DOCSLIB.ORG

CD74 Targeted Nanoparticles As Dexamethasone Delivery System for B Lymphoid Malignancies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
CD74 Targeted Nanoparticles As Dexamethasone Delivery System for B Lymphoid Malignancies CD74 targeted nanoparticles as Dexamethasone Delivery System for B lymphoid malignancies DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Georgia Triantafillou, MPH Integrated Biomedical Sciences Graduate Program The Ohio State University 2011 Dissertation Committee John C. Byrd, MD, advisor Natarajan Muthusamy, PhD co-advisor Robert J.Lee, PhD, co-advisor Mitch A.Phelps, PhD, co-advisor Guido Marcucci, MD committee member Susheela Tridandapani, PhD committee member Copyright page Georgia Triantafillou 2011 ABSTRACT Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia and is not curable with standard therapy. In CLL the B lymphocytes appear morphologically mature but immunologically express less mature B cell makers. Specifically, the CLL B cells co-express surface antigens including CD19, CD20, CD5, CD23. Due to nonspecific delivery of the drugs to malignant as well as normal cells, patients experience numerous side effects. Targeted drug delivery to cancer cells is a desirable goal for all anti cancer strategies. Corticosteroids have been proven to be a beneficial and well established part of CLL treatment. Dexamethasone(DEX) is frequently used in CLL therapies as well as other malignancies and antiinflammatory diseases. However, DEX nonspecifically enters all tissues inducing various toxicities to patients. Therefore, DEX treatment is often discontinued or not administered to certain patients. We aimed to deliver this efficient clinical agent via a targeted delivery vehicle and examine its effect on its target B-CLL cells. The main scope of the work presented is the creation of a sterically stable nanoparticle, an ii immunoliposome (ILP), that has DEX encapsulated in its interior and a monoclonal antibody(Mab) in its exterior targeting CLL B cells expressing the surface antigen that is recognized by the Mab. Chapter 1 is an indroduction to CLL, other B cell malignancies and Mabs as well as DEX in disease treatment and management. The chapter also presents background on targeted delivery via liposomes and immunoliposomes Chapter 2 describes CD74 as the antibody of choice to target the nanoparticle and details the evaluation of the CD74 liposome without drug in vitro . This nanoparticle was shown to be cytotoxic in vitro in cell lines and B CLL cells and mimick abilities of anti-CD74 in vivo. CD74 liposome showed high binding to malignant cells expressing the antigen and induction of leukemic cell apoptosis.This gave us a platform to continue with forming dexamethasone liposome (DEX LIP) particles . In chapter 3 a methodoly was developed to quantitate DEX in vitro and in vivo using Liquid Chromatography tandem Mass Spectometry( LC/MS-MS). The method was adjusted to measure encapsulated DEX inside the liposome in plasma. In this chapter we also describe a pharmacokinetic study in mice comparing DEX as free drug and DEX LIP. Chapter 4 focuses on the evaluation of CD74 DEX LIP in vitro and in vivo. The liposomal DEX targeted with anti- CD74 was evaluated in vitro in cell lines and primary CLL B cells and showed potent cytotoxicity . Immunoliposome efficacy was subsequently, tested in vivo in mouse model iii of lymphoid disease and showed that it significantly increased survival of diseased mice compared to controls.Overall, the study showed therapeutic effect of CD74 DEX LIP and advantage of encapsulating the drug into immunoliposome .Also another in vivo study in mice is described showing that nontargeted DEX LIP has protective effect against non desirable effects of free DEX. Chapter 5 summarizes and discusses the work presented here , as well as presents future directions steming from the studies. The work presented provides evidence that DEX immunoliposomes can have therapeutic effect in B cell malignancies with the possibility to be applied in other disease in which corticosteroids are administered. iv Dedicated to my family v ACKNOWLEDGEMENTS I express my gratitude to Dr. John C. Byrd, my advisor, who is a constant inspiration to strive for the best. I admire his diligence, his energy and his unparalleled memory. He is a brilliant physician and scientist and a great benefit to our society.I also feel privileged for working and learning in his laboratory and having access to clinical samples. I am gratefult to Dr. Natarajan Muthusamy that has continuously guided me and challenged me throughout the last five years. He is an enthusiastic scientist, an inspiring professor and at times he has stood as a father figure. Without his persistence and help this work would have never been completed. I would also like to thank Dr. Mitch Phelps for his guidance and encouragement. I had no idea about mass spectrometry when I started the work in his laboratory and now I feel like the knowledge