US2022089730A1PendingUtilityA1
Antigen binding constructs to target molecules
Est. expiryAug 7, 2035(~9.1 yrs left)· nominal 20-yr term from priority
C07K 2317/53C07K 2317/622A61K 2039/505C07K 16/3069C07K 16/30C07K 16/2815A61K 39/395C07K 16/2809A61P 35/00C07K 16/2803A61K 38/00C07K 14/005A61K 47/6849
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Claims
Abstract
Antigen binding constructs that bind to desired targets are disclosed, for example antibodies, including antibody fragments (such as scFv and minibodies) that bind to a target molecule, and have one or more of the disclosed hinges are described herein. Methods of use are described herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . An amino acid hinge region comprising a sequence of SEQ ID NO: 1 (X n1 CX n2 X n3 CX n4 X n5 C), wherein X n1 can be any amino acid that does not naturally form a covalent crosslinking bond, wherein X n2 is one of: A, R, N, D, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y, or V, wherein X n3 can be any amino acid, wherein X n4 can be any amino acid, and wherein X n5 can be any amino acid.
2 . The amino acid hinge region of claim 1 , wherein X n1 does not form a covalent crosslinking bond with another amino acid (SEQ ID NO: 191).
3 . The amino acid hinge region of claim 1 , wherein X n1 is not a cysteine (SEQ ID NO: 192).
4 . The amino acid hinge region of claim 3 , wherein X n1 is one of: A, R, N, D, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y, or V (SEQ ID NO: 193).
5 . The amino acid hinge region of claim 3 , wherein X n2 is P, V, or E (SEQ ID NO: 194).
6 . The amino acid hinge region of claim 3 , wherein X n2 is P or V (SEQ ID NO: 195).
7 . The amino acid hinge region of claim 5 , wherein X n4 is P, V, or E (SEQ ID NO: 196).
8 . The amino acid hinge region of claim 3 , wherein X n4 is P or V (SEQ ID NO: 197).
9 . The amino acid hinge region of claim 3 , wherein X n3 is P or E (SEQ ID NO: 198).
10 . The amino acid hinge region of claim 3 , wherein X n5 is P or E (SEQ ID NO: 199).
11 . The amino acid hinge region of claim 9 , wherein X n3 is P or E (SEQ ID NO: 200).
12 . The amino acid hinge region of claim 3 , wherein X n2 X n3 is VE (SEQ ID NO: 201).
13 . The amino acid hinge region of claim 3 , wherein X n2 X n3 is PP (SEQ ID NO: 202).
14 . The amino acid hinge region of claim 3 , wherein X n4 X n5 is VE (SEQ ID NO: 203).
15 . The amino acid hinge region of claim 3 , wherein X n4 X n5 is PP (SEQ ID NO: 204).
16 . The amino acid hinge region of claim 3 , wherein X n2 X n3 is VE and X n4 X n5 is PP (SEQ ID NO: 205).
17 . The amino acid hinge region of claim 3 , wherein X n2 X n3 is PP and X n4 X n5 is PP or VE (SEQ ID NO: 206).
18 . The amino acid hinge region of claim 3 , wherein X n2 X n3 is VE and X n4 X n5 is VE or PP (SEQ ID NO: 207).
19 . The amino acid hinge region of claim 3 , further comprising an extension or lower hinge sequence C-terminal to the last cysteine in SEQ ID NO: 1.
20 . The amino acid hinge region of claim 19 , wherein the extension or lower hinge sequence comprises at least one of S, G, A, P, or V.
21 . The amino acid hinge region of claim 20 , wherein the extension sequence comprises at least GGGSSGGGSG (SEQ ID NO: 59).
22 . The amino acid hinge region of claim 20 , wherein a linker sequence comprises at least APPVAGP (SEQ ID NO: 60).
23 . The amino acid hinge region of claim 1 , wherein the hinge region of claim 1 is part of a core hinge region.
24 . The amino acid hinge region of claim 23 , further comprising an upper hinge region adjacent to the core hinge region.
25 . The amino acid hinge region of claim 23 , further comprising a lower hinge or extension region adjacent to the core hinge region.
26 . The amino acid hinge region of claim 25 , further comprising an upper hinge region adjacent to the core hinge region.
27 . The amino acid hinge region of claim 1 , wherein X n1 comprises a serine, a threonine, or an alanine (SEQ ID NO: 209).
28 . The amino acid hinge region of claim 1 , wherein X n1 comprises a serine (SEQ ID NO: 210).
29 . The amino acid hinge region of claim 1 , wherein X n1 comprises an alanine (SEQ ID NO: 211).
30 . The amino acid hinge region of claim 1 , wherein the amino acid hinge region comprises at least one of the following sequences: SCVECPPCP (SEQ ID NO: 56) or TCPPCPPC (SEQ ID NO: 166).
