WO2023186054A1 - Anticorps reconnaissant de manière spécifique c5a et utilisation associée - Google Patents

Anticorps reconnaissant de manière spécifique c5a et utilisation associée Download PDF

Info

Publication number
WO2023186054A1
WO2023186054A1 PCT/CN2023/085301 CN2023085301W WO2023186054A1 WO 2023186054 A1 WO2023186054 A1 WO 2023186054A1 CN 2023085301 W CN2023085301 W CN 2023085301W WO 2023186054 A1 WO2023186054 A1 WO 2023186054A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
acid sequence
sequence seq
seq
antibody
Prior art date
Application number
PCT/CN2023/085301
Other languages
English (en)
Chinese (zh)
Inventor
李忠
缪刘杨
吴飞林
Original Assignee
舒泰神（北京）生物制药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 舒泰神（北京）生物制药股份有限公司 filed Critical 舒泰神（北京）生物制药股份有限公司
Priority to CN202380009755.5A priority Critical patent/CN117203230A/zh
Publication of WO2023186054A1 publication Critical patent/WO2023186054A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/215—Coronaviridae, e.g. avian infectious bronchitis virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/64—General methods for preparing the vector, for introducing it into the cell or for selecting the vector-containing host
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material

Definitions

  • the present application relates to antibodies that specifically recognize complement component 5a (C5a) and their preparation methods and uses, including uses for the treatment of autoimmune diseases, inflammation, cancer, pain, respiratory and/or transplantation-related diseases.
  • C5a complement component 5a
  • C5a is an active peptide in allergic reactions and inflammation, which is formed during the complement cascade by cleavage of complement component C5 by C5 convertase.
  • C5a stimulates mast cell degranulation, tumor necrosis factor- ⁇ (TNF- ⁇ ) and histamine release, and also recruits phagocytes to sites of infection and inflammation by increasing the expression of adhesion molecules on the surface of endothelial cells (Mollnes, T.E. et al. Blood 2002, 100, 1869–1877; Riedemann, N.C. et al. Immunity 2003, 19, 193–202).
  • C5a In some cases of pathological stimulation, such as post-transplant allograft rejection and asthma, C5a also leads to increased vascular permeability (Gueler, F. et al. J. Am. Soc. Nephrol. 2008, 19, 2302–2312; Krug ,N.et al.Am.J.Respir.Crit.Care Med.2001,164,1841-1843; Khan,M.A.et al.Proc.Natl.Acad.Sci.USA 2013,110,6061–6066).
  • Several studies have discussed C5a levels in serum. In a study by Lechner et al., the level of C5a in the control group was 8.34+2.05 (ng/mL) (Lechner, J.
  • TGF- ⁇ transforming growth factor- ⁇
  • C5a is a potent pro-inflammatory molecule that binds to a classic G protein-coupled receptor (GPCR) C5aRI (CD88) and triggers the activation of pro-inflammatory signaling pathways (Li, R. et al. FASEB J. 2013, 27, 855 –864).
  • GPCR G protein-coupled receptor
  • C5aR is widely expressed on non-myeloid cells, such as umbilical vascular endothelial cells (HUVEC), murine dermis, 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, D. L.
  • Patent application WO2011063980 discloses the antibody INab308 (InflaRx) against human C5a
  • WO2012088247 discloses the C5a antibody MEDI-7814 (MedImmune)
  • US10450370 discloses the C5a antibody BNJ383 (Alexion).
  • an isolated anti-C5a antibody comprising: (i) a V H comprising HC-CDR1, HC-CDR2 and HC as shown in the amino acid sequence of SEQ ID NO:25 -CDR3; and VL , which comprises LC-CDR1, LC-CDR2 and LC-CDR3 comprised by VL as shown in the amino acid sequence SEQ ID NO:35; (ii) VH , which comprises the amino acid sequence SEQ ID NO V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in: 26; and V L comprising LC-CDR1, LC-CDR2 and V L as shown in amino acid sequence SEQ ID NO: 36 LC-CDR3; (iii) VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 comprised by VH as shown in the amino acid sequence SEQ ID NO:27; and VL comprising the amino acid sequence SEQ ID LC
  • an isolated anti-C5a antibody comprising: (i) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising and V L ,
  • the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 12, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 20, or Variants of the V L , including substitutions of up to about 5 amino acids in its LC-CDRs;
  • V H the V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC- CDR2, which comprises the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 7, or a variant of the V H whose HC-CDRs comprise substitutions of up to about 5 amino acids; and VL , said VL comprising: LC-CDR1, which includes the amino acid sequence
  • HC-CDR2 which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 8, or a variant of the V H , which HC-CDRs include up to about 5 Substitutions of amino acids; and V L comprising: LC-CDR1 comprising the amino acid sequence SEQ ID NO: 13, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 17, and LC-CDR3 comprising the amino acid sequence SEQ ID NO: 17 Sequence SEQ ID NO: 21, or a variant of the V L containing up to about 5 amino acid substitutions in its LC-CDRs; (iv) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 9, or a variant of the V H , whose HC-CDRs include Substitutions of up to about 5 amino
  • LC-CDR2 which comprises the amino acid sequence SEQ ID NO: 18, and LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 22, or a variant of said V L , which contains up to about 5 LC-CDRs Substitution of amino acids; or (x) V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and HC-CDR3, It comprises the amino acid sequence SEQ ID NO: 11, or a variant of said V H comprising up to about 5 amino acid substitutions in its HC-CDRs; and V L comprising: LC-CDR1 comprising amino acids Sequence SEQ ID NO: 16, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 19, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 24, or a variant of the V L in which LC-CDRs Contains substitutions of up to about 5 amino acids.
  • any of the isolated anti-C5a antibodies as described above which includes: (i) VH , which includes the amino acid sequence shown in SEQ ID NO: 25 or a variant thereof, which variant is identical to SEQ
  • the amino acid sequence shown in ID NO:25 has at least about 80% sequence identity
  • VL which includes the amino acid sequence shown in SEQ ID NO:35 or a variant thereof, which variant is identical to the amino acid sequence shown in SEQ ID NO:35
  • the amino acid sequence shown has at least about 80% sequence identity
  • V H which includes the amino acid sequence shown in SEQ ID NO: 26 or a variant thereof, which variant is identical to the amino acid sequence shown in SEQ ID NO: 26
  • V L comprising the amino acid sequence set forth in SEQ ID NO: 36 or a variant thereof that has at least about 80% identity to the amino acid sequence set forth in SEQ ID NO: 36 % sequence identity
  • V H comprising the amino acid sequence set forth in SEQ ID NO:
  • the isolated anti-C5a antibody binds to human C5a with a Kd value of 0.1 pM to 1 nM.
  • an isolated anti-C5a antibody is provided that competes with any of the isolated anti-C5a antibodies described above for specific binding to C5a. 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.
  • any of the isolated anti-C5a antibodies described above, the isolated anti-C5a antibody comprises an Fc fragment.
  • the isolated anti-C5a antibody is a full-length IgG antibody.
  • the isolated anti-C5a antibody is a full-length IgG1 or IgG4 antibody.
  • the isolated anti-C5a antibody is a chimeric, fully human, or humanized antibody.
  • 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 Fv (scFv), Fv In the group consisting of fragments, dAbs, Fds, nanobodies, diabodies and linear antibodies.
  • an isolated nucleic acid molecule encoding any of the anti-C5a antibodies described above is provided.
  • a vector is provided comprising any of the nucleic acid molecules described above.
  • a host cell is provided, the host cell comprising any one of the anti-C5a antibodies described above, any one of the nucleic acid molecules described above, or any one of the vectors described above.
  • a method for preparing an anti-C5a antibody is provided, which includes: a) culturing any of the above host cells under conditions that can effectively express the anti-C5a antibody; and b) obtaining the expressed anti-C5a antibody from the host cell. C5a antibody.
  • a method of treating a disease or condition in a desired individual comprising administering to the individual an effective amount of any of the anti-C5a antibodies described above.
  • provided is the use of any of the anti-C5a antibodies described above in the preparation of a pharmaceutical composition for treating a disease or condition in a desired individual.
  • the use of any of the anti-C5a antibodies described above or a pharmaceutical composition comprising an anti-C5a antibody in the preparation of a medicament for treating a disease or condition is provided.
  • the disease or disorder is related to the C5a signaling pathway, including autoimmune diseases and/or inflammatory disorders and/or cancer and/or pain and/or respiratory and/or transplant immune dysregulation diseases or disorders .
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • SIRS inflammatory response syndrome
  • a conjugate which includes a monoclonal antibody and a coupling moiety, wherein the monoclonal antibody is any anti-C5a antibody described herein, and the coupling moiety is a radioactive Isotopes, fluorescent substances, luminescent substances, colored substances or enzymes.
  • compositions, kits and manufactured products containing any of the anti-C5a antibodies mentioned above are also provided.
  • kits or article of manufacture includes any one of the anti-C5a antibodies or conjugates described herein.
  • any of the anti-C5a antibodies or conjugates described in this application is directed to the preparation of a kit or article of manufacture for detecting the presence or level of C5a in a sample.
  • an in vitro method of detecting the presence or level of C5a in a sample comprising: a) contacting the sample with any of the methods described herein under conditions that allow the formation of a complex between the antibody and C5a. contact an anti-C5a antibody or conjugate; b) detect the formation of a complex; and c) determine the presence or level of C5a in the sample.
  • a method for diagnosing abnormalities in C5a levels comprising: a) obtaining a sample to be tested, and b) combining the sample to be tested with the method described herein under conditions that allow the formation of a complex between the antibody and C5a. Contact any of the anti-C5a antibodies or conjugates; c) detect the formation of the complex; d) determine the level of C5a in the sample to be tested; and e) determine whether the level of C5a in the sample to be tested is higher than normal Levels of C5a in the sample.
  • the sample is a serum sample or plasma sample.
  • the sample to be tested is derived from a patient in need.
  • the patient has or has not received C5a antibody treatment.
  • Figures 1A-1C are the binding curves of anti-C5a antibodies RH23, RH25, RH32, RH35, RH36, RH58, RH85, RH86, RH92, RH95 and human C5a.
  • the application provides anti-C5a antibody molecules.
  • anti-C5a antibody molecules Through a combination of hybridoma technology, scFv phage library screening, and appropriately designed biochemical and biological experiments, highly efficient antibody molecules capable of binding human C5a and inhibiting the interaction of human C5a with its receptor have been identified.
  • the results presented here demonstrate that the antibodies in this application bind human C5a or human C5a-desArg with high affinity compared to the known anti-C5a antibody INab308.
  • Anti-C5a antibodies provided by this application include, for example, full-length anti-C5a antibodies, anti-C5a single chain antibodies (scFvs), anti-C5a Fc fusion proteins, multispecific (such as bispecific) anti-C5a antibodies, anti-C5a immunoconjugates Connected objects and the like.
  • the application provides an anti-C5a antibody, the anti-C5a antibody comprising: VH , the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 2, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 6, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 12, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 20, or the V Variants of L containing up to about 5 amino acid substitutions in their LC-CDRs.
  • the application provides an anti-C5a antibody, the anti-C5a antibody comprising VH , the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 7, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L Comprising: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 12, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 20, or the V L Variants containing up to about 5 amino acid substitutions in their LC-CDRs.
  • VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 3, and HC-CDR3,
  • the application provides an anti-C5a antibody, the anti-C5a antibody comprising: VH , the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 8, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which contains the amino acid sequence SEQ ID NO: 13, LC-CDR2, which contains the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which contains the amino acid sequence SEQ ID NO: 21, or the V Variants of L containing up to about 5 amino acid substitutions in their LC-CDRs.
  • the application provides an anti-C5a antibody, the anti-C5a antibody comprising: VH , the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 9, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 22, or the V Variants of L containing up to about 5 amino acid substitutions in their LC-CDRs.
  • the application provides an anti-C5a antibody, the anti-C5a antibody comprising: VH , the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 5, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 10, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 22, or the V Variants of L containing up to about 5 amino acid substitutions in their LC-CDRs.
  • the application provides an anti-C5a antibody, the anti-C5a antibody comprising: VH , the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 7, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 22, or the V Variants of L containing up to about 5 amino acid substitutions in their LC-CDRs.
  • the application provides an anti-C5a antibody, the anti-C5a antibody comprising: VH , the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 9, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 12, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 23, or the V Variants of L containing up to about 5 amino acid substitutions in their LC-CDRs.
  • the application provides an anti-C5a antibody, the anti-C5a antibody comprising: VH , the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 7, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which contains the amino acid sequence SEQ ID NO: 15, LC-CDR2, which contains the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which contains the amino acid sequence SEQ ID NO: 22, or the V Variants of L containing up to about 5 amino acid substitutions in their LC-CDRs.
  • the application provides an anti-C5a antibody, the anti-C5a antibody comprising: VH , the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 7, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 22, or the V Variants of L containing up to about 5 amino acid substitutions in their LC-CDRs.
  • the application provides an anti-C5a antibody, the anti-C5a antibody comprising: VH , the VH comprising: HC-CDR1, which comprises the amino acid sequence SEQ ID NO: 1, HC-CDR2, which comprises the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 11, or a variant of the V H containing up to about 5 amino acid substitutions in its HC-CDRs; and V L , the V L includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 16, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 19, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: 24, or the V Variants of L containing up to about 5 amino acid substitutions in their LC-CDRs.
  • nucleic acids encoding anti-C5a antibodies are also provided.
  • compositions containing anti-C5a antibodies are also provided.
  • treatment is a method of obtaining beneficial or desired results, including clinical results.
  • said beneficial or desired clinical results Including but not limited to one or more of the following: alleviating one or more symptoms caused by the disease, reducing the severity of the disease, stabilizing the disease (e.g., preventing or delaying the progression of the disease), preventing or delaying the spread of the disease (e.g., metastasis) , prevent or delay disease recurrence, delay or slow disease progression, improve disease status, alleviate disease (partial or complete), reduce the dose of one or more other drugs required to treat the disease, delay disease progression, improve or improve quality of life , increase body weight, and/or prolong survival.
  • treatment includes reduction of pathological consequences of disease (e.g., for cancer, tumor volume). The methods of the present application contemplate any one or more aspects of these treatments .
  • antibody includes full-length antibodies and antigen-binding fragments thereof.
  • Full-length antibodies include two heavy chains and two light chains.
  • the variable regions of the light and heavy chains are responsible for antigen binding.
  • the variable regions in the two chains usually include three hypervariable loops, called complementarity determining regions (CDRs) (light chain (LC) CDRs include LC-CDR1, LC-CDR2 and LC-CDR3, heavy chain (HC) )CDRs include HC-CDR1, HC-CDR2 and HC-CDR3).
  • CDRs complementarity determining regions
  • the CDR boundaries of the antibodies or antigen-binding fragments disclosed herein may be defined or identified by the Kabat, Chothia or Al-Lazikani conventions (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 flanking segments called framework regions (FRs), which are more conserved than the CDR regions and form a scaffold supporting the hypervariable loops.
  • FRs flanking segments
  • the constant regions of the heavy and light chains are not involved in antigen binding but exhibit a variety of effector functions.
  • Antibodies are classified based on the amino acid sequence of their heavy chain constant region.
  • the five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, characterized by heavy chains of the alpha, delta, epsilon, gamma, and mu types, respectively.
  • major antibody classes are divided into subclasses, such as IgG1 ( ⁇ 1 heavy chain), IgG2 ( ⁇ 2 heavy chain), IgG3 ( ⁇ 3 heavy chain), IgG4 ( ⁇ 4 heavy chain), IgA1 ( ⁇ 1 heavy chain), or IgA2 ( ⁇ 2 heavy chain).
  • antigen-binding fragment includes antibody fragments, e.g., diabodies, Fab, Fab', F(ab') 2 , Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv) 2.
  • Bispecific dsFv (dsFv-dsFv'), disulfide bond-stabilized diabody (ds diabody), single-chain Fv (scFv), scFv dimer (bivalent diabody), Multispecific antibodies consisting of antibody fragments containing one or more CDRs, single domain antibodies, nanobodies, domain antibodies, bivalent domain antibodies, or any other antibody fragment capable of binding to an antigen but not containing a complete antibody structure .
  • the antigen-binding fragment is capable of binding to the same antigen as the parent antibody or parent antibody fragment (eg, parent scFv).
  • Antigen-binding fragments also include fusion proteins containing the above-described antibody fragments.
  • the antigen-binding fragment may include one or more CDRs from a specific human antibody grafted to framework regions from one or more different human antibodies.
  • epitope refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions exhibit competitive binding to an antigen, they may bind to the same epitope on the antigen.
  • a first antibody inhibits binding of a second antibody to a C5a target by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%) at equimolar concentrations , 95%, 98% or 99%), the first antibody "competes" with the second antibody for binding to the C5a target, and vice versa.
  • PCT publication WO 03/48731 describes a cross-competition based high-throughput antibody "epitope classification" approach.
  • the terms “specifically bind,” “specifically recognize,” or “specific for” refer to a measurable and reproducible interaction, e.g., binding of an antibody to a target can The presence of the target in a heterogeneous population of molecules, including biomolecules, is determined.
  • the ability of an antibody to specifically recognize a target means that the antibody binds to the target with higher affinity, avidity, easier and/or longer duration than to other targets.
  • an antibody that specifically recognizes an antigen reacts with one or more epitopes of the antigen with a binding affinity that is at least 10 times greater than its binding affinity to other targets.
  • an "isolated" anti-C5a antibody is an anti-C5a antibody that (1) is not related to a naturally occurring protein, (2) does not contain other proteins from the same source, and (3) is produced from a different species Expressed by cells of the genus, or (4) does not exist in nature.
  • isolated nucleic acid refers to nucleic acids of genomic, cDNA or synthetic origin, or combinations thereof. Depending on its source, the “isolated nucleic acid” refers to (1) not related to all or part of the polynucleotides in the "isolated nucleic acid” found in nature, (2) may not be related to polynucleotides that are not associated with it in the natural state. The nucleotides are operably linked, or (3) do not occur in nature as part of a longer sequence.
  • CDR complementarity determining region
  • chimeric antibody means that a portion of the heavy chain and/or light chain is identical or homologous to the corresponding sequence in an antibody from a specific species or belonging to a specific antibody class or subclass, and this chain(s) Antibodies whose remainder are identical to or homologous to corresponding sequences in antibodies from another genus or belonging to other antibody classes or subclasses, as well as fragments of such antibodies, as long as they have the biological activity in this application ( See U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).
  • Fv is the smallest antibody fragment that contains complete antigen recognition and binding sites. This fragment is a dimer formed by a heavy chain variable domain and a light chain variable domain tightly non-covalently linked. The folding of these two domains results in 6 hypervariable loops (3 loops each in the light chain and heavy chain), which provide the antibody with the amino acid residues for binding to the antigen and confer a binding relationship between the antibody and the antigen. Binding specificity. However, even a single variable domain (or half of an Fv fragment, which contains only the 3 CDRs specific for the antigen) has the ability to recognize and bind the antigen, albeit with lower affinity than the complete binding site.
  • the scFv polypeptide further includes a linker polypeptide between the VH and VL domains that allows the scFv to form an ideal structure for antigen binding.
  • diabody is a small antibody fragment prepared by using a short linker (for example, 5 to 10 residues) between the V H and V L domains to construct an scFv fragment (see the previous paragraph). This allows the variable domains to pair inter-chain rather than intra-chain, producing a bivalent fragment, that is, a fragment with two antigen-binding sites.
  • Bispecific diabodies are heterodimers of two "cross-over" scFv fragments, in which the VH and VL domains of the two antibodies are located on different polypeptide chains.
  • Diabodies are fully described in EP 404,097; WO 93/11161; Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).
  • Humanized forms of non-human (eg, rodent) antibodies are chimeric antibodies, which include minimal sequence from the non-human antibody.
  • humanized antibodies are human immunoglobulins (recipient antibodies) in which the hypervariable region (HVR) residues of the receptor antibody are modified from a non-human species such as mouse, rat, rabbit or Replacement of hypervariable region residues that are non-human mammalian and possess the desired antibody specificity, affinity and performance (donor antibody).
  • HVR hypervariable region residues of the receptor antibody
  • donor antibody residues in the human immunoglobulin framework region are replaced with corresponding non-human residues.
  • humanized antibodies may include residues that are not present in either the recipient antibody or the donor antibody. These modifications can further improve antibody performance.
  • a humanized antibody will contain substantially all, at least one, and usually two variable domains in which all or substantially all of the hypervariable loops correspond to hypervariable loops of a non-human immunoglobulin, and all or Essentially all framework regions are human immunoglobulin sequences.
  • the human antibody optionally also includes at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Percent amino acid sequence identity or “homology” of the polypeptide and antibody sequences identified herein is defined as follows: Sequence comparisons are made where conservative substitutions are considered part of the sequence identity, and the candidate sequence is compared with the candidate sequence to be Compares the percentage of identical amino acid residues in a polypeptide sequence. Percent amino acid sequence identity can be determined by a variety of alignment 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. One skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms required to maximize alignment over the full length of the sequences being compared.
