Cross-reactivity studies animal tissue

Tissue cross-reactivity studies for monoclonal antibody products were originally intended to explore off-target tissue binding. Studies have thus been used to screen candidates to avoid off-target binding. As stated in ICH S6, an animal species that does not express the desired epitope may be of some relevance for assessing toxicity if comparable unintentional tissue cross-reactivity to... 

This chapter will discuss various experimental approaches used to select the relevant species for conduct of toxicology studies for biopharmaceuticals, as well as highlight advances made in scientific approaches and technologies to facilitate this process. Methods discussed include the traditional immunohisto-chemistry and tissue cross-reactivity studies, flow cytometry, protein sequencing, and functional in vitro assays, as well as newer approaches such as utilization of microarray databases for genomic mRNA expression data and use of transcript profiling studies as an adjunct to functional assays, to understand similarity in pharmacological responsiveness between animals and humans. 

Tissue Cross-Reactivity Studies for Monoclonal Antibodies Predictive Value and Use for Selection of Relevant Animal Species for Toxicity Testing... 

Tissue cross-reactivity studies, although burdensome, provide a rational in vitro assay to determine the range and intensity of distribution of potential epitopes reactive with a monoclonal antibody test article prior to its administration to humans. In addition, cross-reactivity studies provide a useful tool to identify animal species for safety assessment. The cross-reactivity profiles of different species can be compared to the profiles obtained in human tissues. The predictive value of the assay lies in incorporating the characteristics of the monoclonal antibody (isotype, subtype, and other molecular modifications) with the biological activity of the molecule itself, and the potential in vivo distribution of it. 

Tissue cross-reactivity (TCR) studies Tissue cross-reactivity studies with human tissues (or cells if applicable) are conducted prior to Phase 1 to search for cross-reactions with the intended target and/or nontarget tissue. In special cases of bispecific antibodies, each parent antibody is evaluated individually in addition to testing the bispecific product. Human cells or tissues are surveyed immunocyto-chemically or immunohistochemically with appropriate controls. Animal species are also surveyed to determine relevant species for toxicology studies. 

In a typical tissue cross-reactivity study (see Appendix J, cryosections of normal human (3 unrelated donors) and/or animal (2 unrelated donors) tissues are stained... 

Tissue cross-reactivity studies comparing human and animal tissues... 

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