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ESTEVA, MILLER, AND TEICHER
gle chemical species or nearly single chemical species. Underconjugated
antibody decreases ADC potency, and highlyconjugated
antibody markedly decreases circulating half-life
and impairs binding to the target protein, thus decreasing
ADC potency and effıcacy. 27 For most ADCs, linkage of three
to four drug molecules per antibody molecule is optimal to
maintain the circulating half-life to near that of the naked
antibody, preserving antibody binding to the target protein,
and delivering a lethal number of drug molecules to the target
cell. Several site-specifıc conjugation approaches are being
explored to achieve ADCs that are single chemical species.
Antibodies with site-specifıc incorporation of non-native
amino acid linker sites can be effıciently produced. 28
FROM THEORY TO PRACTICE: T-DM1 CASE STUDY
Mechanisms of ADC action for T-DM1 include all of the
effects of trastuzumab plus the effects of the conjugated maytansine
derivative. T-DM1 binds HER2, and the HER2/T-
DM1 complex undergoes internalization, followed by
lysosomal degradation. This process results in the intracellular
release of DM1-containing catabolites that bind to tubulin
and prevent microtubule polymerization as well as suppress
microtubule dynamic instability. T-DM1 also has been
shown to retain the mechanisms of action of trastuzumab,
including disruption of the HER3/phosphoinositide 3-kinase
(PI3K)/AKT signaling pathway and Fc receptor–mediated
engagement of immune effector cells, which leads to antibodydependent
cellular cytotoxicity (Fig. 2). 29
INTEGRATION OF T-DM1 IN CLINICAL PRACTICE
The experience with trastuzumab over the past 2 decades has
facilitated the rapid integration of T-DM1 for the treatment
of HER2-positive metastatic breast cancer (HER2 MBC).
HER2 testing must be performed at the time of diagnosis or
recurrence for all invasive breast cancers. HER2 positivity is
defıned as protein expression using immunohistochemistry
(score, 3), or as HER2 gene amplifıcation using fluorescence
in situ hybridization. 30 Unless there is a contraindication,
trastuzumab-based chemotherapy is recommended for
the treatment of HER2 breast cancer in the adjuvant, neoadjuvant,
and metastatic settings. 31 Pertuzumab has been shown to
be effective as part of neoadjuvant taxane/trastuzumab-based
FIGURE 2. Structure of T-DM1 and Mechanisms of Action
T-DM1 binds HER2; the complex is internalized and degraded in lysosomes, releasing DM1. T-DM1 retains the mechanisms of action of trastuzumab, including antibody-dependent cellular
cytotoxicity and HER pathway signaling disruption.
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