  • Fc receptor or "FcR” is used to describe a receptor that binds to the Fc region of an antibody.
  • the FcR described herein is an FcR that binds an IgG antibody, a gamma receptor, including receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and agonist variants of these receptors. Change splicing form.
  • Fc ⁇ RII receptors include Fc ⁇ RIIA (“activating receptor”) and Fc ⁇ RIIB (“inhibitory receptor”), which have similar amino acid sequences and differ mainly in the cytoplasmic domain.
  • the cytoplasmic domain of activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine activation motif (ITAM).
  • the cytoplasmic domain of the inhibitory receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine inhibitory motif (ITIM) (see M.in Annu. Rev. Immunol. 15:203-234 (1997)).
  • ITAM immunoreceptor tyrosine activation motif
  • ITIM immunoreceptor tyrosine inhibitory motif
  • FcR in this application covers other types of FcRs, including FcRs identified in the future.
  • FcR also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgGs to the neonate (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994) )).
  • FcRn refers to the neonatal Fc receptor (FcRn).
  • FcRn is structurally similar to the major histocompatibility complex (MHC) and consists of an ⁇ chain non-covalently bound to ⁇ 2 microglobulin.
  • MHC major histocompatibility complex
  • FcRn plays an important role in the passive transport of immunoglobulin IgGs from mother to newborn and in regulating serum IgG levels.
  • FcRn serves as a rescue receptor that binds and transports endocytosed IgG in an intact form within and between cells and protects them from default degradation pathways.
  • the "CH1 domain" of the human IgG heavy chain constant region generally extends from amino acid 118 to amino acid 215 (EU numbering system).
  • the "hinge region” is generally defined as extending from position Glu 216 to position Pro 230 of human IgG1 (Burton, Molec. Immunol. 22:161-206 (1985)). By placing the first and last cysteine residues that form the inter-heavy chain disulfide bond after the same position as IgG1, the hinge regions of other IgG isotypes can be aligned with the IgG1 sequence.
  • the "CH2 domain" of the human IgG Fc region usually extends from amino acid 231 to amino acid 340.
  • the unique feature of the CH2 domain is that it does not pair closely with another region, but instead has two N-terminal linked branched sugar chains inserted between the two CH2 domains of the intact natural IgG molecule. It is speculated that sugars may serve as a surrogate for domain-to-domain pairing, helping to keep the CH2 domain stable.
  • the "CH3" domain includes the region extending from the C-terminal residues within the Fc region to the CH2 domain (from amino acid 341 to the C-terminus of the antibody sequence, usually amino acid residue 446 or 447 of IgG).
  • a “functional Fc fragment” has the "effector function” possessed by a native Fc region sequence.
  • exemplary “effector functions” include Clq binding; complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors ( Such as B cell receptor; BCR), etc.
  • effector functions typically require the binding of an Fc region to a binding domain (eg, an antibody variable region) and can be assessed using a variety of experimental methods well known in the art.
  • Antibodies with IgG Fc variants that have "altered" FcR binding affinity or ADCC activity have increased or decreased FcR binding activity and/or ADCC activity compared to the 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., a lower apparent Kd or IC50 value) to at least one FcR compared to the parent polypeptide or a polypeptide comprising a native IgG Fc sequence. ).
  • the binding capacity is enhanced 3-fold, such as 5, 10, 25, 50, 60, 100, 150, 200, even up to 500-fold or a 25% to 1000% increase in binding capacity compared to the parent polypeptide.
  • An Fc variant exhibits "reduced binding" to an FcR, having a lower affinity (eg, a higher apparent Kd or IC50 value) for at least one FcR compared to the parent polypeptide. Its binding capacity is reduced by 40% or more compared to the parent polypeptide.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • cytotoxic cells e.g., natural killer cells (NK), neutrophils
  • FcRs Fc receptors
  • Antibodies “arm” cytotoxic cells and are required for this killing.
  • NK cells only express Fc ⁇ RIII
  • monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • FcR FcR on hematopoietic cells
  • Table 3 The expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991).
  • an in vitro ADCC assay can be performed, as described in U.S. Patent No. 5,500,362 or 5,821,337. Effector cells suitable for such experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK).
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • the ADCC activity of the target molecule can also be assessed in vivo, for example in an animal model as disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).
  • the antibody polypeptide is essentially the same in quantity as the wild-type IgG Fc polypeptide (or parent polypeptide) during the experiment, it can more effectively mediate ADCC both in vitro and in vivo.
  • Such variants are generally identified using any in vitro ADCC assay known in the art, such as assays or methods for identifying ADCC activity, such as in animal models and the like. In some embodiments, such variants mediate ADCC 5- to 100-fold, for example, 25- to 50-fold more efficiently than wild-type Fc (or the parent polypeptide).
  • “Complement-dependent cytotoxicity” or “CDC” refers to the lysis of target cells in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (subclasses with appropriate structures) that bind cognate antigens.
  • C1q the first component of the complement system
  • CDC experiments can be performed as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996). Polypeptide variants with altered Fc region amino acid sequences and increased or decreased Clq binding capacity are described in US Patent No. 6,194,551 Bl and WO99/51642. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al. J. Immunol. 164:4178-4184 (2000).
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerates of each other and encode the same amino acid sequence. Nucleotide sequences encoding proteins or RNA may also include introns, for example, nucleotide sequences encoding proteins may include introns in some forms.
  • operably linked refers to a functional linkage between a regulatory sequence and a heterologous nucleotide sequence, thereby allowing expression of the latter.
  • a first nucleotide sequence is operably linked to a second nucleotide sequence when the first nucleotide sequence is in a functional relationship with the second nucleotide sequence.
  • a promoter is operably linked to a coding sequence if it affects the transcription or expression of the coding sequence.
  • operably linked DNA sequences are contiguous and, if necessary, two protein-coding regions can be joined in the same reading frame.
  • “Homology” refers to sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. If the same position of two compared sequences contains the same base or amino acid monomer subunit, for example, the same position of two DNA molecules both contains adenine, then the two DNA molecules are homologous at that position.
  • the percent homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the total number of positions multiplied by 100. For example, if 6 out of 10 positions in two sequences match or are homologous, the two sequences are 60% homologous. For example, the DNA sequences ATTGCC and TATGGC have 50% homology. Generally speaking, when comparing two sequences, the comparison is performed with the purpose of obtaining maximum homology.
  • an “effective amount” of an anti-C5a antibody or composition disclosed herein is an amount sufficient to achieve a specified purpose.
  • An “effective amount” can be determined empirically and by methods known to be relevant to the stated purpose.
  • a therapeutically effective amount refers to an amount of an anti-C5a antibody or composition thereof disclosed herein that is effective in treating a disease or condition in an individual.
  • a therapeutically effective amount of an anti-C5a antibody or composition thereof is one that reduces the number of cancer cells; reduces the size or weight of the tumor; inhibits (i.e., slows or preferably stops to a certain extent) the impact of tumor cells on surrounding cells. Invasion of organs; inhibition (i.e., slowing down or preferably stopping to a certain extent) tumor metastasis; inhibiting tumor growth to a certain extent, and/or alleviating one or more symptoms associated with cancer to a certain extent.
  • a therapeutically effective amount refers to an amount capable of prolonging the survival of a patient. In some embodiments, a therapeutically effective amount refers to an amount capable of improving progression-free survival of a patient.
  • pharmaceutically acceptable refers to a material that has no biological activity or other undesirable properties, e.g., the material can be incorporated into a pharmaceutical composition administered to a patient, and Does not cause significant adverse biological reactions or interact in a deleterious manner with any other components contained in the composition.
  • Pharmaceutically acceptable carriers or excipients preferably meet required standards for toxicological or manufacturing testing and/or are included in the Inactive Ingredient Guidelines prepared by the U.S. Food and Drug Administration.
  • Embodiments of the application described herein should be understood to include embodiments “consisting of” and/or “consisting essentially of.”
  • references herein to "about” a value or parameter include (and describe) variations on the value or parameter itself. For example, descriptions referring to “about X” include descriptions of "X”.
  • reference to "not" a value or parameter generally means and describes “other than” a value or parameter.
  • the method cannot be used to treat type X cancer, meaning the method is typically used to treat other types of cancer besides type X cancer.
  • the application provides anti-C5a antibodies that specifically bind C5a.
  • anti-C5a antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibody molecules comprising heavy chain and/or light chain CDRs as described herein.
  • the application provides isolated antibodies that bind C5a.
  • Contemplated anti-C5a antibodies include, for example, full-length anti-C5a antibodies (e.g., full-length IgG1 or IgG4), anti-C5a single chain antibodies, anti-C5a Fc fusion proteins, multispecific (e.g., bispecific) anti-C5a antibodies, anti-C5a Immunoconjugates, and the like.
  • the anti-C5a antibody is a full-length antibody (eg, full-length IgG1 or IgG4) or an antigen-binding fragment thereof that specifically binds C5a.
  • the anti-C5a antibody is Fab, Fab', F(ab)' 2 , Fab'-SH, single chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, diabody (diabody) or linear antibody.
  • an antibody that specifically binds to C5a means that the affinity of the antibody for binding to C5a is at least 10 times greater than the binding affinity for the non-target (including, for example, 10, 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 times).
  • non-target refers to an antigen that is not C5a.
  • Binding affinity can be determined by methods known in the art, such as ELISA, fluorescence-activated cell sorting (FACS) analysis or radioimmunoprecipitation analysis (RIA).
  • the Kd value can be determined by methods known in the art, such as surface plasmon resonance (SPR) technology or biolayer interference (BLI) technology.
  • non-human anti-C5a antibodies comprising human sequences are discussed broadly herein (eg, human heavy and light chain variable domains comprising human CDR sequences), non-human anti-C5a antibodies are also contemplated.
  • non-human anti-C5a antibodies include the human CDR sequences and non-human framework sequences of the anti-C5a antibodies described herein.
  • the non-human framework sequences include any for use as described herein.
  • non-human anti-C5a antibodies include anti-C5a antibodies generated by grafting one or more human CDR sequences described herein into non-human framework regions (eg, murine or chicken framework region sequences).
  • the complete amino acid sequence of an exemplary human C5a includes or consists of the amino acid sequence shown in SEQ ID NO: 49.
  • the anti-C5a antibodies described herein specifically recognize an epitope in human C5a. In some embodiments, the anti-C5a antibody cross-reacts with C5a of species other than human. In some embodiments, the anti-C5a antibody is fully specific for human C5a and does not cross-react with other non-human species.
  • the anti-C5a antibody cross-reacts with at least one allelic variant of the C5a protein (or fragment thereof).
  • the allelic variant has up to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) compared to the naturally occurring C5a protein (or fragment thereof). , 15, 20, 25 or 30) amino acid substitutions (eg, conservative substitutions).
  • the anti-C5a antibody does not cross-react with any allelic variant of the C5a protein (or fragment thereof).
  • the anti-C5a antibody cross-reacts with at least one interspecies variant of the C5a protein.
  • the C5a protein (or fragment thereof) is human C5a
  • the interspecies variant of the C5a protein (or fragment thereof) is a variant in cynomolgus monkey.
  • the anti-C5a antibody does not cross-react with any interspecies variant of the C5a protein.
  • the anti-C5a antibody comprises an antibody heavy chain constant region and an antibody light chain constant region.
  • the anti-C5a antibody comprises an IgGl type heavy chain constant region.
  • the anti-C5a antibody comprises an IgG2-type heavy chain constant region.
  • the anti-C5a antibody comprises an IgG3 heavy chain constant region.
  • the anti-C5a antibody comprises an IgG4 type heavy chain constant region.
  • the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 45.
  • the heavy chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 46.
  • the anti-C5a antibody comprises a kappa light chain constant region.
  • the light chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 47.
  • the anti-C5a antibody comprises a lambda light chain constant region.
  • the light chain constant region comprises (including consists of or consists essentially of) the amino acid sequence SEQ ID NO: 48.
  • the anti-C5a antibody comprises an antibody heavy chain variable domain and an antibody light chain variable domain.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 2, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 6, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 12, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 20, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-C5a antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 2, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:6; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:12, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:20.
  • the anti-C5a antibody comprises a V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 25; and a V L comprising VL as shown in the amino acid sequence SEQ ID NO:35 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 25 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 25 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 35 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 35.
  • the anti-C5a antibody comprises a VH comprising the amino acid sequence SEQ ID NO:25, and a VL comprising the amino acid sequence SEQ ID NO:35.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, HC -CDR3, which comprises the amino acid sequence SEQ ID NO:7, or a variant of said VH , whose HC-CDRs comprise up to about 5 amino acid substitutions; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 12, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 20, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-C5a antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:7; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:12, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:20.
  • the anti-C5a antibody comprises a VH comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:26; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:36 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 26 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 26 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 36 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 36.
  • the anti-C5a antibody comprises a VH comprising the amino acid sequence SEQ ID NO:26, and a VL comprising the amino acid sequence SEQ ID NO:36.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 8, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 13, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 21, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:8; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:13, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:21.
  • the anti-C5a antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:27; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:37 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 27 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 27 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 37 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 37.
  • the anti-C5a antibody comprises a VH comprising the amino acid sequence SEQ ID NO:27, and a VL comprising the amino acid sequence SEQ ID NO:37.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 9, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 14, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 22, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:9; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:14, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:22.
  • the anti-C5a antibody comprises a V H comprising HC-CDR1, HC-CDR2 and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO : 28; and a V L comprising VL as shown in the amino acid sequence SEQ ID NO:38 contains LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 28 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 28 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 38 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 38.
  • the anti-C5a antibody comprises a VH comprising the amino acid sequence SEQ ID NO:28, and a VL comprising the amino acid sequence SEQ ID NO:38.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 5, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 10, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 14, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 18, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 22, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 5, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 10; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 14, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 18, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:22.
  • the anti-C5a antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:29; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:39 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 29 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 29 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 39 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 39.
  • the anti-C5a antibody comprises a VH comprising the amino acid sequence SEQ ID NO:29, and a VL comprising the amino acid sequence SEQ ID NO:39.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 7, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 14, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 18, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 22, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-C5a antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:7; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:14, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 18, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:22.
  • the anti-C5a antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:30; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO:40 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 30 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 30 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 40 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 40.
  • the anti-C5a antibody comprises a VH comprising the amino acid sequence SEQ ID NO:30, and a VL comprising the amino acid sequence SEQ ID NO:40.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 9, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 12, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 23, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:9; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:12, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:23.
  • the anti-C5a antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence SEQ ID NO:31 of VH ; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 41 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 31 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 41 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 41.
  • the anti-C5a antibody comprises a VH comprising the amino acid sequence SEQ ID NO:31, and a VL comprising the amino acid sequence SEQ ID NO:41.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, HC -CDR3, which comprises the amino acid sequence SEQ ID NO:7, or a variant of said VH , whose HC-CDRs comprise up to about 5 amino acid substitutions; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 15, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 22, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-C5a antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:7; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:15, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 17, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:22.
  • the anti-C5a antibody comprises a V H comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence of SEQ ID NO: 32; and a V L comprising VL as shown in the amino acid sequence SEQ ID NO: 42 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 32 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 32 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and V L comprising the amino acid sequence SEQ ID NO: 42 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 42.
  • the anti-C5a antibody comprises a VH comprising the amino acid sequence SEQ ID NO:32, and a VL comprising the amino acid sequence SEQ ID NO:42.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, HC -CDR3, which comprises the amino acid sequence SEQ ID NO:7, or a variant of said VH , whose HC-CDRs comprise up to about 5 amino acid substitutions; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 14, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 18, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 22, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO:7; and VL , which VL comprises: LC-CDR1, which comprises the amino acid sequence SEQ ID NO:14, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 18, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:22.
  • the anti-C5a antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as set forth in the amino acid sequence SEQ ID NO:33 of VH ; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 43 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 33 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 33 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 43 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 43.
  • the anti-C5a antibody comprises a VH comprising the amino acid sequence SEQ ID NO:33, and a VL comprising the amino acid sequence SEQ ID NO:43.
  • the anti-C5a antibody comprises a V H comprising: HC- CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, HC -CDR3, which comprises the amino acid sequence SEQ ID NO: 11, or a variant of said VH , comprising up to about 5 amino acid substitutions in its HC-CDRs; and VL , said VL comprising: LC-CDR1, It comprises the amino acid sequence SEQ ID NO: 16, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 19, LC-CDR3, which comprises the amino acid sequence SEQ ID NO: 24, or a variant of said V L , whose LC- The CDRs contain substitutions of up to about 5 amino acids.
  • the anti-C5a antibody comprises a VH comprising: HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which comprises the amino acid sequence SEQ ID NO: 11; and VL, which VL comprises : LC-CDR1, which comprises the amino acid sequence SEQ ID NO: 16, LC-CDR2, which comprises the amino acid sequence SEQ ID NO: 19, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:24.
  • the anti-C5a antibody comprises a VH comprising HC-CDR1, HC-CDR2, and HC-CDR3 as shown in the amino acid sequence of SEQ ID NO:34; and a VL comprising VL as shown in the amino acid sequence SEQ ID NO: 44 includes LC-CDR1, LC-CDR2 and LC-CDR3.
  • the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 34 or a variant thereof that is at least about 80% identical to the amino acid sequence SEQ ID NO: 34 (e.g., at least 80%, 85%, 90%, 95%, 96% , 97%, 98%, or 99%) sequence identity; and VL comprising the amino acid sequence SEQ ID NO: 44 or a variant thereof A variant having at least about 80% (eg, at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO: 44.
  • the anti-C5a antibody comprises a VH comprising the amino acid sequence SEQ ID NO:34, and a VL comprising the amino acid sequence SEQ ID NO:44.
  • amino acid substitutions are limited to the "exemplary substitutions” set forth in Table 4 herein. In some embodiments, amino acid substitutions are limited to the "preferred substitutions” set forth in Table 4 herein.
