Summary of Invention

This invention relates to a method to block the invasion of normal, neoplastic inflammatory or immune cells, tissue infiltration, and/or oedema formation through inhibition or modulation of molecules and proteolytic enzymes such as - but not exclusively - matrix metalloproteases (MMP), for the therapy of all diseases whose pathogenesis is related to the above processes, including tumors, non- neoplastic angioproliferative diseases, inflammatory diseases, or autoimmune diseases, the method being based on the use of inhibitors of the protease of the HIV virus (HIV-PI) ) (Indinavir - Saquinavir - Ritonavir - Nelfinavir - Amprenavir - Lopinavir - Ritonavir). The HIV protease inhibitors (PI) are new potent anti-retroviral drugs, which inhibit HIV replication by blocking in a very specific way the HIV protease. Since the introduction of PI in highly active anti-retroviral combination therapies (HAART), it has been noted a significant reduction of Kaposi's sarcoma (KS) incidence and even lesion regression in PI-treated patients. KS is an angio-proliferative cancer that is particularly frequent and aggressive in HIV-infected individuals. Although the anticancer effects were originally attributed to PI antiviral activities, epidemiologists could not draw a clear correlation between HIV suppression by PI, recovery of the immune system, and KS regression. Moreover, it was soon evident that PI were endowed with unpredicted effects on cell and lipid metabolism. This and the fact that KS is an angioproliferative disease (composed by blood vessels and proliferating cells of endothelial origin) suggested to us that PI blocked specific mechanisms related to cancer and angiogenesis, which involve a variety of proteases. Therefore the possible effects of PI on angiogenesis and KS was investigated. Solution to which problem (s) The HIV protease inhibitors (PI) are new potent anti-retroviral drugs, which inhibit HIV replication by blocking in a very specific way the HIV protease. Since the introduction of PI in highly active anti-retroviral combination therapies (HAART), it has been noted a significant reduction of Kaposi's sarcoma (KS) incidence and even lesion regression in PI-treated patients. KS is an angio-proliferative cancer that is particularly frequent and aggressive in HIV-infected individuals. Although the anticancer effects were originally attributed to PI antiviral activities, epidemiologists could not draw a clear correlation between HIV suppression by PI, recovery of the immune system, and KS regression. Moreover, it was soon evident that PI were endowed with unpredicted effects on cell and lipid metabolism. This and the fact that KS is an angioproliferative disease (composed by blood vessels and proliferating cells of endothelial origin) suggested to us that PI blocked specific mechanisms related to cancer and angiogenesis, which involve a variety of proteases. Therefore the possible effects of PI on angiogenesis and KS was investigated. The invention shows that systemic (oral) administration of indinavir or saquinavir to nude mice blocks the development and induces the regression of angioproliferative Kaposi's sarcoma (KS)-like lesions promoted by the subcutaneous inoculation of the animals with primary human KS cells or angiogenic factors including bFGF, or bFGF and VEGF combined. Both PI also blocked angiogenesis induced by bFGF or VEGF in the choriollantoic membrane assay. Moreover, PI also inhibited the in vivo growth of EA-hy 926 tumor cells, an angiogenic-tumor cell line derived from a hybrid between human endothelial and lung adenocarcinoma cells. (as detailed in the table shown over). Key applications - Cancer therapy: since the experimental models used are free of viruses and lack T cells, these data point to direct effects of PI on angiogenesis and tumor growth that are not due to virus suppression, nor to the reconstitution of immune responses against viruses or tumor cells. In fact, block of angiogenesis and tumor lesion formation by PI was found to be mediated by the direct inhibition of endothelial and tumor cell invasion that, in turn, is due to a block of matrix metalloprotease (MMP)-2 proteolytic activation by PI. However, additional effects on other MMPs are likely to be involved. All these affects occur at the same concentrations present in plasma of treated individuals and indicate that PI are MMP inhibitors and act as potent anti-angiogenic and anti-tumor molecules. In addition, we have also found that PI inhibit the development of other experimental tumors including breast, colon, lung and hepatic carcinomas, Burkitt's lymphomas, acute T cell leukemia, acute myelomonocytic leukemia and metastatic melanoma.

Moreover, our unpublished data indicate that PI inhibit vascular permeability and edema formation in a guinea pig model, and have anti-inflammatory effects. These data are in agreement with the inhibitory effects of PI on MMP activation or activity, as these disease models are all mediated by MMPs. Stage of Development: - A phase I clinical study is underway in a 11-site multicenter trial.

National Phases in all major countries.

Developmental Partnership, Out-license, Sale.