Antibodies with engineered ch2 domains, compositions thereof and methods of using the same

Patent metadata

Field	Value
Publication number	US-2019177404-A1
Application number	US-201716309821-A
Country	US
Kind code	A1
Filing date	Jun 14, 2017
Priority date	Jun 15, 2016
Publication date	Jun 13, 2019
Grant date	—

Abstract

The present disclosure relates to antibodies and antibody conjugates having one or more site-specific mutations in the CH2 domain of the heavy chain. The antibody variants disclosed herein can have improved characteristics (e.g., thermal stability, antibody yields, antibody titers, cell-killing) relative to a parent or wild type antibody, including aglycosylated parent or wild type antibodies. Pharmaceutical compositions, diagnostic compositions and kits comprising the same, as well as methods of using these compositions and kits for therapeutic and diagnostic purposes, are also described.

First claim

1 . An antibody comprising at least one amino acid substitution in the CH2 domain of the heavy chain, wherein the at least one amino acid substitution is selected from the group consisting of V264S, V303R, and V305R, and combinations thereof.

2 . The antibody of claim 1 , further comprising at least one amino acid substitution selected from the group consisting of: V262E, V262D, V262K, V262R, and V262S.

3 - 5 . (canceled)

6 . The antibody of claim 1 , wherein the at least one amino acid substitution is V303R.

7 . The antibody of claim 1 , wherein the at least one amino acid substitution is V305R.

8 . The antibody of claim 1 , further comprising an amino acid substitution at position F241 and/or F243 of the CH2 domain.

9 - 14 . (canceled)

15 . The antibody of claim 1 , wherein the antibody comprises at least two amino acid substitutions in the CH2 domain.

16 . The antibody of claim 15 , wherein the antibody comprises at least three amino acid substitutions in the CH2 domain.

17 . The antibody of claim 1 , wherein the antibody is aglycosylated.

18 . The antibody of claim 1 , further comprising one or more non-natural amino acid residues, wherein the one or more non-natural amino acid residues comprises a moiety selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, alkynyl, and tetrazine.

19 - 23 . (canceled)

24 . The antibody of claim 1 , wherein the antibody is a bi-specific antibody.

25 . The antibody of claim 1 , comprising a heavy chain of a type selected from the group consisting of α, δ, ε, and μ.

26 . The antibody of claim 1 , comprising a light chain of a type selected from λ and κ.

27 . The antibody of claim 1 that is of a class or subclass selected from the group consisting of IgA, IgA1, IgA2, IgD, IgE, IgG, IgG1, IgG2, IgG3, IgG4, and IgM.

28 . The antibody of claim 1 that is in a form selected from the group consisting of Fv, Fc, Fab, (Fab′) 2 , single chain Fv (scFv), and full-length antibody.

29 - 31 . (canceled)

32 . The antibody of claim 18 , wherein at least one non-natural amino acid is para-azido phenylalanine or para-azido methyl phenylalanine.

33 . The antibody of claim 18 comprising two or more non-natural amino acid residues.

34 - 36 . (canceled)

37 . The antibody of claim 33 , wherein a second non-natural amino acid residue is para-azido phenylalanine or para-azido methyl phenylalanine.

38 . The antibody of claim 33 , wherein at least one non-natural amino acid residue comprises an tetrazine moiety and at least second non-natural amino acid residue comprises an azide moiety.

39 . An antibody conjugate comprising the antibody of claim 18 linked to one or more therapeutic moieties or labeling moieties by one or more non-natural amino acid residues.

40 - 42 . (canceled)

43 . The antibody conjugate of claim 39 , wherein at least one of said therapeutic moieties or labeling moieties is linked to said antibody via a residue of a non-natural amino acid comprising an azide moiety.

44 . The antibody conjugate of claim 39 , wherein at least one of said therapeutic moieties or labeling moieties is linked to said antibody via a residue of the non-natural amino acid comprising a tetrazine moiety.

45 . The antibody conjugate of claim 39 , wherein at least one of said therapeutic moieties or labeling moieties is linked to said antibody via a residue of the non-natural amino acid comprising an azide moiety and at least one of said therapeutic moieties or labeling moieties is linked to said antibody via a residue of the non-natural amino acid comprising a tetrazine moiety.

46 - 49 . (canceled)

50 . The antibody conjugate of claim 39 , wherein said antibody is linked to said one or more therapeutic moieties or labeling moieties via one or more linkers.

51 - 55 . (canceled)

56 . A composition comprising the antibody of claim 1 , wherein said antibody is substantially pure.

57 . A composition comprising the antibody of claim 1 wherein said antibody is at least 95% by mass of the total antibody mass of said composition.

58 . A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.

59 . A pharmaceutical composition comprising the antibody conjugate of claim 39 and a pharmaceutically acceptable carrier.

60 . A kit comprising an antibody of claim 1 , and instructions for use of the antibody.

61 - 62 . (canceled)

63 . A kit comprising an antibody conjugate of claim 39 , and instructions for use of the antibody.

64 - 65 . (canceled)

66 . A polynucleotide encoding an antibody of claim 1 .

67 . A vector comprising the polynucleotide of claim 66 .

68 . A host cell comprising the vector of claim 67 .

69 - 70 . (canceled)

71 . A method of treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of an antibody drug conjugate of claim 39 .

72 . (canceled)

73 . The method of claim 71 , wherein the disease or condition is selected from a cancer, an autoimmune disease, an inflammatory disease, and an infection.

74 - 80 . (canceled)

Assignees

• Sutro Biopharma Inc

Inventors

• Calarese Daniel
• Yin Gang

Classifications

• C12N2015/8518

  expressing industrially exogenous proteins, e.g. for pharmaceutical use, human insulin, blood factors, immunoglobulins, pseudoparticles · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• C07K16/18 Primary

  against material from animals or humans · CPC title

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title

• C12N15/85

  for animal cells · CPC title