DOCSLIB.ORG

(Cd11b/CD18) Enhances Tumor Response to Radiation by Reducing Myeloid Cell Recruitment

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(Cd11b/CD18) Enhances Tumor Response to Radiation by Reducing Myeloid Cell Recruitment Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment G-One Ahna, Diane Tsenga,b, Cho-Hwa Liaoa, Mary Jo Doriea, Agnieszka Czechowiczb, and J. Martin Browna,1 aDivision of Radiation and Cancer Biology, Department of Radiation Oncology, and bInstitute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305 Edited by Napoleone Ferrara, Genentech, Inc., South San Francisco, CA, and approved March 26, 2010 (received for review October 2, 2009) Despite recent advances in radiotherapy, loco-regional failures are tions of myeloid cells, including adhesion, migration, chemotaxis, still the leading cause of death in many cancer patients. We have phagocytosis, and respiratory burst activity (7). Studies have previously reported that bone marrow-derived CD11b+ myeloid cells reported that antibodies to CD11b or CD18 inhibit these functions are recruited to tumors grown in irradiated tissues, thereby restoring (8) and in vivo administration of the antibodies reduce leukocyte the vasculature and tumor growth. In this study, we examined recruitment into various sites of inflammation (9). Given the whether neutralizing CD11b monoclonal antibodies could inhibit promising preclinical activities of CD11b/CD18 antibodies in the recruitment of myeloid cells into irradiated tumors and inhibit inhibiting myeloid cell adhesion onto endothelium, humanized their regrowth. We observed a significant enhancement of antitu- antibodies [LeukArrest; 23F2G (10)] have been developed and mor response to radiation in squamous cell carcinoma xenografts tested in patients with stroke, multiple sclerosis, or myocardial in mice when CD11b antibodies are administered systemically. His- infarction (11). However, although the antibodies showed excellent tological examination of tumors revealed that CD11b antibodies re- safety profiles, they lacked therapeutic efficacy (10, 11). duced infiltration of myeloid cells expressing S100A8 and matrix In this study, we used CD11b-neutralizing monoclonal anti- metalloproteinase-9. CD11b antibodies further inhibited bone bodies as a means to inhibit the recruitment of myeloid cells to marrow-derived cell adhesion and transmigration to C166 endothe- irradiated tumors. With systemic administration of these CD11b lial cell monolayers and chemotactic stimuli, respectively, to levels antibodies following local tumor irradiation, we observed a signif- comparable to those from CD11b knockout or CD18 hypomorphic icant enhancement of tumor response to radiation accompanied mice. Given the clinical availability of humanized CD18 antibodies, by a reduced infiltration of myeloid cells expressing MMP-9 and we tested two murine tumor models in CD18 hypomorphic or CD11b S100A8 into the tumors. We also observed that CD18 hypo- knockout mice and found that tumors were more sensitive to irradi- morphism, which had lowered CD11b surface expression myeloid ation when grown in CD18 hypomorphic mice but not in CD11b cells, significantly associated with the sensitivity of tumors to ra- knockout mice. When CD18 hypomorphism was partially rescued diation. Together, these results suggest that clinically available by reconstitution with the wild-type bone marrow, the resistance humanized antibodies against CD11b/CD18 could be useful as an of the tumors to irradiation was restored. Our study thus supports adjuvant therapy to radiotherapy. MEDICAL SCIENCES the rationale of using clinically available Mac-1 (CD11b/CD18) anti- bodies as an adjuvant therapy