy chain complementarity determining region (HC-CDR) 1 comprising X 1 LSX 2 H (SEQ ID NO: 70), wherein X 1 Is D or E, X 2 Is I or M;
HC-CDR2 comprising GFX 1 PX 2 X 3 GX 4 TIYAQNFQG (SEQ ID NO: 71), wherein X 1 Is A, D, E, G, L, N, P, Q, S, V or Y, X 2 D, E, F, I, L, N, R, S, T or V, X 3 Is A, D, F, I, L, N, Q or S, X 4 Is D, G, T or V; and
HC-CDR3 comprising GISX 1 X 2 X 3 NDAFDI (SEQ ID NO: 74), wherein X 1 Is D, E or S, X 2 Is A, G, I, V or W, X 3 Is H or W;
and a light chain variable domain (V) L ) Said V is L Comprises the following steps:
a light chain complementarity determining region (LC-CDR) 1 comprising RASQSVX 1 SX 2 YLA (SEQ ID NO: 77) wherein X 1 Is K or S, X 2 Is N, R or S;
LC-CDR2 comprising DASX 1 RX 2 T (SEQ ID NO: 78), wherein X 1 Is A, D, E or S, X 2 Is A, D or S; and
LC-CDR3 comprising QQYYYX 1 X 2 PX 3 T (SEQ ID NO: 79), wherein X 1 Is A, D or I, X 2 Is L, P or S, X 3 Is I, L or T.
2. An isolated anti-C5 a antibody, wherein the anti-C5 a antibody comprises:
V H said V is H Comprises the following steps:
HC-CDR1 comprising an amino acid sequence set forth in any of SEQ ID NOs:1-3, or a variant thereof comprising up to about 3 amino acid substitutions;
HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:6-31 or a variant thereof comprising up to about 3 amino acid substitutions; and
HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs:38-44 or a variant thereof comprising up to about 3 amino acid substitutions;
And V L Said V is L Comprises the following steps:
LC-CDR1 comprising an amino acid sequence set forth in any one of SEQ ID NOs:48-50 or a variant thereof comprising up to about 3 amino acid substitutions;
LC-CDR2 comprising an amino acid sequence set forth in any one of SEQ ID NOs:54-58 or a variant thereof comprising up to about 3 amino acid substitutions; and
LC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs:62-66 or a variant thereof comprising up to about 3 amino acid substitutions.
3. An isolated anti-C5 a antibody, wherein the anti-C5 a antibody comprises: v H Said V is H Comprises a V shown as any one of SEQ ID NOs:80-109 in amino acid sequence H Comprising HC-CDR1, HC-CDR2 and HC-CDR3, and V L Said V is L Comprises ammonia as shown in any one of SEQ ID NOs:118-124V shown in the amino acid sequence L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
4. The isolated anti-C5 a antibody of any one of claims 1-3, comprising:
(i)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 38, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(ii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 6, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(iii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 7, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L Comprises up to about 5 LC-CDRsSubstitution of amino acids;
(iv)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 8, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 40, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 63, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(v)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO 9, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 64, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(vi)V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 10 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 41, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 54, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 62, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(vii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 11, and HC-CDR3, comprising39, or said V, comprising the amino acid sequence SEQ ID NO H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 55, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(viii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(ix)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 13 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 49, LC-CDR2 comprising the amino acid sequence SEQ ID NO 57, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(x)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 14, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID50, LC-CDR2 comprising the amino acid sequence SEQ ID NO 58, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 66, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xi)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 15 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 16, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xiii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 17, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xiv)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 18, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xv)V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 19, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xvi)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 42, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xvii)V H said V is H Comprises the following steps: HC-CDR1, comprising the amino acid sequence SEQ ID NO 2, HC-CDR2, comprising the amino acid sequence SEQ ID NO 12, and HC-CDR3, comprising the amino acid sequence SEQ ID N O43, or said V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xviii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 12 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 44, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xix)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 20 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xx)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 21, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2, comprising56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xxi)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 22 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xxii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 23, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xxiii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 24, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xxiv)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 25 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xxv)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 26 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xxvi)V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 27, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xxvii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 28 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, orV H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xxviii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 29 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(xxix)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 30, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acid sequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; or
(xxx)V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO 31, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H Comprises substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 48, LC-CDR2 comprising the amino acidsSequence SEQ ID NO 56, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 65, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
5. The isolated anti-C5 a antibody of any one of claims 1-4, comprising: v H (ii) comprising an amino acid sequence set forth in any one of SEQ ID NOs:80-109, or a variant thereof having at least about 90% sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 80-109; and V L Comprising an amino acid sequence set forth in any one of SEQ ID NOs:118-124 or a variant thereof having at least about 90% sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 118-124.
