DOCSLIB.ORG

Antigen Binding Protein and Its Use As Addressing Product for the Treatment of Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Antigen Binding Protein and Its Use As Addressing Product for the Treatment of Cancer (19) TZZ 58Z9A_T (11) EP 2 589 609 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.05.2013 Bulletin 2013/19 C07K 16/28 (2006.01) (21) Application number: 11306416.6 (22) Date of filing: 03.11.2011 (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB •Beau-Larvor, Charlotte GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO 74520 Jonzier Epagny (FR) PL PT RO RS SE SI SK SM TR • Goetsch, Liliane Designated Extension States: 74130 Ayze (FR) BA ME (74) Representative: Regimbeau (83) Declaration under Rule 32(1) EPC (expert 20, rue de Chazelles solution) 75847 Paris Cedex 17 (FR) (71) Applicant: PIERRE FABRE MEDICAMENT 92100 Boulogne-Billancourt (FR) (54) Antigen binding protein and its use as addressing product for the treatment of cancer (57) The present invention relates to an antigen bind- of Axl, being internalized into the cell. The invention also ing protein, in particular a monoclonal antibody, capable comprises the use of said antigen binding protein as an of binding specifically to the protein Axl as well as the addressing product in conjugation with other anti- cancer amino and nucleic acid sequences coding for said pro- compounds,such as toxins, radio- elements ordrugs, and tein. From one aspect, the invention relates to an antigen the use of same for the treatment of certain cancers. binding protein, or antigen binding fragments, capable of binding specifically to Axl and, by inducing internalization EP 2 589 609 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 589 609 A1 Description [0001] The present invention relates to a novel antigen binding protein, in particular a monoclonal antibody, capable of binding specifically to the protein Axl as well as the amino and nucleic acid sequences coding for said protein. From 5 one aspect, the invention relates to a novel antigen binding protein, or antigen binding fragments, capable of binding specifically to Axl and, by inducing internalization of Axl, being internalized into the cell. The invention also comprises the use of said antigen binding protein as an addressing product in conjugation with other anti-cancer compounds, such as toxins, radio-elements or drugs, and the use of same for the treatment of certain cancers. [0002] "Axl" (also referred to as "Ufo", "Ark" or "Tyro7") was cloned from patients with chronic myeloid leukemia as 10 an oncogene triggering the transformation when overexpressed by mouse NIH3T3. It belongs to a family of receptor tyrosine kinases (RTKs) called the TAM (Tyro3, Axl, Mer) family, which includes Tyro3 (Rse, Sky, Dtk, Etk, Brt, Tif), Axl, and Mer (Eyk, Nyk, Tyro-12) [Lemke G. Nat. Rev. Immunol. (2008).8, 327-336]. [0003] The human protein Axl is a 894 amino acids protein which sequence is represented in the sequence listing as SEQ ID NO. 29. Amino acids 1-25 corresponding to the signal peptide, the human protein Axl, without the said peptide 15 signal, is represented in the sequence listing as SEQ ID NO. 30. [0004] Gas6, originally isolated as growth arrest-specific gene, is the common ligand for the members of the TAM family [Varnum B.C. et al. Nature (1995). 373, 623-626]. Gas6 exhibits the highest affinity for Axl, followed by Tyro3 and finally by Mer [Nagata K. et al. J. Biol. Chem. (1996). 271, 30022-30027]. Gas6 consists in a γ-carboxyglutamate (Gla)-rich domain that mediates binding to phospholipid membranes, four epidermal growth factor-like domains, and two laminin 20 G-like (LG) domains [Manfioletti G., Brancolini,C., Avanzi,G. & Schneider,C. Mol. Cell Biol. (1993).13, 4976-4985]. As many other RTKs, ligand binding results in receptor dimerization and autophosphorylation of tyrosine residues (tyrosine residues 779, 821 and 866 for the receptor Axl) which serve as docking sites for a variety of intracellular signaling molecules [Linger R.M. Adv. Cancer Res. (2008).100, 35-83]. Moreover, the Axl receptor can be activated through a ligand-independent process. This activation can occur when the Axl receptor is overexpressed. 25 [0005] Gas6/Axl signaling has been shown to regulate various cellular processes including cell proliferation, adhesion, migration and survival in a large variety of cells in vitro [Hafizi S. & Dahlback,B. FEBS J. (2006).273, 5231-5244]. In addition, the TAM receptors are involved in the control of innate immunity; they inhibit the inflammatory responses to pathogens in dendritic cells (DCs) and macrophages. They also drive phagocytosis of apoptotic cells by these immune cells and they are required for the maturation and killing activity of natural killer (NK) cells [Lemke G. Nat. Rev. Immunol. 