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Type 1 diabetes is an autoimmune disease whose clinical onset signifies a lifelong requirement for insulin therapy and increased risk of medical complications. To increase the efficiency and confidence with which drug candidates advance to human type 1 diabetes clinical trials, we have generated and validated a mathematical model of type 1 diabetes(More)
THIOMAB™ drug conjugates (TDCs) with engineered cysteine residues allow site-specific drug conjugation and defined Drug-to-Antibody Ratios (DAR). In order to help elucidate the impact of drug-loading, conjugation site, and subsequent deconjugation on pharmacokinetics and efficacy, we have developed an integrated mathematical model to mechanistically(More)
The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies(More)
PCSK9 is a promising target for the treatment of hyperlipidemia and cardiovascular disease. A Quantitative Systems Pharmacology model of the mechanisms of action of statin and anti-PCSK9 therapies was developed to predict low density lipoprotein (LDL) changes in response to anti-PCSK9 mAb for different treatment protocols and patient subpopulations.(More)
Quantitative and systems pharmacology (QSP) is increasingly being applied in pharmaceutical research and development. One factor critical to the ultimate success of QSP is the establishment of commonly accepted language, technical criteria, and workflows. We propose an integrated workflow that bridges conceptual objectives with underlying technical detail(More)
Antibody drug conjugates (ADC), in which small molecule cytotoxic agents are non-specifically linked to antibodies, can enable targeted delivery of chemotherapeutics to tumor cells. ADCs are often produced and administered as a mixture of conjugated antibodies with different drug to antibody ratios (DAR) resulting in complex and heterogeneous disposition(More)
Several publications describing the use of anti-CD40L monoclonal antibodies (anti-CD40L) for the treatment of type 1 diabetes in non-obese diabetic (NOD) mice have reported different treatment responses to similar protocols. The Entelos Type 1 Diabetes PhysioLab platform, a dynamic large-scale mathematical model of the pathogenesis of type 1 diabetes, was(More)
Type 1 diabetes is a complex, multifactorial disease characterized by T cell-mediated autoimmune destruction of insulin-secreting pancreatic beta cells. To facilitate research in type 1 diabetes, a large-scale dynamic mathematical model of the female non-obese diabetic (NOD) mouse was developed. In this model, termed the Entelos Type 1 Diabetes PhysioLab(More)
Treatment of diseases of the central nervous system by monoclonal antibodies may be limited by the restricted uptake of antibodies across the blood-brain barrier (BBB). An antibody targeting transferrin receptor (TfR) has been shown to take advantage of the receptor-mediated transcytosis properties of TfR in order to cross the BBB in mice, with the uptake(More)
PURPOSE To design and select the next generation of ocular therapeutics, we performed a comprehensive ocular and systemic pharmacokinetic (PK) analysis of a variety of antibodies and antibody fragments, including a novel-designed bispecific antibody. METHODS Molecules were administrated via intravitreal (IVT) or intravenous (IV) injections in rabbits, and(More)