37 research outputs found
Abstract 1193: DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, abrogates the resistance to T-DM1 in HER2-positive gastric cancer: a preclinical study
No full textAbstract
Background Anti-HER2 therapies are beneficial for patients with HER2-positive breast and gastric cancer. T-DM1 is an HER2-targeting antibody-drug conjugate (ADC), which is structurally composed of the anti-HER2 antibody trastuzumab and the tubulin inhibitor DM1. T-DM1 has shown efficacy in patients with advanced breast cancer, but all patients eventually develop resistance to T-DM1. DS-8201a is a novel ADC composed of an anti-HER2 antibody and a novel potent topoisomerase I inhibitor DX-8951 derivative. DS-8201a achieved a high drug-to-antibody-ratio (DAR: 7-8) and homogeneous drug conjugation. The aim of this study was to elucidate the mechanisms of T-DM1 resistance, and evaluate the efficacy of DS-8201a in a T-DM1-resistant HER2-positive gastric cancer cell line.
Materials and methods The T-DM1-resistant NCI-N87 cell line (N87-TDMR) was established by a step-wise method—the parent HER2-positive N87 cell line was exposed to up to 4 µg/ml of T-DM1. The profile of N87-TDMR was assessed by immunoblotting, DNA microarray, and quantitative reverse transcription-PCR (qRT-PCR). The sensitivity of parent N87 and N87-TDMR cells to T-DM1 or DS8201a was assessed by an in vitro growth inhibition assay as well as through the mouse xenograft model study.
Results N87-TDMR cells were found to be resistant to T-DM1 in the in vitro growth inhibition assay (50% growth inhibitory concentration; >10 µg/ml in N87-TDMR, 0.055 µg/ml in N87) as well as in the in vivo xenograft model study, but HER2 expression was maintained in the N87-TDMR cells. A comprehensive expression analysis revealed that N87-TDMR cells showed increased ATP-binding cassette (ABC) transporter expression such as ABCC2 and ABCG2 compared with N87 cells (50.2 times; 8.0 times higher than that measured by qRT-PCR relatively). Inhibition of ABCC2 and ABCG2 by MK571 recovered the sensitivity to T-DM1 in N87-TDMR cells. Since DS-8201a has higher DAR than T-DM1 and the unique topoisomerase I inhibitor, this resistance was expected to be abrogated. DS-8201a showed anti-tumor efficacy against N87-TDMR xenograft cells in the mouse model (relative tumor growth rate: 244.2% with T-DM1, -39.2% with DS-8201a; n=10 for each treatment).
Conclusions The HER2-positive gastric cancer cell line used in this preclinical study acquired resistance to T-DM1 depending on the up-regulation of ABCC2 and ABCG2 expression. However, DS-8201a could abrogate this T-DM1 resistance. These results provide a rationale for DS-8201a to be investigated for its efficacy in patients with T-DM1-resistant breast or gastric cancer.
Citation Format: Yoshikane Nonagase, Naoki Takegawa, Kimio Yonesaka, Kazuko Sakai, Yusuke Ogitani, Junji Tsurutani, Kazuto Nishio, Kazuhiko Nakagawa. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, abrogates the resistance to T-DM1 in HER2-positive gastric cancer: a preclinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1193. doi:10.1158/1538-7445.AM2017-1193</jats:p
Abstract 3092: U3-1402a, a novel HER3-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a potent antitumor efficacy
No full textAbstract
Background HER3 (human epidermal growth factor receptor 3) is a member of HER family, and overexpressed in breast cancer, NSCLC, melanoma, gastric cancer and pancreatic cancer patients` tissues. U3-1402a is an antibody-drug conjugate (ADC) comprised of a fully human anti-HER3 monoclonal immunoglobulin G1 (IgG1) antibody (U3-1287) covalently conjugated via a cleavable peptide linker to exatecan derivative (DXd). The DXd is released after internalization of U3-1402a and leads to apoptosis of the target tumor cells by the inhibition of topoisomerase I. This ADC achieves a high drug-to-antibody-ratio (DAR 7 to 8) with homogeneous conjugation with the topoisomerase I inhibitor. The aim of this study was to preclinically evaluate the efficacy of U3-1402a in breast cancer models.
