Antibodies That Lower Triglycerides, Cholesterol Are May Be New Therapy For Heart Disease
Research suggests that a monoclonal antibody targeting ANGPTL4 may have therapeutic application in the treatment of cardiovascular disease.
Lexicon Pharmaceuticals reported results from preclinical research demonstrating that antibodies directed to a potential new target, angiopoietin-like protein 4 (ANGPTL4), rapidly lower triglycerides and cholesterol.
The results appeared in an article, entitled "Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice," published in the July 10, 2007 edition of the journal Proceedings of the National Academy of Sciences.
Lexicon scientists first identified ANGPTL4 as a potential target for cardiovascular disease using the company's proprietary gene knockout technology. Lexicon scientists create animal models that have alterations in specific genes in order to discover the physiological and behavioral effects that result from the loss of the protein encoded by the gene. Researchers found that animal models in which the ANGPTL4 gene was knocked out had lower triglyceride and cholesterol levels than normal animals.
The ANGPTL4 gene encodes a protein that is secreted into the bloodstream and is now believed to play an important role in triglyceride and cholesterol metabolism. Lexicon's biotherapeutics group developed a monoclonal antibody as an injectable agent targeting the ANGPTL4 protein to reproduce the triglyceride and cholesterol- lowering effects identified in the animal models. Notably, this appears to be the first successful production of a monoclonal antibody to this target.
"High triglycerides and cholesterol are correlated with an increased risk of heart disease," commented Dr. Brian P. Zambrowicz, executive vice president and chief scientific officer at Lexicon and an author on the paper. "The research our team published today may be an important first step in the development of a new treatment for severe cardiovascular disease, which continues to be the leading cause of death in the United States."
Earlier this year, researchers at the University of Texas Southwestern Medical Center in Dallas, the Institute of Molecular Medicine at the University of Texas Health Science Center in Houston, and other collaborating institutions found that individuals with a mutated ANGPTL4 gene have significantly lower triglyceride levels and higher levels of HDL cholesterol (or "good" cholesterol).(1) These results from human genetic studies further support Lexicon's therapeutic strategy based on original observations made using animal models.
Lexicon scientists discovered ANGPTL4's utility as a potential cardiovascular disease target as part of its Genome5000(TM) program, and the discovery was selected for inclusion in its collaboration with Genentech, Inc. The collaboration with Genentech was initiated in December 2002 to discover the functions of secreted proteins and potential antibody targets identified through Genentech's Secreted Protein Discovery Initiative (also referred to as the SPDI program), and was expanded in November 2005 to include the advanced research, development and commercialization of new biologic drugs.
Under the collaboration, Lexicon has the right to develop and commercialize biotherapeutic drugs for up to six targets. Genentech retains an option on the potential development and commercialization of the biotherapeutic drugs that Lexicon develops from the collaboration under a cost and profit sharing arrangement. ANGPTL4, referred to internally as LG842, is one of two targets already chosen by Lexicon for internal development. Lexicon has already generated versions of ANGPTL4 monoclonal antibodies that are currently in preclinical evaluation to identify a potential clinical development candidate.