to radiotherapy. Results Radiation Inhibits Local Angiogenesis but the Vasculature Is Restored S100A8 | vasculogenesis | radiosensitivity in Recurrent Tumors Accompanied by Infiltrating Myeloid Cells. To determine the effects of local irradiation on angiogenesis, we adiotherapy plays a crucial role in cancer treatment, espe- first examined the histology of FaDu human head and neck Rcially for inoperable tumors. Recent advances, including squamous cell carcinoma xenografts grown in immune-deficient image-guided and intensity-modulated radiotherapy, leading to mice that were either unirradiated (control, 0 Gy), harvested higher and more precise dose delivery, has achieved superior shortly after 20 Gy of irradiation (IR 20 Gy), or had recurred treatment outcomes (1). However, despite these advances, re- after irradiation with 20 Gy, which took ≈2 months following currence of the primary tumors still remains the leading cause of irradiation [recurrent (2 mo)] (Fig. 1A). Tumor volumes were death of patients treated with radiotherapy (2). This finding ≈25 and 50% of the unirradiated control for irradiated tumors highlights the fact that we need an improved understanding of and recurrent tumors, respectively (Fig. 1A). By staining for the reasons for treatment failure. endothelial cells and pericytes with CD31 and α-smooth muscle We have previously shown that irradiated tumors, or tumors actin (α-SMA) antibodies, respectively, we found that the irra- grown in previously irradiated tissues (thereby mimicking re- diated tumors had significantly fewer endothelial cells and per- current primary tumors), recruit large numbers of bone marrow- icytes compared with the control tumors (Fig. 1 A and B). + derived CD11b myeloid cells expressing matrix metal- However, when the tumors had recurred after irradiation, the loproteinase-9 (MMP-9) (3). We further demonstrated that these number of endothelial cells had returned to control levels, al- MMP-9-expressing myeloid cells restored tumor vasculature and though the pericyte coverage was partially restored (Fig. 1 A and allowed tumor growth in the irradiated tissues of MMP-9 knockout B). To determine the myeloid cell contribution to the changes in (KO) mice, suggesting that these cells could be an important target in radiotherapy (3). There is strong evidence to suggest that tumor- fi + in ltrating CD11b myeloid cells promote angiogenesis, and do Author contributions: G-O.A., D.T., C.-H.L., M.J.D., A.C., and J.M.B. designed research; G-O.A., so by expressing various proangiogenic and chemoattractant D.T., C.-H.L., M.J.D., and A.C. performed research; G-O.A., D.T., C.-H.L., M.J.D., and A.C. ana- molecules, including VEGF (4), Bv8 (5), and S100A8 (6). How- lyzed data; and G-O.A. and J.M.B. wrote the paper. + ever, despite their tumor-promoting roles, targeting CD11b The authors declare no conflict of interest. myeloid cells as a cancer therapy has proven difficult. This article is a PNAS Direct Submission. CD11b (Mac-1, αMβ2) is the α-subunit of the predominant β2 1To whom correspondence should be addressed. E-mail: [email protected]. (CD18) integrin expressed on monocytes/macrophages and gran- This article contains supporting information online at www.pnas.org/cgi/content/full/ ulocytes (7). This subunit has been shown to mediate many func- 0911378107/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.0911378107 PNAS | May 4, 2010 | vol. 107 | no. 18 | 8363–8368 Downloaded by guest on September 25, 2021 + Control (0 Gy) IR 20 Gy (d14) Recurrent (2 mo) filtration of CD11b myeloid cells, we determined whether anti- ADAPIDAPI Tumor volume bodies to CD11b could reduce the myeloid cell recruitment and *** ) 3 -SMA 250 *** *** m