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Makarova AO, Titov MM, Kalinovsky DV, Kholodenko IV, Kibardin AV, Larin SS, Svirshchevskaya EV, Deyev SM, Kholodenko RV. Endocytosis Properties of GD2-Specific Antibodies in Tumor Cells. BIOCHEMISTRY. BIOKHIMIIA 2025; 90:424-435. [PMID: 40367084 DOI: 10.1134/s0006297925600395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Revised: 02/16/2025] [Accepted: 03/11/2025] [Indexed: 05/16/2025]
Abstract
Antibody-drug conjugates (ADCs) represent one of the most promising classes of monoclonal antibody-based (mAb) targeted cancer therapies. To date, 15 drugs of this class have received clinical approval, with numerous others under investigation in more than 100 clinical trials. Similarly to unconjugated antibodies, ADCs target various tumor markers including carbohydrate antigens such as glycosphingolipids. Among these targets, ganglioside GD2 is considered the most promising marker. Recent studies have demonstrated significant potential for the anti-GD2 ADCs in clinical application. Internalization of the antigen-antibody complexes and their subsequent transport to cellular lysosomes are critical factors that substantially influence ADC efficacy. However, internalization capacity of the GD2-specific antibodies and mechanisms of endocytosis of their complexes with GD2 have been insufficiently characterized. This study investigated internalization mechanisms of the ganglioside GD2 complexes with several of the most relevant GD2-specific antibody formats, namely full-length antibodies, minibodies, and scFv fragments. It was demonstrated that all used antibody variants successfully internalize into the GD2-positive tumor cells and enter their lysosomal compartments. Full-length antibodies and minibodies exhibited high endocytosis efficiency in the GD2-positive cells, occurring through several pathways, primarily macropinocytosis and caveolae-mediated endocytosis. These findings may be of interest for the development of more effective targeted therapeutics for GD2-positive tumors.
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Affiliation(s)
- Alina O Makarova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- Lomonosov Moscow State University, Moscow, 119991, Russia
| | - Matvey M Titov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- Lomonosov Moscow State University, Moscow, 119991, Russia
| | - Daniel V Kalinovsky
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
| | | | - Alexey V Kibardin
- Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia
| | - Sergey S Larin
- Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117997, Russia
| | - Elena V Svirshchevskaya
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
| | - Sergey M Deyev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
- Sechenov First Moscow State Medical University, Moscow, 119992, Russia
- National Research Center "Kurchatov Institute", Moscow, 123182, Russia
| | - Roman V Kholodenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia.
- LLC "Real Target", Moscow, 108841, Russia
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Udofa E, Sankholkar D, Mitragotri S, Zhao Z. Antibody drug conjugates in the clinic. Bioeng Transl Med 2024; 9:e10677. [PMID: 39545074 PMCID: PMC11558205 DOI: 10.1002/btm2.10677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 04/12/2024] [Accepted: 04/18/2024] [Indexed: 11/17/2024] Open
Abstract
Antibody-drug conjugates (ADCs), chemotherapeutic agents conjugated to an antibody to enhance their targeted delivery to tumors, represent a significant advancement in cancer therapy. ADCs combine the precise targeting capabilities of antibodies and the potent cell-killing effects of chemotherapy, allowing for enhanced cytotoxicity to tumors while minimizing damage to healthy tissues. Here, we provide an overview of the current clinical landscape of ADCs, highlighting 11 U.S. Food and Drug Administration (FDA)-approved products and discussing over 500 active clinical trials investigating newer ADCs. We also discuss some key challenges associated with the clinical translation of ADCs and highlight emerging strategies to overcome these hurdles. Our discussions will provide useful guidelines for the future development of safer and more effective ADCs for a broader range of indications.
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Affiliation(s)
- Edidiong Udofa
- Department of Pharmaceutical SciencesUniversity of Illinois ChicagoChicagoIllinoisUSA
| | | | - Samir Mitragotri
- John A. Paulson School of Engineering and Applied SciencesHarvard UniversityCambridgeMassachusettsUSA
- Wyss Institute for Biologically Inspired Engineering at Harvard UniversityBostonMassachusettsUSA
| | - Zongmin Zhao
- Department of Pharmaceutical SciencesUniversity of Illinois ChicagoChicagoIllinoisUSA
- University of Illinois Cancer CenterChicagoIllinoisUSA
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3
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Yin Q, Gao X, Zhang H, Zhang Z, Yu X, He J, Shi G, Hao L. Fe 3O 4-Cy5.5-trastuzumab magnetic nanoparticles for magnetic resonance/near-infrared imaging targeting HER2 in breast cancer. Biomed Mater 2024; 19:035034. [PMID: 38626777 DOI: 10.1088/1748-605x/ad3f61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 04/16/2024] [Indexed: 04/26/2024]
Abstract
This study developed a probe Fe3O4-Cy5.5-trastuzumab with fluorescence and magnetic resonance imaging functions that can target breast cancer with high HER2 expression, aiming to provide a new theoretical method for the diagnosis of early breast cancer. Fe3O4-Cy5.5-trastuzumab nanoparticles were combined with Fe3O4for T2imaging and Cy5.5 for near-infrared imaging, and coupled with trastuzumab for HER2 targeting. We characterized the nanoparticles used transmission electron microscopy, hydration particle size, Zeta potential, UV and Fourier transform infrared spectroscopy, and examined its magnetism, fluorescence, and relaxation rate related properties. CCK-8 and blood biochemistry analysis evaluated the biosafety and stability of the nanoparticles, and validated the targeting ability of Fe3O4-Cy5.5 trastuzumab nanoparticles throughin vitroandin vivocell and animal experiments. Characterization results showed the successful synthesis of Fe3O4-Cy5.5-trastuzumab nanoparticles with a diameter of 93.72 ± 6.34 nm. The nanoparticles showed a T2relaxation rate 42.29 mM-1s-1, magnetic saturation strength of 27.58 emg g-1. Laser confocal and flow cytometry uptake assay showed that the nanoparticles could effectively target HER2 expressed by breast cancer cells. As indicated byin vitroandin vivostudies, Fe3O4-Cy5.5-trastuzumab were specifically taken up and effectively aggregated to tumour regions with prominent NIRF/MR imaging properties. CCK-8, blood biochemical analysis and histological results suggested Fe3O4-Cy5.5-trastuzumab that exhibited low toxicity to major organs and goodin vivobiocompatibility. The prepared Fe3O4-Cy5.5-trastuzumab exhibited excellent targeting, NIRF/MR imaging performance. It is expected to serve as a safe and effective diagnostic method that lays a theoretical basis for the effective diagnosis of early breast cancer. This study successfully prepared a kind of nanoparticles with near-infrared fluorescence imaging and T2imaging properties, which is expected to serve as a new theory and strategy for early detection of breast cancer.
