Novel antiangiogenic peptide agents and their therapeutic and diagnostic use

Abstract

The current invention concerns novel antiangiogenic peptides which correspond to about 10 to about 150 consecutive amino acids of N-terminal sequences of human growth hormone, human placental lactogen, human growth hormone variant hGH-V, and prolactin, and their use in inhibiting angiogenesis and in the diagnosis of diseases of human pregnancy involving abnormalities of placental vascularization.

What is claimed is:  
     
         1 . An anti-angiogenic peptide substantially identical to about 10 to about 150 consecutive amino acids selected from the N-terminal end of human placental lactogen, human growth hormone, or growth hormone variant hGH-V, wherein the peptide 
 (i) inhibits capillary endothelial cell proliferation and organization;    (ii) inhibits angiogenesis in chick chorioallantoic membrane; and    (iii) binds to at least one specific receptor which does not bind an intact full length growth hormone, placental lactogen, or growth hormone variant hGH-V.    
     
     
         2 . The peptide of  claim 1 , wherein the peptide is generated by enzymatic cleavage of growth hormone, placental lactogen, or growth hormone variant hGH-V.  
     
     
         3 . The peptide of  claim 1  having the amino acid sequence of SEQ ID NO: 18.  
     
     
         4 . The peptide of  claim 1  having the amino acid sequence of SEQ ID NO: 24.  
     
     
         5 . The peptide of  claim 1  having the amino acid sequence of SEQ ID NO: 30.  
     
     
         6 . An isolated nucleic acid encoding the peptide of  claim 1 .  
     
     
         7 . The nucleic acid of  claim 6 , wherein the nucleic acid is DNA.  
     
     
         8 . The nucleic acid of  claim 6 , wherein the nucleic acid is RNA.  
     
     
         9 . The nucleic acid of  claim 7 , wherein the nucleic acid comprises a cDNA sequence.  
     
     
         10 . The nucleic acid of  claim 7 , wherein the nucleic acid comprises the sequence of SEQ ID NO: 14.  
     
     
         11 . The nucleic acid of  claim 7 , wherein the nucleic acid comprises the sequence of SEQ ID NO: 20.  
     
     
         12 . The nucleic acid of  claim 7 , wherein the nucleic acid comprises the sequence of SEQ ID NO: 26.  
     
     
         13 . The nucleic acid of  claim 7 , wherein the nucleic acid comprises the sequence of SEQ ID NO: 19.  
     
     
         14 . The nucleic acid of  claim 7 , wherein the nucleic acid comprises the sequence of SEQ ID NO: 13.  
     
     
         15 . The nucleic acid of  claim 7 , wherein the nucleic acid comprises the sequence of SEQ ID NO: 25.  
     
     
         16 . The nucleic acid sequence of  claim 6 , wherein the nucleic acid sequence comprises a vector.  
     
     
         17 . The nucleic acid sequence of  claim 16 , wherein the vector is an expression vector.  
     
     
         18 . A host cell comprising the nucleic acid of  claim 7 .  
     
     
         19 . A method of producing the peptide of  claim 1 , comprising expressing the nucleic acid in the host cell of  claim 18 , and recovering the peptide.  
     
     
         20 . The method of  claim 19 , wherein a peptide product of the expressed nucleic acid is recovered from the host cell and is enzymatically cleaved to generate the peptide of  claim 1 .  
     
     
         21 . A method of treating an angiogenic disease in a subject, the method comprising administering to a subject in need of such treatment an angiogenesis inhibitory effective amount of a peptide of  claim 1 .  
     
     
         22 . The method of  claim 21  wherein the peptide has the amino acid sequence of SEQ ID NO: 18, SEQ ID NO: 24 or SEQ ID NO: 30.  
     
     
         23 . A method of inhibiting tumor formation or growth in a patient, the method comprising administering to the patient an angiogenesis inhibitory effective amount of the peptide of  claim 1 .  
     
     
         24 . The method of  claim 23  wherein the peptide has amino acid sequence SEQ ID NO: 18, SEQ ID NO: 24 or SEQ ID NO: 30.  
     
     
         25 . A method for diagnosing a probable abnormality of placental vascularization during pregnancy comprising assaying a level of at least one of endogenous N-terminal fragments of growth hormone, prolactin, growth hormone variant hGH-V, and placental lactogen in a tissue sample from a patient; and 
 comparing the level of the at least one of endogenous N-terminal fragments to an average level of the at least one of endogenous N-terminal fragments in a normal patient population;    wherein a level of the at least one of endogenous N-terminal fragments higher than the average level is a probable abnormality of placental vascularization during pregnancy.    
     
     
         26 . A method of modulating vascularization of a patient's placenta, the method comprising administering to the patient an angiogenesis inhibitory effective amount of the peptide of  claim 1.