m sensitize the tumors to irradiation. We harvested CD11b mono- ( 200 α e clonal antibodies (IgG2b isotype) from M1/70 hybridoma and first C D 3 1 m 150 ul o 100 determined the dose and timing of the antibodies for in vivo ad- T u m o r v 50 DAPI DAPI ministration. We similarly studied Gr-1 antibodies (IgG2b isotype) 0 lort u r r e n t R 2 0 G y harvested from RB6-8C5 hybridoma. We first observed that Gr-1 o n C D 1 1 b fi + + c C I antibodies ef ciently depleted granulocytes (CD11b Gr-1 cells) R e at 24 h after a single i.p. administration; CD11b antibodies did not affect the leukocyte composition (Fig. S1A and Table S1). CD11b B CD31 α-SMA CD11b CD45 antibodies exhibited a complete epitope blockage with 100 μgat 6 20 4 10 n s i t y ( % ) ** ** *** *** *** *** *** ** 24 h (Fig. S1 C and D), which was partially reversed at 72 h after 4 * administration (Fig. S1E). Therefore, to maintain constant epitope e 10 2 5 e a d 2 blocking of myeloid cells, we treated the mice with CD11b anti- r A bodies at 100 μg per mouse every 2 days. Gr-1 antibodies were 0 0 0 0 C o n t r o l C o n t r o l l lo e n t R e c u r r e n t R e c u r r e n t R e c u r r e n t y y I R 2 0 G y I R 2 0 G y o R 2 0 G G C o n t r rt r administered to a separate group of animals in a similar manner. I R 2 0 o n r uc C I e To monitor epitope blockage by CD11b antibodies or granulo- R cyte depletion by Gr-1 antibodies, we sampled peripheral blood C Control (0 Gy) IR 20 Gy (d14) D CD31 α-SMA from the treated animals once every four days for FACS analysis (%) 4 2 10 *** H D -SMA (Figs. S1 and S2 ). t 3 3 3 4 y A r e a d e n s i t fi α When FaDu tumor-bearing immunode cient mice were treated s 5 c h C D 3 1 2 e with CD11b antibodies following either 12 or 20 Gy of a single dose H o 0 0 fi lo lort of irradiation given locally to the tumors, we observed a signi cant I I R 2 0 G y I R 2 0 G y r C o n t A o n enhancement of tumor response to radiation (Fig. 2 ). Macro- C scopically, the CD11b antibody-treated tumors shrank dramati- Fig. 1. Local irradiation inhibits angiogenesis. (A) Staining of FaDu tumors cally, leading to nearly nonpalpable tumors by the end of the study grown in immunodeficient mice that were not irradiated (control, 0 Gy), (Fig.
Load more

Recommended publications
  • IL-10 and ICOS Differentially Regulate T Cell Responses in the Brain During Chronic 2 Toxoplasma Gondii Infection 3
    bioRxiv preprint doi: https://doi.org/10.1101/418665; this version posted September 15, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 IL-10 and ICOS differentially regulate T cell responses in the brain during chronic 2 Toxoplasma gondii infection 3 4 Carleigh A. O’Brien*, Samantha J. Batista*, Katherine M. Still*, and Tajie H. Harris* 5 6 Affiliations: *Center for Brain Immunology and Glia, Department of Neuroscience, University of 7 Virginia, Charlottesville, VA 22908 8 9 Corresponding Author: 10 Tajie H. Harris, MR-4 Room 6148, 409 Lane Road, Charlottesville, VA 22908 11 Phone: 434-982-6916 12 Fax: 434-9824380 13 Email: [email protected] 14 15 This work was funded by the National Institutes of Health grants R01NS091067 to T.H.H., 16 T32AI007496 to C.A.O, T32AI007046 to S.J.B., and T32GM008328 to K.M.S., as well as the 17 University of Virginia Robert R. Wagner Fellowship to C.A.O. 18 19 20 21 22 23 24 1 bioRxiv preprint doi: https://doi.org/10.1101/418665; this version posted September 15, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 25 Abstract 26 Control of chronic CNS infection with the parasite Toxoplasma gondii requires an ongoing T cell 27 response in the brain. Immunosuppressive cytokines are also important for preventing lethal 28 immunopathology during chronic infection.
