Tissue Cross-Reactivity studies
- Pharmagene Discovery Services
- Mar 9
- 3 min read
Updated: Mar 10
Tissue Cross-Reactivity (TCR) studies are an important component in the safety evaluation of biotherapeutics and antibody-like molecules. They are designed to identify potential off-target binding to human tissues to mitigate risk following systemic exposure, in particular to pharmacologically active antibodies or cytotoxic immunoconjugates.
Reflecting the importance of these assessments, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have issued guidance emphasising the need to perform in vitro TCR studies during therapeutic antibody development and have defined the comprehensive panel of human tissues required to support such studies.
The most important aspect for delivering a robust TCR study is the development and optimisation of the immunohistochemical (IHC) methodology. A desirable dataset for a TCR study is a broadly negative result (indicating no off-target binding) and therefore it is essential that the assay is specific and robust in order to rule out any false negative results.
With 30 years’ expertise in IHC assay development in human tissues, Pharmagene has successfully developed robust binding assays for a broad range of novel therapeutic modalities including monoclonal antibodies; mono-, bi-, and tri-specific antibody-like molecules; scFv fragments; T-cell engagers and antibody-drug conjugates. As antibody engineering technologies and novel therapeutic platforms continue to evolve, the practical challenges of developing robust tissue binding assays for these biotherapeutics in human tissues also continue. Our scientific team thrive on the challenge of optimising binding assays for such novel molecules, and sometimes quite taxing targets.
Pharmagene performs TCR studies in compliance with Good Laboratory Practice (GLP TCR) and performs non-GLP projects using tissue microarrays (TMA) for initial assessments of biotherapeutic candidates before committing to a full GLP TCR study. All our TCR study results are interpreted by qualified pathologists and the output of our GLP TCR service is a report that is suitable for submission as part of an investigational new drug (IND) filing or clinical trial application (CTA).
For GLP TCR studies, the quality of the frozen human tissues used is critically important. These tissues must retain antigenicity and exhibit good morphological preservation to allow adequate interpretation of staining patterns. Pharmagene has an in-house research tissue bank which comprises over 80,000 fixed and frozen, ethically sourced, high-quality human tissue samples obtained with informed consent for commercial research. We have carefully selected, qualified and set apart a dedicated panel of high-quality, true normal, frozen human tissues from our tissue bank to deliver all our TCR studies. The panel includes all the human tissue types recommended for GLP TCR testing by the FDA and the EMA, each from multiple male and female donors, so that we maintain ready access to everything required to execute these studies, especially those tissue types that can be harder to source externally. With the goal of achieving results for a molecule that indicate no off-target binding, it is important to demonstrate the antigenicity of the tissues used. Pharmagene routinely confirms tissue antigenicity during each GLP TCR study, to evidence the suitability and performance of each tissue throughout each assay.
Whilst the focus for TCR studies is safety in humans, evaluating TCR in corresponding animal tissues can provide important supplementary information to aid in species selection for preclinical development or for correlating tissue binding patterns with preclinical safety observations. Pharmagene also supports these species translational studies as required.
Last but not least, working collaboratively with an experienced scientific team during assay development, optimisation and delivery cannot be underestimated. With a dedicated scientific project manager / Study Director appointed from the very start of each project, we pride ourselves on continuity and consistent communication throughout.
Pharmagene offers a unique combination of scientific expertise, high-quality, true normal human tissues, collaborative project management and an established track record of developing binding assays for a range of biotherapeutic modalities to support the conduct of non-GLP and GLP TCR studies.