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Niels J Sijbrandi, Eugen Merkul, Joey A Muns, Dennis Cj Waalboer, Kevin Adamzek, Marije Bolijn, Veronica Montserrat, Govert W Somsen, Rob Haselberg, Paul Jgm Steverink, Hendrik-Jan Houthoff, Guus A M S van Dongen
Greater control is desirable in the stochastic conjugation technology used to synthesize antibody-drug conjugates (ADCs). We have shown recently that a fluorescent dye can be stably conjugated to a monoclonal antibody (mAb) using a bifunctional platinum(II) linker. Here we describe the general applicability of this novel linker technology for the preparation of stable and efficacious ADCs. The ethylenediamineplatinum(II) moiety, herein called Lx®, was coordinated to Desferal® (DFO) or auristatin F (AF) to provide storable "semi-final" products, which were directly conjugated to unmodified mAbs...
November 21, 2016: Cancer Research
Priya Venkatesan
No abstract text is available yet for this article.
November 17, 2016: Lancet Oncology
Azadeh Moghaddas, Ali Borhani
The National Comprehensive Cancer Network (NCCN) has recommended Ado-trastuzumab emtansine (T-DM1) as a preferred agent for patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer and prior trastuzumab therapy. Overexpression of HER2 was reported in other cancer types such as bladder, gastric and urogenital carcinosarcomas similar to what is discovered in breast cancer. Some preclinical studies demonstrated the potential anti-tumor effects of T-DM1 in HER2-positive non-breast cancers...
October 2016: Journal of Research in Pharmacy Practice
Rui Feng, Xiaotian Zhang, Sheng Yang
With the deeper research of the proliferation, invasion and metastasis mechanisms of the gastric cancer, targeted therapy has become a hot spot in this field. The exploration of targeted agents for gastric cancer is mainly concentrated upon the drugs that target human epidermal growth factor receptor (HER) family, the vascular endothelial growth factor (VEGF), the phosphatidylinositol 3-kinase-protein kinase/mammalian target of rapamycin (PI3K/mTOR) and the NF-κB signaling pathways. The targeted drugs relevant to HER family include the Cetuximab, Nimotuzumab, Matuzumab, Panitumumab and Erlotinib which are aimed at HER-1, the Trastuzumab, Pertuzumab and T-DM1 (trastuzumab emtansine) which are aimed at HER-2, and the Lapatinib and Afatinib which are the multi-target agents of HER...
October 25, 2016: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
Yoshikane Nonagase, Kimio Yonesaka, Hisato Kawakami, Satomi Watanabe, Koji Haratani, Takayuki Takahama, Naoki Takegawa, Hiroto Ueda, Junko Tanizaki, Hidetoshi Hayashi, Takeshi Yoshida, Masayuki Takeda, Yasutaka Chiba, Takao Tamura, Kazuhiko Nakagawa, Junji Tsurutani
BACKGROUND: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. RESULTS: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel...
October 19, 2016: Oncotarget
Ping Zhong, Jian Zhang, Chao Deng, Ru Cheng, Fenghua Meng, Zhiyuan Zhong
Low tolerability and tumor selectivity restricts many potent anticancer drugs including mertansine from wide clinical use. Here, glutathione-activatable hyaluronic acid-SS-mertansine prodrug (HA-SS-DM1) was designed and developed to achieve enhanced tolerability and targeted therapy of CD44+ human breast tumor xenografts. DM1 was readily conjugated to HA using 2-(2-pyridyldithio)-ethylamine as a linker. Notably, HA-SS-DM1 with a high DM1 content of 20 wt.% had a mean size of ~170 nm at concentrations above 0...
October 10, 2016: Biomacromolecules
Hsiao-Hsuan Kuo, Wei-Wu Chen
Human epidermal growth factor receptor (HER2)-positive breast cancer is associated with a more aggressive disease and poor prognosis. The development of trastuzumab, a HER2-targeted agent, has changed the paradigm of HER2-positive breast cancer treatment and improved survival rates dramatically. However, metastatic HER2-positive breast cancer patients eventually develop resistance to this treatment regimen eventually. A new anti-HER2 antibody-drug conjugate, Trastuzumab emtansine (T-DM1), has been shown to improve treatment efficacy...