6. The isolated anti-C5 a antibody of claim 5, comprising:
(i)V H comprising the amino acid sequence of SEQ ID NO:80 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 80; and V L Comprising the amino acid sequence of SEQ ID NO. 118 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 118;
(ii)V H (ii) comprising the amino acid sequence of SEQ ID NO:81 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 81; and V L Comprising the amino acid sequence of SEQ ID No. 118 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 118;
(iii)V H (ii) comprising the amino acid sequence of SEQ ID No. 82 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 82; and V L Comprising the amino acid sequence of SEQ ID NO. 118 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 118;
(iv)V H comprising the amino acid sequence SEQ ID NO 83 or a variant thereof having the amino acid sequence SEQ ID NO 83At least about 90% sequence identity; and V L Comprising the amino acid sequence of SEQ ID NO 119 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 119;
(v)V H comprising the amino acid sequence of SEQ ID NO:84 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 84; and V L Comprising the amino acid sequence of SEQ ID No. 120 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 120;
(vi)V H 85 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 85; and V L Comprising the amino acid sequence of SEQ ID NO. 118 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 118;
(vii)V H comprising the amino acid sequence of SEQ ID No. 86 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 86; and V L Comprising the amino acid sequence of SEQ ID NO. 121 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 121;
(viii)V H comprising the amino acid sequence of SEQ ID No. 87 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 87; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(ix)V H comprising the amino acid sequence of SEQ ID NO:88 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 88; and V L Comprising the amino acid sequence of SEQ ID No. 123 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 123;
(x)V H Comprising the amino acid sequence SEQ ID NO. 89 or a variant thereof having at least the amino acid sequence SEQ ID NO. 89About 90% sequence identity; and V L Comprising the amino acid sequence of SEQ ID No. 124 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 124;
(xi)V H comprising the amino acid sequence of SEQ ID No. 90 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 90; and V L 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122;
(xii)V H comprising the amino acid sequence of SEQ ID No. 91 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 91; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xiii)V H comprising the amino acid sequence of SEQ ID No. 92 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 92; and V L 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122;
(xiv)V H Comprising the amino acid sequence of SEQ ID NO:93 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 93; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xv)V H comprising the amino acid sequence SEQ ID NO 94 or a variant thereof having at least about 90% sequence identity to the amino acid sequence SEQ ID NO 94; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xvi)V H comprising the amino acid sequence SEQ ID NO 95 or a variant thereof having at least about the amino acid sequence SEQ ID NO 9590% sequence identity; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xvii)V H comprising the amino acid sequence of SEQ ID NO:96 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 96; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xviii)V H Comprising the amino acid sequence of SEQ ID No. 97 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 97; and V L 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122;
(xix)V H comprising the amino acid sequence of SEQ ID NO 98 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 98; and V L 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122;
(xx)V H comprising the amino acid sequence of SEQ ID NO 99 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 99; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xxi)V H comprising the amino acid sequence of SEQ ID No. 100 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 100; and V L 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122;
(xxii)V H Comprising the amino acid sequence SEQ ID NO 101 or a variant thereof having at least the amino acid sequence SEQ ID NO 101About 90% sequence identity; and V L 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122;
(xxiii)V H comprising the amino acid sequence of SEQ ID No. 102 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 102; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xxiv)V H 103 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 103; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xxv)V H comprising the amino acid sequence of SEQ ID No. 104 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 104; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xxvi)V H 105 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 105; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xxvii)V H 106 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 106; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xxviii)V H 107 or a variant thereof, which variant corresponds to the amino acid sequence SEQ ID107 has at least about 90% sequence identity; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122;
(xxix)V H comprising the amino acid sequence of SEQ ID NO:108 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 108; and V L Comprising the amino acid sequence of SEQ ID NO 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO 122; or
(xxx)V H Comprising the amino acid sequence of SEQ ID No. 109 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 109; and V L Comprising the amino acid sequence of SEQ ID No. 122 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 122.
