Conjugates for the treatment of mesothelioma

Abstract

The present invention provides conjugates of cytokines and targeting peptides that is able to bind to a receptor expressed on tumor-associated vessels or to a component of the extracellular matrix associated to the tumor vessels, for treatment of malignant pleural mesothelioma. In particular, the invention provides conjugates comprising the cytokine TNF linked to a peptide containing the NGR motif. The invention further provides pharmaceutical compositions comprising such conjugate and pharmaceutical formulations comprising conjugates dissolved in appropriate buffers.

1 . A conjugate comprising a targeting peptide and a cytokine for use in the treatment of mesothelioma wherein the targeting peptide is a peptide containing NGR, isoDGR or RGD motif and wherein the cytokine is TNFα or TNFβ. 
     
     
         2 . A conjugate according to  claim 1  wherein the targeting peptide is a peptide containing the NGR motif. 
     
     
         3 . A conjugate according to  claim 2  wherein the targeting peptide is selected from the group consisting of linear or cyclic CNGRCVSGCAGRC, NGRAHA, GNGRG, CVLNGRMEC, CNGRC, CNGRCG, LNGRE, YNGRT LQCICTGNGRGEWKCE, LQCISTGNGRGEWKCE, CICTGNGRGEWKC, CISTGNGRGEWKC, MRCTCVGNGRGEWTCY, MRCTSVGNGRGEWTCY, CTCVGNGRGEWTC and CTSVGNGRGEWTC. 
     
     
         4 . A conjugate according to  claim 2  wherein the cytokine is TNF that is linked to the targeting peptide CNGRC through the spacer G (glycine). 
     
     
         5 . A conjugate according to  claim 3  wherein the cytokine is TNF that is linked to the targeting peptide CNGRC through the spacer G (glycine). 
     
     
         6 . A method for treating mesothelioma comprising administering a conjugate comprising a targeting peptide and a cytokine, wherein the targeting peptide is a peptide containing NGR, isoDGR or RGD motif and wherein the cytokine is TNFα or TNFβ. 
     
     
         7 . A pharmaceutical composition comprising an effective amount of a conjugate comprising a targeting peptide and a cytokine, wherein the targeting peptide is a peptide containing NGR, isoDGR or RGD motif and wherein the cytokine is TNFα or TNFβ together with pharmaceutically acceptable carriers and diluents, for use in the treatment of mesothelioma. 
     
     
         8 . A pharmaceutical composition according to  claim 6  wherein the conjugate comprises TNF linked to the targeting peptide CNGRC through the spacer G. 
     
     
         9 . A pharmaceutical formulation containing a conjugate comprising TNF linked to the targeting peptide CNGRC through the spacer G at concentration in the range of 0.01 to 10 mg/ml together with pharmaceutically acceptable carriers and diluents for use in the treatment of mesothelioma. 
     
     
         10 . A pharmaceutical formulation consisting of 0.150 mg/ml of a conjugate comprising TNF linked to the targeting peptide CNGRC through the spacer G dissolved in a solution of 50 mM Na2HPO4, 150 mM NaCl for use in the treatment of mesothelioma.