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Affiliation(s)
- Qiangqiang Yin
- Department of Molecular Imaging, School of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, People's Republic of China
| | - Xiaolong Gao
- Department of Imaging, Fu Jin Hospital of Traditional Chinese Medicine, Jiamusi, Heilongjiang 156100, People's Republic of China
| | - Hao Zhang
- Department of Molecular Imaging, School of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, People's Republic of China
| | - Zhichen Zhang
- Department of Molecular Imaging, School of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, People's Republic of China
| | - Xiaoyang Yu
- Department of Molecular Imaging, School of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, People's Republic of China
| | - Jialong He
- Department of Molecular Imaging, School of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, People's Republic of China
| | - Guangyue Shi
- Department of Molecular Imaging, School of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, People's Republic of China
| | - Liguo Hao
- Department of Molecular Imaging, School of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, People's Republic of China
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Li J, Jiang Z. Antibody drug conjugates in breast cancer in China: Highlights, challenges, and prospects. Cancer 2024; 130:1371-1377. [PMID: 37921976 DOI: 10.1002/cncr.35093] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 10/03/2023] [Accepted: 10/10/2023] [Indexed: 11/05/2023]
Abstract
Antibody drug conjugates (ADCs) are novel drugs that exert specific cytotoxicity against tumor cells. China approved T-Dxd in May 2023, and their introduction has changed the nation's clinical practice. Although more than 700 ADCs are being investigated worldwide, the challenges that remain in antibody engineering, drug discovery, safety management, resistance, drug selection, and sequencing hinder the further promotion and application of ADCs. Experts in China have discussed the several critical concerns related to clinical practice since 2022. Here, the authors conducted a review of ADCs and then discussed several ADCs explored in China. This study proposes several solutions and strategies to maximize the potential benefit that ADCs can provide to patients with breast cancer.
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Affiliation(s)
- Jianbin Li
- Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Academy of Military Medical Sciences, Beijing, China
| | - Zefei Jiang
- Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, China
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5
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Martin-García D, Téllez T, Redondo M, García-Aranda M. Calcium Homeostasis in the Development of Resistant Breast Tumors. Cancers (Basel) 2023; 15:2872. [PMID: 37296835 PMCID: PMC10251880 DOI: 10.3390/cancers15112872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/16/2023] [Accepted: 05/21/2023] [Indexed: 06/12/2023] Open
Abstract
Cancer is one of the main health problems worldwide. Only in 2020, this disease caused more than 19 million new cases and almost 10 million deaths, with breast cancer being the most diagnosed worldwide. Today, despite recent advances in breast cancer treatment, a significant percentage of patients will either not respond to therapy or will eventually experience lethal progressive disease. Recent studies highlighted the involvement of calcium in the proliferation or evasion of apoptosis in breast carcinoma cells. In this review, we provide an overview of intracellular calcium signaling and breast cancer biology. We also discuss the existing knowledge on how altered calcium homeostasis is implicated in breast cancer development, highlighting the potential utility of Ca2+ as a predictive and prognostic biomarker, as well as its potential for the development of new pharmacological treatments to treat the disease.
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Affiliation(s)
- Desirée Martin-García
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Málaga, Spain; (D.M.-G.); (T.T.)
- Instituto de Investigación Biomédica de Málaga-Plataforma BIONAND (IBIMA-BIONAND), Severo Ochoa, 35, 29590 Málaga, Spain;
| | - Teresa Téllez
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Málaga, Spain; (D.M.-G.); (T.T.)
- Instituto de Investigación Biomédica de Málaga-Plataforma BIONAND (IBIMA-BIONAND), Severo Ochoa, 35, 29590 Málaga, Spain;
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC) and Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Málaga, Spain
| | - Maximino Redondo
- Surgical Specialties, Biochemistry and Immunology Department, Faculty of Medicine, University of Málaga, 29010 Málaga, Spain; (D.M.-G.); (T.T.)
- Instituto de Investigación Biomédica de Málaga-Plataforma BIONAND (IBIMA-BIONAND), Severo Ochoa, 35, 29590 Málaga, Spain;
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC) and Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, Autovia A-7 km 187, 29602 Marbella, Spain
| | - Marilina García-Aranda
- Instituto de Investigación Biomédica de Málaga-Plataforma BIONAND (IBIMA-BIONAND), Severo Ochoa, 35, 29590 Málaga, Spain;
- Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC) and Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Instituto de Investigación Biomédica de Málaga (IBIMA), 29590 Málaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, Autovia A-7 km 187, 29602 Marbella, Spain
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Molecular perspective on targeted therapy in breast cancer: a review of current status. MEDICAL ONCOLOGY (NORTHWOOD, LONDON, ENGLAND) 2022; 39:149. [PMID: 35834030 PMCID: PMC9281252 DOI: 10.1007/s12032-022-01749-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 05/11/2022] [Indexed: 12/24/2022]
Abstract
Breast cancer is categorized at the molecular level according to the status of certain hormone and growth factor receptors, and this classification forms the basis of current diagnosis and treatment. The development of resistance to treatment and recurrence of the disease have led researchers to develop new therapies. In recent years, most of the research in the field of oncology has focused on the development of targeted therapies, which are treatment methods developed directly against molecular abnormalities. Promising advances have been made in clinical trials investigating the effect of these new treatment modalities and their combinations with existing therapeutic treatments in the treatment of breast cancer. Monoclonal antibodies, tyrosine kinase inhibitors, antibody–drug conjugates, PI3K/Akt/mTOR pathway inhibitors, cyclin-dependent kinase 4/6 inhibitors, anti-angiogenic drugs, PARP inhibitors are among the targeted therapies used in breast cancer treatment. In this review, we aim to present a molecular view of recently approved target agents used in breast cancer.
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7
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Yu J, Fang T, Yun C, Liu X, Cai X. Antibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor Family in Cancers. Front Mol Biosci 2022; 9:847835. [PMID: 35295841 PMCID: PMC8919033 DOI: 10.3389/fmolb.2022.847835] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/08/2022] [Indexed: 12/14/2022] Open
Abstract
Members of the human epidermal growth factor receptor (HER) family, which includes HER1 (also known as EGFR), HER2, HER3 and HER4, have played a central role in regulating cell proliferation, survival, differentiation and migration. The overexpression of the HER family has been recognized as one of the most common cellular dysregulation associated with a wide variety of tumor types. Antibody-drug conjugates (ADCs) represent a new and promising class of anticancer therapeutics that combine the cancer specificity of antibodies with cytotoxicity of chemotherapeutic drugs. Two HER2-directed ADCs, trastuzumane-emtansine (T-DM1) and trastuzumab-deruxtecan (DS-8201a), have been approved for HER2-positive metastatic breast cancer by the U.S. Food and Drug Administration (FDA) in 2013 and 2019, respectively. A third HER2-directed ADC, disitamab vedotin (RC48), has been approved for locally advanced or metastatic gastric or gastroesophageal junction cancer by the NMPA (National Medical Products Administration) of China in 2021. A total of 11 ADCs that target HER family receptors (EGFR, HER2 or HER3) are currently under clinical trials. In this review article, we summarize the three approved ADCs (T-DM1, DS-8201a and RC48), together with the investigational EGFR-directed ADCs (ABT-414, MRG003 and M1231), HER2-directed ADCs (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 and SBT6050) and HER3-directed ADC (U3-1402). Lastly, we discuss the major challenges associated with the development of ADCs, and highlight the possible future directions to tackle these challenges.