30 (2008).8, 327-336]. [0006] Weakly expressed on normal cells, it is predominantly observed in fibroblasts, myeloid progenitor cells, mac- rophages, neural tissues, cardiac and skeletal muscle where it supports mainly cell survival. The Gas6/Axl system plays an important role in vascular biology by regulating vascular smooth muscle cell homeostasis [Korshunov V.A., Mohan, A.M., Georger, M.A. & Berk, B.C. Circ. Res. (2006).98, 1446-1452; Korshunov V.A., Daul, M., Massett, M.P. & Berk, 35 B.C. Hypertension (2007).50, 1057-1062]. [0007] In tumor cells, Axl plays an important role in regulating cellular invasion and migration. Over-expression of Axl is associated not only with poor prognosis but also with increased invasiveness of various human cancers as reported for breast, colon, esophageal carcinoma, hepatocellular, gastric, glioma, lung, melanoma, osteosarcoma, ovarian, pros- tate, rhabdomyosarcoma, renal, thyroid and uterine endometrial cancer [Linger R.M. Adv. Cancer Res. (2008).100, 40 35-83 and Verma A. Mol. Cancer Ther. (2011). 10, 1763-1773, for reviews]. In breast cancer, Axl appears to be a strong effector of the Epithelial-to-mesenchymal transition (EMT); EMT program contributes actively to migration and dissem- ination of cancer cells in the organism [Thiery J.P. Curr. Opin. Cell Biol. (2003). 15, 740-746]. [0008] Axl has also been shown to regulate angiogenesis. Indeed knockdown of Axl in endothelial cells impaired tube formation and migration [Holland S.J. et al. Cancer Res. (2005). 65, 9294-9303] as well as disturbed specific angiogenic 45 signaling pathways [Li Y. et al. Oncogene (2009).28, 3442-3455]. [0009] More recently several studies on a range of cellular models described the involvement of an Axl overexpression in drug resistance phenomena. The following table 1 summarized these studies. Table 1 50 Reference Cancer type Therapeutic agent Cellular model Macleod et al., 2005 Ovarian cancer Cisplatin PE01/PEO1CDDP Mahadevan et al., Mahadevan Imatinib inhibitor of c-kit/ GIST GIST882 >GIST-R et al., 2007 PDGFR 55 Lay et al., 2007 NSCLC Doxorubicin CL-1 clones CL1-5F4 clones Hong et al., 2008 AML Doxorubicin/Cisplatin U937 2 EP 2 589 609 A1 (continued) Reference Cancer type Therapeutic agent Cellular model Lapatinib (HER1 and HER2 Liu et al., 2009 Breast Cancer HER2 (+) BT474 (J4) 5 inhibitor) Temozolomide Carboplatin Keating et al., 2010 Astrocytoma G12 A172 Vincristin Ye et al., 2010 NSCLC Erlotinib HCC827 10 [0010] Complete references cited in table 1 above are as follow: - Macleod, K. et al. Cancer Res. (2005).65, 6789-6800 15 - Mahadevan D. et al. Oncogene (2007).26, 3909-3919 - Lay J.D. et al. Cancer Res. (2007).67, 3878-3887 - Hong C.C. et al. Cancer Lett. (2008).268, 314-324 20 - Liu L. et al. Cancer Res. (2009).69, 6871-6878 - Keating A.K. et al. Mol. Cancer Ther. (2010).9, 1298-1307 25 - Ye X. et al. Oncogene (2010).29, 5254-5264 [0011] In such a context the Axl RTK is considered as an interesting target in oncology. Several groups already developed anti-tumoral strategies targeting the gas6/Axl axis, either using naked monoclonal antibodies or targeted small molecules [Verma A. Mol. Cancer Ther. (2011).10, 1763-1773]. 30 [0012] In a first embodiment, the invention relates to an antigen binding protein, or an antigen binding fragment thereof, which i) specifically binds to the human protein Axl, and ii) is internalized following its binding to said human protein Axl. [0013] More generally, the invention relates to the use of the protein Axl for the selection of an antigen binding protein, or an antigen binding fragment thereof, capable of being internalized following its binding to the said target Axl. More particularly, the said target is the extracellular domain of Axl. 35 [0014] In this particular aspect, the present invention is thus directed to anin vitro method for the screening of a compound, or a binding fragment thereof, capable of delivering or internalizing a molecule of interest into mammalian cells, said molecule of interest being covalently linked to said compound, wherein said method comprises the following steps of: 40 a) selecting a compound which is capable of specifically binding the Axl protein, or the extracellular domain (ECD) thereof, or an epitope thereof ; b) optionally, covalently linking said molecule of interest, or a control molecule, to said compound selected in step a) to form a complex; c) contacting said compound selected in step a), or said complex obtained in step b), with a mammal cell, preferably 45 viable cell, expressing at its surface the Axl protein, or a functional fragment thereof; d) determining whether said compound, or said molecule of interest or said complex, has been intracellularly delivered or internalized into said mammalian cell; and e) selecting said compound as a compound capable of delivering or internalizing a molecule of interest into a viable mammalian cell . 50 [0015] In a preferred embodiment, said compound capable of delivering or internalizing a molecule of interest into a viable mammalian cell is a protein (also designated herein polypeptide or peptide) or a protein-like compound comprising a peptidic structure, particularly an amino-acid sequence of at least 5, 10, 15 or more amino acids residues, said amino- acid residue(s) can be glycosylated.