Materials and methods In order to evaluate the pharmacological potential of U3-1402a, in vitro and in vivo studies were performed. In vitro growth inhibition assay evaluated the sensitivity of U3-1402a in HER3-positive human breast cancer cell line (HCC1569) and HER3-negative human cervical carcinoma cell line (C33A). Cells were treated with U3-1402a or MAAA-1181 (payload of U3-1402a) depending on its concentration (U3-1402a: 0.153 to 10 000 ng/mL, MAAA-1181: 2.44 to 160,000 pg/mL). In vivo growth inhibition study evaluated the dose-dependent sensitivity of U3-1402a in HER3-positive breast cancer xenograft model, MDA-MB-453. In addition, several xenograft models with different HER3 expression were tested with its sensitivity to U3-1402a. These models were HCC1569 (human breast cancer cell line, HER3 IHC score 3+), MDA-MB-453 (human breast cancer cell line, HER3 IHC score 2+), NIBIO-G016 (human gastric cancer patient-derived xenograft, HER3 IHC score 1+) and MDA-MB-231 (human breast cancer cell line, HER3 IHC score 0). R
esults In vitro study, U3-1402a exhibited anti-tumor killing activity in HER3-positive human breast cancer cell line, HCC1569. C-33A human cervical carcinoma cell line was not sensitive to U3-1402a even MAAA-1181 itself exhibited anti-tumor killing activity to this cell line. In vivo study, U3-1402a showed dose-dependent anti-tumor killing activity in a HER3-positive breast cancer MDA-MB-453 xenograft model. Finally, in vivo tumor regression was only observed in HER3 2+ and 3+ models.
Conclusions U3-1402a preclinically exhibited its efficacy in breast cancer model in vitro and in vivo. In vivo efficacy was correlated with HER3 expression. These studies suggest that U3-1402a, a novel HER3-targeting ADC, would be efficacious in a broader patient population with HER3 expression like breast cancer, melanoma, NSCLC, gastric cancer and pancreatic cancer.
Citation Format: Suguru Ueno, Kenji Hirotani, Reimar Abraham, Sabine Blum, Birgit Frankenberger, Mauricio Redondo-Muller, Johannes Bange, Yusuke Ogitani, Akiko Zembutsu, Koji Morita, Takashi Nakada, Shuji Majima, Yuki Abe, Toshinori Agatsuma. U3-1402a, a novel HER3-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a potent antitumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3092. doi:10.1158/1538-7445.AM2017-3092</jats:p
A HER2-Targeting Antibody–Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model
No full textAbstract
Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate with a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system–activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only rechallenged CT26.WT-hHER2 cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd upregulated CD86 expression on bone marrow–derived dendritic cells (DC) in vitro and that DS-8201a increased tumor-infiltrating DCs and upregulated their CD86 expression in vivo. DS-8201a also increased tumor-infiltrating CD8+ T cells and enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, combination therapy with DS-8201a and anti–PD-1 antibody was more effective than either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as evidenced by the increased expression of DC markers, augmented expression of MHC class I in tumor cells, and rejection of rechallenged tumor cells by adaptive immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. Furthermore, DS-8201a treatment benefited from combination with anti–PD-1 antibody, possibly due to increased T-cell activity and upregulated PD-L1 expression induced by DS-8201a. Mol Cancer Ther; 17(7); 1494–503. ©2018 AACR.</jats:p
Supplementary materials and methods from A HER2-Targeting Antibody–Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model
No full textSupplementary materials and methods</p
DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance
No full textSupplementary Figures S1-S7 from A HER2-Targeting Antibody–Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model
No full textSupplementary Figure S1. The chemical structure of DS-8201a. Supplementary Figure S2. Importance of targeted delivery by the ADC. Supplementary Figure S3. Reduced antitumor effect of DS-8201a in an immunocompromised mouse model. Supplementary Figure S4. Cell growth inhibition activity of DS-8201a and DXd. Supplementary Figure S5. Increased CD8+ cell infiltration into tumors. Supplementary Figure S6. Reduced antitumor effect of DS-8201a by CD8 depletion. Supplementary Figure S7. DXd, the payload of DS-8201a directly increased expression of MHC class I.</p
