DOCSLIB.ORG

Antibody Therapy of Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Antibody Therapy of Cancer REVIEWS Antibody therapy of cancer Andrew M. Scott1, Jedd D. Wolchok2,3,4,5 and Lloyd J. Old3,4,5 Abstract | The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Antibody–drug conjugates are powerful new treatment options for lymphomas and solid tumours, and immunomodulatory antibodies have also recently achieved remarkable clinical success. The development of therapeutic antibodies requires a deep understanding of cancer serology, protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system and cancer cells. This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials. Antibody-based therapy for cancer has become estab- Cancer serology Fc function The Fc portion of an antibody lished over the past 15 years and is now one of the most The idea that antibodies could serve as ‘magic bullets’ in can activate a number of successful and important strategies for treating patients the diagnosis and therapy of cancer has a long history, immunological pathways with haematological malignancies and solid tumours. The which started soon after their discovery in the late nine- leading to tumour cell killing. fundamental basis of antibody-based therapy of tumours teenth century. A considerable effort over the ensuing This includes complement activation, activation of dates back to the original observations of antigen expres- decades involved the immunization of various animal effector cells and phagocytosis sion by tumour cells through serological techniques in species with human cancer in the hope of generating of tumour cells. the 1960s1. The definition of cell surface antigens that are antisera with some degree of cancer specificity1. Despite expressed by human cancers has revealed a broad array repeated claims of success and much controversy, this of targets that are overexpressed, mutated or selectively approach yielded little of enduring value, with the nota- expressed compared with normal tissues2. A key challenge ble exception of the discovery of carcinoembryonic has been to identify antigens that are suitable for anti- antigen (CEA), which is a marker for colon cancer and body-based therapeutics. Such therapeutics can function other cancers, and α-fetoprotein, which is a marker for through mediating alterations in antigen or receptor func- hepatocellular cancer1,2. The development of inbred tion (such as agonist or antagonist functions), modulat- mice initiated a new era of serological investigation ing the immune system (for example, changing Fc function of cancer, with the emergence of the cytotoxic test as a and T cell activation) or delivering a specific drug that powerful tool to analyse the cell surface reactivity of is conjugated to an antibody that targets a specific anti- alloantibodies. This led to the recognition that the cell 1 Ludwig Institute for Cancer 2–5 Research; University of gen . Molecular techniques that can alter antibody surface is a highly differentiated structure. The identi- Melbourne; and Centre for pharmacokinetics, effector function, size and immunogenicity fication of cell surface differentiation antigens, which PET, Austin Hospital, have emerged as key elements in the development of new were initially used to distinguish lymphocyte subsets, Melbourne, Victoria 3084, antibody-based therapies. Evidence from clinical trials of set the stage for a revolution in biological and biomedi- Australia. antibodies in cancer patients has revealed the importance cal sciences. This revolution was fuelled by the develop- 2Department of Medicine; hybridoma technology 3Ludwig Institute for Cancer of iterative approaches for the selection of antigen targets ment of and analytical tools such as Research; and optimal antibodies, including the affinity and avidity fluorescence-activated cell sorting (FACS). In view 4Ludwig Center for Cancer of antibodies, the choice of antibody construct, the thera- of these remarkable advances, cancer immunologists Immunotherapy, Memorial peutic approach (such as signalling abrogation or immune renewed their search for human cancer-specific anti- Sloan-Kettering Cancer Center, New York, New York effector function) and the need to critically examine the gens and initiated a massive effort to dissect the surface 2 10065-6306, USA. pharmacokinetic and pharmacodynamic properties of structure of human cancer cells with mAbs . More recent 5Weill Cornell Medical antibodies in early clinical trials. This Review summarizes studies have shown that, in addition to changes in the College, New York, New York the steps that are necessary to transform monoclonal anti- surface antigenic structure of cancer cells, tumour stro- 10065-4896, USA. bodies (mAbs) into reagents for human use, the success mal and tumour vascular cells express novel antigens that Correspondence to A.M.S. 6–11 e-mail: andrew.scott@ludwig. of antibodies in the treatment of cancer patients, the chal- distinguish them from their normal counterparts . As edu.au lenges in target and construct selection, and the crucial a consequence, a detailed picture of the surface antigens doi:10.1038/nrc3236 role of the immune system in antibody therapy. of human cancers is emerging, and with bioinformatic 278 | APRIL 2012 | VOLUME 12 www.nature.com/reviews/cancer © 2012 Macmillan Publishers Limited. All rights reserved FOCUS ON TuMour iMMunoLoGY & iMMunotREVIEWSHerAPY 12,13 At a glance example, by cetuximab and trastuzumab) , the induc- tion of effector function primarily through ADCC (for • Antibody-based therapy for cancer has become established