Load more

Recommended publications
  • Methods for Predicting the Survival Time of Patients Suffering from a Lung Cancer
    THETWO TORTOITUUSN 20180252720A1ULLUM HOLATIN ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 / 0252720 A1 DIEU -NOSJEAN et al. (43 ) Pub. Date : Sep . 6 , 2018 (54 ) METHODS FOR PREDICTING THE Publication Classification SURVIVAL TIME OF PATIENTS SUFFERING (51 ) Int . Ci. FROM A LUNG CANCER GOIN 33 /574 ( 2006 .01 ) (71 ) Applicants : INSERM (INSTITUT NATIONAL ( 52 ) U . S . CI. DE LA SANTE ET DE LA CPC .. GOIN 33 /57423 (2013 . 01) ; GOIN 2800/ 52 RECHERCHE MEDICALE ) , Paris ( 2013 . 01 ) (FR ) ; UNIVERSITE PARIS DESCARTES , Paris ( FR ) ; SORBONNE UNIVERSITE , Paris (57 ) ABSTRACT (FR ) ; UNIVERSITE PARIS DIDEROT - PARIS 7 , Paris ( FR ) ; The present invention relates to methods for predicting the ASSISTANCE survival time of patients suffering from a lung cancer . In PUBLIQUE -HOPITAUX DE PARIS particular , the present invention relates to a method for (ADHP ) , Paris (FR ) predicting the survival time of a subject suffering from a lung cancer comprising the steps of i) quantifying the ( 72 ) Inventors: Marie - Caroline DIEU - NOSJEAN , density of regulatory T ( Treg ) cells in a tumor tissue sample Paris (FR ) ; Wolf Herdman obtained from the subject, ii ) quantifying the density of one FRIDMAN , Paris ( FR ) ; Catherine further population of immune cells selected from the group SAUTES - FRIDMAN , Paris ( FR ) ; consisting of TLS -mature DC or TLS - B cells or Tconv cells , Priyanka DEVI, Paris (FR ) CD8 + T cells or CD8 + Granzyme - B + T cells in said tumor tissue sample , iii ) comparing the densities quantified at steps (21 ) Appl. No. : 15/ 754 , 640 i ) and ii ) with their corresponding predetermined reference values and iv ) concluding that the subject will have a short ( 22 ) PCT Filed : Aug .
