Antibodies specifically recognizing C5A and uses thereof

Abstract

The present application relates to antibodies or antigen-binding fragments that specifically recognize complement component 5a (C5a), methods for their preparation and uses.

Description

[Technical field]

[0001] Submit sequence listing as an ASCII TEXT file The contents of the ASCII TEXT text file submitted below are incorporated by reference in its entirety into this application. Sequence Listing in Computer Readable Format (CRF) (Text Name: 202006095269_SEQLIST.txt, Recording Date: 2020.06.10, Size: 96.5KB)

[0002] This application relates to antibodies that specifically recognize complement component 5a (C5a), their production and methods of use, including for use in treating autoimmune and / or inflammatory diseases, cancer, pain, and transplant-related diseases. [Background technology]

[0003] C5a is an active peptide in allergic reactions and inflammatory processes, formed by cleavage of complement component C5 by C5 convertase in the complement cascade. C5a stimulates mast cell degranulation, release of tumor necrosis factor-α (TNF-α) and histamine, and also recruits phagocytes to sites of infection and inflammation by increasing the expression of adhesion factors on the surface of endothelial cells (Mollnes, TE et al. Blood 2002, 100, 1869-1877; Riedemann, NC et al. Immunity 2003, 19, 193-202). In the case of some pathological stimuli, for example in allograft rejection after transplantation and in asthma, C5a further increases vascular permeability (Gueler, F. et al. J. Am. Soc. Nephrol. 2008, 19, 2302-2312; Krug, N. et al. Am. J. Respir. Crit. CareMed. 2001, 164, 1841-1843; Khan, MA et al. Proc. Natl. Acad. Sci. USA 2013, 110, 6061-6066). The level of C5a in serum has been examined in many studies. 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). Other studies have shown that under normal circumstances, due to the rapid clearance of allergy toxins, the levels of C5a in plasma are very low (Oppermann, M. et al. Immunology 1994, 82, 516-521). After treatment with C5a (25 nM), the levels of transforming growth factor-β (TGF-β) in mouse cortical tubular cells are increased, indicating that C5a leads to renal fibrosis and the formation of renal scars (Boor, P. et al. J. Am. Soc. Nephrol. 2007, 18, 1508-1515).

[0004] C5a is a potent pro-inflammatory molecule that binds to the archetypal G-protein-coupled receptor (GPCR) C5aRI (CD88), leading to the activation of pro-inflammatory signaling pathways (Li, R. et al. FASEB J. 2013, 27, 855-864). C5aR is widely expressed in non-myeloid cells, including umbilical vascular endothelial cells (HUVECs), murine skin, liver, lung, and renal proximal tubules (Monsinjon, T. et al. FASEB J. 2003, 17, 1003-1014; Gerard, C. et al. Annu. Rev. Immunol. 1994, 12, 775-808; Haviland, DL et al. J. Immunol. 1995, 154, 1861-1869). Research has also demonstrated that C5aR was expressed in glomerular endothelial cells, but not in podocytes, indicating that C5a may cause proteinuria primarily in renal endothelial cells (Tsai, IJ et al. Cell. Mol. Life Sci. 2015, 72, 3157~3171).

[0005] Therefore, neutralizing C5a and thereby blocking its binding to C5aR provides a method for treating diseases and conditions mediated by C5a. Patent application WO2011063980 discloses an antibody INab308 (InflaRx) against human C5a, WO2012088247 discloses a C5a antibody MEDI-7814 (MedImmune), and US10450370 discloses a C5a antibody BNJ383 (Alexion).

[0006] All publications, patents, patent applications, and the disclosures of any patent applications mentioned in this application are hereby incorporated by reference in their entirety. Summary of the Invention [Means for solving the problem]

[0007] In one aspect, the present application provides an isolated anti-C5a antibody capable of specifically binding to an epitope in human C5a, wherein the isolated anti-C5a antibody specifically binds to at least one of the amino acid residues D at position 31, E at position 32, and R at position 40 in human C5a as set forth in, for example, SEQ ID NO:141. In some embodiments, the isolated anti-C5a antibody specifically binds to, for example, residues 31-40 in human C5a as set forth in, for example, SEQ ID NO:141. In some embodiments, the isolated anti-C5a antibody specifically binds to an epitope, wherein the epitope is (i) DGACVNNDETCEQRAARISLGPR (SEQ ID NO:145) , (ii) NDETCEQRAARISLGPR (SEQ ID NO:146) or (iii) DETCEQRAAR (SEQ ID NO:147) In some embodiments, the isolated anti-C5a antibody is comprised within, consists of, or comprises the sequence: (i) DGACVNNDETCEQRAARISLGPR (SEQ ID NO:145) , (ii) NDETCEQRAARISLGPR (SEQ ID NO:146) or (iii) DETCEQRAAR (SEQ ID NO:147) In some embodiments, the isolated anti-C5a antibody has a Kd value of 0.1 pM to 1 nM for binding to human C5a.

[0008] In some embodiments, any of the isolated anti-C5a antibodies comprises the sequence X 1 YYX 2 Q (SEQ ID NO:67), 1 is D or N, and X 2 is M or I), the sequence LIRX 1 KX 2 X 3 GX 4 TX 5 X 6 X 7 AAS 8One HC-CDR2 containing KG (SEQ ID NO:68) (wherein 1 is K or N, and X 2 is A or V, and X 3 is V, N, or I, and X 4 is G, E, F, H, I, Q or R, and X 5 is T, V or A, and X 6 is Q, E, T or S, and X 7 is Y or F, and X 8 is V or L), and the sequence RX 1 GPPGLX 2 (SEQ ID NO:69) (wherein 1 is A, L or V, and X 2 is T, S or A) H ) and the array RSSQX 1 LLX 2 X 3 X 4 X 5 YX 6 YX 7 D (SEQ ID NO: 70), but 1 is S, R or N, and X 2 is A, H or D, and X 3 is S or T, and X 4 is D or N, and X 5 is G, A or R, and X 6 is N, I, T, E or A, and X 7 is I, M, L or V), array GX 1 SX 2 One LC-CDR2 containing RAS (SEQ ID NO:71) (wherein 1 is G or A, and X 2 is N or K), and the array X 1 QHX 2 X 3 LPX 4 One LC-CDR3 containing X 1 is L or M, and X 2 is R or K, and X 3is A or V, and X 4 is P or L) L ) and

[0009] In some embodiments, a VCR comprises one HC-CDR1 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 1 to 6, one HC-CDR2 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 7 to 29, and one HC-CDR3 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 30 to 38. H and one LC-CDR1 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 39 to 56, one LC-CDR2 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 57 to 59, and one LC-CDR3 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 60 to 66. L and an isolated anti-C5a antibody comprising:

[0010] In some embodiments, the V has an amino acid sequence of any one of SEQ ID NOs:73-111. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and V having any one of the amino acid sequences of SEQ ID NOs: 112 to 140. L V containing LC-CDR1, LC-CDR2 and LC-CDR3 in L and an isolated anti-C5a antibody comprising:

[0011] In some embodiments, (i) a VHC-CDR1 comprising one HC-CDR1 having a sequence with at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:1, one HC-CDR2 having a sequence with at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and one HC-CDR3 having a sequence with at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:30. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:39, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:60. L and (ii) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:8, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:31. H and one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 40, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 61. L and (iii) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:10, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. Hand one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 42, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 61. L and (iv) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:11, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:41, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:57, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:64. H and (v) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:9, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 43, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 63. Land (vi) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:11, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:35. H and one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 44, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 60. L and (vii) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:6, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:18, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:36. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 42, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 61. L and (viii) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:5, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:21, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. Hand one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 42, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 61. L and (ix) a VHC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, a VHC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:10, and a VHC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:53, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:59, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:65. L and (x) a VHC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, a VHC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:23, and a VHC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 42, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 61. Land (xi) a V comprising one HC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:2, one HC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:23, and one HC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:32. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:56, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:61. L and (xii) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:6, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:18, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:36. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:52, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:58, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:61. L and (xiii) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:6, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:18, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:36. Hand one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:53, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:59, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:65. L and (xiv) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:5, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:21, and one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. V containing one HC-CDR3 H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:52, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:58, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:61. L or (xv) one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:5, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:21, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:53, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:59, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:65. Land an isolated anti-C5a antibody comprising:

[0012] In some embodiments, any of the above-mentioned isolated anti-C5a antibodies comprises a V antibody having a sequence having at least 90% sequence identity to any of the amino acid sequences of SEQ ID NOs:73-111. H and a V having a sequence having at least 90% sequence homology with any of the amino acid sequences of SEQ ID NOs: 112 to 140. L In some embodiments, the isolated anti-C5a antibody comprises: (i) a V comprising the amino acid sequence SEQ ID NO:73. H and V comprising the amino acid sequence SEQ ID NO:112 L and (ii) V comprising the amino acid sequence SEQ ID NO:75. H and V comprising the amino acid sequence SEQ ID NO:114 L and (iii) V comprising the amino acid sequence SEQ ID NO:100. H and V comprising the amino acid sequence SEQ ID NO:135 L and (iv) V comprising the amino acid sequence SEQ ID NO:79. H and V comprising the amino acid sequence SEQ ID NO:118 L and (v) V comprising the amino acid sequence SEQ ID NO:85. H and V comprising the amino acid sequence SEQ ID NO:117 L and (vi) V comprising the amino acid sequence SEQ ID NO:88. H and V comprising the amino acid sequence SEQ ID NO:126 L and (vii) V comprising the amino acid sequence SEQ ID NO:93. H and V comprising the amino acid sequence SEQ ID NO:116 L and (viii) V comprising the amino acid sequence SEQ ID NO:97. H and V comprising the amino acid sequence SEQ ID NO:116 L and (ix) V comprising the amino acid sequence SEQ ID NO:77. H and V comprising the amino acid sequence SEQ ID NO:132 L and (x) a V having the amino acid sequence SEQ ID NO:102.H and V comprising the amino acid sequence SEQ ID NO:135 L and (xi) V comprising the amino acid sequence SEQ ID NO:109. H and V comprising the amino acid sequence SEQ ID NO:138 L and (xii) V comprising the amino acid sequence SEQ ID NO:110. H and V comprising the amino acid sequence SEQ ID NO:139 L and (xiii) V comprising the amino acid sequence SEQ ID NO:110. H and V comprising the amino acid sequence SEQ ID NO:140 L and (xiv) V comprising the amino acid sequence SEQ ID NO:111. H and V comprising the amino acid sequence SEQ ID NO:139 L and (xv) V comprising the amino acid sequence SEQ ID NO:111. H and V comprising the amino acid sequence SEQ ID NO:140 L Includes.

[0013] In some embodiments, an isolated anti-C5a antibody is provided that binds to C5a competitively with any of the isolated anti-C5a antibodies described above. In some embodiments, an isolated anti-C5a antibody is provided that specifically binds to the same epitope as any of the isolated anti-C5a antibodies described above.

[0014] In some embodiments, any of the isolated anti-C5a antibodies described above comprises an Fc fragment. In some embodiments, the isolated anti-C5a antibody is a full length IgG antibody. In some embodiments, the isolated anti-C5a antibody is a full length IgG1 or IgG4 antibody. In some embodiments, the isolated anti-C5a antibody is chimeric, fully human, or humanized. In some embodiments, the isolated anti-C5a antibody is an antigen-binding fragment selected from the group consisting of Fab, Fab', F(ab)'2, Fab'-SH, single chain antibody (scFv), Fv fragment, dAb, Fd, nanobody, double chain antibody, and linear antibody.

[0015] In some embodiments, an isolated nucleic acid molecule encoding any of the above anti-C5a antibodies is provided. In some embodiments, a vector comprising any of the above nucleic acid molecules is provided. In some embodiments, a host cell comprising any of the above anti-C5a antibodies, any of the above nucleic acid molecules, or any of the above vectors is provided. In some embodiments, a method of preparing an anti-C5a antibody is provided, comprising a) culturing any of the above host cells under conditions effective to express the anti-C5a antibody, and b) obtaining the expressed anti-C5a antibody from the host cell.

[0016] In some embodiments, there is provided a method for treating a disease or condition in an individual in need thereof, comprising administering to said individual an effective amount of any of the above anti-C5a antibodies. In some embodiments, there is provided a method for preparing a medicament for treating a disease or condition using any of the above C5a antibodies or a pharmaceutical composition comprising a C5a antibody. In some embodiments, the disease or condition is an inflammatory, respiratory or autoimmune disease or condition. In some embodiments, the disease or condition 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 graft rejection in transplant patients, graft versus host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew disease, lupus disease, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer.

[0017] Additionally, pharmaceutical compositions, reagent kits and articles of manufacture comprising any of the above anti-C5a antibodies are provided. [Brief description of the drawings]