over the past 15 years example, by rituximab)14 and the immune modulation and is now one of the most successful and important strategies for treating patients of T cell function (for example, by ipilimumab)15 are the with haematological malignancies and solid tumours. approaches that have been most successful and that have • Evidence from clinical trials of antibodies in cancer patients has revealed the led to the approval of antibodies using these mechanisms importance of iterative approaches for the selection of antigen targets and optimal (discussed below). antibodies. Although most of the antibodies that have been suc- • The killing of tumour cells using monoclonal antibodies (mAbs) can result from direct cessful in the clinic are intact immunoglobulin G (IgG) action of the antibody (through receptor blockade, for example), immune-mediated molecules, multiple approaches for antibody construc- cell killing mechanisms, payload delivery, and specific effects of an antibody on the tion and for the delivery of conjugated cytotoxic drugs tumour vasculature and stroma. have been used (TABLE 1). The broad range of antibody • Tumour antigens that have been successfully targeted include epidermal growth engineering approaches that have been used in the clinic factor receptor (EGFR), ERBB2, vascular endothelial growth factor (VEGF), cytotoxic T 5,6,16 lymphocyte-associated antigen 4 (CTLA4), CD20, CD30 and CD52. has recently been reviewed . • Serological, genomic, proteomic and bioinformatic databases have also been used to Tumour antigens as antibody targets identify antigens and receptors that are overexpressed in tumour cell populations or that are linked to gene mutations identified as driving cancer cell proliferation, The safety and efficacy of therapeutic mAbs in oncol- including EGFRvIII, MET, CTLA4 and fibroblast activation protein (FAP). ogy vary depending on the nature of the target anti- • The successful development of candidate mAbs for the clinic involves a complex gen. Ideally, the target antigen should be abundant and process of scientific and preclinical evaluations that include identification of the accessible and should be expressed homogeneously, physical and chemical properties of the antibody; the detailed specificity analysis of consistently and exclusively on the surface of cancer antigen expression; the study of the immune effector functions and signalling cells. Antigen secretion should be minimal, as secreted pathway effects of the antibody; the analysis of in vivo antibody localization and antigens can bind the antibody in the circulation and distribution in transplanted or syngeneic tumour systems; and the observation of the could prevent sufficient antibody from binding to the in vivo therapeutic activity of the antibody. tumour. If the desired mechanism of action is ADCC or • A major objective for the clinical evaluation of mAbs has been determining the CDC, then it is desirable that the antigen–mAb complex toxicity and therapeutic efficacy of the antibody alone or as a delivery system for should not be rapidly internalized so as to maximize the radioisotopes or other toxic agents. It is also crucial to assess its in vivo specificity by availability of the Fc region to immune effector cells and determining its biodistribution in patients and to assess the ratio of antibody uptake complement proteins, respectively. By contrast, good in the tumour versus normal tissues. internalization is desirable for antibodies or proteins that • Twelve antibodies have received approval from the US Food and Drug Administration deliver toxins into the cancer cell and for antibodies the for the treatment of various solid tumours and haematological malignancies, and a action of which is primarily based on the downregulation
Load more

Recommended publications
  • The Extracellular Matrix: an Accomplice in Gastric Cancer Development and Progression
    cells Review The Extracellular Matrix: An Accomplice in Gastric Cancer Development and Progression Ana Margarida Moreira 1,2,3, Joana Pereira 1,2,4, Soraia Melo 1,2,4 , Maria Sofia Fernandes 1,2, Patrícia Carneiro 1,2 , Raquel Seruca 1,2,4 and Joana Figueiredo 1,2,* 1 Epithelial Interactions in Cancer Group, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; [email protected] (A.M.M.); [email protected] (J.P.); [email protected] (S.M.); [email protected] (M.S.F.); [email protected] (P.C.); [email protected] (R.S.) 2 Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal 3 Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal 4 Medical Faculty, University of Porto, 4200-319 Porto, Portugal * Correspondence: jfi[email protected]; Tel.: +351-220408800; Fax: +351-225570799 Received: 15 January 2020; Accepted: 6 February 2020; Published: 8 February 2020 Abstract: The extracellular matrix (ECM) is a dynamic and highly organized tissue structure, providing support and maintaining normal epithelial architecture. In the last decade, increasing evidence has emerged demonstrating that alterations in ECM composition and assembly strongly affect cellular function and behavior. Even though the detailed mechanisms underlying cell-ECM crosstalk are yet to unravel, it is well established that ECM deregulation accompanies the development of many pathological conditions, such as gastric cancer. Notably, gastric cancer remains a worldwide concern, representing the third most frequent cause of cancer-associated deaths. Despite increased surveillance protocols, patients are usually diagnosed at advanced disease stages, urging the identification of novel diagnostic biomarkers and efficient therapeutic strategies.
