Patent Application

App. No. 18/941,156

Abstract

Claims (93)

1 . An isolated antibody that specifically binds a human LTBP1-proTGFβ complex and a human LTBP3-proTGFβ complex, and does not bind a human GARP-proTGFβ complex;

wherein the antibody does not bind mature TGFβ1, mature TGFβ2 or mature TGFβ3;

wherein the antibody is a fully human or humanized antibody, or antigen-binding fragment thereof,

wherein the antibody comprises at least three of the following six CDRs:

a) CDR-H1: SEQ ID NO: 94, with the proviso that:

i. the threonine residue at position 2 of SEQ ID NO:94 may be substituted with an alanine;

ii. the asparagine residue at position 4 of SEQ ID NO:94 may be substituted with an alanine, tyrosine, aspartate, serine, arginine, or histidine;

iii. the asparagine residue at position 5 of SEQ ID NO:94 may be substituted with a glutamine, serine, glycine, lysine, glutamate, arginine, or histidine;

iv. the tyrosine residue at position 6 of SEQ ID NO:94 may be substituted with a arginine;

v. the proline residue at position 7 of SEQ ID NO:94 may be substituted with a glycine, alanine, leucine, serine, asparagine, valine, aspartate, or glutamine;

vi. the isoleucine residue at position 8 of SEQ ID NO:94 may be substituted with a methionine or leucine; and/or,

vii. the histidine residue at position 9 of SEQ ID NO:94 may be substituted with a phenylalanine, tyrosine, asparagine, or serine;

b) CDR-H2: SEQ ID NO:95, comprising up to six amino acid changes;

c) CDR-H3: SEQ ID NO:96, comprising up to three amino acid changes;

d) CDR-L1: SEQ ID NO:97, comprising up to three amino acid changes;

e) CDR-L2: SEQ ID NO:98, comprising up to three amino acid changes; and,

f) CDR-L3: SEQ ID NO:99, comprising up to three amino acid changes.

2 . (canceled)

3 . An antibody, or antigen-binding fragment thereof, comprising at least three of the following six CDRs:

a) CDR-H1 comprising the amino acid sequence FTF(X 1 )(X 2 )YVMH, wherein: X 1 is S or R; and X 2 is G or S (SEQ ID NO: 392);

b) CDR-H2 comprising the amino acid sequence (X 1 )ISHEG(X 2 )(X 3 )KYYADSVKG, wherein: X 1 is V or S; X 2 is S or G; and X 3 is F or L (SEQ ID NO: 393); and

c) CDR-H3 comprising the amino acid sequence (X 1 )(X 2 )P(X 3 )(X 4 )(X 5 )(X 6 )RRGG(X 7 ) (X 8 )(X 9 ), wherein: X 1 is A or V; X 2 is R, V, G or K; X 3 is R, H or L; X 4 is I, V or G; X 5 is A, S, or L; X 6 is A or V; X 7 is F or Y; X 8 is D, G, R, or S; and, X 9 is Y, G, R, L, V, A or K (SEQ ID NO: 394).

d) CDR-L1 as set forth in SEQ ID NO:97, comprising up to three amino acid changes;

e) CDR-L2 as set forth in SEQ ID NO:98, comprising up to three amino acid changes; and

f) CDR-L3 as set forth in SEQ ID NO:99, comprising up to three amino acid changes.

4 . (canceled)

5 . The antibody according to claim 1 , wherein the antibody comprises:

a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 88; and

a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 89.

6 .- 10 . (canceled)

11 . An antibody, or antigen-binding fragment thereof, which specifically binds human LTBP1-TGFβ1 complex and human LTBP3-TGFβ1 complex, comprising the following six CDRs:

a) CDR-H1 comprising the amino acid sequence FTFRSYVMH (SEQ ID NO: 166);

b) CDR-H2 comprising the amino acid sequence VISHEGS(X 1 )KYYADSVKG, wherein: X 1 is L or G (SEQ ID NO: 366); and

c) CDR-H3 comprising the amino acid sequence A(X 1 )PRIAARRGGFG(X 2 ), wherein: X 1 is V, R or L; and X 2 is Y, S or T (SEQ ID NO: 367);

d) CDR-L1 comprising the amino acid sequence TRS(X 1 )G(X 2 )ID(X 3 )NYVQ, wherein, X 1 is S or H; X 2 is N, L, S or A; and X 3 is N, D or Y (SEQ ID NO: 368);

e) CDR-L2 comprising the amino acid sequence ED(X 1 )(X 2 )RPS, wherein: X 1 is N, For A; and X 2 is Q, I or V (SEQ ID NO: 369); and

f) CDR-L3 comprising the amino acid sequence Q(X 1 )YD(X 2 )(X 3 )(X 4 )Q(X 5 )VV, wherein: X 1 is S or G; X 2 is S, F, Y, D, H or W; X 3 is N, D or S; X 4 is N, A, L, E or T; and X 5 is G, R, A or L (SEQ ID NO: 370).

12 . The antibody, or antigen-binding fragment thereof, according to claim 11 , wherein:

within CDR-H3: X 1 is R or L.

13 . The antibody, or antigen-binding fragment thereof, according to claim 12 , wherein within CDR-L3:

X 2 is Y;

X 3 is D;

X 4 is N or T; and/or

X 5 is A.

14 .- 15 . (canceled)

16 . The antibody, or antigen-binding fragment thereof, according claim 12 , wherein:

within CDR-L1: X 1 is S or H; X 2 is N or A; and X 3 is N, D or Y;

within CDR-L2: X 1 is N or F; and X 2 is Q or V; and

within CDR-L3: X 1 is S or G; X 2 is S, Y, D or W; X 3 is D or S; X 4 is N, L or T; and X 5 is G, R, A or L.