[0018] [Figure 1A]The results shown in Figures 1A-1B are the binding affinity of the exemplary anti-C5a antibodies to human recombinant C5a or endogenous C5a by ELISA analysis. Figure 1A shows the binding curves of Cab01, Cab03, Cab04, Cab05, Cab13 or Cab15 to human recombinant C5a. Figure 1B shows the binding curves of Cab01, Cab03, Cab04, Cab05, Cab13 or Cab15 to human endogenous C5a. [Figure 1B] The results shown in Figures 1A-1B are the binding affinity of the exemplary anti-C5a antibodies to human recombinant C5a or endogenous C5a by ELISA analysis. Figure 1A shows the binding curves of Cab01, Cab03, Cab04, Cab05, Cab13 or Cab15 to human recombinant C5a. Figure 1B shows the binding curves of Cab01, Cab03, Cab04, Cab05, Cab13 or Cab15 to human endogenous C5a. [Figure 2A] The results shown in Figure 2A are the binding affinities of the optimized full-length C5a antibodies Cab05-IgG4, Cab35, Cab38 or Cab42 (reshaped into human IgG1) to human recombinant C5a by ELISA analysis. The results shown in Figure 2B are the binding affinities of the optimized full-length C5a antibodies Cab42, Cab44 or Cab45 (reshaped into human IgG1) to human recombinant C5a by ELISA analysis. The results shown in Figure 2C are the binding affinities of the full-length C5a antibodies Cab01, Cab03, Cab05, Cab13 (reshaped into human IgG4) or the optimized anti-C5a antibody Cab42-IgG1 to cynomolgus C5a by ELISA analysis. [Figure 2B]The results shown in Figure 2A are the binding affinities of the optimized full-length C5a antibodies Cab05-IgG4, Cab35, Cab38 or Cab42 (reshaped into human IgG1) to human recombinant C5a by ELISA analysis. The results shown in Figure 2B are the binding affinities of the optimized full-length C5a antibodies Cab42, Cab44 or Cab45 (reshaped into human IgG1) to human recombinant C5a by ELISA analysis. The results shown in Figure 2C are the binding affinities of the full-length C5a antibodies Cab01, Cab03, Cab05, Cab13 (reshaped into human IgG4) or the optimized anti-C5a antibody Cab42-IgG1 to cynomolgus C5a by ELISA analysis. [Figure 2C] The results shown in Figure 2A are the binding affinities of the optimized full-length C5a antibodies Cab05-IgG4, Cab35, Cab38 or Cab42 (reshaped into human IgG1) to human recombinant C5a by ELISA analysis. The results shown in Figure 2B are the binding affinities of the optimized full-length C5a antibodies Cab42, Cab44 or Cab45 (reshaped into human IgG1) to human recombinant C5a by ELISA analysis. The results shown in Figure 2C are the binding affinities of the full-length C5a antibodies Cab01, Cab03, Cab05, Cab13 (reshaped into human IgG4) or the optimized anti-C5a antibody Cab42-IgG1 to cynomolgus C5a by ELISA analysis. [Figure 3A] The results shown in Figures 3A-3C are the binding affinity of the exemplary full-length C5a antibodies to human native C5 by ELISA analysis. Figure 3A shows the binding curves of Cab01, Cab03, Cab04, Cab05, Cab13 (reshaped into human IgG4) or control antibody INab308 to human native C5. The results shown in Figure 3B are the binding curves of Cab05-IgG4, Cab35, Cab38, Cab42 (reshaped into human IgG1) or control antibody INab308 to human native C5. The results shown in Figure 3C are the binding curves of Cab42, Cab44, Cab45 (reshaped into human IgG1) or control antibody INab308 to human native C5. [Figure 3B]The results shown in Figures 3A-3C are the binding affinity of the exemplary full-length C5a antibodies to human native C5 by ELISA analysis. Figure 3A shows the binding curves of Cab01, Cab03, Cab04, Cab05, Cab13 (reshaped into human IgG4) or control antibody INab308 to human native C5. The results shown in Figure 3B are the binding curves of Cab05-IgG4, Cab35, Cab38, Cab42 (reshaped into human IgG1) or control antibody INab308 to human native C5. The results shown in Figure 3C are the binding curves of Cab42, Cab44, Cab45 (reshaped into human IgG1) or control antibody INab308 to human native C5. [Figure 3C] The results shown in Figures 3A-3C are the binding affinity of the exemplary full-length C5a antibodies to human native C5 by ELISA analysis. Figure 3A shows the binding curves of Cab01, Cab03, Cab04, Cab05, Cab13 (reshaped into human IgG4) or control antibody INab308 to human native C5. The results shown in Figure 3B are the binding curves of Cab05-IgG4, Cab35, Cab38, Cab42 (reshaped into human IgG1) or control antibody INab308 to human native C5. The results shown in Figure 3C are the binding curves of Cab42, Cab44, Cab45 (reshaped into human IgG1) or control antibody INab308 to human native C5. [Figure 4A] The results shown in Figure 4A are the non-specific binding of full-length antibodies Cab01, Cab03, Cab04, Cab05, Cab13 (reconstituted in human IgG4 form) or optimized antibodies Cab35, Cab42 (reconstituted in human IgG1 form) to BV particles, and the results shown in Figure 4B are the low cross-reactivity of Cab35-IgG1 or Cab42-IgG1 antibodies with C5a-negative 293 cells. [Figure 4B]The results shown in Figure 4A are the non-specific binding of full-length antibodies Cab01, Cab03, Cab04, Cab05, Cab13 (reconstituted in human IgG4 form) or optimized antibodies Cab35, Cab42 (reconstituted in human IgG1 form) to BV particles, and the results shown in Figure 4B are the low cross-reactivity of Cab35-IgG1 or Cab42-IgG1 antibodies with C5a-negative 293 cells. [Figure 5A] Figure 5A shows the results of a CD11b blocking experiment, which shows that the C5a antibodies Cab01, Cab03 or Cab05 (reconstituted into human IgG4) can block the increase in CD11b induced by human recombinant C5a and endogenous C5a in human neutrophils. Figure 5B shows the results of a CD11b blocking experiment, which shows that the optimized C5a antibodies Cab42, Cab43, Cab44, Cab45 or Cab46 (reconstituted into human IgG1) can block the increase in CD11b induced by human endogenous C5a in human neutrophils. Figure 5C shows the results of the CD11b blocking experiment, which showed that the optimized anti-C5a antibody Cab42-IgG1 could still block the increase in CD11b expression induced by endogenous human C5a in human neutrophils, even in the presence of 50-fold more molar C5 in the reaction system compared to the control antibody INab308. [Figure 5B]Figure 5A shows the results of a CD11b blocking experiment, which shows that the C5a antibodies Cab01, Cab03 or Cab05 (reconstituted into human IgG4) can block the increase in CD11b induced by human recombinant C5a and endogenous C5a in human neutrophils. Figure 5B shows the results of a CD11b blocking experiment, which shows that the optimized C5a antibodies Cab42, Cab43, Cab44, Cab45 or Cab46 (reconstituted into human IgG1) can block the increase in CD11b induced by human endogenous C5a in human neutrophils. Figure 5C shows the results of the CD11b blocking experiment, which showed that the optimized anti-C5a antibody Cab42-IgG1 could still block the increase in CD11b expression induced by endogenous human C5a in human neutrophils, even in the presence of 50-fold more molar C5 in the reaction system compared to the control antibody INab308. [Figure 5C] Figure 5A shows the results of a CD11b blocking experiment, which shows that the C5a antibodies Cab01, Cab03 or Cab05 (reconstituted into human IgG4) can block the increase in CD11b induced by human recombinant C5a and endogenous C5a in human neutrophils. Figure 5B shows the results of a CD11b blocking experiment, which shows that the optimized C5a antibodies Cab42, Cab43, Cab44, Cab45 or Cab46 (reconstituted into human IgG1) can block the increase in CD11b induced by human endogenous C5a in human neutrophils. Figure 5C shows the results of the CD11b blocking experiment, which showed that the optimized anti-C5a antibody Cab42-IgG1 could still block the increase in CD11b expression induced by endogenous human C5a in human neutrophils, even in the presence of 50-fold more molar C5 in the reaction system compared to the control antibody INab308. [Figure 6A]The results shown in Figures 6A to 6D are plasma hemolytic activity of C5a antibodies. In the typical activation pathway, compared to the control antibody Eculizumab, the anti-C5a antibodies Cab01, Cab03, and Cab05 (remodeled into human IgG4) (Figure 6A) or the optimized anti-C5a antibodies Cab35, Cab42, Cab43, Cab44, Cab45, and Cab46 (remodeled into human IgG1) (Figure 6B) do not suppress plasma hemolytic activity. In the bypass activation pathway, compared to the control antibody Eculizumab, the anti-C5a antibodies Cab01, Cab03, and Cab05 (remodeled into human IgG4) (Figure 6C) or the optimized anti-C5a antibodies Cab35, Cab42, Cab43, Cab44, Cab45, and Cab46 (remodeled into human IgG1) (Figure 6D) do not suppress plasma hemolytic activity. [Figure 6B] The results shown in Figures 6A to 6D are plasma hemolytic activity of C5a antibodies. In the typical activation pathway, compared to the control antibody Eculizumab, the anti-C5a antibodies Cab01, Cab03, and Cab05 (remodeled into human IgG4) (Figure 6A) or the optimized anti-C5a antibodies Cab35, Cab42, Cab43, Cab44, Cab45, and Cab46 (remodeled into human IgG1) (Figure 6B) do not suppress plasma hemolytic activity. In the bypass activation pathway, compared to the control antibody Eculizumab, the anti-C5a antibodies Cab01, Cab03, and Cab05 (remodeled into human IgG4) (Figure 6C) or the optimized anti-C5a antibodies Cab35, Cab42, Cab43, Cab44, Cab45, and Cab46 (remodeled into human IgG1) (Figure 6D) do not suppress plasma hemolytic activity. [Figure 6C]The results shown in Figures 6A to 6D are plasma hemolytic activity of C5a antibodies. In the typical activation pathway, compared to the control antibody Eculizumab, the anti-C5a antibodies Cab01, Cab03, and Cab05 (remodeled into human IgG4) (Figure 6A) or the optimized anti-C5a antibodies Cab35, Cab42, Cab43, Cab44, Cab45, and Cab46 (remodeled into human IgG1) (Figure 6B) do not suppress plasma hemolytic activity. In the bypass activation pathway, compared to the control antibody Eculizumab, the anti-C5a antibodies Cab01, Cab03, and Cab05 (remodeled into human IgG4) (Figure 6C) or the optimized anti-C5a antibodies Cab35, Cab42, Cab43, Cab44, Cab45, and Cab46 (remodeled into human IgG1) (Figure 6D) do not suppress plasma hemolytic activity. [Figure 6D] The results shown in Figures 6A to 6D are plasma hemolytic activity of C5a antibodies. In the typical activation pathway, compared to the control antibody Eculizumab, the anti-C5a antibodies Cab01, Cab03, and Cab05 (remodeled into human IgG4) (Figure 6A) or the optimized anti-C5a antibodies Cab35, Cab42, Cab43, Cab44, Cab45, and Cab46 (remodeled into human IgG1) (Figure 6B) do not suppress plasma hemolytic activity. In the bypass activation pathway, compared to the control antibody Eculizumab, the anti-C5a antibodies Cab01, Cab03, and Cab05 (remodeled into human IgG4) (Figure 6C) or the optimized anti-C5a antibodies Cab35, Cab42, Cab43, Cab44, Cab45, and Cab46 (remodeled into human IgG1) (Figure 6D) do not suppress plasma hemolytic activity. [Figure 7] The results shown in FIG. 7 are the inhibitory effects of different doses of anti-C5a antibody Cab05-IgG4 in C5a-induced neutrophil chemotaxis experiments. [Figure 8] The results shown in FIG. 8 are pharmacokinetic analysis of Cab35-IgG1 or the control antibody INab308 in cynomolgus monkeys by ELISA detection. [Figure 9A]The results shown in Figures 9A-9D are competitive ELISA binding curves of INab308, Cab42-IgG1, BNJ383 or MEDI-7814 antibodies. The results shown in Figure 9A are competitive binding ELISA with INab308, the results shown in Figure 9B are competitive binding ELISA with Cab42-IgG1, the results shown in Figure 9C are competitive binding ELISA with BNJ383 and the results shown in Figure 9D are competitive binding ELISA with MEDI-7814. The results shown in Figures 9E-9F are competitive ELISA binding curves of INab308, Cab42-IgG1 or Cab35-IgG1 antibodies. The results shown in Figure 9E are competitive binding ELISA with INab308 and the results shown in Figure 9F are competitive binding ELISA with Cab35-IgG1. [Figure 9B] The results shown in Figures 9A-9D are competitive ELISA binding curves of INab308, Cab42-IgG1, BNJ383 or MEDI-7814 antibodies. The results shown in Figure 9A are competitive binding ELISA with INab308, the results shown in Figure 9B are competitive binding ELISA with Cab42-IgG1, the results shown in Figure 9C are competitive binding ELISA with BNJ383 and the results shown in Figure 9D are competitive binding ELISA with MEDI-7814. The results shown in Figures 9E-9F are competitive ELISA binding curves of INab308, Cab42-IgG1 or Cab35-IgG1 antibodies. The results shown in Figure 9E are competitive binding ELISA with INab308 and the results shown in Figure 9F are competitive binding ELISA with Cab35-IgG1. [Figure 9C]The results shown in Figures 9A-9D are competitive ELISA binding curves of INab308, Cab42-IgG1, BNJ383 or MEDI-7814 antibodies. The results shown in Figure 9A are competitive binding ELISA with INab308, the results shown in Figure 9B are competitive binding ELISA with Cab42-IgG1, the results shown in Figure 9C are competitive binding ELISA with BNJ383 and the results shown in Figure 9D are competitive binding ELISA with MEDI-7814. The results shown in Figures 9E-9F are competitive ELISA binding curves of INab308, Cab42-IgG1 or Cab35-IgG1 antibodies. The results shown in Figure 9E are competitive binding ELISA with INab308 and the results shown in Figure 9F are competitive binding ELISA with Cab35-IgG1. [Figure 9D] The results shown in Figures 9A-9D are competitive ELISA binding curves of INab308, Cab42-IgG1, BNJ383 or MEDI-7814 antibodies. The results shown in Figure 9A are competitive binding ELISA with INab308, the results shown in Figure 9B are competitive binding ELISA with Cab42-IgG1, the results shown in Figure 9C are competitive binding ELISA with BNJ383 and the results shown in Figure 9D are competitive binding ELISA with MEDI-7814. The results shown in Figures 9E-9F are competitive ELISA binding curves of INab308, Cab42-IgG1 or Cab35-IgG1 antibodies. The results shown in Figure 9E are competitive binding ELISA with INab308 and the results shown in Figure 9F are competitive binding ELISA with Cab35-IgG1. [Figure 9E]The results shown in Figures 9A-9D are competitive ELISA binding curves of INab308, Cab42-IgG1, BNJ383 or MEDI-7814 antibodies. The results shown in Figure 9A are competitive binding ELISA with INab308, the results shown in Figure 9B are competitive binding ELISA with Cab42-IgG1, the results shown in Figure 9C are competitive binding ELISA with BNJ383 and the results shown in Figure 9D are competitive binding ELISA with MEDI-7814. The results shown in Figures 9E-9F are competitive ELISA binding curves of INab308, Cab42-IgG1 or Cab35-IgG1 antibodies. The results shown in Figure 9E are competitive binding ELISA with INab308 and the results shown in Figure 9F are competitive binding ELISA with Cab35-IgG1. [Figure 9F] The results shown in Figures 9A-9D are competitive ELISA binding curves of INab308, Cab42-IgG1, BNJ383 or MEDI-7814 antibodies. The results shown in Figure 9A are competitive binding ELISA with INab308, the results shown in Figure 9B are competitive binding ELISA with Cab42-IgG1, the results shown in Figure 9C are competitive binding ELISA with BNJ383 and the results shown in Figure 9D are competitive binding ELISA with MEDI-7814. The results shown in Figures 9E-9F are competitive ELISA binding curves of INab308, Cab42-IgG1 or Cab35-IgG1 antibodies. The results shown in Figure 9E are competitive binding ELISA with INab308 and the results shown in Figure 9F are competitive binding ELISA with Cab35-IgG1. [Figure 10A] The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10B]The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10C] The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10D] The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10E] The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10F] The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10G]The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10H] The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10I] The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10J] The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10K] The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 10L]The results shown in Figures 10A-10D are the ELISA binding curves of Cab42-IgG1 and C5a mutants. The results shown in Figures 10E-10H are the ELISA binding curves of Cab44-IgG1 and C5a mutants. The results shown in Figures 10I-10L are the ELISA binding curves of Cab45-IgG1 and C5a mutants. [Figure 11A] Figures 11A-11C show the results of Western blotting in which MEDI-7814, Cab42-IgG1, and His antibodies bound to Avih-C5a or Avih-C5a-D31A mutant. Figures 11D-11E show the results of Western blotting in which Cab44-IgG1 and Cab45-IgG1 bound to human Avih-C5a or human Avih-C5a-D31A mutant. Figure 11F shows the results of SDS-PAGE of human Avih-C5a and human C5a mutant Avih-C5a-D31A. [Figure 11B] Figures 11A-11C show the results of Western blotting in which MEDI-7814, Cab42-IgG1, and His antibodies bound to Avih-C5a or Avih-C5a-D31A mutant. Figures 11D-11E show the results of Western blotting in which Cab44-IgG1 and Cab45-IgG1 bound to human Avih-C5a or human Avih-C5a-D31A mutant. Figure 11F shows the results of SDS-PAGE of human Avih-C5a and human C5a mutant Avih-C5a-D31A. [Figure 11C] Figures 11A-11C show the results of Western blotting in which MEDI-7814, Cab42-IgG1, and His antibodies bound to Avih-C5a or Avih-C5a-D31A mutant. Figures 11D-11E show the results of Western blotting in which Cab44-IgG1 and Cab45-IgG1 bound to human Avih-C5a or human Avih-C5a-D31A mutant. Figure 11F shows the results of SDS-PAGE of human Avih-C5a and human C5a mutant Avih-C5a-D31A. [Figure 11D]Figures 11A-11C show the results of Western blotting in which MEDI-7814, Cab42-IgG1, and His antibodies bound to Avih-C5a or Avih-C5a-D31A mutant. Figures 11D-11E show the results of Western blotting in which Cab44-IgG1 and Cab45-IgG1 bound to human Avih-C5a or human Avih-C5a-D31A mutant. Figure 11F shows the results of SDS-PAGE of human Avih-C5a and human C5a mutant Avih-C5a-D31A. [Figure 11E] Figures 11A-11C show the results of Western blotting in which MEDI-7814, Cab42-IgG1, and His antibodies bound to Avih-C5a or Avih-C5a-D31A mutant. Figures 11D-11E show the results of Western blotting in which Cab44-IgG1 and Cab45-IgG1 bound to human Avih-C5a or human Avih-C5a-D31A mutant. Figure 11F shows the results of SDS-PAGE of human Avih-C5a and human C5a mutant Avih-C5a-D31A. [Figure 11F] Figures 11A-11C show the results of Western blotting in which MEDI-7814, Cab42-IgG1, and His antibodies bound to Avih-C5a or Avih-C5a-D31A mutant. Figures 11D-11E show the results of Western blotting in which Cab44-IgG1 and Cab45-IgG1 bound to human Avih-C5a or human Avih-C5a-D31A mutant. Figure 11F shows the results of SDS-PAGE of human Avih-C5a and human C5a mutant Avih-C5a-D31A. [Figure 12A] Figure 12A shows ELISA binding results demonstrating that the Cab42 antibody specifically binds to a polypeptide comprising amino acids 24-46, 30-46, or 31-40 of human C5a as shown in SEQ ID NO: 141. Figure 12B shows ELISA binding results demonstrating that the Inab308 antibody does not bind to any of the three polypeptide-Fc fusions, C5a-p1-Fc, C5a-p2-Fc, or C5a-p4-Fc. [Figure 12B] Figure 12A shows ELISA binding results demonstrating that the Cab42 antibody specifically binds to a polypeptide comprising amino acids 24-46, 30-46, or 31-40 of human C5a as shown in SEQ ID NO: 141. Figure 12B shows ELISA binding results demonstrating that the Inab308 antibody does not bind to any of the three polypeptide-Fc fusions, C5a-p1-Fc, C5a-p2-Fc, or C5a-p4-Fc. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] In one embodiment of the present application, an anti-C5a antibody molecule or antigen-binding fragment is provided. Through the selection of scFv phage library, affinity maturation, and combination of appropriate biochemical design and biological experiments, a highly efficient antibody molecule has been identified that can bind to human C5a and inhibit the action of C5a. The results of the present application show that, compared with known anti-C5a antibodies, our antibody or antigen-binding fragment binds to a different region or epitope of C5a and does not competitively bind to known C5a antibodies. In some embodiments, the isolated anti-C5a antibody or antigen-binding fragment binds to human C5 and C5a. In some embodiments, when a molar excess of natural human C5 is present that is 2-fold or more, the isolated anti-C5a antibody or antigen-binding fragment can still bind to the liberated C5a polypeptide and inhibit the inflammatory response mediated by C5a. Known C5a is an essential part of the pathogenesis of complement-associated disorders, where complement-associated disorders may include, but are not limited to, sepsis, rheumatoid arthritis, and asthma. Since the concentration of C5 in human serum is much higher than that of C5a, anti-C5a antibodies need to be administered at high concentrations and / or frequently if the antibodies bind to C5 and C5a with equal binding capacity. The advantage of the antibodies or antigen-binding fragments of the present application is that they bind to new epitopes of C5a and display extremely low human C5 binding affinity in ELISA binding assays and Biacore assays, so compared to other C5a antibodies, the C5a antibodies of the present application can be administered to humans at lower doses and / or more frequently and have equal or better C5a inhibitory effects. Surprisingly, various biological experiments have demonstrated that our antibodies are more effective than control antibodies.

[0020] Anti-C5a antibodies according to the present application include, for example, full length anti-C5a antibodies, anti-C5a single chain antibodies (scFvs), anti-C5a Fc fusion proteins, multispecific (eg, bispecific) anti-C5a antibodies, anti-C5a immune conjugates, and the like.

[0021] In one aspect, the present application provides an isolated anti-C5a antibody capable of specifically binding to an epitope in human C5a, wherein the isolated anti-C5a antibody specifically binds to at least one of amino acid residues D at position 31, E at position 32, and R at position 40 in human C5a as set forth in SEQ ID NO:141. In some embodiments, the isolated anti-C5a antibody specifically binds to residues 31-40 in human C5a as set forth in SEQ ID NO:141.

[0022] In another embodiment, the present application provides a method for the preparation of a compound having the sequence X 1 YYX 2 Q (SEQ ID NO:67), 1 is D or N, and X 2 is M or I), the sequence LIRX 1 KX 2 X 3 GX 4 TX 5 X 6 X 7 AAS 8 One HC-CDR2 containing KG (SEQ ID NO:68) (wherein 1 is K or N, and X 2 is A or V, and X 3 is V, N, or I, and X 4 is G, E, F, H, I, Q or R, and X 5 is T, V or A, and X 6 is Q, E, T or S, and X 7 is Y or F, and X 8 is V or L), and the sequence RX 1 GPPGLX 2 (SEQ ID NO:69) (wherein 1 is A, L or V, and X 2 is T, S or A) H ) and the array RSSQX 1 LLX 2 X 3 X 4 X 5 YX6 YX 7 D (SEQ ID NO: 70), but 1 is S, R or N, and X 2 is A, H or D, and X 3 is S or T, and X 4 is D or N, and X 5 is G, A or R, and X 6 is N, I, T, E or A, and X 7 is I, M, L or V), array GX 1 SX 2 One LC-CDR2 containing RAS (SEQ ID NO:71) (wherein 1 is G or A, and X 2 is N or K), and the array X 1 QHX 2 X 3 LPX 4 One LC-CDR3 containing X 1 is L or M, and X 2 is R or K, and X 3 is A or V, and X 4 is P or L) L ) and

[0023] Also provided are nucleic acids encoding anti-C5a antibodies, compositions comprising anti-C5a antibodies, methods for preparing and using anti-C5a antibodies.

[0024] definition As stated above, "treatment" or "treating" refers to a method of obtaining a beneficial or expected result, including a clinical outcome. For purposes of this application, the beneficial or expected clinical outcome may include, but is not limited to, one or more of the following: alleviation of one or more symptoms attributable to the disease, reduction in the extent of the disease, stabilization of the disease (e.g., preventing or slowing the progression of the disease), preventing or slowing the spread of the disease (e.g., metastasis), preventing or slowing the recurrence of the disease, slowing or alleviating the progression of the disease, improving the condition of the disease, alleviating the disease (in part or in whole), reducing the dose of one or more other drugs required to treat the disease, slowing the progression of the disease, improving or enhancing the quality of life, weight gain, and / or increasing survival time. At the same time, "treatment" further includes reduction in the pathological outcome of the disease (e.g., in the case of cancer, tumor volume). The methods of this application contemplate any one or more aspects of these treatments.

[0025] The term "antibody" includes full length antibodies and antigen-binding fragments thereof. Full length antibodies contain two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for binding the antigen. The variable regions in the two chains usually contain three hypervariable loops, called complementarity determining regions (CDRs) (light chain (LC) CDRs contain LC-CDR1, LC-CDR2 and LC-CDR3, and heavy chain (HC) CDRs contain HC-CDR1, HC-CDR2 and HC-CDR3). The CDR boundaries of the antibodies or antigen-binding fragments disclosed herein can be defined or recognized according to the Kabat, Chothia or Al-Lazikani rules (Al-Lazikani 1997, Chothia 1985, Chothia 1987, Chothia 1989, Kabat 1987, Kabat 1991). The three CDR regions of the heavy or light chain are inserted between side flap sections called framework regions (FRs), which are more conservative than the CDR regions and form stents supporting the hypervariable loops. The constant regions of the heavy and light chains do not participate in antigen binding but exhibit various effector functions. Antibodies are classified based on the amino acid sequence of their heavy chain constant regions. The five main categories or isotypes of antibodies are IgA, IgD, IgE, IgG and IgM, characterized by having α, δ, ε, γ and μ type heavy chains, respectively. Some of the main antibody categories are divided into subclasses such as IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgA1 (α1 heavy chain) or IgA2 (α2 heavy chain).

[0026] As mentioned above, the term "antigen-binding fragment" refers to an antibody fragment, including, for example, a double-chain antibody, Fab, Fab', F(ab')2, Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized double-chain antibody (ds double-chain antibody), single-chain antibody (scFv), scFv dimer (bivalent double-chain antibody), multispecific antibody composed of antibody fragments containing one or more CDRs, single domain antibody, nanobody, domain antibody, bivalent domain antibody, or any other antibody fragment capable of binding to an antigen but not containing a complete antibody structure. An antigen-binding fragment can bind to the same antigen as the parent antibody or parent antibody fragment (e.g., parent scFv). In some examples, an antigen-binding fragment can contain one or more CDRs from a particular human antibody, which are grafted onto framework regions from one or more different human antibodies.

[0027] As mentioned above, the term "epitope" refers to a specific atom or group of amino acids on an antigen that is bound to an antibody or a portion of an antibody. When two antibodies or portions of antibodies exhibit competitive binding to an antigen, they may bind to the same epitope on the antigen.

[0028] As used herein, a first antibody binds to a C5a target "competitively" with a second antibody if the first antibody, at equimolar concentrations, 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%), and vice versa. PCT publication WO03 / 48731 describes a method for high throughput antibody "epitope typing" based on cross-competition.

[0029] As mentioned above, the terms "specifically bind", "specifically recognize" or "specific for" refer to a measurable and reproducible interaction, for example, the binding of an antibody to a target can be determined in a heterogeneous molecular population, including the presence of the target in a biomolecule. For example, an antibody can specifically recognize a target (which may be an epitope) in that the antibody binds to the target with higher affinity, avidity, easier, and / or longer lasting than the binding to other targets. In some embodiments, an antibody that specifically recognizes an antigen reacts with one or more antigenic determinant clusters of the antigen and has a binding affinity that is at least 10 times higher than the binding affinity to other targets.

[0030] As discussed above, an "isolated" anti-C5a antibody means an anti-C5a antibody that is (1) unrelated to naturally occurring proteins, (2) free from other proteins of the same origin, (3) expressed by cells of a different genus, or (4) not found in nature.

[0031] As stated above, the term "isolated nucleic acid" refers to genomic, cDNA or synthetically derived nucleic acid or a combination thereof. Based on its origin, the "isolated nucleic acid" means that it is (1) free of all or a portion of the polynucleotides found in nature, (2) capable of being operably linked to polynucleotides with which it is not naturally linked, or (3) not present as part of a longer sequence in nature.

[0032] As used herein, the term "CDR" or "complementarity determining region" refers to the non-contiguous antigen-binding sites found within the variable domains of heavy and light chain polypeptides. References Kabat et al., J.Biol.Chem.252:6609~6616(1977), Kabat et al., USDept.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.,273:927~948(1997), MacCallum et al.,J.Mol.Biol.262:732~745(1996), Abhinandan and Martin, Mol.Immunol.,45:3832~3839(2008), LefrancM.P.et These special regions are described in Honegger and Plueckthun, J. Mol. Biol., 309:657-670 (2001), where these definitions include overlapping or subsets of amino acid residues when compared to one another. However, CDRs designated for antibodies or grafted antibodies or variants thereof in either manner of definition are all within the scope of the terms defined and used herein. Table 1 shows the positions of amino acid residues contained in the CDRs defined in each of the above cited references and provides a comparison. CDR prediction algorithms and binding interfaces are well known in the art and are described, for example, in Abhinandan and Martin, Mol. Immunol., 45:3832-3839 (2008), Ehrenmann F. et al., Nucleic Acids Res., 38:D301-D307 (2010), 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 use in this application and in one or more claims that may be included herewith.