    [Show full text]
  • Trade-To-Generic Names
    LIST OF TRADE-TO-GENERIC NAMES Brand Name Generic Name Abraxane® Paclitaxel protein bound particles Adriamycin®, various Doxorubicin Adrucil® (various) Fluorouracil Alimta® Pemetrexed Alkeran® Melphalan Arimidex® Anastrozole Aromasin® Exemestane Arranon® Nelarabine Avastin® Bevacizumab Bexxar® Tositumomab BiCNU® Carmustine (BCNU) Blenoxane® Bleomycin Busulfex® Busulfan Injection Campath® Alemtuzumab Camptosar® Irinotecan (CPT-11) Casodex® Bicalutamide CeeNu® Lomustine (CCNU) Cerubidine® Daunorubicin Clolar® Clofarabine Cosmegen® Dactinomycin Cytadren® Aminoglutethimide Cytosar-U® Cytarabine (ara-C) Cytoxan®, various Cyclophosphamide Dacogen® Decitabine DaunoXome® Daunorubicin liposomal DepotCyt® Cytarabine Liposomal Doxil® Doxorubicin HCL (liposomal injection) DTIC-Dome® Dacarbazine (DTIC) Eldisine® Vindesine Eligard® Leuprolide acetate Ellence® Epirubicin Eloxatin® Oxaliplatin Elspar® Asparaginase EmCyt® Estramustine Erbitux® Cetuximab Etopofos® Etoposide Phosphate Eulexin® Flutamide Fareston® Toremifene Faslodex® Fluvestrant Femara® Letrozole Fludara® Fludarabine Gemzar® Gemcitabine Gleevec® Imatinib Gliadel® Carmustine Wafer Halotestin® Fluoxymesterone Last Updated on January 15, 2007 Brand Name Generic Name Herceptin® Trastuzumab Hexalen® Altretamine Hycamtin® Topotecan Hydrea® Hydroxyurea Idamycin® Idarubicin Ifex® Ifosfamide Intron A® Interferon alfa-2b Iressa® Gefitinib Leukeran® Chlorambucil Leukine® Sargramostim Leustatin® Cladribine Lupron depot® Leuprolide acetate depot Lupron® Leuprolide acetate Matulane® Procarbazine Megace®
    [Show full text]
  • Table of Contents
    ANTICANCER RESEARCH International Journal of Cancer Research and Treatment ISSN: 0250-7005 Volume 32, Number 4, April 2012 Contents Experimental Studies * Review: Multiple Associations Between a Broad Spectrum of Autoimmune Diseases, Chronic Inflammatory Diseases and Cancer. A.L. FRANKS, J.E. SLANSKY (Aurora, CO, USA)............................................ 1119 Varicella Zoster Virus Infection of Malignant Glioma Cell Cultures: A New Candidate for Oncolytic Virotherapy? H. LESKE, R. HAASE, F. RESTLE, C. SCHICHOR, V. ALBRECHT, M.G. VIZOSO PINTO, J.C. TONN, A. BAIKER, N. THON (Munich; Oberschleissheim, Germany; Zurich, Switzerland) .................................... 1137 Correlation between Adenovirus-neutralizing Antibody Titer and Adenovirus Vector-mediated Transduction Efficiency Following Intratumoral Injection. K. TOMITA, F. SAKURAI, M. TACHIBANA, H. MIZUGUCHI (Osaka, Japan) .......................................................................................................... 1145 Reduction of Tumorigenicity by Placental Extracts. A.M. MARLEAU, G. MCDONALD, J. KOROPATNICK, C.-S. CHEN, D. KOOS (Huntington Beach; Santa Barbara; Loma Linda; San Diego, CA, USA; London, ON, Canada) ...................................................................................................................................... 1153 Stem Cell Markers as Predictors of Oral Cancer Invasion. A. SIU, C. LEE, D. DANG, C. LEE, D.M. RAMOS (San Francisco, CA, USA) ................................................................................................
    [Show full text]
  • Journal of Pharmacology and Experimental Therapeutics
    Journal of Pharmacology and Experimental Therapeutics Molecular Determinants of Ligand Selectivity for the Human Multidrug And Toxin Extrusion Proteins, MATE1 and MATE-2K Bethzaida Astorga, Sean Ekins, Mark Morales and Stephen H Wright Department of Physiology, University of Arizona, Tucson, AZ 85724, USA (B.A., M.M., and S.H.W.) Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay-Varina NC 27526, USA (S.E.) Supplemental Table 1. Compounds selected by the common features pharmacophore after searching a database of 2690 FDA approved compounds (www.collaborativedrug.com). FitValue Common Name Indication 3.93897 PYRIMETHAMINE Antimalarial 3.3167 naloxone Antidote Naloxone Hydrochloride 3.27622 DEXMEDETOMIDINE Anxiolytic 3.2407 Chlordantoin Antifungal 3.1776 NALORPHINE Antidote Nalorphine Hydrochloride 3.15108 Perfosfamide Antineoplastic 3.11759 Cinchonidine Sulfate Antimalarial Cinchonidine 3.10352 Cinchonine Sulfate Antimalarial Cinchonine 3.07469 METHOHEXITAL Anesthetic 3.06799 PROGUANIL Antimalarial PROGUANIL HYDROCHLORIDE 100MG 3.05018 TOPIRAMATE Anticonvulsant 3.04366 MIDODRINE Antihypotensive Midodrine Hydrochloride 2.98558 Chlorbetamide Antiamebic 2.98463 TRIMETHOPRIM Antibiotic Antibacterial 2.98457 ZILEUTON Antiinflammatory 2.94205 AMINOMETRADINE Diuretic 2.89284 SCOPOLAMINE Antispasmodic ScopolamineHydrobromide 2.88791 ARTICAINE Anesthetic 2.84534 RITODRINE Tocolytic 2.82357 MITOBRONITOL Antineoplastic Mitolactol 2.81033 LORAZEPAM Anxiolytic 2.74943 ETHOHEXADIOL Insecticide 2.64902 METHOXAMINE Antihypotensive Methoxamine
