Putative Markers for Thedetection of Breast Carcinoma Cells in Blood
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R&D Day for Investors and Analysts
R&D Day for Investors and Analysts November 16, 2020 Seagen 2020 R&D Day Clay Siegall, Ph.D. Roger Dansey, M.D. Nancy Whiting, Pharm.D Megan O’Meara, M.D. Shyra Gardai, Ph.D. President & Chief Chief Medical Officer EVP, Corporate Strategy VP, Early Stage Executive Director, Executive Officer Alliances and Development Immunology Communications 2 Forward-Looking Statements Certain of the statements made in this presentation are forward looking, such as those, among others, relating to the Company’s potential to achieve the noted development and regulatory milestones in 2021 and in future periods; anticipated activities related to the Company’s planned and ongoing clinical trials; the potential for the Company’s clinical trials to support further development, regulatory submissions and potential marketing approvals in the U.S. and other countries; the opportunities for, and the therapeutic and commercial potential of ADCETRIS, PADCEV, TUKYSA, tisotumab vedotin and ladiratuzumab vedotin and the Company’s other product candidates and those of its licensees and collaborators; the potential to submit a BLA for accelerated approval of tisotumab vedotin; the potential for data from the EV-301 and EV-201 cohort 2 clinical trials to support additional regulatory approvals of PADCEV; the potential for the approval of TUKYSA by the EMA; the therapeutic potential of the Company’s SEA technology and of the Company’s early stage pipeline agents including SGN-B6A, SGN-STNV, SGN-CD228A, SEA-CD40, SEA-TGT, SEA-BCMA and SEA-CD70; as well as other statements that are not historical fact. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. -
Quantitation of the Number of Molecules of Glycophorins C and D on Normal Red Blood Cells Using Radioiodinatedfab Fragments of Monoclonal Antibodies
Quantitation of the Number of Molecules of Glycophorins C and D on Normal Red Blood Cells Using RadioiodinatedFab Fragments of Monoclonal Antibodies By Jon Smythe, Brigitte Gardner, andDavid J. Anstee Two rat monoclonal antibodies (BRAC 1 and BRAC 1 1 ) cytes. Fabfragments of BRAC 1 1 and ERIC 10 gave values have been produced. BRAC 1 recognizes an epitope com- of 143,000 molecules GPC per red blood cell (RBC). Fab mon to the human erythrocyte membrane glycoproteins fragments of BRAC1 gave 225,000 molecules of GPC and glycophorin C (GPC) and glycophorin D (GPD). BRAC 11 GPD per RBC. These results indicate that GPC and GPD is specific for GPC. Fabfragments of these antibodies and together are sufficiently abundantto provide membrane at- BRlC 10, a murine monoclonal anti-GPC,were radioiodin- tachment sites for all ofthe protein 4.1 in normal RBCs. ated and used in quantitative binding assays to measure 0 1994 by The American Societyof Hematology. the number of GPC and GPD molecules on normal erythro- HE SHAPE AND deformability of the mature human (200,000)" and those reported for GPC (50,000).7 This nu- Downloaded from http://ashpublications.org/blood/article-pdf/83/6/1668/612763/1668.pdf by guest on 24 September 2021 T erythrocyte is controlled by a flexible two-dimensional merical differencehas led to the suggestion that a significant lattice of proteins, which together comprise the membrane proportion of protein 4.1 in normal erythrocyte membranes skeleton.' The major components of the skeleton are spec- must be bound to sites other than GPC and GPD.3 The trin, actin, ankyrin, and protein 4.1. -
CAR- T Cell Immunotherapies
