Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer

Junttila, Teemu T.; Li, Guangmin; Parsons, Kathryn L.; Phillips, Gail Lewis; Sliwkowski, Mark X.

doi:10.1007/s10549-010-1090-x

Cited by 449 publications

(387 citation statements)

References 31 publications

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“…Small differences were evident for the respective in vitro cytotoxicity in high-expressing HER2 (3þ) cell lines, and antitumor activity studies in vivo in high HER2-expressing breast cancer xenografts. For both ADCs, these data are in line with previous publications (12,(26)(27)(28), although this first head-tohead comparison presented here shows that SYD985, especially in vivo, is more active than T-DM1 in high HER2-expressing tumors.…”

Section: Discussionsupporting

confidence: 93%

The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers

Lee

Groothuis

Ubink

et al. 2015

Molecular Cancer Therapeutics

157

131

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SYD985 is a HER2-targeting antibody-drug conjugate (ADC) based on trastuzumab and vc-seco-DUBA, a cleavable linkerduocarmycin payload. To evaluate the therapeutic potential of this new ADC, mechanistic in vitro studies and in vivo patientderived xenograft (PDX) studies were conducted to compare SYD985 head-to-head with T-DM1 (Kadcyla), another trastuzumab-based ADC. SYD985 and T-DM1 had similar binding affinities to HER2 and showed similar internalization. In vitro cytotoxicity assays showed similar potencies and efficacies in HER2 3þ cell lines, but in cell lines with low HER2 expression, SYD985 was 3-to 50-fold more potent than T-DM1. In contrast with T-DM1, SYD985 efficiently induced bystander killing in vitro in HER2-negative (HER2 0) cells mixed with HER2 3þ, 2þ, or 1þ cell lines. At pH conditions relevant for tumors, cathepsin-B cleavage studies showed efficient release of the active toxin by SYD985 but not by T-DM1. These in vitro data suggest that SYD985 might be a more potent ADC in HER2-expressing tumors in vivo, especially in low HER2-expressing and/or in heterogeneous tumors. In line with this, in vivo antitumor studies in breast cancer PDX models showed that SYD985 is very active in HER2 3þ, 2þ, and 1þ models, whereas T-DM1 only showed significant antitumor activity in HER2 3þ breast cancer PDX models. These properties of SYD985 may enable expansion of the target population to patients who have low HER2-expressing breast cancer, a patient population with still unmet high medical need. Mol Cancer Ther; 14(3); 692-703. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 93%

The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers

Lee

Groothuis

Ubink

et al. 2015

Molecular Cancer Therapeutics

157

131

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“…DM1 is a potent microtubule polymerization inhibitor that induces mitotic arrest and kills tumor cells at subnanomolar concentration (4). It is 25-to 270-fold more potent than paclitaxel and 180-to 4,000-fold more potent than doxorubicin (5,6). However, its side effects and lack of specificity prevented it from clinical use (7).…”

Section: Introductionmentioning

confidence: 99%

Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity

Yan

Endo

Shen

et al. 2016

Molecular Cancer Therapeutics

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Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized mAb directed against HER2, and a microtubule inhibitor, DM1, conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1-induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse models to investigate the mechanisms of T-DM1-induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is colocalized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in mice and induces inflammation and necrosis in liver tissues, and that T-DM1-induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNFa in liver tissues is significantly increased in mice treated with T-DM1 as compared with those treated with trastuzumab or vehicle. We propose that T-DM1-induced upregulation of TNFa enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphologic change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1-induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs. Mol Cancer Ther; 15(3); 480-90. Ó2015 AACR.

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“…Kadcyla ® est un ADC dérivé d'Herceptin ® . Des études précliniques suggèrent qu'il conserve les mécanismes d'action d'Herceptin ® , l'induction de l'apoptose par inhibition de la voie de signalisation PI3K (phosphoinositide 3-kinase)/AKT (protéine kinase B), l'inhibition du shedding de HER2 et l'induction de la cytotoxicité cellulaire dépendante des anticorps (ADCC) [16]. De plus, il présente une activité antitumorale dans les modèles expérimentaux résistant à l'Herceptin ® et au Tyverb ® [16,17].…”

Section: Un Développement Clinique Riche En Rebondissements…unclassified

“…Des études précliniques suggèrent qu'il conserve les mécanismes d'action d'Herceptin ® , l'induction de l'apoptose par inhibition de la voie de signalisation PI3K (phosphoinositide 3-kinase)/AKT (protéine kinase B), l'inhibition du shedding de HER2 et l'induction de la cytotoxicité cellulaire dépendante des anticorps (ADCC) [16]. De plus, il présente une activité antitumorale dans les modèles expérimentaux résistant à l'Herceptin ® et au Tyverb ® [16,17]. L'homologation de Kadcyla ® s'appuie sur les résultats de l'étude de phase III EMILIA, qui a comparé Kadcyla ® utilisé seul au traitement de référence associant Tyverb ® et Xeloda ® , chez 991 patientes souffrant de cancer du sein HER2-positif avancé ou métastatique et ayant été précédemment traitées par l'Herceptin ® et un taxane [18].…”

Section: Un Développement Clinique Riche En Rebondissements…unclassified

La montée en puissance des immunoconjugués en oncologie

Vigne

Sassoon

2014

Med Sci (Paris)

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Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer

Cited by 449 publications

References 31 publications

The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers

The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers

Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity

La montée en puissance des immunoconjugués en oncologie

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