Peptides comprising an isodgr motif

Abstract

Disclosed herein are peptides which include an isoDGR motif and which selectively inhibit αvβ3 integrin. In some embodiments, the isoDGR motif results from the deamidation of an NGR motif.

1 - 111 . (canceled) 
     
     
         112 . A peptide comprising a  D DGR motif. 
     
     
         113 . A peptide according to  claim 112  comprising the sequence X D DGRX′, wherein:
 (a) X is selected from the group consisting of L, V, A, C, G, Y, P, H, K, Q and I; and 
 (b) X′ is selected from the group consisting of C, G, H, L, E, T, Q, R, S and P. 
 
     
     
         114 . A peptide according to  claim 112 , wherein the peptide comprises a sequence selected from the group consisting of C D DGRCVSGCAGRC,  D DGRAHA, G D DGRG, CVL D DGRMEC, C D DGRC, C D DGRCG, L D DGRE, Y D DGRT, LQCICTG D DGRGEWKCE, LQCISTG D DGRGEWKCE, CICTG D DGRGEWKC, CISTG D DGRGEWKC, MRCTCVG D DGRGEWTCY, MRCTSVG D DGRGEWTCY, CTCVG D DGRGEWTC and CTSVG D DGRGEWTC. 
     
     
         115 . A peptide according to  claim 114 , wherein the peptide comprises a sequence selected from the group consisting of cycloCVL D DGRMEC, linear C D DGRC, cyclic C D DGRC, linear C D DGRCG and cyclic C D DGRCG. 
     
     
         116 . A peptide according to  claim 112 , wherein the peptide comprises a deamidation product of an extracellular matrix protein or a fragment or derivative thereof. 
     
     
         117 . A peptide according to  claim 116 , wherein the peptide comprises a deamidation product of fibronectin, vitronectin, collagen, laminin, or a fragment or derivative thereof. 
     
     
         118 . A peptide according to  claim 117 , wherein the peptide comprises a deamidation product of the FN-I 5 , FN-I 7 , FN-II 1  or FN-III 9  module of fibronectin or a fragment or derivative thereof. 
     
     
         119 . A peptide according to  claim 112 , wherein the peptide inhibits tumor growth. 
     
     
         120 . A peptide according to  claim 112 , wherein the peptide inhibits angiogenisis. 
     
     
         121 . A peptide according to  claim 112 , wherein the peptide does not comprise an additional therapeutic agent. 
     
     
         122 . A peptide according to  claim 121 , wherein the additional therapeutic agent is an anti-cancer peptide. 
     
     
         123 . A peptide according to  claim 121 , wherein the additional therapeutic agent is a cytokine. 
     
     
         124 . A peptide according to  claim 112 , wherein the peptide comprises a turn involving the G and R residues of the DGR motif. 
     
     
         125 . A peptide according to  claim 112 , wherein the peptide comprises up to 350 amino acids. 
     
     
         126 . A peptide according to  claim 112 , other than when formed by metabolism of a peptide comprising the NGR motif. 
     
     
         127 . A conjugation product comprising a peptide as defined in  claim 112 , and a drug, cytokine, cytokine fragment, toxin, apoptotic peptide, biological response modifier, radionuclide, viral particle, gene or an imaging compound. 
     
     
         128 . A pharmaceutical composition comprising an effective amount of a peptide as defined in  claim 112 . 
     
     
         129 . A composition according to  claim 128  together with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         130 . A composition according to  claim 128  comprising essentially no peptide having a corresponding NGR motif. 
     
     
         131 . A conjugation product between a peptide as defined  claim 112 , and a cytokine. 
     
     
         132 . A conjugation product between a cytokine and a targeting moiety comprising the DGR motif, wherein the DGR is a  D DGR. 
     
     
         133 . A conjugation product according to  claim 132 , wherein the targeting moiety comprises the sequence X D DGRX′ wherein:
 (a) X is selected from the group consisting of L, V, A, C, G, Y, P, H, K, Q and I; and 
 (b) X′ is selected from the group consisting of C, G, H, L, E, T, Q, R, S and P. 
 
