US2004234531A1PendingUtilityA1
Chimeric human leukocyte antigen and epitope-bearing molecules having immunosuppressant activity
Priority: May 7, 2001Filed: May 7, 2002Published: Nov 25, 2004
Est. expiryMay 7, 2021(expired)· nominal 20-yr term from priority
G01N 33/564A61P 37/00C07K 14/70539G01N 33/505G01N 33/56977G01N 2333/70539G01N 2800/042C07K 2319/30C07K 2319/00
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Claims
Abstract
The present invention relates to chimeric molecules that comprise human major histocompatibility complex elements, linked to epitopes of interest, that have been joined together to form dimers or higher multimers. Such chimeric molecules may be used to treat or prevent diseases associated with autoimmunity, particularly diabetes. It is based, at least in part, on the discovery that a chimeric molecule comprising an IILA-DR element linked to an epitope of GAD65, an antigen associated with autoimmune diabetes, stimulated the secretion of the inhibitory cytokine IL-10 from CD4 T cells of Type I diabetic patients.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A chimeric protein heterodimer comprising a first and a second subunit, wherein (a) the first subunit comprises a protein comprising (i) at least one domain of a human immunoglobulin constant region; (ii) at least 90 percent of the extracellular domains of a first Class II Human Leukocyte Antigen component selected from the group consisting of an alpha chain and a beta chain; and (iii) a peptide comprising an epitope associated with a human autoimmune disease; and (b) the second subunit comprises a protein comprising at least 90 percent of the extracellular domains of a second Class II Human Leukocyte Antigen component selected from the group consisting of an alpha chain and a beta chain, wherein if the first component is a beta chain, the second component is an alpha chain and if the first component is an alpha chain, the second component is a beta chain.
2 . A dimer comprising two chimeric proteins according to claim 1 .
3 . The dimer of claim 2 , where the two chimeric proteins are joined by disulfide bonds.
4 . The dimer of claim 2 , where the two chimeric proteins are joined by chemical crosslinking other than a disulfide bond.
5 . A multimer comprising at least three chimeric proteins according to claim 1 .
6 . The multimer of claim 5 , wherein the chimeric proteins are joined by chemical crosslinking.
7 . The multimer of claim 6 , where the chemical crosslinker is a polyalkylene glycol.
8 . The chimeric protein of claim 1 , linked to a toxic agent.
9 . The chimeric protein of claim 8 , where the toxic agent is doxorubicin.
10 . A chimeric protein heterodimer comprising a first and a second subunit, wherein (a) the first subunit comprises a protein comprising (i) at least one domain of a human immunoglobulin constant region; (ii) at least 90 percent of the extracellular domains of a first Class II Human Leukocyte Antigen component selected from the group consisting of an alpha chain and a beta chain; and (iii) a peptide comprising an epitope associated with autoimmune diabetes; and (b) the second subunit comprises a protein comprising at least 90 percent of the extracellular domains of a second Class II Human Leukocyte Antigen component selectee from the group consisting of an alpha chain and a beta chain, wherein if the first component is a beta chain, the second component is an alpha chain and if the first component is an alpha chain, the second component is a beta chain.
11 . A dimer comprising two chimeric proteins according to claim 10 .
12 . The dimer of claim 11 , where the two chimeric proteins are joined by disulfide bonds.
13 . The dimer of claim 11 , where the two chimeric proteins are joined by chemical crosslinking other than a disulfide bond.
14 . A multimer comprising at least three chimeric proteins according to claim 1 .
15 . The multimer of claim 14 , wherein the chimeric proteins are joined by chemical crosslinking.
16 . The multimer of claim 15 , where the chemical crosslinker is a polyalkylene glycol.
17 . The chimeric protein of claim 10 , linked to a toxic agent.
18 . The chimeric protein of claim 17 , where the toxic agent is doxorubicin.
19 . A chimeric protein heterodimer comprising a first and a second subunit, wherein (a) the first subunit comprises a protein comprising (i) at least one domain of a human immunoglobulin constant region; (ii) at least 90 percent of the extracellular domains of a first Class II Human Leukocyte Antigen component selected from the group consisting of an alpha chain and a beta chain; and (iii) a peptide comprising a peptide fragment of human glutamic acid decarboxylase 65; and (b) the second subunit comprises a protein comprising at least 90 percent of the extracellular domains of a second Class II Human Leukocyte Antigen component selected from the group consisting of an alpha chain and a beta chain, wherein if the first component is a beta chain, the second component is an alpha chain and if the first component is an alpha chain, the second component is a beta chain.