31 . The amino acid hinge region of claim 1 , wherein the amino acid hinge region comprises at least one of the following sequences: ERKSCVECPPCP (SEQ ID NO: 167), EPKSSDKTHT (SEQ ID NO: 46), and CPPCPPC (SEQ ID NO: 52).
32 . The amino acid hinge region of claim 1 , wherein the amino acid hinge region comprises at least one of the following sequences: ERKSCVECPPCPGGGSSGGGSG (SEQ ID NO: 34) or ERKSCVECPPCPAPPVAGP (SEQ ID NO: 33) or EPKSSDKTHTCPPCPPCGGGSSGGGSG (SEQ ID NO: 26) or EPKSSDKTHTCPPCPPCAPELLGGP (SEQ ID NO: 25).
33 . An amino acid hinge region comprising a sequence of SEQ ID NO: 2 (X n1 X n2 X n3 X n4 X n5 X n6 CX n7 X n8 CX n9 X n10 C), wherein X n1 can be any m amino acids, wherein m is any number of amino acids of any type, wherein X n2 can be any amino acid, wherein X n3 can be any amino acid, wherein X n4 can be any amino acid, wherein X n5 can be any amino acid, wherein X n6 can be any amino acid other than a cysteine, wherein X 17 can be any amino acid, wherein X n8 can be any amino acid, wherein X n9 can be any amino acid, and wherein X n10 can be any amino acid.
34 . The amino acid hinge region of claim 33 , wherein X n1 is not a cysteine (SEQ ID NO: 213).
35 . The amino acid hinge region of claim 33 , wherein X n2 is not a cysteine (SEQ ID NO: 214).
36 . The amino acid hinge region of claim 33 , wherein X n2 is a D (SEQ ID NO: 215).
37 . The amino acid hinge region of claim 33 , wherein X n3 is a K (SEQ ID NO: 216).
38 . The amino acid hinge region of claim 33 , wherein X n4 is a T (SEQ ID NO: 217).
39 . The amino acid hinge region of claim 33 , wherein X n5 is an H (SEQ ID NO: 218).
40 . The amino acid hinge region of claim 33 , wherein X n6 is a T (SEQ ID NO: 219).
41 . The amino acid hinge region of claim 33 , wherein X n1 is a P or a V (SEQ ID NO: 220).
42 . The amino acid hinge region of claim 33 , wherein X n8 is a P or an E (SEQ ID NO: 221).
43 . The amino acid hinge region of claim 33 , wherein X n9 is a P or a V (SEQ ID NO: 222).
44 . The amino acid hinge region of claim 33 , wherein X n10 is a P or an E (SEQ ID NO: 223).
45 . The amino acid hinge region of claim 33 , further comprising a CXXC (SEQ ID NO: 224) or CXXC (SEQ ID NO: 225) motif that is positioned in front of X 1 .
46 . The amino acid hinge region of claim 33 , further comprising a X n11 X n12 C sequence immediately attached to the C-terminal cysteine in SEQ ID NO: 1, wherein X 11 can be any amino acid, and wherein X n12 can be any amino acid (SEQ ID NO: 244).
47 . The amino acid hinge region of claim 46 , wherein X n1 is a P or a V, and wherein X n12 is a P or an E (SEQ ID NO: 227).
48 . The amino acid hinge region of claim 33 , wherein X n1 is a serine, X n2 is a D, X n3 is a K, X n4 is a T, X n5 is an H, X n6 is a T, X n7 is a P, X n8 is a P, X 19 is a P, and X n10 is a P (SEQ ID NO: 228).
49 . The amino acid hinge region of claim 33 , wherein the hinge region comprises at least one of the following sequences: CPPCPPC (SEQ ID NO: 52), CPPCVECPPC (SEQ ID NO: 53), or CPPCPPCPPC (SEQ ID NO: 54).
50 . The amino acid hinge region of claim 33 , wherein the hinge region comprises at least one of the following sequences: EPKSSDKTHTCPPCPPC (SEQ ID NO: 168), EPKSSDKTHTCPPCVECPPC (SEQ ID NO: 169), or EPKSSDKTHTCPPCPPCPPC (SEQ ID NO: 170).
51 . The amino acid hinge region of claim 33 , wherein the hinge region comprises at least one of the following sequences: EPKSSDKTHTCPPCPPCGGGSSGGGSG (SEQ ID NO: 26), EPKSSDKTHTCPPCVECPPCGGGSSGGGSG (SEQ ID NO: 28), or EPKSSDKTHTCPPCPPCPPCGGGSSGGGSG (SEQ ID NO: 30).
52 . An amino acid hinge region comprising:
a core hinge sequence of at least one of: CVECPPCP (SEQ ID NO: 57), CPPCPPC (SEQ ID NO: 52), or CPPCPPCPPC (SEQ ID NO: 54), or CPPCVECPPC (SEQ ID NO: 53) linked to; an upper hinge sequence of ELKTPLGDTTHT (SEQ ID NO: 48) or EPKSSDKTHT (SEQ ID NO: 46).