CAR T Therapy Current Status Future Challenges Introduction Basics of CAR T Therapy Cytotoxic T Lymphocytes are Specific and Potent Effector Cells Ultrastructure of CTL-mediated apoptosis The CTL protrudes deeply into cytoplasm of melanoma cell 3 Peter Groscurth, and Luis Filgueira Physiology 1998;13:17-21 What is CAR T Therapy? • CAR T therapy is the name given to chimeric antigen receptor (CAR) genetically modified T cells that are designed to recognize specific antigens on tumor cells resulting in their activation and proliferation eventually resulting in significant and durable destruction of malignant cells • CAR T cells are considered “a living drug” since they tend to persist for long periods of time • CAR T cells are generally created from the patients own blood cells although this technology is evolving to develop “off the shelf” CAR T cells 4 CAR T cells: Mechanism of Action T cell Tumor cell CAR enables T cell to Expression of recognize tumor cell antigen CAR Viral DNA Insertion Antigen Tumor cell apoptosis CAR T cells multiply and release cytokines 5 Chimeric Antigen Receptors Antigen binding VH Antigen Binding Domain domain scFv Single-chain variable fragment (scFv) bypasses MHC antigen presentation, allowing direct activation of T cell by cancer cell antigens VL Hinge region Hinge region Essential for optimal antigen binding Costimulatory Domain: CD28 or 4-1BB Costimulatory Enhances proliferation, cytotoxicity and domain persistence of CAR T cells Activation Domains Signaling Domain: CD3-zeta chain CD3-zeta chain Proliferation -
Galectin-3 Promotes Aβ Oligomerization and Aβ Toxicity in a Mouse Model of Alzheimer’S Disease
Cell Death & Differentiation (2020) 27:192–209 https://doi.org/10.1038/s41418-019-0348-z ARTICLE Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer’s disease 1,2 1,3 1 1 1,2 4,5 Chih-Chieh Tao ● Kuang-Min Cheng ● Yun-Li Ma ● Wei-Lun Hsu ● Yan-Chu Chen ● Jong-Ling Fuh ● 4,6,7 3 1,2,3 Wei-Ju Lee ● Chih-Chang Chao ● Eminy H. Y. Lee Received: 1 October 2018 / Revised: 13 April 2019 / Accepted: 2 May 2019 / Published online: 24 May 2019 © ADMC Associazione Differenziamento e Morte Cellulare 2019. This article is published with open access Abstract Amyloid-β (Aβ) oligomers largely initiate the cascade underlying the pathology of Alzheimer’s disease (AD). Galectin-3 (Gal-3), which is a member of the galectin protein family, promotes inflammatory responses and enhances the homotypic aggregation of cancer cells. Here, we examined the role and action mechanism of Gal-3 in Aβ oligomerization and Aβ toxicities. Wild-type (WT) and Gal-3-knockout (KO) mice, APP/PS1;WT mice, APP/PS1;Gal-3+/− mice and brain tissues from normal subjects and AD patients were used. We found that Aβ oligomerization is reduced in Gal-3 KO mice injected with Aβ, whereas overexpression of Gal-3 enhances Aβ oligomerization in the hippocampi of Aβ-injected mice. Gal-3 expression shows an age-dependent increase that parallels endogenous Aβ oligomerization in APP/PS1 mice. Moreover, Aβ oligomerization, Iba1 expression, GFAP expression and amyloid plaque accumulation are reduced in APP/ PS1;Gal-3+/− mice compared with APP/PS1;WT mice. -
MUC1-C Oncoprotein As a Target in Breast Cancer: Activation of Signaling Pathways and Therapeutic Approaches
Oncogene (2013) 32, 1073–1081 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches DW Kufe Mucin 1 (MUC1) is a heterodimeric protein formed by two subunits that is aberrantly overexpressed in human breast cancer and other cancers. Historically, much of the early work on MUC1 focused on the shed mucin subunit. However, more recent studies have been directed at the transmembrane MUC1-C-terminal subunit (MUC1-C) that functions as an oncoprotein. MUC1-C interacts with EGFR (epidermal growth factor receptor), ErbB2 and other receptor tyrosine kinases at the cell membrane and contributes to activation of the PI3K-AKT and mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathways. MUC1-C also localizes to the nucleus where it activates the Wnt/b-catenin, signal transducer and activator of transcription (STAT) and NF (nuclear factor)-kB RelA pathways. These findings and the demonstration that MUC1-C is a druggable target have provided the experimental basis for designing agents that block MUC1-C function. Notably, inhibitors of the MUC1-C subunit have been developed that directly block its oncogenic function and induce death of breast cancer cells in vitro and in xenograft models. On the basis of these findings, a first-in-class MUC1-C inhibitor has entered phase I evaluation as a potential agent for the treatment of patients with breast cancers who express this oncoprotein. Oncogene (2013) 32, 1073–1081; doi:10.1038/onc.2012.158; published online 14 May 2012 Keywords: MUC1; breast cancer; oncoprotein; signaling pathways; targeted agents INTRODUCTION In breast tumor cells with loss of apical–basal polarity, the The mucin (MUC) family of high-molecular-weight glycoproteins MUC1-N/MUC1-C complex is found over the entire cell mem- 2 8 evolved in metazoans to provide protection for epithelial cell brane. -
