US2011189206A1PendingUtilityA1
Antibody Targeting Through a Modular Recognition Domain
Est. expiryJan 3, 2028(~1.5 yrs left)· nominal 20-yr term from priority
Inventors:Carlos F. Barbas, Iii
A61P 35/00A61P 43/00A61P 19/02C07K 2319/74C07K 2319/035C07K 16/32A61K 47/62C12N 9/0002C07K 16/40A61K 39/395G01N 33/6845A61K 38/08C07K 16/2848C07K 16/2863A61K 47/66C07K 7/06C07K 2317/56C07K 2317/24C07K 19/00C07K 14/00C07K 2319/70C07K 7/08
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Claims
Abstract
Antibodies containing one or more modular recognition domains (MRDs) used to target the antibodies to specific sites are described. The use of the antibodies containing one or more modular recognition domains to treat disease, and methods of making antibodies containing one or more modular recognition domains are also described.
Claims
exact text as granted — not AI-modified1 . An isolated full length antibody comprising a modular recognition domain (MRD).
2 . The antibody of claim 1 , wherein the antibody and the MRD are operably linked through a linker peptide.
3 . The antibody of claim 2 , wherein the linker peptide is between 2 to 20 peptides.
4 . The antibody of claim 2 , wherein the linker peptide is between 4 to 15 peptides.
5 . The antibody of claim 2 , wherein the linker peptide comprises the sequence GGGS (SEQ ID NO:1) (SEQ ID. NO.: 1).
6 . The antibody of claim 2 , wherein the linker peptide comprises the sequence SSGGGGSGGGGGGSS (SEQ ID NO:2) (SEQ ID. NO 2).
7 . The antibody of claim 2 , wherein the linker peptide comprises the sequence SSGGGGSGGGGGGSSRSS (SEQ ID NO:19) (SEQ ID NO 19).
8 . The antibody of claim 1 , wherein the MRD is operably linked to the C-terminal end of the heavy chain of the antibody.
9 . The antibody of claim 1 , wherein the MRD is operably linked to the N-terminal end of the heavy chain of the antibody.
10 . The antibody of claim 1 , wherein the MRD is operably linked to the C-terminal end of the light chain of the antibody.
11 . The antibody of claim 1 , wherein the MRD is operably linked to the N-terminal end of the light chain of the antibody.
12 . The antibody of claim 1 , wherein two or more MRDs are operably linked to any terminal end of the antibody.
13 . The antibody of claim 1 , wherein there are two or more MRDs operably linked to two or more terminal ends of the antibody.
14 . The antibody of claim 1 , wherein the target of the MRD is an integrin.
15 . The antibody of claim 14 , wherein the integrin-targeting MRD comprises the sequence YCRGDCT (SEQ ID NO:3) (SEQ ID. NO.: 3).
16 . The antibody of claim 14 , wherein the integrin-targeting MRD comprises the sequence PCRGDCL (SEQ ID NO:4) (SEQ ID. NO.: 4)).
17 . The antibody of claim 14 , wherein the integrin-targeting MRD comprises the sequence TCRGDCY (SEQ ID NO:5) (SEQ ID. NO.: 5).
18 . The antibody of claim 14 , wherein the integrin-targeting MRD comprises the sequence LCRGDCF (SEQ ID NO:6) (SEQ ID. NO.: 6).
19 . The antibody of claim 15 wherein the target of the MRD is an angiogenic cytokine.
20 . The antibody of claim 19 , wherein the angiogenic cytokine-targeting MRD comprises the sequence MGAQTNFMPMDDLEQRLYEQFILQQGLE (SEQ ID NO:7) (SEQ ID. NO.: 7).
21 . The antibody of claim 19 , wherein the angiogenic cytokine-targeting MRD comprises the sequence MGAQTNFMPMDNDELLLYEQFILQQGLE (SEQ ID NO:8) (SEQ ID. NO.: 8).
22 . The antibody of claim 19 , wherein the angiogenic cytokine-targeting MRD comprises the sequence MGAQTNFMPMDATETRLYEQFILQQGLE (SEQ ID NO:9) (SEQ ID. NO.: 9).
