Current Immunotherapy Approaches in Non-Hodgkin Lymphomas
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ENSG Gene Encodes Effector TCR Pathway Costimulation Inhibitory/Exhaustion Synapse/Adhesion Chemokines/Receptors
ENSG Gene Encodes Effector TCR pathway Costimulation Inhibitory/exhaustion Synapse/adhesion Chemokines/receptors ENSG00000111537 IFNG IFNg x ENSG00000109471 IL2 IL-2 x ENSG00000232810 TNF TNFa x ENSG00000271503 CCL5 CCL5 x x ENSG00000139187 KLRG1 Klrg1 x ENSG00000117560 FASLG Fas ligand x ENSG00000121858 TNFSF10 TRAIL x ENSG00000134545 KLRC1 Klrc1 / NKG2A x ENSG00000213809 KLRK1 Klrk1 / NKG2D x ENSG00000188389 PDCD1 PD-1 x x ENSG00000117281 CD160 CD160 x x ENSG00000134460 IL2RA IL-2 receptor x subunit alpha ENSG00000110324 IL10RA IL-10 receptor x subunit alpha ENSG00000115604 IL18R1 IL-18 receptor 1 x ENSG00000115607 IL18RAP IL-18 receptor x accessory protein ENSG00000081985 IL12RB2 IL-12 receptor x beta 2 ENSG00000186810 CXCR3 CXCR3 x x ENSG00000005844 ITGAL CD11a x ENSG00000160255 ITGB2 CD18; Integrin x x beta-2 ENSG00000156886 ITGAD CD11d x ENSG00000140678 ITGAX; CD11c x x Integrin alpha-X ENSG00000115232 ITGA4 CD49d; Integrin x x alpha-4 ENSG00000169896 ITGAM CD11b; Integrin x x alpha-M ENSG00000138378 STAT4 Stat4 x ENSG00000115415 STAT1 Stat1 x ENSG00000170581 STAT2 Stat2 x ENSG00000126561 STAT5a Stat5a x ENSG00000162434 JAK1 Jak1 x ENSG00000100453 GZMB Granzyme B x ENSG00000145649 GZMA Granzyme A x ENSG00000180644 PRF1 Perforin 1 x ENSG00000115523 GNLY Granulysin x ENSG00000100450 GZMH Granzyme H x ENSG00000113088 GZMK Granzyme K x ENSG00000057657 PRDM1 Blimp-1 x ENSG00000073861 TBX21 T-bet x ENSG00000115738 ID2 ID2 x ENSG00000176083 ZNF683 Hobit x ENSG00000137265 IRF4 Interferon x regulatory factor 4 ENSG00000140968 IRF8 Interferon -
Cd160 Mouse Shrna Plasmid (Locus ID 54215) – TR514223 | Origene
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TR514223 Cd160 Mouse shRNA Plasmid (Locus ID 54215) Product data: Product Type: shRNA Plasmids Product Name: Cd160 Mouse shRNA Plasmid (Locus ID 54215) Locus ID: 54215 Synonyms: AU045688; By55 Vector: pRS (TR20003) Format: Retroviral plasmids Components: Cd160 - Mouse, 4 unique 29mer shRNA constructs in retroviral untagged vector(Gene ID = 54215). 5µg purified plasmid DNA per construct Non-effective 29-mer scrambled shRNA cassette in pRS Vector, TR30012, included for free. RefSeq: BC021596, NM_001163496, NM_001163497, NM_018767 Summary: CD160 antigen: Receptor on immune cells capable to deliver stimulatory or inhibitory signals that regulate cell activation and differentiation. Exists as a GPI-anchored and as a transmembrane form, each likely initiating distinct signaling pathways via phosphoinositol 3- kinase in activated NK cells and via LCK and CD247/CD3 zeta chain in activated T cells (By similarity). Receptor for both classical and non-classical MHC class I molecules (PubMed:16177084). Receptor or ligand for TNF superfamily member TNFRSF14, participating in bidirectional cell-cell contact signaling between antigen presenting cells and lymphocytes. Upon ligation of TNFRSF14, provides stimulatory signal to NK cells enhancing IFNG production and anti-tumor immune response (PubMed:25711213). On activated CD4+ T cells, interacts with TNFRSF14 and downregulates CD28 costimulatory signaling, restricting memory and alloantigen-specific immune response (By similarity). In the context of bacterial infection, acts as a ligand for TNFRSF14 on epithelial cells, triggering the production of antimicrobial proteins and proinflammatory cytokines (PubMed:22801499).[UniProtKB/Swiss-Prot Function] shRNA Design: These shRNA constructs were designed against multiple splice variants at this gene locus. -
Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse
Welcome to More Choice CD Marker Handbook For more information, please visit: Human bdbiosciences.com/eu/go/humancdmarkers Mouse bdbiosciences.com/eu/go/mousecdmarkers Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse CD3 CD3 CD (cluster of differentiation) molecules are cell surface markers T Cell CD4 CD4 useful for the identification and characterization of leukocytes. The CD CD8 CD8 nomenclature was developed and is maintained through the HLDA (Human Leukocyte Differentiation Antigens) workshop started in 1982. CD45R/B220 CD19 CD19 The goal is to provide standardization of monoclonal antibodies to B Cell CD20 CD22 (B cell activation marker) human antigens across laboratories. To characterize or “workshop” the antibodies, multiple laboratories carry out blind analyses of antibodies. These results independently validate antibody specificity. CD11c