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IT SAR* Targeted with a mAb Alternatively spliced extradomain-B of fibronectin Philogen (Fibromun/L19-TNF) •• TNFα *Soft Tissue Sarcoma Clinical stage codes M MEL Toxic to tumor neovasculature and activates the endothelium; highly toxic if used systemically Preclinical/Discovery OTC Over-the-Counter Not targeted with a mAb Boehringer Ingelheim (Beromun; isolated limb perfusion) M SAR • Phase 1 NDA New Drug Application Beromun Limited to use in isolated limb perfusion •• Phase 2 BLA Biologics License Application ••• Phase 3 MAA Marketing Authorization Application (Europe's NDA) Long-acting SC Merck (Sylatron/peginterferon α-2b) M MEL Class has M Marketed D Dormant/discontinued Less frequent injections Ñ february 2017 known G Generic Failed survival IB FKD Therapies Oy (Instiladrin/rAdIFN w/ Syn3) •• UCC RCT Randomized Controlled Trial CP Compounding Pharmacy benefit Interferon-α (IFNα) Genetically modified non-replicating virus to the tumor Adenovirus expressing IFNα2b IST Investigator-Sponsored Trial PD(L)1 immuno-oncology 21 22 M NHL PDUFA PDUFA POC: Unknown • Enhances T-cell and DC response via a poorly-characterized MoA M MEL • Associated with dose-limiting AEs, including influenza-like symptoms (fatigue, fever, headache and muscle SC/IM/IC Merck (Intron-A/interferon α-2b) M CLL ANDA Abbreviated New Drug Application POC: Validated aches), nausea, dizziness, anorexia, depression and leukopenia Merck (SC Intron-A/interferon α-2b + IV Keytruda/pembrolizumab) MEL FAILED OL Off-label POC: Failed IFNα2b Roche (IV Tecentriq/atezolizumab + SC interferon-α2b) • Inton-A Short-acting more frequent M NHL Routes of delivery injections M MEL IV Intravenous IB Intravesical/Intrabladder CLL MDS SC Roche (recombinant interferon alfa-2a (Roferon-A)) M •• Innate Pharma/Bristol-Myers Squibb Provide IFNα2a ID Intradermal IC Intracerebral ST • (lirilumab IV+ Opdivo/nivolumab IV) Unknown Multikine mixture IT/SC CEL-SCI (Multikine) ••• HNC RCT:YE17 IM Intramuscular EC Epicutaneous RCT:2H16 AML •• broadly-acting survival Proprietary mix of 19 cytokines, chemokines and other immune system molecules (no antigens, not a vaccine). PDAC RCT:YE16 SC Subcutaneous IN Intranasal MM •• Anti-KIR mAbs •• •• GBM RCT:MY16 PO Oral Dosage AML •• KIR is an inhibitory receptor on NK cells that binds HLA-C on tumor cells cytokines benefit Multikine: YE17 CRC CLL •• Innate Pharma/Bristol-Myers Squibb (lirilumab) IV Poorly-defined MOA •• IVT Intravitreal QD Once a day •• PC Intrathercal Intrathecal BID Twice a day HNC PO Eli Lilly (LY2157299/galunisertib) + IV Bristol-Myers Squibb (Opdivo/nivolumab) •• OC •/•• IT Intratumoral TID Three times a day OC •/•• PO Eli Lilly (LY2157299/galunisertib) • ST TD Transdermal QW Once a week CLL •/•• Innate Pharma/AstraZeneca (IPH2201) IV Anti-NKG2A mAbs TGFβ kinase inhibitor MedPacto (TEW-7197) • ST Disinhibit NK cells Bristol-Myers Squibb/Rigel IPL Intrapleural Q2W Once every 2 weeks NKG2A is an inhibitory receptor on NK cells and some CD8+ T cells that binds overexpressed HLA-E on tumor cells. The Cheot Poteta Cae The Cheot Scholar Rock/Janssen IP Intraperitoneal QM Once a month lirilumab+pembrolizumab 3Q18 hto Anti-TGFβ mAb Novartis (Xoma-089) ••• MEL RCT:MY18 hto aet 22 aet 21 2 othea aet Incyte (INCB24360/epacadostat) PO + Merck (Keytruda/pembrolizumab) IV •/•• ST ArGEN-X (ARGX-115) •• ST Innate Pharma (IPH4031) Anti-MICA/MICB mAbs 22 Inhibit TGFβ pathway Anti-GARP mAb - inhibitor of TGFβ release Incyte (INCB24360/epacadostat/INCB24360) PO •• MDS MICA/B overexpression on tumor cells disrupts costimulatory signaling through NKG2D on NK cells and some T cells. • Enhances tumor growth, promotes formation of tumor stroma, and increases metastatic potential AML • Glycostem Therapeutics (oNKord) IV +Bristol-Myers Squibb (Opdivo/nivolumab) IV •/•• OC • TGFβ acts as a tumor growth suppressor during early tumorigenesis. Huabo Biopharm (HB-002) Celgene TGFβ- and VEGF-targeting bifunctional fusion protein Incyte (INCB24360/epacadostat) PO + Roche (Tecentriq/atezolizumab) IV • NSCLC Fate Therapeutics Derived from stem cells $60B • Suppresses Treg activity •• OC Ziopharm Isarna (Trabedersen) IV •• CC galunisertib: MY18 TGFβ2 antisense Nantkwest (haNK) IV High-affinity binding to antibodies Off-the-shelf human NK cell line •• MDS ST Added synergy with mAbs such as Rituxin or Herceptin Incyte (INCB24360/epacadostat) PO •/•• Tilos Therapeutics MCC •• Irradiated cell line TGFβ pathway inhibition