23 . The antibody of claim 19 , wherein the angiogenic cytokine-targeting MRD is selected from the group consisting of:
(SEQ ID NO: 10)
(SEQ ID. NO.: 10)
AQQEECEWDPWTCEHMGSGSATGGSGSTASSGSGSATHQEECEWDPWTCE
HMLE;
(SEQ ID NO: 21)
AQQEECEFAPWTCEHM;
(SEQ ID NO: 23)
AQQEECEFAPWTCEHMGSGSATGGSGSTASSGSGSATHQEECEFAPWTCE
HMLE;
(SEQ ID NO: 24)
AQQEECELAPWTCEHM;
(SEQ ID NO: 26)
AQQEECELAPWTCEHMGSGSATGGSGSTASSGSGSATHQEECELAPWTCE
HMLE;
(SEQ ID NO: 27)
AQQEECEFSPWTCEHM;
(SEQ ID NO: 29)
AQQEECEFSPWTCEHMGSGSATGGSGSTASSGSGSATHQEECEFSPWTCE
HM LE2xConFS;
(SEQ ID NO: 30)
AQQEECELEPWTCEHM;
(SEQ ID NO: 32)
AQQEECELEPWTCEHMGSGSATGGSGSTASSGSGSATHQEECELEPWTCE
HMLE;
(SEQ ID NO: 33)
AQQEECEFAPWTCEHMGSGSATGGSGSTASSGSGSATHQEECELAPWTCE
HMLE;
and
(SEQ ID NO: 34)
AQQEECEFAPWTCEHMGSGSATGGSGSTASSGSGSATHQEECEFSPWTCE
HMLE.
24 . The antibody of claim 19 , wherein the angiogenic cytokine-targeting MRD comprises the sequence
(SEQ ID NO: 11)
(SEQ ID. NO.: 11)
MGAQTNFMPMDNDELLNYEQFILQQGLE.
25 . The antibody of claim 19 , wherein the angiogenic cytokine-targeting MRD comprises the sequence PXDNDXLLNY (SEQ ID NO:12) (SEQ ID. NO.: 12), where X is selected from one of the 20 naturally-occurring amino acids.
26 . The antibody of claim 1 , wherein the target of the MRD is ErbB2.
27 . The antibody of claim 1 , wherein the target of the MRD is VEGF.
28 . The antibody of claim 27 , wherein the VEGF-targeting MRD comprises the sequence VEPNCDIHVMWEWECFERL (SEQ ID NO:13) (SEQ ID. NO.: 13).
29 . The antibody of claim 1 , wherein the target of the MRD is an insulin-like growth factor-I receptor.
30 . The antibody of claim 29 , wherein the insulin-like growth factor-I receptor-targeting MRD is selected from the group consisting of:
SFYSCLESLVNGPAEKSRGQWDGCRKK;
(SEQ ID NO: 14)
(SEQ ID. NO.: 14)
NFYQCIEMLASHPAEKSRGQWQECRTGG;
(SEQ ID NO: 35)
NFYQCIEQLALRPAEKSRGQWQECRTGG;
(SEQ ID NO: 36)
NFYQCIDLLMAYPAEKSRGQWQECRTGG;
(SEQ ID NO: 37)
NFYQCIERLVTGPAEKSRGQWQECRTGG;
(SEQ ID NO: 38)
NFYQCIEYLAMKPAEKSRGQWQECRTGG;
(SEQ ID NO: 39)
NFYQCIEALQSRPAEKSRGQWQECRTGG;
(SEQ ID NO: 40)
NFYQCIEALSRSPAEKSRGQWQECRTGG;
(SEQ ID NO: 41)
NFYQCIEHLSGSPAEKSRGQWQECRTG;
(SEQ ID NO: 42)
NFYQCIESLAGGPAEKSRGQWQECRTG;
(SEQ ID NO: 43)
NFYQCIEALVGVPAEKSRGQWQECRTG;
(SEQ ID NO: 44)
NFYQCIEMLSLPPAEKSRGQWQECRTG;
(SEQ ID NO: 45)
NFYQCIEVFWGRPAEKSRGQWQECRTG;
(SEQ ID NO: 46)
NFYQCIEQLSSGPAEKSRGQWQECRTG;
(SEQ ID NO: 47)
NFYQCIELLSARPAEKSRGQWAECRAG;
(SEQ ID NO: 48)
and
NFYQCIEALARTPAEKSRGQWVECRAP.
(SEQ ID NO: 49)
31 . The antibody of claim 1 , wherein the target of the MRD is a tumor antigen.
32 . The antibody of claim 1 , wherein the target of the MRD is CD20.
33 . The antibody of claim 1 , wherein the target of the MRD is an epidermal growth factor receptor (EGFR).
34 . The antibody of claim 33 , wherein the EGFR-targeting MRD comprises the sequence
(SEQ ID NO: 16)
(SEQ ID. NO.: 16)
VDNKFNKELEKAYNEIRNLPNLNGWQMTAFIASLVDDPSQSANLLAEAKK
LNDAQA PK.