    [Show full text]
  • Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients
    antibodies Review Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients Andrew T. Lucas 1,2,3,*, Ryan Robinson 3, Allison N. Schorzman 2, Joseph A. Piscitelli 1, Juan F. Razo 1 and William C. Zamboni 1,2,3 1 University of North Carolina (UNC), Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA; [email protected] (J.A.P.); [email protected] (J.F.R.); [email protected] (W.C.Z.) 2 Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-919-966-5242; Fax: +1-919-966-5863 Received: 30 November 2018; Accepted: 22 December 2018; Published: 1 January 2019 Abstract: The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small molecule drugs, though their clinical use still requires optimization. The pharmacology of mAbs/ADCs is complex and because ADCs are comprised of multiple components, individual agent characteristics and patient variables can affect their disposition. To further improve the clinical use and rational development of these agents, it is imperative to comprehend the complex mechanisms employed by antibody-based agents in traversing numerous biological barriers and how agent/patient factors affect tumor delivery, toxicities, efficacy, and ultimately, biodistribution.
    [Show full text]
  • Etude Des Résistances Adaptatives Aux Inhibiteurs De Tyrosine Kinase De L’EGFR Dans Les Cancers Bronchiques
    Thèse d’exercice Faculté de Pharmacie Année 2020 Thèse N° MÉMOIRE DU DIPLÔME D'ÉTUDES SPÉCIALISÉES D’INNOVATION PHARMACEUTIQUE ET RECHERCHE TENANT LIEU DE THÈSE D’EXERCICE POUR LE DIPLÔME D’ÉTAT DE DOCTEUR ENPHARMACIE Présentée et soutenue publiquement le 24 septembre 2020 par Sarah FIGAROL Née le 19 septembre 1989 à Toulouse Etude des résistances adaptatives aux inhibiteurs de tyrosine kinase de l’EGFR dans les cancers bronchiques Thèse dirigée par Gilles Favre Examinateurs : M. Franck Saint-Marcoux, président du jury M.Gilles Favre, directeur de thèse M. Jean-Marie Canonge, juge M. Julien Mazières, juge M. Antonio Maraver, juge Thèse d’exercice Faculté de Pharmacie Année 2020 Thèse N° MÉMOIRE DU DIPLÔME D'ÉTUDES SPÉCIALISÉES D’INNOVATION PHARMACEUTIQUE ET RECHERCHE TENANT LIEU DE THÈSE D’EXERCICE POUR LE DIPLÔME D’ÉTAT DE DOCTEUR ENPHARMACIE Présentée et soutenue publiquement le 24 septembre 2020 par Sarah FIGAROL Née le 19 septembre 1989 à Toulouse Etude des résistances adaptatives aux inhibiteurs de tyrosine kinase de l’EGFR dans les cancers bronchiques Thèse dirigée par Gilles Favre Examinateurs : M. Franck Saint-Marcoux, président du jury M.Gilles Favre, directeur de thèse M. Jean-Marie Canonge, juge M. Julien Mazières, juge M. Antonio Maraver, juge Sarah FIGAROL | Thèse d’exercice | Université de Limoges |2020 3 Licence CC BY-NC-ND 3.0 Liste des enseignants Le 1er septembre 2019 PROFESSEURS : BATTU Serge CHIMIE ANALYTIQUE CARDOT Philippe CHIMIE ANALYTIQUE ET BROMATOLOGIE DESMOULIERE Alexis PHYSIOLOGIE DUROUX Jean-Luc BIOPHYSIQUE,
    [Show full text]
  • Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
    Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models.