7. An isolated anti-C5 a antibody, wherein the anti-C5 a antibody comprises:
heavy chain variable domain (V) H ) Said V is H Comprises the following steps:
a heavy chain complementarity determining region (HC-CDR) 1 comprising ELSMH (SEQ ID NO: 3);
HC-CDR2 comprising GFDPX 1 X 2 GETAYAQKFQG (SEQ ID NO: 72), where X 1 Is E or R, X 2 Is D or L; and
HC-CDR3 comprising GISX 1 X 2 WNDAFDI (SEQ ID NO: 75), where X 1 Is D or S, X 2 Is G, I or W;
and a light chain variable domain (V) L ) Said V is L Comprises the following steps:
a light chain complementarity determining region (LC-CDR) 1 comprising RASQSVRNDLA (SEQ ID NO: 51);
LC-CDR2 comprising DASDRAT (SEQ ID NO: 59); and
LC-CDR3 comprising QQYMDSHPLT (SEQ ID NO: 67).
8. An isolated anti-C5 a, wherein the anti-C5 a antibody comprises:
V H said V is H Comprises the following steps:
HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 3 or a variant thereof comprising up to about 3 amino acid substitutions;
HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:32-34 or a variant thereof comprising up to about 3 amino acid substitutions; and
HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs:38-39 and 42, or a variant thereof comprising substitutions of up to about 3 amino acids;
and V L Said V is L Comprises the following steps:
an LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 51 or a variant thereof comprising up to about 3 amino acid substitutions;
an LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 59 or a variant thereof comprising up to about 3 amino acid substitutions; and
LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO. 67 or a variant thereof comprising up to about 3 amino acid substitutions.
9. An isolated anti-C5 a antibody, wherein the anti-C5 a antibody comprises: v H Said V is H Comprising a V as set forth in any one of the amino acid sequences of SEQ ID NOs:110-114 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3, and V L Said V is L Comprising V as shown in amino acid sequence SEQ ID NO 125 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
10. The isolated anti-C5 a antibody of any one of claims 7-9, comprising:
(i)V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 38, or else the V H Variant of (1), HSubstitutions in the C-CDRs of up to about 5 amino acids; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(ii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(iii)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 33, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids;
(iv)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 34, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 39, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3, comprising67, or said V, comprising the amino acid sequence SEQ ID NO L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; or
(v)V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 3, HC-CDR2 comprising the amino acid sequence SEQ ID NO 32, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 42, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 51, LC-CDR2 comprising the amino acid sequence SEQ ID NO 59, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 67, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
11. The isolated anti-C5 a antibody of any one of claims 7-10, comprising: v H Comprising an amino acid sequence set forth in any one of SEQ ID NOs:110-114, or a variant thereof having at least about 90% sequence identity to an amino acid sequence set forth in any one of SEQ ID NOs: 110-114; and V L Comprising the amino acid sequence set forth in SEQ ID NO:125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 125.
12. The isolated anti-C5 a antibody of claim 11, comprising:
(i)V H comprising the amino acid sequence of SEQ ID NO. 110 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO. 110; and V L Comprising the amino acid sequence of SEQ ID No. 125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 125;
(ii)V H Comprising the amino acid sequence of SEQ ID No. 111 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 111; and V L 125 or a variant thereof, said variant being associated with ammonia125 has at least about 90% sequence identity;
(iii)V H (ii) comprising the amino acid sequence of SEQ ID No. 112 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 112; and V L Comprising the amino acid sequence of SEQ ID No. 125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 125;
(iv)V H comprising the amino acid sequence of SEQ ID No. 113 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 113; and V L Comprising the amino acid sequence of SEQ ID No. 125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 125; or
(v)V H Comprising the amino acid sequence SEQ ID NO:114 or a variant thereof having at least about 90% sequence identity to the amino acid sequence SEQ ID NO: 114; and V L Comprising the amino acid sequence of SEQ ID No. 125 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 125.
