Immunogenicity in Clinical Practice and Drug Development: When is it Significant?

Managing immunogenicity in clinical practice and during drug development was a recent topic at the ASCPT 2019 annual meeting. This commentary expands on the discussion to facilitate a broader engagement across the community. The intent is to provide a rationale for ongoing research into the current gaps in assessing and interpreting immunogenicity in drug development and managing clinical immunogenicity for an approved drug. The following are highlighted: (i) Immunogenicity Considerations in Clinical Practice, (ii) Immunogenicity Testing and Current Limitations, (iii) Immunogenicity Risk Assessment and Mitigation, and (iv) Quantitative Systems Pharmacology (QSP) models of Immunogenicity

High Degree of Heterogeneity in Alzheimer's Disease Progression Patterns

There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4–6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline

Advanced material against human (Including Covid‐19) and plant viruses: nanoparticles as a feasible strategy

The SARS‐CoV‐2 virus outbreak revealed that these nano‐pathogens have the ability to rapidly change lives. Undoubtedly, SARS‐CoV‐2 as well as other viruses can cause important global impacts, affecting public health, as well as, socioeconomic development. But viruses are not only a public health concern, they are also a problem in agriculture. The current treatments are often ineffective, are prone to develop resistance, or cause considerable adverse side effects. The use of nanotechnology has played an important role to combat viral diseases. In this review three main aspects are in focus: first, the potential use of nanoparticles as carriers for drug delivery. Second, its use for treatments of some human viral diseases, and third, its application as antivirals in plants. With these three themes, the aim is to give to readers an overview of the progress in this promising area of biotechnology during the 2017–2020 period, and to provide a glance at how tangible is the effectiveness of nanotechnology against viruses. Future prospects are also discussed. It is hoped that this review can be a contribution to general knowledge for both specialized and non‐specialized readers, allowing a better knowledge of this interesting topic.REDES‐ANID. Grant Number: 180003 Universidad de La Frontera. Grant Number: DI20‐1003 FAPESP. Grant Numbers: 2018/08194‐2, 2018/02832‐7 CNPq. Grant Numbers: 404815/2018‐9, 313117/2019‐5 CONICYT/FAPESP. Grant Number: 2018/08194‐2 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. Grant Numbers: 001, ANID/FONDAP/15130015 FCT. Grant Number: PTDC/CTM‐TEX/28295/2017 FEDER POCI Portugal 2020 program COMPETE. Grant Number: UID/CTM/00264/2019 FCT/MCTE

Trajectories of dementia-related cognitive decline in a large mental health records derived patient cohort

Background: Modeling trajectories of decline can help describe the variability in progression of cognitive impairment in dementia. Better characterisation of these trajectories has significant implications for understanding disease progression, trial design and care planning. Methods: Patients with at least three Mini-mental State Examination (MMSE) scores recorded in the South London and Maudsley NHS Foundation Trust Electronic Health Records, UK were selected (N = 3441) to form a retrospective cohort. Trajectories of cognitive decline were identified through latent class growth analysis of longitudinal MMSE scores. Demographics, Health of Nation Outcome Scales and medications were compared across trajectories identified. Results: Four of the six trajectories showed increased rate of decline with lower baseline MMSE. Two trajectories had similar initial MMSE scores but different rates of decline. In the faster declining trajectory of the two, a higher incidence of both behavioral problems and sertraline prescription were present. Conclusions: We find suggestive evidence for association of behavioral problems and sertraline prescription with rate of decline. Further work is needed to determine whether trajectories replicate in other datasets

A tumor cord model for Doxorubicin delivery and dose optimization in solid tumors