17 . The antibody, or antigen-binding fragment thereof, according to claim 16 , wherein:

within CDR-L1: X 1 is S; X 2 is N; and X 3 is N or Y;

within CDR-L2: X 1 is N; and X 2 is Q or V; and

within CDR-L3: X 1 is S or G; X 2 is S, Y or W; X 3 is D; X 4 is N or T; and X 5 is G, R or A.

18 .- 20 . (canceled)

21 . The antibody, or antigen-binding fragment thereof, according to claim 16 , wherein:

a) CDR-H1 comprises the amino acid sequence of SEQ ID NO: 166;

b) CDR-H2 comprises the amino acid sequence of SEQ ID NO: 167;

c) CDR-H3 comprises the amino acid sequence of SEQ ID NO: 168;

d) CDR-L1 comprises the amino acid sequence of SEQ ID NO: 169;

e) CDR-L2 comprises the amino acid sequence of SEQ ID NO: 170; and

f) CDR-L3 comprises the amino acid sequence of SEQ ID NO: 171.

22 . The antibody, or antigen-binding fragment thereof, according to claim 11 , which comprises:

a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 318; and

a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 319.

23 . The antibody, or antigen-binding fragment thereof, according to claim 11 , which competes or cross-competes with an antibody having a heavy chain variable region sequence as set forth in SEQ ID NO: 318 and light chain variable region sequence as set forth in SEQ ID NO: 319.

24 . (canceled)

25 . The antibody, or antigen-binding fragment thereof, according to claim 11 , which does not show detectable binding to a human GARP-proTGFβ1 complex, as measured by BioLayer Interferometry (BLI)-based in vitro binding assay, under the same assay conditions as used to measure binding to human LTBP1-proTGFβ1 complex and a human LTBP3-TGFβ1 complex.

26 . The antibody, or antigen-binding fragment thereof, according to claim 11 , which binds a human LTBP1-proTGFβ1 complex and a human LTBP3-TGFβ1 complex with a K D that is at least 50 times lower than the K D when binding to a human GARP-proTGFβ1 complex under the same assay conditions.

27 . The antibody, or antigen-binding fragment thereof, according to claim 11 , which does not show detectable binding to an LRRC33-proTGFβ1 complex, as measured by BioLayer Interferometry (BLI)-based in vitro binding assay, under the same assay conditions as used to measure binding to human LTBP1-proTGFβ1 complex and human LTBP3-TGFβ1 complex.

28 . The antibody, or antigen-binding fragment thereof, according to claim 11 , wherein the antibody, or antigen-binding fragment thereof has:

a monovalent half-binding-time (t½) of at least 45 minutes for each of hLTBP1-proTGFβ1 and hLTBP3-proTGFβ1 complexes, as measured by Surface Plasmon Resonance (SPR)-based in vitro binding assay; and/or

a monovalent t½ of less than 5 minutes for each of hGARP-proTGFβ1 and hLRRC33-proTGFβ1 complexes, as measured by SPR.

29 . (canceled)

30 . The antibody, or antigen-binding fragment thereof, according to claim 11 , which binds a human LTBP1-proTGFβ1 complex and a human LTBP3-TGFβ1 complex with a K D of <5 nM as measured by Bio-Layer Interferometry (BLI), optionally <1 nM.

31 . The antibody, or antigen-binding fragment thereof, according to claim 11 , which is cross-reactive with mouse LTBP1-proTGFβ1 and/or mouse LTBP3-proTGFβ1.

32 . (canceled)

33 . The antibody, or antigen-binding fragment thereof, according to claim 11 , wherein the antibody, or antigen-binding fragment thereof, binds a mouse LTBP1-proTGFβ1 complex and/or a mouse LTBP3-proTGFβ1 complex with a K D of <10 nM as measured by Bio-Layer Interferometry (BLI).

34 . (canceled)

35 . The antibody, or antigen-binding fragment thereof, according to claim 11 , wherein the antibody, or antigen-binding fragment thereof cross-reacts with human and murine LTBP1-proTGFβ1 and LTBP3-proTGFβ1 complexes, each with a K D of <5 nM or optionally <1 nM.

36 . The antibody, or antigen-binding fragment thereof, according to claim 11 , wherein the antibody is an IgG4 or IgG1 subtype, optionally wherein the antibody is a human IgG4 subtype and comprises a backbone substitution of Ser to Pro that produces an IgG1-like hinge.

37 . A pharmaceutical composition comprising the antibody of claim 11 and a pharmaceutically acceptable excipient.

38 . (canceled)

39 . A composition comprising a multi-dose vial containing the pharmaceutical composition of claim 37 .

40 . A composition comprising a single-dose syringe containing the pharmaceutical composition of claim 37 , optionally wherein the syringe is a disposable syringe.

41 . A method for the treatment of a fibrotic condition in a human subject, wherein the treatment comprises administration of the composition of claim 37 to the subject in an amount effective to treat the fibrotic disorder.

42 .- 43 . (canceled)

44 . The method of claim 41 fibrotic disorder is a muscle fibrosis, optionally wherein the muscle fibrosis is a muscular dystrophy, further optionally wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD).

45 .- 54 . (canceled)

55 . A method for making a composition of claim 37 , comprising an antibody, or antigen-binding fragment thereof, that specifically binds a human LTBP1-proTGFβ complex and a human LTBP3-proTGFβ complex, the method comprising steps of:

i) selecting an antibody or an antigen-binding fragment thereof that dissociates from human LTBP1-proTGFβ complex and a human LTBP3-proTGFβ complex with t½ of at least 45 minutes, and,

ii) formulating the antibody or fragment into a pharmaceutical composition,

thereby making the composition comprising the antibody or fragment.

56 .- 59 . (canceled)

Assignments (9)