acquired in his laboratory is invaluable. Also thank you for all the support and understanding, I always felt that I could be open about everything in our meetings.Thanks to all the lab members of the Phelps lab that have been critical in completing my work vi Also I am grateful to Dr.Robert J.Lee for introducing me to the world of nanoparticles ,guding me and giving me access to techniques and equipment to design and complete the formulations.The collaboration with Dr.Lee was crucial in completing this work I also want to thank Dr.Guido Marcucci and Dr. Susheela Tridandapani for being my committee members and helping me complete my goals. All of the individuals mentioned above have contributed into making my work truly diverse and integrated. In Dr.Byrd’s lab I want to thank all the former and present members that have worked with me because they have all helped me in some ways. In particular, I would like to thank Dr.Rosa Lapalombella for her help and her friendship that have been very supportive throughout the years. Also, Asha Ramannuni who has been a good friend. In addition, I would like to thank Frank Frissora and Carolyn Cheney for being the first people to teach me techniques in the lab and for always being supportive and helping regardless of the time requirements. I want to thank William Towns and Matt Stefanovski for making mouse work enjoyable and creating a great working environment.I will miss our conversations . I am grateful to Dr. Erin Hertlein for her help , her conversations and her support.In addition, I want to give special thanks to all the graduate students in the Byrd lab since we all had to deal with similar situations and you have all helped me in different ways. vii Special thanks to Dr. Bo Yu that has helped me with the formulations of the nanoparticles and for the great conversations. Also I am grateful for the help and great friendship of Yicheng Mao that has been crucial in completing this work. Thank you to Dr. Lapo Allinari, a remarkable physician scientist and good friend. I want to express my deepest gratitude to all the patients that have suffered from CLL and have so kindly given consent so we can improve science, achieve translational research and possibly one day beat this disease. I would like to thank all my friends around the world that have kept in touch and have supported me throughout my PhD pursuit. Your friendship is invaluable. I am always grateful to my fiance, Jon, for all the years of encouragement and support. Thank you for always believing in me. No matter what your schedule is and even when you are on call you always put me first. Your love and dedication has been a driving force to complete this work and enjoy our lives together. To my parents, thank you for raising me with good values , believing in me and helping me accomplish my dreams. You have been incredibly supportive of any decision I have ( rationally) made and even though I have been so far I always felt close to you. I could have never completed my studies if I did not know I always had you by my side. There are not enough words to express viii my love and appreciation. My sister, my nieces and nephew are a constant source of joy for me.Sometimes when everything else seemed wrong just a laughter from you was all it took to make things just fine.Vaso you are my best friend. I cannot imagine my life without you.Thank you to everyone that has helped me emotionally, physically and professionally. ix VITA September ,1982………...................................................Born-Athens, Greece 2004………………………………………………………………………BS, Biology Kent State University 2005………..............................................................................MPH, Ohio State University 2006 to present…………...……….......................................Graduate Research Associate Integrated Biomedical Graduate Sciences program, The Ohio State University x PUBLICATIONS 1.Triantafillou G, Mao Y, Hertlein E, Towns W, Stefanovski M Jarjoura D., Phelps M.A , Marcucci G, Lee, RJ, , Muthusamy N., Byrd JC . Milatuzumab Immunoliposomes as Dexamethasone Carriers to CLL B Cells Extend Survival of Diseased Mice and Minimize Drug Associated Side Effects. Blood, 2011, in preparation 2. Triantafillou G. He L, Lee, RJ, Muthusamy N., Byrd JC ,Phelps M.A. Method for detection of encapsulated liposomal dexamethasone in mice using liquid chromatography tandem mass spectrometry. J.Chrom.B ,2011, in preparation 3. Chan KK, Liu Z, Xie Z, Chiu M, Wang H, Chen P, Dunkerson S, Chiu M, Liu S, Triantafillou G, Garzon R, Croce CM, Byrd JC, Muthusamy N, Marcucci G. A Novel Ultrasensitive Hybridization-Based ELISA Method for 2- Methoxyphosphorothiolate MicroRNAs and Its In vitro and In vivo Application. AAPS J. 2010 Dec;12(4):556-68. 4. Hertlein E*, Triantafillou G*, Sass EJ, Hessler JD, Zhang X, Jarjoura D, Lucas DM, Muthusamy N, Goldenberg DM, Lee RJ, Byrd JC. Milatuzumab immunoliposomes induce cell death in CLL by promoting accumulation of CD74 on the surface of B cells.