Membrane-Bound Mucins: the Mechanistic Basis for Alterations in the Growth and Survival of Cancer Cells
Oncogene (2010) 29, 2893–2904 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc REVIEW Membrane-bound mucins: the mechanistic basis for alterations in the growth and survival of cancer cells S Bafna1, S Kaur1 and SK Batra1,2 1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA and 2Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA Mucins (MUC) are high molecular weight O-linked tethered mucins are quite distinct from the classic glycoproteins whose primary functions are to hydrate, extracellular complex mucins forming the mucous layers protect, and lubricate the epithelial luminal surfaces of the of the gastrointestinal and respiratory tracts. These ducts within the human body. The MUC family is epithelial membrane-tethered mucins are the transmem- comprised of large secreted gel forming and transmem- brane (TM) molecules, expressed by most glandular and brane (TM) mucins. MUC1, MUC4, and MUC16 are the ductal epithelial cells (Taylor-Papadimitriou et al., well-characterized TM mucins and have been shown to be 1999). Several TM mucins (MUC1, MUC3A, MUC3B, aberrantly overexpressed in various malignancies includ- MUC4, MUC 12, MUC13, MUC15, MUC16, MUC17, ing cystic fibrosis, asthma, and cancer. Recent studies MUC20, and MUC21) (human mucins are designated have uncovered the unique roles of these mucins in the as MUC, whereas other species mucins are designated as pathogenesis of cancer. These mucins possess specific Muc) have been identified so far (Moniaux et al., 2001; domains that can make complex associations with various Chaturvedi et al., 2008a; Itoh et al., 2008). -
(EMA) Is Preferentially Expressed by ALK Positive Anaplastic Large Cell Lymphoma, in The
J Clin Pathol 2001;54:933–939 933 MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly J Clin Pathol: first published as on 1 December 2001. Downloaded from hypoglycosylated form R L ten Berge*, F G M Snijdewint*, S von MensdorV-Pouilly, RJJPoort-Keesom, J J Oudejans, J W R Meijer, R Willemze, J Hilgers, CJLMMeijer Abstract 30–50% of cases, a chromosomal aberration Aims—To investigate whether MUC1 such as the t(2;5)(p23;q35) translocation gives mucin, a high molecular weight trans- rise to expression of the anaplastic lymphoma membrane glycoprotein, also known as kinase (ALK) protein,2 identifying a subgroup epithelial membrane antigen (EMA), dif- of patients with systemic ALCL with excellent fers in its expression and degree of glyco- prognosis.3–6 ALK expression seems specific for sylation between anaplastic large cell systemic nodal ALCL; it is not found in classic lymphoma (ALCL) and classic Hodgkin’s Hodgkin’s disease (HD)7–11 or primary cutane- disease (HD), and whether MUC1 ous ALCL.7101213Morphologically, these lym- immunostaining can be used to diVerenti- phomas may closely resemble systemic ALCL, ate between CD30 positive large cell being also characterised by CD30 positive lymphomas. tumour cells with abundant cytoplasm, large Methods/Results—Using five diVerent irregular nuclei, and a prominent single monoclonal antibodies (E29/anti-EMA, nucleolus or multiple nucleoli.1 Clinically, DF3, 139H2, VU-4H5, and SM3) that however, classic HD and primary cutaneous distinguish between various MUC1 glyco- ALCL have a more favourable prognosis than 12 14–16 Department of forms, high MUC1 expression (50–95% of ALK negative systemic ALCL. -
Epithelial Mucin-1 (MUCI) Expression and MA5 Anti-MUC1 Monoclonal Antibody Targeting in Multiple Myeloma I