35 . The antibody of claim 33 , wherein the EGFR-targeting MRD comprises the sequence
(SEQ ID NO: 17)
(SEQ ID. NO.: 17)
VDNKFNKEMWIAWEEIRNLPNLNGWQMTAFIASLVDDPSQSANLLAEAKK
LNDAQAPK.
36 . The antibody of claim 1 , wherein the target of the MRD is the ErbB2 receptor.
37 . The antibody of claim 36 , wherein the ErbB2 receptor-targeting MRD comprises the sequence
(SEQ ID NO: 18)
(SEQ ID. NO.: 18)
VDNKFNKEMRNAYWEIALLPNLNNQQKRAFIRSLYDDPSQSANLLAEAKK
LNDAQAPK.
38 . The antibody of claim 1 , wherein the target of the MRD is the ErbB3 receptor.
39 . The antibody of claim 1 , wherein the target of the MRD is tumor-associated surface antigen epithelial cell adhesion molecule (Ep-CAM).
40 . The antibody of claim 1 , wherein the target of the MRD is an angiogenic factor.
41 . The antibody of claim 40 , wherein the antibody binds to a cell surface antigen selected from the group consisting of EGFR, ErbB2, ErbB3, ErbB4, CD20 insulin-like growth factor-I receptor, or prostate specific membrane antigen.
42 . The antibody of claim 1 , wherein the target of the MRD is an angiogenic receptor.
43 . The antibody of claim 42 , wherein the antibody binds to a cell surface antigen selected from the group consisting of EGFR, ErbB2, ErbB3, ErbB4, CD20, insulin-like growth factor-I receptor, or prostate specific membrane antigen.
44 . The antibody of claim 42 , wherein the antibody binds to an angiogenic factor.
45 . The antibody of claim 42 , wherein the antibody binds to an angiogenic receptor.
46 . The antibody of claim 1 , wherein the target of the MRD is a cell surface antigen.
47 . The antibody of claim 46 , wherein the antibody binds to a cell surface antigen.
48 . The antibody of claim 47 , wherein the cell surface antigen is selected from the group consisting of EGFR, ErbB2, ErbB3, ErbB4, CD20, insulin-like growth factor-I receptor, or prostate specific membrane antigen.
49 . The antibody of claim 46 , wherein the antibody binds to an angiogenic factor.
50 . The antibody of claim 46 , wherein the antibody binds to an angiogenic receptor.
51 . The antibody of claim 1 , wherein the MRD is a vascular homing peptide.
52 . The antibody of claim 51 , wherein the vascular homing peptide-targeting MRD comprises the sequence ACDCRGDCFCG (SEC) ID NO:15) (SEQ ID. NO.: 15).
53 . The antibody of claim 1 , wherein the MRD is a nerve growth factor (NGF).
54 . An isolated polynucleotide comprising a nucleotide sequence of the antibody of claim 1 .
55 . A vector comprising the polynucleotide of claim 54 .
56 . A vector comprising the polynucleotide of claim 54 in which the nucleotide sequence of the polynucleotide is operatively linked with a regulatory sequence that controls expression of the polynucleotide in a host cell.
57 . A host cell comprising the vector of claim 55 , or progeny of the cell.
58 . A method of treating a disease comprising administering to a subject in need thereof, an antibody of claim 1 .
59 . The method of claim 58 , wherein the disease is cancer.
60 . The method of claim 58 , wherein an additional therapeutic agent is administered to the subject.
61 . A method of inhibiting angiogenesis comprising administering to a subject in need thereof, an antibody of claim 1 .
62 . The method of claim 61 , wherein an additional therapeutic agent is administered to the subject.
63 . A method of modulating angiogenesis comprising administering to a subject in need thereof, an antibody of claim 1 .
64 . The method of claim 63 , wherein an additional therapeutic agent is administered to the subject.
65 . A method of inhibiting tumor growth comprising administering to a subject in need thereof, an antibody of claim 1 .
66 . The method of claim 65 , wherein an additional therapeutic agent is administered to the subject.
67 . A method for producing a full length antibody comprising one or more MRDs, said method comprising selecting for a MRD using an MRD binding target, wherein the MRD is derived from a phage display library.
68 . A method for producing a full length antibody comprising one or more MRDs, said method comprising selecting for a MRD using an MRD binding target, wherein the MRD is derived from natural ligands.
69 . The antibody of claim 1 , wherein the antibody is a chimeric or humanized antibody.