[0033] [Table 1]

[0034] The term "chimeric antibody" refers to antibodies in which a portion of the heavy and / or light chains corresponds to or is homologous to corresponding sequences in antibodies from a particular genus or belonging to a particular antibody class or subclass, and the remainder of the chains corresponds to or is homologous to corresponding sequences in antibodies from another genus or belonging to another antibody class or subclass, and fragments of such antibodies, which may have biological activity herein (see US Patent Nos. 4, 816, 567, and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).

[0035] "Fv" is the smallest antibody fragment that contains a complete antigen recognition and binding site. The fragment is a dimer formed by tight non-covalent association of one heavy chain variable domain and one light chain variable domain. The folding of the two domains induces six hypervariable loops (three loops each in the light chain and heavy chain), which provide the antibody with amino acid residues for binding to the antigen and confer specificity to bind to the antigen. However, even a single variable domain (or half of an Fv fragment, which contains only three CDRs with specificity for the antigen) has the ability to recognize and bind to an antigen, albeit with a lower affinity than the complete binding site.

[0036] A "single-chain Fv", which may be abbreviated as "sFv" or "scFv", is a VFv that is linked to a single polypeptide chain. H and V LIn some embodiments, the scFv polypeptide is an antibody fragment comprising the V H and V L The scFv further comprises a linking polypeptide between the domains, and the linking polypeptide allows the scFv to form an ideal structure for antigen binding. For an overview of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0037] The term "double-chain antibodies" refers to small antibody fragments prepared by constructing scFv fragments (see the contents of the previous paragraph) with a short joint (e.g., 5-10 residues) between the VH and VL domains, whereby the variable domains pair inter-chain instead of intra-chain, generating one bivalent fragment, i.e., a fragment with two antigen-binding sites. Bispecific double-chain antibodies are isodimers of two "crossover" scFv fragments, in which the VH and VL domains of the two antibodies are located on different polypeptide chains. Double-chain antibodies are described extensively in EP 404,097, WO93 / 11161, and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0038] "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies, which contain minimal sequence derived from the non-human antibody. Often, humanized antibodies are human immunoglobulins (acceptor antibody) in which hypervariable region (HVR) residues of the acceptor antibody are replaced by hypervariable region residues from a non-human species such as mouse, rat, rabbit or a non-human mammal (donor antibody) that have the desired antibody specificity, affinity, and performance. In some cases, residues within the framework regions of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also include residues that are not present in either the acceptor or donor antibody. These modifications can further improve antibody performance. Usually, humanized antibodies contain almost all, at least one, and usually two, variable domains, in which all or almost all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or almost all of the framework regions are human immunoglobulin sequences. Preferably, the human antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically a human immunoglobulin constant region. For specific details, see Jones et al., Nature 321:522-525 (1986), Riechmann et al., Nature 332:323-329 (1988), and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

[0039] The "percentage of amino acid sequence identity" or "homology" between the polypeptide and antibody sequences identified in this application is defined as the percentage of identical amino acid residues in the candidate sequence and the polypeptide sequence to be compared, where conservative substitutions are considered to be part of the sequence identity. The percentage of amino acid sequence identity can be determined by various comparison methods within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. Those skilled in the art can determine appropriate parameters for the measurement comparison, including any algorithms necessary to maximize the comparison over the entire length of the sequences to be compared. However, for the purposes of this application, the percentage of amino acid sequence identity values ​​are generated using the sequence comparison computer program MUSCLE (Edgar, RC, Nucleic Acids Research 32(5):1792-1797, 2004; Edgar, RC, BMC Bioinformatics 5(1):113, 2004).

[0040] The term "Fc receptor" or "FcR" is used to describe a receptor that binds to an antibody Fc region. In some embodiments, the FcR of the present application is an FcR that binds to an IgG antibody (gamma receptor), including receptors of the FcγRI, FcγRII and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences and differ primarily in their cytoplasmic domains. The cytoplasmic domain of the activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM). The cytoplasmic domain of the inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) (see M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). The term further includes allotypes, e.g., the FcγRIIIA allotypes FcγRIIIA-Phe158, FcγRIIIA-Val158, FcγRIIA-R131, and / or FcγRIIA-H131. FcRs are described in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). The term FcR in this application includes other types of FcRs, including FcRs identified in the future. The term FcR also includes the neonatal receptor FcRn, which is responsible for transferring maternal IgGs to the neonate (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0041] The term "FcRn" refers to the neonatal Fc receptor (FcRn). FcRn is structurally similar to the major histocompatibility complex (MHC) and is composed of an α chain noncovalently bound to β2-microglobulin. The various 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 the mother to the neonate and in the regulatory control of serum IgG levels. As a salvage receptor, FcRn can bind and transport pinocytosed IgG intact within and between cells, thus avoiding them from the default degradation pathway.

[0042] The "CH1 domain" of a human IgG Fc region typically extends from amino acid 118 to amino acid 215 (EU numbering system).

[0043] The "hinge region" is usually defined as extending from Glu at position 216 to Pro at position 230 of human IgG1 (Burton, Molec. Immunol. 22:161-206 (1985)). The IgG1 sequence can be compared to the hinge regions of other IgG isotypes by placing the first and last cysteine ​​residues that form the inter-heavy chain disulfide bond in the same positions as in IgG1.

[0044] The "CH2 domain" of the human IgG Fc region typically extends from amino acid 231 to amino acid 340. What is unique about the CH2 domain is that it does not pair closely with another region, but inserts two branched N-terminally linked glycans between the two CH2 domains of the intact native IgG molecule. It is speculated that the saccharides may be an alternative for domain-domain pairing, helping to maintain the stability of the CH2 domain. Burton, Molec. Immunol. 22:161-206 (1985).

[0045] The "CH3" domain comprises that portion of the Fc region extending from the C-terminal residue to the CH2 domain (from amino acid 341 to the C-terminus of the antibody sequence, usually amino acid residue 446 or 447 for IgG).

[0046] A "functional Fc fragment" has an "effector function" possessed by a native Fc region sequence. Exemplary "effector functions" include C1q binding, complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, degradation of cell surface receptors (e.g., B cell receptor, BCR), etc. Such effector functions usually require binding of the Fc region to a binding domain (e.g., an antibody variable region), and can be assessed by various experimental methods known in the art.

[0047] An IgG Fc variant antibody with "altered" FcR binding affinity or ADCC activity has enhanced or diminished FcR binding activity and / or ADCC activity compared to a parent polypeptide or a polypeptide comprising a native Fc sequence. An Fc variant that exhibits "enhanced binding" to an FcR has a higher binding affinity (e.g., lower apparent Kd or IC50 value) to at least one FcR compared to a parent polypeptide or a polypeptide comprising a native IgG Fc sequence. In some embodiments, the binding capacity is enhanced by 3-fold, e.g., 5, 10, 25, 50, 60, 100, 150, 200, or even 500-fold, or the avidity is increased by 25%-1000%, compared to the parent polypeptide. An Fc variant that exhibits "reduced binding" to an FcR has a lower affinity (e.g., higher apparent Kd or IC50 value) to at least one FcR compared to the parent polypeptide. The binding capacity is reduced by 40% or more compared to the parent polypeptide.

[0048] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" is a form of cytotoxicity in which secreted Ig binds to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer cells (NK), neutrophils, and macrophages), allowing these cytotoxic effector cells to specifically bind to antigen-bearing target cells and then kill the target cells with cytotoxins. Antibodies "arm" the cytotoxic cells and are necessary for such killing. Of the major cell types that mediate ADCC, NK cells express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991) summarizes the expression of FcRs on hematopoietic cells. To evaluate the ADCC activity of a target molecule, in vitro ADCC experiments can be performed, as described in U.S. Patent No. 5,500,362 or 5,821,337. Effector cells applied in such experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Preferably, the ADCC activity of a target molecule can also be evaluated in vivo, as described in, for example, the animal model disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).

[0049] A polypeptide comprising an Fc region variant may exhibit "enhanced ADCC activity" or mediate ADCC effects more effectively in the presence of human effector cells than a polypeptide comprising wild-type IgG Fc or a parent polypeptide, and the polypeptide comprising the Fc region variant may mediate ADCC more effectively in vitro or in vivo when the polypeptide comprises approximately the same number of wild-type IgG Fc-containing polypeptides (or the parent polypeptide) in an experiment. Typically, any in vitro ADCC experimental method known in the art, such as an experiment or method for identifying ADCC activity, is employed to identify such variants, such as in an animal model. In some embodiments, such variants are 5-100 times more efficient at mediating ADCC than the wild-type Fc (or the parent polypeptide), such as 25-50 times more efficient.

[0050] "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 binding of the first component of the complement system (C1q) to an antibody (of the appropriate structural subclass) bound to a homologous antigen. To assess complement activation, a CDC experiment can be performed as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996). U.S. Patent No. 6,194,551 B1 and WO 99 / 51642 describe polypeptide variants with altered Fc region amino acid sequences and increased or decreased C1q binding capacity. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0051] Unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that encode the same amino acid sequence in a degenerate form among each other. A nucleotide sequence encoding a protein or RNA may contain introns, e.g., a nucleotide sequence encoding a protein contains introns in some form.

[0052] The term "operably linked" refers to the regulatory control of the functional link between a sequence and a heterologous nucleotide sequence to allow the latter to be expressed. For example, a first nucleotide sequence is operably linked to a second nucleotide sequence when they are in a functional relationship. For example, a promoter and a coding sequence are operably linked if the promoter affects the transcription or expression of the coding sequence. Usually, operably linked DNA sequences are contiguous and, if necessary, can link two protein coding regions in the same reading frame.

[0053] "Homology" refers to sequence similarity or sequence identity between two polypeptides or two nucleic acid molecules. If the same position in two comparison sequences is the same base or amino acid monomer subunit, for example, if the same position in two DNA molecules is both adenine, the two DNA molecules are homologous at that position. The homology rate between two sequences refers to the ratio of the number of matching or homologous positions shared by the two sequences to the total number of positions multiplied by 100. For example, if 6 positions out of 10 positions in two sequences are matching or homologous, the homology of the two sequences is 60%. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. Usually, when comparing two sequences, the comparison is performed with the aim of maximum homology.

[0054] An "effective amount" of an anti-C5a antibody or composition disclosed herein means an amount sufficient to achieve a particular purpose. An "effective amount" can be determined empirically in a manner related to said purpose that is known.

[0055] The term "therapeutically effective amount" refers to a dose of the anti-C5a antibody or composition disclosed herein that can effectively treat a disease or condition in an individual. For example, in the case of cancer, a therapeutically effective amount of the anti-C5a antibody or composition can reduce the number of cancer cells, reduce the size or weight of the tumor, inhibit (i.e., reduce to a certain extent, and preferably stop) the penetration of tumor cells into surrounding organs, inhibit (i.e., reduce to a certain extent, and preferably stop) the metastasis of the tumor, inhibit the growth of the tumor to a certain extent, and / or alleviate to a certain extent one or more symptoms associated with the cancer. The anti-C5a antibody or composition disclosed herein can inhibit and / or kill existing tumor cells to a certain extent, and may be cytostatic or cytotoxic. In some embodiments, a therapeutically effective amount refers to a dose that can extend the survival of a patient. In some embodiments, a therapeutically effective amount refers to a dose that can improve the progression-free survival of a patient.

[0056] As used herein, "pharmacologically acceptable" or "pharmacologically compatible" refers to a material that has no biological activity or other undesirable properties, e.g., the material can be added to a pharmaceutical composition administered to a patient without causing a significant adverse biological reaction or does not interact in a deleterious manner with any other components contained in the composition. Preferably, a pharma- ceutical or excipient that is pharma- ceutical acceptable meets the necessary standards of toxicology or manufacturing detection and / or is included in the inactive ingredient guidelines developed by the U.S. Food and Drug Administration.

[0057] It should be understood that the embodiments of the present application described herein include embodiments that are "consisting of" and / or "consisting essentially of."

[0058] As used herein, "about" refers to a numerical value or parameter and includes (describes) a variant on the value or parameter itself. For example, a statement about "about X" includes the statement of "X."

[0059] As used herein, "not" a value or parameter generally refers to something "other than" a value or parameter. For example, the method cannot be used to treat cancer type X, meaning that the method is generally used to treat other types of cancers besides cancer type X.

[0060] As employed in this application and the following claims, the singular forms "a," "one," and "the" include plural referents unless the context clearly indicates otherwise.

[0061] Anti-C5a antibody On the other hand, the present application provides an anti-C5a antibody that specifically binds to C5a. The anti-C5a antibody may include, but is not limited to, a humanized antibody, a chimeric antibody, a murine antibody, a human antibody, and an antibody molecule comprising the heavy and / or light chain CDRs of the present application. On the other hand, the present application provides an isolated antibody that binds to C5a. The expected anti-C5a antibodies include, for example, a full-length anti-C5a antibody (e.g., full-length IgG1 or IgG4), an anti-C5a single-chain antibody, an anti-C5a Fc fusion protein, a multispecific (e.g., bispecific) anti-C5a antibody, an anti-C5a immune complex, and the like. In some embodiments, the anti-C5a antibody is a full-length antibody (e.g., full-length IgG1 or IgG4) or an antigen-binding fragment thereof, and specifically binds to C5a. In some embodiments, the anti-C5a antibody is a Fab, Fab', F(ab)'2, Fab'-SH, single chain antibody (scFv), Fv fragment, dAb, Fd, nanobody, double chain antibody or linear antibody. In some embodiments, an antibody that specifically binds to C5a refers to an antibody whose binding affinity to C5a is at least 10 times (including, for example, 10, 102, 103, 104, 105, 106, or 107 times) higher than its binding affinity to a non-target. In some embodiments, a non-target refers to an antigen that is not C5a. The binding affinity can be measured by methods known in the art, such as ELISA, fluorescence activated cell sorting (FACS) analysis, or radioimmunoprecipitation analysis (RIA). The Kd value can be measured by methods known in the art, such as surface plasmon resonance (SPR) technology or biolayer interference technology (BLI).

[0062] Although the present application broadly contemplates anti-C5a antibodies comprising human sequences (e.g., human heavy and light chain variable domains comprising human CDR sequences), non-human anti-C5a antibodies are also contemplated. In some embodiments, the non-human anti-C5a antibodies comprise human CDR sequences of the anti-C5a antibodies of the present application and non-human framework region sequences, and in some embodiments, the non-human framework region sequences comprise any sequence for generating heavy and / or light chain variable domains using one or more human CDR sequences of the present application, including mammals such as mouse, rat, rabbit, pig, cow (e.g., dairy cow, bull, buffalo), deer, sheep, goat, chicken, cat, dog, mink, primates (e.g., marmoset, rhesus monkey), and the like. In some embodiments, the non-human anti-C5a antibodies include anti-C5a antibodies generated by grafting one or more human CDR sequences of the present application onto a non-human framework region (e.g., mouse or chicken framework region sequences).

[0063] The complete amino acid sequence of an exemplary human C5a comprises or consists of the amino acid sequence SEQ ID NO:141.

[0064] In some embodiments, the anti-C5a antibodies of the present application specifically recognize an epitope in human C5a. In some embodiments, the anti-C5a antibodies cross-react with C5a of other species other than human. In some embodiments, the anti-C5a antibodies are completely specific for human C5a and do not cross-react with other non-human species or types.

[0065] In some embodiments, the anti-C5a antibody of the present application specifically binds to a linear epitope in human C5a. In some embodiments, the anti-C5a antibody of the present application specifically binds to a non-linear epitope in C5a. In some embodiments, the anti-C5a antibody of the present application specifically binds to an epitope in human C5a, wherein the isolated anti-C5a antibody specifically binds to at least one of the amino acid residues D at position 31, E at position 32, and R at position 40 in human C5a as shown in SEQ ID NO:141. In some embodiments, the isolated anti-C5a antibody specifically binds to residues 31 to 40 in human C5a as shown in SEQ ID NO:141.

[0066] In some embodiments, the anti-C5a antibody cross-reacts with at least one allelic variant of the C5a protein (or fragment thereof). In some embodiments, the 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-C5a antibody does not cross-react with any allelic variant of the C5a protein (or fragment thereof).

[0067] In some embodiments, the anti-C5a antibody cross-reacts with at least one species variant of the C5a protein. In some embodiments, for example, the C5a protein (or fragment thereof) is human C5a and the species variant of the C5a protein (or fragment thereof) is a cynomolgus monkey variant. In some embodiments, the anti-C5a antibody does not cross-react with any species variant of the C5a protein.

[0068] In some embodiments, any anti-C5a antibody of the present application comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the anti-C5a antibody comprises an IgG1-type heavy chain constant region. In some embodiments, the anti-C5a antibody comprises an IgG2-type heavy chain constant region. In some embodiments, the anti-C5a antibody comprises an IgG3-type heavy chain constant region. In some embodiments, the anti-C5a antibody comprises an IgG4-type heavy chain constant region. In some embodiments, the heavy chain constant region comprises (including consisting of, or consisting essentially of) the amino acid sequence SEQ ID NO:142. In some embodiments, the heavy chain constant region comprises (including consisting of, or consisting essentially of) the amino acid sequence SEQ ID NO:143. In some embodiments, the anti-C5a antibody comprises a lambda light chain constant region. In some embodiments, the anti-C5a antibody comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises (including consists of, or consists essentially of) the amino acid sequence of SEQ ID NO:144. In some embodiments, the anti-C5a antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.

[0069] In some embodiments, the isolated anti-C5a antibody has the sequence X 1 YYX 2 Q (SEQ ID NO:67), 1 is D or N, and X 2 is M or I), the sequence LIRX 1 KX 2 X 3 GX 4 TX 5 X 6 X 7 AAS 8 One HC-CDR2 containing KG (SEQ ID NO:68) (wherein 1 is K or N, and X 2 is A or V, and X 3 is V, N, or I, and X 4is G, E, F, H, I, Q or R, and X 5 is T, V or A, and X 6 is Q, E, T or S, and X 7 is Y or F, and X 8 is V or L), and the sequence RX 1 GPPGLX 2 (SEQ ID NO:69) (wherein 1 is A, L or V, and X 2 is T, S or A) H and the array RSSQX 1 LLX 2 X 3 X 4 X 5 YX 6 YX 7 D (SEQ ID NO: 70), but 1 is S, R or N, and X 2 is A, H or D, and X 3 is S or T, and X 4 is D or N, and X 5 is G, A or R, and X 6 is N, I, T, E or A, and X 7 is I, M, L or V), array GX 1 SX 2 One LC-CDR2 containing RAS (SEQ ID NO:71) (wherein 1 is G or A, and X 2 is N or K), and the array X 1 QHX 2 X 3 LPX 4 One LC-CDR3 containing X 1 is L or M, and X 2 is R or K, and X 3 is A or V, and X 4 is P or L) L ) and

[0070] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 having a sequence that has at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 1 to 6, one HC-CDR2 having a sequence that has at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 7 to 29, and one HC-CDR3 having a sequence that has at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 30 to 38. H Includes.

[0071] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 having an amino acid sequence of any one of SEQ ID NOs: 1 to 6, one HC-CDR2 having an amino acid sequence of any one of SEQ ID NOs: 7 to 29, and one HC-CDR3 having an amino acid sequence of any one of SEQ ID NOs: 30 to 38. H Includes.

[0072] In some embodiments, the anti-C5a antibody comprises one LC-CDR1 having a sequence that has at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 39 to 56, one LC-CDR2 having a sequence that has at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 57 to 59, and one LC-CDR3 having a sequence that has at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 60 to 66. L Includes.

[0073] In some embodiments, the anti-C5a antibody comprises one LC-CDR1 having an amino acid sequence of any one of SEQ ID NOs: 39 to 56, one LC-CDR2 having an amino acid sequence of any one of SEQ ID NOs: 57 to 59, and one LC-CDR3 having an amino acid sequence of any one of SEQ ID NOs: 60 to 66. L Includes.

[0074] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 having a sequence that has at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 1 to 6, one HC-CDR2 having a sequence that has at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 7 to 29, and one HC-CDR3 having a sequence that has at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 30 to 38. H and one LC-CDR1 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 39 to 56, one LC-CDR2 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 57 to 59, and one LC-CDR3 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 60 to 66. L Includes.

[0075] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 having an amino acid sequence of any one of SEQ ID NOs: 1 to 6, one HC-CDR2 having an amino acid sequence of any one of SEQ ID NOs: 7 to 29, and one HC-CDR3 having an amino acid sequence of any one of SEQ ID NOs: 30 to 38. H and a V having one LC-CDR1 having an amino acid sequence of any one of SEQ ID NOs: 39 to 56, one LC-CDR2 having an amino acid sequence of any one of SEQ ID NOs: 57 to 59, and one LC-CDR3 having an amino acid sequence of any one of SEQ ID NOs: 60 to 66. L Includes.

[0076] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:1, one HC-CDR2 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:7, and one HC-CDR3 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:30. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:39, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:60. L Includes.

[0077] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:7, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:30. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:39, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:60. L Includes.

[0078] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:8, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:31. Hand one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 40, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 61. L Includes.

[0079] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:8, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:31. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:40, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L Includes.

[0080] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:10, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 42, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 61. L Includes.

[0081] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L Includes.

[0082] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:11, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:41, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:57, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:64. L Includes.

[0083] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:11, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:41, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:64.L Includes.

[0084] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:9, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 43, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 63. L Includes.

[0085] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:43, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:63. L Includes.

[0086] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:11, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:35. H and one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 44, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 60. L Includes.

[0087] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:11, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:35. H and V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:44, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:60. L Includes.