53 . An amino acid hinge region for an antibody comprising:
an upper hinge region that comprises no amino acids capable of crosslinking with a corresponding amino acid; and a core hinge region connected to a C-terminus of the upper hinge region, wherein the core hinge region comprises at least three cysteines per strand.
54 . The amino acid hinge region of 52, wherein the amino acid hinge region further comprises a lower hinge or extension region connected C-terminal to the core hinge region, wherein the lower hinge or extension sequence is at least one of: APPVAGP (SEQ ID NO: 60), APELLGGP (SEQ ID NO: 58), and/or GGGSSGGGSG (SEQ ID NO: 59).
55 . The amino acid hinge region of 52, wherein the upper hinge region comprises no cysteines that crosslink within the upper hinge region.
56 . The amino acid hinge region of claim 52 , wherein the upper hinge region comprises no cysteines.
57 . The amino acid hinge region of claim 52 , further comprising a lower hinge or extension region.
58 . The amino acid hinge region of claim 52 , wherein the lower hinge or extension region comprises at least one of: GGGSSGGGSG (SEQ ID NO: 59) or APPVAGP (SEQ ID NO: 60) or APELLGGP (SEQ ID NO: 58).
59 . The amino acid hinge region of claim 1 , wherein when located within a minibody, and wherein when the minibody is administered to a human subject, clearance of the minibody from the subject occurs primarily through a liver.
60 . The amino acid hinge region of claim 1 , wherein, when located within a minibody, and wherein when the minibody is administered to a human subject, clearance of the minibody from the subject does not occur primarily through a kidney.
61 . The amino acid hinge region of claim 1 , wherein the hinge region is within an antibody.
62 . The amino acid hinge region of claim 1 , wherein the hinge region is within an antibody binding fragment.
63 . The amino acid hinge region of claim 1 , wherein the hinge region is within a minibody.
64 . The amino acid hinge region of claim 1 , wherein the hinge region is within a monospecific antibody.
65 . The amino acid hinge region of claim 1 , wherein the hinge region comprises at least three cysteines per strand.
66 . The amino acid hinge region of claim 1 , wherein the hinge region comprises at least four cysteines per strand.
67 . The amino acid hinge region of claim 1 , wherein the hinge region comprises at least five cysteines per strand.
68 . The amino acid hinge region claim 65 , wherein cysteines are distributed throughout the amino acid hinge region in a repeating CXX or CXY motif.
69 . The amino acid hinge region of claim 1 , wherein the hinge region is within a bispecific antibody.
70 . The amino acid hinge region of claim 69 , wherein the bispecific antibody is assembled in a 1:1 ratio.
71 . The amino acid hinge region of claim 69 , wherein the bispecific antibody comprises an antibody fragment.
72 . The amino acid hinge region of claim 71 , wherein the bispecific antibody is a minibody.
73 . A pharmaceutical composition comprising the amino acid hinge region of claim 1 , wherein less than 5% aggregation of an antibody is present in the composition.
74 . A pharmaceutical composition comprising the amino acid hinge region of claim 1 .
75 . The pharmaceutical composition of claim 73 , wherein at least 1 microgram to 100 mg of the antibody is present.
76 . A minibody comprising a core hinge region, wherein the core hinge region comprises at least three cysteines per strand forming at least three disulfide bonds within the core hinge region.
77 . The minibody of claim 76 , wherein the first residue of the core region is a serine.
78 . The minibody of claim 76 , wherein the core hinge region comprises SCVECPPCP (SEQ ID NO: 56).
79 . A minibody comprising a sequence X n1 CX n2 X n3 CX n4 X n5 C (SEQ ID NO: 3), wherein SEQ ID NO: 3 is located as the core hinge region of the minibody, and wherein X n1 can be any amino acid or no amino acid, X n2 can be any amino acid, X n3 can be any amino acid, X n4 can be any amino acid, and X n5 can be any amino acid.
80 . The minibody of claim 79 , wherein X n1 is any amino acid other than a cysteine (SEQ ID NO: 229).
81 . The minibody of claim 79 , wherein X n1 is a serine (SEQ ID NO: 230).
82 . A variant minibody hinge comprising:
a first altered amino acid position, wherein the first altered position is an amino acid that in a native antibody hinge would be a cysteine, and has been altered in the first altered position so that it does not form a disulfide bond; and at least three cysteines per strand C-terminal to the first altered amino acid position.
83 . The amino acid hinge region of claim 1 , wherein the hinge region consists of SEQ ID NO: 1.
84 . The amino acid hinge region of claim 1 , wherein SEQ ID NO: 1 is a core hinge region, and wherein the core hinge region essentially consists of SEQ ID NO: 1.
85 . The amino acid hinge region of claim 84 , wherein the core hinge region consists of SEQ ID NO: 1.Cited by (0)
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