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Affiliation(s)
| | | | | | | | - Xiaoqing Cai
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
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8
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Ceci C, Lacal PM, Graziani G. Antibody-drug conjugates: Resurgent anticancer agents with multi-targeted therapeutic potential. Pharmacol Ther 2022; 236:108106. [PMID: 34990642 DOI: 10.1016/j.pharmthera.2021.108106] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/23/2021] [Accepted: 12/29/2021] [Indexed: 12/18/2022]
Abstract
Antibody-drug conjugates (ADCs) constitute a relatively new group of anticancer agents, whose first appearance took place about two decades ago, but a renewed interest occurred in recent years, following the success of anti-cancer immunotherapy with monoclonal antibodies. Indeed, an ADC combines the selectivity of a monoclonal antibody with the cell killing properties of a chemotherapeutic agent (payload), joined together through an appropriate linker. The antibody moiety targets a specific cell surface antigen expressed by tumor cells and/or cells of the tumor microenvironment and acts as a carrier that delivers the cytotoxic payload within the tumor mass. Despite advantages in terms of selectivity and potency, the development of ADCs is not devoid of challenges, due to: i) low tumor selectivity when the target antigens are not exclusively expressed by cancer cells; ii) premature release of the cytotoxic drug into the bloodstream as a consequence of linker instability; iii) development of tumor resistance mechanisms to the payload. All these factors may result in lack of efficacy and/or in no safety improvement compared to unconjugated cytotoxic agents. Nevertheless, the development of antibodies engineered to remain inert until activated in the tumor (e.g., antibodies activated proteolytically after internalization or by the acidic conditions of the tumor microenvironment) together with the discovery of innovative targets and cytotoxic or immunomodulatory payloads, have allowed the design of next-generation ADCs that are expected to possess improved therapeutic properties. This review provides an overview of approved ADCs, with related advantages and limitations, and of novel targets exploited by ADCs that are presently under clinical investigation.
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Affiliation(s)
- Claudia Ceci
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | | | - Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; IDI-IRCCS, Via Monti di Creta 104, 00167 Rome, Italy.
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9
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Extracellular production of an anti-HER2 single-chain variable antibody fragment in Escherichia coli. Process Biochem 2021. [DOI: 10.1016/j.procbio.2021.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Clark AS, Yau C, Wolf DM, Petricoin EF, van 't Veer LJ, Yee D, Moulder SL, Wallace AM, Chien AJ, Isaacs C, Boughey JC, Albain KS, Kemmer K, Haley BB, Han HS, Forero-Torres A, Elias A, Lang JE, Ellis ED, Yung R, Tripathy D, Nanda R, Wulfkuhle JD, Brown-Swigart L, Gallagher RI, Helsten T, Roesch E, Ewing CA, Alvarado M, Crane EP, Buxton M, Clennell JL, Paoloni M, Asare SM, Wilson A, Hirst GL, Singhrao R, Steeg K, Asare A, Matthews JB, Berry S, Sanil A, Melisko M, Perlmutter J, Rugo HS, Schwab RB, Symmans WF, Hylton NM, Berry DA, Esserman LJ, DeMichele AM. Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2 + breast cancer in the adaptively randomized I-SPY2 trial. Nat Commun 2021; 12:6428. [PMID: 34741023 PMCID: PMC8571284 DOI: 10.1038/s41467-021-26019-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 09/10/2021] [Indexed: 12/02/2022] Open
Abstract
HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.
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Affiliation(s)
- Amy S Clark
- University of Pennsylvania, Philadelphia, PA, USA.
| | - Christina Yau
- University of California San Francisco, San Francisco, CA, USA
| | - Denise M Wolf
- University of California San Francisco, San Francisco, CA, USA
| | | | | | - Douglas Yee
- University of Minnesota, Minneapolis, MN, USA
| | | | | | - A Jo Chien
- University of California San Francisco, San Francisco, CA, USA
| | | | | | | | | | | | - Hyo S Han
- Moffitt Cancer Center, Tampa, FL, USA
| | | | | | - Julie E Lang
- University of Southern California, Los Angeles, CA, USA
| | | | | | | | | | | | | | | | | | - Erin Roesch
- University of California San Diego, San Diego, CA, USA
| | - Cheryl A Ewing
- University of California San Francisco, San Francisco, CA, USA
| | | | | | | | | | | | - Smita M Asare
- University of California San Francisco, San Francisco, CA, USA
| | - Amy Wilson
- University of California San Francisco, San Francisco, CA, USA
| | - Gillian L Hirst
- University of California San Francisco, San Francisco, CA, USA
| | - Ruby Singhrao
- University of California San Francisco, San Francisco, CA, USA
| | - Katherine Steeg
- University of California San Francisco, San Francisco, CA, USA
| | - Adam Asare
- University of California San Francisco, San Francisco, CA, USA
| | | | | | | | | | | | - Hope S Rugo
- University of California San Francisco, San Francisco, CA, USA
| | | | | | - Nola M Hylton
- University of California San Francisco, San Francisco, CA, USA
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11
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Chauhan G, Pathak DP, Ali F, Dubey P, Khasimbi S. In vitro Evaluation of Isatin derivatives as Potent Anti-Breast Cancer Agents against MCF-7, MDA MB 231, MDA-MB 435 and MDA-MB 468 Breast Cancers cell lines: A Review. Anticancer Agents Med Chem 2021; 22:1883-1896. [PMID: 34477529 DOI: 10.2174/1871520621666210903130152] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 06/29/2021] [Accepted: 07/12/2021] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Breast cancer (BC) is one of the most frequent malignancy and most common reasons of impermanence in women. The backbone of therapy for BC is principally chemotherapy, but due to its non-specific nature between normal cells and cancer cells and severe side effects are the main barriers in its therapy. So, there is an intense requirement for the enlargement of more efficacious, more specific and safer anti-BC agents. OBJECTIVE Isatin (IST) is an endogenous molecule which is a principal class of heterocyclic compounds and exhibits a wide range of therapeutic activities which can be used as a starting material for the synthesis of several drug molecules. Many literatures were reported previously on different pharmacological activities of IST derivatives and particularly on anticancer activity but this review mainly focus on anti-BC activities of IST derivatives through MCF-7, MDA MB 231, MDA-MB 435 and MDA-MB 468 cell lines. Here in we mentioned, a total 33 IST derivatives (compound 24- 56) which shown good anti-BC activity. IST derived compounds are also available in market and are used for various cancer types like sunitinib for renal cell carcinoma (RCC) and Nintedanib used for the cryptogenic fibrosing alveolitis treatment but when evaluated for BC did not get much success. CONCLUSION This review mainly highlights anti-BC activities of various IST analogues using MCF-7, MDA MB 231, MDA-MB 435 and MDA-MB 468 cell lines, display the potent compound of the series and structure-activity relationships of compounds with molecular docking also. So, this study mainly shows the importance of IST as major sources for drug design and development of newer anti-BC drugs.