[0088] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:6, one HC-CDR2 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:18, and one HC-CDR3 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:36. Hand one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 42, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 61. L Includes.

[0089] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:36. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L Includes.

[0090] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:5, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:21, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 42, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 61. L Includes.

[0091] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:21, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L Includes.

[0092] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:10, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:53, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:59, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:65. L Includes.

[0093] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:59, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:65.L Includes.

[0094] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:23, and one HC-CDR3 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 42, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO: 61. L Includes.

[0095] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:23, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L Includes.

[0096] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:2, one HC-CDR2 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:23, and one HC-CDR3 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:56, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:61. L Includes.

[0097] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:23, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:56, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L Includes.

[0098] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:6, one HC-CDR2 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:18, and one HC-CDR3 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:36. Hand one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:52, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:58, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:61. L Includes.

[0099] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:36. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:58, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L Includes.

[0100] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:6, one HC-CDR2 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:18, and one HC-CDR3 comprising a sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO:36. H and one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:53, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:59, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:65. L Includes.

[0101] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:36. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:59, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:65. L Includes.

[0102] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:5, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:21, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:52, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:58, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:61. L Includes.

[0103] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:21, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:58, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61.L Includes.

[0104] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:5, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:21, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:32. H and one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:53, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:59, and one LC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:65. L Includes.

[0105] In some embodiments, the anti-C5a antibody comprises one HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:21, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32. H and one LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:59, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:65. L Includes.

[0106] In some embodiments, the anti-C5a antibody comprises a V sequence having at least 90% sequence identity to any of the amino acid sequences of SEQ ID NOs: 1-38. Hand a VL comprising a sequence having at least 90% sequence identity to any of the amino acid sequences of SEQ ID NOs: 39 to 66. In some embodiments, the anti-C5a antibody comprises a VH comprising an amino acid sequence of any of SEQ ID NOs: 1-38 and a VL comprising an amino acid sequence of any of SEQ ID NOs: 39 to 66. L Includes.

[0107] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 1, 7, and 30. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 39, 57 and 60. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 1, 7, and 30. H and V comprising the amino acid sequences shown in SEQ ID NOs: 39, 57 and 60. L Includes.

[0108] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 2, 8, and 31. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 40, 57 and 61. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 2, 8, and 31. H and V comprising the amino acid sequences shown in SEQ ID NOs: 40, 57 and 61. L Includes.

[0109] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 2, 10, and 32. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 42, 57 and 61. LIn some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 2, 10, and 32. H and V comprising the amino acid sequences shown in SEQ ID NOs: 42, 57 and 61. L Includes.

[0110] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 2, 11, and 32. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 41, 57 and 64. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 2, 11, and 32. H and V comprising the amino acid sequences shown in SEQ ID NOs: 41, 57 and 64. L Includes.

[0111] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 2, 9, and 32. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 43, 57 and 63. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 2, 9, and 32. H and V comprising the amino acid sequences shown in SEQ ID NOs: 43, 57 and 63. L Includes.

[0112] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 2, 11, and 35. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 44, 57 and 60. LIn some embodiments, the anti-C5a antibody comprises a VFG comprising the amino acid sequence set forth in SEQ ID NOs: 2, 11, and 35. H and V comprising the amino acid sequences shown in SEQ ID NOs: 44, 57 and 60. L Includes.

[0113] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 6, 18, and 36. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 42, 57 and 61. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 6, 18, and 36. H and V comprising the amino acid sequences shown in SEQ ID NOs: 42, 57 and 61. L Includes.

[0114] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs:5, 21, and 32. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 42, 57 and 61. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 5, 21, and 32. H and V comprising the amino acid sequences shown in SEQ ID NOs: 42, 57 and 61. L Includes.

[0115] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 2, 10, and 32. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 53, 59 and 65. LIn some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 2, 10, and 32. H and V comprising the amino acid sequences shown in SEQ ID NOs: 53, 59 and 65. L Includes.

[0116] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 2, 23, and 32. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 42, 57 and 61. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 2, 23, and 32. H and V comprising the amino acid sequences shown in SEQ ID NOs: 42, 57 and 61. L Includes.

[0117] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 2, 23, and 32. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 56, 57 and 61. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 2, 23, and 32. H and V comprising the amino acid sequences shown in SEQ ID NOs: 56, 57 and 61. L Includes.

[0118] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 6, 18, and 36. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 52, 58 and 61. LIn some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 6, 18, and 36. H and V comprising the amino acid sequences shown in SEQ ID NOs: 52, 58 and 61. L Includes.

[0119] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs: 6, 18, and 36. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 53, 59 and 65. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 6, 18, and 36. H and V comprising the amino acid sequences shown in SEQ ID NOs: 53, 59 and 65. L Includes.

[0120] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs:5, 21, and 32. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 52, 58 and 61. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 5, 21, and 32. H and V comprising the amino acid sequences shown in SEQ ID NOs: 52, 58 and 61. L Includes.

[0121] In some embodiments, the anti-C5a antibody comprises a V sequence having an amino acid sequence having at least 90% sequence identity to SEQ ID NOs:5, 21, and 32. H and V comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NOs: 53, 59 and 65. LIn some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence set forth in SEQ ID NOs: 5, 21, and 32. H and V comprising the amino acid sequences shown in SEQ ID NOs: 53, 59 and 65. L Includes.

[0122] In some embodiments, the anti-C5a antibody comprises a VH having an amino acid sequence of any one of SEQ ID NOs:73 to 111, the VH comprising HC-CDR1, HC-CDR2 and HC-CDR3. H and V having any one of the amino acid sequences of SEQ ID NOs: 112 to 140. L V containing LC-CDR1, LC-CDR2 and LC-CDR3 in L Includes.

[0123] In some embodiments, the anti-C5a antibody comprises one, two or three HC-CDRs in the amino acid sequence SEQ ID NO:73. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:75. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:100. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:79. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:85. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:88. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:93. HIn some embodiments, the anti-C5a antibody comprises a VHC-CDR comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:97. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:77. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:102. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:109. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:110. H In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three HC-CDRs within the amino acid sequence SEQ ID NO:111. H Includes.

[0124] In some embodiments, the anti-C5a antibody comprises one, two or three LC-CDRs in the amino acid sequence SEQ ID NO:112. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three LC-CDRs within the amino acid sequence SEQ ID NO:114. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three LC-CDRs within the amino acid sequence SEQ ID NO:135. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three LC-CDRs within the amino acid sequence SEQ ID NO:118. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three LC-CDRs within the amino acid sequence SEQ ID NO:117. LIn some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three LC-CDRs within the amino acid sequence SEQ ID NO:126. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three LC-CDRs within the amino acid sequence SEQ ID NO:116. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three LC-CDRs within the amino acid sequence SEQ ID NO:132. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three LC-CDRs within the amino acid sequence SEQ ID NO:138. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three LC-CDRs within the amino acid sequence SEQ ID NO:139. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising one, two or three LC-CDRs within the amino acid sequence SEQ ID NO:140. L Includes.

[0125] In some embodiments, the anti-C5a antibody has the VVIII sequence of SEQ ID NO:73. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and V having SEQ ID NO:112 L V containing LC-CDR1, LC-CDR2 and LC-CDR3 in L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:75. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and V having SEQ ID NO:114 L V containing LC-CDR1, LC-CDR2 and LC-CDR3 in L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:100. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in Hand a VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 in VL having SEQ ID NO:135. L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:79. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and a VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 in VL having SEQ ID NO:118. L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:85. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and a VL having SEQ ID NO: 117, comprising LC-CDR1, LC-CDR2 and LC-CDR3. L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:88. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and a VL having SEQ ID NO: 126, comprising LC-CDR1, LC-CDR2 and LC-CDR3. L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:93. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and a VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 in VL having SEQ ID NO:116. L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:97. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and a VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 in VL having SEQ ID NO:116. L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:77. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in Hand V having SEQ ID NO:132 L V containing LC-CDR1, LC-CDR2 and LC-CDR3 in L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:102. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and V having SEQ ID NO:135 L In some embodiments, the anti-C5a antibody comprises a VL having SEQ ID NO: 109, and a VL comprising LC-CDR1, LC-CDR2 and LC-CDR3 in H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and V having SEQ ID NO:138 L V containing LC-CDR1, LC-CDR2 and LC-CDR3 in L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:110. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and V having SEQ ID NO:139 L V containing LC-CDR1, LC-CDR2 and LC-CDR3 in L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:110. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and V having SEQ ID NO:140 L V containing LC-CDR1, LC-CDR2 and LC-CDR3 in L In some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:111. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and V having SEQ ID NO:139 L V containing LC-CDR1, LC-CDR2 and LC-CDR3 in LIn some embodiments, the anti-C5a antibody comprises a V having SEQ ID NO:111. H V including HC-CDR1, HC-CDR2 and HC-CDR3 in H and V having SEQ ID NO:140 L V containing LC-CDR1, LC-CDR2 and LC-CDR3 in L Includes.

[0126] In some embodiments, the anti-C5a antibody comprises an amino acid sequence of any of SEQ ID NOs:73-111 or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to an amino acid sequence of any of SEQ ID NOs:73-111. H and a V that includes an amino acid sequence of any one of SEQ ID NOs: 112 to 140 or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to an amino acid sequence of any one of SEQ ID NOs: 112 to 140. L In some embodiments, the anti-C5a antibody comprises a VFGV comprising any one of the amino acid sequences of SEQ ID NOs:73-111. H and V comprising any one of the amino acid sequences of SEQ ID NOs: 112 to 140. L Includes.

[0127] In some embodiments, the anti-C5a antibody comprises the amino acid sequence SEQ ID NO:73 or a variant sequence having at least 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:73. H and V, comprising the amino acid sequence SEQ ID NO:112 or a variant sequence having at least 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:112. LIn some embodiments, the anti-C5a antibody comprises a VVL comprising the amino acid sequence SEQ ID NO:73. H and V comprising the amino acid sequence SEQ ID NO:112 L Includes.

[0128] In some embodiments, the anti-C5a antibody comprises an amino acid sequence SEQ ID NO:75 or a variant sequence having at least 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:75. H and V, comprising the amino acid sequence SEQ ID NO:114 or a variant sequence having at least 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:114. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence SEQ ID NO:75. H and V comprising the amino acid sequence SEQ ID NO:114 L Includes.

[0129] In some embodiments, the anti-C5a antibody comprises the amino acid sequence SEQ ID NO:100 or a variant sequence having at least 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:100. H and V, comprising the amino acid sequence SEQ ID NO:135 or a variant sequence having at least 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:135. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence SEQ ID NO:100. H and V comprising the amino acid sequence SEQ ID NO:135 L Includes.

[0130] In some embodiments, the anti-C5a antibody comprises an amino acid sequence SEQ ID NO:79 or a variant sequence having at least 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:79. H and V, comprising the amino acid sequence SEQ ID NO:118 or a variant sequence having at least 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:118. L In some embodiments, the anti-C5a antibody comprises a VVL comprising the amino acid sequence SEQ ID NO:79. H and V comprising the amino acid sequence SEQ ID NO:118 L Includes.

[0131] In some embodiments, the anti-C5a antibody comprises a V sequence comprising the amino acid sequence SEQ ID NO:85 or a variant sequence having at least 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:85. H and V, comprising the amino acid sequence SEQ ID NO:117 or a variant sequence having at least 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:117. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence SEQ ID NO:85. H and V comprising the amino acid sequence SEQ ID NO:117 L Includes.

[0132] In some embodiments, the anti-C5a antibody comprises the amino acid sequence SEQ ID NO:88 or a variant sequence having at least 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:88. H and a V that includes the amino acid sequence SEQ ID NO:126 or a variant sequence having at least 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:126. L In some embodiments, the anti-C5a antibody comprises a VVL comprising the amino acid sequence SEQ ID NO:88. H and V comprising the amino acid sequence SEQ ID NO:126 L Includes.

[0133] In some embodiments, the anti-C5a antibody comprises the amino acid sequence SEQ ID NO:93 or a variant sequence having at least 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:93. H and V, comprising the amino acid sequence SEQ ID NO:116 or a variant sequence having at least 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:116. L In some embodiments, the anti-C5a antibody comprises a VVL comprising the amino acid sequence SEQ ID NO:93. H and V comprising the amino acid sequence SEQ ID NO:116 L Includes.

[0134] In some embodiments, the anti-C5a antibody comprises the amino acid sequence SEQ ID NO:97 or a variant sequence having at least 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:97.H and V, comprising the amino acid sequence SEQ ID NO:116 or a variant sequence having at least 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:116. L In some embodiments, the anti-C5a antibody comprises a VVL comprising the amino acid sequence SEQ ID NO:97. H and V comprising the amino acid sequence SEQ ID NO:116 L Includes.

[0135] In some embodiments, the anti-C5a antibody comprises a V sequence that includes the amino acid sequence SEQ ID NO:77 or a variant sequence that has at least 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:77. H and V, comprising the amino acid sequence SEQ ID NO:132 or a variant sequence having at least 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:132. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence SEQ ID NO:77. H and V comprising the amino acid sequence SEQ ID NO:132 L Includes.

[0136] In some embodiments, the anti-C5a antibody comprises the amino acid sequence SEQ ID NO:102 or a variant sequence having at least 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:102. H and V, comprising the amino acid sequence SEQ ID NO:135 or a variant sequence having at least 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:135.L In some embodiments, the anti-C5a antibody comprises a V sequence comprising the amino acid sequence SEQ ID NO:102. H and V comprising the amino acid sequence SEQ ID NO:135 L Includes.

[0137] In some embodiments, the anti-C5a antibody comprises an amino acid sequence SEQ ID NO:109 or a variant sequence having at least 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:109. H and V, comprising the amino acid sequence SEQ ID NO:138 or a variant sequence having at least 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:138. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising the amino acid sequence SEQ ID NO:109. H and V comprising the amino acid sequence SEQ ID NO:138 L Includes.

[0138] In some embodiments, the anti-C5a antibody comprises a V sequence comprising the amino acid sequence SEQ ID NO:110 or a variant sequence having at least 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:110. H and V, comprising the amino acid sequence SEQ ID NO: 139 or a variant sequence having at least 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: 139. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence SEQ ID NO:110. H and V comprising the amino acid sequence SEQ ID NO:139 L Includes.

[0139] In some embodiments, the anti-C5a antibody comprises a V sequence comprising the amino acid sequence SEQ ID NO:110 or a variant sequence having at least 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:110. H and V, comprising the amino acid sequence SEQ ID NO:140 or a variant sequence having at least 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:140. L In some embodiments, the anti-C5a antibody comprises a VV comprising the amino acid sequence SEQ ID NO:110. H and V comprising the amino acid sequence SEQ ID NO:140 L Includes.

[0140] In some embodiments, the anti-C5a antibody comprises a V sequence comprising the amino acid sequence SEQ ID NO:111 or a variant sequence having at least 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:111. H and V, comprising the amino acid sequence SEQ ID NO: 139 or a variant sequence having at least 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: 139. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising the amino acid sequence SEQ ID NO:111. H and V comprising the amino acid sequence SEQ ID NO:139 L Includes.

[0141] In some embodiments, the anti-C5a antibody comprises a V sequence comprising the amino acid sequence SEQ ID NO:111 or a variant sequence having at least 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:111. H and V, comprising the amino acid sequence SEQ ID NO:140 or a variant sequence having at least 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:140. L In some embodiments, the anti-C5a antibody comprises a V sequence comprising the amino acid sequence SEQ ID NO:111. H and V comprising the amino acid sequence SEQ ID NO:140 L Includes.

[0142] In some embodiments, the functional epitope can be analyzed by combinatorial alanine scanning. In this process, combinatorial alanine scanning technology can be used to identify the amino acids in C5a protein that are required for interaction with anti-C5a antibody. In some embodiments, the epitope is conformational, and at the same time, the epitope can be identified using the crystal structure of anti-C5a antibody bound to C5a protein.

[0143] In some embodiments, the present application provides an antibody that binds to C5a competitively with any of the anti-C5a antibodies of the present application. In some embodiments, the present application provides an antibody that binds to an epitope in C5a competitively with any of the anti-C5a antibodies of the present application. In some embodiments, the present application provides an antibody comprising an amino acid sequence of any of SEQ ID NOs:73-111. H and V comprising any one of the amino acid sequences of SEQ ID NOs: 112 to 140. L and an anti-C5a antibody molecule comprising the amino acid sequence of any one of SEQ ID NOs:73 to 111. Hand V comprising any one of the amino acid sequences of SEQ ID NOs: 112 to 140. L and an anti-C5a antibody that binds to C5a competitively with an anti-C5a antibody comprising the above structure.

[0144] In some embodiments, a competition experiment can be used to identify a monoclonal antibody that binds to C5a competitively with the anti-C5a antibody of the present application. A competition experiment can determine whether two antibodies bind to the same epitope by recognizing the same or spatially overlapping epitopes, or by one antibody competitively inhibiting the binding of another antibody to an antigen. In some embodiments, such a competing antibody binds to the same epitope as the antibody of the present application. Some exemplary competition experiments may include, but are not limited to, the conventional experiments mentioned in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). Detailed exemplary methods for analyzing the epitope to which an antibody binds are as described in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, NJ). In some embodiments, antibodies bind to the same epitope if each antibody blocks 50% or more of the binding of the other antibody. In some embodiments, an antibody that competes with an anti-C5a antibody of the present application is a chimeric antibody, a humanized antibody, or a fully human antibody.

[0145] Exemplary anti-C5a antibody sequences are shown in Tables 2 and 3, where the CDRs are numbered according to the Kabat definition. Those skilled in the art will recognize that there are various known algorithms that predict the location of CDRs to define the light and heavy chain variable regions of an antibody. Antibodies based on prediction algorithms that include the CDRs, VH and / or VL sequences of the antibodies described above, but are not exemplified in the tables below, are also included within the scope of this application.

[0146]

Table 2-1

[0147]

Table 2-2

[0148]

Table 2-3

[0149]

Table 2-4

[0150]

Table 2-5

[0151]

Table 2-6

[0152]

Table 2-7

[0153]

Table 2-8

[0154]

Table 2-9

[0155]

Table 2-10

[0156]

Table 2-11

[0157]

Table 2-12

[0158]

Table 2-13

[0159]

Table 2-14

[0160]

Table 2-15

[0161]

Table 2-16

[0162]

Table 2-17

[0163]

Table 3-1

[0164]

Table 3-2

[0165]

Table 3-3

[0166]

Table 3-4

[0167]

Table 3-5

[0168]

Table 3-6

[0169]

Table 3-7

[0170]

Table 3-8

[0171]

Table 3-9

[0172]

Table 3-10

[0173]

Table 3-11

[0174]

Table 3-12

[0175]

Table 3-13

[0176]

Table 3-14

[0177]

Table 3-15

[0178]

Table 3-16

[0179]

Table 3-17

[0180]

Table 3-18

[0181]

Table 3-19

[0182]

Table 3-20

[0183] C5a The complement system is composed of more than 30 proteins and is activated in response to tissue injury, pathogen or other foreign body invasion. Complement component 5a (C5a) was first described as a cleavage product of complement factor 5 (C5), which has chemotactic and allergotoxic properties (Shin et al., 1968). The precursor C5a protein contains 1676 amino acids, has a molecular mass of 188 kDa, and its gene is located at 9q33-9q34 (Wetsel et al., 1988). Human C5a is a glycoprotein containing approximately 11 kDa and 74 amino acids, generated by cleavage of the α-chain of C5 by C5 convertase, although N-linked glycosylation is not essential for its function. The properties of C5a indicate that it is an important component of the innate immune response, but existing evidence indicates that C5a may also play a role in adaptive immunity (Kohl, 2006). Although C5a is not necessarily a causative factor in the pathogenesis of inflammatory diseases, many inflammatory diseases generate excessive or uncontrollable C5a, indicating that C5a can promote and sustain inflammatory responses (Guo and Ward, 2005). C5a has four antiparallel α-helices linked by peptide loops and is stabilized by three critical disulfide bonds (Monk et al., 2007). Mutagenesis and antibody studies have defined several essential residues that provide interactions with the receptor (reviewed in Monk et al., 2007).