    [Show full text]
  • Certain Tadalafil Or Any Salt Solvate Thereof and Products Containing
    In the Matter of Certain Tadalafil or any Salt or Solvate Thereof and Products Containing Same Investigation No. 337-TA-539 Publication 3992 May2008 U.S. International Trade Commission Washington, i::>C 20436 U.S. International Trade Commission COMMISSIONERS Daniel R. Pearson, Chairman Shara L. Aranoff, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson* Dean A. Pinkert* *Coirmissioner Marcia E. Miller, whose term ended on September 6, 2005, participated in the decision to institute the investigation. Commissioner Shara L. Aranoff, whose term commenced on September 6, 2005, participated in all subsequent phases of the investigation. Commissioner Irving A. Williamson was sworn in on February 7, 2007, and Commissioner Dean A. Pinkert was sworn in on February 26, '2007; they did not participate in this investigation. Commissioner Stephen Koplan, whose term ended on February 6, 2007, and Commissioner Jennifer A. Hillman, whose term ended on February 23, 2007, did participate in this investigation. ' 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 In the Matter of Certain Tadalafil or any Salt or Solvate Thereof and Products Containing Same Investigation No. 337-TA-539 Publication 3992 May 2008 UNITED STATES INTERNATIONAL TRADE COMMISSION Washington, D.C. 20436 ) In the Matter of ) ) CERTAIN TADALAFIL OR ANY SALT OR ) Inv. No. 337-TA-539 SOLVATETHEREOFANDPRODUCTS ) CONTAINING SAME ) ~~~~~~~~~~~~~~~~~> NOTICE OF COMMISSION ISSUANCE OF GENERAL EXCLUSION ORDER; DECISION TO GRANT MOTION TO FILE A SURREPLY; TERMINATION OF THE INVESTIGATION AGENCY: U.S. International Trade Commission.
    [Show full text]
  • Bristol-Myers Squibb 2019 Annual Report
    We’re inspired by a single vision: 2019 ANNUAL REPORT Our Mission To discover, develop and deliver innovative medicines that help patients prevail over serious diseases Our Vision To be the world's leading biopharma company that transforms patients' lives through science The patient stories shared in this Annual Report depict individual patient responses to our medicines or investigational compounds and are not representative of all patient responses. In addition, there is no guarantee that potential drugs or indications still in development will receive regulatory approval. Bristol Myers Squibb 2019 Annual Report Myers Bristol Made Strong® is a registered mark of the Made Strong organization. Used with permission. Letter from the Chairman and CEO At Bristol Myers Squibb, we are inspired by our mission – to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. Every day, we focus on innovations that drive meaningful breakthroughs so we can bring life-saving medicines to people around the world. 2019 was a transformative year for us. A BIOPHARMA LEADER THE POWER OF FOLLOWING THE SCIENCE The acquisition of Celgene Corporation significantly We start this next chapter at a time when unprecedented advanced our strategy to create a leading biopharma scientific breakthroughs are advancing the treatment company by bringing together the speed and agility of disease as never before. Bristol Myers Squibb is well of a biotech with the global scale and resources of an positioned in scientific hubs of innovation in the U.S. and established pharmaceutical company. Our new company globally, and we collaborate with a broad network of global has strong commercial franchises in oncology, hematology, partners across our disease areas of focus to sustain our immunology and cardiovascular disease, one of the most leadership and continue to transform patient outcomes.
    [Show full text]
  • 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).
    [Show full text]
  • Lilly ICOS' Cialis® (Tadalafil) Reaches $1 Billion Global Sales Milestone
    July 21, 2005 Lilly ICOS' Cialis® (tadalafil) Reaches $1 Billion Global Sales Milestone -- Latest figures confirm success of Cialis in the global ED marketplace -- BOTHELL, Wash. and INDIANAPOLIS, Ind. – Lilly ICOS LLC (NYSE: LLY and NASDAQ: ICOS), marketer of tadalafil , a PDE5 inhibitor indicated for the treatment of erectile dysfunction (ED), announced today that the drug has achieved $1 billion in global sales since launching in Europe a little more than two years ago . In January 2005, tadalafil became the leading ED treatment in France, a lead it has held through May, based on the latest market share data . It is also performing very well in other countries, including the United Kingdom, Italy, Germany, United States, Canada, Australia, Mexico and Brazil . "We are very pleased with the performance of Cialis and the steady development of the brand since its launch two years ago," said Rich Pilnik, President of Lilly's EMEA region. "Millions of men suffer from ED and the growth of the market demonstrates that patients are speaking to their healthcare providers about ED and seeking treatment options." Tadalafil was the second PDE5 inhibitor drug to become available in Europe. It is currently marketed in approximately 100 countries including the United States, Australia, Brazil, Mexico, Canada and across Europe and Asia. "Passing the $1 billion mark is an important milestone for Lilly ICOS and a great accomplishment for the Cialis team" said Paul Clark, Chairman and Chief Executive Officer of ICOS Corporation. "Since 2003, men with erectile dysfunction have had a choice of oral treatments for their condition - a condition which may impact on relationships and daily life." About ED ED is defined as the consistent inability to attain and maintain an erection sufficient for sexual intercourse.