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Affiliation(s)
- Garima Chauhan
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Mehrauli-Badarpur Road, Sector 3, Pushp Vihar, New Delhi, Delhi 110017, India
| | - Dharam Pal Pathak
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Mehrauli-Badarpur Road, Sector 3, Pushp Vihar, New Delhi, Delhi 110017, India
| | - Faraat Ali
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Mehrauli-Badarpur Road, Sector 3, Pushp Vihar, New Delhi, Delhi 110017, India
| | - Pragya Dubey
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Mehrauli-Badarpur Road, Sector 3, Pushp Vihar, New Delhi, Delhi 110017, India
| | - Shaik Khasimbi
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Mehrauli-Badarpur Road, Sector 3, Pushp Vihar, New Delhi, Delhi 110017, India
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12
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Characterization of constitutive ER-phagy of excess membrane proteins. PLoS Genet 2020; 16:e1009255. [PMID: 33275594 PMCID: PMC7744050 DOI: 10.1371/journal.pgen.1009255] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 12/16/2020] [Accepted: 11/05/2020] [Indexed: 11/19/2022] Open
Abstract
Thirty percent of all cellular proteins are inserted into the endoplasmic reticulum (ER), which spans throughout the cytoplasm. Two well-established stress-induced pathways ensure quality control (QC) at the ER: ER-phagy and ER-associated degradation (ERAD), which shuttle cargo for degradation to the lysosome and proteasome, respectively. In contrast, not much is known about constitutive ER-phagy. We have previously reported that excess of integral-membrane proteins is delivered from the ER to the lysosome via autophagy during normal growth of yeast cells. Whereas endogenously expressed ER resident proteins serve as cargos at a basal level, this level can be induced by overexpression of membrane proteins that are not ER residents. Here, we characterize this pathway as constitutive ER-phagy. Constitutive and stress-induced ER-phagy share the basic macro-autophagy machinery including the conserved Atgs and Ypt1 GTPase. However, induction of stress-induced autophagy is not needed for constitutive ER-phagy to occur. Moreover, the selective receptors needed for starvation-induced ER-phagy, Atg39 and Atg40, are not required for constitutive ER-phagy and neither these receptors nor their cargos are delivered through it to the vacuole. As for ERAD, while constitutive ER-phagy recognizes cargo different from that recognized by ERAD, these two ER-QC pathways can partially substitute for each other. Because accumulation of membrane proteins is associated with disease, and constitutive ER-phagy players are conserved from yeast to mammalian cells, this process could be critical for human health.
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13
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Bashraheel SS, Domling A, Goda SK. Update on targeted cancer therapies, single or in combination, and their fine tuning for precision medicine. Biomed Pharmacother 2020; 125:110009. [PMID: 32106381 DOI: 10.1016/j.biopha.2020.110009] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 02/04/2020] [Accepted: 02/12/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Until recently, patients who have the same type and stage of cancer all receive the same treatment. It has been established, however, that individuals with the same disease respond differently to the same therapy. Further, each tumor undergoes genetic changes that cause cancer to grow and metastasize. The changes that occur in one person's cancer may not occur in others with the same cancer type. These differences also lead to different responses to treatment. Precision medicine, also known as personalized medicine, is a strategy that allows the selection of a treatment based on the patient's genetic makeup. In the case of cancer, the treatment is tailored to take into account the genetic changes that may occur in an individual's tumor. Precision medicine, therefore, could be defined in terms of the targets involved in targeted therapy. METHODS A literature search in electronic data bases using keywords "cancer targeted therapy, personalized medicine and cancer combination therapies" was conducted to include papers from 2010 to June 2019. RESULTS Recent developments in strategies of targeted cancer therapy were reported. Specifically, on the two types of targeted therapy; first, immune-based therapy such as the use of immune checkpoint inhibitors (ICIs), immune cytokines, tumor-targeted superantigens (TTS) and ligand targeted therapeutics (LTTs). The second strategy deals with enzyme/small molecules-based therapies, such as the use of a proteolysis targeting chimera (PROTAC), antibody-drug conjugates (ADC) and antibody-directed enzyme prodrug therapy (ADEPT). The precise targeting of the drug to the gene or protein under attack was also investigated, in other words, how precision medicine can be used to tailor treatments. CONCLUSION The conventional therapeutic paradigm for cancer and other diseases has focused on a single type of intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy as well as combination therapies.
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Affiliation(s)
- Sara S Bashraheel
- Protein Engineering Unit, Life and Science Research Department, Anti-Doping Lab-Qatar (ADLQ), Doha, Qatar; Drug Design Group, Department of Pharmacy, University of Groningen, Groningen, Netherlands
| | - Alexander Domling
- Drug Design Group, Department of Pharmacy, University of Groningen, Groningen, Netherlands
| | - Sayed K Goda
- Cairo University, Faculty of Science, Chemistry Department, Giza, Egypt.
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14
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Viale G, Morganti S, Ferraro E, Zagami P, Marra A, Curigliano G. What therapies are on the horizon for HER2 positive breast cancer? Expert Rev Anticancer Ther 2019; 19:811-822. [PMID: 31448640 DOI: 10.1080/14737140.2019.1660164] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Introduction: Despite dramatic improvements in survival achieved with currently available anti-HER2 agents, HER2-positive metastatic breast cancer remains an almost invariably deadly disease, with primary or acquired resistance to HER2-directed agents developing during treatment. Many efforts are focused on identifying new agents that may more effectively inhibit HER2 signaling and on possible combination strategies. Areas covered: This review summarizes the landscape of drugs under development for HER2-positive metastatic breast cancer, as antibody-drug conjugates, monoclonal anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors. Moreover, available data for possible combination of anti-HER2 drugs and different agents, as immunotherapy, PI3K/mTOR inhibitors, CDK4/6 inhibitors currently under evaluation are reviewed. These strategies may overcome mechanisms of resistance and further improve patient outcomes. Expert opinion: Identification of valuable predictive biomarkers is needed to better inform choice of treatment sequence for the individual patient and limit the financial toxicity of these agents.
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Affiliation(s)
- Giulia Viale
- Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology IRCCS , Milan , Italy.,Department of Oncology and Haematology, University of Milan , Milan , Italy
| | - Stefania Morganti
- Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology IRCCS , Milan , Italy.,Department of Oncology and Haematology, University of Milan , Milan , Italy
| | - Emanuela Ferraro
- Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology IRCCS , Milan , Italy.,Department of Oncology and Haematology, University of Milan , Milan , Italy
| | - Paola Zagami
- Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology IRCCS , Milan , Italy.,Department of Oncology and Haematology, University of Milan , Milan , Italy
| | - Antonio Marra
- Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology IRCCS , Milan , Italy.,Department of Oncology and Haematology, University of Milan , Milan , Italy
| | - Giuseppe Curigliano
- Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology IRCCS , Milan , Italy.,Department of Oncology and Haematology, University of Milan , Milan , Italy
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15
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Shen Y, Yang T, Cao X, Zhang Y, Zhao L, Li H, Zhao T, Xu J, Zhang H, Guo Q, Cai J, Gao B, Yu H, Yin S, Song R, Wu J, Guan L, Wu G, Jin L, Su Y, Liu Y. Conjugation of DM1 to anti-CD30 antibody has potential antitumor activity in CD30-positive hematological malignancies with lower systemic toxicity. MAbs 2019; 11:1149-1161. [PMID: 31161871 PMCID: PMC6748589 DOI: 10.1080/19420862.2019.1618674] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
An anti-CD30 antibody-drug conjugate incorporating the antimitotic agent DM1 and a stable SMCC linker, anti-CD30-MCC-DM1, was generated as a new antitumor drug candidate for CD30-positive hematological malignancies. Here, the in vitro and in vivo pharmacologic activities of anti-CD30-MCC-DM1 (also known as F0002-ADC) were evaluated and compared with ADCETRIS (brentuximab vedotin). Pharmacokinetics (PK) and the safety profiles in cynomolgus monkeys were assessed. Anti-CD30-MCC-DM1 was effective in in vitro cell death assays using CD30-positive lymphoma cell lines. We studied the properties of anti-CD30-MCC-DM1, including binding, internalization, drug release and actions. Unlike ADCETRIS, anti-CD30-MCC-DM1 did not cause a bystander effect in this study. In vivo, anti-CD30-MCC-DM1 was found to be capable of inducing tumor regression in subcutaneous inoculation of Karpas 299 (anaplastic large cell lymphoma), HH (cutaneous T-cell lymphoma) and L428 (Hodgkin's disease) cell models. The half-lives of 4 mg/kg and 12 mg/kg anti-CD30-MCC-DM1 were about 5 days in cynomolgus monkeys, and the tolerated dose was 30 mg/kg in non-human primates, supporting the tolerance of anti-CD30-MCC-DM1 in humans. These results suggest that anti-CD30-MCC-DM1 presents efficacy, safety and PK profiles that support its use as a valuable treatment for CD30-positive hematological malignancies.