October 2016: Hu Li za Zhi the Journal of Nursing
Stephen R Adams, Howard C Yang, Elamprakash N Savariar, Joe Aguilera, Jessica L Crisp, Karra A Jones, Michael A Whitney, Scott M Lippman, Ezra E W Cohen, Roger Y Tsien, Sunil J Advani
Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression...
October 4, 2016: Nature Communications
Maria F Mercogliano, Mara De Martino, Leandro Venturutti, Martín A Rivas, Cecilia J Proietti, Gloria Inurrigarro, Isabel Frahm, Daniel H Allemand, Ernesto Gil Deza, Sandra Ares, Felipe G Gercovich, Pablo Guzmán, Juan C Roa, Patricia V Elizalde, Roxana Schillaci
Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hampered its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it. Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFɑ-blocking antibodies effectiveness respectively...
October 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Kohei Shitara, Atsushi Ohtsu
In recent years, various new agents have been investigated for the treatment of advanced gastric cancer (AGC). The anti-HER2 antibody trastuzumab has been shown to prolong the overall survival of patients with HER2-positive AGC and has become a standard treatment. However, lapatinib, or ado-trastuzumab emtansine (T-DM1), did not show survival benefit in AGC, although it has shown remarkable efficacy for HER2-positive breast cancer. The efficacy of the anti-vascular endothelial growth factor receptor monoclonal antibody ramucirumab for pretreated gastric cancer is a milestone for antiangiogenic therapy for AGC...
October 2016: Journal of the National Comprehensive Cancer Network: JNCCN
Alexandre Goyon, Alain Beck, Jean-Luc Veuthey, Davy Guillarme, Szabolcs Fekete
To separate proteins solely based on their difference in hydrodynamic volume in size exclusion chromatography (SEC), the ionic strength of the mobile phase has to be increased in order to avoid secondary ionic interactions between proteins and the stationary phase. However, adding salts to the mobile phase can have a serious effect on protein aggregation and can lead to artifacts. In the present study, several monoclonal antibodies (mAbs) and the antibody-drug conjugate (ADC), trastuzumab emtansine were selected to study the effect of mobile phase salt additive on aggregation measurements...
September 26, 2016: Journal of Pharmaceutical and Biomedical Analysis
David H Ilson
PURPOSE OF REVIEW: This article reviews the recent seminal studies in esophagogastric cancer. RECENT FINDINGS: Regular low aspirin use may reduce the risk of esophagogastric cancer. Laparoscopic resection of locally advanced gastric cancer appears equivalent to open resection. There is no survival benefit for the addition of postoperative radiation therapy to adjuvant chemotherapy after primary gastric cancer resection. For tumors of the esophagus and gastroesophageal junction, the combination of preoperative radiation therapy with concurrent chemotherapy may be required to ensure achievement of a negative surgical margin and to reduce local tumor recurrence...
November 2016: Current Opinion in Gastroenterology
Quang A Le, Yuna H Bae, Jenny H Kang
PURPOSE: The EMILIA trial demonstrated that trastuzumab emtansine (T-DM1) significantly increased the median profession-free and overall survival relative to combination therapy with lapatinib plus capecitabine (LC) in patients with HER2-positive advanced breast cancer (ABC) previously treated with trastuzumab and a taxane. We performed an economic analysis of T-DM1 as a second-line therapy compared to LC and monotherapy with capecitabine (C) from both perspectives of the US payer and society...
October 2016: Breast Cancer Research and Treatment
Kadoaki Ohashi, Katsuyuki Hotta, Taizo Hirata, Keisuke Aoe, Toshiyuki Kozuki, Kiichiro Ninomiya, Hiroe Kayatani, Hiroyuki Yanai, Shinichi Toyooka, Shiro Hinotsu, Minoru Takata, Katsuyuki Kiura
The treatment outcome has been unsatisfactory for patients with non-small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers...