CD11c Dendritic Cell CD123 CD123 While the CD nomenclature has been developed for use with human antigens, it is applied to corresponding mouse antigens as well as antigens from other species. However, the mouse and other species NK Cell CD56 CD335 (NKp46) antibodies are not tested by HLDA. Human CD markers were reviewed by the HLDA. New CD markers Stem Cell/ CD34 CD34 were established at the HLDA9 meeting held in Barcelona in 2010. For Precursor hematopoetic stem cell only hematopoetic stem cell only additional information and CD markers please visit www.hcdm.org. Macrophage/ CD14 CD11b/ Mac-1 Monocyte CD33 Ly-71 (F4/80) CD66b Granulocyte CD66b Gr-1/Ly6G Ly6C CD41 CD41 CD61 (Integrin b3) CD61 Platelet CD9 CD62 CD62P (activated platelets) CD235a CD235a Erythrocyte Ter-119 CD146 MECA-32 CD106 CD146 Endothelial Cell CD31 CD62E (activated endothelial cells) Epithelial Cell CD236 CD326 (EPCAM1) For Research Use Only. -
Proteomics and Drug Repurposing in CLL Towards Precision Medicine
cancers Review Proteomics and Drug Repurposing in CLL towards Precision Medicine Dimitra Mavridou 1,2,3, Konstantina Psatha 1,2,3,4,* and Michalis Aivaliotis 1,2,3,4,* 1 Laboratory of Biochemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece; [email protected] 2 Functional Proteomics and Systems Biology (FunPATh)—Center for Interdisciplinary Research and Innovation (CIRI-AUTH), GR-57001 Thessaloniki, Greece 3 Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece 4 Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology, GR-70013 Heraklion, Greece * Correspondence: [email protected] (K.P.); [email protected] (M.A.) Simple Summary: Despite continued efforts, the current status of knowledge in CLL molecular pathobiology, diagnosis, prognosis and treatment remains elusive and imprecise. Proteomics ap- proaches combined with advanced bioinformatics and drug repurposing promise to shed light on the complex proteome heterogeneity of CLL patients and mitigate, improve, or even eliminate the knowledge stagnation. In relation to this concept, this review presents a brief overview of all the available proteomics and drug repurposing studies in CLL and suggests the way such studies can be exploited to find effective therapeutic options combined with drug repurposing strategies to adopt and accost a more “precision medicine” spectrum. Citation: Mavridou, D.; Psatha, K.; Abstract: CLL is a hematological malignancy considered as the most frequent lymphoproliferative Aivaliotis, M. Proteomics and Drug disease in the western world. It is characterized by high molecular heterogeneity and despite the Repurposing in CLL towards available therapeutic options, there are many patient subgroups showing the insufficient effectiveness Precision Medicine. -
Tools for Cell Therapy and Immunoregulation
RnDSy-lu-2945 Tools for Cell Therapy and Immunoregulation Target Cell TIM-4 SLAM/CD150 BTNL8 PD-L2/B7-DC B7-H1/PD-L1 (Human) Unknown PD-1 B7-1/CD80 TIM-1 SLAM/CD150 Receptor TIM Family SLAM Family Butyrophilins B7/CD28 Families T Cell Multiple Co-Signaling Molecules Co-stimulatory Co-inhibitory Ig Superfamily Regulate T Cell Activation Target Cell T Cell Target Cell T Cell B7-1/CD80 B7-H1/PD-L1 T cell activation requires two signals: 1) recognition of the antigenic peptide/ B7-1/CD80 B7-2/CD86 CTLA-4 major histocompatibility complex (MHC) by the T cell receptor (TCR) and 2) CD28 antigen-independent co-stimulation induced by interactions between B7-2/CD86 B7-H1/PD-L1 B7-1/CD80 co-signaling molecules expressed on target cells, such as antigen-presenting PD-L2/B7-DC PD-1 ICOS cells (APCs), and their T cell-expressed receptors. Engagement of the TCR in B7-H2/ICOS L 2Ig B7-H3 (Mouse) the absence of this second co-stimulatory signal typically results in T cell B7-H1/PD-L1 B7/CD28 Families 4Ig B7-H3 (Human) anergy or apoptosis. In addition, T cell activation can be negatively regulated Unknown Receptors by co-inhibitory molecules present on APCs. Therefore, integration of the 2Ig B7-H3 Unknown B7-H4 (Mouse) Receptors signals transduced by co-stimulatory and co-inhibitory molecules following TCR B7-H5 4Ig B7-H3 engagement directs the outcome and magnitude of a T cell response Unknown Ligand (Human) B7-H5 including the enhancement or suppression of T cell proliferation, B7-H7 Unknown Receptor differentiation, and/or cytokine secretion. -
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. -
1 Activity of the Second Generation BTK Inhibitor Acalabrutinib In
