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Fattori E.,Istituto di Ricerche di Biologia Molecolare P. Angeletti | Cappelletti M.,Istituto di Ricerche di Biologia Molecolare P. Angeletti | Lo Surdo P.,Biochemistry and Molecular Biology Unit | Calzetta A.,Biochemistry and Molecular Biology Unit | And 7 more authors.
Journal of Lipid Research | Year: 2012

Successful development of drugs against novel targets crucially depends on reliable identification of the activity of the target gene product in vivo and a clear demonstration of its specific functional role for disease development. Here, we describe an immunological knockdown (IKD) method, a novel approach for the in vivo validation and functional study of endogenous gene products. This method relies on the ability to elicit a transient humoral response against the selected endogenous target protein. Antitarget antibodies specifically bind to the target protein and a fraction of them effectively neutralize its activity. We applied the IKD method to the in vivo validation of plasma PCSK9 as a potential target for the treatment of elevated levels of plasma LDL-cholesterol. We show that immunization with human-PCSK9 in mice is able to raise antibodies that cross-react and neutralize circulating mouse-PCSK9 protein thus resulting in increased liver LDL receptor levels and plasma cholesterol uptake. These findings closely resemble those described in PCSK9 knockout mice or in mice treated with antibodies that inhibit PCSK9 by preventing the PCSK9/LDLR interaction. Our data support the IKD approach as an effective method to the rapid validation of new target proteins. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc. Source

Sharma R.,Lehigh Valley Physician Group | Buitrago S.,Laboratory Animal Resources | Pitoniak R.,Roswell Park Cancer Institute | Gibbs J.F.,State University of New York at Buffalo | And 4 more authors.
Pancreas | Year: 2014

OBJECTIVES: We have previously demonstrated activity of Apo2L/TRAIL against patient pancreatic tumor xenografts. Here, we have examined the influence of the tumor implantation site on therapeutic response of orthotopic tumors and their metastases to Apo2L/TRAIL. METHODS: Sensitivity of 6 patient pancreatic tumor xenografts to Apo2L/TRAIL was determined in a subcutaneous model. To compare the response of orthotopic tumors, cells from subcutaneous xenografts were injected into the pancreas. Tumor growth was confirmed by histological examination of selected mice, and then treatment was started. When all control mice developed externally palpable tumors, the experiment was terminated, and pancreatic weights compared between control and treated groups. Magnetic resonance imaging was used to quantitate the response of orthotopic and metastatic tumors. RESULTS: The sensitivity to Apo2L/TRAIL observed in subcutaneous tumors was maintained in orthotopic tumors. Metastatic spread was observed with orthotopic tumor implantation. In an orthotopic model of a sensitive tumor, primary and metastatic tumor burden was significantly reduced, and median survival significantly extended by Apo2L/TRAIL therapy. CONCLUSIONS: Our data provide evidence that the site of tumor engraftment does not alter the inherent sensitivity of patient xenografts to Apo2L/TRAIL, and these results highlight the potential of Apo2L/TRAIL therapy against primary and metastatic pancreatic cancer. © 2014 by Lippincott Williams and Wilkins. Source

Goodnow R.A.,40 Kingsland Street | Hicks A.,40 Kingsland Street | Sidduri A.,40 Kingsland Street | Kowalczyk A.,40 Kingsland Street | And 38 more authors.
Journal of Medicinal Chemistry | Year: 2010

The inhibition of LTB4 binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B4 (LTB4) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB4 binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB4 and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development. © 2010 American Chemical Society. Source

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