Trastuzumab-MMAU Antibody-Auristatin Conjugates: Valine-Glucoserine Linker with Stabilized Maleimide Conjugation Improves In Vivo Efficacy and Tolerability.

Antibody-drug conjugates (ADC) have shown impressive clinical activity with approval of many agents in hematologic and solid tumors. However, challenges remain with both efficacy and safety of ADCs. This study describes novel trastuzumab-auristatin conjugates with the hydrophilic monomethylauristatin E (MMAE) prodrug MMAU, and optimization of a glycopeptide linker leading to a wider therapeutic window.

AI/ML Models to Predict the Severity of Drug-Induced Liver Injury for Small Molecules.

Drug-induced liver injury (DILI), believed to be a multifactorial toxicity, has been a leading cause of attrition of small molecules during discovery, clinical development, and postmarketing. Identification of DILI risk early reduces the costs and cycle times associated with drug development. In recent years, several groups have reported predictive models that use physicochemical properties or and assay endpoints; however, these approaches have not accounted for liver-expressed proteins and drug molecules.

Applications of microphysiological systems to disease models in the biopharmaceutical industry: Opportunities and challenges.

Disease models enable researchers to investigate, test, and identify therapeutic targets that would alter the patients’ disease condition and improve quality of life. Advances in genetic alteration and analytical techniques have enabled rapid devel­opment of disease models using preclinical animals and cell cultures. However, success rates of drug development remain low due to limited recapitulation of clinical pathophysiology by these models.

Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology.

Background: Conventional preclinical models often miss drug toxicities, meaning the harm these drugs pose to humans is only realized in clinical trials or when they make it to market. This has caused the pharmaceutical industry to waste considerable time and resources developing drugs destined to fail. Organ-on-a-Chip technology has the potential improve success in drug development pipelines, as it can recapitulate organ-level pathophysiology and clinical responses; however, systematic and quantitative evaluations of Organ-Chips' predictive value have not yet been reported.

Liver safety evaluation of endothelin receptor antagonists using HepatoPac : A single model impact assessment on hepatocellular health, function and bile acid disposition.

Marketed (bosentan, ambrisentan) and discontinued (sitaxsentan, CI-1034) endothelin receptor antagonists were examined in the human micropatterned hepatocyte co-culture (MPCC) model HepatoPac . Differences across hepatocellular health (cellular adenosine triphosphate/glutathione content), function (urea production/albumin secretion) and taurocholic acid transport (biliary clearance/excretion index) were compared using amiodarone and ciclosporin A as positive controls. Ambrisentan had the weakest potency in all six endpoints, while sitaxsentan, bosentan and CI-1034 had more potent effects on hepatobiliary transport than health/function endpoints.

Establishment of a hepatocyte-kupffer cell coculture model for assessment of proinflammatory cytokine effects on metabolizing enzymes and drug transporters.

Elevated levels of proinflammatory cytokines associated with infection and inflammation can modulate cytochrome P450 enzymes, leading to potential disease-drug interactions and altered small-molecule drug disposition. We established a human-derived hepatocyte-Kupffer cell (Hep:KC) coculture model to assess the indirect cytokine impact on hepatocytes through stimulation of KC-mediated cytokine release and compared this model with hepatocytes alone. Characterization of Hep:KC cocultures showed an inflammation response after treatment with lipopolysaccharide and interleukin (IL)-6 (indicated by secretion of various cytokines).

Prediction of cartilage compressive modulus using multiexponential analysis of T(2) relaxation data and support vector regression.

Evaluation of mechanical characteristics of cartilage by magnetic resonance imaging would provide a noninvasive measure of tissue quality both for tissue engineering and when monitoring clinical response to therapeutic interventions for cartilage degradation. We use results from multiexponential transverse relaxation analysis to predict equilibrium and dynamic stiffness of control and degraded bovine nasal cartilage, a biochemical model for articular cartilage. Sulfated glycosaminoglycan concentration/wet weight (ww) and equilibrium and dynamic stiffness decreased with degradation from 103.

Improved MR-based characterization of engineered cartilage using multiexponential T2 relaxation and multivariate analysis.

Noninvasive monitoring of tissue quality would be of substantial use in the development of cartilage tissue engineering strategies. Conventional MR parameters provide noninvasive measures of biophysical tissue properties and are sensitive to changes in matrix development, but do not clearly distinguish between groups with different levels of matrix development. Furthermore, MR outcomes are nonspecific, with particular changes in matrix components resulting in changes in multiple MR parameters.

Multivariate analysis of cartilage degradation using the support vector machine algorithm.

An important limitation in MRI studies of early osteoarthritis is that measured MRI parameters exhibit substantial overlap between different degrees of cartilage degradation. We investigated whether multivariate support vector machine analysis would permit improved tissue characterization. Bovine nasal cartilage samples were subjected to pathomimetic degradation and their T(1), T(2), magnetization transfer rate (k(m) ), and apparent diffusion coefficient (ADC) were measured.

Characterization of engineered cartilage constructs using multiexponential T₂ relaxation analysis and support vector regression.

Increased sensitivity in the characterization of cartilage matrix status by magnetic resonance (MR) imaging, through the identification of surrogate markers for tissue quality, would be of great use in the noninvasive evaluation of engineered cartilage. Recent advances in MR evaluation of cartilage include multiexponential and multiparametric analysis, which we now extend to engineered cartilage. We studied constructs which developed from chondrocytes seeded in collagen hydrogels.

Mapping proteoglycan-bound water in cartilage: Improved specificity of matrix assessment using multiexponential transverse relaxation analysis.

Association of MR parameters with cartilage matrix components remains an area of ongoing investigation. Multiexponential analysis of nonlocalized transverse relaxation data has previously been used to quantify water compartments associated with matrix macromolecules in cartilage. We extend this to mapping the proteoglycan (PG)-bound water fraction in cartilage, using mature and young bovine nasal cartilage model systems, toward the goal of matrix component-specific imaging.

Nondestructive assessment of engineered cartilage constructs using near-infrared spectroscopy.

Noninvasive assessment of engineered cartilage properties would enable better control of the developing tissue towards the desired structural and compositional endpoints through optimization of the biochemical environment in real time. The objective of this study is to assess the matrix constituents of cartilage using near-infrared spectroscopy (NIRS), a technique that permits full-depth assessment of developing engineered tissue constructs. Mid-infrared (mid-IR) and NIR data were acquired from full-thickness cartilage constructs that were grown up to 4 weeks with and without mechanical stimulation.

Magnetic resonance studies of macromolecular content in engineered cartilage treated with pulsed low-intensity ultrasound.

Noninvasive monitoring of matrix development in tissue-engineered cartilage constructs would permit ongoing assessment with the ability to modify culture conditions during development to optimize tissue characteristics. In this study, chondrocytes seeded in a collagen hydrogel were exposed for 20 min/day to pulsed low-intensity ultrasound (PLIUS) at 30 mWcm(-2) and cultured for up to 5 weeks. Biochemical assays, histology, immunohistochemistry, Fourier transform infrared spectroscopy, and magnetic resonance imaging (MRI) were performed at weeks 3 and 5 after initiation of growth.