Load more

Recommended publications
  • 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]
  • Single-Cell RNA Sequencing Identifies Candidate Renal
    BASIC RESEARCH www.jasn.org Single-Cell RNA Sequencing Identifies Candidate Renal Resident Macrophage Gene Expression Signatures across Species Kurt A. Zimmerman,1 Melissa R. Bentley,1 Jeremie M. Lever ,2 Zhang Li,1 David K. Crossman,3 Cheng Jack Song,1 Shanrun Liu,4 Michael R. Crowley,3 James F. George,5 Michal Mrug,2,6 and Bradley K. Yoder1 1Department of Cell, Developmental, and Integrative Biology, 2Division of Nephrology, Department of Medicine, 3Department of Genetics, 4Department of Biochemistry and Molecular Genetics, and 5Division of Cardiothoracic Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama; and 6Department of Veterans Affairs Medical Center, Birmingham, Alabama ABSTRACT Background Resident macrophages regulate homeostatic and disease processes in multiple tissues, in- cluding the kidney. Despite having well defined markers to identify these cells in mice, technical limita- tions have prevented identification of a similar cell type across species. The inability to identify resident macrophage populations across species hinders the translation of data obtained from animal model to human patients. Methods As an entry point to determine novel markers that could identify resident macrophages across species, we performed single-cell RNA sequencing (scRNAseq) analysis of all T and B cell–negative CD45+ innate immune cells in mouse, rat, pig, and human kidney tissue. Results We identified genes with enriched expression in mouse renal resident macrophages that were also present in candidate resident macrophage populations across species. Using the scRNAseq data, we defined a novel set of possible cell surface markers (Cd74 and Cd81) for these candidate kidney resident macrophages. We confirmed, using parabiosis and flow cytometry, that these proteins are indeed enriched in mouse resident macrophages.
    [Show full text]
  • Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins
    Send Orders for Reprints to [email protected] Recent Patents on Anti-Cancer Drug Discovery, 2014, 9, 35-65 35 Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins Franco Dosio1,*, Barbara Stella1, Sofia Cerioni1, Daniela Gastaldi2 and Silvia Arpicco1 1Dipartimento di Scienza e Tecnologia del Farmaco, University of Torino, Torino, I-10125, Italy; 2Dipartimento di Bio- tecnologie Molecolari e Scienze per la Salute, University of Torino, Torino, I-10125, Italy Received: December 13, 2012; Accepted: February 21, 2013; Revised: March 7, 2013 Abstract: Antibody-delivered drugs and toxins are poised to become important classes of cancer therapeutics. These bio- pharmaceuticals have potential in this field, as they can selectively direct highly potent cytotoxic agents to cancer cells that present tumor-associated surface markers, thereby minimizing systemic toxicity. The activity of some conjugates is of particular interest receiving increasing attention, thanks to very promising clinical trial results in hematologic cancers. Over twenty antibody-drug conjugates and eight immunotoxins in clinical trials as well as some recently approved drugs, support the maturity of this approach. This review focuses on recent advances in the development of these two classes of biopharmaceuticals: conventional toxins and anticancer drugs, together with their mechanisms of action. The processes of conjugation and purification, as reported in the literature and in several patents, are discussed and the most relevant results in clinical trials are listed. Innovative technologies and preliminary results on novel drugs and toxins, as reported in the literature and in recently-published patents (up to February 2013) are lastly examined. Keywords: Antibody drug conjugate, anticancer agents, auristatins immunotoxin, calicheamicins, cross-linkers, duocarmycins, maytansinoids.