13. An isolated anti-C5 a antibody, wherein the anti-C5 a antibody comprises: v H Comprising the V as shown in the amino acid sequence SEQ ID NO. 115 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3; and V L Comprising a V as shown in the amino acid sequence SEQ ID NO:126 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
14. The isolated anti-C5 a antibody of claim 13, comprising: v H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 4, HC-CDR2 comprising the amino acid sequence SEQ ID NO 35, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 45, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 52, LC-CDR2 comprising an amino acidSequence SEQ ID NO 60, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 68, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
15. The isolated anti-C5 a antibody of any one of claims 13-14, comprising:
V H (ii) comprising the amino acid sequence set forth in SEQ ID No. 115 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID No. 115; and V L Comprising the amino acid sequence set forth in SEQ ID NO:126 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 126.
16. An isolated anti-C5 a antibody, wherein the anti-C5 a antibody comprises:
heavy chain variable domain (V) H ) Said V is H Comprises the following steps:
heavy chain complementarity determining region (HC-CDR) 1 comprising NYAIN (SEQ ID NO: 5);
HC-CDR2 comprising GIX 1 PFFGX 2 EDYAQKFQG (SEQ ID NO: 73), where X 1 Is V or Y, X 2 Is T or W; and
HC-CDR3 comprising DLLX 1 GFDI (SEQ ID NO: 76), wherein X 1 Is E or H;
and a light chain variable domain (V) L ) Said V is L Comprises the following steps:
a light chain complementarity determining region (LC-CDR) 1 comprising RASHIDIETWLA (SEQ ID NO: 53);
LC-CDR2 comprising GASNLQS (SEQ ID NO: 61); and
LC-CDR3 comprising QANNELPYT (SEQ ID NO: 69).
17. An isolated anti-C5 a antibody, wherein the anti-C5 a antibody comprises:
V H said V is H Comprises the following steps:
HC-CDR1 comprising the amino acid sequence set forth in SEQ ID NO. 5 or a variant thereof comprising up to about 3 amino acid substitutions;
HC-CDR2 comprising an amino acid sequence set forth in any of SEQ ID NOs:36-37, or a variant thereof comprising up to about 3 amino acid substitutions; and
HC-CDR3 comprising an amino acid sequence set forth in any of SEQ ID NOs:46-47 or a variant thereof comprising up to about 3 amino acid substitutions;
and V L Said V is L Comprises the following steps:
LC-CDR1 comprising the amino acid sequence shown in SEQ ID NO. 53 or a variant thereof comprising up to about 3 amino acid substitutions;
LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO. 61 or a variant thereof comprising up to about 3 amino acid substitutions; and
an LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:69 or a variant thereof comprising up to about 3 amino acid substitutions.
18. An isolated anti-C5 a antibody, wherein the anti-C5 a antibody comprises: v H Said V is H Comprising a V as shown in any one of SEQ ID NOs:116-117 H Comprising HC-CDR1, HC-CDR2 and HC-CDR3, and V L Said V is L Comprising V as shown in amino acid sequence SEQ ID NO:127 L Comprising LC-CDR1, LC-CDR2 and LC-CDR3.
19. The isolated anti-C5 a antibody of any one of claims 16-18, comprising:
(i)V H said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 36 and HC-CDR3 comprising the amino acid sequence SEQ ID NO 46, or else the V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising ammonia69, or said V L A variant of (a) comprising substitutions in the LC-CDRs of up to about 5 amino acids; or
(ii)V H Said V is H Comprises the following steps: HC-CDR1 comprising the amino acid sequence SEQ ID NO 5, HC-CDR2 comprising the amino acid sequence SEQ ID NO 37, and HC-CDR3 comprising the amino acid sequence SEQ ID NO 47, or said V H A variant of (a) comprising substitutions of up to about 5 amino acids in the HC-CDRs; and V L Said V is L Comprises the following steps: LC-CDR1 comprising the amino acid sequence SEQ ID NO 53, LC-CDR2 comprising the amino acid sequence SEQ ID NO 61, and LC-CDR3 comprising the amino acid sequence SEQ ID NO 69, or said V L Comprising substitutions of up to about 5 amino acids in the LC-CDRs.