70 . A peptide comprising the sequence
NFYQCIX 1 X 2 LX 3 X 4 X 5 PAEKSRGQWQECRTGG (SEQ ID NO:58), wherein X 1 is E or D X 2 is any amino acid; X 3 is any amino acid; X 4 is any amino acid and X s is any amino acid.
71 . A peptide of claim 70 , selected from the group consisting of:
NFYQCIEMLASHPAEKSRGQWQECRTGG;
(SEQ ID NO: 35)
NFYQCIEQLALRPAEKSRGQWQECRTGG;
(SEQ ID NO: 36)
NFYQCIDLLMAYPAEKSRGQWQECRTGG;
(SEQ ID NO: 37)
NFYQCIERLVTGPAEKSRGQWQECRTGG;
(SEQ ID NO: 38)
NFYQCIEYLAMKPAEKSRGQWQECRTGG;
(SEQ ID NO: 39)
NFYQCIEALQSRPAEKSRGQWQECRTGG;
(SEQ ID NO: 40)
NFYQCIEALSRSPAEKSRGQWQECRTGG;
(SEQ ID NO: 41)
NFYQCIEHLSGSPAEKSRGQWQECRTG;
(SEQ ID NO: 42)
NFYQCIESLAGGPAEKSRGQWQECRTG;
(SEQ ID NO: 43)
NFYQCIEALVGVPAEKSRGQWQECRTG;
(SEQ ID NO: 44)
NFYQCIEMLSLPPAEKSRGQWQECRTG;
(SEQ ID NO: 45)
NFYQCIEVFWGRPAEKSRGQWQECRTG;
(SEQ ID NO: 46)
and
NFYQCIEQLSSGPAEKSRGQWQECRTG.
(SEQ ID NO: 47)
72 . A peptide selected from
(SEQ ID NO: 20)
MGAQINFMPMDNDELLLYEQFILQQGLEGGSGSTASSGSGSSLGAQTNFM
PMDNDELLLY;
(SEQ ID NO: 48)
NFYQCIELLSARPAEKSRGQWAECRAG;
or
(SEQ ID NO: 49)
NFYQCIEALARTPAEKSRGQWVECRAP.
73 . A peptide selected from the group consisting of:
X n EFAPWTX n where n is from about 0 to 50 amino acid residues (SEQ ID NO: 22); X n ELAPWTX n where n is from about 0 to 50 amino acid residues (SEQ ID NO: 25); X n EFSPWTX n where n is from about 0 to 50 amino acid residues (SEQ ID NO: 28); X n ELEPWTX n where n is from about 0 to 50 amino acid residues (SEQ ID NO: 31); and Xn AQQEECEX I X 2 PWTCEHMX n where n is from about 0 to 50 amino acid residues and X, X 1 and X 2 are any amino acid (SEQ ID NO:57).
74 . A peptide of claim 73 , wherein the peptide is selected from the group consisting of:
(SEQ ID NO: 21)
AQQEECEFAPWTCEHM;
(SEQ ID NO: 23)
AQQEECEFAPWTCEHMGSGSATGGSGSTASSGSGSATHQEECEFAPWTCE
HMLE;
(SEQ ID NO: 24)
AQQEECELAPWTCEHM;
(SEQ ID NO: 26)
AQQEECELAPWTCEHMGSGSATGGSGSTASSGSGSATHQEECELAPWTCE
HMLE;
(SEQ ID NO: 27)
AQQEECEFSPWTCEHM;
(SEQ ID NO: 29)
AQQEECEFSPWTCEHMGSGSATGGSGSTASSGSGSATHQEECEFSPWTCE
HM LE2xConFS;
(SEQ ID NO: 30)
AQQEECELEPWTCEHM;
(SEQ ID NO: 32)
AQQEECELEPWTCEHMGSGSATGGSGSTASSGSGSATHQEECELEPWTCE
HMLE;
(SEQ ID NO: 33)
AQQEECEFAPWTCEHMGSGSATGGSGSTASSGSGSATHQEECELAPWTCE
HMLE;
(SEQ ID NO: 34)
AQQEECEFAPWTCEHMGSGSATGGSGSTASSGSGSATHQEECEFSPWTCE
HMLE;
and
(SEQ ID NO: 10)
(SEQ ID. NO.: 10)
AQQEECEWDPWTCEHMGSGSATGGSGSTASSGSGSATHQEECEWDPWTCE
HMLE.
75 . An antigen-binding construct comprising a protein scaffold which is linked to one or more epitope-binding domains wherein the antigen-binding construct has at least two antigen binding sites at least one of which is from an epitope binding domain and at least one of which is from a paired VH/VL domain.
76 . An antigen-binding construct of claim 75 wherein the binding construct has specificity for more than one antigen.
