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US-20260125455-A1 - HUMAN C6 BINDING MOLECULES FOR TREATING DISEASES

US20260125455A1US 20260125455 A1US20260125455 A1US 20260125455A1US-20260125455-A1

Abstract

Provided herein are human C6 binding molecules and nucleic acid sequences encoding such molecules. In particular embodiments, provided herein are human C6 binding molecules (e.g., monoclonal antibodies or antigen binding fragments thereof) with particular light and/or heavy chains variable regions, or light chain and/or heavy chain CDRs, and methods for using such molecules to treat a disease, such as a complement-mediated disease.

Inventors

  • Feng Lin

Assignees

  • THE CLEVELAND CLINIC FOUNDATION

Dates

Publication Date
20260507
Application Date
20231020

Claims (20)

  1. 1 . A composition comprising a human C6 binding molecule, wherein said human C6 binding molecule comprises: a) a heavy chain variable region, wherein said heavy chain variable region comprises: i) a CDRH1 amino acid sequence comprising SEQ ID NO: 14, 22, 30, 38, or 46, or any of the preceding with one with one or two conservative amino acid changes, ii) a CDRH2 amino acid sequence comprising SEQ ID NO:15, 23, 31, 39, or 47, or any of the preceding with one or two conservative amino acid changes, and iii) a CDRH3 amino acid sequence comprising SEQ ID NO: 16, 24, 32, 40, or 48, or any of the preceding with one with one or two conservative amino acid changes, and/or; b) a light chain variable region, wherein said light chain variable region comprises; i) a CDRL1 amino acid sequence comprising SEQ ID NO: 18, 26, 34, 42, or 50, or any of the preceding with one with one or two conservative amino acid changes, ii) a CDRL2 amino acid sequence comprising SEQ ID NO: 19, 27, 35, 43, or 51, or any of the preceding with one with one or two conservative amino acid changes, and iii) a CDRL3 amino acid sequence comprising SEQ ID NO: 20, 28, 36, 44, or 52, or any of the preceding with one with one or two conservative amino acid changes.
  2. 2 . The composition of claim 1 , wherein said human C6 binding molecule is an antibody, minibody, diabody, scFv, or antibody fragment capable of binding human C6.
  3. 3 . The composition of claim 2 , wherein said antibody fragment is a Fab, F(ab′)2 or Fv antibody fragment.
  4. 4 . The composition of claim 2 , wherein said antibody or antibody fragment comprises at least an antigen binding portion of: 1) C601 HFKC4 HuG4K (aka 3713) antibody, 2) C601 HFKI HuG4K antibody, 3) C601 HPKI HuG4K antibody, 4) C601 HOKC4 HuG4K antibody, or 5) C601 HPKC4 HuG4K antibody.
  5. 5 . The composition of claim 1 , wherein said heavy chain and/or light chain variable region comprises a human framework region.
  6. 6 . The composition of claim 1 , wherein said human C6 binding molecule further comprises a light chain constant region and a CH1 heavy chain constant region.
  7. 7 . The composition of claim 6 , wherein said C6 binding molecule further comprises a CH2 heavy chain constant region and/or a CH3 heavy chain constant region.
  8. 8 . The composition of claim 7 , wherein said light chain constant region is human or a humanized murine, and/or wherein said CH1, CH2, and CH3 heavy chain constant regions are human or are humanized murine.
  9. 9 . The composition of claim 1 , wherein said human C6 binding molecule is an antibody or antigen binding portion thereof that has an Fc region characterized in that it: i) has an Fc cellular binding site; or ii) has a Fc complement binding site.
  10. 10 . The composition of claim 1 , wherein said human C6 binding molecule comprises an antibody, wherein the light chain constant region of said antibody is selected from: IgG Kappa and IgG Lambda, and wherein the heavy chain constant region of said antibody is selected from: IgG1, IgG2, IgG3, and IgG4.
  11. 11 . The composition of claim 1 , wherein said human C6 binding molecule comprises an antibody, or antigen binding portion thereof, which is glycosylated or non-glycosylated.
  12. 12 . The composition of claim 1 , further comprising a physiologically tolerable buffer.
  13. 13 . The composition of claim 1 , wherein said heavy chain variable regions comprises SEQ ID NO: 13, 21, 29, 37, or 45, or any of the preceding with one or more conservative amino acid changes.
  14. 14 . The composition of claim 1 , wherein said light chain variable region comprises SEQ ID NO: 17, 25, 33, 41, or 49, or any of the preceding with one or more conservative amino acid changes.
  15. 15 . A composition comprising at least one of the following: a) a first nucleic acid sequence encoding a heavy chain variable region, wherein said heavy chain variable region comprises: i) a CDRH1 amino acid sequence comprising SEQ ID NO: 14, 22, 30, 38, or 46, or any of the preceding with one with one or two conservative amino acid changes, ii) a CDRH2 amino acid sequence comprising SEQ ID NO:15, 23, 31, 39, or 47, or any of the preceding with one or two conservative amino acid changes, and iii) a CDRH3 amino acid sequence comprising SEQ ID NO: 16, 24, 32, 40, or 48, or any of the preceding with one with one or two conservative amino acid changes, and/or; b) a second nucleic acid sequence encoding a light chain variable region, wherein said light chain variable region comprises: i) a CDRL1 amino acid sequence comprising SEQ ID NO: 18, 26, 34, 42, or 50, or any of the preceding with one with one or two conservative amino acid changes, ii) a CDRL2 amino acid sequence comprising SEQ ID NO: 19, 27, 35, 43, or 51, or any of the preceding with one with one or two conservative amino acid changes, and iii) a CDRL3 amino acid sequence comprising SEQ ID NO: 20, 28, 36, 44, or 52, or any of the preceding with one with one or two conservative amino acid changes.
  16. 16 . The composition of claim 15 , further comprising an expression vector, and wherein said first and/or second nucleic acid sequences are present in said expression vector.
  17. 17 . The composition of claim 15 , wherein said light and heavy chain variable regions are part of a human C6 binding molecule.
  18. 18 . The composition of claim 17 , wherein said human C6 binding molecule is an antibody, minibody, diabody, scFv, or antibody fragment capable of binding human C6.
  19. 19 . The composition of claim 18 , wherein said antibody fragment is a F(ab′)2, Fab or Fv antibody fragment.
  20. 20 . The composition of claim 18 , wherein said antibody or antibody fragment comprises at least an antigen binding portion of: 1) C601 HFKC4 HuG4K (aka clone 3713) antibody, 2) C601 HFKI HuG4K antibody, 3) C601 HPKI HuG4K antibody, 4) C601 HOKC4 HuG4K antibody, or 5) C601 HPKC4 HuG4K antibody.