  • functional epitopes can be resolved by combined alanine scanning methods.
  • combinatorial alanine scanning techniques can be used to identify amino acids in the C5a protein that are necessary for interaction with anti-C5a antibodies.
  • the epitope is conformational and the crystal structure of an anti-C5a antibody bound to the C5a protein can be used to identify the epitope.
  • the application provides antibodies that compete for binding to C5a with any of the anti-C5a antibodies described herein.
  • antibodies are provided that are capable of binding to an epitope on C5a competitively with any of the anti-C5a antibodies described herein.
  • an anti-C5a antibody is provided that binds to the same epitope as an anti-C5a antibody molecule comprising VH and VL , wherein the VH comprises the amino acid set forth in any of SEQ ID NOs: 25-34 sequence, and the V L comprises the amino acid sequence shown in any one of SEQ ID NOs: 35-44.
  • an anti-C5a antibody that competes for binding to C5a with an anti-C5a antibody comprising VH and VL , wherein the VH comprises the amino acid sequence set forth in any one of SEQ ID NOs: 25-34 , and the V L includes the amino acid sequence shown in any one of SEQ ID NOs: 35-44.
  • competition experiments can be used to identify monoclonal antibodies that compete with the anti-C5a antibodies described herein for binding to C5a. Competition experiments can determine whether two antibodies bind the same epitope by identifying the same or spatially overlapping epitope or by one antibody competitively inhibiting the binding of another antibody to the antigen. In certain embodiments, such competing antibodies bind the same epitope as the antibodies described herein.
  • Some exemplary competition experiments include, but are not limited to, conventional experiments as mentioned in Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.).
  • each antibody is said to bind the same epitope if it blocks 50% or more of the binding of the other antibody.
  • the antibody that competes with an anti-C5a antibody described herein is a chimeric antibody, a humanized antibody, or a fully human antibody.
  • Exemplary anti-C5a antibody sequences are shown in Table 2 and Table 3, where CDR numbering is performed according to Kabat definition. Those skilled in the art will recognize that there are a variety of known algorithms for predicting the location of CDRs and defining antibody light and heavy chain variable regions. Antibodies containing the CDRs, VH and/or VL sequences of antibodies as described herein, but based on prediction algorithms other than those exemplified in the table below are also within the scope of the present application.
  • Complement component 5a (C5a) was first described as a cleavage product of complement factor 5 (C5) with chemotactic and anaphylatoxin properties (Shin et al., 1968).
  • the precursor of C5a, C5 protein contains 1676 amino acids, has a molecular weight of 188 kDa, and its gene is located at 9q33–9q34 (Wetsel et al., 1988).
  • Human C5a is an approximately 11 kDa glycoprotein containing 74 amino acids produced by C5 convertase cleavage of the ⁇ chain of C5, but N-linked glycosylation is not essential for its function.
  • the properties of C5a suggest that it is an important component of the innate immune response, but existing evidence suggests that C5a may also play a role in adaptive immunity (Kohl, 2006).
  • C5a is not necessarily a trigger of inflammatory diseases, excessive or uncontrolled C5a is produced in many inflammatory diseases, suggesting that C5a can promote and maintain inflammatory responses (Guo and Ward, 2005).
  • C5a has four antiparallel ⁇ -helices connected by peptide loops and is made more stable by three key disulfide bonds (Monk et al., 2007). Mutagenesis and antibody studies have identified several essential residues that provide interaction with the receptor (reviewed by Monk et al., 2007).
  • the complement cascade can be activated through four pathways: the classical pathway, the alternative pathway, the mannan-binding lectin pathway (MBL) or the exogenous protease pathway (Ricklin and Lambris, 2007).
  • the classical pathway and the lectin pathway are activated by recognition of antibody complexes formed on the surface of pathogens and mannose on bacterial surfaces, respectively. Both pathways result in cleavage of C4 by serine proteases, forming C4a and C4b. After C4b binds to C2, it leads to the generation of C2a under the action of protease. C4b and C2a form the C3 convertase (C4b2a) in the classical pathway.
  • the alternative pathway can be activated by foreign body surfaces or "slow transport", resulting in spontaneous hydrolysis of C3, which subsequently binds to factor B and forms C3 convertase (C3bBb) in the alternative pathway, which continues to maintain low levels Activation of the complement cascade, thereby ensuring a rapid response to invading pathogens (Ricklin and Lambris, 2007).
  • the above three pathways can form C3 convertase, and C3 convertase further cleaves the C3 protein to form C3a and C3b.
  • C3b can promote cell recognition of pathogen surfaces and clearance of pathogens, and can also form C5 convertase (C4b2aC3b or C3bBbC3b) with C3 convertase (C4b2a or C3bBb), and then C5 convertase further cleaves C5 to produce C5a and C5b.
  • C5b proceeds to initiate the assembly of the membrane attack complex (MAC; C5b-9).
  • the complement cascade is tightly regulated by a series of soluble membrane-bound regulatory proteins that prevent complement activation products from targeting host tissues (Ricklin and Lambris, 2007). However, this control can be circumvented through some exogenous pathways.
  • thrombin can directly cleave C3 and C5, causing activation of the complement system (Amara et al., 2008).
  • activated neutrophils and alveolar macrophages can cleave C5 to produce C5a through secreted serine proteases (Amara et al., 2008).
  • Carboxypeptidase on the plasma and cell surface can remove the arginine at the C-terminus of the protein, so the C5a produced by C5 cleavage can be rapidly metabolized by it to form C5adesArg (Bokisch and Muller-Eberhard, 1970).
  • C5adesArg Compared with C5a, C5adesArg has reduced potency, resulting in reduced binding affinity to the classical C5a receptor CD88 (Higginbottom et al., 2005). C5a and C5adesArg can be cleared rapidly in the body. About 50% of C5a and C5adesArg are cleared from the circulation within 2-3 minutes. In addition, some C5a is mediated after binding to CD88 on leukocytes and other cells (Oppermann and Gotze, 1994). However, a second receptor, C5a-like receptor 2 (C5L2), can more efficiently remove complement fragments by rapidly internalizing C5a/C5adesArg and, in particular, C5adesArg, allowing it to be retained and degraded in certain cell types (Scola (2009). In contrast, CD88-expressing cells internalize C5a and release a higher proportion of C5a in an undegraded, presumably active form. Plasma C5a can also be cleared by the liver (Chenoweth and Goodman , 1983).
  • C5a binds CD88 and C5L2 with similarly high affinity.
  • the affinity of C5adesArg for C5L2 is similar to that of C5a ( 12nM), but has 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 cluster with other chemokine receptor genes such as the formyl peptide receptor family and bradykinin receptors. 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 and physically separate sites. The first "recognition” site is located at the extracellular amino terminus (N-terminus) of the receptor, which binds to the C5a N-terminus and disulfide-linked core. The second “activation” site is formed by the transmembrane domain of the receptor, which binds to the C-terminus of C5a and leads to the generation of a specific signaling pathway mediated by the receptor-coupled G protein (Monk et al., 2007 ).
  • C5L2 Cell types that express C5L2 are broadly the same as those that express CD88, such as neutrophils, monocytes, lymphocytes, macrophages, as well as non-myeloid cells such as vascular smooth muscle cells and cells of tissue origin such as the adrenal gland. , heart, liver, lung, spleen and brain), but under non-inflammatory conditions, the expression level of C5L2 is significantly lower than that of CD88 (Gao et al., 2005). The function of C5L2 is unknown. Some experimental data suggest that C5L2 may serve as a decoy receptor without signal transduction function.
  • C5L2 has anti-inflammatory functions, possibly by reducing the amount of C5a that can bind to CD88.
  • C5L2 can act as a positive regulator that is critical for C5a and C3a signaling, at least in mice (Chen et al., 2007).
  • C5L2 was found to be critical for promoting C5a signaling in neutrophils, macrophages, and fibroblasts, whereas lack of C5L2 in vivo resulted in ovalbumin-induced airway hyperresponsiveness and inflammation (Chen et al. , 2007).
  • a mouse model of “late” sepsis (100% lethality) only simultaneous blockade of C5L2 and CD88 was protective (Rittirsch et al., 2008).
  • the anti-C5a antibody is a full-length anti-C5a antibody.
  • the full-length anti-C5a antibody is IgA, IgD, IgE, IgG, or IgM.
  • the full-length anti-C5a antibody comprises an IgG constant region, such as that of IgG1, IgG2, IgG3, IgG4, or a variant thereof.
  • the full-length anti-C5a antibody comprises a lambda light chain constant region.
  • the full-length anti-C5a antibody comprises a kappa light chain constant region.
  • the full-length anti-C5a antibody is a full-length human anti-C5a antibody. In some embodiments, the full-length anti-C5a antibody comprises mouse immunoglobulin Fc sequence. In some embodiments, the full-length anti-C5a antibody comprises an Fc sequence that has been altered or otherwise altered such that it has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. Effector functions of (CDC).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • a full-length anti-C5a antibody comprising an IgG1 constant region that specifically binds to C5a.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG2 constant region is provided, the anti-C5a antibody specifically binding to C5a.
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a full-length anti-C5a antibody comprising an IgG3 constant region is provided, the anti-C5a antibody specifically binding to C5a.
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region is provided, the anti-C5a antibody specifically binding to C5a.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, which variant includes substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids; HC-CDR2, which includes SEQ ID NOs: The amino acid sequence shown in any one of 2-5, or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC-CDR3, which comprises SEQ ID NOs: 6 - the amino acid sequence shown in any one of 11 or a variant thereof, the variant comprising a substitution of up to about 3 (eg 1, 2 or 3) amino acids; and b) a light chain variable domain, the light chain variable domain
  • the chain variable domain includes: LC-CDR1, which includes the
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG2 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, which variant includes substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids; HC-CDR2, which includes SEQ ID NOs: The amino acid sequence shown in any one of 2-5, or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC-CDR3, which comprises SEQ ID NOs: 6 - the amino acid sequence shown in any one of 11 or a variant thereof, the variant comprising a substitution of up to about 3 (eg 1, 2 or 3) amino acids; and b) a light chain variable domain, the light chain variable domain
  • the chain variable domain includes: LC-CDR1, which includes the
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a full-length anti-C5a antibody comprising an IgG3 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, which variant includes a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids, HC-CDR2, which includes SEQ ID NOs: The amino acid sequence shown in any one of 2-5, or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC-CDR3, which comprises SEQ ID NOs: 6 - the amino acid sequence shown in any one of 11 or a variant thereof, the variant comprising a substitution of up to about 3 (eg 1, 2 or 3) amino acids; and b) a light chain variable domain, the light chain variable domain
  • the chain variable domain includes: LC-CDR1, which includes
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence shown in SEQ ID NO: 1 or a variant thereof, which variant includes substitutions of up to about 3 (e.g., 1, 2 or 3) amino acids; HC-CDR2, which includes SEQ ID NOs: The amino acid sequence shown in any one of 2-5, or a variant thereof, the variant comprising a substitution of up to about 3 (e.g., 1, 2 or 3) amino acids; and HC-CDR3, which comprises SEQ ID NOs: 6 - the amino acid sequence shown in any one of 11 or a variant thereof, the variant comprising a substitution of up to about 3 (eg 1, 2 or 3) amino acids; and b) a light chain variable domain, the light chain variable domain
  • the chain variable domain includes: LC-CDR1, which includes the
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence shown in SEQ ID NO:1, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs:2-5, and HC-CDR3, which includes SEQ ID NOs:6-11 The amino acid sequence shown in any one of them, or a variant of the heavy chain variable domain, the HC-CDR sequence of which contains at most about 5 (such as 1, 2, 3, 4 or 5) amino acid substitutions; and b) a light chain variable domain comprising: LC-CDR1 comprising the amino acid sequence shown in any one of SEQ ID NOs: 12-16, LC-CDR2 comprising SEQ ID The amino acid sequence shown in any one of NOs: 17-19, and LC-CDR3, which includes the amino acid sequence shown in any one
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region wherein the anti-C5a antibody comprises a) a heavy chain variable domain comprising: HC-CDR1, It includes the amino acid sequence shown in SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence shown in any of SEQ ID NOs: 2-5, and HC-CDR3, which includes the amino acid sequence shown in any of SEQ ID NOs: 6-11 Any of the amino acid sequences shown, or a variant of the heavy chain variable domain, comprising up to about 5 (e.g., 1, 2, 3, 4 or 5) amino acid substitutions in the HC-CDR sequence; and b) Light chain variable domain, the light chain variable domain comprising: LC-CDR1, comprising the amino acid sequence shown in any one of SEQ ID NOs: 12-16, LC-CDR2, comprising SEQ ID NOs: The amino acid sequence shown in any one of 17-19, and LC-CDR3, which includes the amino acid sequence shown
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence shown in SEQ ID NO:1, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs:2-5, and HC-CDR3, which includes SEQ ID NOs:6-11 The amino acid sequence shown in any one of; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 12-16 , LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 17-19, and LC-CDR3, which includes the amino acid sequence shown in any one of SEQ ID NOs: 20-24.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence shown in SEQ ID NO:1, HC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs:2-5, and HC-CDR3, which includes SEQ ID NOs:6-11 The amino acid sequence shown in any one of; and b) a light chain variable domain, the light chain variable domain comprising: LC-CDR1, which includes the amino acid sequence shown in any one of SEQ ID NOs: 12-16 , LC-CDR2, which includes the amino acid sequence shown in any one of SEQ ID NOs: 17-19, and LC-CDR3, which includes the amino acid sequence shown in any one of SEQ ID NOs: 20-24.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 2, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 6; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 12, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:20.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 12, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:20.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 8; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 13, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty one.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 9; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty two.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 5, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 10; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty two.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty two.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 9; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 12, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty three.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 15, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty two.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty two.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 11; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 16, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 19, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty four.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 2, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 6; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 12, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:20.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 12, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO:20.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 8; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 13, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty one.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 9; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty two.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 5, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 10; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty two.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty two.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 9; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 12, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty three.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 15, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 17, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty two.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 14, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 18, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty two.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: a) a heavy chain variable domain, the heavy chain variable domain comprising: HC-CDR1 , which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 11; and b) a light chain variable domain,
  • the light chain variable domain includes: LC-CDR1, which includes the amino acid sequence SEQ ID NO: 16, LC-CDR2, which includes the amino acid sequence SEQ ID NO: 19, and LC-CDR3, which includes the amino acid sequence SEQ ID NO: :twenty four.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region wherein the anti-C5a antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: 25-34 Any amino acid sequence shown or a variant thereof, which variant has at least about 80% (such as at least 80%, 85%, 90%, 95%) with the amino acid sequence shown in any one of SEQ ID NOs: 25-34 %, 96%, 97%, 98% or 99% ) sequence identity; and a light chain variable domain ( VL ) comprising the amino acid sequence shown in any one of SEQ ID NOs: 35-44 Or a variant thereof that shares at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%) with the amino acid sequence shown in any one of SEQ ID NOs: 35-44 , 98% or 99%) sequence identity.
  • VH heavy chain variable domain
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG2 constant region wherein the anti-C5a antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: 25-34 Any amino acid sequence shown or a variant thereof, which variant has at least about 80% (such as at least 80%, 85%, 90%, 95%) with the amino acid sequence shown in any one of SEQ ID NOs: 25-34 %, 96%, 97%, 98% or 99%) sequence identity; and a light chain variable domain ( VL ) comprising the amino acid sequence shown in any one of SEQ ID NOs: 35-44 Or a variant thereof that shares at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%) with the amino acid sequence shown in any one of SEQ ID NOs: 35-44 , 98% or 99%) sequence identity.
  • VH heavy chain variable domain
  • the IgG2 is human IgG2.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG3 constant region wherein the anti-C5a antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: 25-34 Any amino acid sequence shown or a variant thereof, which variant has at least about 80% (such as at least 80%, 85%, 90%, 95%) with the amino acid sequence shown in any one of SEQ ID NOs: 25-34 %, 96%, 97%, 98% or 99% ) sequence identity; and a light chain variable domain ( VL ) comprising the amino acid sequence shown in any one of SEQ ID NOs: 35-44 Or a variant thereof that shares at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%) with the amino acid sequence shown in any one of SEQ ID NOs: 35-44 , 98% or 99%) sequence identity.
  • VH heavy chain variable domain
  • the IgG3 is human IgG3.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region wherein the anti-C5a antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: 25-34 Any amino acid sequence shown or a variant thereof, which variant has at least about 80% (such as at least 80%, 85%, 90%, 95%) with the amino acid sequence shown in any one of SEQ ID NOs: 25-34 %, 96%, 97%, 98% or 99% ) sequence identity; and a light chain variable domain ( VL ) comprising the amino acid sequence shown in any one of SEQ ID NOs: 35-44 Or a variant thereof that shares at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%) with the amino acid sequence shown in any one of SEQ ID NOs: 35-44 , 98% or 99%) sequence identity.
  • VH heavy chain variable domain
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgGl constant region comprising an IgGl constant region
  • the anti-C5a antibody comprises: a heavy chain variable domain ( VH ) comprising SEQ ID NOs: 25- The amino acid sequence shown in any one of SEQ ID NOs: 35-44, and the light chain variable domain (V L ), said (V L ) comprising the amino acid sequence shown in any one of SEQ ID NOs: 35-44.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region wherein the anti-C5a antibody comprises: a heavy chain variable domain ( VH ), the VH comprising SEQ ID NOs: 25-34 The amino acid sequence shown in any one, and the light chain variable domain ( VL ), the VL comprising the amino acid sequence shown in any one of SEQ ID NOs: 35-44.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region wherein the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 25 or a variant thereof, the variant having the same amino acid sequence SEQ ID NO:25 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:35 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:35 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region wherein the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 26 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:26 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:36 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:36 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region wherein the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 27 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:27 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:37 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:37 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region wherein the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 28 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:28 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:38 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:38 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region wherein the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 29 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:29 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:39 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region wherein the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 30 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:30 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:40 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:40 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region wherein the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:31 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:41 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:41 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 32 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:32 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:42 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:42 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region wherein the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 33 or a variant thereof, the variant is identical to the amino acid sequence SEQ ID NO:33 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:43 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:43 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG1 constant region wherein the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 34 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:34 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:44 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:44 Identity.
