Biomarkers of Immunotherapy Response: Current State-of-the-Art and Emerging Trends

ACT 2024 Annual Meeting

LC-MS for improving decision making and mitigating risk in process development

CASSS MS 2024 -- Host-cell proteins (HCPs) pose a risk both to patient safety by means of immunogenic response, and to drug substance integrity by enzymatic digestion and degradation. Effective removal of the impurities while minimizing loss of the drug substance is a major challenge and milestone in the drug development life-cycle. ELISA offers excellent sensitivity for HCP content but is only able to provide total HCP abundance and is reliant on expensive polyclonal reagents. LC-MS is able to identify and quantify individual HCPs, allowing a purification strategy to be developed around known impurities using a quality-by-design approach in-line with ICH Q14. A phase-appropriate approach to HCP characterisation should be carefully considered in-line with the phase of product development for efficient process development and risk mitigation.

Formulation development to limit protein glycation

CASSS MS 2024 -- Formulation development is a crucial element of biopharmaceutical development, to maintain structural integrity whilst minimising the level of post-translational modifications (PTMs). Labcorp has developed a standardised workflow for formulation development. Following a design of experiments (DoE) study on thermally stressed pembrolizumab, a potential stability issue with glycation was identified. In this study, the effect of formulation on glycation and the effect of glycation on antigen binding were assessed in the forced degradation of lead formulations phase. The study also gave the opportunity to test the feasibility of an LC-MS multi‑attribute monitoring (MAM) method for monitoring glycation.

Evaluation of immunosuppression in a murine model of respiratory syncytial virus (RSV) infection

ERS Congress 2024 -- Respiratory syncytial virus (RSV) is a major global pathogen, predominantly affecting infants, often leading to bronchiolitis and lower respiratory tract disease (LRTD). RSV is mainly replicated in respiratory ciliated epithelium and analysis of patient samples with severe RSV has shown significantly elevated neutrophil and macrophage content, enriched with pro-inflammatory cytokines such as TNFα, IL-6, IL-1a, IL-8, IL-9, IL-10 and IL-17, which impact the pathogenesis of RSV infection. Currently there are no licensed vaccines for this pathogen, and therefore the implementation of functional animal models for studying this virus is of high importance. This study aimed to establish a murine model of RSV infection, which induced clinical signs and inflammatory responses representative of human RSV infection.

Further exploring the automated touchscreen-based mCANTAB device: Testing for motor precision and employing a self-ordered spatial search paradigm

Eurotox 2024 -- In the early stages of developing drugs that affect the central nervous system, regulatory authorities often request an examination to understand whether the new drug might affect cognitive function or development. We have conducted a study that evaluated the effect of scopolamine (used as a reference compound), on simple discrimination (SD) tasks, which caused learning impairment, as expected. In this study, we reported two additional investigations. First, we investigated the precision of touch responses as a potential influence on discrimination performance by evaluating the effect of target size on the performance of animals. Second, we assessed whether the self-ordered spatial search (SOSS) paradigm task can be trained under these experimental conditions in parallel to the main discrimination tasks. The period of training was defined by success in discrimination tasks, with the SOSS paradigm trained as feasible within this period. 

Integrated micronucleus and multi-endpoint screen for identification and classification of in vitro genotoxicants

EMGS 2024 -- Screening for in vitro genotoxicity can remove potential hazards and identify lead candidates early in development. The in vitro micronucleus (IVMN) assay is routinely used to screen compounds for induction of chromosome damage with low compound requirement and faster turnaround times. However, micronucleus induction can arise via non-DNA reactive modes of actions, which can be important information when identifying compounds for further development. The in vitro MultiFlow® assay is a multiplexed flow cytometric based assay for prediction of genotoxic mode of action (clastogenic, aneugenic or non-genotoxic) based on changes in ɣH2AX, p53, phospo-histone H3 (pHH3) and polyploidy. Integrating IVMN and MultiFlow® endpoints can provide genotoxic mode of action information and better understanding of any apparent genotoxic response. Human TK6 cells were exposed to known clastogens, aneugens and non-genotoxicants and analysed at 4 and 24 hours for compound-induced changes in p53, ɣH2AX, phospo-histone H3 and polyploidy using the MultiFlow® assay and at 24 hours for induction of micronuclei (MN).

Labcorp to Acquire Select Outreach Services from Ballad Health

Transfer of outreach services brings enhanced global resources to region, including expanded access to advanced testing, innovative digital tools for improved patient experience and achieves Ballad Health’s goal of continuing to lower the cost of health care JOHNSON CITY, Tenn.

Method qualification for the preparation of PBMC cells from human blood with a view to evaluate safety, tolerability, dosimetry and preliminary activity of radioligands on cancer patients

DMDG Open 2024 -- Peripheral blood mononuclear cell (PBMC) isolation is a widely used technique within clinical analysis. Their isolation leads to a host of downstream applications, including measurement of biomarkers and measurement of the immune response to a given treatment. Preparation of human PBMC cells from blood samples containing radioligands are required to support multisite clinical trials (a Phase I, open-label, multi-centre study). This study involved collaboration across both our US and UK sites and the qualification of the human PBMC method was adapted from that used at the Labcorp Madison facility to isolate animal PBMCs. The ultimate aim of this study was to demonstrate method robustness and produce the required yield of PBMC cells to support subsequent clinical analysis by ensuring reproducibility of the method and enabling any modifications to account differences of equipment between sites. Furthermore, the US team also investigated the effects of processing at set times post-blood draw to simulate the effects of the shipping process from multiple sites and the effects this had on PBMC yield.