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Affiliation(s)
- Yijun Shen
- a Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University , Shanghai , China.,b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Tong Yang
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Xuemei Cao
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Yifan Zhang
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Li Zhao
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Hua Li
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Teng Zhao
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Jun Xu
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Hengbin Zhang
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Qingsong Guo
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Junli Cai
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Bei Gao
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Helin Yu
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Sicheng Yin
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Ruiwen Song
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Jingsong Wu
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Lingyu Guan
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Guanghao Wu
- c Department of Technical Quality, Shanghai Jiaolian Drug Research and Development Co., Ltd , Shanghai , China
| | - Li Jin
- a Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University , Shanghai , China
| | - Yong Su
- b R&D Department of Genetic Engineering, Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd ., Shanghai , China
| | - Yanjun Liu
- c Department of Technical Quality, Shanghai Jiaolian Drug Research and Development Co., Ltd , Shanghai , China
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16
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Glatt DM, Beckford Vera DR, Prabhu SS, Mumper RJ, Luft JC, Benhabbour SR, Parrott MC. Synthesis and Characterization of Cetuximab-Docetaxel and Panitumumab-Docetaxel Antibody-Drug Conjugates for EGFR-Overexpressing Cancer Therapy. Mol Pharm 2018; 15:5089-5102. [PMID: 30226780 DOI: 10.1021/acs.molpharmaceut.8b00672] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The safety and efficacy of anticancer antibody-drug conjugates (ADCs) depend on the selection of tumor-targeting monoclonal antibody (mAb), linker, and drug, as well as their specific chemical arrangement and linkage chemistry. In this study, we used a heterobifunctional cross-linker to conjugate docetaxel (DX) to cetuximab (CET) or panitumumab (PAN). The resulting ADCs were investigated for their in vitro EGFR-specific cytotoxicity and in vivo anticancer activity. Reaction conditions, such as reducing agent, time, temperature, and alkylation buffer, were optimized to yield potent and stable ADCs with consistent batch-to-batch drug-to-antibody ratios (DARs). ADCs were synthesized with DARs from 0.4 to 3.0, and all retained their EGFR affinity and specificity after modification. ADCs were sensitive to cell surface wildtype EGFR expression, demonstrating more cytotoxicity in EGFR-expressing A431 and MDA-MB-231 cell lines compared to U87MG cells. A431 tumor-bearing mice treated once weekly for four weeks with 100 mg/kg cetuximab-docetaxel ADC (C-SC-DX, DAR 2.5) showed durable anticancer responses and improved overall survival compared to the same treatment regimen with 1 mg/kg DX, 100 mg/kg CET, or a combination 1 mg/kg DX and 100 mg/kg CET. New treatment options are emerging for patients with both wild-type and mutated EGFR-overexpressing cancers, and these studies highlight the potential role of EGFR-targeted ADC therapies as a promising new treatment option.
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Affiliation(s)
- Dylan M Glatt
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy , University of North Carolina at Chapel Hill , 125 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States
| | - Denis R Beckford Vera
- Department of Radiology, Biomedical Research Imaging Center , University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States
| | - Shamit S Prabhu
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy , University of North Carolina at Chapel Hill , 125 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States
| | - Russell J Mumper
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy , University of North Carolina at Chapel Hill , 125 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States
| | - J Christopher Luft
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy , University of North Carolina at Chapel Hill , 125 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States
| | - S Rahima Benhabbour
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy , University of North Carolina at Chapel Hill , 125 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States.,UNC-NCSU Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States
| | - Matthew C Parrott
- Department of Radiology, Biomedical Research Imaging Center , University of North Carolina at Chapel Hill , Marsico Hall, 125 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States
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17
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Al-Mahmood S, Sapiezynski J, Garbuzenko OB, Minko T. Metastatic and triple-negative breast cancer: challenges and treatment options. Drug Deliv Transl Res 2018; 8:1483-1507. [PMID: 29978332 PMCID: PMC6133085 DOI: 10.1007/s13346-018-0551-3] [Citation(s) in RCA: 343] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The major current conventional types of metastatic breast cancer (MBC) treatments include surgery, radiation, hormonal therapy, chemotherapy, or immunotherapy. Introducing biological drugs, targeted treatment and gene therapy can potentially reduce the mortality and improve the quality of life in patients with MBC. However, combination of several types of treatment is usually recommended. Triple negative breast cancer (TNBC) accounts for 10-20% of all cases of breast carcinoma and is characterized by the low expression of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2). Consequently, convenient treatments used for MBC that target these receptors are not effective for TNBC which therefore requires special treatment approaches. This review discusses the occurrence of MBC, the prognosis and predictive biomarkers of MBC, and focuses on the novel advanced tactics for treatment of MBC and TNBC. Nanotechnology-based combinatorial approach for the suppression of EGFR by siRNA and gifitinib is described.
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Affiliation(s)
- Sumayah Al-Mahmood
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854-8020, USA
| | - Justin Sapiezynski
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854-8020, USA
| | - Olga B Garbuzenko
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854-8020, USA
| | - Tamara Minko
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854-8020, USA.
- Rutgers Cancer Institute, New Brunswick, NJ, 08903, USA.
- Environmental and Occupational Health Sciences Institute, Rutgers, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.
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18
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Wüstemann T, Haberkorn U, Babich J, Mier W. Targeting prostate cancer: Prostate-specific membrane antigen based diagnosis and therapy. Med Res Rev 2018; 39:40-69. [PMID: 29771460 DOI: 10.1002/med.21508] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 04/05/2018] [Accepted: 04/16/2018] [Indexed: 12/12/2022]
Abstract
The high incidence rates of prostate cancer (PCa) raise demand for improved therapeutic strategies. Prostate tumors specifically express the prostate-specific membrane antigen (PSMA), a membrane-bound protease. As PSMA is highly overexpressed on malignant prostate tumor cells and as its expression rate correlates with the aggressiveness of the disease, this tumor-associated biomarker provides the possibility to develop new strategies for diagnostics and therapy of PCa. Major advances have been made in PSMA targeting, ranging from immunotherapeutic approaches to therapeutic small molecules. This review elaborates the diversity of PSMA targeting agents while focusing on the radioactively labeled tracers for diagnosis and endoradiotherapy. A variety of radionuclides have been shown to either enable precise diagnosis or efficiently treat the tumor with minimal effects to nontargeted organs. Most small molecules with affinity for PSMA are based on either a phosphonate or a urea-based binding motif. Based on these pharmacophores, major effort has been made to identify modifications to achieve ideal pharmacokinetics while retaining the specific targeting of the PSMA binding pocket. Several tracers have now shown excellent clinical usability in particular for molecular imaging and therapy as proven by the efficiency of theranostic approaches in current studies. The archetypal expression profile of PSMA may be exploited for the treatment with alpha emitters to break radioresistance and thus to bring the power of systemic therapy to higher levels.