     
     
         134 . A conjugation product according to  claim 132 , wherein the targeting moiety is selected from the group consisting of C D DGRCVSGCAGRC,  D DGRAHA, G D DGRG, CVL D DGRMEC, C D DGRC, C D DGRCG, L D DGRE, Y D DGRT, LQCICTG D DGRGEWKCE, LQCISTG D DGRGEWKCE, CICTG D DGRGEWKC, CISTG D DGRGEWKC, MRCTCVG D DGRGEWTCY, MRCTSVG D DGRGEWTCY, CTCVG D DGRGEWTC and CTSVG D DGRGEWTC. 
     
     
         135 . A conjugation product according to  claim 134 , wherein the targeting moiety is selected from the group consisting of cycloCVL D DGRMEC, linear C D DGRC, cyclic C D DGRC, linear C D DGRCG and cyclic C D DGRCG. 
     
     
         136 . A conjugation product according to  claim 131 , wherein the cytokine is derivatized with polyethylene glycol or an acyl residue. 
     
     
         137 . A conjugation product according to  claim 131 , wherein the cytokine is further conjugated with a compound selected from the group consisting of an antibody, an antibody fragment, and biotin, wherein said antibody or fragment thereof is directed to a compound selected from the group consisting of a tumoral antigen, a tumoral angiogenic marker, and a component of the extracellular matrix. 
     
     
         138 . A conjugation product according to  claim 137 , wherein the cytokine is TNF and is conjugated to both the targeting moiety and a compound selected from the group consisting of an antibody, and antibody fragment, and biotin. 
     
     
         139 . A conjugation product according to  claim 131 , other than when formed in vivo by metabolism of a peptide comprising the NGR motif. 
     
     
         140 . A conjugation product according to  claim 131 , wherein the cytokine is linked to the peptide or targeting moiety through a spacer. 
     
     
         141 . A conjugation product according to  claim 140 , wherein the spacer is a glycine (G). 
     
     
         142 . A conjugation product according to  claim 131 , wherein the cytokine is selected from the group consisting of TNF, IFN-γ, IL-12, IP-10, IL-7 and EMAP II. 
     
     
         143 . A conjugation product according to  claim 131 , wherein the cytokine is TNF or IFNγ. 
     
     
         144 . A conjugation product according to  claim 143 , wherein the cytokine is TNF. 
     
     
         145 . A conjugation product according to  claim 144 , wherein the cytokine is TNFα or TNFβ. 
     
     
         146 . A pharmaceutical composition comprising an effective amount of a conjugation product as claimed in  claim 131 , together with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         147 . A pharmaceutical composition comprising an effective amount of a conjugation product of TNF and a peptide as defined in  claim 112 , and an effective amount of IFNγ or a polynucleotide encoding therefor. 
     
     
         148 . A composition according to  claim 128 , in the form of an injectable solution or suspension or a liquid for infusions. 
     
     
         149 . A composition according to  claim 128 , in the form of liposomes. 
     
     
         150 . A composition according to  claim 128 , further comprising another antitumor agent or a diagnostic tumor-imaging compound. 
     
     
         151 . A composition according to  claim 150 , wherein the other antitumor agent is doxorubicin, melphalan, cis-platin, gemcitabine or taxol. 
     
     
         152 . A method of treating or diagnosing a patient suffering from disorders involving αvβ3 comprising administering the peptide of  claim 112 . 
     
     
         153 . A method of treating or diagnosing a patient suffering from osteoporosis, arthritis, diabetic retinopathy, macular degeneration, restenosis or hemangioma comprising administering the peptide  claim 112 . 
     
     
         154 . A method of treating or diagnosing a patient suffering from cancer comprising administering peptide  claim 112 . 
     
     
         155 . A method according to  claim 154 , wherein cancer comprises a solid tumor.