[0184] The complement cascade can be activated through four pathways: the canonical pathway, the atypical pathway, the mannan-binding lectin pathway (MBL) or the exogenous protease pathway (Ricklin and Lambris, 2007). The canonical pathway and the lectin pathway are activated by the recognition of antibody complexes formed on the surface of pathogens and mannose on the surface of bacteria, respectively. In both pathways, a serine protease cleaves C4 to form C4a and C4b. C4b binds to C2, which then generates C2a through the action of proteases, and C4b and C2a form the C3 convertase (C4b2a) in the canonical pathway. The atypical pathway can be activated by foreign surfaces or "slow-speed transport", which leads to spontaneous hydrolysis of C3, which then binds with factor B to form C3 convertase (C3bBb) in the atypical pathway, which ensures that the atypical pathway can sustain a low level of complement cascade activation and rapidly respond to invading pathogens (Ricklin and Lambris, 2007). All three pathways can form C3 convertase, which further cleaves C3 protein to form C3a and C3b. C3b can facilitate cellular recognition of pathogen surfaces and pathogen elimination, and can also form C3 convertase (C4b2a or C3bBb) and C5 convertase (C4b2aC3b or C3bBbC3b), which then further cleaves C5 to generate C5a and C5b. C5b continues to initiate the assembly of the membrane attack complex (MAC, C5b-9). The complement cascade is tightly regulated by a series of soluble and membrane-bound regulatory proteins that prevent complement activation products from targeting host tissues (Ricklin and Lambris, 2007). However, such controls can be circumvented by several extrinsic pathways; for example, thrombin can directly cleave C3 and C5 and activate the complement system (Amara et al., 2008). Also, activated neutrophils and alveolar macrophages can cleave C5 by secreted serine proteases to generate C5a (Amara et al., 2008).Plasma and cell surface carboxypeptidases can remove arginine from the C-terminus of proteins and thus rapidly metabolize C5a generated by the degradation of C5 to form C5adesArg (Bokisch and Muller-Eberhard, 1970). Compared to C5a, C5adesArg has reduced potency and reduced binding affinity to the typical C5a receptor, CD88 (Higginbottom et al., 2005). C5a and C5adesArg can be rapidly cleared in the body, with approximately 50% of C5a and C5adesArg being cleared from the circulation within 2–3 min, and some C5a being cleared mediated by binding to CD88 on leukocytes and other cells (Oppermann and Gotze, 1994). However, a second type of receptor, C5a-like receptor 2 (C5L2), can more effectively remove complement fragments and rapidly internalize C5a / C5adesArg, especially C5adesArg, leaving it there to be degraded in some cell types (Scola et al., 2009). Conversely, cells expressing CD88 internalize C5a and then release a higher proportion of it, which may be in an undegraded, active form. Plasma C5a can also be cleared by the liver (Chenoweth and Goodman, 1983).

[0185] CD88 C5a binds to CD88 and C5L2 with similar high affinity. Conversely, C5adesArg has a similar affinity for C5L2 (~12 nM) to C5a, but a much lower affinity for CD88 (~660 nM≒) (Monk et al., 2007). CD88 and C5L2 share 35% sequence homology and are located in the same region of chromosome 19 (19q13.3-19q13.4). They are clustered with other chemokine receptor genes (e.g., formyl peptide receptor family and tachykinin peptide receptor). Both are glycosylated seven-transmembrane proteins with a molecular weight of approximately 45 kDa. CD88 is a G protein-coupled receptor and a member of the rhodopsin gene family (Monk et al., 2007). Binding of C5a to CD88 is thought to occur at two distinct, physically separated sites. The first "recognition" site is located at the extracellular amino terminus (N-terminus) of the receptor and binds to the N-terminus of C5a and the core linked via disulfide bonds, while the second "activation" site is formed in the transmembrane domain of the receptor and binds to the C-terminus of C5a, generating specific signaling pathways mediated by receptor-coupled G proteins (Monk et al., 2007).

[0186] C5L2 The cell types expressing C5L2 are almost the same as those expressing CD88, such as neutrophils, monocytes, lymphocytes, macrophages, and non-bone marrow cells (e.g., vascular smooth muscle cells) and cells derived from tissues (e.g., adrenal gland, heart, liver, lung spleen and brain), but in non-inflammatory conditions, the expression content of C5L2 is significantly lower than that of CD88 (Gao et al., 2005). The function of C5L2 is unclear. Some experimental data shows that C5L2 can be a lure receptor without signaling function. Studies have found that knocking out or blocking C5L2 leads to the progression of inflammatory responses in mice (Gao et al., 2005; Gerard et al., 2005). This indicates that C5L2 has an anti-inflammatory function and can act by reducing the amount of C5a that can bind to CD88. C5L2 can also act as a positive regulator and is crucial for C5a and C3a signaling, at least in mice (Chen et al., 2007). In vitro, studies have found that C5L2 is crucial for promoting C5a signaling in neutrophils, macrophages, and fibroblasts, and that lack of C5L2 in vivo leads to ovalbumin-induced airway hyperresponsiveness and inflammation (Chen et al., 2007). Also, in a mouse model of "end-stage" sepsis (100% fatality), C5L2 must be blocked simultaneously with CD88 to be protective (Rittirsch et al., 2008).

[0187] Full-length anti-C5a antibody In some embodiments, the anti-C5a antibody is a full-length anti-C5a antibody. In some embodiments, the full-length anti-C5a antibody is IgA, IgD, IgE, IgG, or IgM. In some embodiments, the full-length anti-C5a antibody comprises an IgG constant region, such as the constant region of IgG1, IgG2, IgG3, IgG4, or a variant thereof. In some embodiments, the full-length anti-C5a antibody comprises a lambda light chain constant region. In some embodiments, the full-length anti-C5a antibody comprises a kappa light chain constant region. In some embodiments, the full-length anti-C5a antibody is a full-length human anti-C5a antibody. In some embodiments, the full-length anti-C5a antibody comprises a mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-C5a antibody has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effector function by comprising a modified or otherwise altered Fc sequence.

[0188] Thus, for example, in some embodiments, a full-length anti-C5a antibody is provided that comprises an IgG1 constant region, said anti-C5a antibody specifically binding to C5a. In some embodiments, said IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0189] In some embodiments, a full-length anti-C5a antibody is provided that comprises an IgG2 constant region, wherein the anti-C5a antibody specifically binds to C5a. 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:144.

[0190] In some embodiments, a full-length anti-C5a antibody is provided that comprises an IgG3 constant region, wherein the anti-C5a antibody specifically binds to C5a. 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:144.

[0191] In some embodiments, a full-length anti-C5a antibody is provided that comprises an IgG4 constant region, wherein the anti-C5a antibody specifically binds to C5a. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0192] In some embodiments, a full-length anti-C5a antibody comprising an IgG1 constant region is provided, the anti-C5a antibody comprising: a) a VH comprising one HC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence of any of SEQ ID NOs: 1 to 6, one HC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence of any of SEQ ID NOs: 7 to 29, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence of any of SEQ ID NOs: 30 to 38; and b) a VH comprising one LC-CDR1 comprising a sequence having at least 90% sequence identity with the amino acid sequence of any of SEQ ID NOs: 39 to 56, one LC-CDR2 comprising a sequence having at least 90% sequence identity with the amino acid sequence of any of SEQ ID NOs: 57 to 59, and one HC-CDR3 comprising a sequence having at least 90% sequence identity with the amino acid sequence of any of SEQ ID NOs: 30 to 38. and a VL comprising one LC-CDR3 comprising a sequence having at least 90% sequence identity to any one of the amino acid sequences of SEQ ID NO:60-66. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0193] In some embodiments, a full-length anti-C5a antibody comprising an IgG2 constant region is provided, the anti-C5a antibody comprising: a) a V-CDR1 comprising one HC-CDR1 having a sequence having at least 90% sequence identity with an amino acid sequence of any of SEQ ID NOs: 1 to 6, one HC-CDR2 having a sequence having at least 90% sequence identity with an amino acid sequence of any of SEQ ID NOs: 7 to 29, and one HC-CDR3 having a sequence having at least 90% sequence identity with an amino acid sequence of any of SEQ ID NOs: 30 to 38; H and b) a V comprising one LC-CDR1 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 39 to 56, one LC-CDR2 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 57 to 59, and one LC-CDR3 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 60 to 66. L 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:144.

[0194] In some embodiments, a full-length anti-C5a antibody comprising an IgG3 constant region is provided, the anti-C5a antibody comprising: a) a V-CDR1 comprising one HC-CDR1 having a sequence having at least 90% sequence identity with an amino acid sequence of any of SEQ ID NOs: 1 to 6, one HC-CDR2 having a sequence having at least 90% sequence identity with an amino acid sequence of any of SEQ ID NOs: 7 to 29, and one HC-CDR3 having a sequence having at least 90% sequence identity with an amino acid sequence of any of SEQ ID NOs: 30 to 38; Hand b) a V comprising one LC-CDR1 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 39 to 56, one LC-CDR2 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 57 to 59, and one LC-CDR3 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 60 to 66. L In some embodiments, the IgG3 is a human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0195] In some embodiments, a full-length anti-C5a antibody comprising an IgG4 constant region is provided, the anti-C5a antibody comprising: a) a V-CDR1 comprising one HC-CDR1 having a sequence having at least 90% sequence identity with an amino acid sequence of any of SEQ ID NOs: 1 to 6, one HC-CDR2 having a sequence having at least 90% sequence identity with an amino acid sequence of any of SEQ ID NOs: 7 to 29, and one HC-CDR3 having a sequence having at least 90% sequence identity with an amino acid sequence of any of SEQ ID NOs: 30 to 38; H and b) a V comprising one LC-CDR1 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 39 to 56, one LC-CDR2 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 57 to 59, and one LC-CDR3 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 60 to 66. Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0196] In some embodiments, a full-length anti-C5a antibody comprising an IgG1 constant region is provided, the anti-C5a antibody comprising: a) a V-CDR1 comprising one HC-CDR1 having an amino acid sequence of any one of SEQ ID NOs: 1 to 6, one HC-CDR2 having an amino acid sequence of any one of SEQ ID NOs: 7 to 29, and one HC-CDR3 having an amino acid sequence of any one of SEQ ID NOs: 30 to 38; H and b) a V having one LC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs: 39 to 56, one LC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs: 57 to 59, and one LC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs: 60 to 66. Land. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0197] In some embodiments, a full-length anti-C5a antibody comprising an IgG4 constant region is provided, the anti-C5a antibody comprising: a) a V-CDR1 comprising one HC-CDR1 having an amino acid sequence of any one of SEQ ID NOs: 1 to 6, one HC-CDR2 having an amino acid sequence of any one of SEQ ID NOs: 7 to 29, and one HC-CDR3 having an amino acid sequence of any one of SEQ ID NOs: 30 to 38; H and b) a V having one LC-CDR1 comprising any one of the amino acid sequences of SEQ ID NOs: 39 to 56, one LC-CDR2 comprising any one of the amino acid sequences of SEQ ID NOs: 57 to 59, and one LC-CDR3 comprising any one of the amino acid sequences of SEQ ID NOs: 60 to 66. Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0198] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:7, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:30; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:39, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:60. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0199] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:8, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:31; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:40, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0200] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0201] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:11, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:41, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:64. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0202] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:43, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:63. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0203] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:11, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:35; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:44, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:60. Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0204] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:36; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0205] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:21, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0206] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:59, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:65. Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0207] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:23, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0208] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:23, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:56, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0209] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:36; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:58, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0210] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:36; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:59, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:65. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0211] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:21, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:58, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0212] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:21, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:59, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:65. Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0213] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:7, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:30; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:39, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:60. L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0214] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:8, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:31; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:40, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0215] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0216] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:11, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:41, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:64. L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0217] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:43, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:63. L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0218] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:11, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:35; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:44, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:60. Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0219] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:36; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0220] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:21, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0221] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:59, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:65. Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0222] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:23, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:42, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0223] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:23, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:56, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:57, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0224] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:36; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:58, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0225] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:6, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:18, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:36; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:59, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:65. L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0226] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:21, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:52, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:58, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:61. L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0227] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising: a) one HC-CDR1 comprising the amino acid sequence SEQ ID NO:5, one HC-CDR2 comprising the amino acid sequence SEQ ID NO:21, and one HC-CDR3 comprising the amino acid sequence SEQ ID NO:32; H and b) a V comprising one LC-CDR1 comprising the amino acid sequence SEQ ID NO:53, one LC-CDR2 comprising the amino acid sequence SEQ ID NO:59, and one LC-CDR3 comprising the amino acid sequence SEQ ID NO:65. Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0228] In some embodiments, a full-length anti-C5a antibody is provided that comprises an IgG1 constant region, the anti-C5a antibody comprising an amino acid sequence of any of SEQ ID NOs: 73-111 or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of any of SEQ ID NOs: 73-111. H and a V that includes an amino acid sequence of any one of SEQ ID NOs: 112 to 140 or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to an amino acid sequence of any one of SEQ ID NOs: 112 to 140. Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0229] In some embodiments, a full-length anti-C5a antibody comprising an IgG2 constant region is provided, the anti-C5a antibody comprising a V-type constant region comprising an amino acid sequence of any of SEQ ID NOs: 73-111 or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of any of SEQ ID NOs: 73-111. H and a V that includes an amino acid sequence of any one of SEQ ID NOs: 112 to 140 or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to an amino acid sequence of any one of SEQ ID NOs: 112 to 140. L 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:144.

[0230] In some embodiments, a full-length anti-C5a antibody comprising an IgG3 constant region is provided, the anti-C5a antibody comprising an amino acid sequence of any of SEQ ID NOs: 73-111 or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of any of SEQ ID NOs: 73-111. H and a V that includes an amino acid sequence of any one of SEQ ID NOs: 112 to 140 or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to an amino acid sequence of any one of SEQ ID NOs: 112 to 140. L In some embodiments, the IgG3 is a human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0231] In some embodiments, a full-length anti-C5a antibody comprising an IgG4 constant region is provided, the anti-C5a antibody comprising a V-type constant region comprising an amino acid sequence of any of SEQ ID NOs: 73-111 or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence of any of SEQ ID NOs: 73-111. H and a V that includes an amino acid sequence of any one of SEQ ID NOs: 112 to 140 or a variant sequence having at least 90% (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) sequence identity to an amino acid sequence of any one of SEQ ID NOs: 112 to 140. Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0232] In some embodiments, a full-length anti-C5a antibody is provided that comprises an IgG1 constant region, the anti-C5a antibody comprising a V sequence comprising any one of the amino acid sequences of SEQ ID NOs:73-111. H and V comprising any one of the amino acid sequences of SEQ ID NOs: 112 to 140. L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0233] In some embodiments, a full-length anti-C5a antibody comprising an IgG4 constant region is provided, the anti-C5a antibody comprising a V sequence comprising any one of the amino acid sequences of SEQ ID NOs:73-111. H and V comprising any one of the amino acid sequences of SEQ ID NOs: 112 to 140. Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0234] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:73. H and V comprising the amino acid sequence SEQ ID NOs:112 L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0235] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:75. H and V comprising the amino acid sequence SEQ ID NOs:114 Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0236] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising the amino acid sequence SEQ ID NOs:100. H and V comprising the amino acid sequence SEQ ID NOs:135 L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0237] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:79. H and V comprising the amino acid sequence SEQ ID NOs:118 Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0238] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:85. H and V comprising the amino acid sequence SEQ ID NOs:117 L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0239] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:88. H and V comprising the amino acid sequence SEQ ID NOs:126 Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0240] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:93. H and V comprising the amino acid sequence SEQ ID NOs:116 L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0241] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:97. H and V comprising the amino acid sequence SEQ ID NOs:116 Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0242] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:77. H and V comprising the amino acid sequence SEQ ID NOs:132 L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0243] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:102. H and V comprising the amino acid sequence SEQ ID NOs:135 Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0244] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:109. H and V comprising the amino acid sequence SEQ ID NOs:138 L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0245] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:110. H and V comprising the amino acid sequence SEQ ID NOs:139 Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0246] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:110. H and V comprising the amino acid sequence SEQ ID NOs:140 L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0247] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:111. H and V comprising the amino acid sequence SEQ ID NOs:139 Land In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0248] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG1 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:111. H and V comprising the amino acid sequence SEQ ID NOs:140 L and In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:142 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0249] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:73. H and V comprising the amino acid sequence SEQ ID NOs:112 Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0250] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:75. H and V comprising the amino acid sequence SEQ ID NOs:114 L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0251] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising the amino acid sequence SEQ ID NOs:100. H and V comprising the amino acid sequence SEQ ID NOs:135 Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0252] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:79. H and V comprising the amino acid sequence SEQ ID NOs:118 L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0253] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:85. H and V comprising the amino acid sequence SEQ ID NOs:117 Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0254] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:88. H and V comprising the amino acid sequence SEQ ID NOs:126 L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0255] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:93. H and V comprising the amino acid sequence SEQ ID NOs:116 Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0256] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:97. H and V comprising the amino acid sequence SEQ ID NOs:116 L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0257] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:77. H and V comprising the amino acid sequence SEQ ID NOs:132 Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0258] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising the amino acid sequence SEQ ID NOs:102. H and V comprising the amino acid sequence SEQ ID NOs:135 L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0259] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:109. H and V comprising the amino acid sequence SEQ ID NOs:138 Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0260] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:110. H and V comprising the amino acid sequence SEQ ID NOs:139 L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0261] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:110. H and V comprising the amino acid sequence SEQ ID NOs:140 Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0262] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:111. H and V comprising the amino acid sequence SEQ ID NOs:139 L and. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0263] In some embodiments, a full-length anti-C5a antibody is provided comprising an IgG4 constant region, the anti-C5a antibody comprising a VDG comprising the amino acid sequence SEQ ID NOs:111. H and V comprising the amino acid sequence SEQ ID NOs:140 Land. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0264] binding affinity Binding affinity is expressed as Kd, Koff, Kon or Ka. As used herein, the term Koff refers to the rate constant at which an antibody dissociates from an antigen / antibody complex, and is measured by a kinetic selection device. The term Kon refers to the binding rate constant at which an antibody binds 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 antigen concentration required for an antibody molecule solution to reach equilibrium with the antigen occupying half of all antibody binding sites, and is equal to Koff / Kon. The measurement of Kd assumes that all binding molecules are in solution. When an antibody is linked to a cell wall, for example in a yeast expression system, the corresponding equilibrium dissociation rate constant is expressed as EC50, which is one good approximation of Kd. The affinity binding constant Ka is the reciprocal of the dissociation constant Kd.

[0265] The dissociation constant (Kd) can be an index reflecting the affinity between an antibody moiety and an antigen. For example, the Scatchard method can be used to easily analyze antibodies marked with various markers and a Biacore instrument (manufactured by Amersham Biosciences) to analyze the interaction between biomolecules by surface plasmon resonance based on the user manual or the accompanying reagent kit. The Kd values ​​obtained by these methods are expressed in units of M. An antibody that specifically binds to a target has a Kd value of, for example, ≦10-7 M, ≦10 -8 M, ≦10 -9 M, ≦10 -10 M, ≦10 -11 M, ≦10 -12 M or ≦10 -13 It may have a Kd value of M.

[0266] The binding specificity of the antibody can be experimentally determined by methods known in the art, which may include, but are not limited to, Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore tests and peptide scans.

[0267] In some embodiments, the anti-C5a antibody specifically binds to the C5a target and has a Kd value of 10 -7 M~10 -13 M (e.g., 10 -7 M~10 -13 M, 10 -8 M~10 -13 M, 10 -9 M~10 -13 M, or 10 -10 M~10 -12 M). Thus, in some embodiments, the Kd value of binding between the anti-C5a antibody and C5a is 10 -7 M~10 -13 M, 1×10 -7 M~5×10 -13 M, 10 -7 M~10 -12 M, 10 -7 M~10 -11 M, 10 -7 M~10 -10 M, 10 -7 M~10 -9 M, 10 -8 M~10 -13 M, 1×10 -8 M~5×10 -13 M, 10 -8 M~10 -12 M, 10 -8 M~10 -11 M, 10 -8 M~10 -10 M, 10-8 M~10 -9 M, 5×10 -9 M~1×10 -13 M, 5×10 -9 M~1×10 -12 M, 5×10 -9 M~1×10 -11 M, 5×10 -9 M~1×10 -10 M, 10 -9 M~10 -13 M, 10 -9 M~10 -12 M, 10 -9 M~10 -11 M, 10 -9 M~10 -10 M, 5×10 -10 M~1×10 -13 M, 5×10 -10 M~1×10 -12 M, 5×10 -10 M~1×10 -11 M, 10 -10 M~10 -13 M, 1×10 -10 M~5×10 -13 M, 1×10 -10 M~1×10 -12 M, 1×10 -10 M~5×10 -12 M, 1×10 -10 M~1×10 -11 M, 10 -11 M~10 -13 M, 1×10 -11 M~5×10 -13 M, 10 -11 M~10 -12 M, 10 -12 M~10 -13 In some embodiments, the Kd value of binding between the anti-C5a antibody and C5a is 10 -7 M~10 -13 It's M.

[0268] In some embodiments, the Kd value of binding between the anti-C5a antibody and the non-target is higher than the Kd value of the anti-C5a antibody and the target, and in some embodiments cited herein, the binding affinity of the anti-C5a antibody to the target (e.g., C5a) is higher than the binding affinity of the anti-C5a antibody to the non-target. In some embodiments, the non-target refers to a non-C5a antigen. In some embodiments, the Kd value of binding between the anti-C5a antibody (against C5a) and the non-C5a target is at least 10-fold, e.g., 10-100-fold, 100-1000-fold, 10 3 ~10 4 Double, 10 4 ~10 5 Double, 10 5 ~10 6 Double, 10 6 ~10 7 Double, 10 7 ~10 8 Double, 10 8 ~10 9 Double, 10 9 ~10 10 Double, 10 10 ~10 11 Double, 10 11 ~10 12 Times different.

[0269] In some embodiments, the Kd value of binding between the anti-C5a antibody and a non-target is 10 -1 M~10 -6 M (e.g., 10 -1 M~10 -6 M, 10 -1 M~10 -5 M, 10 -2 M~10 -4 In some embodiments, the non-target refers to a non-C5a antigen. Thus, in some embodiments, the Kd value of binding between an anti-C5a antibody and a non-C5a target is 10 -1 M~10 -6 M, 1×10 -1 M~5×10 -6 M, 10 -1 M~10 -5 M, 1×10 -1 M~5×10 -5 M, 10-1 M~10 -4 M, 1×10 -1 M~5×10 -4 M, 10 -1 M~10 -3 M, 1×10 -1 M~5×10 -3 M, 10 -1 M~10 -2 M, 10 -2 M~10 -6 M, 1×10 -2 M~5×10 -6 M, 10 -2 M~10 -5 M, 1×10 -2 M~5×10 -5 M, 10 -2 M~10 -4 M, 1×10 -2 M~5×10 -4 M, 10 -2 M~10 -3 M, 10 -3 M~10 -6 M, 1×10 -3 M~5×10 -6 M, 10 -3 M~10 -5 M, 1×10 -3 M~5×10 -5 M, 10 -3 M~10 -4 M, 10 -4 M~10 -6 M, 1×10 -4 M~5×10 -6 M, 10 -4 M~10 -5 M, 10 -5 M~10 -6 It's M.

