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The cholesterol link: What do an eminent biochemist from the past and an immunotherapy pioneer from the present have in common?

Wistar’s expertise has traditionally been in the study of cancer biology and immunology — very broad and complex fields that entail multidisciplinary approaches and investigations.

It so happened that David Kritchevsky, Ph.D., an eminent biochemist and expert in human nutrition, worked at Wistar for five decades starting in 1957, generating a vast amount of scientific knowledge on the role of lipids in atherosclerosis, or fat deposits in blood vessels, and prompting early work on the effect of diet on the risk of cancer. 

During his tenure at Wistar, Kritchevsky contributed more than 420 research publications and authored the influential textbook Cholesterol, which explored the biologic functions of cholesterol and still is the most comprehensive source of information on this subject.

Fast forward to 2018 and cholesterol is once again illuminated at Wistar in the work of David Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research at the Institute, who applied his novel synthetic DNA-encoded monoclonal antibody (DMAb) technology as a lipid-lowering therapy.

While Kritchevsky’s seminal studies highlighted the mechanisms linking high blood cholesterol to cardiovascular disease, Weiner’s approach is directed at finding next generation therapeutic strategies to fight elevated cholesterol. 

Since Kritchevsky’s pioneering work, effective cholesterol-lowering medications called statins have come on the market and are now widely used. However, while highly effective, statins have been linked to muscle pain, digestive problems and may cause liver damage.

These side effects have prompted the search for alternative therapeutic approaches, including monoclonal antibodies that target PSCK9, a protein involved in regulating cholesterol levels in the bloodstream. 

A recent large clinical trial has shown the benefit of this new therapy in reducing cardiovascular risk among patients with elevated cholesterol and a previous heart attack episode. However, monoclonal antibody-based therapies face manufacturing complexity and issues related to the requirement of repeated dosing, which translate into high costs and create patient compliance issues. Therefore, making the PSCK9 antibody therapy available to the general population is a challenge and development of effective alternatives is critical. The Weiner team at Wistar is working to advance their DMAb technology for use in different disease areas, including cancer and infectious diseases. Anti-PSCK9 therapy provides an ideal opportunity to test this technology for chronic diseases. 

DMAbs consist of an engineered synthetic DNA blueprint that is delivered by intramuscular injection and instructs the body on how to make a certain designed antibody, entirely bypassing the bioprocess and manufacturing steps. 

Weiner and collaborators created anti-PSCK9 DMAbs that induced a significant decrease in total cholesterol and non-high-density lipoprotein cholesterol (non-HDL-C), an important parameter for evaluating cardiovascular risk, in mouse models. This study confirms the versatility of DMAbs and provides a proof of principle that they may be developed as a new option for coronary artery disease.     

The science of cholesterol is coming full circle at Wistar, from early discoveries to next generation therapies.