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Affiliation(s)
- Till Wüstemann
- Department for Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
| | - Uwe Haberkorn
- Department for Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - John Babich
- Department for Radiology, Weill Cornell Medicine, New York, NY, USA
| | - Walter Mier
- Department for Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
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19
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Spangler B, Kline T, Hanson J, Li X, Zhou S, Wells JA, Sato AK, Renslo AR. Toward a Ferrous Iron-Cleavable Linker for Antibody–Drug Conjugates. Mol Pharm 2018; 15:2054-2059. [DOI: 10.1021/acs.molpharmaceut.8b00242] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Benjamin Spangler
- Graduate Program in Chemistry & Chemical Biology, University of California, San Francisco, California 94143, United States
| | - Toni Kline
- Sutro Biopharma, Inc., South San Francisco, California 94080, United States
| | - Jeffrey Hanson
- Sutro Biopharma, Inc., South San Francisco, California 94080, United States
| | - Xiaofan Li
- Sutro Biopharma, Inc., South San Francisco, California 94080, United States
| | - Sihong Zhou
- Sutro Biopharma, Inc., South San Francisco, California 94080, United States
| | | | - Aaron K. Sato
- Sutro Biopharma, Inc., South San Francisco, California 94080, United States
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20
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Amoury M, Bauerschlag D, Zeppernick F, von Felbert V, Berges N, Di Fiore S, Mintert I, Bleilevens A, Maass N, Bräutigam K, Meinhold-Heerlein I, Stickeler E, Barth S, Fischer R, Hussain AF. Photoimmunotheranostic agents for triple-negative breast cancer diagnosis and therapy that can be activated on demand. Oncotarget 2018; 7:54925-54936. [PMID: 27448975 PMCID: PMC5342391 DOI: 10.18632/oncotarget.10705] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 05/29/2016] [Indexed: 11/25/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous disease in which the tumors do not express estrogen receptor (ER), progesterone receptor (PgR) or human epidermal growth factor receptor 2 (HER2). Classical receptor-targeted therapies such as tamoxifen or trastuzumab are therefore unsuitable and combinations of surgery, chemotherapy and/or radiotherapy are required. Photoimmunotheranostics is a minimally invasive approach in which antibodies deliver nontoxic photosensitizers that emit light to facilitate diagnosis and produce cytotoxic reactive oxygen species to induce apoptosis and/or necrosis in cancer cells. We developed a panel of photoimmunotheranostic agents against three TNBC-associated cell surface antigens. Antibodies against epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) were conjugated to the highly potent near-infrared imaging agent/photosensitizer IRDye®700DX phthalocyanine using SNAP-tag technology achieving clear imaging in both breast cancer cell lines and human biopsies and highly potent phototherapeutic activity with IC50values of 62–165 nM against five different cell lines expressing different levels of EGFR, EpCAM and CSPG4. A combination of all three reagents increased the therapeutic activity against TNBC cells by up to 40%.
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Affiliation(s)
- Manal Amoury
- Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, Helmholtz-Institute for Biomedical Engineering, 52074 Aachen, Germany
| | - Dirk Bauerschlag
- Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany
| | - Felix Zeppernick
- Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Verena von Felbert
- Department of Dermatology, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Nina Berges
- Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, Helmholtz-Institute for Biomedical Engineering, 52074 Aachen, Germany
| | - Stefano Di Fiore
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 52074 Aachen, Germany
| | - Isabell Mintert
- Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Andreas Bleilevens
- Department of Nuclear Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Nicolai Maass
- Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany
| | - Karen Bräutigam
- Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, 23538 Lübeck, Germany
| | - Ivo Meinhold-Heerlein
- Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Elmar Stickeler
- Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Stefan Barth
- Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 52074 Aachen, Germany.,Current address: Institute of Infectious Disease and Molecular Medicine (IDM), Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Rainer Fischer
- Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 52074 Aachen, Germany.,Institute of Molecular Biotechnology, RWTH Aachen University, 52074 Aachen, Germany
| | - Ahmad Fawzi Hussain
- Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany
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Abstract
This last decade has yielded more robust development of cancer treatments and first-in-class agents than ever before. Since 2006, nearly one hundred new drugs have received regulatory approval for the treatment of hematological and solid organ neoplasms. Moreover, older conventional therapies have received approval for new clinical indications and are being used in combination with these newer small-molecule targeted treatments. The nervous system is vulnerable to many of the traditional cancer therapies, manifesting both already well-described acute and chronic toxicities. However, newer agents may produce toxicities that may seem indistinguishable from the underlying cancer. Early recognition of neurotoxicities from new therapeutics is vital to avoid irreversible neurological injury. This review focuses on cancer therapies in use in the last 10 years and approved by the FDA from January 2006 through January 1, 2017.
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Affiliation(s)
- Alicia M Zukas
- Department of Neurology, Virginia Commonwealth University, Richmond, Virginia
| | - David Schiff
- Department of Neurology, University of Virginia, Charlottesville, Virginia
- Department of Neurological Surgery, and Medicine, University of Virginia, Charlottesville, Virginia
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22
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Wagh A, Song H, Zeng M, Tao L, Das TK. Challenges and new frontiers in analytical characterization of antibody-drug conjugates. MAbs 2018; 10:222-243. [PMID: 29293399 DOI: 10.1080/19420862.2017.1412025] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Antibody-drug conjugates (ADCs) are a growing class of biotherapeutics in which a potent small molecule is linked to an antibody. ADCs are highly complex and structurally heterogeneous, typically containing numerous product-related species. One of the most impactful steps in ADC development is the identification of critical quality attributes to determine product characteristics that may affect safety and efficacy. However, due to the additional complexity of ADCs relative to the parent antibodies, establishing a solid understanding of the major quality attributes and determining their criticality are a major undertaking in ADC development. Here, we review the development challenges, especially for reliable detection of quality attributes, citing literature and new data from our laboratories, highlight recent improvements in major analytical techniques for ADC characterization and control, and discuss newer techniques, such as two-dimensional liquid chromatography, that have potential to be included in analytical control strategies.