[0270] In some embodiments, when an anti-C5a antibody specifically recognizes a C5a target with high binding affinity and binds to a non-target with low binding affinity, the Kd value of the binding between the anti-C5a antibody and the C5a target is 10 -7 M~10 -13 M (e.g., 10 -7 M~10 -13 M, 10 -8 M~10 -13 M, 10-9 M~10 -13 M, 10 -10 M~10 -12 M) and the Kd value for binding to a non-target is 10 -1 M~10 -6 M (e.g., 10 -1 M~10 -6 M, 10 -1 M~10 -5 M, 10 -2 M~10 -4 M).

[0271] In some embodiments, when referring to an anti-C5a antibody specifically recognizing C5a, the binding affinity of the anti-C5a antibody is compared to the binding affinity of a control anti-C5a antibody (e.g., INab308). In some embodiments, the Kd value of the binding between the control anti-C5a antibody and C5a is at least twice, for example, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 10-100 times, 100-1000 times, 1 ... 3 ~10 4 It may be double.

[0272] nucleic acid Nucleic acid molecules encoding anti-C5a antibodies are also contemplated. In some embodiments, a nucleic acid (or a group of nucleic acids) encoding a full-length anti-C5a antibody is provided, including any full-length anti-C5a antibody of the present application. In some embodiments, the nucleic acid (or group of nucleic acids) of an anti-C5a antibody of the present application may include a nucleic acid sequence encoding a polypeptide tag (e.g., a protein purification tag, a His tag, an HA tag).

[0273] At the same time, the present application further contemplates an isolated host cell comprising an anti-C5a antibody, an isolated nucleic acid encoding an anti-C5a antibody polypeptide component, or a vector encoding a nucleic acid comprising an anti-C5a antibody polypeptide component of the present application.

[0274] The present application further includes variants of these nucleic acid sequences, for example variants further including nucleotide sequences that hybridize to the nucleic acid sequences encoding the anti-C5a antibodies of the present application under at least moderately stringent hybridization conditions.

[0275] Accordingly, the present application further provides a vector into which the nucleic acid sequence of the present application can be inserted.

[0276] In brief, the nucleic acid can be operably linked to regulatory control elements at the 5' and 3' ends, including a promoter (e.g., a lymphocyte-specific promoter) and a 3' untranslated region (UTR), by inserting a natural or synthetic nucleic acid encoding an anti-C5a antibody into a suitable expression vector, and expressing the anti-C5a antibody (e.g., a full-length anti-C5a antibody). The vector is adaptable for replication and integration in eukaryotic host cells. Typical cloning and expression vectors include transcription and translation terminators, initiation sequences and promoters that regulate and control the expression of the target nucleic acid sequence.

[0277] The nucleic acids of the present application can also be used in nucleic acid immunization and gene therapy by using standard gene delivery schemes. Nucleic acid delivery methods are known in the art. See, for example, US Pat. Nos. 5,399,346, 5,580,859, and 5,589,466, the entire contents of which are incorporated herein by reference. In some embodiments, the present application further provides gene therapy vectors.

[0278] Nucleic acids can be cloned into many types of vectors. For example, nucleic acids can be cloned into vectors, which may include, but are 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.

[0279] The expression vector can also be provided to cells 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: A Laboratory Manual, Cold Spring Harbor Laboratory, New York) and other virology or molecular biology manuals. Viruses that can be used as vectors can include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. Usually, a suitable vector includes an origin of replication that works in at least one organism, a promoter sequence, a convenient restriction enzyme site, and one or more selective markers (for example, including WO01 / 96584, WO01 / 29058, and USPat.No.6326193).

[0280] Many virus-based systems for transferring genes into mammalian cells have already been developed. For example, retroviruses provide a convenient platform for gene delivery systems. Using techniques known in the art, a selected gene can be inserted into a vector and packaged into a retroviral particle. The recombinant virus is then isolated and delivered to the subject's cells, either in vivo or ex vivo. Many retroviral systems are known in the art. In some embodiments, adenoviral vectors are used. Many adenoviral vectors are known in the art. In some embodiments, lentiviral vectors are used. Vectors derived from retroviruses, such as lentiviruses, are suitable tools for achieving long-term gene transfer, since the genetic modification can be stably integrated and propagated in offspring cells for a long period of time. Lentiviral vectors have the added advantage over tumor-derived retroviruses, such as murine leukemia viruses, because they can transduce non-proliferating cells, such as liver cells. At the same time, they also have the added advantage of being less immunogenic.

[0281] Other promoter elements, such as enhancers, regulate the frequency of transcription initiation. Recently, many promoters have also been found to contain functional elements downstream of the start site, but they are usually located 30-110 bp upstream of the start site. The spacing between promoter elements is usually flexible, so that elements can shuffle or move relative to one another and still maintain promoter function. In the thymidine kinase (tk) promoter, activity only decreases when the spacing between promoter elements is increased to 50 bp.

[0282] One example of a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. The promoter sequence is one strong constitutive promoter sequence and can drive high level expression of polynucleotide sequences operably linked thereto. Another example of a suitable promoter is the elongation factor 1 alpha (EF-1 alpha) promoter. However, other constitutive promoters may be used, including but not limited to simian virus 40 (SV40) 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. Also, the present application should not be limited to the use of only constitutive promoters, and inducible promoters are also part of the present application. The use of an inducible promoter provides a molecular switch that can turn on expression of a polynucleotide sequence operably linked to it when such expression is needed and turn off expression when it is not needed. Inducible promoters may include, but are not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.

[0283] In some embodiments, expression of the anti-C5a antibody is inducible. In some embodiments, the nucleic acid sequence encoding the anti-C5a antibody is operably linked to an inducible promoter, including any of the inducible promoters described herein.

[0284] Inducible promoters The use of an inducible promoter provides a molecular switch that can turn on expression of a polynucleotide sequence operably linked thereto when expression is required and turn off expression when expression is not required. Exemplary inducible promoters applied to eukaryotic cells may include, but are not limited to, hormone-regulated elements (see, e.g., Mader, S. and White, JH (1993) Proc. Natl. Acad. Sci. USA 90:5603-5607), synthetic ligand-regulated elements (see, e.g., Spencer, DM et al (1993) Science 262:1019-1024), and ionizing radiation-regulated control elements (see, e.g., Manome, Y. et al. (1993) Biochemistry 32:10607-10613, Datta, R. et al. (1992) Proc. Natl. Acad. Sci. USA 89:1014-10153). For other exemplary inducible promoters for use in in vivo or in vitro mammalian systems, see Gingrich et al. (1998) Annual Rev. Neurosci 21:377-405. In some embodiments, the inducible promoter system for expressing an anti-C5a antibody is the Tet system. In some embodiments, the inducible promoter system for expressing an anti-C5a antibody is the E. coli lac repression system.

[0285] One exemplary inducible promoter system used in this application is the Tet system. The system is based on the Tet system described by Gossen et al. (1993). In one exemplary embodiment, the target polynucleotide is controlled by a promoter that contains one or more Tet operon (TetO) sites. In the inactive state, the Tet inhibitor (TetR) binds to the TetO site and suppresses transcription of the promoter. In the active state, when an inducer, such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox) or an active analog thereof, is present, the inducer releases TetR from TetO, causing transcription to occur. Doxycycline is a member of the tetracycline antibiotic family and its chemical name is 1-dimethylamino-2,4a,5,7-pentahydroxy-11-methyl-4,6-dioxane-1,4a,11,11a,12,12a-hexahydrotetracene-3-formamide.

[0286] In one embodiment, TetR is codon-optimized and applied for expression in mammalian cells, such as mouse or human cells. Due to the degeneracy of the genetic code, many amino acids are encoded by more than one codon, and a given nucleic acid sequence can have a large number of variants without any change in the encoded amino acid sequence. However, many organisms have differences in codon usage, also called "codon preferences" (i.e., the preference for a given amino acid to use a particular codon). Codon preferences are usually associated with the existence of a dominant tRNA species for a particular codon, which in turn increases the efficiency of mRNA translation. Thus, codon optimization can be used to customize coding sequences from a particular species (e.g., prokaryotes) to enhance expression in different species (e.g., eukaryotes).

[0287] Other specific variants 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 transcription activator protein (tTA), which is composed of TetR fused to the strong transcription activation domain of herpes simplex virus VP16, regulates the expression of a target nucleic acid under the transcriptional control of a tetracycline-responsive promoter element (TRE). The TRE element is composed of a TetO sequence tandem fused to a promoter (usually the smallest promoter sequence derived from the human cytomegalovirus immediate early promoter). In the absence of Tc or Dox, tTA binds to the TRE and activates the transcription of the target gene. In the presence of Tc or Dox, tTA cannot bind to the TRE and the target gene cannot be expressed.

[0288] Conversely, in the Tet-On system, transcription is active in the presence of Tc or Dox. The Tet-On system is based on the transcriptional activator rtTA, which is regulated by reverse tetracycline. Like tTA, rtTA is a fusion protein composed of a TetR inhibitor and a VP16 transcriptional activation domain. However, a change of four amino acids in the DNA binding region of TetR alters the binding properties of rtTA, and it can only recognize the tetO sequence in the target gene recombinant TRE in the presence of Dox. Thus, in the Tet-On system, rtTA can activate the transcription of the target gene regulated by the TRE only when Dox is present.

[0289] Another inducible promoter system is the lac inhibitor system of E. coli (see Brown et al., Cell 49:603-612 (1987)). The Lac inhibitor system functions by regulating and controlling the transcription of a target polynucleotide operably linked to a promoter containing the lac operon (lacO). The Lac inhibitor (lacR) binds to LacO, further preventing transcription of the target polynucleotide. Expression of the target polynucleotide is induced by an appropriate inducer, such as isopropyl-β-D-thiogalactopyranoside (IPTG).

[0290] To assess the expression of a polypeptide or a portion thereof, the expression vector introduced into the cells may further include a selectable marker gene or a reporter gene or both, so as to recognize and select expressing cells from a population of cells transfected or infected via a viral vector. In another aspect, the selectable marker can be carried on a single DNA fragment and used in co-transfection experiments. Either the selectable marker gene or the reporter gene can be linked to either side of appropriate regulatory control sequences so as to be expressed in the host cell. Useful selectable markers include, for example, antibiotic resistance genes, such as neo and similar genes.

[0291] Reporter genes can be used to identify potential transfected cells and to evaluate the function of regulatory control sequences. Typically, a reporter gene is a gene that is not present in or expressed by a recipient organism or tissue, and encodes a polypeptide, the expression of which is indicated by some easily detectable property, such as enzymatic activity. After the DNA is introduced into the recipient cells, the expression of the reporter gene is detected at a suitable 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., 2000 FEBS Letters 479:79-82). Suitable expression systems are known and can be prepared by known techniques or obtained commercially. Typically, the construct with the smallest 5' side flap region capable of displaying the highest expression level of the reporter gene is identified as the promoter. Such a promoter region can be linked to a reporter gene and used to evaluate the ability of a substance in modulating transcription driven by the promoter.

[0292] In some embodiments, a nucleic acid is provided that encodes any of the full-length anti-C5a antibodies of the present application. In some embodiments, the nucleic acid comprises one or more nucleic acid sequences encoding full-length anti-C5a antibody heavy and light chains. In some embodiments, each of the one or more nucleic acid sequences is comprised in a single vector. In some embodiments, at least some of the nucleic acid sequences are comprised in the same vector. In some embodiments, all of the nucleic acid sequences are comprised in the same vector. The vector can be selected from, for example, a mammalian expression vector and a viral vector (e.g., vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses).

[0293] Methods for introducing and expressing genes into cells are well known in the art. In the context of an expression vector, the vector can be easily introduced into a host cell, such as a mammalian cell, a bacteria, a yeast or an insect cell, by any method in the art. For example, the expression vector can be introduced into a host cell by physical, chemical or biological methods.

[0294] Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, lipofection, particle gun technology, microinjection, electroporation, and the like. Methods for preparing cells containing vectors and / or exogenous nucleic acids are well known in the art. See, for example, Green and Sambrook (2013, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). In some embodiments, polynucleotides are introduced into host cells by calcium phosphate transfection.

[0295] Biological methods of introducing target polynucleotides into host cells include the use of DNA and RNA vectors. Viral vectors, especially retroviral vectors, are already the most widely used method of inserting genes into mammalian cells, such as human cells. Other viral vectors can be derived from lentiviruses, poxviruses, herpes simplex virus type 1, adenoviruses, and adeno-associated viruses, etc. See USPat.Nos.5350674 and 5585362.

[0296] Chemical methods for introducing polynucleotides into host cells include colloidal dispersion systems such as macromolecular complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system used as a delivery vector in vivo and in vitro is a liposome (e.g., an artificial membrane vesicle).

[0297] When using a non-viral delivery system, an exemplary delivery vector is a liposome. It is contemplated that a lipid formulation can be used to introduce a nucleic acid into a host cell (in vitro, ex vivo, or in vivo). Alternatively, the nucleic acid can be bound to a lipid. A nucleic acid bound to a lipid can be encapsulated in the aqueous interior of a liposome, dispersed within the lipid bilayer of a liposome, linked to a liposome by a linking molecule attached to the liposome and the oligonucleotide, embedded in a liposome, complexed with a liposome, dispersed in a solution containing lipids and mixed with lipids, bound to lipids, suspended in lipids, contained in or mixed with micelles, or otherwise bound to lipids. The lipid, lipid / DNA, or lipid / expression vector-related compositions are not limited to any particular structure in solution. For example, they can exist in bilayer structures, micelles, or "collapsed" structures. They can be simply dispersed in a solution or can form aggregates that are non-uniform in size or shape. Lipids are fatty substances and can be naturally occurring or synthetic lipids. For example, lipids include lipid droplets that naturally occur in the cytoplasm, compounds containing long chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols and aldehydes.

[0298] Regardless of how exogenous nucleic acid is introduced into a host cell or otherwise exposed to the inhibitors of the present application, various experiments can be performed to confirm that the recombinant DNA sequence is present in the host cell. Such experiments include, for example, "molecular biology" experiments well known to those skilled in the art, such as Southern and Northern blotting, RT-PCR and PCR. "Biochemistry" experiments, for example, detect the presence or absence of a particular polypeptide, and identification by, for example, immunological methods (ELISAs and Western blots) or experiments according to the present application, are all within the scope of the present application.

[0299] Preparation of anti-C5a antibody In some embodiments, the anti-C5a antibody is a monoclonal antibody or is derived from a monoclonal antibody. In some embodiments, the anti-C5a antibody comprises a VH and VL derived from a monoclonal antibody, or a variant thereof. In some embodiments, the anti-C5a antibody further comprises a CH1 and CL region derived from a monoclonal antibody, or a variant thereof. Monoclonal antibodies can be prepared by methods known in the art, including, for example, hybridoma methods, phage display methods, or methods using recombinant DNA. Exemplary phage display methods are also described herein and in the Examples below.

[0300] In the hybridoma method, a hamster, mouse or other suitable host animal is usually immunized with an immunizing agent to induce lymphocytes that produce or can produce antibodies that specifically bind to the immunizing agent. Alternatively, lymphocytes can be immunized ex vivo. The immunizing agent may include a polypeptide or a fusion protein of the target protein. Typically, peripheral blood lymphocytes (PBLs) are used when cells of human origin are required, and spleen cells or lymph node cells are used when cells of non-human mammalian origin are required. A suitable fusing agent, such as polyethylene glycol, is used to fuse lymphocytes with an immortalized cell line to form hybridoma cells. The immortalized cell line is usually a transformed mammalian cell, particularly a myeloma cell of rodent, bovine and human origin. Typically, a rat or mouse myeloma cell line is used. The hybridoma cells can be cultured in a suitable medium, preferably containing a substance that inhibits the growth or survival of one or more unfused immortalized cells. For example, if the parent cells are deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), the hybridoma cell culture medium usually contains hypoxanthine, methotrexate and thymidine (HAT medium), which can inhibit the growth of HGPRT-deficient cells.

[0301] In some embodiments, the immortalized cell line fuses efficiently, ensures high-level and stable expression of antibodies by selected antibody-producing cells, and is sensitive to some media, such as HAT medium. In some embodiments, the immortalized cell line is a mouse myeloma cell line, such as those available from the Solkar Cell Depository Center, San Diego, Calif., and the American Institute of Classical Culture Collection, Manassas, Va. In the meantime, the use of human myeloma and mouse-human hybridization myeloma cell lines in the preparation of human-derived monoclonal antibodies is further described.

[0302] The medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies against the polypeptide. The binding specificity of the monoclonal antibodies produced by the hybridoma cells can be determined by immunoprecipitation or in vitro binding assays, for example, radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or assays are known in the art. The binding affinity of the monoclonal antibodies can be determined, for example, by the Scatchard analysis described in Munson and Pollard, Anal. Biochem., 107:220 (1980).

[0303] After identifying the desired hybridoma cells, they can be subcloned to the target clone by limiting dilution and cultured by standard methods. Suitable media for this purpose include, for example, modified Eagle's medium (DMEM) and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in ascites form within a mammalian body.

[0304] The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as protein A-agarose gel, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0305] In some embodiments, the anti-C5a antibody, based on any of the anti-C5a antibodies of the present application, comprises the sequence of a clone selected from an antibody library (e.g., a phage library displaying scFv or Fab fragments). The clone can be identified by screening a combinatorial library of antibody fragments having the required activity. For example, various methods are known in the art for producing phage display libraries and screening these libraries to obtain antibodies with the required binding characteristics. These methods are reviewed, e.g., in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001) and described, e.g., in McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352:624-628 (1991); 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, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al. 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).

[0306] In some phage display methods, V is expressed by polymerase chain reaction (PCR) as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). H and V LAll components of the gene are cloned separately and randomly recombined in a phage library, after which phages capable of binding to the antigen are selected. The phages usually display antibody fragments in the form of scFv or Fab fragments. The immunization-derived library phage provide high affinity antibodies to the immunogen, without the need to construct hybridoma cells. Alternatively, natural libraries (e.g., human-derived) can be cloned to provide a single antibody source against a variety of non-self and self antigens without the need for immunization, as described, for example, in Griffiths et al., EMBO J, 12:725-734 (1993). Finally, natural libraries can also be prepared by cloning unrearranged V-gene fragments derived from stem cells, using PCR primers containing random sequences to encode the CDR3 hypervariable regions, and completing the rearrangement in vitro, as described, for example, in Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example, US Pat. No. 5750373, US Patent Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0307] The anti-C5a antibody is prepared by a method of selecting an anti-C5a antibody portion capable of specifically binding to the target C5a in a library by phage display. The library may be a human scFv phage display library, and may comprise at least 1×10 9 (e.g., at least 1 × 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 1×10 11) unique unique human antibody fragments. In some embodiments, the library is a human natural library, constructed with DNA extracted from PMBCs and spleens of healthy subjects, and includes all human heavy and light chain subfamilies. In some embodiments, the library is a human natural library, constructed with DNA extracted from PMBCs isolated from patients with various diseases, such as autoimmune disease patients, cancer patients, and infectious disease patients. In some embodiments, the library is a semi-synthetic human library, in which the heavy chain CDR3 is fully randomized and all amino acids (except cysteine) have the same probability of occurring at any given position. (See, e.g., Hoet, RM et al., Nat. Biotechnol. 23(3):344-348, 2005). In some embodiments, the length of 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 some embodiments, the library is a fully synthetic phage display library. In some embodiments, the library is a non-human phage display library.

[0308] Phage clones with high affinity to target C5a can be selected by repeated binding of phage to target C5a, which is bound to a solid support (e.g., beads for solution harvesting or mammalian cells for cell harvesting), followed by removal of unbound phage and elution of specifically bound phage. Bound phage clones are then eluted and used to infect suitable host cells, such as E. coli XL1-Blue, for expression and purification. Phage clones that specifically bind to C5a are enriched by multiple harvests (e.g., 2, 3, 4, 5, 6 or more), e.g., solution harvesting, cell harvesting, or a combination of both. Specific binding of enriched phage clones to target C5a can be detected by any method known in the art, including, e.g., ELISA and FACS.

[0309] Another method for screening antibody libraries is to display proteins on the surface of yeast cells. Wittrup et al. (US Patents 6,699,658 and 6,696,251) develop a method for yeast cell display libraries. In this yeast display system, one component contains a yeast lectin protein (Aga1) anchored to the yeast cell wall, and another component contains a second subunit of the lectin protein Aga2, which can be linked to the Aga1 protein via a disulfide bond and further displayed on the yeast cell surface. The Aga1 protein is expressed by integrating the Aga1 gene into the yeast chromosome. After fusing a single-chain variable fragment (scFv) library with the Aga2 gene in a yeast display plasmid and transforming, the library can be retained in yeast due to the presence of an additional nutritional marker. Both Aga1 and Aga2 proteins are expressed under the control of a galactose-inducible promoter.