Description

The present application claims priority to U.S. Provisional application Ser. No. 63/380,391, filed Oct. 21, 2022, which is herein incorporated by reference in its entirety. FIELD OF THE INVENTION Provided herein are human C6 binding molecules and nucleic acid sequences encoding such molecules. In particular embodiments, provided herein are human C6 binding molecules (e.g., monoclonal antibodies or antigen binding fragments thereof) with particular light and/or heavy chains variable regions, or light chain and/or heavy chain CDRs, and methods for using such molecules to treat a disease, such as a complement-mediated disease. BACKGROUND OF THE INVENTION Complement activation is a key function of the immune system and occurs via three pathways: the classical, alternative and lectin pathways. All pathways result in the cleavage of C5 into C5a and C5b, whereupon the C5b cleavage product binds to C6. Subsequent binding of C7, C8 and multiple C9 molecules leads to assembly of a membrane attack complex on the target cell membrane. However, multiple diseases are caused by excessive membrane attack complex formation and the damage this does to host tissues. A therapeutic approach to inhibit membrane attack complex formation has been to target C5 with an antibody (eculizumab) that prevents its cleavage. Although this has been used successfully to treat complement-mediated disease, an anti-C5 may not be ideal due concomitant suppression of C5a-initiated inflammation, fast turnover of C5 leading to high requirements for antibody and some patients being incompletely responsive or unresponsive to treatment. SUMMARY OF THE INVENTION Provided herein are human C6 binding molecules and nucleic acid sequences encoding such molecules. In particular embodiments, provided herein are human C6 binding molecules (e.g., monoclonal antibodies or antigen binding fragments thereof) with particular light and/or heavy chains variable regions, or light chain and/or heavy chain CDRs, and methods for using such molecules to treat a disease, such as a complement-mediated disease. In some embodiments, provided herein are compositions comprising a human C6 binding molecule, wherein the human C6 binding molecule comprises: a) a heavy chain variable region, or a first nucleic acid sequence encoding the heavy chain variable region, wherein the heavy chain variable region comprises: i) a CDRH1 amino acid sequence comprising SEQ ID NO: 14, 22, 30, 38, or 46, or any of the preceding with one with one or two conservative amino acid changes, ii) a CDRH2 amino acid sequence comprising SEQ ID NO: 15, 23, 31, 39, or 47, or any of the preceding with one or two conservative amino acid changes, and iii) a CDRH3 amino acid sequence comprising SEQ ID NO: 16, 24, 32, 40, or 48, or any of the preceding with one with one or two conservative amino acid changes, and/or; b) a light chain variable region, or a second nucleic acid sequence encoding the light chain variable region, wherein the light chain variable region comprises: i) a CDRL1 amino acid sequence comprising SEQ ID NO: 18, 26, 34, 42, or 50, or any of the preceding with one with one or two conservative amino acid changes, ii) a CDRL2 amino acid sequence comprising SEQ ID NO: 19, 27, 35, 43, or 51, or any of the preceding with one with one or two conservative amino acid changes, and iii) a CDRL3 amino acid sequence comprising SEQ ID NO: 20, 28, 36, 44, or 52, or any of the preceding with one with one or two conservative amino acid changes. In certain embodiments, the a human C6 binding molecule binds the FIM domain of human C6. In some embodiments, provided herein are methods of treating or preventing a complement-mediated disease comprising: treating a subject with a human C6 binding molecule as recited above and herein, or an expression vector encoding such human C6 binding molecule, and wherein the subject has, or is suspected to develop, a complement-mediated disease. In certain embodiments, provide herein are methods of inhibiting Membrane Attack Complex (MAC) formation or activity in a subject comprising: administering to the subject a human C6 binding molecule as recited above and herein, or an expression vector encoding said human C6 binding molecule, in an amount effective to inhibit MAC formation or activity in the subject. In other embodiments, provided herein are methods of inhibiting of treating, preventing, or reducing symptoms of a disorder mediated by undesired activity of the complement system in a subject comprising: administering to the subject an effective amount of the human C6 binding molecule as recited above and herein, or an expression vector encoding said human C6 binding molecule. In further embodiments, the complement-mediated disease is selected from the group consisting of: membrane-proliferative glomerulonephritis, cold agglutinin disease, catastrophic antiphospholipid syndrome, antibody-mediated transplantation rejection, ischemia/reperfusion injury, rheumatoid arthritis, a