CD47 related compositions and methods for treating immunological diseases and disorders
First Claim
1. A fusion polypeptide comprising an extracellular domain of CD47 fused to a human IgG1 Fc polypeptide, wherein the Fc polypeptide comprises a substitution or a deletion of a cysteine residue in the hinge region, wherein the substituted or deleted cysteine residue is the cysteine residue most proximal to the amino terminus of the hinge region of the Fc portion of a wildtype human IgG1 immunoglobulin, and wherein the Fc polypeptide further comprises a substitution or deletion of an aspartate residue immediately adjacent to the cysteine residue most proximal to the amino terminus of the hinge region of the Fc portion of a wildtype human IgG1 immunoglobulin, wherein the fusion polypeptide alters the immunoresponsiveness of an immune cell.
2 Assignments
0 Petitions
Accused Products
Abstract
Provide herein are fusion polypeptides that comprise a CD47 extracellular domain or a variant thereof that is fused to a Fc polypeptide. The fusion polypeptides are useful for treating an immunological disease or disorder in a subject according to the methods described herein. The fusion polypeptides are capable of suppressing immunoresponsiveness of an immune cell, inhibiting production of proinflammatory cytokines, including inhibiting immune complex-induced production of cytokines.
140 Citations
129 Claims
- 1. A fusion polypeptide comprising an extracellular domain of CD47 fused to a human IgG1 Fc polypeptide, wherein the Fc polypeptide comprises a substitution or a deletion of a cysteine residue in the hinge region, wherein the substituted or deleted cysteine residue is the cysteine residue most proximal to the amino terminus of the hinge region of the Fc portion of a wildtype human IgG1 immunoglobulin, and wherein the Fc polypeptide further comprises a substitution or deletion of an aspartate residue immediately adjacent to the cysteine residue most proximal to the amino terminus of the hinge region of the Fc portion of a wildtype human IgG1 immunoglobulin, wherein the fusion polypeptide alters the immunoresponsiveness of an immune cell.
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2-3. -3. (canceled)
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28-29. -29. (canceled)
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52-54. -54. (canceled)
- 58. An isolated antibody, or antigen-binding fragment thereof, (a) that specifically binds to CD47 and (b) that competitively inhibits binding of a CD47 ligand (i) to CD47 and (ii) to a viral CD47-like polypeptide.
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60-61. -61. (canceled)
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64-70. -70. (canceled)
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73-75. -75. (canceled)
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76. An agent that specifically binds to CD47 and that inhibits binding of a viral CD47-like polypeptide to at least one CD47 ligand.
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77-80. -80. (canceled)
- 82. (canceled)
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83. A method for identifying an agent that alters immunoresponsiveness of an immune cell comprising:
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(a) contacting (i) a candidate agent;
(ii) a viral CD47-like polypeptide; and
(iii) a CD47 ligand, under conditions and for a time sufficient to permit interaction between the CD47 ligand and the viral CD47-like polypeptide;(b) determining a level of binding of the viral CD47-like polypeptide to the CD47 ligand in the presence of the candidate agent and comparing a level of binding of the viral CD47-like polypeptide to the CD47 ligand in the absence of the candidate agent, wherein a decrease in the level of binding of the viral CD47-like polypeptide to the CD47 ligand in the presence of the candidate agent indicates that the candidate agent inhibits binding of the viral CD47-like polypeptide to the CD47 ligand; (c) contacting (i) the candidate agent;
(ii) a CD47 ligand; and
(iii) an immune cell that expresses CD47, under conditions and for a time sufficient to permit interaction between a CD47 ligand and CD47; and(d) determining a level of binding of the CD47 ligand to the immune cell in the presence of the candidate agent and comparing a level of binding of the CD47 ligand to the immune cell in the absence of the candidate agent, wherein a decrease in the level of binding of the CD47 ligand to the immune cell in the presence of the candidate agent indicates that the candidate agent alters immunoresponsiveness of the immune cell.
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84-86. -86. (canceled)
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88. (canceled)
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90. (canceled)
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92-94. -94. (canceled)
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95. A method for treating an immunological disease or disorder in a subject comprising administering to the subject a composition that comprises (a) a pharmaceutically suitable carrier;
- and either (i) an agent that specifically binds to CD47 and that impairs binding of a viral CD47-like polypeptide to a CD47 ligand or (ii) an agent that specifically binds to a CD47 ligand and specifically impairs binding of a viral CD47-like polypeptide to the CD47 ligand.
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96-99. -99. (canceled)
- 100. A method of treating a disease or disorder associated with alteration of at least one of cell migration, cell proliferation, and cell differentiation in a subject, wherein the method comprises administering to the subject a pharmaceutically suitable carrier and either (a) an agent that specifically binds to CD47 and that impairs binding of a viral CD47-like polypeptide to a CD47 ligand or (b) an agent that specifically binds to a CD47 ligand and specifically impairs binding of a viral CD47-like polypeptide to the CD47 ligand.
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102-110. -110. (canceled)
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111. A method of activating an immune cell comprising contacting the immune cell with either (a) an agent that specifically binds to CD47 and that impairs binding of a viral CD47-like polypeptide to a CD47 ligand, or (b) an agent that specifically binds to a CD47 ligand and that impairs binding of a viral CD47-like polypeptide to a CD47 ligand under conditions and a time sufficient to permit the immune cell and the agent to interact, wherein the CD47 ligand is present on the cell surface of the immune cell, thereby activating the immune cell.
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112-119. -119. (canceled)
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120. A method of manufacture for producing an agent that suppresses immunoresponsiveness of an immune cell, comprising:
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(a) identifying an agent that alters immunoresponsiveness of an immune cell, wherein the step of identifying comprises; (I) contacting (i) a candidate agent;
(ii) a viral CD47-like polypeptide; and(iii) a CD47 ligand, under conditions and for a time sufficient to permit interaction between the CD47 ligand and the viral CD47-like polypeptide; and (II) determining a level of binding of the viral CD47-like polypeptide to the CD47 ligand in the presence of the candidate agent and comparing a level of binding of the viral CD47-like polypeptide to the CD47 ligand in the absence of the candidate agent, wherein a decrease in the level of binding of the viral CD47-like polypeptide to the CD47 ligand in the presence of the candidate agent indicates that the candidate agent inhibits binding of the viral CD47-like polypeptide to the CD47 ligand; (III) contacting (i) the candidate agent;
(ii) a CD47 ligand; and
(2) an immune cell that expresses CD47, under conditions and for a time sufficient to permit interaction between the CD47 ligand and CD47; and(IV) determining a level of binding of the CD47 ligand to the immune cell in the presence of the candidate agent and comparing a level of binding of the CD47 ligand to the immune cell in the absence of the candidate agent, wherein a decrease in the level of binding of the CD47 ligand to the immune cell in the presence of the candidate agent indicates that the candidate agent alters immunoresponsiveness of the immune cell; and (b) producing the agent identified in step (a).
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121-126. -126. (canceled)
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128. A fusion polypeptide comprising an extracellular domain of a viral CD47 polypeptide fused to an Fc polypeptide.
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129-131. -131. (canceled)
Specification