Immunoconjugates for the treatment of tumours

Abstract

A pharmaceutical composition comprising a conjugate of a cytokine and a tumor targeting moiety (TTM) and a pharmaceutically acceptable excipient, wherein the cytokine is present in an amount which does not induce a negative feedback mechanism.

1 . A pharmaceutical composition comprising a conjugate of a cytokine and a tumor targeting moiety (TTM) and a pharmaceutically acceptable carrier, diluent or excipient, wherein the cytokine is present in an amount which does not induce a negative feedback mechanism.  
     
     
         2 . A pharmaceutical composition according to  claim 1  wherein the cytokine is present in an amount which does not induce soluble cytokine receptor shedding.  
     
     
         3 . A pharmaceutical composition according to  claim 1  wherein the conjugate is present in an amount to provide a dosage in the range of 0.5 to 500 ng/kg.  
     
     
         4 . A pharmaceutical composition according to  claim 1  wherein the conjugate is present in an amount to provide a dosage in the range of 1 to 50 ng/kg.  
     
     
         5 . A pharmaceutical composition according to  claim 1  wherein the conjugate is present in an amount to provide a dosage in the range of 5 to 15 ng/kg.  
     
     
         6 . A pharmaceutical composition according to  claim 1  wherein the conjugate is present in an amount such that the conjugate, or a metabolite thereof, is provided to the blood plasma of a patient to be treated in an amount of no greater than about 35,000 ng/day for a 70 kg patient.  
     
     
         7 . A pharmaceutical composition according to  claim 1  wherein the cytokine is an inflammatory cytokine.  
     
     
         8 . A pharmaceutical composition according to  claim 1  wherein the cytokine is a chemotherapeutic cytokine.  
     
     
         9 . A pharmaceutical composition according to  claim 1  wherein the cytokine is TNFα, TNFβ, IFNα, IFNβ, IFNγ, IL-1, 2, 4, 6, 12, 15, EMAP II, vascular endothelial growth factor (VEGF), PDGF, PD-ECGF or a chemokine.  
     
     
         10 . A pharmaceutical composition according to  claim 1  wherein the cytokine is TNF-α, TNF-β or IFN-γ.  
     
     
         11 . A pharmaceutical composition according to  claim 1  wherein the TTM is a tumor vasculature targeting moiety (TVTM).  
     
     
         12 . A pharmaceutical composition according to  claim 11  wherein the TVTM is a binding partner of a tumor vasculature receptor, marker or other extracellular component.  
     
     
         13 . A pharmaceutical composition according to  claim 1  wherein the TTM is a binding partner of a tumor receptor, marker or other extracellular component.  
     
     
         14 . A pharmaceutical composition according to  claim 1  wherein the TTM is an antibody or ligand, or a fragment thereof.  
     
     
         15 . A pharmaceutical composition according to  claim 1  wherein the TTM is contains the NGR or RGD motif, or is HIV-tat, Annexin V, Osteopontin, Fibronectin, Collagen Type I or IV, Hyaluronate, Ephrin, or is a binding partner to oncofetal fibronectin; or a fragment thereof.  
     
     
         16 . A pharmaceutical composition according to  claim 1  wherein the TTM contains the NGR motif.  
     
     
         17 . A pharmaceutical composition according to  claim 1  wherein the TTM is CNGRCVSGCAGRC, NGRAHA, GNGRG, cycloCVLNGRMEC, linear or cyclic CNGRC.  
     
     
         18 . A pharmaceutical composition according to  claim 1  wherein the TTM contains the NGR motif.  
     
     
         19 . A pharmaceutical composition according to  claim 1  wherein the TTM is targeted to VEGFR, ICAM 1, 2 or 3, PECAM-1, CD31, CD13, VCAM-1, Selectin, Act R11, ActRIIB, ActRI, ActRIB, CD44, aminopeptidase A, aminopeptidase N (CD13), αvβ3 integrin, αvβ5 integrin, FGF-1, 2, 3, or 4, IL-IR, EPHR, MMP, NG2, tenascin, oncofetal fibronectin, PD-ECGFR, TNFR, PDGFR or PSMA.  
     
     
         20 . A pharmaceutical composition according to  claim 1  wherein the conjugate is in the form of a fusion protein.  
     
     
         21 . A pharmaceutical composition according to  claim 1  wherein the conjugate is in the form of nucleic acid.  
     
     
         22 . A pharmaceutical composition according to  claim 1  wherein the composition further comprises another antitumor agent or diagnostic tumor-imaging compound.  
     
     
         23 . A pharmaceutical composition according to  claim 22  wherein the further antitumor agent is doxorubicin, melphalan or cisplatin.  
     
     
         24 . [canceled] 
     
     
         25 . A method of treating or diagnosing cancer comprising administering to a patient in need of the same a conjugate as defined in  claim 1  in an effective amount, wherein said amount does not induce a negative feedback mechanism.