    [Show full text]
  • The Role of Biological Therapy in Metastatic Colorectal Cancer After First-Line Treatment: a Meta-Analysis of Randomised Trials
    REVIEW British Journal of Cancer (2014) 111, 1122–1131 | doi: 10.1038/bjc.2014.404 Keywords: colorectal; biological; meta-analysis The role of biological therapy in metastatic colorectal cancer after first-line treatment: a meta-analysis of randomised trials E Segelov1, D Chan*,2, J Shapiro3, T J Price4, C S Karapetis5, N C Tebbutt6 and N Pavlakis2 1St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2052, Australia; 2Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia; 3Monash University and Cabrini Hospital, Melbourne, VIC 3800, Australia; 4The Queen Elizabeth Hospital and University of Adelaide, Woodville South, SA 5011, Australia; 5Flinders University and Flinders Medical Centre, Flinders Centre for Innovation in Cancer, Bedford Park, SA, 5042, Australia and 6Austin Health, VIC 3084, Australia Purpose: Biologic agents have achieved variable results in relapsed metastatic colorectal cancer (mCRC). Systematic meta-analysis was undertaken to determine the efficacy of biological therapy. Methods: Major databases were searched for randomised studies of mCRC after first-line treatment comparing (1) standard treatment plus biologic agent with standard treatment or (2) standard treatment with biologic agent with the same treatment with different biologic agent(s). Data were extracted on study design, participants, interventions and outcomes. Study quality was assessed using the MERGE criteria. Comparable data were pooled for meta-analysis. Results: Twenty eligible studies with 8225 patients were identified. The use of any biologic therapy improved overall survival with hazard ratio (HR) 0.87 (95% confidence interval (CI) 0.82–0.91, Po0.00001), progression-free survival (PFS) with HR 0.71 (95% CI 0.67–0.74, Po0.0001) and overall response rate (ORR) with odds ratio (OR) 2.38 (95% CI 2.03–2.78, Po0.00001).
    [Show full text]
  • Antibody Drug Conjugate Development in Gastrointestinal Cancers: Hopes and Hurdles from Clinical Trials
    Wu et al. Cancer Drug Resist 2018;1:204-18 Cancer DOI: 10.20517/cdr.2018.16 Drug Resistance Review Open Access Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials Xiaorong Wu, Thomas Kilpatrick, Ian Chau Department of Medical oncology, Royal Marsden Hospital NHS foundation trust, Sutton SM2 5PT, UK. Correspondence to: Dr. Ian Chau, Department of Medical Oncology, Royal Marsden Hospital NHS foundation trust, Downs Road, Sutton SM2 5PT, UK. E-mail: [email protected] How to cite this article: Wu X, Kilpatrick T, Chau I. Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials. Cancer Drug Resist 2018;1:204-18. http://dx.doi.org/10.20517/cdr.2018.16 Received: 31 Aug 2018 First Decision: 8 Oct 2018 Revised: 13 Nov 2018 Accepted: 16 Nov 2018 Published: 19 Dec 2018 Science Editors: Elisa Giovannetti, Jose A. Rodriguez Copy Editor: Cui Yu Production Editor: Huan-Liang Wu Abstract Gastrointestinal (GI) cancers represent the leading cause of cancer-related mortality worldwide. Antibody drug conjugates (ADCs) are a rapidly growing new class of anti-cancer agents which may improve GI cancer patient survival. ADCs combine tumour-antigen specific antibodies with cytotoxic drugs to deliver tumour cell specific chemotherapy. Currently, only two ADCs [brentuximab vedotin and trastuzumab emtansine (T-DM1)] have been Food and Drug Administration approved for the treatment of lymphoma and metastatic breast cancer, respectively. Clinical research evaluating ADCs in GI cancers has shown limited success. In this review, we will retrace the relevant clinical trials investigating ADCs in GI cancers, especially ADCs targeting human epidermal growth receptor 2, mesothelin, guanylyl cyclase C, carcinogenic antigen-related cell adhesion molecule 5 (also known as CEACAM5) and other GI malignancy specific targets.
