Comparison of intratracheal and inhaled AAV pulmonary deposition in two species

ACT 2024 -- Cell and gene therapies (CGT) offer an attractive approach to treating monogenic pulmonary diseases. Standard nonclinical inhalation (INH) exposure systems require greater volumes of test article than other parenteral routes of administration because multiple animals are simultaneously dosed on a single exposure system with innate inefficiencies. Because clinical treatment with CGT modalities will likely only require single or infrequent dose administration, intratracheal (IT) administration offers an alternative route for pulmonary delivery; however, IT dosing requires anesthesia. Customized administration techniques for IT administration to cynomolgus monkey (NHP) and nose-only inhalation to mice were set up for delivery of an adeno-associated virus (AAV). Results from the mouse study were presented previously, while here the hypothesis tested is regarding achieved lung doses and test article usage.

A 29-day two-dose and 3-day one-dose research and development study of intrathecal injection or epidural infusion in rats

ACT 2024 -- Treatment for neurological disorders is widely an unmet need. According to Feigin et al., 15 neurological disorders were identified to be the underlying cause in approximately 9 million global deaths in 2016. Administration directly into the intrathecal (IT) or epidural spaces bypasses the blood-brain barrier to enhance CNS drug distribution and efficacy while reducing systemic drug exposure and side effects. The purpose of this study was to evaluate the tolerability and feasibility of IT injection of Omnipaque 300 and/or artificial cerebral spinal fluid (aCSF) or epidural infusion of Omnipaque 300 and sterile saline in rats.

Development of an electrochemiluminescence-based immunoassay to evaluate T cell-dependent IgG and IgM responses to keyhole limpet hemocyanin (KLH) administration in the juvenile New Zealand white rabbit

ACT 2024 -- The T cell-dependent antibody response (TDAR) assay is an in vivo functional assay capable of characterizing the immune response to an immunogen. It is used for safety assessments, in conjunction with other toxicologic endpoints, to evaluate test article-induced immune modulation. The TDAR assay is a critical component in preclinical safety assessments of large-molecule biologics and routinely performed in rodents, dogs and nonhuman primates. In this method development study, we seek to establish a TDAR assay in juvenile rabbits. Rabbits were chosen for this study because they are sensitive to a number of agents known to cause reproductive or developmental toxicity. Rabbits historically have been used as the second species in safety evaluation studies of this type (evaluating potentially teratogenic agents) and are recommended by appropriate regulatory agencies. The New Zealand white rabbit was selected based on availability of historical control data and susceptibility to known developmental toxicants.

The power of movement: How physical activity can reduce the risk of breast cancer

Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer related deaths among women in the United States. The steady increase in the number of patients diagnosed with breast cancer has been attributed to lifestyle changes that have taken place since the 1980s, including increased use of alcohol and tobacco, high-fat and high-sugar diets, women opting to not have children or to delay pregnancy, and low levels of physical activity. Regular physical activity and maintaining a healthy weight have been associated with a lower risk of developing multiple chronic diseases and 13 different types of cancer, including breast cancer. Studies have shown that women who get regular physical activity have lower risk of developing breast cancer than women who do not exercise. 

Labcorp Launches New Global Trial Connect Enhancements to Streamline Site Workflow

BURLINGTON, N.C. (November 12, 2024) — Labcorp (NYSE: LH), a global leader of innovative and comprehensive laboratory services, announced today enhancements to Global Trial Connect, a suite of digital, data and operational solutions available to Labcorp Central Laboratory clients aimed at increasing the speed of clinical trials at the heart of clinical research – investigator sites.  

Labcorp Global Trial Connect Site workflow facilitation

The increased complexity of clinical trials is causing an increased burden on investigator sites leading to less time with their patients. As part of our commitment to streamlining clinical trial operations for both sites and sponsors through our Labcorp Global Trial Connect delivers site workflow facilitation that enables accelerated trial delivery to drive critical therapies to patients in need. Reduce Errors: Fully digital lab requisitions integrated with patient visit workflows. Simplify Sample Collection: Step-by-step guided workflows minimize burdens on sites. Real-time access to sample location: with end-to-end sample oversight.

