Tissue Cross Reactivity (TCR)
Tissue Cross Reactivity assessment of a therapeutic antibody or antibody-like molecule is an essential pre-clinical investigation that forms part of a regulatory Investigational New Drug (IND) or Clinical Trial Application (CTA). TCR is a series of ex-vivo immunohistochemical (IHC) screening assays performed primarily to identify off-target binding, but also to potentially identify previously unknown sites of on-target binding. The presence or absence of IHC staining in frozen tissues ex vivo may be used to indicate potential organ toxicity in vivo as well as providing additional justification for the choice of animal toxicity models used to generate pre-clinical safety data.
- Dedicated team of Scientists with over 20 years of experience and expertise in performing TCR screening
- Experience and expertise in developing protocols for novel antibody classes including: murine, humanized, chimeric, fully human, antibody cocktails, Fab/VH fragments, fusion proteins, bispecific superantigens, biomers, tetramers and nanobodies, as well as variable regions attached to various carrier backbones
- Custom antibody/protein labeling services available
- Dedicated and experienced Scientists to develop and optimize IHC staining protocols to generate robust and meaningful cross reactivity data
- Experienced Study Directors with extensive Histology and IHC knowledge to advise and guide
- Licensed facilities with access to high quality frozen human and animal tissues covering both FDA and EMA regulatory guidelines
- Assessment of tissue suitability for each study to ensure tissue and antigenic integrity (see images below)
- Manual and automated IHC staining platforms available, allowing flexibility and customization of IHC methods
- Expert Pathologists (MRCPath, FRCPath, American Board Certified) with experience in evaluating and interpreting staining from TCR assessments
- Flexible reporting criteria to ensure study endpoints are met
It is expected that for an IND/CTA submission for most biotherapeutics, a TCR study is conducted to primarily identify off-target binding, but also to pick up previously unknown sites of on-target binding. Such a study can be used to give an indication of potential organ toxicity in vivo and also to compare patterns of staining between human and animal tissue, providing additional justification for the choice of animal toxicity models used to generate other pre-clinical safety data.
TCR studies are conducted at Covance sites based in the United Kingdom at both Harrogate and Huntingdon. Both sites belong to the UK GLP compliance monitoring program, run by the UK GLP Monitoring Authority (UK GLPMA) which is part of the Medicines and Healthcare Products Regulatory Authority (MHRA).
Both the Harrogate and Huntingdon sites have been performing these studies since 1997. Dedicated teams of Scientists with immunohistochemistry (IHC) and histology experience are involved in all aspects of the study to ensure IHC staining protocols are optimized to generate and deliver meaningful data.
For human TCR studies, Covance has access to all the frozen tissues as per the US FDA and EMA requirements. Both sites are licensed by the United Kingdom Human Tissue Authority (UK HTA). For animal species TCR studies, Covance has frozen tissues from all the most frequently used toxicology models (Primate, Mini-Pig, Dog, Rodent).
Custom antibody labelling procedures (e.g. Biotin, FITC, Alexa488) can be performed by Covance if required. Pre-complex procedures can also be used if labelling procedures are not deemed appropriate. Covance appreciates that test article quantities may be limited and while ideally a minimum of 30 mgs is requested for labelling procedures, if necessary we can work with significantly less test article quantities. Covance is happy to discuss other test article requirements for your TCR study further.
The time required to complete a TCR study depends on the IHC protocol development and optimization stage. Development and optimization of a suitable and robust IHC protocol is typically completed within 6 weeks. Draft data/report from the TCR assessment is typically available within a further 6 weeks following successful development and optimization of the IHC staining protocol.
Experienced pathologists review all TCR studies. Pathologists are available to discuss the results during all stages of the study from IHC staining protocol development/optimization through to the tissue panel staining. Staining intensity, cellular location, tissue distribution and frequency of staining are routinely recorded, however Covance is happy to discuss inclusion of additional specific pathology endpoint criteria.