Publications by authors named "L D Lehman-McKeeman"
Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to quantitatively integrate preclinical pharmacology and toxicology data for determining the therapeutic index (TI) of an interleukin-10 (IL-10) fragment crystallizable (Fc) fusion protein. Mouse Fc fused with mouse IL-10 (mFc-mIL-10) was studied in mice for antitumor efficacy, and the elevation of interleukin-18 (IL-18) was examined as a PD biomarker. The mFc-mIL-10 EC for the IL-18 induction was estimated to be 2.
View Article and Find Full Text PDFFragment crystallizable (Fc) fusion is commonly used for extending the half-life of biotherapeutics such as cytokines. In this work, we studied the pharmacokinetics of Fc-fused interleukin-10 (IL-10) proteins that exhibited potent antitumor activity in mouse syngeneic tumor models. At pharmacologically active doses of ≥0.
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- BMS-986020, a drug being tested for its effects on lysophosphatidic acid receptors, showed hepatobiliary toxicity in a Phase 2 clinical trial, leading to elevated liver enzymes and bile acids.
- Nonclinical studies indicated that BMS-986020's toxicity is due to its ability to inhibit specific liver transporters and mitochondrial function, unlike two other similar compounds (BMS-986234 and BMS-986278) that showed minimal effects.
- The findings suggest that the hepatobiliary toxicity observed in patients taking BMS-986020 is caused by mechanisms unrelated to its action as an LPA antagonist, supporting that its adverse effects are not seen with the other tested compounds.
Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P has been shown to result in lymphopenia.
View Article and Find Full Text PDFEfforts aimed at increasing the in vivo potency and reducing the elimination half-life of and led to the identification of aryl ether and thioether-derived bicyclic S1P differentiated modulators -. The effects of analogs - on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded , and the predicted margin of safety against the cardiovascular effects of would be large enough for human studies.
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