    [Show full text]
  • Single-Cell RNA Sequencing Demonstrates the Molecular and Cellular Reprogramming of Metastatic Lung Adenocarcinoma
    ARTICLE https://doi.org/10.1038/s41467-020-16164-1 OPEN Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma Nayoung Kim 1,2,3,13, Hong Kwan Kim4,13, Kyungjong Lee 5,13, Yourae Hong 1,6, Jong Ho Cho4, Jung Won Choi7, Jung-Il Lee7, Yeon-Lim Suh8,BoMiKu9, Hye Hyeon Eum 1,2,3, Soyean Choi 1, Yoon-La Choi6,10,11, Je-Gun Joung1, Woong-Yang Park 1,2,6, Hyun Ae Jung12, Jong-Mu Sun12, Se-Hoon Lee12, ✉ ✉ Jin Seok Ahn12, Keunchil Park12, Myung-Ju Ahn 12 & Hae-Ock Lee 1,2,3,6 1234567890():,; Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell tran- scriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions. 1 Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea.
    [Show full text]
  • CD29 Identifies IFN-Γ–Producing Human CD8+ T Cells With
    + CD29 identifies IFN-γ–producing human CD8 T cells with an increased cytotoxic potential Benoît P. Nicoleta,b, Aurélie Guislaina,b, Floris P. J. van Alphenc, Raquel Gomez-Eerlandd, Ton N. M. Schumacherd, Maartje van den Biggelaarc,e, and Monika C. Wolkersa,b,1 aDepartment of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, The Netherlands; bLandsteiner Laboratory, Oncode Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; cDepartment of Research Facilities, Sanquin Research, 1066 CX Amsterdam, The Netherlands; dDivision of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and eDepartment of Molecular and Cellular Haemostasis, Sanquin Research, 1066 CX Amsterdam, The Netherlands Edited by Anjana Rao, La Jolla Institute for Allergy and Immunology, La Jolla, CA, and approved February 12, 2020 (received for review August 12, 2019) Cytotoxic CD8+ T cells can effectively kill target cells by producing therefore developed a protocol that allowed for efficient iso- cytokines, chemokines, and granzymes. Expression of these effector lation of RNA and protein from fluorescence-activated cell molecules is however highly divergent, and tools that identify and sorting (FACS)-sorted fixed T cells after intracellular cytokine + preselect CD8 T cells with a cytotoxic expression profile are lacking. staining. With this top-down approach, we performed an un- + Human CD8 T cells can be divided into IFN-γ– and IL-2–producing biased RNA-sequencing (RNA-seq) and mass spectrometry cells. Unbiased transcriptomics and proteomics analysis on cytokine- γ– – + + (MS) analyses on IFN- and IL-2 producing primary human producing fixed CD8 T cells revealed that IL-2 cells produce helper + + + CD8 Tcells.