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Affiliation(s)
- Anil Wagh
- a Molecular & Analytical Development , Bristol-Myers Squibb , New Jersey , USA
| | - Hangtian Song
- a Molecular & Analytical Development , Bristol-Myers Squibb , New Jersey , USA
| | - Ming Zeng
- a Molecular & Analytical Development , Bristol-Myers Squibb , New Jersey , USA
| | - Li Tao
- a Molecular & Analytical Development , Bristol-Myers Squibb , New Jersey , USA
| | - Tapan K Das
- a Molecular & Analytical Development , Bristol-Myers Squibb , New Jersey , USA
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23
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Ding S, Xiong J, Lei D, Zhu XL, Zhang HJ. Recombinant nanocomposites by the clinical drugs of Abraxane ® and Herceptin ® as sequentially dual-targeting therapeutics for breast cancer. J Cancer 2018; 9:502-511. [PMID: 29483955 PMCID: PMC5820917 DOI: 10.7150/jca.22163] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 11/09/2017] [Indexed: 11/30/2022] Open
Abstract
Breast cancer greatly threatens the health of women all over the word despite of several effective drugs. Targeted therapy for breast cancer is limited to human epidermal growth factor receptor 2 (HER2). Herceptin®, monoclonal antibody against HER2, is now widely used in HER2(+) breast cancer. Abraxane®, the current gold standard for paclitaxel (PTX) delivery, has shown superiority in breast cancer based on nanoparticle albumin bound technology. Despite these advances, further novel targeted therapy with more improved anti-tumor efficacy for breast cancer is still urgently needed. Here, we report the recombinant nanocomposites (NPs) composed of the above two clinical drugs of Abraxane® and Herceptin® (Abra/anti-HER2), which at first migrates to the tumor region through the unique targeting mechanism of human serum albumin (HSA) of Abraxane®, and sequentially further precisely recognize the HER2(+) breast cancer cells due to Herceptin®. The Abra/anti-HER2 NPs were fabricated by a “one-step” synthesis using EDC/NHS. In vitro analysis of cell viability, apoptosis and cell cycle revealed that Abra/anti-HER2 NPs showed more anti-tumor efficacy against HER2(+) SK-BR-3 cells than Abraxane® at equivalent PTX concentration. In addition, in HER2(+) breast cancer xenograft model, Abra/anti-HER2 NPs significantly inhibited tumor growth with less side effects. Moreover, the properties of more precise target and delayed release of PTX were proved by NIRF imaging. Thus, our results indicate that Abra/anti-HER2 NPs could represent a next-generation sequentially dual-targeting therapeutic agent for HER2(+) breast cancer.
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Affiliation(s)
- Shuang Ding
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, Jiangsu, P.R. China
| | - Jian Xiong
- Department of Hematology, Dongfeng General Hospital, Hubei University of Medcine, Shiyan 442000, Hubei, P.R. China
| | - Dan Lei
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, Jiangsu, P.R. China
| | - Xiao-Li Zhu
- Department of Respiration, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, Jiangsu, P.R. China
| | - Hai-Jun Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, Jiangsu, P.R. China
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Ait-Oudhia S, Zhang W, Mager DE. A Mechanism-Based PK/PD Model for Hematological Toxicities Induced by Antibody-Drug Conjugates. AAPS JOURNAL 2017. [DOI: 10.1208/s12248-017-0113-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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25
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Liu R, Chen X, Dushime J, Bogalhas M, Lazar AC, Ryll T, Wang L. The impact of trisulfide modification of antibodies on the properties of antibody-drug conjugates manufactured using thiol chemistry. MAbs 2017; 9:490-497. [PMID: 28136017 DOI: 10.1080/19420862.2017.1285478] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Antibody-drug conjugates (ADCs) are promising biotherapeutic agents for the treatment of cancer. The careful monitoring of critical quality attributes is important for ADCs' development, manufacturing and production. In this work, the effect of the presence of a trisulfide bond in the monoclonal antibody (mAb) conjugated to DM4 cytotoxic payload through a disulfide-bond linker sulfo-SPDB (sSPDB) was investigated. Three lots of antibody containing variable levels of trisulfide bonds were used. The identity and levels of trisulfide bonds were determined by liquid chromatography/ mass spectrometry (MS)/MS analysis. The antibodies were conjugated to sSPDB-DM4 to generate ADCs. Further analysis indicated that the drug-to-antibody ratio (DAR) value, a critical quality attribute, slightly increased for the conjugates made from antibody containing higher levels of trisulfide bond. Also, higher fragmentation levels were observed in the conjugates with more trisulfide bond. Detailed characterization by MS revealed that a small amount of DM4 payload was directly attached to inter-chain cysteine residues by disulfide or trisulfide bonds. Overall, our investigation indicated that the trisulfide bond present in the mAb could react with DM4 during the conjugation process. Therefore, the presence of trisulfide bonds in the antibody moiety should be carefully monitored and well controlled during the development of a maytansinoid ADC.
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Affiliation(s)
- Renpeng Liu
- a Analytical and Pharmaceutical Science Department , ImmunoGen Inc. Waltham , MA , USA
| | - Xuan Chen
- a Analytical and Pharmaceutical Science Department , ImmunoGen Inc. Waltham , MA , USA
| | - Junia Dushime
- a Analytical and Pharmaceutical Science Department , ImmunoGen Inc. Waltham , MA , USA
| | - Megan Bogalhas
- a Analytical and Pharmaceutical Science Department , ImmunoGen Inc. Waltham , MA , USA
| | - Alexandru C Lazar
- a Analytical and Pharmaceutical Science Department , ImmunoGen Inc. Waltham , MA , USA
| | - Thomas Ryll
- a Analytical and Pharmaceutical Science Department , ImmunoGen Inc. Waltham , MA , USA
| | - Lintao Wang
- a Analytical and Pharmaceutical Science Department , ImmunoGen Inc. Waltham , MA , USA
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Abstract
Through years of evolutionary selection pressures, organisms have developed potent toxins that coincidentally have marked antineoplastic activity. These natural products have been vital for the development of multiagent treatment regimens currently employed in cancer chemotherapy, and are used in the treatment of a variety of malignancies. Therefore, this review catalogs recent advances in natural product-based drug discovery via the examination of mechanisms of action and available clinical data to highlight the utility of these novel compounds in the burgeoning age of precision medicine. The review also highlights the recent development of antibody-drug conjugates and other immunotoxins, which are capable of delivering highly cytotoxic agents previously deemed too toxic to elicit therapeutic benefit preferentially to neoplastic cells. Finally, the review examines natural products not currently used in the clinic that have novel mechanisms of action, and may serve to supplement current chemotherapeutic protocols.
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Liu M, Li Z, Yang J, Jiang Y, Chen Z, Ali Z, He N, Wang Z. Cell-specific biomarkers and targeted biopharmaceuticals for breast cancer treatment. Cell Prolif 2016; 49:409-20. [PMID: 27312135 PMCID: PMC6496337 DOI: 10.1111/cpr.12266] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 05/04/2016] [Indexed: 12/13/2022] Open
Abstract
Breast cancer is the second leading cause of cancer death among women, and its related treatment has been attracting significant attention over the past decades. Among the various treatments, targeted therapy has shown great promise as a precision treatment, by binding to cancer cell-specific biomarkers. So far, great achievements have been made in targeted therapy of breast cancer. In this review, we first discuss cell-specific biomarkers, which are not only useful for classification of breast cancer subtyping but also can be utilized as goals for targeted therapy. Then, the innovative and generic-targeted biopharmaceuticals for breast cancer, including monoclonal antibodies, non-antibody proteins and small molecule drugs, are reviewed. Finally, we provide our outlook on future developments of biopharmaceuticals, and provide solutions to problems in this field.