Activity of the Second Generation BTK Inhibitor Acalabrutinib in Canine and Human B-cell Non-Hodgkin Lymphoma Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Bonnie Kate Harrington Graduate Program in Comparative and Veterinary Medicine The Ohio State University 2018 Dissertation Committee John C. Byrd, M.D., Advisor Amy J. Johnson, Ph.D. Krista La Perle, D.V.M., Ph.D. William C. Kisseberth, D.V.M., Ph.D. 1 Copyrighted by Bonnie Kate Harrington 2018 2 Abstract Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton’s Tyrosine Kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In these studies, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy reported to be similar to human diffuse large B-cell lymphoma (DLBCL), as well as primary human chronic lymphocytic leukemia (CLL) cells. We demonstrated that acalabrutinib potently inhibited BTK activity and downstream B-cell receptor (BCR) effectors in CLBL1, a canine B-cell lymphoma cell line, primary canine lymphoma cells, and primary CLL cells. Compared to ibrutinib, acalabrutinib is a more specific inhibitor and lacked off-target effects on the T-cell and NK cell kinase IL-2 inducible T-cell kinase (ITK) and epidermal growth factor receptor (EGFR). Accordingly, acalabrutinib did not antagonize antibody dependent cell cytotoxicity mediated by NK cells. Finally, acalabrutinib inhibited proliferation and viability in CLBL1 cells and primary CLL cells and abrogated chemotactic migration in primary CLL cells. To support our in vitro findings, we conducted a clinical trial using companion dogs with spontaneously occurring B-cell lymphoma. -
Ublituximab (TG-1101) in Combination with Umbralisib (TGR-1202) for Chronic Lymphocytic Leukaemia NIHRIO (HSRIC) ID: 12230 NICE ID: 9540
NIHR Innovation Observatory Evidence Briefing: SEPTEMBER 2017 Ublituximab (TG-1101) in combination with umbralisib (TGR-1202) for chronic lymphocytic leukaemia NIHRIO (HSRIC) ID: 12230 NICE ID: 9540 LAY SUMMARY Chronic lymphocytic leukaemia is a type of blood cancer that develops inside the bone marrows. This produces abnormal types of white blood cells (lymphocytes) which do not function properly, hence, do not protect from infections the way they should do. Chronic types of leukaemia develop slowly over a long time. Symptoms of this cancer usually only develop at a later stage of the disease. They may include frequent infections, persistent tiredness, shortness of breath, pale skin, bleeding and bruising more easily and others. The cause of chronic lymphocytic leukaemia is not yet fully understood but risk factors may include age (older people), exposure to chemicals, family history, gender or ethnicity. Ublituximab in combination with umbralisib is under development for the treatment of chronic lymphocytic leukaemia and other types of blood cancers. They both act in different ways to suppress the production and growth of the abnormal lymphocytes caused by bindings to certain cells and proteins in the body that produces the cancer. If licensed, it will offer an additional treatment option for patients with chronic lymphocytic leukaemia. This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. This briefing presents independent research funded by the National Institute for Health Research (NIHR). -
Development of Red Blood Cell Autoantibodies Following Treatment with Checkpoint Inhibitors
CASE R EP O RT Development of red blood cell autoantibodies following treatment with checkpoint inhibitors: a new class of anti-neoplastic, immunotherapeutic agents associated with immune dysregulation L.L.W. Cooling, J. Sherbeck, J.C. Mowers, and S.L. Hugan Ipilimumab, nivolumab, and pembrolizumab represent a new Table 1. Checkpoint inhibitors class of immunotherapeutic drugs for treating patients with Drug class (trade name, manufacturer) advanced cancer. Known as checkpoint inhibitors, these drugs act to upregulate the cellular and humoral immune response Anti-CTLA-4 to tumor antigens by inhibiting T-cell autoregulation. As a Ipilimumab (Yervoy, Bristol-Myers Squibb) consequence, they can be associated with immune-related adverse Tremelimumab (AstraZeneca, compassionate use only) events (irAEs) due to loss of self-tolerance, including rare cases of immune-related cytopenias. We performed a retrospective Anti-PD-1 clinical chart review, including serologic, hematology, and Nivolumab (Opdivo, Bristol-Myers Squibb) chemistry laboratory results, of two patients who developed Pembrolizumab (Keytruda, Merck Sharp & Dohme) red blood cell (RBC) autoantibodies during treatment with a Pidilizumab (Medivations, in clinical trials) checkpoint inhibitor. Serologic testing of blood samples from these patients during induction therapy with ipilimumab and Anti-PD-L1 nivolumab, respectively, showed their RBCs to be positive by Atezolizumab (Genentech, in clinical trials) the direct antiglobulin test (IgG+, C3+) and their plasma to Durvalumab (AstraZeneca, approved bladder cancer) contain panreactive RBC autoantibodies. Neither patient had evidence of hemolysis. Both patients developed an additional CTLA-4 = cytotoxic T-lymphocyte–associated antigen 4; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death ligand 1. -
Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix
United States International Trade Commission Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix USITC Publication 4208 December 2010 U.S. International Trade Commission COMMISSIONERS Deanna Tanner Okun, Chairman Irving A. Williamson, Vice Chairman Charlotte R. Lane Daniel R. Pearson Shara L. Aranoff Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix Publication 4208 December 2010 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 15, 2010, set forth at the end of this publication, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the United States International Trade Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement changes to the Pharmaceutical Appendix, effective on January 1, 2011. Table 1 International Nonproprietary Name (INN) products proposed for addition to the Pharmaceutical Appendix to the Harmonized Tariff Schedule INN CAS Number Abagovomab 792921-10-9 Aclidinium Bromide 320345-99-1 Aderbasib 791828-58-5 Adipiplon 840486-93-3 Adoprazine 222551-17-9 Afimoxifene 68392-35-8 Aflibercept 862111-32-8 Agatolimod -
Inhibitors Targeting Bruton’S Tyrosine Kinase in Cancers
Leukemia (2021) 35:312–332 https://doi.org/10.1038/s41375-020-01072-6 REVIEW ARTICLE Lymphoma Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances 1 2 1 2 1 Tingyu Wen ● Jinsong Wang ● Yuankai Shi ● Haili Qian ● Peng Liu Received: 2 April 2020 / Revised: 27 September 2020 / Accepted: 15 October 2020 / Published online: 29 October 2020 © The Author(s) 2020. This article is published with open access Abstract Bruton’s tyrosine kinase (BTK) inhibitor is a promising novel agent that has potential efficiency in B-cell malignancies. It took approximately 20 years from target discovery to new drug approval. The first-in-class drug ibrutinib creates possibilities for an era of chemotherapy-free management of B-cell malignancies, and it is so popular that gross sales have rapidly grown to more than 230 billion dollars in just 6 years, with annual sales exceeding 80 billion dollars; it also became one of the five top-selling medicines in the world. Numerous clinical trials of BTK inhibitors in cancers were initiated in the last decade, and ~73 trials were intensively announced or updated with extended follow-up data in the most recent 3 years. In this review, we summarized the significant milestones in the preclinical discovery and clinical development of BTK inhibitors to better 1234567890();,: 1234567890();,: understand the clinical and commercial potential as well as the directions being taken. Furthermore, it also contributes impactful lessons regarding the discovery and development of other novel therapies. Introduction (DLBCL), follicular lymphoma (FL), multiple myeloma (MM), marginal zone lymphoma (MZL), mantle cell lym- B-cell malignancies include non-Hodgkin lymphomas phoma (MCL) and Waldenström’s macroglobulinemia (NHLs) and chronic lymphocytic leukaemia. -
New Biological Therapies: Introduction to the Basis of the Risk of Infection
New biological therapies: introduction to the basis of the risk of infection Mario FERNÁNDEZ RUIZ, MD, PhD Unit of Infectious Diseases Hospital Universitario “12 de Octubre”, Madrid ESCMIDInstituto de Investigación eLibraryHospital “12 de Octubre” (i+12) © by author Transparency Declaration Over the last 24 months I have received honoraria for talks on behalf of • Astellas Pharma • Gillead Sciences • Roche • Sanofi • Qiagen Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Paul Ehrlich (1854-1915) • “side-chain” theory (1897) • receptor-ligand concept (1900) • “magic bullet” theory • foundation for specific chemotherapy (1906) • Nobel Prize in Physiology and Medicine (1908) (together with Metchnikoff) Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author 1981: B-1 antibody (tositumomab) anti-CD20 monoclonal antibody 1997: FDA approval of rituximab for the treatment of relapsed or refractory CD20-positive NHL 2001: FDA approval of imatinib for the treatment of chronic myelogenous leukemia Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Functional classification of targeted (biological) agents • Agents targeting soluble immune effector molecules • Agents targeting cell surface receptors