77 . An antigen-binding construct of claim 75 wherein the antigen-binding construct is capable of binding two or more antigens selected from VEGF, IGF-1R and EGFR.
78 . An antigen-binding construct of claim 75 wherein the antigen-binding construct is capable of binding TNF.
79 . An antigen-binding construct of claim 75 wherein the scaffold is an IgG scaffold.
80 . An antigen-binding construct of claim 75 wherein the protein scaffold comprises a monovalent antibody.
81 . An antigen-binding construct of claim 75 wherein the IgG scaffold comprises all the domains of an antibody.
82 . An antigen-binding construct of claim 75 wherein at least one of the epitope binding domains is directly attached to the Ig scaffold with a linker comprising from 1 to 20 amino acids.
83 . An antigen-binding construct of claim 82 wherein at least one of the epitope binding domains is directly attached to the Ig scaffold with a linker that is GGGS (SEQ ID NO:1).
84 . An antigen-binding construct of claim 77 comprising an epitope binding domain attached to the Ig scaffold at the N-terminus of the light chain.
85 . An antigen-binding construct of claim 77 comprising an epitope binding domain attached to the Ig scaffold at the N-terminus of the heavy chain.
86 . An antigen-binding construct of claim 77 comprising an epitope binding domain attached to the Ig scaffold at the C-terminus of the light chain.
87 . An antigen-binding construct of claim 77 comprising an epitope binding domain attached to the Ig scaffold at the C-terminus of the heavy chain.
88 . An antigen-binding construct of claim 75 which has 4 antigen binding sites and which is capable of binding 4 antigens simultaneously.
89 . An antigen-binding construct of claim 75 for use in medicine.
90 . An antigen-binding construct of claim 75 for use in the manufacture of a medicament for treating cancer or arthritis.
91 . A method of treating a patient suffering from cancer or arthritis, comprising administering a therapeutic amount of an antigen-binding construct of claim 75 .
92 . An antigen-binding construct of claim 75 for the treatment of cancer or arthritis.
93 . A polynucleotide sequence encoding a heavy chain of an antigen binding construct of claim 75 .
94 . A polynucleotide encoding a light chain of an antigen binding construct of claim 75 .
95 . A recombinant transformed or transfected host cell comprising one or more polynucleotide sequences encoding a heavy chain and a light chain of an antigen binding construct of claim 75 .
96 . A pharmaceutical composition comprising an antigen binding construct of claim 75 and a pharmaceutically acceptable carrier.
97 . An antibody construct comprising an antibody which is linked to one or more MRDs, wherein the construct has at least two antigen binding sites at least one of which is from an MRD and at least one of which is from the antibody combining site.
98 . The construct of claim 97 , wherein the construct has specificity for more than one antigen.
99 . The construct of claim 97 , wherein the construct is capable of binding two or more antigens selected from VEGF, IGF-1R, and EGFR.
100 . The construct of claim 97 , wherein the construct is capable of binding TNF.
101 . The construct of claim 97 , wherein the antibody is an IgG antibody.
102 . The construct of claim 97 wherein the antibody comprises a monovalent antibody.
103 . The construct of claim 97 , wherein at least one of the MRDs is directly attached to the antibody with a linker comprising from 2 to 20 amino acids.
104 . The construct of claim 103 , wherein at least one MRD is directly attached to the antibody with a linker that is GGGS (SEQ ID NO:1).
105 . The construct of claim 99 comprising an MRD operably linked to the antibody at the N-terminal end of the light chain.
106 . The construct of claim 99 , comprising an MRD operably linked to the antibody at the N-terminal end of the heavy chain.
107 . The construct of claim 99 , comprising an MRD operably linked to the antibody at the C-terminal end of the light chain.
108 . The construct of claim 99 , comprising an MRD operably linked to the C-terminal end of the heavy chain.
109 . An antigen-binding construct of claim 97 which has 4 antigen binding sites and which is capable of binding 4 antigens simultaneously.
110 . The construct of claim 97 for use in therapeutic purposes.
111 . The construct of claim 97 for use in the manufacture of a medicament for treating cancer or arthritis.
112 . A method of treating a patient with cancer or arthritis, comprising administering a therapeutic amount of the construct of claim 97 .
113 . The construct of claim 97 , for the treatment of cancer or arthritis.
114 . A polynucleotide sequence encoding the construct of claim 97 .
115 . A host cell comprising the polynucleotide of claim 97 .
116 . A therapeutic composition comprising the construct of claim 97 and a physiologically tolerable carrier.Join the waitlist — get patent alerts
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