Vol. 5, 3065s-3072s, October 1999 (Suppl.) Clinical Cancer Research 3065s Epithelial Mucin-1 (MUCI) Expression and MA5 Anti-MUC1 Monoclonal Antibody Targeting in Multiple Myeloma I J. Burton, z D. Mishina, T. Cardillo, K. Lew, cGy/mCi of injected dose compared with 3099 cGy/mCi of A. Rubin, D. M. Goldenberg, and D. V. Gold tumor-absorbed dose delivered by nonspecific antibody. Garden State Cancer Center, Belleville, New Jersey 07109 [J. B., D. M., T. C., K. L., D. M. G., D. V. G.], and St. Joseph's Hospital and Introduction Medical Center, Paterson, New Jersey 07503 [A. R.] MM 3 is a B-cell malignancy that appears to result from the transformation and monoclonal expansion of a cell with char- acteristics of a plasma cell, i.e., a terminally differentiated B cell Abstract (1, 2). The expression by MM cells of certain non-B-cell anti- Multiple myeloma (MM) is the second most common gens also raises the possibility of the transformation of an hematological cancer in the United States. It is typically earlier, more multipotent lymphoid precursor cell. As with nor- incurable, even with myeloablative chemotherapy and stem- mal plasma cells, this degree of terminal differentiation is as- cell transplantation. The epithelial mucin-1 (MUC1) glyco- sociated with the complete or partial loss of certain B-cell- protein is expressed by normal and malignant epithelial cells associated antigens, such as surface immunoglobulin and CDs but has also been shown to be expressed by MM cells. MUC1 19-22 (CD19 is expressed on normal plasma cells; Ref. 3). -
Syndecan-1 Depletion Has a Differential Impact on Hyaluronic Acid Metabolism and Tumor Cell Behavior in Luminal and Triple-Negative Breast Cancer Cells
International Journal of Molecular Sciences Article Syndecan-1 Depletion Has a Differential Impact on Hyaluronic Acid Metabolism and Tumor Cell Behavior in Luminal and Triple-Negative Breast Cancer Cells Sofía Valla 1,2 , Nourhan Hassan 3 , Daiana Luján Vitale 2,4 , Daniela Madanes 5, Fiorella Mercedes Spinelli 2,4, Felipe C. O. B. Teixeira 3, Burkhard Greve 6 , Nancy Adriana Espinoza-Sánchez 3,6 , Carolina Cristina 1,2, Laura Alaniz 2,4,* and Martin Götte 3,* 1 Laboratorio de Fisiopatología de la Hipófisis, Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Libertad 555, Junín (B6000), Buenos Aires 2700, Argentina; sofi[email protected] (S.V.); [email protected] (C.C.) 2 Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CITNOBA, UNNOBA-UNSAdA-CONICET), Buenos Aires 2700, Argentina; [email protected] (D.L.V.); fi[email protected] (F.M.S.) 3 Department of Gynecology and Obstetrics, Münster University Hospital, Domagkstrasse 11, 48149 Münster, Germany; [email protected] (N.H.); [email protected] (F.C.O.B.T.); [email protected] (N.A.E.-S.) 4 Laboratorio de Microambiente Tumoral, Centro de Investigaciones Básicas y Aplicadas (CIBA), Universidad Nacional del Noroeste de la Provincia de Buenos Aires (UNNOBA), Libertad 555, Junín (B6000), Citation: Valla, S.; Hassan, N.; Vitale, Buenos Aires 2700, Argentina 5 Laboratorio de Inmunología de la Reproducción, Instituto de Biología y Medicina Experimental—Consejo D.L.; Madanes, D.; Spinelli, F.M.; Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Vuelta de Obligado 2490, Ciudad Teixeira, F.C.O.B.; Greve, B.; Autónoma de Buenos Aires (C1428ADN), Buenos Aires 2700, Argentina; [email protected] Espinoza-Sánchez, N.A.; Cristina, C.; 6 Department of Radiotherapy—Radiooncology, Münster University Hospital, Robert-Koch-Str. -
The CD44-Initiated Pathway of T-Cell Extravasation Uses VLA-4 but Not LFA-1 for Firm Adhesion
The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion Mark H. Siegelman, … , Diana Stanescu, Pila Estess J Clin Invest. 2000;105(5):683-691. https://doi.org/10.1172/JCI8692. Article Leukocytes extravasate from the blood in response to physiologic or pathologic demands by means of complementary ligand interactions between leukocytes and endothelial cells. The multistep model of leukocyte extravasation involves an initial transient interaction (“rolling” adhesion), followed by secondary (firm) adhesion. We recently showed that binding of CD44 on activated T lymphocytes to endothelial hyaluronan (HA) mediates a primary adhesive interaction under shear stress, permitting extravasation at sites of inflammation. The mechanism for subsequent firm adhesion has not been elucidated. Here we demonstrate that the