Use of Tissue Cross-reactivity Studies in the Development of Antibody-based Biopharmaceuticals History, Experience, Methodology, and Future Directions

• Published in: Toxicologic Pathology Vol. 38; no. 7; pp. 1138 - 1166
• Main Authors: Leach, Michael W., Halpern, Wendy G., Johnson, Carol W., Rojko, Jennifer L., MacLachlan, Tim K., Chan, Curtis M., Galbreath, Elizabeth J., Ndifor, Anthony M., Blanset, Diann L., Polack, Evelyne, Cavagnaro, Joy A.
• Format: Book Review Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01-12-2010; Sage Publications
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Binding Sites, Antibody; Biological and medical sciences; Clinical trial. Drug monitoring; Cross Reactions - immunology; Drug Design; Drug Discovery; Drug Evaluation, Preclinical - methods; General pharmacology; Humans; Immunohistochemistry - methods; Medical sciences; Pharmacology. Drug treatments; biotherapeutics; drug development; regulatory affairs; tissue cross-reactivity study; immunohistochemistry; ex vivo assay; Drug; Immunohistochemistry; Ex vivo; Methodology; Antibody; Biopharmaceuticals; Research and development
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623310382559

Tissue cross-reactivity (TCR) studies are screening assays recommended for antibody and antibody-like molecules that contain a complementarity-determining region (CDR), primarily to identify off-target binding and, secondarily, to identify sites of on-target binding that were not previously identified. At the present time, TCR studies involve the ex vivo immunohistochemical (IHC) staining of a panel of frozen tissues from humans and animals, are conducted prior to dosing humans, and results are filed with the initial IND/CTA to support first-in-human clinical trials. In some cases, a robust TCR assay cannot be developed, and in these cases the lack of a TCR assay should not prevent a program from moving forward. The TCR assay by itself has variable correlation with toxicity or efficacy. Therefore, any findings of interest should be further evaluated and interpreted in the context of the overall pharmacology and safety assessment data package. TCR studies are generally not recommended for surrogate molecules or for comparability assessments in the context of manufacturing/cell line changes. Overall, the design, implementation, and interpretation of TCR studies should follow a case-by-case approach.