    [Show full text]
  • Monoclonal Antibodies As Treatment Modalities in Head and Neck Cancers
    AIMS Medical Science, Volume 2 (4): 347–359. DOI: 10.3934/medsci.2015.4.347 Received date 29 August 2015, Accepted date 28 October 2015， Published date 3 November 2015 http://www.aimspress.com/ Review article Monoclonal Antibodies as Treatment Modalities in Head and Neck Cancers Vivek Radhakrishnan *, Mark S. Swanson, and Uttam K. Sinha Department of Otolaryngology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA * Correspondence: E-mail: [email protected]; Tel.: 714-423-0679. Abstract: The standard treatments of surgery, radiation, and chemotherapy in head and neck squamous cell carcinomas (HNSCC) causes disturbance to normal surrounding tissues, systemic toxicities and functional problems with eating, speaking, and breathing. With early detection, many of these cancers can be effectively treated, but treatment should also focus on retaining the function of the proximal nerves, tissues and vasculature surrounding the tumor. With current research focused on understanding pathogenesis of these cancers in a molecular level, targeted therapy using monoclonal antibodies (MoAbs), can be modified and directed towards tumor genes, proteins and signal pathways with the potential to reduce unfavorable side effects of current treatments. This review will highlight the current MoAb therapies used in HNSCC, and discuss ongoing research efforts to develop novel treatment agents with potential to improve efficacy, increase overall survival (OS) rates and reduce toxicities. Keywords: monoclonal antibodies; hnscc, cetuximab; cisplatin; tumor antigens; immunotherapy; genome sequencing; HPV tumors AIMS Medical Science Volume 2, Issue 4, 347-359. 348 1. Introduction Head and neck cancer accounts for about 3% of all cancers in the United States.
    [Show full text]
  • Patient Resource Free
    PATIENT RESOURCE FREE Third Edition CancerUnderstanding Immunotherapy Published in partnership with CONTENT REVIEWED BY A DISTINGUISHED PRP MEDICAL PATIENT ADVISORY RESOURCE BOARD PUBLISHING® Understanding TABLE OF CONTENTS Cancer Immunotherapy Third Edition IN THIS GUIDE 1 Immunotherapy Today 2 The Immune System 4 Immunotherapy Strategies 6 Melanoma Survivor Story: Jane McNee Chief Executive Officer Mark A. Uhlig I didn’t look sick, so I didn’t want to act sick. Publisher Linette Atwood Having and treating cancer is only one part of your life. Co-Editor-in-Chief Charles M. Balch, MD, FACS Jane McNee, melanoma survivor Co-Editor-in-Chief Howard L. Kaufman, MD, FACS Senior Vice President Debby Easum 7 The Road to Immunotherapy Vice President, Operations Leann Sandifar 8 Cancer Types Managing Editor Lori Alexander, MTPW, ELS, MWC™ 14 Side Effects Senior Editors Dana Campbell Colleen Scherer 15 Glossary Graphic Designer Michael St. George 16 About Clinical Trials Medical Illustrator Todd Smith 16 Cancer Immunotherapy Clinical Trials by Disease Production Manager Jennifer Hiltunen 35 Support & Financial Resources Vice Presidents, Amy Galey Business Development Kathy Hungerford 37 Notes Stephanie Myers Kenney Account Executive Melissa Amaya Office Address 8455 Lenexa Drive CO-EDITORS-IN-CHIEF Overland Park, KS 66214 For Additional Information [email protected] Charles M. Balch, MD, FACS Advisory Board Visit our website at Professor of Surgery, The University of Texas PatientResource.com to read bios of MD Anderson Cancer Center our Medical and Patient Advisory Board. Editor-in-Chief, Patient Resource LLC Editor-in-Chief, Annals of Surgical Oncology Past President, Society of Surgical Oncology For Additional Copies: To order additional copies of Patient Resource Cancer Guide: Understanding Cancer Immunotherapy, Howard L.
    [Show full text]
  • Intraperitoneal Chemotherapy for Gastric Cancer with Peritoneal Carcinomatosis: Is HIPEC the Only Answer?
    Modern Chemotherapy, 2014, 3, 11-19 Published Online April 2014 in SciRes. http://www.scirp.org/journal/mc http://dx.doi.org/10.4236/mc.2014.32003 Intraperitoneal Chemotherapy for Gastric Cancer with Peritoneal Carcinomatosis: Is HIPEC the Only Answer? Ka-On Lam1*, Betty Tsz-Ting Law2, Simon Ying-Kit Law2, Dora Lai-Wan Kwong1 1Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China 2Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China Email: *[email protected] Received 13 January 2014; revised 16 February 2014; accepted 26 February 2014 Academic Editor: Stephen L. Chan, The Chinese University of Hong Kong, Hong Kong, China Copyright © 2014 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/ Abstract Gastric cancer with peritoneal carcinomatosis is notorious for its dismal prognosis. While the pa- thophysiology of peritoneal dissemination is still controversial, the rapid downhill course is uni- versal. Patients usually suffer abdominal distension, intestinal obstruction and various complica- tions before they succumb after a median of 3 - 6 months. Although not adopted in most interna- tional treatment guidelines, intraperitoneal chemotherapy has growing evidence compared with conventional systemic chemotherapy for the treatment of peritoneal carcinomatosis. Cytoreduc- tive surgery with hyperthermic intraperitoneal chemotherapy is well-established for clinical ben- efit but is technically demanding with substantial treatment-related morbidities and mortality. On the other hand, normothermic intraperitoneal chemotherapy in the form of bidirectional neoad- juvant treatment is promising with various newer chemotherapeutic agents.