July 9, 2016: Clinical Lung Cancer
Yan Chen, Michael T Kim, Laura Zheng, Galahad Deperalta, Fred Jacobson
The antibody-drug conjugate, trastuzumab emtansine (Kadcyla), is produced by attachment of the antitubulin drug, DM1, to lysine amines via a heterobifunctional linker, SMCC (succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate). Following the reaction of the N-hydroxysuccinimide activated linker with antibody lysines to produce a linker-modified intermediate (Tmab-MCC), DM1 is added to yield the desired product. In addition to the expected distribution of drug-linked forms (from 0 to 8), mass spectrometry also demonstrates the presence of a second distribution shifted by about +222 Da...
September 21, 2016: Bioconjugate Chemistry
Haiqiang Cao, Zhaoling Dan, Xinyu He, Zhiwen Zhang, Haijun Yu, Qi Yin, Yaping Li
Cancer metastasis leads to high mortality of breast cancer and is difficult to treat because of the poor delivery efficiency of drugs. Herein, we report the wrapping of a drug-carrying liposome with an isolated macrophage membrane to improve delivery to metastatic sites. The macrophage membrane decoration increased cellular uptake of the emtansine liposome in metastatic 4T1 breast cancer cells and had inhibitory effects on cell viability. In vivo, the macrophage membrane enabled the liposome to target metastatic cells and produced a notable inhibitory effect on lung metastasis of breast cancer...
August 23, 2016: ACS Nano
Sung-Bae Kim, Hans Wildiers, Ian E Krop, Melanie Smitt, Ron Yu, Sanne Lysbet de Haas, Antonio Gonzalez-Martin
In the phase III TH3RESA study (NCT01419197), 602 patients with HER2-positive advanced breast cancer who received prior taxane therapy and ≥2 HER2-directed regimens, including trastuzumab and lapatinib (advanced setting), were randomized to trastuzumab emtansine (T-DM1) or treatment of physician's choice (TPC). A statistically significant progression-free survival (PFS) benefit favoring T-DM1 was demonstrated. Here, we examine the relationship between HER2-related biomarkers and PFS in an exploratory analysis...
November 15, 2016: International Journal of Cancer. Journal International du Cancer
Chunze Li, Bei Wang, Dan Lu, Jin Y Jin, Yuying Gao, Kiyoshi Matsunaga, Yuriko Igawa, Ihsan Nijem, Michael Lu, Alexander Strasak, Nataliya Chernyukhin, Sandhya Girish
PURPOSE: Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities. METHODS: Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy...
September 2016: Cancer Chemotherapy and Pharmacology
Daniel Sanghoon Shin, Timothy Sherry, Michael E Kallen, Steven Wong, Alexandra Drakaki
CASE 1: A 67-year-old Asian female was diagnosed with locally advanced high-grade salivary duct carcinoma in June 2011. Molecular analysis revealed human epidermal growth factor receptor 2 (HER-2) amplification. She received adjuvant therapy with carboplatin/paclitaxel/ trastuzumab and maintenance of trastuzumab. Upon disease progression, trastuzumab could not be continued due to lack of financial coverage. Instead, she was treated with compassionate use of lapatinib from April 2013 and standard 5-fluorouracil...
May 2016: Case Reports in Oncology
Liuxi Chen, Lan Wang, Henry Shion, Chuanfei Yu, Ying Qing Yu, Lei Zhu, Meng Li, Weibin Chen, Kai Gao
The biopharmaceutical industry has become increasingly focused on developing biosimilars as less expensive therapeutic products. As a consequence, the regulatory approval of two antibody-drug conjugates (ADCs), Kadcyla® and Adcetris® has led to the development of biosimilar versions by companies located worldwide. Because of the increased complexity of ADC samples that results from the heterogeneity of conjugation, it is imperative that close attention be paid to the critical quality attributes (CQAs) that stem from the conjugation process during ADC biosimilar development process...
July 5, 2016: MAbs
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