<p>Abstract</p> <p>Background</p> <p>Doxorubicin is a common anticancer agent used in the treatment of a number of neoplasms, with the lifetime dose limited due to the potential for cardiotoxocity. This has motivated efforts to develop optimal dosage regimes that maximize anti-tumor activity while minimizing cardiac toxicity, which is correlated with peak plasma concentration. Doxorubicin is characterized by poor penetration from tumoral vessels into the tumor mass, due to the highly irregular tumor vasculature. I model the delivery of a soluble drug from the vasculature to a solid tumor using a tumor cord model and examine the penetration of doxorubicin under different dosage regimes and tumor microenvironments.</p> <p>Methods</p> <p>A coupled ODE-PDE model is employed where drug is transported from the vasculature into a tumor cord domain according to the principle of solute transport. Within the tumor cord, extracellular drug diffuses and saturable pharmacokinetics govern uptake and efflux by cancer cells. Cancer cell death is also determined as a function of peak intracellular drug concentration.</p> <p>Results</p> <p>The model predicts that transport to the tumor cord from the vasculature is dominated by diffusive transport of free drug during the initial plasma drug distribution phase. I characterize the effect of all parameters describing the tumor microenvironment on drug delivery, and large intercapillary distance is predicted to be a major barrier to drug delivery. Comparing continuous drug infusion with bolus injection shows that the optimum infusion time depends upon the drug dose, with bolus injection best for low-dose therapy but short infusions better for high doses. Simulations of multiple treatments suggest that additional treatments have similar efficacy in terms of cell mortality, but drug penetration is limited. Moreover, fractionating a single large dose into several smaller doses slightly improves anti-tumor efficacy.</p> <p>Conclusion</p> <p>Drug infusion time has a significant effect on the spatial profile of cell mortality within tumor cord systems. Therefore, extending infusion times (up to 2 hours) and fractionating large doses are two strategies that may preserve or increase anti-tumor activity and reduce cardiotoxicity by decreasing peak plasma concentration. However, even under optimal conditions, doxorubicin may have limited delivery into advanced solid tumors.</p

An exactly solvable, spatial model of mutation accumulation in cancer

One of the hallmarks of cancer is the accumulation of driver mutations which increase the net reproductive rate of cancer cells and allow them to spread. This process has been studied in mathematical models of well mixed populations, and in computer simulations of three-dimensional spatial models. But the computational complexity of these more realistic, spatial models makes it difficult to simulate realistically large and clinically detectable solid tumours. Here we describe an exactly solvable mathematical model of a tumour featuring replication, mutation and local migration of cancer cells. The model predicts a quasi-exponential growth of large tumours, even if different fragments of the tumour grow sub-exponentially due to nutrient and space limitations. The model reproduces clinically observed tumour growth times using biologically plausible rates for cell birth, death, and migration rates. We also show that the expected number of accumulated driver mutations increases exponentially in time if the average fitness gain per driver is constant, and that it reaches a plateau if the gains decrease over time. We discuss the realism of the underlying assumptions and possible extensions of the model

Characterization of an Ovine Bilateral Critical Sized Bone Defect Iliac Wing Model to Examine Treatment Modalities Based on Bone Tissue Engineering

Critical sized bone defect (CSBD) animal models are used to evaluate and confirm efficacy and potency of new treatment modalities based on bone tissue engineering before the latter can be applied in clinical practice. In this study, a bilateral CSBD model in the iliac wings of sheep is described in detail. To demonstrate that this is a large animal CSBD model in sheep, bone healing within the defect left empty (negative control) or filled with autologous corticocancellous bone graft (clinical gold standard, positive control) was assessed using micro-CT, histology, histomorphometric, and fluorochrome analysis. After three months, new bone into the defect site was formed across the whole defect in the positive controls but limited to the edge of the defects in the negative controls. Bone volume in the positive controls was statistically higher than in the negative controls, with the latter having less than 10% new bone growth. There were no intraoperative or postoperative complications. The model described here represents a reliable and reproducible bilateral CSBD in sheep with low morbidity that can be used for in vivo evaluation of new treatment modalities based on bone tissue engineering

Immunogenicity in Clinical Practice and Drug Development: When is it Significant?

Managing immunogenicity in clinical practice and during drug development was a recent topic at the ASCPT 2019 annual meeting. This commentary expands on the discussion to facilitate a broader engagement across the community. The intent is to provide a rationale for ongoing research into the current gaps in assessing and interpreting immunogenicity in drug development and managing clinical immunogenicity for an approved drug. The following are highlighted: (i) Immunogenicity Considerations in Clinical Practice, (ii) Immunogenicity Testing and Current Limitations, (iii) Immunogenicity Risk Assessment and Mitigation, and (iv) Quantitative Systems Pharmacology (QSP) models of Immunogenicity