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cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes.
No full textLoss of MHC class I and IFNγ sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. The cellular (c)-IAPs regulate classical and alternative NF-κB signaling. Induction of non-canonical NF-κB signaling with IAP antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We now show that induction of non-canonical NF-κB signaling induces T cell-dependent immune responses even in β2m-/- tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild type mice, but not mice incapable of antigen-specific T cell responses, IAP antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Activation of non-canonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade due to loss of MHC class I or IFNγ sensing
An integrated outsourcing practice of nonclinical LC-MS bioanalysis and toxicokinetics at Novartis small molecule drug development
No full textWith decommissioning of internal regulated bioanalytical (BA) and toxicokinetic (TK) capabilities, Novartis has relied on external service providers (ESPs) for all nonclinical LC-MS BA and majority of the associated TK work since 2017. This paper outlines an integrated outsourcing practice of the Novartis nonclinical LC-MS BA/TK group, which covers the roles and responsibilities of Novartis nonclinical LC-MS BA/TK expert scientific monitors, selection of ESPs for Novartis nonclinical LC-MS BA/TK studies, qualification of BA/TK ESPs, study conduct and completion, ESP oversight and evaluation, issue mitigation, and future perspectives
Myeloid-Derived Suppressor Cells as a Potential Biomarker and Therapeutic Target in COVID-19
No full textClinical presentations of COVID-19 are highly variable, yet the precise mechanisms that govern the pathophysiology of different disease courses remain poorly defined. Across the spectrum of disease severity, COVID-19 impairs both innate and adaptive host immune responses by activating innate immune cell recruitment, while resulting in low lymphocyte counts. Recently, several reports have shown that patients with severe COVID-19 exhibit a dysregulated myeloid cell compartment, with increased myeloid-derived suppressor cells (MDSCs) correlating with disease severity. MDSCs, in turn, promote virus survival by suppressing T-cell responses and driving a highly pro-inflammatory state through the secretion of various mediators of immune activation. Here, we summarize the evidence on MDSCs and myeloid cell dysregulation in COVID-19 infection and discuss the potential of MDSCs as biomarkers and therapeutic targets in COVID-19 pneumonia and associated disease
Best practices on critical reagent characterization, qualification, and life cycle management for HCP immunoassays
No full textThe performance of immunoassays for the detection and quantification of host cell proteins (HCPs) in biopharmaceuticals depends on the quality of the critical assay reagents. Not only their preparation, but also a stringent life-cycle management, including reagent qualification, requalification and replacement, plays a crucial role in ensuring consistent and reliable results. To provide a cross-industry perspective on HCP reagent management, we conducted a survey on common practices among several pharmaceutical and biotech companies. Based on its outcome, as well as informed by a corresponding roundtable session (“Managing critical reagents over time”) at the BioPharmaceutical Emerging Best Practices Association (BEBPA) HCP conference in 2019, this work presents specific recommendations and proven concepts to support immunoassay reagent management for monitoring HCPs
LAG3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies
No full textWhile the initial pathology of Parkinson’s disease and other α-synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α-synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α-synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α-synuclein pathology ex vivo. The overall survival of A53T α-synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α-synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α-synucleinopathies is not universally valid
α-Arylation of (Hetero)aryl Ketones in Aqueous Surfactant Media
No full textα-Arylation reactions can be performed in water, enabled by a designer surfactant,under mild conditions and in the absence
of organic co-solvents. A multitude of aryl and heteroaryl ketones are amenable to coupling with functionalized aryl halides.
Use of a lipophilic base that can gain entry to the micellar inner cores mediates enolization. In some cases, palladium loadings
as low as 2500 ppm (0.25 mol %) are sufficient for coupling in a completely recyclable medium, exemplifying chemistry in
water
Amorphous Solid Dispersions (ASDs) – “The influence of material properties, manufacturing processes and technologies in drug product development"
No full textPoorly water-soluble drugs pose a significant challenge in developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve oral absorption of such compounds by enhancing aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these, the conversion to amorphous form has gained a lot of attention over the last decades for its underlying scientific merit, innovative scope in adaptation of technologies and transformative ability in the performance of new medicines for patients. However, since amorphous forms are thermodynamically unstable, the materials and technologies utilized to enable the conversion of crystalline drug into amorphous state, and finally into the desired dosage form and the methods of characterization of these systems play a critical role in defining the quality, stability, processability and in-vivo performance of the amorphous formulation and have been extensively studied in drug development. Several successfully launched ASD based drug products point to an industrial relevance and increasing maturity of technologies for ASD development.
This article discusses the influence of various material properties, manufacturing processes and technologies in the development of ASD , and recent advances in the analytical tools to characterize their stability and ability to be processed into suitable, patient-centric dosage forms. The unmet need for the development of novel polymers for ASDs is also discussed
Continuous Flow Acylation of (Hetero)aryllithiums with Polyfunctional N,N-Dimethylamides and Tetramethylurea in Toluene
No full textThe continuous flow reaction of various aryl or heteroaryl bromides in toluene in the presence of THF (1.0 equiv) with sec -BuLi (1.1 equiv) provided at 25 °C within 40 sec the corresponding aryllithiums which were acylated with various functionalized N,N-dimethylamides including easily enolizable amides at -20 °C within 27 sec, producing highly functionalized ketones in 48-90% yield (36 examples). This method was well suited for the preparation of α-chiral ketones such as naproxene and ibuprofen derived ketones with 99% ee . A one-pot stepwise bis-addition of two different lithium organometallics to 1,1,3,3-tetramethyurea (TMU) provided unsymmetrical ketones in 69-79% yield (9 examples)
Overcoming obstacles in the development of antigen-specific immunotherapies for type 1 diabetes
No full textAntigen-specific immunotherapy (ASI) holds great promise for type 1 diabetes (T1D). Preclinical success for this approach has been demonstrated in vivo, however, clinical translation is still pending. Reasons explaining the slow progress to approve ASI therapies are complex and span all stages of research and development, in both academic and industry environments. The basic four hurdles comprise a lack of translatability of pre-clinical research to human trials; an absence of robust prognostic and predictive biomarkers for disease outcome; a need for a clear regulatory path addressing this therapeutic modality; and the limited acceptance to intervene at the pre-symptomatic stages of disease. The core theme to address these challenges is collaboration—early, transparent, and engaged interactions between academic labs, pharmaceutical research and clinical development teams, advocacy groups, and regulatory agencies to drive a fundamental shift in how we think and treat T1D
Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1
No full textThe nuclear receptor-related 1 protein, Nurr1, is a transcription factor critical for the development and maintenance of dopamine-producing neurons in the substantia nigra pars compacta, a cell population that progressively loses the ability to make dopamine and degenerates in Parkinson’s disease. Recently, we demonstrated that Nurr1 binds directly to and is regulated by the endogenous dopamine metabolite 5,6-dihydroxyindole (DHI). Unfortunately, DHI is an unstable compound, and thus a poor tool for studying Nurr1 function. Here, we report that 5-chloroindole, an unreactive analog of DHI, binds directly to the Nurr1 ligand binding domain with micromolar affinity and stimulates the activity of Nurr1, including the transcription of genes governing the synthesis and packaging of dopamine