    [Show full text]
  • Vanderbilt Univ. V. ICOS Corp
    United States Court of Appeals for the Federal Circuit 2009-1258 VANDERBILT UNIVERSITY, Plaintiff-Appellant, v. ICOS CORPORATION, Defendant-Appellee. Robert S. Brennan, Miles & Stockbridge P.C., of Baltimore, Maryland, argued for plaintiff-appellant. With him on the brief were Donald E. English, Jr.; Kurt C. Rommel and James T. Carmichael, of McLean, Virginia. Of counsel were Leona Marx and David Williams, II, Vanderbilt University, of Nashville, Tennessee. Kevin M. Flowers, Marshall, Gerstein & Borun LLP, of Chicago, Illinois, argued for defendant-appellee. With him on the brief were Thomas I. Ross and Matthew C. Nielsen. Of counsel on the brief were Paul R. Cantrell, Donald L. Corneglio and Dan L. Wood, Eli Lilly and Company, of Indianapolis, Indiana. Appealed from: United States District Court for the District of Delaware Judge Sue L. Robinson United States Court of Appeals for the Federal Circuit 2009-1258 VANDERBILT UNIVERSITY, Plaintiff-Appellant, v. ICOS CORPORATION, Defendant-Appellee. Appeal from the United States District Court for the District of Delaware in case no. 05-CV-506, Judge Sue L. Robinson. __________________________ DECIDED: April 7, 2010 __________________________ Before MICHEL, Chief Judge, CLEVENGER and DYK, Circuit Judges. Opinion for the court filed by Circuit Judge CLEVENGER. Opinion concurring in part and dissenting in part filed by Circuit Judge DYK. CLEVENGER, Circuit Judge. This is an appeal from the United States District Court for the District of Delaware in a patent action that Vanderbilt University ("Vanderbilt") brought against ICOS Corporation ("ICOS") on July 20, 2005. Vanderbilt filed suit under 35 U.S.C. § 256 alleging that Vanderbilt scientists Jackie D.
    [Show full text]
  • Appeals Court Says Pfizer's Method of Use Patent Invalid
    Date: January 23, 2002 Refer to: (317) 277-8503 – Angela Sekston (Lilly) (425) 415-2207 - Lacy Fitzpatrick (ICOS) STATEMENT TO THE MEDIA UK Court of Appeal Rules in Lilly ICOS’ Favor: Appeals Court Says Pfizer’s Method of Use Patent Invalid Lilly ICOS LLC today announced that the UK Court of Appeal in London upheld a lower court’s ruling that found Pfizer’s entire “method of use” patent for PDE inhibitors to treat erectile dysfunction (ED) was invalid. This decision follows a December 2001 hearing in which Pfizer attempted to reinstate its method of use patent that was struck down by the High Court of Justice in London on November 8, 2000. Lilly ICOS offered the following statement regarding the decision: Lilly ICOS is pleased with the Court of Appeal’s decision. This ruling confirms what we have believed all along—that Pfizer's broad method of use patent was invalid. This decision makes it clear that Pfizer is not entitled to exclusivity in the field of ED in the UK. This decision is consistent with the decision of the Opposition Division of the European Patent Office which ruled last summer that Pfizer’s method of use patent was invalid. This decision leaves unaffected Pfizer’s compound patent for sildenafil. Lilly ICOS is investigating Cialis (tadalafil) for the treatment of sexual dysfunction. Requests for marketing approval of Cialis are currently under review by US and European regulatory agencies. Lilly ICOS LLC is a joint venture between ICOS Corporation (NASDAQ: ICOS) and Eli Lilly and Company (NYSE: LLY). Eli Lilly and Company, a leading innovation-driven corporation, is developing a growing portfolio of best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations.
