Why are human TCR studies important?

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Human TCR studies are designed to identify potential off-target binding to healthy human tissue, thereby helping to assess and mitigate safety risks associated with systemic exposure, in particular to pharmacologically active antibodies or cytotoxic immunoconjugates. TCR studies can also detect previously unknown sites of on-target binding which may provide an opportunity to expand the potential indications for the biotherapeutic.

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In addition to human tissue assessments, Pharmagene® Discovery Services can perform TCR studies using tissues from relevant non-clinical species. This supports the interpretation of toxicology findings, helps assess the relevance of animal models, and provides valuable context for non-clinical safety evaluations.

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At what stage should you commission a TCR study?

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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. Therefore, it is important to factor these studies into your development plan before Investigational New Drug (IND) filing.

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Pharmagene® recommends scheduling a TCR study once a candidate has been nominated. Identification of off-target tissue binding at an early stage enables informed decision-making and may reduce downstream development risks.  Non-GLP TCR studies using tissue microarrays (TMAs) can be integrated even earlier in the lead optimisation phase, in particular where a decision may be required between molecules with differing structural features.

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Why choose Pharmagene® as your TCR service provider?

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Our highly experienced team has successfully delivered TCR data for numerous studies in support of IND submissions. These studies have included a wide range of novel biotherapeutic modalities (see below for further details).

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Pharmagene® works in a highly collaborative way, tailors proposals to meet your specific project requirements and can perform both GLP and non-GLP TCR studies.

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Our biorepository contains all the human tissues recommended for TCR testing by the FDA and the EMA (fully consented for commercial research), available from at least three male and three female donors. Our established tissue cohort is immediately available for studies and comprises “true normal” rather than tumour-adjacent biosamples.  We have performed additional QC on the samples and donor data, meaning you can have confidence in the results with efficient timelines and therefore a more cost-effective approach.

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Pharmagene® has held GLP Statements of Compliance from the MHRA since 2010 and has had a Human Tissue Authority (HTA) licence since 2007.

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What if I have multiple potential candidates or I’m not ready for a full GLP study?

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Pharmagene® can use its TCR tissue microarrays (TMAs) to triage potential candidates, or for preliminary assessment before commencing a full GLP-TCR study. These TMAs contain representative cores from all FDA- and EMA-recommended tissue types included in the comprehensive TCR assessment. However, while TMA-based studies provide a cost-effective means of identifying potential binding liabilities and can inform candidate selection, they do not fully capture the morphological complexity present in full-face tissue sections.

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Consequently, TMA screening should be considered complementary to, rather than a replacement for, a full TCR study.

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What types of molecules has Pharmagene® assessed in TCR studies?

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Our expert team has extensive experience working with a diverse portfolio of novel biotherapeutics including monoclonal antibodies, mono-, bi- and tri-specific binding molecules, T-cell engagers, scFv fragments and antibody-drug conjugates, including molecules designed against both human and non-human (e.g. viral) targets. Our highly skilled immunohistochemistry (IHC) team specialises in thorough, robust assay development and troubleshooting, enabling us to successfully support programmes involving increasingly complex and challenging molecules.

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What are the labelling requirements?

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For assessing human antibodies, we typically recommend labelling the test item with Alexa Fluor 488 or fluorescein isothiocyanate (FITC). A similarly labelled isotype control should also be provided for use as a negative control. If you are unable to provide the labelled molecules, Pharmagene® can arrange for the conjugation to be performed on your behalf by one of our trusted third-party providers.

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How much of the biotherapeutic test item is needed?

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Typically, only 500–1,000 µg of labelled biotherapeutic is required. If you would like Pharmagene® to arrange the labelling for you, then we would typically need ~2 mg.

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Do I need to wait until my GMP batch is available?

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If Good Manufacturing Practice (GMP) material is not initially available, Pharmagene® can perform assay development using research-grade material and subsequently perform a bridging study once the GMP batch becomes available. This approach minimises development delays, enables seamless transition to GMP material, and helps accelerate overall project timelines.

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Every TCR study brings its own scientific and practical considerations, from selecting the right study approach to assay development and test-item preparation. By engaging with an experienced TCR partner early, you can identify potential challenges, establish an appropriate study strategy and generate the data needed to support confident decisions as your biotherapeutic progresses through development.

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