  • the IgG1 is human IgG1.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 25 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:25 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:35 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:35 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 26 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:26 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:36 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:36 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 27 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:27 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:37 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:37 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 28 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:28 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:38 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:38 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 29 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:29 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:39 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:39 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 30 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:30 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:40 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:40 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising an IgG4 constant region, wherein the anti-C5a antibody comprises: V H comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof, the variant having the same amino acid sequence SEQ ID NO:31 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:41 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:41 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 32 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:32 having at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:42 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:42 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 33 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:33 has at least about 80% sequence identity; and VL comprising the amino acid sequence SEQ ID NO:43 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:43 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • a full-length anti-C5a antibody comprising an IgG4 constant region comprising: V H comprising the amino acid sequence SEQ ID NO: 34 or a variant thereof, the variant being identical to the amino acid sequence SEQ ID NO:34 has at least about 80% sequence identity; and V L comprising the amino acid sequence SEQ ID NO:44 or a variant thereof that has at least about 80% sequence identity with the amino acid sequence SEQ ID NO:44 Identity.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:46 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:48.
  • Binding affinity is expressed as Kd, Koff, Kon or Ka.
  • Koff refers to the rate constant for the dissociation of an antibody from an antigen/antibody complex, as measured by a kinetic selection device.
  • Kon refers to the binding rate constant at which an antibody binds to an antigen to form an antigen/antibody complex.
  • the equilibrium dissociation constant Kd used in this article refers to the dissociation constant when a specific antibody-antigen interacts. It refers to the antigen concentration required when the antigen occupies half of all antibody binding sites in the antibody molecule solution and reaches equilibrium, which is equal to Koff /Kon. The determination of Kd assumes that all bound molecules are in solution.
  • the corresponding equilibrium dissociation rate constant is expressed as EC50, which is a good approximation of Kd.
  • the affinity binding constant Ka is the reciprocal of the dissociation constant Kd.
  • the dissociation constant (Kd) can be used as an indicator of the affinity of the reactive antibody moiety to the antigen.
  • Kd dissociation constant
  • a simple analysis can be performed by the Scatchard method using antibodies labeled with various markers and a Biacore instrument (manufactured by Amersham Biosciences) to analyze interactions between biomolecules by surface plasmon resonance according to the user manual or the included kit. .
  • the Kd value obtained using these methods is expressed in the unit M.
  • Antibodies that specifically bind a target may have, for example, ⁇ 10 -7 M, ⁇ 10 -8 M, ⁇ 10 -9 M, ⁇ 10 -10 M, ⁇ 10 -11 M , ⁇ 10 -12 M, or ⁇ 10 - Kd value of 13 M.
  • the binding specificity of an antibody can be determined experimentally by methods known in the art. These methods include, but are not limited to, Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIAcore testing, and peptide scanning.
  • the anti-C5a antibody specifically binds to the C5a target with a Kd value of 10 -7 M to 10 -13 M (e.g., 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M or 10 -10 M to 10 -12 M).
  • the Kd value of the binding between the anti-C5a antibody and C5a is 10 -7 M to 10 -13 M, 1 ⁇ 10 -7 M to 5 ⁇ 10 -13 M, 10 -7 M to 10 -12 M, 10 -7 M to 10 -11 M, 10 -7 M to 10 -10 M, 10 -7 M to 10 -9 M, 10 -8 M to 10 -13 M , 1 ⁇ 10 -8 M to 5 ⁇ 10 -13 M, 10 -8 M to 10 -12 M, 10 -8 M to 10 -11 M, 10 -8 M to 10 -10 M, 10 -8 M to 10 -9 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -13 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -12 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -11 M, 5 ⁇ 10 -9 M to 1 ⁇ 10 -10 M, 10 -9 M to 10 -13 M, 10 -9 M to 10 -12 M, 10 -9 M to 10 -12 M, 10 -9 M to 10 -11 M, 10 -9 M to 10 -10 M
  • the Kd value for binding between the anti-C5a antibody and the non-target is higher than the Kd value for the anti-C5a antibody binding to the target, and in some embodiments cited herein, the Kd value for the anti-C5a antibody binding to the target (e.g., C5a)
  • the binding affinity is higher than the binding affinity of the anti-C5a antibody to the non-target.
  • non-target refers to an antigen other than C5a.
  • the Kd value of the anti-C5a antibody (for C5a) binding to the non-C5a target is at least 10-fold different, such as 10-100 times, 100-1000 times, 10 3 -10 4 times, 10 4 -10 5 times, 10 5 -10 6 times, 10 6 -10 7 times, 10 7 -10 8 times, 10 8 -10 9 times , 10 9 -10 10 times, 10 10 -10 11 times, 10 11 -10 12 times .
  • the anti-C5a antibody binds to a non-target with a Kd value of 10 -1 M to 10 -6 M (e.g., 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M).
  • the non-target refers to an antigen other than C5a.
  • the Kd value for binding between the anti-C5a antibody and the non-C5a target is 10 -1 M to 10 -6 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -6 M, 10 -1 M to 10 -5 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -5 M, 10 -1 M to 10 -4 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -4 M, 10 - 1 M to 10 -3 M, 1 ⁇ 10 -1 M to 5 ⁇ 10 -3 M, 10 -1 M to 10 -2 M, 10 -2 M to 10 -6 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -6 M, 10 -2 M to 10 -5 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -5 M, 10 -2 M to 10 -4 M, 1 ⁇ 10 -2 M to 5 ⁇ 10 -4 M, 10 -2 M to 10 -3 M, 10 -3 M to 10 -6 M, 1 ⁇ 10 -3 M to 5 ⁇ 10 -6 M, 10 -3 M to 10 -6 M, 1 ⁇ 10 -3 M to 10
  • an anti-C5a antibody when it is referred to that an anti-C5a antibody specifically recognizes a C5a target with high binding affinity and binds to a non-target with low binding affinity, the anti-C5a antibody binds to the C5a target with a Kd value of 10 -7 M to 10 -13 M (for example, 10 -7 M to 10 -13 M, 10 -8 M to 10 -13 M, 10 -9 M to 10 -13 M, 10 -10 M to 10 -12 M), and with The Kd value for non-target binding is 10 -1 M to 10 -6 M (eg, 10 -1 M to 10 -6 M, 10 -1 M to 10 -5 M, 10 -2 M to 10 -4 M).
  • the binding affinity of the anti-C5a antibody is compared to the binding affinity of a control anti-C5a antibody (eg, INab308).
  • the Kd value of the binding between the control anti-C5a antibody and C5a can be at least 2 times, such as 2 times, 3 times, 4 times the Kd value of the binding between the anti-C5a antibody and C5a described herein. , 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 10-100 times, 100-1000 times, 10 3 -10 4 times.
  • nucleic acid molecules encoding anti-C5a antibodies are also considered.
  • a nucleic acid (or set of) nucleic acids encoding a full-length anti-C5a antibody is provided, including any of the full-length anti-C5a antibodies described herein.
  • the nucleic acid (or set of nucleic acids) of the anti-C5a antibody described herein may also include a nucleic acid sequence encoding a polypeptide tag (eg, protein purification tag, His tag, HA tag).
  • isolated host cells comprising an anti-C5a antibody, an isolated nucleic acid encoding an anti-C5a antibody polypeptide component, or a vector comprising a nucleic acid encoding an anti-C5a antibody polypeptide component described herein.
  • variants include nucleotide sequences that hybridize under at least moderately stringent hybridization conditions to a nucleic acid sequence encoding an anti-C5a antibody of the present application.
  • the present application also provides a vector into which the nucleic acid sequence of the present application can be inserted.
  • a natural or synthetic nucleic acid encoding an anti-C5a antibody is inserted into a suitable expression vector such that the nucleic acid is operably linked to 5' and 3' regulatory elements, such as a promoter (e.g., lymphocyte-specific promoter) and 3' untranslated region (UTR), which can express anti-C5a antibodies (such as full-length anti-C5a antibodies).
  • the vector may be suitable for replication and integration in eukaryotic host cells.
  • Typical cloning and expression vectors contain transcriptional and translational terminators, initiation sequences, and promoters that regulate expression of the nucleic acid sequence of interest.
  • nucleic acids described herein can also be used for nucleic acid immunization and gene therapy using standard gene delivery protocols.
  • Nucleic acid delivery methods are known in the art. See, for example, U.S. Pat. Nos. 5,399,346, 5,580,859, 5,589,466, the entire contents of which are incorporated herein by reference.
  • the application also provides gene therapy vectors.
  • Nucleic acids can be cloned into many types of vectors.
  • nucleic acids can be cloned into vectors including, but not limited to, plasmids, phagemids, phage derivatives, animal viruses, and cosmids.
  • Vectors of particular interest include expression vectors, replication vectors, probe generation vectors and sequencing vectors.
  • expression vectors can be provided to cells in the form of viral vectors.
  • 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 include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses.
  • suitable vectors include an origin of replication functional in at least one organism, promoter sequences, convenient restriction enzyme sites, and one or more selectable markers (see, e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326,193).
  • retroviruses provide a convenient platform for gene delivery systems.
  • the selected genes can be inserted into vectors and packaged in retroviral particles using techniques known in the art.
  • the recombinant virus is then isolated and delivered to the subject's cells in vivo or in vitro.
  • Many retroviral systems are known in the art.
  • adenoviral vectors are used.
  • Many adenoviral vectors are known in the art.
  • lentiviral vectors are used.
  • Vectors derived from retroviruses, such as lentiviruses are suitable tools for long-term gene transfer because they enable long-term stable integration of the transgene and propagation in progeny cells.
  • Lentiviral vectors have an additional advantage over tumor-derived retroviruses such as murine leukemia virus in that they can transduce non-dividing cells such as hepatocytes. At the same time, it has the additional advantage of low immunogenicity.
  • promoter elements such as enhancers, regulate the frequency of transcription initiation. Typically they are located 30-110 bp upstream of the start site, although recently many promoters have been found to also contain functional elements downstream of the start site.
  • the spacing between promoter elements is usually flexible, so that promoter function is maintained when elements are interchanged or moved with each other. In the thymidine kinase (tk) promoter, activity does not begin to decrease until the spacing between promoter elements increases to 50 bp.
  • tk thymidine kinase
  • a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence that can drive high-level expression of any polynucleotide sequence operably linked to it.
  • CMV immediate early cytomegalovirus
  • EF-1 ⁇ elongation factor 1 ⁇
  • constitutive promoters may also 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, such as but not limited to actin promoter, myosin promoter, Hemoglobin promoter and creatine kinase promoter.
  • SV40 simian virus 40
  • MMTV mouse mammary tumor virus
  • HV-LTR human immunodeficiency virus long terminal repeat
  • MoMuLV promoter avian leukemia virus promoter
  • Epstein-Barr virus immediate early promoter Epstein-Barr virus immediate early promoter
  • Rous sarcoma virus promoter Rous sarcoma virus promoter
  • human gene promoters such as but not
  • an inducible promoter provides a molecular switch that turns on the expression of the polynucleotide sequence to which it is operably linked when such expression is desired, and turns off expression when it is not.
  • Inducible promoters include, but are not limited to, metallothionein promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.
  • expression of anti-C5a antibodies is inducible.
  • a nucleic acid sequence encoding an anti-C5a antibody is operably linked to an inducible promoter, including any of the inducible promoters described herein.
  • an inducible promoter provides a molecular switch that turns on the expression of a polynucleotide sequence operably linked to it when expression is desired, and turns off expression when expression is not needed.
  • exemplary inducible promoters suitable for use in eukaryotic cells include, but are not limited to, hormone regulatory elements (see, e.g., Mader, S. and White, J.H. (1993) Proc. Natl. Acad. Sci. USA 90:5603-5607) , synthetic ligand regulatory elements (see Spencer, D.M. et al (1993) Science 262:1019-1024) and ionizing radiation regulatory elements (see Manome, Y. et al.
  • inducible promoter system used to express anti-C5a antibodies is the Tet system.
  • inducible promoter system used to express anti-C5a antibodies is an E. coli lac repressor system.
  • Tet system An exemplary inducible promoter system used in this application is the Tet system. This system is based on the Tet system described by Gossen et al. (1993).
  • the target polynucleotide is controlled by a promoter containing one or more Tet operator (TetO) sites.
  • TetO Tet operator
  • TetR Tet repressor
  • the activated state for example, in the presence of inducers such as tetracycline (Tc), anhydrotetracycline, doxycycline (Dox) or their active analogs, the inducer causes TetR to be released from TetO, resulting in transcription. .
  • Doxycycline is a member of the tetracycline antibiotic family, its chemical name is 1-dimethylamino-2,4a,5,7-pentahydroxy-11-methyl-4,6-dioxy-1,4a ,11,11a,12,12a-hexahydrotetraene-3-carboxamide.
  • TetR is codon-optimized for expression in mammalian cells, such as mouse or human cells. Due to the degeneracy of the genetic code, most amino acids are encoded by more than one codon, resulting in a large number of variants in the sequence of a given nucleic acid without any change in the sequence of its encoded amino acid. However, many organisms have differences in codon usage, also known as "codon preference" (i.e., the preference for a given amino acid to use a specific codon). Codon preference is often associated with the presence of dominant tRNA species for specific codons, which in turn increases the efficiency of mRNA translation. Coding sequences derived from a specific species (e.g., prokaryotes) can thus be tailored through codon optimization to enhance their expression in different species (e.g., eukaryotes).
  • a specific species e.g., prokaryotes
  • Tet-Off transcription is inactive in the presence of Tc or Dox.
  • tTA tetracycline-regulated transcriptional activator
  • TRE tetracycline-responsive promoter element
  • rtTA is a fusion protein composed of the TetR repressor and the VP16 transcriptional activation domain.
  • a 4-amino acid change in the DNA-binding region of TetR changes the binding properties of rtTA, causing it to only recognize the tetO sequence on the target transgene TRE in the presence of Dox. Therefore, in the Tet-On system, rtTA can activate the transcription of TRE-regulated target genes only in the presence of Dox.
  • lac repressor system of E. coli (see Brown et al., Cell 49:603-612 (1987)).
  • the Lac repressor system functions by regulating the transcription of a target polynucleotide operably linked to a promoter containing the lac operator (lacO).
  • lacO lac operator
  • LacR Lac repressor
  • lacR binds to LacO, thereby preventing the transcription of the target polynucleotide.
  • Expression of the polynucleotide of interest is induced by a suitable inducer, for example, isopropyl- ⁇ -D thiogalactopyranoside (IPTG).
  • IPTG isopropyl- ⁇ -D thiogalactopyranoside
  • the expression vector to be introduced into the cell may also contain a selectable marker gene or a reporter gene or both to facilitate the identification and selection of expressing cells from a population of cells transfected or infected with the viral vector.
  • the selectable marker can be carried on separate DNA fragments and used in co-transfection experiments.
  • Either the selectable marker gene or the reporter gene can be flanked by appropriate regulatory sequences to enable expression in the host cell.
  • Useful selectable markers include, for example, antibiotic resistance genes such as neo and similar genes.
  • Reporter genes can be used to identify potentially transfected cells and evaluate the function of regulatory sequences.
  • a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and encodes a polypeptide whose expression is manifested by some readily detectable property, such as enzymatic activity. After the DNA is introduced into the recipient cells, the expression of the reporter gene is detected at the appropriate time.
  • Suitable reporter genes may include genes encoding luciferase, ⁇ -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 well known and can be prepared by known techniques or commercially available.
  • the construct with the smallest 5' flanking region that shows the highest expression level of the reporter gene is considered the promoter.
  • Such promoter regions can be linked to reporter genes and used to assess the ability of certain substances to regulate promoter-driven transcription.
  • nucleic acids encoding any of the full-length anti-C5a antibodies described herein are provided.
  • the nucleic acid includes one or more nucleic acid sequences encoding full-length anti-C5a antibody heavy and light chains.
  • each of the one or more nucleic acid sequences is contained in a separate vector.
  • at least some of the nucleic acid sequences are included in the same vector.
  • all nucleic acid sequences are contained in the same vector.
  • Vectors may be selected, for example, from mammalian expression vectors and viral vectors (eg, vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses and lentiviruses).
  • mammalian expression vectors and viral vectors eg, vectors derived from retroviruses, adenoviruses, adeno-associated viruses, herpesviruses and lentiviruses.
  • the vector can be readily introduced into host cells, such as mammalian cells, bacteria, yeast or insect cells, by any method in the art.
  • expression vectors can be introduced into host cells by physical, chemical or biological methods.
  • polynucleotides are introduced into the host cell by calcium phosphate transfection.
  • Biological methods for introducing polynucleotides of interest into host cells include the use of DNA and RNA vectors.
  • Viral vectors especially retroviral vectors, have become the most widely used method for inserting genes into mammalian cells, such as human cells.
  • Other viral vectors can be derived from lentivirus, poxvirus, herpes simplex virus type 1, adenovirus, adeno-associated virus, etc. See, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362.
  • colloidal dispersion systems such as polymer complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems including oil-in-water emulsions, micelles, and mixed gels pellets and liposomes.
  • colloidal dispersion systems such as polymer complexes, nanocapsules, microspheres, magnetic beads, and lipid-based systems including oil-in-water emulsions, micelles, and mixed gels pellets and liposomes.
  • liposomes eg, artificial membrane vesicles.
  • an exemplary delivery vehicle is liposomes.
  • lipid formulations to introduce nucleic acids into host cells (in vitro, ex vivo, or in vivo).
  • the nucleic acid can be associated with lipids.
  • the nucleic acid bound to the lipid can be packaged into the aqueous interior of the liposome, spread within the lipid bilayer of the liposome, and connected to the liposome through a linker molecule that binds to the liposome and the oligonucleotide.
  • Lipid, lipid/DNA or lipid/expression vector related compositions are not limited to any particular structure in solution. For example, they may exist in bilayer structures, in micelles or in "collapsed" structures. They can also simply disperse in solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances that can be naturally occurring or synthetic lipids.
  • lipids include lipid droplets that occur naturally in the cytoplasm, as well as a class of compounds containing long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, aminoalcohols, and aldehydes.
  • experiments can be performed in order 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. For example, Southern and Northern blotting, RT-PCR and PCR; "biochemical” experiments, such as detecting the presence or absence of a specific polypeptide, such as by immunological methods (ELISAs and Western blots) or by experiments described in this article All fall within the scope of this application.
  • the anti-C5a antibody is a monoclonal antibody or is derived from a monoclonal antibody. In some embodiments, the anti-C5a antibody comprises VH and VL from a monoclonal antibody, or a variant thereof. In some embodiments, the anti-C5a antibody further includes CH1 and CL regions from a monoclonal antibody, or variants thereof.
  • Monoclonal antibodies can be prepared using, for example, methods known in the art, including hybridoma cell methods, phage display methods, or using recombinant DNA methods. Additionally, exemplary phage display methods are described herein and in the Examples below.
  • an immune agent is usually used to immunize hamsters, mice or other suitable host animals to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to the immune agent.
  • lymphocytes can be immunized in vitro.
  • Immunizing agents may include polypeptides or fusion proteins of the protein of interest.
  • PBLs peripheral blood lymphocytes
  • spleen cells or lymph node cells are used.
  • Lymphocytes are fused to immortalized cell lines using an appropriate fusion agent, such as polyethylene glycol, to form hybridoma cells.
  • Immortal cell lines are typically transformed mammalian cells, particularly myeloma cells of rodent, bovine, and human origin. Typically, rat or mouse myeloma cell lines are used.
  • Hybridoma cells can be cultured in a suitable medium, which preferably contains one or more substances that inhibit the growth or survival of unfused immortal cells. For example, if the parent cells lack the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), the hybridoma cell culture medium usually includes hypoxanthine, aminopterin, and thymidine (HAT medium), which can Prevents the growth of HGPRT-deficient cells.
  • HGPRT hypoxanthine-guanine phosphoribosyltransferase
  • the immortalized cell lines fuse efficiently, ensure high-level and stable expression of the antibody by the selected antibody-producing cells, and are sensitive to certain media, such as HAT media.
  • the immortal cell line is a mouse myeloma cell line, available from, for example, the Salk Cell Collection in San Diego, California, and the American Type Culture Collection in Manassas, Virginia. Also described are human myeloma and mouse-human hybrid myeloma cell lines for the preparation of human monoclonal antibodies.
  • the culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the polypeptide.
  • the binding specificity of monoclonal antibodies produced by hybridoma cells can be determined by immunoprecipitation or in vitro binding experiments, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). Such techniques or analytical methods are known in the art.
  • the binding affinity of a monoclonal antibody can be determined by Scatchard analysis as described, for example, in Munson and Pollard, Anal. Biochem., 107:220 (1980).
  • hybridoma cells After the desired hybridoma cells are identified, the clones of interest can be subcloned 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, hybridoma cells can be grown in mammals in the form of ascites fluid.
  • DMEM modified Eagle's medium
  • RPMI-1640 medium RPMI-1640
  • Monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascitic fluid by conventional immunoglobulin purification methods, such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity Chromatography.
  • immunoglobulin purification methods such as protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity Chromatography.
  • the anti-C5a antibody comprises sequences selected from clones of an antibody library (eg, a phage library displaying scFv or Fab fragments).
  • the clones can be identified by screening a combinatorial library of antibody fragments with the desired activity.
