Non-clinical safety evaluations of next-generation therapeutic antibodies

Abstract

Since the first monoclonal antibody was approved by FDA in 1986, numerous therapeutic antibodies have been developed along with advances in antibody engineering and finally, the number of approved therapeutic antibodies by FDA exceeded 100 in 2021. Although therapeutic antibodies were thought to be safer than conventional small molecule drugs, non-clinical safety evaluations of antibodies become more important because antibody-specific toxicity has been found. The depletion of target molecules for antibody drugs is a problem due to the limited number of promising targets. However, to overcome this, some technologies which can enhance the activity of antibodies and enable to add new functions to antibodies have been developed. In particular, bispecific antibodies and antibody-drug conjugates are considered to be attracting technologies as the next-generation antibody modalities. Several drugs applying these technologies have been approved in a recent decade. On the other hand, there is still plenty of room for improvement in these technologies which sometimes occur unexpected toxicity, so the safety of drugs applying these technologies should be carefully evaluated. Here some important considerations for the non-clinical safety evaluations of bispecific antibodies and antibody-drug conjugates are discussed based on a literature review of these types of antibody drugs (approved or terminated due to toxicity).