Monoclonal antibodies as a therapeutic to prevent Type 2 Diabetes

University Of Kentucky, Lexington KY

Investigators

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Abstract

ABSTRACT- PROJECT 2 Type 2 diabetes (T2DM) impacts a staggering 462 million individuals globally, with approximately 70% of prediabetic patients transitioning to T2DM. Understanding the driving factors behind this progression is crucial, necessitating the development of therapeutics to prevent the onset of T2DM. Genetic studies conducted on individuals with Neonatal Progeroid Syndrome (NPS) unveiled a novel hormone called asprosin, characterized by its glucogenic and orexigenic functions. Recent investigations have uncovered a third critical role for asprosin—its detrimental impact on insulin secretion from pancreatic β cell line. Asprosin, therefore, emerges as a pivotal factor linking the three core components of prediabetes to the flourishing progression of T2DM: heightened hepatic glucose production, compromised β cell function, and increased energy accretion. We recently identified Protein Tyrosine Phosphatase type δ (Ptprd) as the receptor that asprosin engages for its orexigenic function. While Ptprd is also expressed in the β cells of humans and mice, the functional relevance of it is currently unknown. We hypothesize that asprosin directly affects β cell function via the Ptprd receptor and neutralizing asprosin/Ptprd signaling can prevent T2DM by acting as a single remedy for treatment of three maladies: β cell dysfunction, hyperphagia, and hyperglycemia. While the effects of asprosin neutralization on β cell function remains to be seen, we have previously shown through a series of experiments in mice that pharmacologic inhibition of asprosin using mouse anti-asprosin monoclonal antibodies (mAb) neutralizes asprosin’s glucogenic and orexigenic function. The mice treated with the anti-asprosin mAb display reduced hepatic glucose production and reduced appetite. This evidence paves the way for further development of research grade mouse mAb towards a clinical grade fully human mAb, an investigational new drug application and subsequent human trials for prevention of T2DM, a defining physical ailment of our time. We will test the role of pancreatic β cells asprosin/Ptprd signaling in development of T2DM and explore the potential of anti-asprosin monoclonal antibodies as a preventive therapeutic in the following 2 aims: (1) Determine the role of asprosin/Ptprd signaling in regulation of β cell function, and (2) Asprosin neutralization as a therapeutic strategy for prevention of T2DM in mice. By the conclusion of this award period, we anticipate not only discovering a novel function of asprosin-Ptprd signaling but also having a leading fully-human anti-asprosin monoclonal antibody with a well-established efficacy, pharmacokinetics, and toxicity profile. This achievement is poised to significantly advance T2DM prevention drug development strategies.