  • various methods are known in the art for generating phage display libraries and screening these libraries for antibodies with desired binding properties. These methods are reviewed, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, N.J., 2001), and in, e.g., McCafferty et al.
  • phage display methods all components of the V H and V L genes are cloned separately through polymerase chain reaction (PCR), randomly recombined in a phage library, and then screened for phages that can bind the antigen, such as Winter et al. ., Ann. Rev. Immunol., 12:433-455 (1994). Phages typically display antibody fragments as scFv fragments or as Fab fragments. Immunogenically derived library phages provide high-affinity antibodies against immunogens without the need to construct hybridoma cells.
  • PCR polymerase chain reaction
  • natural libraries can be cloned to provide a single source of antibodies against multiple non-self and self-antigens without the need for any immunization, as in Griffiths et al., EMBOJ, 12:725-734 (1993) described in.
  • natural libraries can also be prepared by cloning non-rearranged V-gene fragments from stem cells and using PCR primers containing random sequences to encode the CDR3 hypervariable region and completing the rearrangement in vitro, such as Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992).
  • Patent publications describing human antibody phage libraries include, for example, US Pat. No. 5,750,373 and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0 292936 and 2009/0002360.
  • the anti-C5a antibody is prepared by phage display screening library for anti-C5a antibody portions that can specifically bind to target C5a.
  • the library may be a human scFv phage display library with 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 ) diversity of unique human antibody fragments.
  • the library is a human natural library, constructed from DNA extracted from PMBCs and spleens of healthy subjects, containing all human heavy and light chain subfamilies.
  • the library is a human natural library constructed from DNA extracted from PMBCs isolated from patients with various diseases, such as patients with autoimmune diseases, cancer patients, and patients with infectious diseases.
  • the library is a semi-synthetic human library in which the heavy chain CDR3s are completely random and all amino acids (except cysteine) are present with equal probability at any given position. (See, eg, Hoet, RM et al., Nat. Biotechnol. 23(3):344-348, 2005).
  • the heavy chain CDR3 length of the semi-synthetic human library ranges from 5 to 24 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23 or 24) between amino acids.
  • the library is a fully synthetic phage display library.
  • the library is a non-human phage display library.
  • Phage clones with high affinity for target C5a can be screened by iterative binding of phage to target C5a bound to a solid support (e.g., beads for solution panning or mammalian cells for cell panning) ), followed by removal of unbound phage and elution of specifically bound phage. Subsequently, bound phage clones are eluted and used to infect suitable host cells, such as E. coli XL1-Blue, for expression and purification. Phage clones that specifically bind C5a can be enriched by multiple rounds of panning (eg, 2, 3, 4, 5, 6, or more rounds), such as solution panning, cell panning, or a combination of both. Specific binding of the enriched phage clones to the target C5a can be detected by any method known in the art, including, for example, ELISA and FACS.
  • Another way to screen antibody libraries is to display proteins on the surface of yeast cells.
  • Wittrup et al. (US Patents 6,699,658 and 6,696,251) developed a method for displaying libraries in yeast cells.
  • one component includes the yeast lectin protein (Aga1), which is anchored to the yeast cell wall, and the other component includes the second subunit of the lectin protein Aga2, which can pass through disulfide bonds. Binds to the Aga1 protein and is displayed on the surface of yeast cells.
  • Aga1 protein is expressed by integrating the Aga1 gene into the yeast chromosome.
  • a single-chain variable fragment (scFv) library is fused to the Aga2 gene in a yeast display plasmid and, after transformation, is retained in yeast due to the presence of an additional nutritional marker. Both Aga1 and Aga2 proteins are expressed under the control of galactose-inducible promoters.
  • the human antibody V gene library (V H and V K fragments) was obtained by PCR using a set of degenerate primers (Sblattero, D. and Bradbury, A. Immunotechnology 3, 271-278 1998).
  • PCR templates were derived from commercially available RNA or cDNA, including PBMC, spleen, lymph nodes, bone marrow, and tonsils.
  • Independent V H and V K PCR libraries were combined and assembled into scFv formats by overlap extension PCR (Sheets, MD et al, Proc. Natl. Acad. Sci. USA 95, 6157–61621998).
  • yeast scFv display library To construct a yeast scFv display library, the resulting scFv PCR product was cloned into a yeast display plasmid in yeast via 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).
  • Anti-C5a antibodies can be screened using a mammalian cell display system, in which the antibody moiety is displayed on the cell surface and antibodies specifically targeting C5a are isolated by antigen-directed screening methods (as described in U.S. patent No. 7,732,195B2).
  • a Chinese hamster ovary (CHO) cell library displaying a large number of human IgG antibody genes can be created and used to discover clones expressing high-affinity antibody genes.
  • An alternative display system has been developed that allows the same protein to be simultaneously displayed and secreted on the cell surface through alternative splicing, in which the phenotype of the displayed protein remains correlated with the genotype, allowing for simultaneous biophysical and cell function-based analyses. Characterize the secreted soluble antibodies.
  • This method overcomes many of the limitations of previous mammalian cell displays and enables direct screening and maturation of antibodies in the form of full-length, glycosylated IgGs (Peter M. Bowers, et al, Methods 2014, 65: 44-56).
  • Transient expression systems are suitable for a single round of antigen selection prior to antibody gene recovery and are therefore most useful for selecting antibodies from smaller libraries.
  • Stable exosome vectors offer an attractive option. Exosome vectors can be efficiently transfected and stably maintained at low copy numbers, allowing for multiple rounds of panning and elucidation of more complex antibody libraries.
  • the IgG library was constructed based on the ligation of germline sequence V gene fragments isolated from a pool of human donors and rearranged (D)J regions. RNA collected from 2000 human blood samples was reverse transcribed into cDNA, VH and VK fragments were amplified using VH and VK specific primers, and purified by gel extraction. The VH and VK fragments were subcloned into display vectors containing IgG1 or K constant regions respectively, and then electroporated or transduced 293T into cells to prepare IgG libraries.
  • V H and V K are ligated to generate scFv, which is then subcloned into a display vector and electroporated or transduced into 293T cells.
  • IgG libraries are constructed based on germline sequence V gene fragments and rearranged (D)J regions isolated from a group of donors, which can be mice, rats, rabbits or monkeys.
  • Monoclonal antibodies can also be prepared by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567.
  • DNA encoding the monoclonal antibodies described herein can be readily isolated and sequenced by conventional methods (eg, by oligonucleotide probes that specifically bind to genes encoding the light and heavy chains of murine antibodies).
  • Hybridoma cells as described above or the C5a-specific phage clones of the present application can be used as a source of such DNA.
  • the DNA can be placed into an expression vector, which can then be transfected into host cells, such as simian COS cells, Chinese hamster ovary cancer (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain the expression in the recombinant host.
  • host cells such as simian COS cells, Chinese hamster ovary cancer (CHO) cells, or myeloma cells that do not produce immunoglobulins, to obtain the expression in the recombinant host.
  • Monoclonal antibodies synthesized in cells may also be modified, for example by substituting coding sequences for human heavy and light chain constant regions and/or substituting framework regions for homologous non-human sequences (U.S. Patent No.
  • non-immunoglobulin polypeptide is covalently linked to the coding sequence for an immunoglobulin.
  • This non-immunoglobulin polypeptide can replace the constant region of the antibody in this application, or can replace an antigen-binding site in the variable domain of the antibody in this application, forming a chimeric bivalent antibody.
  • the antibody may be a monovalent antibody.
  • Methods of preparing monovalent antibodies are known in the art. For example, one involves a recombinant expression method involving an immunoglobulin light chain and a modified heavy chain.
  • the heavy chain is usually truncated at any position in the Fc region to prevent the heavy chains from cross-linking with each other.
  • the relevant cysteine residues are substituted with other amino acid residues or deleted to prevent cross-linking.
  • In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce antibody fragments, particularly Fab fragments, can be accomplished using any method known in the art.
  • Antibody variable domains with the desired binding specificity can be fused to immunoglobulin constant regions. Fusions to the immunoglobulin heavy chain constant region, including at least part of the hinge, CH2 and CH3 regions, are preferred. In some embodiments, the first heavy chain constant region (CH1), which contains the necessary sites for light chain binding, is present in at least one fusion. DNA encoding the immunoglobulin heavy chain fusion, and if desired, DNA encoding the immunoglobulin light chain, is inserted into a separate expression vector and co-transfected into a suitable host organism.
  • the anti-C5a antibody (eg, full-length anti-C5a antibody) can be a fully human antibody or a humanized antibody.
  • Humanized forms of non-human (e.g., mouse) antibody portions are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (e.g., Fv, Fab, Fab', F(ab') 2 , scFv, or other fragments of antibodies Antigen binder sequences), which generally include minimal sequences derived from non-human immunoglobulins.
  • Humanized antibodies include human immunoglobulins, immunoglobulin chains or fragments thereof (recipient antibodies) in which the residues of the acceptor CDRs are replaced by non-human (donor antibody) CDRs with the desired specificity, affinity and properties. Residue substitutions, such as mouse, rat or rabbit CDRs. In some embodiments, human immunoglobulin Fv framework residues are replaced with corresponding non-human residues. Humanized antibodies may also contain amino acid residues that neither belong to the recipient antibody nor are in the introduced CDR or framework sequence.
  • a humanized antibody contains at least one, and usually two variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are common to human immunoglobulins. sequence.
  • humanized antibodies typically contain one or more amino acid residues introduced from a non-human source. Those non-human amino acid residues are often referred to as "implanted” residues, usually from the "imported” variable domain. According to some embodiments, humanization can be performed essentially as described by Winter and colleagues (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 human antibodies with rodent CDRs or CDR sequences. Thus, this "humanized” antibody portion (U.S. Patent No.
  • a humanized antibody portion is a typical human antibody portion in which some CDR residues and possibly some framework region residues are replaced by residues from similar positions in rodent antibodies.
  • Fully human antibodies are an alternative to humanization. For example, it is now possible to generate transgenic animals (eg, mice) that are capable of producing a complete library of fully human antibodies upon immunization without producing endogenous immunoglobulins. For example, it has been reported that homozygous deletion of the antibody heavy chain junction region (JH) gene in chimeric and germline mutant mice completely inhibits endogenous antibody production.
  • JH antibody heavy chain junction region
  • Transferring human germline immunoglobulin gene arrays into such germline mutant mice can produce human antibodies in response to antigen stimulation, see, e.g., akobovits et al., PNAS USA, 90:2551 (1993); Jakobovits et al ., Nature, 362:255-258 (1993); Bruggemann et al., Year in Immunol., 7:33 (1993); U.S. Patent Nos. 5,545,806, 5,569,825, 5,591,669, 5,545,807; and WO 97/17852.
  • Fully human antibodies can be prepared by introducing human immunoglobulin loci into transgenic animals (eg, mice in which the endogenous immunoglobulin genes have been partially or completely silenced). After antigen stimulation, the production of fully human antibodies can be found to be very similar to their production in humans in all aspects, including gene rearrangement, assembly, and antibody libraries. This method is used in, for example, U.S. Patent Nos.
  • Fully human antibodies can also be produced by activating B cells in vitro (see U.S. 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 technology of Cole et al. and Boerner et al. It 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).
  • the amino acid sequences of anti-C5a antibody variants are also contemplated.
  • the amino acid sequences of antibody variants can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues in the antibody amino acid sequence.
  • the final construct can be accomplished by any combination of deletions, insertions, and substitutions of amino acid residues to give it the desired characteristics. For example, antigen binding.
  • anti-C5a antibody variants with one or more amino acid substitutions are provided.
  • Target sites for substitution mutations include hypervariable regions (HVRs) and framework regions (FRs).
  • Amino acid substitutions can be introduced into the antibody of interest and the product screened for the desired activity, for example, improved biological activity, maintained/improved antigen binding capacity, reduced immunogenicity, or improved ADCC or CDC.
  • Amino acids are divided into different categories based on the nature of their side chains:
  • Acidic amino acids aspartic acid Asp, glutamic acid Glu;
  • Aromatic amino acids tryptophan Trp, tyrosine Tyr, phenylalanine Phe.
  • Substitutions of non-conservative amino acids involve substitution of one category for another category.
  • An exemplary substitution variant is an affinity matured antibody, which can be conveniently produced using, for example, phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated, variant antibody moieties are displayed on phage, and those screened for specific biological activity (e.g., biological activity based on a reactive oxygen species (ROS) release assay or binding affinity) Variants. Alterations (eg, substitutions) can be made in regions of HVRs to obtain improved biological activity or antibody affinity based on reactive oxygen species (ROS) release assays.
  • ROS reactive oxygen species
  • Alterations can occur in "hot spots" of HVR, i.e., codon-encoded residues that are highly mutated during somatic cell maturation (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or detect the binding affinity of the resulting variants VH and VL at specific decisive residues (SDRs).
  • SDRs decisive residues
  • variable genes selected for affinity maturation are introduced into the variable genes selected for affinity maturation by any of a variety of methods, such as error-prone PCR, strand shuffling, or oligonucleotide-directed mutagenesis. .
  • Secondary libraries are then created. The library is screened to identify antibody variants with the desired affinity.
  • Another way to introduce diversity includes the HVR-mediated manner, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding are specifically recognized, for example, using alanine scanning mutagenesis or modeling. Usually the CDR-H3 and CDR-L3 regions are particularly focused targets.
  • substitutions, insertions, or deletions may occur within one or more HVRs, so long as such changes do not substantially reduce the ability of the antibody to bind the antigen.
  • conservative changes eg, conservative substitutions provided herein
  • HVRs that do not substantially reduce binding affinity. These changes may occur outside the HVR "hot zone" or SDRs area.
  • each HVR is either unchanged or contains no more than 1, 2, or 3 amino acid substitutions.
  • a useful method for identifying amino acid residues or regions of an antibody that can be targeted mutated is called "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244:1081-1085 .
  • target residues e.g., charged residues such as arginine, aspartic acid, histidine, lysine, and glutamic acid
  • neutral or negatively charged amino acids e.g., , alanine or glutamic acid
  • Further substitutions can be introduced at amino acid positions to demonstrate functional sensitivity of the position to the initial substitution.
  • the contact sites between the antibody and the antigen are identified through the crystal structure of the antigen-antibody complex. These contact site residues and adjacent residues can be targeted or eliminated as substitution candidates. Screen variants to determine if they have the desired properties.
  • Insertions of amino acid sequences including fusions at the amino and/or carboxyl terminus, ranging in length from 1 residue to polypeptides containing 100 or more residues, and including insertion of 1 or more amino acid residues within the sequence base.
  • terminal insertions include antibodies with a methionyl residue at the N-terminus.
  • Other insertional variants of antibody molecules include fusion of an enzyme (eg, ADEPT) or peptides that increase the serum half-life of the antibody to the N- or C-terminus of the antibody molecule.
  • one or more amino acid modifications are introduced into the Fc region of an antibody described herein (eg, a full-length anti-C5a antibody or an anti-C5a antibody fusion protein), thereby generating Fc region variants.
  • Fc region variants have enhanced ADCC potency, typically associated with binding to Fc receptors (FcRs).
  • Fc region variants have reduced ADCC efficacy.
  • changes or mutations in the Fc sequence affecting its potency For example, WO 00/42072 and Shields et al. J Biol. Chem. 9(2):6591-6604 (2001) describe enhanced binding to FcRs or Attenuated antibody variants. The contents of these publications are incorporated herein by reference.
  • ADCC Antibody-dependent cell-mediated cytotoxicity
  • NK cells activated by antibodies.
  • NK cells express the Fc receptor CD16. This receptor recognizes and binds to the Fc portion of the antibody molecule bound to the surface of the target cell.
  • the most common Fc receptors on the surface of NK cells are CD16 or Fc ⁇ RIII.
  • Binding of Fc receptors to the Fc region of antibodies results in activation of NK cells, release of cell lytic granules, and subsequent target cell apoptosis.
  • the killing effect of ADCC on tumor cells can be measured through specific experiments of NK-92 cells transfected with high-affinity FcR. The results were compared with wild-type NK-92, which does not express FcR.
  • the application also provides anti-C5a antibody variants (e.g., full-length anti-C5a antibody variants) that comprise an Fc region with some, but not all, of the effector functions such that they have an extended half-life in vivo, yet specifically
  • the effector function (such as CDC or ADCC) is non-essential or deleterious, making this anti-C5a antibody an ideal candidate for this application. Reduction/elimination of CDC and/or ADCC activity is confirmed by performing cytotoxicity assays in vitro and/or in vivo.
  • Fc receptor (FcR) binding assays are used to confirm that the antibody lacks Fc ⁇ R binding ability (and therefore may lack ADCC activity) but still retains FcRn binding ability.
  • NK cells only express Fc ⁇ RIII
  • monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • Table 3 The expression of FcR on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet Annu. Rev. Immunol. 9:457-492 (1991).
  • Non-limiting examples of in vitro assessment of ADCC activity of target molecules are described in US Pat. No. 5,500,362 (see, e.g., Hellstrom, I.
  • CYTOTOX 96 TM Nonradioactive Cell Toxicity assays (Promega, Madison, Wis.). Effector cells used in these assays include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK).
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • the ADCC activity of the target molecule is performed in vivo Detection, for example, in animal models, as described in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998).
  • a C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q , thereby lacking CDC activity.
  • a CDC assay 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 MJ Glennie, Blood 103:2738-2743 (2004)). Determined using methods known in the art FcRn binding and clearance/half-life in vivo (see, eg, Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).
  • Antibodies with reduced effector function include substitution of one or more residues at residues 238, 265, 269, 270, 297, 327, and 329 of the Fc region (U.S. Pat. No. 6,737,056). These Fc variants include Fc variants with substitutions of two or more residues at positions 265, 269, 270, 297 and 327, including the Fc variant known as "DANA" which has substitutions at residues 265 and 297. The base is substituted with alanine (U.S. Pat. No. 7,332,581).
  • an anti-C5a antibody eg, a full-length anti-C5a antibody
  • an Fc region variant with one or more amino acid substitutions capable of enhancing ADCC effects.
  • the Fc region variant contains one or more amino substitutions capable of enhancing the ADCC effect at positions 298, 333 and/or 334 (EU residue numbering) of the Fc region.
  • the anti-C5a antibody (eg, full-length anti-C5a antibody) variant includes amino acid substitutions at positions S298A, E333A, and K334A in the Fc region.
  • changes in the Fc region result in changes (i.e., enhancement or attenuation) of Clq binding and/or complement-dependent cytotoxicity (CDC), see U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. al., J. Immunol. 164:4178-4184 (2000).
  • changes in the Fc region result in changes (i.e., enhancement or attenuation) of Clq binding and/or complement-dependent cytotoxicity (CDC), see U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. al., J. Immunol. 164:4178-4184 (2000).
  • an anti-C5a antibody e.g., a full-length anti-C5a antibody
  • an Fc region variant with one or more amino acid substitutions capable of extending half-life or enhancing interaction with an Fc receptor (FcRn ) combination is provided that includes an Fc region variant with one or more amino acid substitutions capable of extending half-life or enhancing interaction with an Fc receptor (FcRn ) combination.
  • FcRn Fc receptor
  • Fc variants contain 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or One or more substitutions in residue 434, for example, substitution of residue 434 in the Fc region (U.S. Pat. No. 7,371,826).
  • anti-C5a antibodies eg, full-length anti-C5a antibodies
  • Fc variants described herein or combinations thereof.
  • anti-C5a antibodies provided herein are altered to increase or decrease the extent of glycosylation of the anti-NGF antibody. Adding or deleting glycosylation sites on the anti-C5a antibody can be conveniently achieved by changing the amino acid sequence of the anti-NGF antibody or its polypeptide portion to add or remove one or more glycosylation sites.
  • the anti-C5a antibody contains an Fc region that can change the sugar attached to it.
  • Natural antibodies produced by mammalian cells typically contain branched biantennary oligosaccharides that are often linked to the Fc region CH2 domain Asn297 via an N-link, 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, as well as trehalose linked to GlcNAc in the "stem" portion of the biantennary oligosaccharide structure.
  • the anti-C5a antibodies of the present application can be subjected to oligosaccharide modifications, thereby producing anti-C5a antibody variants with certain improved properties.
  • N-glycans linked to the CH2 domain of the Fc region are heterogeneous.
  • Antibodies or Fc fusion proteins produced in CHO cells are fucosylated by fucosyltransferase activity, see Shoji-Hosaka et al., J. Biochem. 2006, 140:777-83.
  • a small proportion of naturally occurring afucosylated IgGs can be detected in human serum.
  • N-glycosylation of the Fc region is important for its binding to Fc ⁇ R; afucosylated N-glycan enhances the binding ability of Fc to Fc ⁇ RIIIa.
  • the enhanced binding ability to FcRIIIa results in enhanced ADCC effect, which is advantageous in certain antibody therapeutic applications that require cytotoxicity.
  • enhanced effector function may be detrimental when Fc-mediated cytotoxicity is not required.
  • the Fc fragment or CH2 domain is non-glycosylated.
  • glycosylation is prevented by mutating the N-glycosylation site in the CH2 domain.
  • anti-C5a antibody eg, full-length anti-C5a antibody
  • variants comprise an Fc region in which the carbohydrate structure linked to the Fc region has reduced fucose or lacks fucose, which may Will enhance ADCC function.