with mAb against latency iTeos Therapeutics/Pfizer AML • Nantkwest (aNK/NK-92) IV associated peptides ioMET Pharma/Merck No added specificity Not antigen-specific RedX Oncology Fortress Bio Bristol-Myers Squibb/Flexus AML •/•• (CNDO-109-activated allogeneic NK cells) IV Provide NK cells Y/ Y/ IDO Nektar (NKTR-218) Can be manufactured at central facility Expressed by tumor cells and APC 1 1 2 Ensemble Therapeutics AML •/•• University of Texas M.D. Anderson Cancer Center IV aNK:YE16 Ex vivo IL-21-activated allogeneic NK cells Patient-specific manufacturing /1 /1 Pfizer/iTeos Therapeutics 3 1 11 ioMET Pharma Must be manufactured in-house TDO SMM •• University of Arkansas/Millenium IV See ‘T-cell Growth Factors’ NK-cell growth factors /1 /1 RedX Oncology Ex vivo-expanded autologous NK cells 1 23 22 Inhibit IDO) and/or TDO • Upregulated in hepatocytes and in the brain • Potential for on-target toxicity Bristol-Myers Squibb/Flexus T/1 ioMET Pharma IDO and TDO deplete tryptophan. Low tryptophan levels promote Treg differentiation and suppress DC function, which dampen the immune response. 2 11 RedX Oncology See Immuno-Oncology: CAR-T Bristol-Myers Squibb/Flexus Antigen-specific epacadostat+pembrolizumab: MY18 Dual IDO/TDO /1 Roche/Curadev (RG70099) 1 PO NewLink Genetics (NLG8189/indoximod) •/•• Shielded from Other Unknown target in IDO/TDO pathway ST •/•• Nektar (NKTR-214) IV Reduced IL-2Rα binding Selective for effector T cells over 2 PEGylation enhances tumor targeting activating T cells in Target other components of the IDO/TDO pathway KYN Therapeutics Allows for receptor recycling regulatory T cells Signal NK Cell Tumor Cells Regulatory T Cell Kynurenine peripheral blood •/•• BC Eliminate Siglec family Sialyated glycan PD1 CD27 •/•• NSCLC ST • Roche (RO6874281) IV Broad range PO Incyte (Jakafi/Ruxolitinib) • ST Anti-fibroblast activation protein (FAP) antibody fusion Antibody capillary leak PDAC Antigen target is expressed in wide range of tumor types Reduced IL- KIR MHC Class I CTLA4 Neurophil •• targeting to Selective for syndrome, JAK1/2 PO NSCLC 2Rα binding Inhibitory Inhibit Janus kinase (JAK) Gilead (Momelotinib) • effector T cells over more CD96 TNFRSF25 VEGF tumor Allows for receptor Signal Decrease inflammatory cytokines that recruit MDSCs Incyte (INCB-39110) •/•• ST ST • IV CD155 Roche (RO6895882) Narrow range Localization may still be recycling regulatory T cells convenient JAK1 Anti-carcinoembryonic antigen (CEA) antibody fusion TIGIT •• PDAC RCT:MY17 •• HNC RCT:3Q17 Antigen target is expressed in subset of tumor types driven by IL-2 binding GITR LAG3 dosing UCC RCT:MY17 OC RCT:YE17 DIS- •• •• CONTINUED Merck KGaA (Selectikine/EMD 521873) IV Not shielded from MICA family 4-1BB ICOS NSCLC RCT:YE17 Anti-DNA antibody Stimulatory NKGR2 •• activating T cells in Signal PO Acerta Therapeutics (ACP196/acalabrutinib) + IV Merck (Keytruda/pembrolizumab) •/•• GBM RAET1/ULBP family OX40 CD25 MEL •• Philogen (Darleukin/L19-IL-2) IV Broad range peripheral blood Second-generation BTK inhibitor REDX Oncology Alternatively spliced extra-domain B (EDB) of fibronectin IL-2 Antigen target is expressed in wide range of tumor types Potential for better safety profile (lower infection risk, bleeding risk, and GI tox) due to improved specificity Advinus Therapeutics MCC •• • Canonical T cell growth factor AML Inhibit Bruton’s tyrosine kinase (BTK) M MCL • Philogen (Teleukin/F16-IL2) IV IL-2 fused • Induces activation and proliferation of NK cells, B Target myeloid-derived suppressor cells (MDSCs) ECM glycoprotein tenascin-C Not selective for Targeting BTK inhibits MDSC migration into tissues and expression of suppressive factors such as nitric oxide (NO) as well as Tregs PO AbbVie/JNJ (Imbruvica/ibrutinib) M CLL cells and monocytes to targeting MDSCs are immature myeloid cells that maintain the immunosuppressive tumor microenvironment via the production of arginase, IDO, ROS and suppressive cytokines. First-generation BTK inhibitor •/•• ST NHL •/•• Alopexx (DI-Leu16-IL2) IV effector T cells PO IV PDAC Anti-CD20 antibody molecule Proleukin • Selectivity problems associated with: • BTK: infection risk | EGFR: GI tox, and rash | JAK3: bleeding AbbVie/JNJ (Imbruvica/ibrutinib) + AstraZeneca (MEDI-4736/durvalumab) •/•• MEL •/•• acalabrutinib+Keytruda: MY17 UCC •/•• Narrow range AstraZeneca (PO AZD5069 + IV durvalumab) •/•• PDAC MM •/•• IV Antigen target is expressed in subset of tumor types Class has confirmed overall CXCR2 PO AstraZeneca (AZD5069) •/•• HNC Altor Bioscience (ALT-801) p53-specific single chain TCR NK RCC M survival benefit and has Inhibit IL-8/IL-8RB (CXCR2) signaling IV Bristol-Myers Squibb (Humax-IL-8) •/•• ST MEL •• Nestle Health Science (Proleukin/aldesleukin) IV Paracrine signaling by tumor-derived IL-8 to CXCR1 and CXCR2 promotes the trafficking of neutrophils and MDSCs into the tumor microenvironment. IL-8 also has a role in the development IL-8 Associated with capillary leak syndrome, must be dosed in specialized setting induced long-term cures of cancer stem cells. PO Dompe (Reparixin) •• BC MEL •• Lion