    [Show full text]
  • Understanding History, and Not Repeating It. Neuroprotection For
    Clinical Neurology and Neurosurgery 129 (2015) 1–9 Contents lists available at ScienceDirect Clinical Neurology and Neurosurgery jo urnal homepage: www.elsevier.com/locate/clineuro Review Understanding history, and not repeating it. Neuroprotection for acute ischemic stroke: From review to preview a a b b,c a,b,c,d,∗ Stephen Grupke , Jason Hall , Michael Dobbs , Gregory J. Bix , Justin F. Fraser a Department of Neurosurgery, University of Kentucky, Lexington, USA b Department of Neurology, University of Kentucky, Lexington, USA c Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA d Department of Radiology, University of Kentucky, Lexington, USA a r t i c l e i n f o a b s t r a c t Article history: Background: Neuroprotection for ischemic stroke is a growing field, built upon the elucidation of the Received 17 April 2014 biochemical pathways of ischemia first studied in the 1970s. Beginning in the early 1990s, means by Received in revised form 7 November 2014 which to pharmacologically intervene and counteract these pathways have been sought, though with Accepted 13 November 2014 little clinical success. Through a comprehensive review of translations from laboratory to clinic, we aim Available online 3 December 2014 to evaluate individual mechanisms of action, while highlighting potential barriers to success that will guide future research. Keywords: Methods: The MEDLINE database and The Internet Stroke Center clinical trials registry were queried Acute stroke Angiography for trials involving the use of neuroprotective agents in acute ischemic stroke in human subjects. For the purpose of the review, neuroprotective agents refer to medications used to preserve or protect the Brain ischemia Drug trials potentially ischemic tissue after an acute stroke, excluding treatments designed to re-establish perfusion.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,258.268 B2 Wu Et Al
    USOO8258268B2 (12) United States Patent (10) Patent No.: US 8,258.268 B2 Wu et al. (45) Date of Patent: Sep. 4, 2012 (54) DUAL VARIABLE DOMAIN 5,624,821 A 4/1997 Winter et al. MMUNOGLOBULIN AND USES THEREOF 5,627,052 A 5/1997 Schrader et al. 5,641,870 A 6/1997 Rinderknecht et al. 5,648,260 A 7, 1997 Winter et al. (75) Inventors: Chengbin Wu, Shrewsbury, MA (US); 5,658,727 A 8, 1997 Barbas et al. Tariq Ghayur, Holliston, MA (US); 5,677,171 A 10, 1997 Hudziak et al. 5,679,377 A 10, 1997 Bernstein et al. Richard W. Dixon, Jefferson, MA (US); 5,693,762 A 12/1997 Queen et al. Jochen G. Salfeld, North Grafton, MA 5,698,426 A 12/1997 Huse et al. (US) 5,714,350 A 2f1998 CO et al. 5,714,352 A 2f1998 Jakobovits (73) Assignee: Abbott Laboratories, Abbott Park, IL 5,723,323 A 3, 1998 Kauffman et al. 5,733,743 A 3, 1998 Johnson et al. (US) 5,736,137 A 4, 1998 Anderson et al. 5,750,753 A 5/1998 Kimae et al. (*) Notice: Subject to any disclaimer, the term of this 5,763,192 A 6/1998 Kauffman et al. patent is extended or adjusted under 35 5,766,886 A 6/1998 Studnicka et al. 5,780,225 A 7/1998 Wigler et al. U.S.C. 154(b) by 0 days. 5,814,476 A 9, 1998 Kauffman et al. 5,817483. A 10, 1998 Kauffman et al.