20. The isolated anti-C5 a antibody of any one of claims 16-19, comprising: v H (ii) comprising the amino acid sequence set forth in any one of SEQ ID NOs:116-117 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 116-117; and V L Comprising the amino acid sequence set forth in SEQ ID NO:127 or a variant thereof having at least about 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 127.
21. The isolated anti-C5 a antibody of claim 20, comprising:
(i)V H comprising the amino acid sequence of SEQ ID No. 116 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID No. 116; and V L Comprising the amino acid sequence of SEQ ID NO:127 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 127; or
(ii)V H Comprising the amino acid sequence SEQ ID NO:117 or a variant thereof having at least about 90% sequence identity to the amino acid sequence SEQ ID NO: 117; and V L Comprising the amino acid sequence SEQ ID NO 127 or a variant thereof, said variant being associated with ammonia127 has at least about 90% sequence identity to the amino acid sequence of SEQ ID NO.
22. An anti-C5 a antibody isolated according to any one of claims 1-21, wherein said anti-C5 a antibody comprises an Fc fragment.
23. The isolated anti-C5 a antibody of claim 22, wherein said anti-C5 a antibody is a full-length IgG antibody.
24. The isolated anti-C5 a antibody of claim 23, wherein said anti-C5 a antibody is a full-length IgG1, igG2, igG3, or IgG4 antibody.
25. The isolated anti-C5 a antibody according to any one of claims 1-24, wherein said anti-C5 a antibody is a chimeric, fully human or humanized antibody.
26. The isolated anti-C5 a antibody according to any one of claims 1-21, wherein the anti-C5 a antibody is an antigen binding fragment selected from the group consisting of Fab, fab ', F (ab)' 2 Fab' -SH, single chain antibodies (scFv), fv fragments, dAbs, fd, nanobodies, diabodies and linear antibodies.
27. A nucleic acid molecule encoding the anti-C5 a antibody of any one of claims 1-26.
28. A vector comprising the nucleic acid molecule of claim 27.
29. An isolated host cell comprising the anti-C5 a antibody of any one of claims 1-26, the nucleic acid molecule of claim 27, or the vector of claim 28.
30. A method of making an anti-C5 a antibody, comprising:
a) Culturing the host cell of claim 29 under conditions effective to express an anti-C5 a antibody; and is
b) Obtaining the expressed anti-C5 a antibody from the host cell.
31. A pharmaceutical composition comprising the anti-C5 a antibody of any one of claims 1-26, the nucleic acid molecule of claim 27, the vector of claim 28, the isolated host cell of claim 29, or an antibody produced by the method of claim 30, and a pharmaceutically acceptable carrier.
32. Use of the anti-C5 a antibody of any one of claims 1-26, the nucleic acid molecule of claim 27, the vector of claim 28, the isolated host cell of claim 29, the antibody produced by the method of claim 30, or the pharmaceutical composition of claim 31 in the preparation of a medicament for treating a disease or disorder in a subject in need thereof.
33. The use according to claim 32, wherein the disease or disorder is an autoimmune disease, inflammation, cancer, pain, respiratory and/or transplantation related disease.
34. The use of claim 33, wherein the disease or disorder is selected from the group consisting of inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion-related injury, acute lung injury, pneumonia, acute and chronic transplant rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, solid renal failure, rheumatoid arthritis, autoimmune disease, bechterew's disease, lupus-like disease, inflammatory bowel disease, crohn's disease, tumor growth, and solid organ cancer.
CN202210791619.3A 2021-07-06 2022-07-05 Antibody for specifically recognizing C5A and application thereof Pending CN115925918A (en)

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CN202110762546 2021-07-06

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