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The present invention provides a variety of isolated peptides and peptidomimetics, which can be useful, for example, in constructing the conjugates of the invention or, where the peptide itself has biological activity, in unconjugated form as a therapeutic for treating any of a variety of cardiovascular diseases as described below. Thus, the present invention provides an isolated peptide or peptidomimetic which has a length of less than 60 residues and includes the amino acid sequence CRPPR (SEQ ID NO: 1) or a peptidomimetic thereof. The invention further provides an isolated peptide or peptidomimetic which has a length of less than 60 residues and includes the amino acid sequence CARPAR (SEQ ID NO: 5) or a peptidomimetic thereof, or amino acid sequence CPKRPR (SEQ ID NO: 6) or a peptidomimetic thereof.

Inventors: Lianglin Zhang, Jason A. Hoffman, Erkki Ruoslahti
Current U.S. Classification: 530/330; 514/1.9; 514/2.4; 514/3.7; 514/8.1; 514/13.3; 514/14.7; 514/16.1; 514/16.3; 514/16.4; 514/19.1; 530/328; 530/329

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Referenced by

Citing PatentFiling dateIssue dateOriginal AssigneeTitle
US7807624Jan 5, 2007Oct 5, 2010Affinergy, Inc.Methods and compositions for promoting attachment of cells of endothelial cell lineage to medical devices
US8188221May 8, 2009May 29, 2012Burnham Institute for Medical Research
The Regents of the University of California, UCSF		Peptide homing to brain tumors

Claims

1. An isolated peptide or peptidomimetic, said isolated peptide selected from the group consisting of a peptide having a length of less than 60 residues and comprising the amino acid sequence CRPPR (SEQ ID NO: 1), a peptide comprising the amino acid sequence GRKSKTV (SEQ ID NO: 14), a peptide having a length of less than 150 residues and comprising the amino acid sequence CARPAR (SEQ ID NO: 5), a peptide having a length of less than 50 residues and comprising the amino acid sequence CPKRPR (SEQ ID NO: 6), a peptide having a length of less than 400 residues and comprising the amino acid sequence CKRAVR (SEQ ID NO: 7), a peptide comprising the amino acid sequence RNSWKPN (SEQ ID NO: 16), a peptide comprising the amino acid sequence RGSSS (SEQ ID NO: 9), a peptide having a length of less than 400 residues and comprising the amino acid sequence RSTRANP (SEQ ID NO: 18), a peptide having a length of less than 400 residues and comprising the amino acid sequence PKTRRVP (SEQ ID NO: 20), and a peptide having a length of less than 400 residues and comprising the amino acid sequence SGMARTK (SEQ ID NO: 22), or a peptidomimetic thereof.

2. The isolated peptide or peptidomimetic of claim 1, which is a peptide.

3-11. (canceled)

12. An isolated peptide or peptidomimetic, said isolated peptide selected from the group consisting of a peptide comprising the amino acid sequence CXGRKSKTVZC (SEQ ID NO: 15), a peptide comprising the amino acid sequence CXRNSWKPNZC (SEQ ID NO: 17), a peptide comprising the amino acid sequence CXRSTRANPZC (SEQ ID NO: 19), a peptide comprising the amino acid sequence CXPKTRRVPZC (SEQ ID NO: 21), and a peptide comprising the amino acid sequence CXSGMARTKZC (SEQ ID NO: 23), or a peptidomimetic thereof,

wherein X=0 to 20 independently selected residues and

wherein Z=0 to 20 independently selected residues.

13-63. (canceled)

64. A method of isolating one or more homing molecules that selectively homes to heart vasculature, comprising:

(a) contacting HLP/CRIP2, receptor clone 9, Sigirr/TIR8, MpcII-3-related protein, or bc10, or a fragment thereof, with a library of molecules under conditions suitable for specific binding of a molecule to HLP/CRIP2, receptor clone 9, Sigirr/TIR8, MpcII-3-related protein, or bc10, respectively;

(b) assaying for specific binding of a molecule to HLP/CRIP2, receptor clone 9, Sigirr/TIR8, MpcII-3-related protein, or bc10, respectively; and

(c) separating one or more binding molecules from the library, thereby isolating one or more homing molecules that selectively homes to heart vasculature and specifically binds HLP/CRIP2, receptor clone 9, Sigirr/TIR8, MpcII-3-related protein, or bc10, respectively.

65. The method of claim 64, wherein step (a) comprises contacting purified HLP/CRIP, receptor clone 9, Sigirr/TIR8, MpcII-3-related protein, or bc10, respectively, or a fragment thereof, with said library of molecules.

66. The method of claim 64, wherein step (a) comprises contacting a cell expressing cell surface HLP/CRIP2, receptor clone 9, Sigirr/TIR8, MpcII-3-related protein, or bc10, respectively, or a fragment thereof, with said library of molecules.