[0310] Human antibody V gene banks (VH and VK fragments) are obtained by PCR using a group of degenerate primers (Sblattero, D. and Bradbury, A. Immunotechnology 3, 271-278 1998). PCR templates are derived from commercially available RNA or cDNA, including PBMC, spleen, lymph nodes, bone marrow and tonsils. Independent V H and V K The PCR libraries are assembled into scFv format by PCR extension overlay (Sheets, MD et al, Proc. Natl. Acad. Sci. USA 95, 6157-6162 1998). To construct a yeast scFv display library, the resulting scFv PCR products are cloned into a yeast display plasmid in yeast by homologous recombination (Chao, G, et al, Nat Protoc. 2006, 1(2):755-68. Miller KD, et al. Current Protocols in Cytometry 4.7.1-4.7.30, 2008).

[0311] Anti-C5a antibodies can be selected using a mammalian cell display system, where a portion of the antibody is displayed on the cell surface, and the antibody specific to the target C5a is isolated by an antigen-guided selection method (e.g., as described in US patent No. 7732195B2). A Chinese hamster ovary (CHO) cell library that displays a large amount of human IgG antibody genes can be established and used to find clones that express high affinity antibody genes. Another display system has been developed that allows the same protein to be simultaneously displayed on the cell surface and secreted by alternative splicing, where the phenotype of the displayed protein is maintained in relation to the genotype, and the secreted soluble antibody can be simultaneously displayed in biophysical and cell function-based analyses. This method overcomes many limitations of traditional mammalian cell display and can directly select and mature antibodies in the form of full-length, glycosylated IgGs (Peter M. Bowers, et al, Methods 2014, 65:44-56). Transient expression systems are most useful for selecting antibodies from small libraries because they are applied in a single round of antigen selection performed before the antibody genes are restored. Stable release vectors provide attractive selection. Release vectors can be efficiently transfected and stably maintained at low copy numbers, allowing multiple rounds of harvesting and analysis of more complex antibody libraries.

[0312] The IgG library is constructed based on the ligation of species-sequenced V gene fragments isolated from a group of human donors with rearranged (D)J regions. RNA collected from 2000 human blood samples was reverse transcribed into cDNA and the V H and V K Using specific primers H and V K The fragment is amplified and purified by gel extraction. H and V KThe fragments are subcloned into a display vector containing the IgG1 or K constant region, respectively, and then electroporated or transduced into 293T cells to prepare an IgG library. H and V K and ligated to produce scFv, which are then subcloned into a display vector and electroporated or transduced into 293T cells. As is well known, IgG libraries are constructed based on species-sequenced V gene fragments and rearranged (D)J regions isolated from a group of donors, which can be mice, rats, rabbits, or monkeys.

[0313] Monoclonal antibodies can also be prepared by recombinant DNA methods, for example as described in US Patent No. 4816567. DNA encoding the monoclonal antibodies of the present application can be easily isolated and sequenced by conventional methods (e.g., oligonucleotide probes capable of specifically binding to genes encoding the light and heavy chains of mouse-derived antibodies). The hybridoma cells described above or the C5a-specific phage clones of the present application can be the source of such DNA. After isolation, the DNA can be placed into an expression vector, which can then be transfected into host cells such as monkey COS cells, Chinese hamster ovary carcinoma (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain the monoclonal antibodies synthesized in the recombinant host cells. The DNA may be modified, for example, by substituting human heavy and light chain constant regions into the coding sequence and / or substituting framework regions for homologous non-human sequences (US Patent No. 4816567, Morrison et al., supra), or by covalently linking the coding sequence of all or part of a non-immunoglobulin polypeptide to the coding sequence of an immunoglobulin. Such a non-immunoglobulin polypeptide may replace the constant region of an antibody in the present application or replace one antigen-binding site in the variable domain of an antibody in the present application to form a chimeric bivalent antibody.

[0314] The antibody may be a monovalent antibody. Methods for preparing monovalent antibodies are known in the art, for example, methods involving recombinant expression of immunoglobulin light chains and modified heavy chains. Usually, the heavy chains are truncated at any position in the Fc region to prevent heavy chains from cross-linking with each other. Alternatively, the relevant cysteine ​​residues are replaced with other amino acid residues or deleted to prevent cross-linking.

[0315] In vitro methods are also applicable to the preparation of monovalent antibodies. Digestion of antibodies to produce antibody fragments, in particular Fab fragments, can be performed by any method known in the art.

[0316] Antibody variable domains with the necessary binding specificities (antibody-antigen binding sites) can be fused to immunoglobulin constant regions. Fusions to immunoglobulin heavy chain constant regions are preferred, including at least part of the hinge, CH2 and CH3 regions. In some embodiments, the first heavy chain constant region (CH1), containing the site necessary for light chain binding, is present in at least one of the fusions. DNA encoding the immunoglobulin heavy chain fusions, optionally further comprising DNA encoding the immunoglobulin light chain, are inserted into a separate expression vector and co-transfected into a suitable host organism.

[0317] Fully Human and Humanized Antibodies The anti-C5a antibody (e.g., full-length anti-C5a antibody) may be a fully human antibody or a humanized antibody. Humanized forms of non-human (e.g., murine) antibody moieties are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (e.g., Fv, Fab, Fab', F(ab')2, scFv, or other antigen-binding subsequences of antibodies), which usually contain minimal sequences derived from non-human immunoglobulins. Humanized antibodies comprise a human immunoglobulin, immunoglobulin chain or fragment thereof (acceptor antibody) in which the acceptor CDR residues are replaced by CDR residues of non-human origin (donor antibody) with the required specificity, affinity, and performance, such as mouse, rat, or rabbit CDRs. In some examples, human immunoglobulin Fv framework region residues are replaced by the corresponding non-human residues. Humanized antibodies may further comprise amino acid residues that do not belong to the acceptor antibody or to the introduced CDR or framework region sequences. Usually, a humanized antibody contains at least one, and usually two, variable domains, in which all or almost all of the CDR regions correspond to those of a non-human immunoglobulin and all or almost all of the framework regions are human immunoglobulin shared sequences.

[0318] Typically, a humanized antibody contains one or more amino acid residues of non-human origin. These amino acid residues of non-human origin are usually referred to as "import" residues and usually come from an "import" variable domain. According to some embodiments, humanization can be performed essentially according to the method of Winter and coworkers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by replacing the corresponding sequences of a human antibody with rodent CDRs or CDR sequences. Thus, such "humanized" antibody portions (US Patent No. 4,816,567) are essentially less than fully human antibodies, whose variable domains have already been replaced by the corresponding sequences of 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 replaced by residues from analogous sites derived from rodent antibodies.

[0319] Fully human antibodies are an alternative to humanization. For example, it is now possible to prepare genetically engineered animals (e.g., mice) that can produce a complete, fully human antibody library after immunization but that do not produce endogenous immunoglobulins. For example, it has been reported that homozygous deletion of the antibody heavy-chain joining region (JH) gene in chimeric and species-based mutant mice completely suppresses endogenous antibody production. By transferring a human species-based immunoglobulin gene array into such a species-based mutant mouse, human antibodies can be produced under antigen stimulation, see, for example, Jakobovits et al., PNAS USA, 90:2551 (1993), Jakobovits et al., Nature, 362:255-258 (1993), Bruggemann et al., Year in Immunol., 7:33 (1993), US Patent Nos. 5545806, 5569825, 5591669, 5545807, and WO97 / 17852. Alternatively, fully human antibodies can be prepared by introducing human immunoglobulin loci into a transgenic animal (e.g., a mouse in which some or all of the endogenous immunoglobulin genes have already been silenced). After antigen stimulation, the production of fully human antibodies can be found to be very similar to that in humans in various aspects, including gene rearrangement, assembly, and antibody libraries. Such methods 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, 10:779-783 (1992); Lonberg et al., Nature, 368:856-859 (1994); Morrison, Nature, 368:812-13 (1994); Fishwild et al., Nature Biotechnology, 14:845-851 (1996); Neuberger, Nature Biotechnology, 14:826 (1996); Lonberg and Huszar, Intern. Rev. Immunol., 13:65-93 (1995).

[0320] Fully human antibodies may be produced by activating B cells in vitro (see US Patents 5,567,610 and 5,229,275) or by using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). The techniques of 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).

[0321] Anti-C5a antibody variants In some embodiments, the amino acid sequence of the anti-C5a antibody variant (e.g., full-length anti-C5a antibody) according to the present application is also contemplated. For example, it may be necessary to improve the binding affinity and / or other biological activities of the antibody. The amino acid sequence of the antibody variant can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletion and / or insertion and / or substitution of residues in the antibody amino acid sequence. Any combination of deletion, insertion and substitution of amino acid residues can be used to complete the final construction and provide the required characteristics, for example, antigen binding.

[0322] In some embodiments, anti-C5a antibody variants are provided that have one or more amino acid substitutions. Target sites for substitution mutations include hypervariable regions (HVRs) and framework regions (FRs). Amino acid substitutions can be introduced into the target antibody to select products with desired activities, such as improved biological activity, retained / improved antigen binding ability, reduced immunogenicity, or improved ADCC or CDC.

[0323] Conservative substitutions are as shown in Table 4 below.

[0324] [Table 4]

[0325] Amino acids are classified into different categories based on the properties of their side chains. a, Hydrophobic amino acids: Norleucine, Met, Ala, Valine, 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. Amino acids that affect chain direction: glycine Gly, proline Pro, f, Aromatic amino acids: tryptophan Trp, tyrosine Tyr, phenylalanine Phe.

[0326] Non-conservative amino acid substitutions involve substituting one of the above categories for another category.

[0327] One exemplary substitution mutant is an affinity matured antibody, which can be readily produced using affinity maturation techniques based on, for example, phage display. Briefly, one or more CDR residues are mutated, portions of the mutant antibody are displayed on phage, and mutants with a particular biological activity (e.g., biological activity or binding affinity based on reactive oxygen species (ROS) release assay) are selected. Modifications (e.g., substitutions) can be made in the HVRs region to obtain improved biological activity or antibody affinity based on reactive oxygen species (ROS) release assay. Modifications are made in "hotspot regions" of the HVRs, i.e., residues encoded by codons where high frequency mutations occur during somatic maturation (see, for example, Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or at specific critical residues (SDRs), to obtain the resulting mutant Vs. H and V L The method of constructing and reselecting affinity from a secondary library has already been described in several publications, for example, Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)).

[0328] In some affinity maturation examples, diversity is introduced into the variable genes selected for affinity maturation by any of a variety of methods (e.g., error-prone PCR, strand recombination, or oligonucleotide directed mutagenesis). A secondary library is then generated. The library is screened to identify antibody variants with the required affinity. Another method of introducing diversity involves HVR-mediated schemes, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically recognized and mutagenized or modeled, for example, by alanine scanning. Typically, the CDR-H3 and DR-L3 regions are particularly important targets.

[0329] In some embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, provided that such modifications do not appreciably reduce the ability of the antibody to bind antigen. For example, conservative modifications (e.g., conservative substitutions according to the present application) may be produced in HVRs that do not appreciably reduce binding affinity. These modifications may occur outside the "hotspot regions" or SDRs of the HVRs. In some embodiments, the mutant V H and V L The sequences may be such that each HVR is unaltered or contains no more than one, two or three amino acid substitutions.

[0330] As described in Cunningham and Wells (1989) Science, 244:1081-1085, a useful method that can identify amino acid residues or regions in an antibody that can be targeted mutated is called "alanine scanning mutagenesis". 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 replaced by neutral or negatively charged amino acids (e.g., alanine or glutamic acid) to determine whether the interaction of the antibody with the antigen is affected. Substitutions are further introduced at amino acid positions to demonstrate that the positions are functionally sensitive to the initial substitution. Or / and contact sites between the antibody and the antigen are identified by crystal structures of antigen-antibody complexes. These contact site residues and adjacent residues can be targeted or removed as substitution candidates. The mutants are screened to determine whether they have the required properties.

[0331] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions and range in length from one residue to polypeptides containing 100 or more residues, including the insertion of one or more amino acid residues into the sequence. An example of a terminal insertion includes an antibody with a methionyl residue at the N-terminus. Other insertional variants of antibody molecules include the fusion of an enzyme (e.g., ADEPT) to the N- or C-terminus of the antibody molecule, or a polypeptide which increases the serum half-life of the antibody.

[0332] Fc region variants In some embodiments, one or more amino acid modifications are introduced into the Fc region of an antibody of the present application (e.g., a full-length anti-C5a antibody or an anti-C5a antibody fusion protein) to generate an Fc region variant. In some embodiments, the Fc region variant has an enhanced ADCC effect, typically associated with Fc-bound receptors (FcRs). In some embodiments, the Fc region variant has a reduced ADCC effect. There are many examples where modifications or mutations of the Fc sequence affect its effect, for example, WO00 / 42072 and Shields et al. J Biol. Chem. 9(2):6591-6604 (2001) describe antibody variants with enhanced or reduced binding to FcRs. The contents of these publications are incorporated herein by reference.

[0333] 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 which effector cells of the immune system actively degrade target cells (e.g., cancer cells) when antigens on the surface of the target cell membrane are bound by specific antibodies (e.g., anti-C5a antibodies). Usually, the ADCC effect involves NK cells activated by antibodies. NK cells express the Fc receptor CD16, which recognizes and binds to the Fc portion of antibody molecules bound to the surface of target cells. The most common Fc receptor on the surface of NK cells is CD16 or FcγRIII. Binding of the Fc receptor to the antibody Fc region leads to the activation of NK cells, the release of cytolytic particles, and subsequent target cell apoptosis. The killing effect of ADCC against tumor cells can be measured by specificity experiments in which NK-92 cells are transfected with high affinity FcR. The results are compared with wild-type NK-92, which does not express FcR.

[0334] In some embodiments, the present application further provides an anti-C5a antibody variant (e.g., a full-length anti-C5a antibody variant) that includes some, but not all, effector function Fc region, has an extended half-life in the body, but where certain effector functions (e.g., CDC or ADCC) are not essential or are deleterious, making such anti-C5a antibodies ideal candidates for the present application. In vitro and / or in vivo cytotoxicity detection is performed to confirm the reduction / elimination of CDC and / or ADCC activity. For example, Fc receptor (FcR) binding test is performed to confirm that the antibody lacks FcγR binding ability (and thus may lack ADCC activity) but still retains FcRn binding ability. Among the main cells mediating ADCC, NK cells express only FcγRIII, while monocytes express FcγRI, FcγRII and FcγRIII. Table 3 on page 464 of Ravetch and Kinet Annu. Rev. Immunol. 9:457-492 (1991) summarizes the expression of FcR in hematopoietic cells. Non-limiting examples of assessing ADCC activity of a target molecule in vitro are described in US Pat. No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986) and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985)), US Pat. No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)), or non-radioactive detection methods (e.g., ACTI (商標) Flow cytometry non-radioactive cytotoxicity detection (CellTechnology, Inc. Mountain View, Calif.) and CYTOTOX 96 (商標)Non-radioactive cytotoxicity detection (see Promega, Madison, Wis.) can be employed. Effector cells used in such detection experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Alternatively, the ADCC activity of the target molecule can be detected in vivo, for example, in an animal model, as described in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). At the same time, a C1q binding test can be performed to confirm that the antibody cannot bind to C1q and lacks CDC activity. See, for example, the C1q and C3c binding ELISA in WO2006 / 029879 and WO2005 / 100402. To assess the status of complement activation, CDC detection can be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and M. J. Glennie, Blood 103:2738-2743 (2004)). FcRn binding and body clearance / half-life are measured using methods known in the art (see, for example, Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[0335] Antibodies with reduced effector function include those with substitutions of one or more residues at Fc region residue positions 238, 265, 269, 270, 297, 327 and 329 (US Pat. No. 6737056). These Fc variants include Fc variants with substitutions of two or more residues at positions 265, 269, 270, 297 and 327, including an Fc variant designated "DANA" in which residues 265 and 297 are substituted with alanine (US Pat. No. 7332581).

[0336] Such antibody variants with improved or decreased ability to bind to FcRs have been described (see, e.g., US Pat. No. 6737056, WO 2004 / 056312, and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001)).

[0337] In some embodiments, anti-C5a antibody (e.g., full-length anti-C5a antibody) variants are provided, including Fc region variants with one or more amino acid substitutions capable of enhancing ADCC effect. In some embodiments, the Fc region variants include one or more amino acid substitutions capable of enhancing ADCC effect, and the positions of these substitutions are at positions 298, 333 and / or 334 (EU residue numbering) of the Fc region. In some embodiments, the anti-C5a antibody (e.g., full-length anti-C5a antibody) variants include amino acid substitutions at positions S298A, E333A and K334A of the Fc region.

[0338] In some embodiments, modifications of the Fc region result in altered (i.e., enhanced or attenuated) C1q binding and / or complement dependent cytotoxicity (CDC), see US Pat. Nos. 6, 194, 551, WO 99 / 51642, and Idusogie et al., J. Immunol. 164:4178-4184 (2000).

[0339] In some examples, anti-C5a antibody (e.g., full-length anti-C5a antibody) variants are provided that include Fc region variants with one or more amino acid substitutions to extend half-life or enhance binding to Fc receptors (FcRn). Antibodies with extended half-life and improved binding to FcRn are described in US 2005 / 0014934A1 (Hinton et al.). These antibody Fc regions include one or more amino acid substitutions to enhance binding of the Fc region to FcRn. These Fc variants comprise one or more substitutions of residues at positions 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424 or 434 in the Fc region, e.g., substitution of residue at position 434 in the Fc region (US Pat. No. 7,371,826).

[0340] Also see, for examples of other Fc region variants, see Duncan & Winter, Nature 322:738-40 (1988), US Pat. No. 5648260, US Pat. No. 5624821 and WO 94 / 29351.

[0341] The present application contemplates anti-C5a antibodies (eg, full length anti-C5a antibodies) comprising any of the Fc variants described herein or combinations thereof.

[0342] Glycosylation variants In some embodiments, the anti-C5a antibodies of the present application (e.g., full-length anti-C5a antibodies) are modified to increase or decrease the degree of glycosylation of the anti-NGF antibody. By modifying the amino acid sequence of the anti-NGF antibody or a polypeptide portion thereof, one or more glycosylation sites can be increased or removed, which can facilitate the addition or deletion of glycosylation sites on the anti-C5a antibody.

[0343] Here, the anti-C5a antibody comprises an Fc region, and the sugars linked thereto can be modified. Natural antibodies produced by mammalian cells typically comprise branched multi-antennary oligosaccharides, which are typically linked to the CH2 domain Asn297 of the Fc region via an N-linkage, see, e.g., Wright et al., TIBTECH 15:26-32 (1997). The oligosaccharides can include a variety of sugars, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, trehalose linked to the GlcNAc "stem" of the multi-antennary oligosaccharide structure. In some embodiments, oligosaccharide modifications can be made to the anti-C5a antibodies of the present application to generate anti-C5a antibody variants with certain improved properties.

[0344] The N-polysaccharide linked to the CH2 domain of the Fc region is 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. Normally, a small proportion of naturally occurring non-fucosylated IgGs can be detected in human serum. N-glycosylation of the Fc region is important for its binding to FcγR, but deglycosylated N-polysaccharide enhances the binding ability of Fc to FcγRIIIa. The enhanced binding ability to FcRIIIa enhances the ADCC effect, which is advantageous in the use of some antibody therapeutics that require cytotoxicity.

[0345] In some embodiments, enhanced effector function may be detrimental when Fc-mediated cytotoxicity is not required. In some embodiments, the Fc fragment or CH2 domain is not glycosylated. In some embodiments, the N-glycosylation site in the CH2 domain is mutated to prevent its glycosylation.

[0346] In some embodiments, an anti-C5a antibody (e.g., a full-length anti-C5a antibody) variant is provided that includes an Fc region and the saccharide structure linked to the Fc region has reduced fucoidan or lacks fucoidan, which may enhance ADCC function. Specifically, the present application provides an anti-C5a antibody that has reduced fucoidan relative to the same anti-C5a antibody produced by wild-type CHO cells, i.e., that has less fucoidan compared to an antibody produced by a native CHO cell (e.g., a CHO cell producing a native glycosylation pattern, a CHO cell containing a native FUT8 gene). In some embodiments, the N-linked polysaccharide of the anti-C5a antibody has less than 50%, 40%, 30%, 20%, 10% or 5% fucoidan. For example, the fucoidan content of the anti-C5a antibody may be 1%-80%, 1%-65%, 5%-65%, or 20%-40%. In some embodiments, the N-linked polysaccharide of the anti-C5a antibody does not contain fucoidan, i.e., where the anti-C5a antibody is completely free of fucoidan, or is fucoidan-free or deglycosylated. The fucoidan content is determined by calculating the total average fucoidan content in the glycan linked to Asn297 relative to all glycan structures (e.g., complex, hybridization, or mannose structures) linked to Asn297 as measured by MALDI-TOF mass spectrometry, as described in WO2008 / 077546. By Asn297 is meant the asparagine residue located at position 297 of the Fc region (EU Fc region residue numbering system). However, due to changes in the antibody microsequence, Asn297 may be located ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. These fucosylation variants may have enhanced ADCC function. See, e.g., US Patent Publication Nos. US 2003 / 0157108 (Presta, L.), US 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd).Examples of publications related to "deglycosylated" or "fucoidan-depleted" antibody variants include US 2003 / 0157108, WO2000 / 61739, WO2001 / 29246, US 2003 / 0115614, US 2002 / 0164328, US 2004 / 0093621, US 2004 / 0132140, US 2004 / 0110704, US 2004 / 0110282, US 2004 / 0109865, WO2003 / 085119, WO2003 / 084570, WO2005 / 035586, WO2005 / 035778, WO2005 / 053742, WO2002 / 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 deglycosylated antibodies include Lec13 CHO cells, which are deficient in protein fucosylation function (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003 / 0157108 A1; Presta, L, and WO2004 / 056312 A1; Adams et al., in particular Example 11), and gene knockout cell lines, such as CHO cells with α-1,6-fucosyltransferase gene, FUT8 gene knockout (Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al. al., Biotechnol. Bioeng., 94(4):680-688 (2006), and WO2003 / 085107).