    [Show full text]
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • Consideration Toward Safety Guidance for Targeted Alpha Therapy in Japan
    TAT-11, Ottawa Consideration toward Safety Guidance for Targeted Alpha Therapy in Japan Tsuneo YANO1), Koki HASEGAWA2), Tatsuhiko SATO3),1) Akiko HACHISUKA4), Koichi FUKASE5), Yoko HIRABAYASHI6) April 2nd, 2019 1) QiSS-Targeted Alpha Therapy Research, Research Center for Nuclear Physics, Osaka University 2) Center for Instrumental Analysis, Kyoto Pharmaceutical University 3) Nuclear Science and Engineering Center, Japan Atomic Energy Agency 4) Division of Biochemistry, National Institute of Health Sciences 5) Department of Chemistry, Graduate School of Science, Osaka University 6) Center for Biological Safety & Research, National Institute of Health Sciences TAT-11, Ottawa Preclinical Safety Evaluation 1) to identify an initial safe dose and subsequent dose escalation scheme in human 2) to identify potential target organs for toxicity and to examine whether such toxicity is reversible 3) to identify safety parameters for clinical monitoring We focused on both astatine 211At and actinium 225Ac as the alpha-emitters. We also discuss on initial human-dose and dose escalation, organ identification to suspect toxicity and evaluation items for monitoring upon considering physical half-lives, drug stabilities and accumulation into targeted cells. We also propose the selection method of TAT drug candidates which is satisfied with safety profile including delayed-type toxicities under our new evaluation system with histopathological examination. TAT-11, Ottawa Characteristics of Alpha Particle extremely High LET very Short Range Cell size: 10-100 mm α-particle Range: 40-90 mm Vessel β α LET: 100keV/mm Normal cells β-particle Range: 800-5000 mm LET: 0.8keV/mm Tumor cells TAT-11, Ottawa Strategy for Safety Evaluation at Preclinical Stage Problems to be solved 89Y-ibritumomab tiuxetan instead of 90Y- When stable isotope corresponding to alpha nuclide is existed, toxicity test is conducted by its labeled test compound.
    [Show full text]
  • Soluble Epcam Levels in Ascites Correlate with Positive Cytology And
    Seeber et al. BMC Cancer (2015) 15:372 DOI 10.1186/s12885-015-1371-1 RESEARCH ARTICLE Open Access Soluble EpCAM levels in ascites correlate with positive cytology and neutralize catumaxomab activity in vitro Andreas Seeber1,2,3†, Agnieszka Martowicz1,4†, Gilbert Spizzo1,2,5, Thomas Buratti6, Peter Obrist7, Dominic Fong1,5, Guenther Gastl3 and Gerold Untergasser1,2,3* Abstract Background: EpCAM is highly expressed on membrane of epithelial tumor cells and has been detected as soluble/ secreted (sEpCAM) in serum of cancer patients. In this study we established an ELISA for in vitro diagnostics to measure sEpCAM concentrations in ascites. Moreover, we evaluated the influence of sEpCAM levels on catumaxomab (antibody) - dependent cellular cytotoxicity (ADCC). Methods: Ascites specimens from cancer patients with positive (C+, n = 49) and negative (C-, n = 22) cytology and ascites of patients with liver cirrhosis (LC, n = 31) were collected. All cell-free plasma samples were analyzed for sEpCAM levels with a sandwich ELISA system established and validated by a human recombinant EpCAM standard for measurements in ascites as biological matrix. In addition, we evaluated effects of different sEpCAM concentrations on catumaxomab-dependent cell-mediated cytotoxicity (ADCC) with human peripheral blood mononuclear cells (PBMNCs) and human tumor cells. Results: Our ELISA showed a high specificity for secreted EpCAM as determined by control HEK293FT cell lines stably expressing intracellular (EpICD), extracellular (EpEX) and the full-length protein (EpCAM) as fusion proteins. The lower limit of quantification was 200 pg/mL and the linear quantification range up to 5,000 pg/mL in ascites as biological matrix.
    [Show full text]