Calcitonin Gene-Related Peptide Is an Important Regulator of Cutaneous Immunity: Effect on Dendritic Cell and T Cell Functions
No full textAbstract
Some cutaneous inflammations are induced by percutaneous exposure to foreign Ags, and many chemical mediators regulate this inflammation process. One of these mediators, calcitonin gene-related peptide (CGRP), is a neuropeptide released from nerve endings in the skin. CGRP binds to its receptors composed of receptor activity-modifying protein 1 and calcitonin receptor-like receptor to modulate immune cell function. We show that CGRP regulates skin inflammation under physiological conditions, using contact hypersensitivity (CHS) models of receptor activity-modifying protein 1–deficient mice. CGRP has different functions in CHS responses mediated by Th1 or Th2 cells; it inhibits Th1-type CHS, such as 2,4,6-trinitrochlorobenzene–induced CHS, but promotes Th2-type CHS, such as FITC-induced CHS. CGRP inhibits the migration of Langerin+ dermal dendritic cells to the lymph nodes in 2,4,6-trinitrochlorobenzene–induced CHS, and upregulates IL-4 production of T cells in the draining lymph nodes in FITC-CHS. These findings suggest that CGRP regulates several types of CHS reactions under physiological conditions and plays an important role in cutaneous immunity.</jats:p
Abstract A145: DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a potent anti-tumor efficacy with differentiation from T-DM1 in preclinical studies
No full textPharmacokinetics of trastuzumab deruxtecan (T-DXd), a novel anti-HER2 antibody-drug conjugate, in HER2-positive tumour-bearing mice
No full textTrastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate (ADC), comprising an anti-HER2 antibody (Ab) at a drug-to-Ab ratio of 7–8 with the topoisomerase I inhibitor DXd. In this study, we investigated the pharmacokinetics (PK), biodistribution, catabolism, and excretion profiles of T-DXd in HER2-positive tumour-bearing mice.Following intravenous (iv) administration of T-DXd, the PK profiles of T-DXd and total Ab (the sum of conjugated and unconjugated Ab) were almost similar, indicating that the linker is stable during circulation. Biodistribution studies using radiolabelled T-DXd demonstrated tumour-specific distribution and long-term retention. DXd was the main catabolite released from T-DXd in tumours, with exposure levels at least five times higher than those in normal tissues and seven times higher than those achieved by non-targeted control ADC. Following iv administration of DXd, it was rapidly cleared from the circulation (T1/2; 1.35 h) and excreted mainly through faeces as its intact form.The PK profiles reveal that T-DXd effectively delivers the expected payload, DXd, to tumours, while minimising payload exposure to the systemic circulation and normal tissues. The released DXd is rapidly cleared from systemic circulation, presumably via the bile with negligible metabolism, and excreted through the faeces. Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate (ADC), comprising an anti-HER2 antibody (Ab) at a drug-to-Ab ratio of 7–8 with the topoisomerase I inhibitor DXd. In this study, we investigated the pharmacokinetics (PK), biodistribution, catabolism, and excretion profiles of T-DXd in HER2-positive tumour-bearing mice. Following intravenous (iv) administration of T-DXd, the PK profiles of T-DXd and total Ab (the sum of conjugated and unconjugated Ab) were almost similar, indicating that the linker is stable during circulation. Biodistribution studies using radiolabelled T-DXd demonstrated tumour-specific distribution and long-term retention. DXd was the main catabolite released from T-DXd in tumours, with exposure levels at least five times higher than those in normal tissues and seven times higher than those achieved by non-targeted control ADC. Following iv administration of DXd, it was rapidly cleared from the circulation (T1/2; 1.35 h) and excreted mainly through faeces as its intact form. The PK profiles reveal that T-DXd effectively delivers the expected payload, DXd, to tumours, while minimising payload exposure to the systemic circulation and normal tissues. The released DXd is rapidly cleared from systemic circulation, presumably via the bile with negligible metabolism, and excreted through the faeces.</p