    [Show full text]
  • Antibody Drug Conjugates in Lymphoma
    Review: Clinical Trial Outcomes Nathwani & Chen Antibody drug conjugates in lymphoma 6 Review: Clinical Trial Outcomes Antibody drug conjugates in lymphoma Clin. Investig. (Lond.) Antibody drug conjugates (ADCs) are comprised of monoclonal antibodies physically Nitya Nathwani1 & Robert linked to cytotoxic molecules. They expressly target cancer cells by delivering cytotoxic Chen*,1 agents to cells displaying specific antigens, and minimize damage to normal tissue. The 1Department of Hematology & Hematopoietic Cell Transplantation, City efficacy and tolerability of these agents are primarily determined by the target antigen, of Hope, Duarte, CA, USA the cytotoxic agent and the linker connecting the cytotoxic agent to the monoclonal *Author for correspondence: antibody. Following advances in technology, clinical trials have demonstrated greater Tel.: +626 256 4673 (ext. 65298) efficacy for ADCs compared with the corresponding naked monoclonal antibodies. Fax: +626 301 8116 This review summarizes the features of current clinically active ADCs in lymphoma and [email protected] emphasizes recent clinical data elucidating the benefit of antibody-directed delivery of cytotoxic agents to tumor cells. Keywords: antibody drug conjugates • lymphoma • monoclonal antibodies Lymphoma is the most common hematologic concentration and poor performance status malignancy, and is subdivided into two main are adverse prognostic factors. SEER (Sur- types: Hodgkin lymphoma (HL) and non- veillance, Epidemiology and End Results) Hodgkin lymphoma (NHL). In the United data from the National Cancer Institute, States, there are an estimated 731,277 people 2013 has revealed a significant improvement 10.4155/CLI.14.73 living with or in remission from lymphoma. in survival rates in this group of diseases in In 2013, there were an estimated 79,030 new the last four decades.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,161,992 B2 Jefferies Et Al
    US009 161992B2 (12) United States Patent (10) Patent No.: US 9,161,992 B2 Jefferies et al. (45) Date of Patent: Oct. 20, 2015 (54) P97 FRAGMENTS WITH TRANSFER 4,683.202 A 7, 1987 Mullis ACTIVITY 4,704,362 A 11/1987 Itakura et al. 4,766,075 A 8, 1988 Goeddeletal. (71) Applicant: biosis Technologies, Inc., Richmond 4,800,1594,784.950 A 11/19881/1989 MullisHagen et al. (CA) 4,801,542 A 1/1989 Murray et al. 4.866,042 A 9, 1989 Neuwelt (72) Inventors: Wilfred Jefferies, South Surrey (CA); 4,935,349 A 6/1990 McKnight et al. Mei Mei Tian, Coquitlam (CA): 4.946,778 A 8, 1990 Ladner et al. Timothy Vitalis, Vancouver (CA) 5,091,513 A 2f1992 Huston et al. 5,132,405 A 7, 1992 Huston et al. (73) Assignee: biOasis Technologies, Inc., British 5, 186,941 A 2f1993 Callahan et al. Columbia (CA) 5,672,683 A 9, 1997 Friden et al. 5,677,171 A 10, 1997 Hudziak et al. c - r 5,720,937 A 2f1998 Hudziak et al. (*) Notice: Subject to any disclaimer, the term of this 5,720,954. A 2f1998 Hudziak et al. patent is extended or adjusted under 35 5,725,856 A 3, 1998 Hudziak et al. U.S.C. 154(b) by 0 days. 5,770,195 A 6/1998 Hudziak et al. 5,772,997 A 6/1998 Hudziak et al. (21) Appl. No.: 14/226,506 5,844,093 A 12/1998 Kettleborough et al. 5,962,012 A 10, 1999 Lin et al.