20 . A dimer comprising two chimeric proteins according to claim 19 .
21 . The dimer of claim 20 , where the two chimeric proteins are joined by disulfide bonds.
22 . The dimer of claim 20 , where the two chimeric proteins are joined by chemical crosslinking other than a disulfide bond.
23 . A multimer comprising at least three chimeric proteins according to claim 19 .
24 . The multimer of claim 23 , wherein the chimeric proteins are joined by chemical crosslinking.
25 . The multimer of claim 24 , where the chemical crosslinker is a polyalkylene glycol.
26 . The chimeric protein of claim 19 , linked to a toxic agent.
27 . The chimeric protein of claim 26 , where the toxic agent is doxorubicin.
28 . The chimeric protein of claim 19 , wherein the Class II Human Leukocyte Antigen beta chain is of serotype HLA-DR4.
29 . The chimeric protein of claim 19 , wherein the glutamic acid decarboxylase peptide fragment comprises the sequence PRLIAFTSEHSHFSL (SEQ ID NO:10).
30 . The chimeric protein of claim 20 , wherein the glutamic acid decarboxylase peptide fragment comprises the sequence PRLIAFTSEHSHFSL (SEQ ID NO:10).
31 . The chimeric protein of claim 21 , wherein the glutamic acid decarboxylase peptide fragment comprises the sequence PRLIAFTSEHSHFSL (SEQ ID NO:10).
32 . The chimeric protein of claim 22 , wherein the glutamic acid decarboxylase peptide fragment comprises the sequence PRLIAFTSEHSHFSL (SEQ ID NO:10).
33 . The chimeric protein of claim 23 , wherein the glutamic acid decarboxylase peptide fragment comprises the sequence PRLIAFTSEHSHFSL (SEQ ID NO:10).
34 . The chimeric protein of claim 24 , wherein the glutamic acid decarboxylase peptide fragment comprises the sequence PRLIAFTSEHSHFSL (SEQ ID NO:10).
35 . The chimeric protein of claim 25 , wherein the glutamic acid decarboxylase peptide fragment comprises the sequence PRLIAFTSEHSHFSL (SEQ ID NO:10).
36 . The chimeric protein of claim 26 , wherein the glutamic acid decarboxylase peptide fragment comprises the sequence PRLIAFTSEHSHFSL (SEQ ID NO:10).
37 . The chimeric protein of claim 27 , wherein the glutamic acid decarboxylase peptide fragment comprises the sequence PRLIAFTSEHSHFSL (SEQ ID NO:10).
38 . The chimeric protein of claim 28 , wherein the glutamic acid decarboxylase peptide fragment comprises the sequence PRLIAFTSEHSHFSL (SEQ ID NO:10).
39 . A chimeric protein heterodimer comprising a first and a second subunit, wherein (a) the first subunit comprises a protein comprising (i) at least one domain of a human immunoglobulin constant region; (ii) at least 90 percent of the extracellular domains of a first Class II Human Leukocyte Antigen component selected from the group consisting of an alpha chain and a beta chain; and (iii) a peptide comprising a peptide fragment of human proinsulin; and (b) the second subunit comprises a protein comprising at least 90 percent of the extracellular domains of a second Class II Human Leukocyte Antigen component selected from the group consisting of an alpha chain and a beta chain, wherein if the first component is a beta chain, the second component is an alpha chain and if the first component is an alpha chain, the second component is a beta chain.
40 . A dimer comprising two chimeric proteins according to claim 39 .
41 . The dimer of claim 40 , where the two chimeric proteins are joined by disulfide bonds.
42 . The dimer of claim 40 , where the two chimeric proteins are joined by chemical crosslinking other than a disulfide bond.
43 . A multimer comprising at least three chimeric proteins according to claim 40 .
44 . The multimer of claim 43 , wherein the chimeric proteins are joined by chemical crosslinking.
45 . The multimer of claim 44 , where the chemical crosslinker is a polyalkylene glycol.
46 . The chimeric protein of claim 39 , linked to a toxic agent.