  • anti-C5a antibodies that have reduced fucose relative to the same anti-C5a antibody produced by wild-type CHO cells. That is, they are characterized by having smaller amounts of fucose than antibodies produced by native CHO cells (e.g., CHO cells that produce the native glycosylated form, CHO cells that contain the native FUT8 gene).
  • the N-linked glycan of the anti-C5a antibody has less than 50%, 40%, 30%, 20%, 10%, or 5% fucose.
  • the fucose content of the anti-C5a antibody may be 1%-80%, 1%-65%, 5%-65%, or 20%-40%.
  • the N-linked glycans of the anti-C5a antibody do not comprise fucose, i.e., wherein the anti-C5a antibody contains no fucose at all, or is free of fucose or afucosylated.
  • the fucose content is calculated by calculating the average fucose content within the sugar chain attached to Asn297 relative to the total of all sugar structures attached to Asn297 (such as complex, hybrid or mannose structures) measured by MALDI-TOF mass spectrometry. determined by quantity, as described in WO 2008/077546.
  • Asn297 refers to the asparagine residue located at position 297 in the Fc region (EU Fc region residue numbering system). However, due to minor sequence changes in the antibody, Asn297 can also 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 functions. See, for example, US Patent Publication Nos.
  • Cell lines capable of producing afucosylated antibodies include Lec13 CHO cells lacking protein fucosylation function (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US PatAppl No US 2003 /0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially Example 11), and gene knockout cell lines, such as ⁇ -1,6-fucosyltransferase gene, FUT8 Gene knockout CHO cells (see Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94 (4): 680-688 (2006); and WO2003/085107).
  • Anti-C5a antibody (eg, full-length anti-C5a antibody) variants further provide bisecting oligosaccharides, eg, wherein the biantennary oligosaccharide linked to the Fc region of the anti-C5a antibody is bisected by GlcNAc.
  • Such anti-C5a antibody (eg, full-length anti-C5a antibody) variants may have reduced fucosylation and/or enhanced ADCC function. Examples of such antibody variants are in WO 2003/011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana et al.); US 2005/0123546 (Umana et al.), and Ferrara et al.
  • anti-C5a antibody eg, full-length anti-C5a antibody
  • anti-C5a antibody variants that have 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 WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).
  • the anti-C5a antibody (eg, full-length anti-C5a antibody) variant comprises an Fc region capable of binding Fc ⁇ RIII.
  • 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 is identical to an anti-C5a antibody having a human wild-type IgG1 Fc region. Compared with other identical anti-C5a antibodies (eg, full-length anti-C5a antibodies), they have enhanced ADCC activity in the presence of human effector cells.
  • cysteine-engineered anti-C5a antibody eg, a full-length anti-C5a antibody
  • the substitution residue occurs at an accessible site of the anti-C5a antibody.
  • reactive thiol groups are located in accessible sites of the anti-C5a antibody and can be used to couple the anti-C5a antibody to other moieties, such as a drug moiety or a linker-drug moiety, to prepare anti-C5a immunoconjugates as further described herein.
  • Cysteine-engineered anti-C5a antibodies eg, full-length anti-C5a antibodies
  • anti-C5a antibodies eg, full-length anti-C5a antibodies
  • anti-C5a antibodies can be further modified to include other non-protein moieties known in the art and readily available.
  • Suitable moieties for derivatizing anti-C5a antibodies include, but are not limited to, water-soluble polymers.
  • Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymer, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1 , 3-dioxopentane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acid (homopolymer or random copolymer), dextran or poly(n- vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymer, propylene oxide/ethylene oxide copolymer, polyoxyethylated polyols (such as glycerol), polyvinyl alcohol, and mixtures thereof.
  • PEG polyethylene glycol
  • ethylene glycol/propylene glycol copolymer carboxymethylcellulose
  • dextran polyvinyl alcohol
  • polyvinylpyrrolidone poly-1 , 3-diox
  • Polyethylene glycol propionaldehyde offers advantages in manufacturing due to its stability in water.
  • the polymers can be of any molecular weight and can be branched or unbranched.
  • the number of polymers attached to the anti-C5a antibody can vary, and if more than one polymer is attached, they can be the same or different molecules.
  • the amount and/or type of polymer used for derivatization can be determined based on considerations including, but not limited to, the need to improve the properties or functionality of the anti-C5a antibody, whether the anti-C5a antibody derivative is useful under specific conditions. Treatment etc.
  • compositions comprising any of the anti-C5a antibodies (eg, full-length anti-C5a antibodies), nucleic acids encoding the antibodies, vectors comprising nucleic acids encoding the antibodies, or host cells comprising the nucleic acids or vectors described herein. substances, also referred to here as preparations).
  • a pharmaceutical composition comprising any of the anti-C5a antibodies described herein and a pharmaceutically acceptable carrier.
  • a suitable anti-C5a antibody can be obtained by mixing an anti-C5a antibody of the desired purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980))
  • Antibody preparations are prepared in the form of lyophilized preparations or liquid preparations.
  • Acceptable carriers, excipients or stabilizers are non-toxic to the recipient at the doses and concentrations used and include buffers such as phosphates, citric acid and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g.
  • Octadecyldimethylbenzyl ammonium chloride hexamethylammonium chloride; benzalkonium chloride; benzethonium chloride; phenol; butanol or benzyl alcohol; alkyl parabens, such as p-hydroxybenzoate Methyl formate or propyl parahydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than 10 residues) peptides; proteins, e.g.
  • 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 dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes such as zinc-protein complex); and/or non-ionic surfactants such as TWEEN TM , PLURONICS TM or polyethylene glycol (PEG); exemplary formulations are as described in WO98/56418, expressly incorporated herein by reference.
  • Lyophilized formulations suitable for subcutaneous administration are described in WO97/04801. Such lyophilized formulations can be reconstituted with appropriate diluents into high protein concentration formulations, and the reconstituted formulations can be administered subcutaneously to the individuals to be treated herein. Cationic liposomes or liposomes can be used to deliver the anti-C5a antibodies of the present application to cells.
  • the formulations described herein may also contain one or more other active substances necessary for the treatment of specific conditions, preferably substances with complementary activities and no adverse reactions to each other.
  • other active substances necessary for the treatment of specific conditions, preferably substances with complementary activities and no adverse reactions to each other.
  • it may be desirable to further include antineoplastic agents, growth inhibitory agents, cytotoxic agents, or chemotherapeutic agents. These molecules are present in combination and in amounts effective for the intended purpose. Effective amounts of other substances will depend on the amount of anti-C5a antibody in the formulation, the type of disease or condition or treatment, and other factors as discussed above.
  • These drugs are typically used at the same dosages and routes of administration as described herein, or at 1% to 99% of currently used dosages.
  • the anti-C5a antibodies can also be embedded in microcapsules prepared, for example, by coacervation techniques and interfacial polymerization, such as in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, respectively). , microemulsions, nanoparticles and nanocapsules) or in macroemulsions - microcapsules and poly(methyl methacrylate) microcapsules. Sustained release formulations can be prepared.
  • sustained release formulations of anti-C5a antibodies can be prepared.
  • suitable examples of sustained release formulations include solid hydrophobic polymeric semipermeable matrices containing the antibodies (or fragments thereof) in the form of shaped articles, for example, films or microcapsules.
  • sustained-release matrices include polyester, hydrogel (eg, poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid (U.S. Pat. No.
  • L-glutamine Acid and L-glutamic acid ethyl ester copolymer non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymer such as LUPRON DEPOTTM (a biodegradable product composed of lactic acid-glycolic acid copolymer and leuprolide acetate) injection microspheres) and poly-D(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic-glycolic acid can release molecules over 100 days, certain hydrogels can release proteins in much shorter time periods.
  • encapsulated antibodies When encapsulated antibodies stay in the body for a long time, they will denature or aggregate due to exposure to a humid environment at 37°C, which may lead to loss of biological activity or changes in immunogenicity.
  • Reasonable strategies can be designed to stabilize anti-C5a antibodies based on the corresponding mechanisms. For example, if the aggregation mechanism is found to be through thiodisulfide exchange to form intermolecular S-S bonds, this can be achieved by modifying sulfhydryl residues, lyophilizing in acidic solutions, controlling water content, using appropriate additives, and developing specific polymers. matrix composition to achieve stabilization.
  • the anti-C5a antibody (eg, full-length anti-C5a antibody) is formulated with citrate, sodium chloride, acetate, succinate, glycine, polysorbate 80 (Tween 80), or in any combination of the above buffers.
  • Preparations for in vivo administration must be sterile. This can be easily accomplished, for example, by applying sterile filtration membrane filtration.
  • Anti-C5a antibodies may be administered to an individual (e.g., a mammal, such as a human) to treat diseases and/or conditions resulting from dysregulation of the C5a signaling pathway (e.g., autoimmune and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune dysregulation diseases), including but not limited to inflammatory response syndrome (SIRS), sepsis , severe sepsis, septic shock, ischemia/reperfusion-related injury, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft-versus-host reaction, glomerular disease, glomerulonephritis, renal failure of entities, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth and solid organ cancers.
  • SIRS inflammatory response syndrome
  • sepsis severe sepsis
  • septic shock ischemia/reper
  • the present application provides a method for treating diseases and/or conditions caused by dysregulation of the C5a signaling pathway (e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplantation for immune dysregulation diseases), comprising administering to an 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), such as any of the methods described herein.
  • a composition e.g., a pharmaceutical composition
  • an anti-C5a antibody e.g., a full-length anti-C5a antibody
  • the subject is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a pharmaceutical composition comprising a C5a antibody (e.g., a full-length anti-C5a antibody) that specifically binds an epitope on human C5a, wherein the epitope Contains the amino acid residues of human C5a.
  • a pharmaceutical composition comprising a C5a antibody (e.g., a full-length anti-C5a antibody) that specifically binds an epitope on human C5a, wherein the epitope Contains the amino acid residues of human C5a.
  • the anti-C5a antibody is a full-length antibody.
  • the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, In the group consisting of Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway 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), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 2, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 6, or said Variants of VH comprising up to about 5 amino acid substitutions in the HC-CDRs; and light chain variable domains (VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 12.
  • a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1,
  • the anti-C5a antibody is a full-length antibody. In some embodiments, the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence set forth in SEQ ID NO: 25 or Variants thereof, which have at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:25; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:35 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:35.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • disease comprising administering to the individual an effective amount of a composition
  • an anti-C5a antibody described herein is a full-length anti-C5a antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a method for treating diseases associated with the C5a signaling pathway 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), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7, or said Variants of VH comprising up to about 5 amino acid substitutions in the HC-CDRs; and light chain variable domains (VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 12.
  • a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1,
  • the anti-C5a antibody is a full-length antibody. In some embodiments, the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic transplant rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence set forth in SEQ ID NO: 26 or Variants thereof, which have at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:26; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:36 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:36.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • disease comprising administering to the individual an effective amount of a composition
  • an anti-C5a antibody described herein is a full-length anti-C5a antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a method for treating diseases associated with the C5a signaling pathway 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), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 8, or said Variants of VH comprising up to about 5 amino acid substitutions in the HC-CDRs; and light chain variable domains (VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 13.
  • a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1,
  • the anti-C5a antibody is a full-length antibody. In some embodiments, the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence set forth in SEQ ID NO: 27 or Variants thereof, which have at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:27; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:37 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:37.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • disease comprising administering to the individual an effective amount of a composition
  • an anti-C5a antibody described herein is a full-length anti-C5a antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a method for treating diseases associated with the C5a signaling pathway 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), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 9, or said Variants of VH comprising up to about 5 amino acid substitutions in the HC-CDRs; and light chain variable domains (VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 14.
  • a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1,
  • the anti-C5a antibody is a full-length antibody. In some embodiments, the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence set forth in SEQ ID NO: 28 or Variants thereof, which have at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:28; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:38 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:38.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • disease comprising administering to the individual an effective amount of a composition
  • an anti-C5a antibody described herein is a full-length anti-C5a antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a method for treating diseases associated with the C5a signaling pathway 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), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 5, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 10, or said Variants of VH comprising up to about 5 amino acid substitutions in the HC-CDRs; and light chain variable domains (VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 14.
  • a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1,
  • the anti-C5a antibody is a full-length antibody. In some embodiments, the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic transplant rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence set forth in SEQ ID NO: 29 or Variants thereof, which have at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:29; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:39 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:39.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • disease comprising administering to the individual an effective amount of a composition
  • an anti-C5a antibody described herein is a full-length anti-C5a antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a method for treating diseases associated with the C5a signaling pathway 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), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7, or said Variants of VH comprising up to about 5 amino acid substitutions in the HC-CDRs; and light chain variable domains (VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 14.
  • a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1,
  • the anti-C5a antibody is a full-length antibody.
  • the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence set forth in SEQ ID NO: 30 or Variants thereof, which have at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:30; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:40 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:40.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • disease comprising administering to the individual an effective amount of a composition
  • an anti-C5a antibody described herein is a full-length anti-C5a antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a method for treating diseases associated with the C5a signaling pathway 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), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 9, or said Variants of VH comprising up to about 5 amino acid substitutions in the HC-CDRs; and light chain variable domains (VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 12.
  • a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1,
  • the anti-C5a antibody is a full-length antibody. In some embodiments, the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence set forth in SEQ ID NO: 31 or Variants thereof, which have at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:31; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:41 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:41.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • disease comprising administering to the individual an effective amount of a composition
  • an anti-C5a antibody described herein is a full-length anti-C5a antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a method for treating diseases associated with the C5a signaling pathway 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), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7, or said Variants of VH comprising up to about 5 amino acid substitutions in the HC-CDRs; and light chain variable domains (VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 15.
  • a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1,
  • the anti-C5a antibody is a full-length antibody. In some embodiments, the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence set forth in SEQ ID NO: 32 or Variants thereof, which variants have at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:32; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:42 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:42.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • disease comprising administering to the individual an effective amount of
  • an anti-C5a antibody described herein is a full-length anti-C5a antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a method for treating diseases associated with the C5a signaling pathway 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), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 4, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 7, or said Variants of VH comprising up to about 5 amino acid substitutions in the HC-CDRs; and light chain variable domains (VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 14.
  • a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1,
  • the anti-C5a antibody is a full-length antibody. In some embodiments, the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic transplant rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence set forth in SEQ ID NO: 33 or Variants thereof, which have at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:33; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:43 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:43.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • disease comprising administering to the individual an effective amount of a composition
  • an anti-C5a antibody described herein is a full-length anti-C5a antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • a method for treating diseases associated with the C5a signaling pathway 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), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1, HC-CDR2, which includes the amino acid sequence SEQ ID NO: 3, and HC-CDR3, which includes the amino acid sequence SEQ ID NO: 11, or the Variants of VH comprising up to about 5 amino acid substitutions in the HC-CDRs; and light chain variable domains (VL ) comprising: LC- CDR1 comprising the amino acid sequence SEQ ID NO: 16.
  • a pharmaceutical composition comprising an anti-C5a antibody (e.g., a full-length anti-C5a antibody), a heavy chain variable domain ( VH ), said V H includes: HC-CDR1, which includes the amino acid sequence SEQ ID NO: 1,
  • the anti-C5a antibody is a full-length antibody. In some embodiments, the full-length anti-C5a antibody is an IgGl or IgG4 antibody.
  • the disease or disorder is selected from, for example, inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injury, acute lung injury, pneumonia, acute and chronic graft rejection, graft-versus-host reaction, glomerular disease, glomerulonephritis, entities of renal failure, rheumatoid arthritis, autoimmune diseases, Bechterew's disease, lupus-like diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • the individual is a human.
  • a method for treating diseases associated with the C5a signaling pathway comprising administering to the individual an effective amount of a composition comprising an anti-C5a antibody, wherein the antibody comprises: VH , the VH comprising the amino acid sequence set forth in SEQ ID NO: 34 or Variants thereof, which have at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:34; and VL , which VL comprises the amino acid sequence shown in SEQ ID NO:44 or a variant thereof A variant having at least about 80% sequence identity with the amino acid sequence shown in SEQ ID NO:44.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • diseases associated with the C5a signaling pathway e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • disease comprising administering to the individual an effective amount of a composition
  • an anti-C5a antibody described herein is a full-length anti-C5a antibody comprising an IgGl or IgG4 constant region.
  • the IgG1 is human IgG1.
  • the IgG4 is human IgG4.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:45.
  • the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 46.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:47.
  • the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 48.
  • the subject is a mammal (eg, human, non-human primate, rat, mouse, cow, horse, porcine, sheep, goat, dog, cat, etc.).
  • the individual is a human.
  • the individual is a clinical patient, clinical trial volunteer, experimental animal, etc.
  • the individual is less than 60 years old (including, for example, less than 50, 40, 30, 25, 20, 15, or 10 years old).
  • the individual is older than 60 years old (including, for example, older than 70, 80, 90, or 100 years old).
  • the individual is diagnosed with or genetically predisposed to one or more diseases or conditions described herein (e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or or pain and/or respiratory and/or transplant immune disorders).
  • the individual has one or more risk factors associated with one or more diseases or conditions described herein.
  • the application provides a method of delivering an anti-C5a antibody (e.g., any of the anti-C5a antibodies described herein, e.g., an isolated anti-C5a antibody) to cells in an individual that express C5a on their surface, said The method includes administering to the individual a composition comprising an anti-C5a antibody.
  • an anti-C5a antibody e.g., any of the anti-C5a antibodies described herein, e.g., an isolated anti-C5a antibody
  • autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune dysregulation diseases or any other diseases showing aberrant expression of C5a and clinical description of these diseases are known in the art. Such methods include, but are not limited to, immunohistochemistry, PCR, and fluorescence in situ hybridization (FISH), for example.
  • FISH fluorescence in situ hybridization
  • the anti-C5a antibodies e.g., full-length anti-C5a antibodies
  • compositions described herein are combined with a second, third, or fourth agent (including, for example, an anti-tumor agent, a growth inhibitory agent, a cytotoxic agent or chemotherapeutic agents) to treat diseases related to the C5a signaling pathway.
  • a second, third, or fourth agent including, for example, an anti-tumor agent, a growth inhibitory agent, a cytotoxic agent or chemotherapeutic agents
  • Cancer treatments are evaluated using, for example, tumor regression, reduction in tumor weight or size, time to progression, survival, progression-free survival, overall response rate, duration of response, quality of life, protein expression levels and/or activity.
  • Methods of determining the effectiveness of treatment may be employed, including, for example, detection of response by radiographic imaging.
  • the effect of treatment is evaluated as percent tumor growth inhibition (%TGI), calculated using the equation 100 - (T/C ⁇ 100), where T is the relative mean tumor volume of the treated tumor and C is Relative mean tumor volume of untreated tumors.
  • %TGI percent tumor growth inhibition
  • the %TGI is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95% or more than 95%.
  • the therapeutic effect is assessed by changes in granulocyte morphology and/or an increase in the number of viable granulocytes.
  • therapeutic efficacy is assessed by increased secretion of cytokines by monocytes.
  • an anti-C5a antibody eg, isolated anti-C5a antibody
  • the dosage of an anti-C5a antibody composition administered to an individual may vary depending on the particular composition, the mode of administration, and the type of disease being treated.
  • the amount of the composition e.g., a composition comprising an anti-C5a antibody
  • the amount of anti-C5a antibody composition is sufficient to produce a complete response in an individual.
  • the amount of anti-C5a antibody composition is sufficient to produce a partial response in an individual.
  • the anti-C5a antibody composition is administered at a dose (e.g., when administered alone) sufficient to produce greater than 20%, 25%, 30%, 35%, or more in a population of individuals treated with the anti-C5a antibody composition.
  • An individual's response to the treatment methods described herein can be determined, for example, by the level of RECIST.
  • the amount of the composition is sufficient to prolong progression-free survival in an individual. In some embodiments, the amount of the composition is sufficient to prolong the overall survival of the subject. In some embodiments, the amount of the composition (eg, when administered alone) is sufficient to produce greater than 50%, 60%, 70%, or 77% of clinical benefit in a population of individuals treated with an anti-C5a antibody composition.
  • the amount of a composition is before treatment or with An amount sufficient to control symptoms and reduce the risk of exacerbation compared to the corresponding activity in other subjects not receiving treatment.
  • the magnitude of this effect can be measured using standard methods, such as in vitro assays of purified enzymes, cell-based assays, animal models, or human trials.
  • the amount of anti-C5a antibody (e.g., full-length anti-C5a antibody) in the composition is less than the amount that causes a toxic effect (i.e., an amount that is greater than a clinically acceptable level of toxicity) when the composition is administered to an individual. effect), or at a level at which potential side effects can be controlled or tolerated.
  • a toxic effect i.e., an amount that is greater than a clinically acceptable level of toxicity
  • the amount of the composition approximates the maximum tolerated dose (MTD) of the composition. In some embodiments, the amount of the composition is greater than 80%, 90%, 95%, or 98% of the MTD.
  • the amount of anti-C5a antibody (eg, full-length anti-C5a antibody) in the composition ranges from 0.001 ⁇ g to 1000 ⁇ g.
  • the effective amount of anti-C5a antibody eg, full-length anti-C5a antibody in the composition ranges from 0.1 ⁇ g/kg to 100 mg/kg based on body weight.
  • Anti-C5a antibody compositions can be administered to an individual (e.g., a human) by a variety of routes, including, for example, intravenous injection, intraarterial administration, intraperitoneal injection, intrapulmonary administration, oral administration, inhalation administration, intravascular administration, Intramuscular, intratracheal, subcutaneous, intraocular, intrathecal, mucosal or transdermal administration.
  • a sustained release formulation of the composition is used.
  • the composition is administered intravenously.
  • the composition is administered intraarterially.
  • the composition is administered intraperitoneally.
  • the composition is administered intrahepatically.
  • the composition is administered by hepatic artery infusion.
  • the composition is administered to a site distal to the first lesion.
  • an article of manufacture comprising a substance that can be used to treat diseases associated with the C5a signaling pathway (e.g., autoimmune diseases and/or inflammatory disorders and or cancer and/or pain and/or respiratory and/or transplant immune disorders), or for delivering an anti-C5a antibody (e.g., a full-length anti-C5a antibody) to cells expressing C5a on their surface.
  • the article of manufacture may include a container and a label or package insert on or accompanying the container. Suitable containers include, for example, bottles, vials, syringes, and the like. Containers can be made from a variety of materials, such as glass or plastic.
  • the container contains a composition effective for treating the disease or condition described herein and has a sterile port (eg, the container may be an IV bag or a vial with a hypodermic needle-pierceable cap). At least one active substance in the composition is the anti-C5a antibody described in this application.
  • the label or package insert identifies the specific condition for which the composition is used to treat.
  • the label or package insert further contains instructions for administering the anti-C5a antibody composition to a patient. Articles and kits including combination therapies are considered within the scope of this article.
  • Package insert means the instructions usually included in the commercial packaging of therapeutic products that contain information on indications, usage, dosage, administration, contraindications and/or warnings relevant to the use of these therapeutic products.
  • the package insert indicates that the composition can be used to treat diseases associated with the C5a signaling pathway (e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or Transplant immune disorders).
  • the package insert states that the composition can be used to treat conditions including 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-like diseases , inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancers.
  • SIRS inflammatory response syndrome
  • the article of manufacture may further include a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffer, Green's solution, or dextrose solution.
  • a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffer, Green's solution, or dextrose solution.
  • kits that can be used for various purposes, for example for the treatment of diseases associated with the C5a signaling pathway (e.g. autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or immune disorders), or for delivering anti-C5a antibodies (eg, full-length anti-C5a antibodies) to cells expressing C5a on their surface, optionally in combination with an article of manufacture.
  • Kits of the present application include one or more containers comprising an anti-C5a antibody composition (or single dose form and/or article of manufacture) and, in some embodiments, further comprising another agent (e.g., an agent described herein ) and/or instructions for use consistent with any method described herein.
  • the kit may further include instructions for selecting individuals suitable for treatment. Instructions for use accompanying the kit in this application are usually written instructions on the label or package insert (e.g., a sheet of paper included in the kit), machine-readable instructions (e.g., instructions on a magnetic or optical storage disc) Also acceptable.
  • the kit includes a composition comprising an anti-C5a antibody (eg, a full-length anti-C5a antibody).
  • a kit includes: a) a composition comprising any one of the anti-C5a antibodies described herein, and b) an effective amount of at least one other agent capable of enhancing the effects of the anti-C5a antibody (e.g., treating effect, detection effect).
  • a kit includes: a) a composition comprising any one of the anti-C5a antibodies described herein, and b) administering the anti-C5a antibody composition to an individual for treating a disease associated with the C5a signaling pathway (e.g., Instructions for use in autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders).
  • a disease associated with the C5a signaling pathway e.g., Instructions for use in autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • a kit includes: a) a composition comprising any one of the anti-C5a antibodies described herein, and b) an effective amount of at least one other agent capable of enhancing the effects of the anti-C5a antibody (e.g., treating effect, detecting effect) and c) administering anti-C5a antibody compositions and other substances to an individual for the treatment of diseases associated with the C5a signaling pathway (e.g., autoimmune diseases and/or inflammatory conditions and/or cancer and/or pain and /or respiratory and/or transplant immune disorders) instructions for use.
  • the anti-C5a antibody and other substances may be present in separate containers or in the same container.
  • the kit may include one specific composition or two or more compositions, one of which includes an anti-C5a antibody and another of which includes another agent.
  • the kit includes a nucleic acid (or a set of nucleic acids) encoding an anti-C5a antibody (eg, a full-length anti-C5a antibody).
  • the kit comprises: a) a nucleic acid (or set of nucleic acids) encoding an anti-C5a antibody (eg, a full-length anti-C5a antibody), and b) a host expressing the nucleic acid (or set of nucleic acids) cell.
  • the kit comprises: a) a nucleic acid (or a set of) nucleic acids encoding an anti-C5a antibody (e.g., a full-length anti-C5a antibody), and b) instructions for: i) in a host cell Expressing an anti-C5a antibody, ii) preparing a composition comprising the anti-C5a antibody, and iii) administering the composition comprising the anti-C5a antibody to an individual to treat a disease associated with the C5a signaling pathway (e.g., autoimmune disease and/or inflammatory disorder and/or cancer and/or pain and/or respiratory and/or transplant immune disorders).
  • a disease associated with the C5a signaling pathway e.g., autoimmune disease and/or inflammatory disorder and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • the kit includes: a) a nucleic acid (or a set of nucleic acids) encoding an anti-C5a antibody (eg, a full-length anti-C5a antibody), b) a host cell expressing the nucleic acid (or a set of nucleic acids) , and c) instructions for use in: i) expressing an anti-C5a antibody in a host cell, ii) preparing a composition comprising an anti-C5a antibody, and iii) administering a composition comprising an anti-C5a antibody to an individual to treat patients with C5a signaling Pathway related diseases (eg autoimmune diseases and/or inflammatory disorders and/or cancer and/or pain and/or respiratory and/or transplant immune disorders).
  • C5a signaling Pathway related diseases eg autoimmune diseases and/or inflammatory disorders and/or cancer and/or pain and/or respiratory and/or transplant immune disorders.
  • kits for detection and/or diagnosis comprising any of the anti-C5a antibodies described herein.
  • the kit includes a conjugate comprising any anti-C5a antibody described herein and a coupling moiety, wherein the coupling moiety is a radioactive isotope, a fluorescent substance, a luminescent substance , colored substances or enzymes.
  • it relates to the use of any of the anti-C5a antibodies described in this application or the conjugate of the invention in preparing a kit for detecting the presence or level of C5a in a sample.
  • an in vitro method of detecting the presence or level of C5a in a sample comprising: a) contacting the sample with any of the methods described herein under conditions that allow the formation of a complex between the antibody and C5a. contacting an anti-C5a antibody or conjugate; and b) detecting the formation of a complex; and c) determining the presence or level of C5a in the sample.
  • a method for diagnosing abnormalities in C5a levels comprising: a) obtaining a sample to be tested, and b) combining the sample to be tested with the method described herein under conditions that allow the formation of a complex between the antibody and C5a. Contact any of the anti-C5a antibodies or conjugates; c) detect the formation of the complex; d) determine the level of C5a in the sample to be tested; and e) determine whether the level of C5a in the sample to be tested is higher than normal Levels of C5a in group samples.
  • the sample is a serum sample or plasma sample.
  • the sample to be tested is derived from a patient in need.
  • the patient has or has not received C5a antibody treatment.
  • kits described in this application are packaged in a suitable form.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (eg, sealed mylar or plastic bags), and the like. Kits may optionally provide other components such as buffers and instructions. Accordingly, the present application also provides articles including vials, bottles, jars, flexible packaging (eg, sealed Mylar or plastic bags), and the like.
  • Containers may be unit dose, bulk (eg, multi-dose packaging) or subunit dose.
  • a kit is provided that contains a sufficient dose of an anti-C5a antibody as described herein (e.g., a full-length anti-C5a antibody) to effectively treat an individual for a long period of time, such as one week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or longer time.
  • the kit may also contain multiple unit doses of the anti-C5a antibody, the pharmaceutical composition and instructions for use, and be packaged in quantities sufficient for storage and use in pharmacies, such as hospital pharmacies and compounding pharmacies.
  • complement component 5a complement component 5a, C5a
  • Bavih-C5a Biotin-Avi-10his-C5a
  • Example 1 Preparation of recombinant human C5a and screening of anti-C5a single chain antibodies (scFv)
  • the cDNA encoding human C5a (synthesized by Shanghai Jierui Bioengineering Co., Ltd.) was constructed into the prokaryotic expression vector pTWIN1 or the eukaryotic expression vector pTT5 by subcloning. Add His tag or other tags commonly used by those skilled in the art at the end of the cDNA encoding the above protein.
  • the pTWIN1-C5a and pTT5-Avi-10his-C5a expression vectors were constructed and produced. Among them, “his” or “His” represents the His tag, and "Avi” represents the avidin tag.
  • the eukaryotic expression vector pTT5-Avi-10his-C5a was transfected into 293F cells, and the above cells were cultured at 37°C, 8% CO 2 , and 120 rpm for 5 days. Collect cell culture fluid. According to the operating instructions, a nickel column (Ni) was used to purify the protein expressing His tag. The specific operation is as follows: Immobilized metal affinity chromatography (IMAC) is performed using Ni-NTA from QIAGEN Company.
  • IMAC Immobilized metal affinity chromatography
  • buffer A1 50mM Na 3 PO 4 , 0.15M NaCl, pH 7.2
  • the pH of the culture supernatant was adjusted to 7.2, and the sample was loaded at room temperature with a flow rate of 150cm/h.
  • the column was equilibrated again with 6 column volumes of A1 buffer at a flow rate of 150 cm/h.
  • 10 times the column volume of 50mM PB solution (containing 0.15M NaCl and 0.2M imidazole, pH 7.2) was used for elution, and the eluent was collected.
  • the recombinant human C5a prokaryotic expression vector pTWIN1-C5a was transformed into E. coli and expanded cultured. After collecting the bacterial cells, add 300ml of 50mM Tris solution, stir to dissolve, and place in a -40°C refrigerator overnight. The next day, the above samples were taken out and thawed, and the cells were disrupted using an ultrasonic disruptor. After centrifugation, take the supernatant and filter the supernatant with a 0.8um filter membrane.
  • Avi-10His-C5a was biotinylated using biotinylated ligase B0101A (GeneCopoeia). Briefly, BufferA/B and BirA ligase were added to Avi-10His-C5a and incubated at 30°C for 2 hours. Biotinylated Avi-10His-C5a was named Bavih-C5a. Biotinylation efficiency was detected by ELISA method. Briefly, the starting concentration of Bavih-C5a was set to 500ng/ml, diluted at a ratio of 1:2, and then coated on the ELISA plate after dilution. SA-HRP was used to detect the signal, and biotinylated standards were used as controls. The Bavih-C5a biotinylation labeling efficiency was determined to be 70%.
  • Construct scFv antibody phage display library use recombinant human C5a as the antigen, immunize rabbits together with adjuvant, collect the animal serum after immunization, and detect the total IgG titer in the rabbit serum after immunization by ELISA. After several rounds of immunization, peripheral blood, lymph nodes, and spleen were used to establish a phage display library. Briefly, peripheral blood, lymph nodes and spleens of immunized rabbits were collected, RNA was extracted, and cDNA was obtained by reverse transcription. VH and VK fragments were amplified using VH and VK specific primers.
  • VH and VK were ligated to construct scFv and cloned into the phage display plasmid pDAN5. Subsequently, the plasmid was electroporated into E. coli TG1, and the phage was used to infect E. coli TG1 to obtain a scFv antibody phage display library.
  • scFv single chain antibodies
  • 2x10 11 PFU of the phage scFv library was added to Bavih-C5a and incubated at 37°C for 2 hours. Phage that bind to human C5a are captured by streptavidin-coated magnetic beads, while unbound phage are washed away. After washing 8-15 times with TBST solution (as the number of screening rounds increases, the number of washes increases), Glycine-HCl solution (pH 2.2) is used to elute the phage that specifically binds human C5a.
  • the obtained positive scFv antibody is reconstituted into a human IgG1 or IgG4 antibody molecule having a heavy chain constant region of human IgG1 or IgG4 and a human kappa or lambda light chain constant region.
  • V L and V H were amplified from the phage expression vector and constructed into the eukaryotic expression vector pTT5-K (containing the kappa constant region) or pTT5-L (containing the lambda constant region) and pTT5-H1 (containing the IgG1 heavy chain constant region) respectively. ) or pTT5-H4 (containing the IgG4 heavy chain constant region).
  • the plasmid expressing the light chain and the plasmid expressing the heavy chain were co-transfected into 293F cells. Cultivate for 5 days at 37°C, 8% CO 2 , 120 rpm, and purify the culture solution using a Protein A affinity chromatography column. Briefly, the Protein A column was first equilibrated with 6 column volumes of PBS buffer (containing 50 mM PBS and 0.15 M NaCl, pH 7.2) at a flow rate of 150 cm/h. The pH of the culture supernatant was adjusted to 7.2, and the sample was loaded at room temperature with a flow rate of 150cm/h. After complete equilibrium, 50 mM sodium citrate buffer (pH 3.5) was added for elution, and the eluate was collected.
  • PBS buffer containing 50 mM PBS and 0.15 M NaCl, pH 7.2
  • Each antibody sample was first diluted to 10 ⁇ g/mL, followed by gradient dilution in a 1:3 ratio. Add the gradient diluted samples to a 96-well plate, 100 ⁇ L per well, and incubate at 37°C for 1 hour. Then wash 6 times with TBST solution, add goat anti-human IgG Fc-AP antibody (SouthernBiotech, 2048-04; 1:2500), 100 ⁇ L per well, and incubate at 37°C for 1 hour. After washing with TBST plate washer 6 times, add 50 ⁇ L of pNPP to each well, incubate at 37°C for 10 min, and terminate the reaction with 3M NaOH. The absorbance value at 410 nm was read and a binding curve was generated by PRISM.
  • each antibody sample was first diluted to 10 ⁇ g/mL, followed by gradient dilution in a 1:3 ratio. Add the gradient diluted samples to a 96-well plate, 100 ⁇ L per well, and incubate at 37°C for 1 hour. Then wash with TBST solution 6 times, add anti-human Fc-AP antibody (1:2500), 100 ⁇ L per well, and incubate at 37°C for 1 hour.
  • ROS Reactive oxygen species
  • C5a can stimulate neutrophils to release reactive oxygen species (ROS), thereby promoting neutrophils to participate in a wide range of inflammatory responses. Based on this mechanism, induced neutrophils were used to detect the blocking effect of anti-C5a antibodies.
  • the HL-60 cell line is human promyelocytic leukemia cells. Briefly, HL60 cells were treated with 1mM dibutyryl cAMP sodium salt (sigma, D0260) for 48 hours to induce their differentiation. The cells shrank to a spindle shape and became neutral. Granulocytic differentiation. C5a stimulates ROS production in differentiated HL-60 cells in a dose-dependent manner.
  • ROS reactive oxygen species
  • the inhibition rates with only C5a stimulation and without C5a stimulation were calculated as 0% and 100%, respectively.
  • the experimental data were normalized to calculate the IC 50 value of the C5a antibody.
  • Anti-C5a antibodies RH23, RH25, RH32, RH35, RH36, RH58, RH85, RH86, RH92, and RH95 (reconstituted in the form of adult IgG4) can all inhibit ROS release well and are comparable to the control antibody INab308. .
  • Example 3 In vivo effect of anti-C5a antibody in treating ARDS caused by coronavirus
  • ARDS animal disease model and normal control group A total of 46 C5a humanized mice (purchased from Shanghai Southern Model Biotechnology Co., Ltd.) were used. 40 of them were administered 4, 3 and 2 days before the experiment.
  • mice were injected with adenovirus carrying and expressing SARS-CoV-2 N protein (see Ting Gao et al., https://doi.org/10.1101/2020.03.29.20041962), 7.5 ⁇ 10 8 PFU/100 ⁇ L/mouse/time/ day, the disease model groups were divided into model control group, high-dose group (10mg/kg), medium-dose group (3mg/kg) and low-dose group (1mg/kg). On day 0 (the day of the experiment), mice were injected with the corresponding doses of antibodies in parentheses. The remaining 6 mice were injected with 100 ⁇ L of 0.9% sodium chloride solution as a normal control group.
  • mice in the disease model control group and each experimental group were injected with LPS-K235 (Sigma-Aldrich) at a concentration of 1 mg/mL, 100 ⁇ L/mouse. All reagents in this study were administered by tail vein injection. The survival of mice in each group was observed and analyzed at 12h, 24h, 36h, 48h, 60h and 72h after administration. 72 hours after antibody administration, the mice were anesthetized, and blood was collected from the orbits. use A series of blood analyzers perform whole blood white blood cell counting and classification, including white blood cell count (WBC), neutrophils (Neut), lymphocytes (Lymph), and monocytes (Mono). ELISA method was used to detect the levels of GM-CSF, IL-1 ⁇ , IL-6, TNF- ⁇ , MCP-1 and other cytokines.
  • the anti-C5a antibody RH86 of the present application can effectively reduce or prevent the death of mice caused by coronavirus and improve the survival rate of mice.
  • the levels of WBC, Lymph and Mono of mice in the model control group were reduced, and the levels of GM-CSF, IL-1 ⁇ , IL-6, TNF- ⁇ , and MCP-1 were significantly increased. There is a statistically significant difference between them (P ⁇ 0.05).
  • the three dose experimental groups administered anti-C5a antibody (RH86) all showed an increase in the number of WBC and Lymph, GM-CSF, IL-1 ⁇ , IL-6, TNF- ⁇ , MCP- 1.
  • C5a levels decreased in a dose-dependent manner.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Mycology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Pulmonology (AREA)
  • Communicable Diseases (AREA)
  • Urology & Nephrology (AREA)
  • Transplantation (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne un anticorps reconnaissant de manière spécifique C5a. L'anticorps a une activité de liaison élevée au C5a humain ou au C5a-desArg humain. En outre, la présente invention concerne également une séquence nucléotidique codant pour l'anticorps, un vecteur et une cellule comprenant la séquence nucléotidique, une composition pharmaceutique comprenant l'anticorps, une utilisation de l'anticorps dans la préparation d'un médicament pour le traitement de maladies auto-immunes et d'une inflammation, du cancer, de la douleur, de maladies liées à la respiration et/ou à la transplantation, et une utilisation de l'anticorps ou d'un conjugué de celui-ci dans la préparation d'un kit pour détecter la présence ou le niveau de C5a.
PCT/CN2023/085301 2022-04-02 2023-03-31 Anticorps reconnaissant de manière spécifique c5a et utilisation associée WO2023186054A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380009755.5A CN117203230A (zh) 2022-04-02 2023-03-31 特异性识别c5a的抗体及其应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210350226 2022-04-02
CN202210350226.9 2022-04-02