67. The method of claim 64, wherein said HLP/CRIP2, receptor clone 9, Sigirr/TIR8, MpcII-3-related protein, or bc10 is human or murine HLP/CRIP2.

68. (canceled)

69. The method of claim 64, wherein said library of molecules is a library of small molecules, peptides and peptidomimetics, or antibodies and antigen-binding fragments thereof.

70-96. (canceled)

97. A method of directing a moiety to heart vasculature in a subject, comprising administering to the subject a conjugate which comprises a moiety linked to an antibody, or antigen-binding fragment thereof, that selectively homes to heart vasculature, said antibody specifically binding HLP/CRIP2 (SEQ ID NO: 25), SEQ ID NO:27, Sigirr/TIR8 (SEQ ID NO: 29), SEQ ID NO: 33, or bc10 (SEQ ID NO: 35),

thereby directing said moiety to heart vasculature.

98. The method of claim 97, wherein said antibody is a monoclonal antibody.

99. The method of claim 97, wherein said antibody has biologic activity.

100. The method of claim 97, wherein said moiety is a detectable moiety.

101. The method of claim 97, wherein said moiety is a therapeutic agent.

102. The method of claim 101, wherein said therapeutic agent is selected from the group angiogenic agent, anti-thrombotic agent, anti-inflammatory agent, immunosuppressive agent, anti-arrhythmic agent, tumor necrosis factor inhibitor, endothelin inhibitor, angiotensin-converting enzyme inhibitor, calcium antagonist, antibiotic agent, antiviral agent and viral vector.

103-126. (canceled)

127. A conjugate, comprising a therapeutic agent linked to a homing molecule that selectively homes to heart vasculature, said homing molecule specifically binding cysteine-rich protein 2 (HLP/CRIP2; SEQ ID NO: 25), single Ig IL-2 receptor related protein (Sigirr/TIR8; SEQ ID NO: 29), SEQ ID NO: 33, murine bladder cancer-associated protein homolog (bc10; SEQ ID NO: 35).

128. The conjugate of claim 127, wherein said homing molecule homes to the heart in vivo with a selectivity of at least 5-fold relative to non-recombinant phage.

129. The conjugate of claim 127, wherein said homing molecule is a peptide or peptidomimetic.

130-135. (canceled)

136. The conjugate of claim 133, wherein said homing peptide or peptidomimetic is conformationally constrained.

137. The conjugate of claim 127, wherein said homing molecule is an antibody or antigen-binding fragment thereof.

138. The conjugate of claim 127 wherein said therapeutic agent is selected from the group angiogenic agent, anti-thrombotic agent, anti-inflammatory agent, immunosuppressive agent, anti-arrhythmic agent, tumor necrosis factor inhibitor, endothelin inhibitor, angiotensin-converting enzyme (ACE) inhibitor, calcium antagonist, antibiotic agent, antiviral agent and viral vector.

139. The conjugate of claim 138, wherein said therapeutic agent is an angiogenic agent.

140. The conjugate of claim 138, wherein said therapeutic agent is an anti-thrombotic agent.

141. A method of directing a moiety to heart vasculature in a subject, comprising administering to the subject a conjugate which comprises a moiety linked to a homing molecule that selectively homes to heart vasculature, said homing molecule specifically binding cysteine-rich protein 2 (HLP/CRIP2; SEQ ID NO: 25), Sigirr/TIR8 (SEQ ID NO: 29), SEQ ID NO: 33, or murine bladder cancer-associated protein homolog (bc10; SEQ ID NO: 35),

thereby directing said moiety to heart vasculature.

142. The method of claim 141, wherein said homing molecule homes to the heart in vivo with a selectivity of at least 5-fold relative to non-recombinant phage.

143. The method of claim 141, wherein said homing molecule is a peptide or peptidomimetic.

144-149. (canceled)

150. The method of claim 147, wherein said homing peptide or peptidomimetic is conformationally constrained.

151. The method of claim 141, wherein said homing molecule is an antibody or antigen-binding fragment thereof.

152. The method of claim 141, wherein said moiety is a detectable moiety.

153. The method of claim 152, wherein said detectable moiety is a radionuclide or paramagnetic ion.

154. The method of claim 141, wherein said moiety is a therapeutic agent.

155. The method of claim 154, wherein said therapeutic agent is selected from the group angiogenic agent, anti-thrombotic agent, anti-inflammatory agent, immunosuppressive agent, anti-arrhythmic agent, tumor necrosis factor inhibitor, endothelin inhibitor, angiotensin-converting enzyme (ACE) inhibitor, calcium antagonist, antibiotic agent, antiviral agent and viral vector.

156-241. (canceled)

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