Advances in preclinical evaluation of experimental antibody-drug conjugates

The ability to chemically modify monoclonal antibodies with the attachment of specific functional groups has opened up an enormous range of possibilities for the targeted treatment and diagnosis of cancer in the clinic. As the number of such antibody-based drug candidates has increased, so too has the need for more stringent and robust preclinical evaluation of their in vivo performance to maximize the likelihood that time, research effort, and money are only spent developing the most effective and promising candidate molecules for translation to the clinic. Concurrent with the development of antibody-drug conjugate (ADC) technology, several recent advances in preclinical research stand to greatly increase the experimental rigor by which promising candidate molecules can be evaluated. These include advances in preclinical tumor modeling with the development of patient-derived tumor organoid models that far better recapitulate many aspects of the human disease than conventional subcutaneous xenograft models. Such models are amenable to genetic manipulation, which will greatly improve our understanding of the relationship between ADC and antigen and stringently evaluate mechanisms of therapeutic response. Finally, tumor development is often not visible in these in vivo models. We discuss how the application of several preclinical molecular imaging techniques will greatly enhance the quality of experimental data, enabling quantitative pre- and post-treatment tumor measurements or the precise assessment of ADCs as effective diagnostics. In our opinion, when taken together, these advances in preclinical cancer research will greatly improve the identification of effective candidate ADC molecules with the best chance of clinical translation and cancer patient benefit.