Ensuring that monoclonal antibodies are specific to a single, primary target receptor is increasingly being recognised as a critical step in the development of these essential biological therapies. Tissue cross reactivity (TCR) studies have traditionally been used to uncover potential off-target events that warrant further investigation. TCR shows binding that can occur in certain tissues, which, in turn, may indicate an off-target issue. While providing useful information as to the whereabouts of a potential cross-reactivity, this approach does not provide information on the identities (or even the number) of off-targets that may need to be considered.
Specificity screening using cell microarray technology identifies relevant interactions between an antibody and over 6,200 human proteins that are expressed in human cells. This highly specific platform reveals the number and, crucially, the identity of any secondary targets discovered. The incredibly low rate of false positives provides confidence that a screen will not return erroneous results and has led to the widespread acceptance of the data by both sponsors and regulators.
Antibody off-target screening – what data are produced?
The example presented here outlines a typical pre-IND off-target screen that was conducted on a human monoclonal antibody (mAb) provided by Simcere. The antibody has been developed for a solid tumour indication and is one of Simcere’s many candidates that are currently in preclinical or clinical development. In addition to its extensive pipeline, Simcere’s marketed pharmaceuticals span diverse therapeutic areas, including oncology, central nervous system disorders, and autoimmune diseases.
The primary target of Simcere’s test antibody was disclosed to Retrogenix prior to the study; however, only the anonymised data is shown below.