    [Show full text]
  • The Chemokine System in Innate Immunity
    Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press The Chemokine System in Innate Immunity Caroline L. Sokol and Andrew D. Luster Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 Correspondence: [email protected] Chemokines are chemotactic cytokines that control the migration and positioning of immune cells in tissues and are critical for the function of the innate immune system. Chemokines control the release of innate immune cells from the bone marrow during homeostasis as well as in response to infection and inflammation. Theyalso recruit innate immune effectors out of the circulation and into the tissue where, in collaboration with other chemoattractants, they guide these cells to the very sites of tissue injury. Chemokine function is also critical for the positioning of innate immune sentinels in peripheral tissue and then, following innate immune activation, guiding these activated cells to the draining lymph node to initiate and imprint an adaptive immune response. In this review, we will highlight recent advances in understanding how chemokine function regulates the movement and positioning of innate immune cells at homeostasis and in response to acute inflammation, and then we will review how chemokine-mediated innate immune cell trafficking plays an essential role in linking the innate and adaptive immune responses. hemokines are chemotactic cytokines that with emphasis placed on its role in the innate Ccontrol cell migration and cell positioning immune system. throughout development, homeostasis, and in- flammation. The immune system, which is de- pendent on the coordinated migration of cells, CHEMOKINES AND CHEMOKINE RECEPTORS is particularly dependent on chemokines for its function.
    [Show full text]
  • Potent Cytotoxicity of Anti-CD20/CD74 Bispecific Antibodies in Mantle Cell and Other Lymphomas
    From www.bloodjournal.org by guest on September 11, 2016. For personal use only. LYMPHOID NEOPLASIA Dual-targeting immunotherapy of lymphoma: potent cytotoxicity of anti-CD20/CD74 bispecific antibodies in mantle cell and other lymphomas Pankaj Gupta,1 David M. Goldenberg,2 Edmund A. Rossi,3 Thomas M. Cardillo,1 John C. Byrd,4 Natarajan Muthusamy,4 Richard R. Furman,5 and Chien-Hsing Chang1,3 1Immunomedics Inc, Morris Plains, NJ; 2Garden State Cancer Center, Center for Molecular Medicine and Immunology, Morris Plains, NJ; 3IBC Pharmaceuticals, Morris Plains, NJ; 4Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH; and 5Weill-Cornell Medical College, New York, NY We describe the use of novel bispecific more potent than their parental mAbs in cells and normal B cells from whole blood hexavalent Abs (HexAbs) to enhance anti- vitro. The juxtaposition of CD20 and CD74 ex vivo and significantly extended the sur- cancer immunotherapy. Two bispecific on MCL cells by the HexAbs resulted in vival of nude mice bearing MCL xenografts HexAbs [IgG-(Fab)4 constructed from vel- homotypic adhesion and triggered intra- in a dose-dependent manner, thus indicat- tuzumab (anti-CD20 IgG) and milatu- cellular changes that include loss of mito- ing stability and antitumor activity in vivo. zumab (anti-CD74 IgG)] show enhanced chondrial transmembrane potential, pro- Such bispecific HexAbs may constitute a cytotoxicity in mantle cell lymphoma duction of reactive oxygen species, rapid new class of therapeutic agents for im- (MCL) and other lymphoma/leukemia cell and sustained phosphorylation of ERKs proved cancer immunotherapy, as shown lines, as well as patient tumor samples, and JNK, down-regulation of pAkt and here for MCL and other CD20؉/CD74؉ without a crosslinking Ab, compared with Bcl-xL, actin reorganization, and lyso- malignancies.
    [Show full text]
  • Cell Survival in a Pathway Induced by CD74 Factor/Scatter Factor
    c-Met and Its Ligand Hepatocyte Growth Factor/Scatter Factor Regulate Mature B Cell Survival in a Pathway Induced by CD74 This information is current as Maya Gordin, Melania Tesio, Sivan Cohen, Yael Gore, Frida of September 28, 2021. Lantner, Lin Leng, Richard Bucala and Idit Shachar J Immunol published online 16 July 2010 http://www.jimmunol.org/content/early/2010/07/16/jimmun ol.0902566 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/07/16/jimmunol.090256 Material 6.DC1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 28, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 16, 2010, doi:10.4049/jimmunol.0902566 The Journal of Immunology c-Met and Its Ligand Hepatocyte Growth Factor/Scatter Factor Regulate Mature B Cell Survival in a Pathway Induced by CD74 Maya Gordin,* Melania Tesio,* Sivan Cohen,* Yael Gore,* Frida Lantner,* Lin Leng,† Richard Bucala,† and Idit Shachar* The signals regulating the survival of mature splenic B cells have become a major focus in recent studies of B cell immunology.