    [Show full text]
  • Integrins As Therapeutic Targets: Successes and Cancers
    cancers Review Integrins as Therapeutic Targets: Successes and Cancers Sabine Raab-Westphal 1, John F. Marshall 2 and Simon L. Goodman 3,* 1 Translational In Vivo Pharmacology, Translational Innovation Platform Oncology, Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany; [email protected] 2 Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; [email protected] 3 Translational and Biomarkers Research, Translational Innovation Platform Oncology, Merck KGaA, 64293 Darmstadt, Germany * Correspondence: [email protected]; Tel.: +49-6155-831931 Academic Editor: Helen M. Sheldrake Received: 22 July 2017; Accepted: 14 August 2017; Published: 23 August 2017 Abstract: Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments. Keywords: integrin; therapy; clinical trial; efficacy; health care economics 1. Introduction Integrins are heterodimeric cell-surface adhesion molecules found on all nucleated cells. They integrate processes in the intracellular compartment with the extracellular environment. The 18 α- and 8 β-subunits form 24 different heterodimers each having functional and tissue specificity (reviewed in [1,2]).
    [Show full text]
  • ICOS) Receptor Agonist, Feladilimab, Alone and in Combination with Pembrolizumab: Results from INDUCE-1 Relapsed/Refractory Melanoma Expansion Cohorts
    Inducible T-cell co-stimulatory (ICOS) receptor agonist, feladilimab, alone and in combination with pembrolizumab: results from INDUCE-1 relapsed/refractory melanoma expansion cohorts M Maio MD PhD1, JS Weber MD PhD2, M Vieito Villar MD3, FL Opdam PharmD MD PhD4, V Moreno MD PhD5, O Hamid MD6, J Trigo MD7, M Chisamore PhD8, M Balas PharmD9, S Yadavilli MS9, DC Turner PhD9, C Henry PhD9, X Ji PhD9, C Ellis BA9, M Ballas MD MPH9, A Hoos MD PhD9, A Italiano MD PhD10 1University Hospital of Siena, Siena, Italy; 2Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA; 3Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain; 4The Netherlands Cancer Institute, Amsterdam, Netherlands; 5START Madrid-FJD, University Hospital “Fundacion Jimenez Diaz”, Madrid, Spain; 6The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, California, USA; 7Hospital Virgen de la Victoria y Regiona, IBIMA, Málaga, Spain; 8Merck & Co., Inc., Kenilworth, NJ, USA; 9GlaxoSmithKline, Collegeville, PA, USA; 10Institut Bergonié, Bordeaux, France Presenting author: Michele Maio, MD PhD ([email protected]) Disclosure Information Michele Maio I have the following financial relationships to disclose: Advisor/Consultant for: BMS, Roche, AZ, MSD, Merck, PierreFabre, and Alfasigma Travel/Accommodations/Expenses: BMS, AZ, Roche, MSD, Merck, Amgen, Pierre Fabre, and Alfasigma Patents/Royalties/Intellectual Property: DNA hypomethylating agents for cancer therapy Stocks/Shares held in: Theravance Honoraria:
    [Show full text]
  • Comirnaty, INN-COVID-19 Mrna Vaccine (Nucleoside-Modified)
    19 February 2021 EMA/707383/2020 Corr.1*1 Committee for Medicinal Products for Human Use (CHMP) Assessment report Comirnaty Common name: COVID-19 mRNA vaccine (nucleoside-modified) Procedure No. EMEA/H/C/005735/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 1 * Correction dated 19 February 2021 to clarify ERA statement Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us An agency of the European Union Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 © European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier ...................................................................................... 8 1.2. Steps taken for the assessment of the product ......................................................... 9 2. Scientific discussion .............................................................................. 11 2.1. Problem statement ............................................................................................. 11 2.1.1. Disease or condition ......................................................................................... 11 2.1.2. Epidemiology and risk factors ...........................................................................
    [Show full text]