Publications (1)

Publication Number Publication Date
WO2023186054A1 true WO2023186054A1 (fr) 2023-10-05

Family

ID=88199478

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/085301 WO2023186054A1 (fr) 2022-04-02 2023-03-31 Anticorps reconnaissant de manière spécifique c5a et utilisation associée

Country Status (2)

Country Link
CN (1) CN117203230A (fr)
WO (1) WO2023186054A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HK1029595A1 (en) * 1997-06-25 2001-04-06 Univeristy Of Queensland Cyclic antagonists of c5a receptors and g protein-coupled receptors
CN102741283A (zh) * 2009-11-26 2012-10-17 因弗拉克斯有限责任公司 具有高阻断活性的抗-C5a结合部分
AU2013200223A1 (en) * 2005-11-04 2013-01-31 Genentech, Inc. Use of Complement Pathway Inhibitors to Treat Ocular Diseases
CN103201289A (zh) * 2010-04-30 2013-07-10 阿雷克森制药公司 抗-c5a抗体和使用所述抗体的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HK1029595A1 (en) * 1997-06-25 2001-04-06 Univeristy Of Queensland Cyclic antagonists of c5a receptors and g protein-coupled receptors
AU2013200223A1 (en) * 2005-11-04 2013-01-31 Genentech, Inc. Use of Complement Pathway Inhibitors to Treat Ocular Diseases
CN102741283A (zh) * 2009-11-26 2012-10-17 因弗拉克斯有限责任公司 具有高阻断活性的抗-C5a结合部分
CN103201289A (zh) * 2010-04-30 2013-07-10 阿雷克森制药公司 抗-c5a抗体和使用所述抗体的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CAROLINE S. COLLEY, BOJANA POPOVIC, SUDHARSAN SRIDHARAN, JUDIT E. DEBRECZENI, DAVID HARGEAVES, MICHAEL FUNG, LING–LING AN, B: "Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors", MABS, US , pages 1 - 14, XP055425527, ISSN: 1942-0862, DOI: 10.1080/19420862.2017.1384892 *
CHEN CHEN, LV RUO-YUN, WEI JING-SHUANG: "Role of C5a in inflammatory reaction and development of anti-C5a antibody drugs", CHINESE JOURNAL OF BIOLOGICALS, CHINESE PREVENTIVE MEDICINE ASSOCIATION, CHINA, vol. 28, no. 5, 31 May 2015 (2015-05-31), China , XP055889587, ISSN: 1004-5503 *

Also Published As

Publication number Publication date
CN117203230A (zh) 2023-12-08

Similar Documents

Publication Publication Date Title
WO2022052974A1 (fr) Anticorps reconnaissant de manière spécifique le récepteur alpha de l'interleukine 4 et leurs utilisations
JP2023011887A (ja) 顆粒球－マクロファージコロニー刺激因子受容体αを特異的に認識する抗体及びその使用
WO2023138521A1 (fr) Anticorps reconnaissant spécifiquement fasl et application associée
TW202334235A (zh) 特異性識別ＦａｓＬ的抗體及其應用
WO2021259160A1 (fr) Anticorps reconnaissant de manière spécifique c5a et leurs utilisations
WO2023186054A1 (fr) Anticorps reconnaissant de manière spécifique c5a et utilisation associée
WO2023217068A1 (fr) Anticorps reconnaissant de manière spécifique gdf15 et son utilisation
WO2022166739A1 (fr) Anticorps reconnaissant spécifiquement la lymphopoïétine stromale thymique et leurs utilisations
WO2023030501A1 (fr) Anticorps capable de reconnaître de manière spécifique fcrn et son utilisation
WO2024056010A1 (fr) Anticorps reconnaissant spécifiquement nkg2a et utilisation associée
WO2024067344A1 (fr) Anticorps pour reconnaître spécifiquement les ligands light et son utilisation
WO2023066171A1 (fr) Anticorps se liant spécifiquement un antigène de surface pré-s1 du virus de l'hépatite b et application de l'anticorps
WO2023016538A1 (fr) Anticorps reconnaissant spécifiquement fcrn et leurs utilisations
TW202334232A (zh) 特異性識別C5aR1之抗體及其應用
CN115925918A (zh) 特异性识别c5a的抗体及其应用
TW202340238A (zh) 分離的抗體或抗原結合片段、其製備方法、編碼其的核酸分子、包含其的載體、宿主細胞和藥用組合物及其用途

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 202380009755.5

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23778419

Country of ref document: EP

Kind code of ref document: A1