    [Show full text]
  • Monoclonal Antibodies in Myeloma
    Monoclonal Antibodies in Myeloma Pia Sondergeld, PhD, Niels W. C. J. van de Donk, MD, PhD, Paul G. Richardson, MD, and Torben Plesner, MD Dr Sondergeld is a medical student at the Abstract: The development of monoclonal antibodies (mAbs) for University of Giessen in Giessen, Germany. the treatment of disease goes back to the vision of Paul Ehrlich in Dr van de Donk is a hematologist in the the late 19th century; however, the first successful treatment with department of hematology at the VU a mAb was not until 1982, in a lymphoma patient. In multiple University Medical Center in Amsterdam, The Netherlands. Dr Richardson is the R.J. myeloma, mAbs are a very recent and exciting addition to the Corman Professor of Medicine at Harvard therapeutic armamentarium. The incorporation of mAbs into Medical School, and clinical program current treatment strategies is hoped to enable more effective and leader and director of clinical research targeted treatment, resulting in improved outcomes for patients. at the Jerome Lipper Myeloma Center, A number of targets have been identified, including molecules division of hematologic malignancy, depart- on the surface of the myeloma cell and components of the bone ment of medical oncology, Dana-Farber Cancer Institute in Boston, MA. Dr Plesner marrow microenvironment. Our review focuses on a small number is a professor of hematology at the Univer- of promising mAbs directed against molecules on the surface of sity of Southern Denmark and a consultant myeloma cells, including CS1 (elotuzumab), CD38 (daratumumab, in the department of hematology at Vejle SAR650984, MOR03087), CD56 (lorvotuzumab mertansine), and Hospital in Vejle, Denmark.
    [Show full text]
  • CD74 Interferes with the Expression of Fas Receptor on the Surface Of
    Berkova et al. Journal of Experimental & Clinical Cancer Research 2014, 33:80 http://www.jeccr.com/content/33/1/80 RESEARCH Open Access CD74 interferes with the expression of fas receptor on the surface of lymphoma cells Zuzana Berkova1, Shu Wang1, Xue Ao1, Jillian F Wise1, Frank K Braun1, Abdol H Rezaeian1, Lalit Sehgal1, David M Goldenberg2,3 and Felipe Samaniego1* Abstract Background: Resistance to Fas-mediated apoptosis limits the efficacy of currently available chemotherapy regimens. We identified CD74, which is known to be overexpressed in hematological malignancies, as one of the factors interfering with Fas-mediated apoptosis. Methods: CD74 expression was suppressed in human B-lymphoma cell lines, BJAB and Raji, by either transduction with lentivirus particles or transfection with episomal vector, both encoding CD74-specific shRNAs or non-target shRNA. Effect of CD74 expression on Fas signaling was evaluated by comparing survival of mice hydrodynamically transfected with vector encoding full-length CD74 or empty vector. Sensitivity of cells with suppressed CD74 expression to FasL, edelfosine, doxorubicin, and a humanized CD74-specific antibody, milatuzumab, was evaluatedbyflowcytometryandcomparedto control cells. Fas signaling in response to FasL stimulation and the expression of Fas signaling components were evaluated by Western blot. Surface expression of Fas was detected by flow cytometry. Results: We determined that cells with suppressed CD74 are more sensitive to FasL-induced apoptosis and Fas signaling-dependent chemotherapies, edelfosine and doxorubicin, than control CD74-expressing cells. On the other hand, expression of full-length CD74 in livers protected the mice from a lethal challenge with agonistic anti-Fas antibody Jo2. A detailed analysis of Fas signaling in cells lacking CD74 and control cells revealed increased cleavage/activation of pro-caspase-8 and corresponding enhancement of caspase-3 activation in the absence of CD74, suggesting that CD74 affects the immediate early steps in Fas signaling at the plasma membrane.
    [Show full text]