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Affiliation(s)
- Mei Liu
- School of Biological Science and Medical EngineeringSoutheast UniversityNanjingChina
| | - Zhiyang Li
- School of Biological Science and Medical EngineeringSoutheast UniversityNanjingChina
- Department of Laboratory MedicineNanjing Drum Tower Hospital Clinical CollegeNanjing UniversityNanjingChina
| | - Jingjing Yang
- School of Chemistry and Chemical EngineeringSoutheast UniversityNanjingChina
| | - Yanyun Jiang
- School of Chemistry and Chemical EngineeringSoutheast UniversityNanjingChina
| | - Zhongsi Chen
- School of Biological Science and Medical EngineeringSoutheast UniversityNanjingChina
| | - Zeeshan Ali
- School of Chemistry and Chemical EngineeringSoutheast UniversityNanjingChina
| | - Nongyue He
- School of Biological Science and Medical EngineeringSoutheast UniversityNanjingChina
| | - Zhifei Wang
- School of Chemistry and Chemical EngineeringSoutheast UniversityNanjingChina
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28
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Godman B, Malmström RE, Diogene E, Gray A, Jayathissa S, Timoney A, Acurcio F, Alkan A, Brzezinska A, Bucsics A, Campbell SM, Czeczot J, de Bruyn W, Eriksson I, Yusof FAM, Finlayson AE, Fürst J, Garuoliene K, Guerra Júnior A, Gulbinovič J, Jan S, Joppi R, Kalaba M, Magnisson E, McCullagh L, Miikkulainen K, Ofierska-Sujkowska G, Pedersen HB, Selke G, Sermet C, Spillane S, Supian A, Truter I, Vlahović-Palčevski V, Vien LE, Vural EH, Wale J, Władysiuk M, Zeng W, Gustafsson LL. Are new models needed to optimize the utilization of new medicines to sustain healthcare systems? Expert Rev Clin Pharmacol 2015; 8:77-94. [PMID: 25487078 DOI: 10.1586/17512433.2015.990380] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Medicines have made an appreciable contribution to improving health. However, even high-income countries are struggling to fund new premium-priced medicines. This will grow necessitating the development of new models to optimize their use. The objective is to review case histories among health authorities to improve the utilization and expenditure on new medicines. Subsequently, use these to develop exemplar models and outline their implications. A number of issues and challenges were identified from the case histories. These included the low number of new medicines seen as innovative alongside increasing requested prices for their reimbursement, especially for oncology, orphan diseases, diabetes and HCV. Proposed models center on the three pillars of pre-, peri- and post-launch including critical drug evaluation, as well as multi-criteria models for valuing medicines for orphan diseases alongside potentially capping pharmaceutical expenditure. In conclusion, the proposed models involving all key stakeholder groups are critical for the sustainability of healthcare systems or enhancing universal access. The models should help stimulate debate as well as restore trust between key stakeholder groups.
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Affiliation(s)
- Brian Godman
- Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
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Suzuki M, Yamanoi A, Machino Y, Ootsubo M, Izawa KI, Kohroki J, Masuho Y. Effect of trastuzumab interchain disulfide bond cleavage on Fcγ receptor binding and antibody-dependent tumour cell phagocytosis. J Biochem 2015; 159:67-76. [PMID: 26254483 DOI: 10.1093/jb/mvv074] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 06/25/2015] [Indexed: 01/08/2023] Open
Abstract
The Fc domain of human IgG1 binds to Fcγ receptors (FcγRs) to induce effector functions such as phagocytosis. There are four interchain disulfide bonds between the H and L chains. In this study, the disulfide bonds within the IgG1 trastuzumab (TRA), which is specific for HER2, were cleaved by mild S-sulfonation or by mild reduction followed by S-alkylation with three different reagents. The cleavage did not change the binding activities of TRA to HER2-bearing SK-BR-3 cells. The binding activities of TRA to FcγRIIA and FcγRIIB were greatly enhanced by modification with mild reduction and S-alkylation with ICH2CONH2 or N-(4-aminophenyl) maleimide, while the binding activities of TRA to FcγRI and FcγRIIIA were decreased by any of the four modifications. However, the interchain disulfide bond cleavage by the different modifications did not change the antibody-dependent cell-mediated phagocytosis (ADCP) of SK-BR-3 cells by activated THP-1 cells. The order of FcγR expression levels on the THP-1 cells was FcγRII > FcγRI > FcγRIII and ADCP was inhibited by blocking antibodies against FcγRI and FcγRII. These results imply that the effect of the interchain disulfide bond cleavage on FcγRs binding and ADCP is dependent on modifications of the cysteine residues and the FcγR isotypes.
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Affiliation(s)
- Mami Suzuki
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan and Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino-shi, Tokyo 191-8512, Japan
| | - Ayaka Yamanoi
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan and
| | - Yusuke Machino
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan and
| | - Michiko Ootsubo
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan and
| | - Ken-ichi Izawa
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan and
| | - Junya Kohroki
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan and
| | - Yasuhiko Masuho
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan and
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Lipatova Z, Segev N. A Role for Macro-ER-Phagy in ER Quality Control. PLoS Genet 2015; 11:e1005390. [PMID: 26181331 PMCID: PMC4504476 DOI: 10.1371/journal.pgen.1005390] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 06/23/2015] [Indexed: 11/18/2022] Open
Abstract
The endoplasmic-reticulum quality-control (ERQC) system shuttles misfolded proteins for degradation by the proteasome through the well-defined ER-associated degradation (ERAD) pathway. In contrast, very little is known about the role of autophagy in ERQC. Macro-autophagy, a collection of pathways that deliver proteins through autophagosomes (APs) for degradation in the lysosome (vacuole in yeast), is mediated by autophagy-specific proteins, Atgs, and regulated by Ypt/Rab GTPases. Until recently, the term ER-phagy was used to describe degradation of ER membrane and proteins in the lysosome under stress: either ER stress induced by drugs or whole-cell stress induced by starvation. These two types of stresses induce micro-ER-phagy, which does not use autophagic organelles and machinery, and non-selective autophagy. Here, we characterize the macro-ER-phagy pathway and uncover its role in ERQC. This pathway delivers 20-50% of certain ER-resident membrane proteins to the vacuole and is further induced to >90% by overexpression of a single integral-membrane protein. Even though such overexpression in cells defective in macro-ER-phagy induces the unfolded-protein response (UPR), UPR is not needed for macro-ER-phagy. We show that macro-ER-phagy is dependent on Atgs and Ypt GTPases and its cargo passes through APs. Moreover, for the first time the role of Atg9, the only integral-membrane core Atg, is uncoupled from that of other core Atgs. Finally, three sequential steps of this pathway are delineated: Atg9-dependent exit from the ER en route to autophagy, Ypt1- and core Atgs-mediated pre-autophagsomal-structure organization, and Ypt51-mediated delivery of APs to the vacuole.
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Affiliation(s)
- Zhanna Lipatova
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Nava Segev
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, United States of America
- * E-mail:
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31
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Kamdje AHN, Etet PFS, Vecchio L, Tagne RS, Amvene JM, Muller JM, Krampera M, Lukong KE. New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers. World J Clin Cases 2014; 2:769-786. [PMID: 25516852 PMCID: PMC4266825 DOI: 10.12998/wjcc.v2.i12.769] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 07/12/2014] [Accepted: 09/23/2014] [Indexed: 02/05/2023] Open
Abstract
Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy, including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin, Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed.
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