Abstract
T-DM1 is an antibody-drug conjugate in which an anti-HER2 monoclonal antibody, trastuzumab, is linked to a tubulin polymerization inhibitor, DM1. T-DM1 is taken up by HER2-positive cells (internalization) and then cytotoxic DM-1 is released, inducing cell death. National health insurance was extended to cover the use of T-DM1 to treat HER2-positive breast cancer that had previously been treated with trastuzumab, but its subsequent clinical development was not an easy process but instead a series of failures. This is because T-DM1 is only effective against cells to which trastuzumab is bound, representing a glaring flaw in this groundbreaking drug delivery system. In other words, the development of T-DM1 failed while HER2 loss was not taken into account. HER2 loss is a phenomenon whereby modification, i.e. anti-HER2 therapy, causes a change in HER2 status in a heterogeneous tumor consisting of some cells that are HER2-positive and some that are HER2-negative. New antibody-drug conjugates should be developed in the future with this point in mind.
