Monoclonal antibodies for inhibition of laminin-8 expression to inhibit human gliomas

Abstract

Using gene array technology, we observed that an increase of the alpha-4 chain-containing Laminin-8 correlated with poor prognosis for patients with brain gliomas. We established that inhibition of Laminin-8 expression by a new generation of highly specific and stable antisense oligonucleotides (Morpholino™) against chains of Laminin-8 could slow or stop the spread of glioma. This was demonstrated in an in vitro model using human glioblastoma multiforme cell lines M059K and U-87MG co-cultured with normal human brain microvascular endothelial cells (HBMVEC). Using Western blot analysis and immunohistochemistry, we confirmed that antisense treatment effectively blocked laminin-8 protein synthesis. Antisense oligonucleotides against both alpha-4 and β1 chains of laminin-8 blocked significantly the invasion of co-cultures through Matrigel. The results show that Laminin-8 may not only contribute to glioma progression and recurrence as part of the neovascularization process but also by directly increasing the invasive potential of tumor cells.

1 . A method for reducing invasiveness of a human glioma comprising the step of contacting said glioma with a composition that inhibits expression of Laminin-8 by said glioma. 
     
     
         2 . The method according to  claim 1 , wherein Laminin-8 expression is inhibited by inhibiting the expression of Laminin α4 chain. 
     
     
         3 . The method according to  claim 1 , wherein Laminin-8 expression is inhibited by inhibiting the expression of Laminin β1 chain. 
     
     
         4 . The method according to  claim 1 , wherein Laminin-8 expression is inhibited by inhibiting the expression of both Laminin α4 chain and Laminin β1 chain. 
     
     
         5 . The method according to  claim 1 , wherein the composition includes a monoclonal antibody. 
     
     
         6 - 12 . (canceled)