47 . The chimeric protein of claim 46 , where the toxic agent is doxorubicin.
48 . The chimeric protein of claim 39 , wherein the Class II Human Leukocyte Antigen beta chain is of serotype HLA-DR4.
49 . The chimeric protein of claim 39 , wherein the proinsulin peptide fragment comprises the sequence GAGSLQPLALEGSLQKRG (SEQ ID NO: 43).
50 . The chimeric protein of claim 40 , wherein the proinsulin peptide fragment comprises the sequence GAGSLQPLALEGSLQKRG (SEQ ID NO: 43).
51 . The chimeric protein of claim 41 , wherein the proinsulin peptide fragment comprises the sequence GAGSLQPLALEGSLQKRG (SEQ ID NO: 43).
52 . The chimeric protein of claim 42 , wherein the proinsulin peptide fragment comprises the sequence GAGSLQPLALEGSLQKRG (SEQ ID NO: 43).
53 . The chimeric protein of claim 43 , wherein the proinsulin peptide fragment comprises the sequence GAGSLQPLALEGSLQKRG (SEQ ID NO: 43).
54 . The chimeric protein of claim 44 , wherein the proinsulin peptide fragment comprises the sequence GAGSLQPLALEGSLQKRG (SEQ ID NO: 43).
55 . The chimeric protein of claim 45 , wherein the proinsulin peptide fragment comprises the sequence GAGSLQPLALEGSLQKRG (SEQ ID NO: 43).
56 . The chimeric protein of claim 46 , wherein the proinsulin peptide fragment comprises the sequence GAGSLQPLALEGSLQKRG (SEQ ID NO: 43).
57 . The chimeric protein of claim 47 , wherein the proinsulin peptide fragment comprises the sequence GAGSLQPLALEGSLQKRG (SEQ ID NO: 43).
58 . The chimeric protein of claim 48 , wherein the proinsulin peptide fragment comprises the sequence GAGSLQPLALEGSLQKRG (SEQ ID NO: 43).
59 . The chimeric protein of claim 39 , wherein the proinsulin peptide fragment comprises the sequence LALEGSLQK (SEQ ID NO: 45).
60 . The chimeric protein of claim 48 , wherein the proinsulin peptide fragment comprises the sequence LALEGSLQK (SEQ ID NO: 45).
61 . A method of identifying a predisposition to an autoimmune disorder in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 1 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
62 . A method of identifying a predisposition to an autoimmune disorder in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 2 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
63 . A method of identifying a predisposition to an autoimmune disorder in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 5 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
64 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 10 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
65 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 11 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
66 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 14 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
67 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 19 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
68 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 20 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
69 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 23 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
70 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 28 , where the HLA class II components in the chimeric protein are compatible with HLA class I determinants of the subject.
71 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 29 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
72 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 30 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
73 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 33 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
74 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 38 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
75 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 39 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
76 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 40 , where the HLA class II components in the chimeric protein are compatible with HLA class I determinants of the subject.
77 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 43 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
78 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 48 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
79 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 49 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
80 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 50 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
81 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 58 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
82 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 59 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
83 . A method of identifying a predisposition to autoimmune diabetes in a human subject comprising detecting the presence of T cells in the subject which bind to a chimeric protein according to claim 60 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
84 . A method of treating a human subject suffering from an autoimmune disorder comprising administering, to the subject, an effective amount of a chimeric protein according to claim 1 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
85 . A method of treating a human subject suffering from an autoimmune disorder comprising administering, to the subject, an effective amount of a chimeric protein according to claim 2 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
86 . A method of treating a human subject suffering from an autoimmune disorder comprising administering, to the subject, an effective amount of a chimeric protein according to claim 5 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
87 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 10 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
88 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 11 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
89 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 14 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
90 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 19 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
91 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 20 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
92 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 23 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
93 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 28 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
94 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 29 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
95 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 30 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
96 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 33 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
97 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 38 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
98 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 39 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
99 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 40 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
100 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 43 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
101 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 48 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
102 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 49 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
103 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 50 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
104 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 58 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
105 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 59 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.
106 . A method of treating a human subject suffering from autoimmune diabetes comprising administering, to the subject, an effective amount of a chimeric protein according to claim 60 , where the HLA class II components in the chimeric protein are compatible with HLA class II determinants of the subject.Join the waitlist — get patent alerts
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