integrin VLA-4 is used in secondary adhesion after CD44-mediated primary adhesion of human and mouse T cells in vitro, and by mouse T cells in an in vivo model. We show that clonal cell lines and polyclonally activated normal T cells roll under physiologic shear forces on hyaluronate and require VCAM-1, but not ICAM-1, as ligand for subsequent firm adhesion. This firm adhesion is also VLA-4 dependent, as shown by antibody inhibition. Moreover, in vivo short-term homing experiments in a model dependent on CD44 and HA demonstrate that superantigen-activated T cells require VLA-4, but not LFA-1, for entry into an inflamed peritoneal site. Thus, extravasation of activated T cells initiated by CD44 binding to HA depends upon VLA-4–mediated firm adhesion, which may explain the frequent association of these adhesion receptors with diverse chronic inflammatory processes. -
Characterization and Function of Medium and Large Extracellular
bioRxiv preprint doi: https://doi.org/10.1101/623553; this version posted April 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Characterization and function of medium and large extracellular vesicles from plasma and urine by surface antigens and Annexin V Ko Igami1, 2, 3, Takeshi Uchiumi1*, Saori Ueda1, Kazuyuki Kamioka2, 4, Daiki Setoyama1, Kazuhito Gotoh1, Masaru Akimoto1, Shinya Matsumoto1 and Dongchon Kang1 1Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 2Kyushu Pro Search Limited Liability Partnership, 4-1, Kyudaishimmachi, Nishi- ku, Fukuoka, 819-0388, Japan. 3Business Management Division, Clinical Laboratory Business Segment, LSI Medience Corporation, 13-4, Uchikanda 1-chome, Chiyoda-ku, Tokyo, 101-8517, Japan. 4Medical Solutions Department, LSI Medience Corporation, 3- 30-1, Shimura, Itabashi-ku, Tokyo, 174-8555, Japan. Running title: Characterization of plasma and urine extracellular microvesicles Keywords: microvesicle, cell-derived microvesicle, peptidase, plasma, urine *Correspondence to: Takeshi Uchiumi, Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel: (+81) 92-642-5750; Fax: (+81) 92-642-5772 1 bioRxiv preprint doi: https://doi.org/10.1101/623553; this version posted April 30, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. -
Regulation of Cellular Adhesion Molecule Expression in Murine Oocytes, Peri-Implantation and Post-Implantation Embryos
Cell Research (2002); 12(5-6):373-383 http://www.cell-research.com Regulation of cellular adhesion molecule expression in murine oocytes, peri-implantation and post-implantation embryos 1,2 1,2 2 1, DAVID P LU , LINA TIAN , CHRIS O NEILL , NICHOLAS JC KING * 1Department of Pathology, University of Sydney, NSW 2006 Australia 2Human Reproduction Unit, Department of Physiology, University of Sydney, Royal North Shore Hospital, NSW 2065, Australia ABSTRACT Expression of the adhesion molecules, ICAM-1, VCAM-1, NCAM, CD44, CD49d (VLA-4, α chain), and CD11a (LFA-1, α chain) on mouse oocytes, and pre- and peri-implantation stage embryos was examined by quantitative indirect immunofluorescence microscopy. ICAM-1 was most strongly expressed at the oocyte stage, gradually declining almost to undetectable levels by the expanded blastocyst stage. NCAM, also ex- pressed maximally on the oocyte, declined to undetectable levels beyond the morula stage. On the other hand, CD44 declined from highest expression at the oocyte stage to show a second maximum at the com- pacted 8-cell/morula. This molecule exhibited high expression around contact areas between trophectoderm and zona pellucida during blastocyst hatching. CD49d was highly expressed in the oocyte, remained signifi- cantly expressed throughout and after blastocyst hatching was expressed on the polar trophectoderm. Like CD44, CD49d declined to undetectable levels at the blastocyst outgrowth stage. Expression of both VCAM- 1 and CD11a was undetectable throughout. The diametrical temporal expression pattern of ICAM-1 and NCAM compared to CD44 and CD49d suggest that dynamic changes in expression of adhesion molecules may be important for interaction of the embryo with the maternal cellular environment as well as for continuing development and survival of the early embryo.