[0347] Anti-C5a antibody (e.g., full-length anti-C5a antibody) variants further provide bisected oligosaccharides, for example, in which the multiantennary oligosaccharides linked to the anti-C5a antibody Fc region are bisected by GlcNAc. Such anti-C5a antibody (e.g., full-length anti-C5a antibody) variants may have reduced fucosylation and / or enhanced ADCC function. Examples of such antibody variants are described in WO2003 / 011878 (Jean-Mairet et al.), US 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). Further provided are anti-C5a antibody (e.g., full-length anti-C5a antibody) variants having at least one galactose residue in the oligosaccharide linked to the Fc region. Such anti-C5a antibody variants may have enhanced CDC function. Such variants are described, for example, in WO1997 / 30087 (Patel et al.), WO1998 / 58964 (Raju, S.), and WO1999 / 22764 (Raju, S.).

[0348] In some embodiments, the anti-C5a antibody (e.g., full length anti-C5a antibody) variant comprises an Fc region capable of binding to FcγRIII. In some embodiments, the anti-C5a antibody (e.g., full length anti-C5a antibody) variant comprising an Fc region has ADCC activity in the presence of human effector cells (e.g., T cells) or has enhanced ADCC activity in the presence of human effector cells compared to an otherwise identical anti-C5a antibody (e.g., full length anti-C5a antibody) that has a human wild-type IgG1 Fc region.

[0349] Cysteine ​​engineered mutants In some embodiments, a cysteine ​​engineered anti-C5a antibody (e.g., a full-length anti-C5a antibody) needs to be prepared, in which one or more amino acid residues in the antibody are replaced by a cysteine ​​residue. In some embodiments, the replaced residues appear at accessible sites in the anti-C5a antibody. By replacing those residues with cysteines, active sulfhydryl groups are located at accessible sites in the anti-C5a antibody, which can be used to couple the anti-C5a antibody to other moieties, such as drug moieties or linker-drug moieties, to prepare anti-C5a immunoconjugates as further described herein. Cysteine ​​engineered anti-C5a antibodies (e.g., full-length anti-C5a antibodies) can be prepared, for example, as described in US Pat. Nos. 7, 521, 541.

[0350] derivative In some embodiments, the anti-C5a antibodies of the present application (e.g., full-length anti-C5a antibodies) can be further modified to include other non-protein moieties known in the art and readily obtainable. Moieties applied to derivatize anti-C5a antibodies can include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers can include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers), dextran or poly(n-vinylpyrrolidone), polyethylene glycol, propylene glycol homopolymers, propylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerin), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde is advantageous during manufacturing due to its stability in water. The polymer can have any molecular weight, and the number of polymers linked to the anti-C5a antibody, which may be branched or unbranched, can vary, and when linked to one or more multimers, they can be the same or different molecules. Typically, the number and / or type of polymers for derivatization can be determined based on the following considerations, which may include, but are not limited to, the property or function of the anti-C5a antibody that needs to be improved, whether the anti-C5a antibody derivative will be used to treat a particular condition, etc.

[0351] Pharmaceutical Compositions The present application further provides compositions (e.g., pharmaceutical compositions, also referred to herein as formulations) comprising any of the anti-C5a antibodies (e.g., full length anti-C5a antibodies), nucleic acids encoding the antibodies, vectors comprising nucleic acids encoding the antibodies, and host cells comprising a nucleic acid or vector of the present application. In some embodiments, a pharmaceutical composition is provided comprising any of the anti-C5a antibodies of the present application and a pharma- ceutical acceptable vector.

[0352] A suitable anti-C5a antibody formulation can be obtained by mixing an anti-C5a antibody having the required purity with any pharma- ceutically acceptable vector, excipient or stabilizer (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)) and prepared in the form of a lyophilized or liquid formulation. Acceptable vectors, excipients or stabilizers are non-toxic to recipients at the dosages and concentrations employed and include buffers including phosphate, citric acid and other organic acids, antioxidants including ascorbic acid and methionine, preservatives (e.g., octadecyldimethylbenzylammonium chloride, hexamethylammonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butanol or benzyl alcohol, parahydroxybenzoic acid alkyl esters such as methyl or propyl parahydroxybenzoate, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol), low molecular weight (fewer than 10 residues) polypeptides, serum albumin, gelatin or glycerol. 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 counterions such as sodium, metal complexes (e.g., zinc-protein complexes), and / or non-ionic surfactants such as TWEEN®, PLURONIC® S, or polyethylene glycol (PEG), exemplary formulations are described in WO 98 / 56418, which 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 a formulation with a high protein concentration, and the reconstituted formulation can be administered to an individual awaiting treatment in this application by subcutaneous administration.Cationic liposomes or liposomes can be used to deliver the anti-C5a antibodies herein to cells.

[0353] In addition to the anti-C5a antibody (e.g., full-length anti-C5a antibody), the formulations of the present application may further include other active substances necessary for the treatment of one or more specific pathologies, preferably substances that have complementary activities and do not adversely react with each other. For example, in addition to the anti-C5a antibody, it may be necessary to further include an anti-tumor agent, a growth inhibitor, a cytotoxic agent, or a chemotherapeutic agent. These molecules are present in combination in amounts effective for the anticipated purpose. The effective amount of the other substances depends on the content of anti-C5a antibody in the formulation, the type of disease or pathology or treatment, and other factors mentioned above. These agents are typically used in the same doses and administration routes described in the present application, or at 1% to 99% of the current usage.

[0354] The anti-C5a antibody (e.g., full-length anti-C5a antibody) may be embedded in microcapsules prepared, for example, by aggregation techniques and interfacial polymerization, for example, in hydroxymethylcellulose or gelatin-microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in coarse emulsions, respectively. Sustained release formulations can be prepared.

[0355] Sustained release formulations of anti-C5a antibodies (e.g., full-length anti-C5a antibodies) can be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the antibody (or fragments thereof), these matrices being 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(ethylene alcohol)), polylactic acid (US Pat. No. 3773919), copolymers of L-glutamic acid and L-ethyl glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D(-)-3-hydroxybutyric acid. Polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid can release molecules for over 100 days, while some hydrogels can release proteins within shorter time periods. When encapsulated antibodies stay in the body for a long time, they may denature or aggregate due to exposure to a humid environment at 37°C, leading to loss of biological activity or altered immunogenicity. Depending on the corresponding mechanism, a rational policy can be designed to stabilize anti-C5a antibodies. For example, if we find that the aggregation mechanism is the exchange of thiodisulfides to form intermolecular SS bonds, we can achieve stabilization by modifying sulfhydryl residues, lyophilizing in acidic solutions, controlling water content, using appropriate additives, and developing specific polymer matrix compositions.

[0356] In some embodiments, the anti-C5a antibody (e.g., a full-length anti-C5a antibody) is formulated in a buffer containing citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 (Tween 80), or any combination thereof.

[0357] Preparations for internal administration must be sterile, which can be readily accomplished, for example, by filtration through sterile filtration membranes.

[0358] Therapeutic method using anti-C5a antibody Anti-C5a antibodies (e.g., full-length anti-C5a antibodies) and / or compositions of the present application can be administered to an individual (e.g., a mammal such as a human) to treat diseases and / or conditions associated with high expression of C5a and diseases and / or conditions caused by dysfunction of C5a, such as autoimmune diseases and / or inflammatory diseases and / or cancer and / or pain and / or transplant immunity characterized by high expression of C5a and / or abnormal function of C5a.

[0359] Thus, in some embodiments of the present application, there is provided a method for preventing, treating, maintaining, alleviating and / or suppressing a disease or condition characterized by high expression of C5a and / or abnormal function of C5a (e.g., inflammatory disorders, autoimmune disorders, cancer, pain and transplant immunity) in an individual, the method comprising administering to the individual an effective amount of a composition (e.g., a pharmaceutical composition) comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), e.g., any of the anti-C5a antibodies (e.g., a full-length anti-C5a antibody) described in the present application.

[0360] In some embodiments, the disease or condition is selected from the group consisting of, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia / reperfusion-associated injury, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, renal failure entities, rheumatoid arthritis, autoimmune diseases, Bechterew disease, lupus disease, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer. In some embodiments, the individual is a human.

[0361] For example, in some embodiments, a method is provided for treating an individual suffering from an autoimmune disease and / or an inflammatory condition and / or cancer and / or pain and / or transplant immunity characterized by high expression of C5a and / or abnormal function of C5a, comprising administering to the individual an effective amount of a pharmaceutical composition of a C5a antibody (e.g., a full-length anti-C5a antibody) that specifically binds to an epitope in human C5a, wherein the isolated anti-C5a antibody specifically binds to any of amino acid residues D at position 31, E at position 32, and R at position 40 in human C5a as shown in SEQ ID NO:141. In some embodiments, the isolated anti-C5a antibody specifically binds to residues 31 to 40 in human C5a as shown in SEQ ID NO:141. In some embodiments, the anti-C5a antibody is a full-length antibody. In some embodiments, the full-length antibody is an IgG1 or IgG4 antibody. In some embodiments, the disease or condition is selected from inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia / reperfusion-associated injury, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew disease, lupus disease, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer. In some embodiments, the individual is a human.

[0362] In some embodiments, a method is provided for treating an individual suffering from an autoimmune disease and / or an inflammatory condition and / or cancer and / or pain and / or transplant immunity characterized by high expression of C5a and / or abnormal function of C5a (e.g., inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia / reperfusion associated injury, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft versus host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus disease, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer), comprising administering to the individual an effective amount of a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), wherein the anti-C5a antibody is selected from the group consisting of the sequence X1 YYX 2 Q (SEQ ID NO:67), but not including X 1 is D or N, and X 2 is M or I), the sequence LIRX 1 KX 2 X 3 GX 4 TX 5 X 6 X 7 AAS 8 One HC-CDR2 containing KG (SEQ ID NO:68) (wherein 1 is K or N, and X 2 is A or V, and X 3 is V, N, or I, and X 4 is G, E, F, H, I, Q or R, and X 5 is T, V or A, and X 6 is Q, E, T or S, and X 7 is Y or F, and X 8 is V or L), and the sequence RX 1 GPPGLX 2 (SEQ ID NO:69) (wherein 1 is A, L or V, and X 2 is T, S or A) H ) and the array RSSQX 1 LLX 2 X 3 X 4 X 5 YX 6 YX 7 D (SEQ ID NO: 70), but 1 is S, R or N, and X 2 is A, H or D, and X 3 is S or T, and X 4 is D or N, and X 5 is G, A or R, and X 6 is N, I, T, E or A, and X 7 is I, M, L or V), array GX 1 SX 2One LC-CDR2 containing RAS (SEQ ID NO:71) (wherein 1 is G or A, and X 2 is N or K), and the array X 1 QHX 2 X 3 LPX 4 One LC-CDR3 containing X 1 is L or M, and X 2 is R or K, and X 3 is A or V, and X 4 is P or L) L ) and

[0363] In some embodiments, a method is provided for treating an individual suffering from an autoimmune disease and / or an inflammatory condition and / or cancer and / or pain and / or transplant immunity characterized by high expression of C5a and / or abnormal function of C5a (e.g., inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia / reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft versus host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus disease, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer), comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the anti-C5a antibody comprises one HC-CDR1, SEQ ID NOs: 1-6, 20 or 25, 25 or 26, 26 or 27, 27 or 28, 28 or 29, 30 or 31, 32 or 33, 34 or 35, 36 or 37, 37 or 38, 38 or 39, 39 or 40, 40 or 41, 42 or 43, 44 or 45, 45 or 46, 46 or 47, 47 or 48, 48 or 49, 50 or 51, 52 or 53, 53 or 54, 54 or 55, 55 or 56, 57 or 58, 59 or 60, 61 or 62, 63 or 64, 64 or 65, 65 or 66, 66 or 67, 67 or 68, 68 or 69, 70 or 71, 7 A V comprising one HC-CDR2 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs:7 to 29, and one HC-CDR3 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs:30 to 38. Hand one LC-CDR1 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 39 to 56, one LC-CDR2 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 57 to 59, and one LC-CDR3 having a sequence having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 60 to 66. L Includes.

[0364] In some embodiments, a method is provided for treating an individual suffering from an autoimmune disease and / or an inflammatory condition and / or cancer and / or pain and / or transplant immunity characterized by high expression of C5a and / or abnormal function of C5a (e.g., inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia / reperfusion-related injury, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew disease, lupus disease, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer), comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the anti-C5a antibody is a V5A antibody having at least 90% sequence identity to an amino acid sequence of any of SEQ ID NOs:73-111. H and V having at least 90% sequence identity with any of the amino acid sequences of SEQ ID NOs: 112 to 140. L Includes.

[0365] In some embodiments, the anti-C5a antibody of the present application is a full-length anti-C5a 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 SEQ ID NO:142. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:144.

[0366] In some embodiments, a method is provided for treating an individual suffering from an autoimmune disease and / or an inflammatory condition and / or cancer and / or pain and / or transplant immunity characterized by high expression of C5a and / or abnormal function of C5a (e.g., inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia / reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft versus host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus disease, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer), comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the anti-C5a antibody comprises one HC-CDR1, SEQ ID NO:1, a sequence having at least 90% sequence identity with the amino acid sequence set forth in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID V comprising one HC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:7, and one HC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:30. Hand one LC-CDR1 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:39, one LC-CDR2 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:57, and one LC-CDR3 having a sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:60. L Includes.

[0367] In some embodiments, the anti-C5a antibody of the present application comprises a V polypeptide comprising the amino acid sequence SEQ ID NO:73. H and V comprising the amino acid sequence SEQ ID NO:112 L and In some embodiments, the anti-C5a antibody of the present application is a full-length anti-C5a 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:142. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:143. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:144.

[0368] In some embodiments, a method is provided for treating an individual suffering from an autoimmune disease and / or an inflammatory condition and / or cancer and / or pain and / or transplant immunity characterized by high expression of C5a and / or abnormal function of C5a (e.g., inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia / reperfusion associated injury, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft versus host reaction,...

Claims

1. (i) a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 1, a HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 7, and a HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 30; Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 39, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 57, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

60. Ｌ and, (ii) a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 2, a HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 8, and a HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 31; Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 40, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 57, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

61. Ｌ and, (iii) a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 2, a HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 10, and a HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 32; Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 42, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 57, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

61. Ｌ and, (iv) a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 2, a HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 9, and a HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 32; Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 43, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 57, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

63. Ｌ and, (v) V comprising an HC-CDR1 having an amino acid sequence represented by SEQ ID NO: 2, an HC-CDR2 having an amino acid sequence represented by SEQ ID NO: 23, and an HC-CDR3 having an amino acid sequence represented by SEQ ID NO:

32. Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 42, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 57, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

61. Ｌ and, (vi) V comprising an HC-CDR1 having an amino acid sequence represented by SEQ ID NO: 2, an HC-CDR2 having an amino acid sequence represented by SEQ ID NO: 23, and an HC-CDR3 having an amino acid sequence represented by SEQ ID NO:

32. Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 56, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 57, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

61. Ｌ and, (vii) a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 6, a HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 18, and a HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 36; Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 52, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 58, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

61. Ｌ and, (viii) a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 6, a HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 18, and a HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 36; Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 53, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 59, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

65. Ｌ and, (ix) a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 5, a HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 21, and a HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 32; Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 52, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 58, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

61. Ｌ and, or (x) a V-CDR1 having an amino acid sequence represented by SEQ ID NO: 5, a HC-CDR2 having an amino acid sequence represented by SEQ ID NO: 21, and a HC-CDR3 having an amino acid sequence represented by SEQ ID NO: 32; Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 53, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 59, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

65. Ｌ and, (xi) a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 2, a HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 9, and a HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 32; Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 41, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 57, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

62. Ｌ and, or (xii) a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 2, a HC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 26, and a HC-CDR3 comprising the amino acid sequence shown in SEQ ID NO: 32; Ｈ and a V-CDR1 comprising the amino acid sequence shown in SEQ ID NO: 42, a LC-CDR2 comprising the amino acid sequence shown in SEQ ID NO: 57, and a LC-CDR3 comprising the amino acid sequence shown in SEQ ID NO:

61. Ｌ and, Including, An isolated anti-C5a antibody or antigen-binding fragment thereof.

2. (xiii) V comprising the amino acid sequence SEQ ID NO: 73 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO:

73. Ｈ and the amino acid sequence SEQ ID NO: 112 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO: 112; and Ｌ and, (xiv) V comprising the amino acid sequence SEQ ID NO: 75 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO:

75. Ｈ and V comprising the amino acid sequence SEQ ID NO: 114 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

114. Ｌ and, (xv) V comprising the amino acid sequence SEQ ID NO: 100 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO:

100. Ｈ and V comprising the amino acid sequence SEQ ID NO: 135 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

135. Ｌ and, (xvi) a V sequence comprising the amino acid sequence SEQ ID NO: 85 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO: 85; Ｈ and V comprising the amino acid sequence SEQ ID NO: 117 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

117. Ｌ and, (xvii) a V sequence comprising the amino acid sequence SEQ ID NO: 102 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO: 102; Ｈ and V comprising the amino acid sequence SEQ ID NO: 135 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

135. Ｌ and, (xviii) V comprising the amino acid sequence SEQ ID NO: 109 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO:

109. Ｈ and V comprising the amino acid sequence SEQ ID NO: 138 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

138. Ｌ and, (xix) a V sequence comprising the amino acid sequence SEQ ID NO: 110 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO: 110; Ｈ and V comprising the amino acid sequence SEQ ID NO: 139 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

139. Ｌ and, (xx) V comprising the amino acid sequence SEQ ID NO: 110 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

110. Ｈ and V comprising the amino acid sequence SEQ ID NO: 140 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

140. Ｌ and, (xxi) V comprising the amino acid sequence SEQ ID NO: 111 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO:

111. Ｈ and V comprising the amino acid sequence SEQ ID NO: 139 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

139. Ｌ and, or (xxii) V comprising the amino acid sequence SEQ ID NO:111 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO:

111. Ｈ and V comprising the amino acid sequence SEQ ID NO: 140 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

140. Ｌ and, (xxiii) V comprising the amino acid sequence SEQ ID NO: 76 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO:

76. Ｈ and V comprising the amino acid sequence SEQ ID NO: 115 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

115. Ｌ and, or (xxiv) V comprising the amino acid sequence SEQ ID NO: 105 or a variant sequence having at least 90% sequence identity to the amino acid sequence SEQ ID NO:

105. Ｈ and V comprising the amino acid sequence SEQ ID NO: 135 or a variant sequence having at least 90% sequence identity with the amino acid sequence SEQ ID NO:

135. Ｌ and, Including, 2. An isolated anti-C5a antibody or antigen-binding fragment thereof according to claim 1.

3. the anti-C5a antibody or antigen-binding fragment thereof comprises an Fc fragment; 3. An isolated anti-C5a antibody or antigen-binding fragment thereof according to claim 1 or 2.

4. The anti-C5a antibody or antigen-binding fragment thereof is a full-length IgG antibody.

4. An isolated anti-C5a antibody or antigen-binding fragment thereof according to claim 3.

5. The anti-C5a antibody or antigen-binding fragment thereof is a full-length IgG1 or IgG4 antibody.

5. An isolated anti-C5a antibody or antigen-binding fragment thereof according to claim 4.

6. The anti-C5a antibody or antigen-binding fragment thereof is selected from the group consisting of Fab, Fab', F(ab)'2, Fab'-SH, single chain antibody (scFv), Fv fragment, dAb, Fd, nanobody, double chain antibody and linear antibody; 3. An isolated anti-C5a antibody or antigen-binding fragment thereof according to claim 1 or 2.

7. A nucleic acid encoding the anti-C5a antibody or antigen-binding fragment thereof according to any one of claims 1 to 6. Nucleic acid molecule.

8. The nucleic acid molecule according to claim 7, vector.

9. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, the nucleic acid molecule according to claim 7, or the vector according to claim 8. Isolated host cells.

10. a) culturing the host cell of claim 9 under conditions that allow effective expression of an anti-C5a antibody or an antigen-binding fragment thereof; b) obtaining the expressed anti-C5a antibody or antigen-binding fragment thereof from the host cell; A method for preparing an anti-C5a antibody or antigen-binding fragment thereof.

11. 9. A method for the treatment of a cancer, comprising administering to a patient a therapeutically effective amount of ... Pharmaceutical compositions.

12. An anti-C5a antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, a nucleic acid molecule according to claim 7, a vector according to claim 8, an isolated host cell according to claim 9, or a pharmaceutical composition according to claim 11, Use in the preparation of a medicament for treating a disease or condition in an individual in need thereof.

13. The disease or condition is selected from the group consisting of inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia / reperfusion associated injury, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft versus host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus disease, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.

13. The use according to claim 12.

Images