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  • Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon

    Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon

    www.nature.com/scientificreports OPEN Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon Receptor and Gq-Coupled Received: 17 November 2017 Accepted: 9 July 2018 Receptors Published: xx xx xxxx Jeremy P. McAleer1, Jun Fan2, Bryanna Roar1, Donald A. Primerano2 & James Denvir2 Th17 cells contribute to host defense on mucosal surfaces but also provoke autoimmune diseases when directed against self-antigens. Identifying therapeutic targets that regulate Th17 cell diferentiation and/or cytokine production has considerable value. Here, we study the aryl hydrocarbon receptor (AhR)- dependent transcriptome in human CD4 T cells treated with Th17-inducing cytokines. We show that the AhR reciprocally regulates IL-17 and IL-22 production in human CD4 T cells. Global gene expression analysis revealed that AhR ligation decreased IL21 expression, correlating with delayed upregulation of RORC during culture with Th17-inducing cytokines. Several of the AhR-dependent genes have known roles in cellular assembly, organization, development, growth and proliferation. We further show that expression of GPR15, GPR55 and GPR68 positively correlates with IL-22 production in the presence of the AhR agonist FICZ. Activation of GPR68 with the lorazepam derivative ogerin resulted in suppression of IL-22 and IL-10 secretion by T cells, with no efect on IL-17. Under neutral Th0 conditions, ogerin and the Gq/11 receptor inhibitor YM254890 blunted IL-22 induction by FICZ. These data reveal the AhR- dependent transcriptome in human CD4 T cells and suggest the mechanism through which the AhR regulates T cell function may be partially dependent on Gq-coupled receptors including GPR68.
  • Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction in Patients with Diabetes Mellitus

    Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction in Patients with Diabetes Mellitus

    International Journal of Impotence Research (2002) 14, 466–471 ß 2002 Nature Publishing Group All rights reserved 0955-9930/02 $25.00 www.nature.com/ijir Phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction in patients with diabetes mellitus MA Vickers1,2* and R Satyanarayana1 1Department of Surgery, Togus VA Medical Center, Togus, Maine, USA; and 2Department of Surgery, Division of Urology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has become a first-line therapy for diabetic patients with erectile dysfunction (ED). The efficacy in this subgroup, based on the Global Efficacy Question, is 56% vs 84% in a selected group of non-diabetic men with ED. Two novel PDE5 inhibitors, tadalafil (Lilly ICOS) and vardenafil (Bayer), have recently completed efficacy and safety clinical trials in ‘general’ and diabetic study populations and are now candidates for US FDA approval. A summary analysis of the phase three clinical trials of sildenafil, tadalafil and vardenafil in both study populations is presented to provide a foundation on which the evaluation of the role of the individual PDE5 inhibitors for the treatment of patients with ED and DM can be built. International Journal of Impotence Research (2002) 14, 466–471. doi:10.1038=sj.ijir.3900910 Keywords: phosphodiesterase inhibitor; erectile dysfunction; diabetes mellitus; sildenafil; tadalafil; vardenafil Introduction (NO), vasointestinal peptide and prostacyclin, de- creases. Additionally, the endothelial cells that line the cavernosal arteries and sinusoids have a Pathophysiology of ED in diabetes decreased response to nitric oxide due to increased production of advanced glycation end-products and changes associated with insulin resistance.5,6 The Diabetes mellitus is a risk factor for erectile diabetic also experiences a decreased level of dysfunction (ED).