Cell and Gene Therapy Answers: Top considerations for ocular cell and gene therapies

As the field of ocular cell and gene therapies advances, biopharma companies face unique challenges in bringing these innovative treatments from the lab to the clinic. To shed light on the complexities and opportunities in this growing area of therapeutic research, we sat down with Labcorp Study Director and Nonclinical Ocular Toxicology Lead, Peter Sonnentag, to discuss four crucial aspects of ocular cell and gene therapies: the preclinical development process, regulatory requirements for ophthalmic gene therapy programs, the role of immune suppression in both cell and gene therapies and the distinct characteristics that contribute to a successful preclinical program. Here’s what to know. 

Receptor occupancy analysis with solid tumor: Measurement with flow cytometry

China Bioanalysis Forum 2024 -- Drug-target engagement studies are essential to understand molecular pharmacology and pharmacokinetic/pharmacodynamic (PK/PD) relationships. The ability of drugs to penetrate the tumor and bind their target is critical for the successful treatment of solid tumors. Flow cytometry-based receptor occupancy (RO) assays are frequently used for measuring and quantifying the binding of a drug, which is regarded as a critical PD biomarker for the quantitative evaluation of PK/PD relationships and can provide useful information for initial dose range finding in early phases of clinical trials. RO assays are typically performed on fresh blood specimens. However, evaluating RO for the drugs that target receptors on solid tumor tissues (such as ADC drugs) is perceived to be very difficult if not impossible. In this study, we explored the feasibility of flow cytometry-based RO assay with solid tumor tissue samples in clinical trials through a CDX mouse model.

Using in-vivo samples to aid assay transfer of an ADC PK assay: Lesson learned from a case study

China Bioanalysis Forum 2024 -- Antibody-drug conjugates (ADCs) represent a rapidly evolving area of drug development and hold significant promise. It combines the target specificity of monoclonal antibodies with the anticancer activity of small-molecule therapeutics. Method transfers occur for a number of reasons. Typically, when a program is in early clinical states, there is usually only a single lab supporting the clinical bioanalysis for the study. However, if the program expands into multiple clinical studies and multiple countries, the bioanalytical work needs may exceed the support of a single lab. Therefore, it could be necessary to establish the bioanalytical assay in other labs, including in other countries. Per M10, cross-validation is required to demonstrate how the reported data are related when multiple bioanalytical labs are involved in one study or across studies that are going to be combined or compared to support special dosing regimens, or regulatory decisions regarding safety, efficacy and labelling. ADC is a complex modality in structure. Biotransformation in vivo can lead to additional changes in drug-to-antibody ratios resulting in dynamically changing mixtures. It makes that cross-validation for ADC more challenging as compared to other biologics. This poster proposes to use in-vivo samples as an effective approach to guide the assay transfer for an ADC PK assay.

Hybrid (LBA)-LC-MS/MS methodology covers the different dimensions of ADC bioanalysis

China Bioanalysis Forum 2024 -- An antibody-drug conjugate (ADC) is generally composed of a small-molecule drug, also known as a payload, and an antibody or antibody fragment, conjugated together by a chemical linker. In accordance with recommended guidelines, it is advised to primarily detect the conjugated antibody/Ab-conjugated payload (ADC), total antibody (conjugated antibody and unconjugated antibody), and free small molecule compounds in pharmacokinetic (PK) studies of ADCs. So, three bioanalytical methods are typically employed in ADC bioanalysis: free toxin PK assay, ADC PK assay (Ab-conjugated payload), total antibody PK assay. Recently the hybrid (LBA)-LC-MS/MS has been used on ADC bioanalysis and has covered ADC PK assay and total antibody PK assay, plus regular LC-MS/MS method for free toxin assay, LC-MS/MS platform provides additional valuable solutions for ADC bioanalysis.