Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody–Cytotoxic Drug Conjugate

Abstract

HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigenexpressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was determined in mouse breast cancer models, and toxicity was assessed in rats as measured by body weight loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concentrations of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was observed on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addition, trastuzumab-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clinical development. [Cancer Res 2008;68(22):9280-90]

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

“…Treatment with activated PanP-DM1 resulted in the remarkable G2/M phase arrest, which may directly lead to cell apoptosis ( Fig 4B and C). 27,35 The percentage of cells in the G2/M phase increased from 19.69 § 1.809% to 30.92 § 1.097% in activated PanP-DM1-treated culture and from 19.69 § 1.809% to 25.92 § 1.092 % in PanP-DM1-treated culture (Fig 4C). These results revealed that non-activated PanP-DM1 was less effective than activated PanP-DM1 in inducing G2/M arrest on A431 cells (P<0.05), which is likely attributable to reduced antigen-binding ability.…”

“…In addition, a preliminary toxicity study was performed in BALB/c mice and tumor-bearing nude mice by comparing the changes on body weight with injection of PanP-DM1. [26][27][28] To conclude, these data suggest that PanP-DM1, the first cancer-selective PDC for EGFR-targeted therapy, holds promise for clinical development because of its high potency and improved cancer selectivity.…”

Efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2–positive breast cancer

“…The high potency of the cytotoxic DM1 moiety has been suggested as a key factor in the enhanced activity of this compound. 4,5 In the second-line setting, the pivotal EMILIA study compared T-DM1 with lapatinib plus capecitabine among patients with HER2+ breast cancer who had previously been treated with trastuzumab and a taxane; T-DM1 showed remarkable activity with an acceptable toxicity profile. 6 There is, however, relatively limited real-world information about the effectiveness and safety of T-DM1 in Hong Kong Chinese patients.…”

Les immunoconjugués, anticorps « armés » pour combattre le cancer

“…Plusieurs versions de T-DM1 ont été synthétisées et comparées chez l'animal. La version T-MCC-DM1 (Figure 3), présentant une liaison thioéther (couplage sur les rési-dus lysine de l'anticorps), a été sélectionnée pour une évaluation chez l'homme sur la base d'une stabilité et d'une efficacité supérieures, dans différents modèles animaux de cancer du sein, aux versions liées par pont disulfure [11]. Cet immunoconjugué est actuellement en phase clinique II pour le traitement du cancer du sein.…”