    [Show full text]
  • Lonidamine Induces Apoptosis in Drug-Resistant Cells Independently of the P53 Gene
    Lonidamine induces apoptosis in drug-resistant cells independently of the p53 gene. D Del Bufalo, … , A Sacchi, G Zupi J Clin Invest. 1996;98(5):1165-1173. https://doi.org/10.1172/JCI118900. Research Article Lonidamine, a dichlorinated derivative of indazole-3-carboxylic acid, was shown to play a significant role in reversing or overcoming multidrug resistance. Here, we show that exposure to 50 microg/ml of lonidamine induces apoptosis in adriamycin and nitrosourea-resistant cells (MCF-7 ADR(r) human breast cancer cell line, and LB9 glioblastoma multiform cell line), as demonstrated by sub-G1 peaks in DNA content histograms, condensation of nuclear chromatin, and internucleosomal DNA fragmentation. Moreover, we find that apoptosis is preceded by accumulation of the cells in the G0/G1 phase of the cell cycle. Interestingly, lonidamine fails to activate the apoptotic program in the corresponding sensitive parental cell lines (ADR-sensitive MCF-7 WT, and nitrosourea-sensitive LI cells) even after long exposure times. The evaluation of bcl-2 protein expression suggests that this different effect of lonidamine treatment in drug-resistant and -sensitive cell lines might not simply be due to dissimilar expression levels of bcl-2 protein. To determine whether the lonidamine-induced apoptosis is mediated by p53 protein, we used cells lacking endogenous p53 and overexpressing either wild-type p53 or dominant-negative p53 mutant. We find that apoptosis by lonidamine is independent of the p53 gene. Find the latest version: https://jci.me/118900/pdf
    [Show full text]
  • Effect of Lonidamine on Systemic Therapy of DB-1 Human Melanoma Xenografts with Temozolomide KAVINDRA NATH 1, DAVID S
    ANTICANCER RESEARCH 37 : 3413-3421 (2017) doi:10.21873/anticanres.11708 Effect of Lonidamine on Systemic Therapy of DB-1 Human Melanoma Xenografts with Temozolomide KAVINDRA NATH 1, DAVID S. NELSON 1, JEFFREY ROMAN 1, MARY E. PUTT 2, SEUNG-CHEOL LEE 1, DENNIS B. LEEPER 3 and JERRY D. GLICKSON 1 Departments of 1Radiology and 2Biostatistics & Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, U.S.A.; 3Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, U.S.A. Abstract. Background/Aim: Since temozolomide (TMZ) is stages. However, following recurrence with metastasis, the activated under alkaline conditions, we expected lonidamine prognosis is poor. Mutationally-activated BRAF is found in (LND) to have no effect or perhaps diminish its activity, but 40-60% of all melanomas with most common substitution of initial results suggest it may actually enhance either or both valine to glutamic acid at codon 600 (p. V600E) (3). Overall short- and long-term activity of TMZ in melanoma xenografts. survival is approaching two years using agents that target this Materials and Methods: Cohorts of 5 mice with subcutaneous mutation (4, 5). MEK, RAS and other signal transduction xenografts ~5 mm in diameter were treated with saline inhibitors, in combination with mutant BRAF inhibitors, have (control (CTRL)), LND only, TMZ only or LND followed by been used to deal with melanoma resistance to these agents TMZ at t=40 min (time required for maximal tumor (6). Treatment with anti-programmed death-1 (PD-1) acidification). Results: Mean tumor volume for LND+TMZ for checkpoint inhibitor immunotherapy currently produces the period between 6 and 26 days was reduced compared to durable response in about 25% of melanoma patients (7-10).
    [Show full text]
  • Mepact, INN-Mifamurtide
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT MEPACT 4 mg powder for concentrate for dispersion for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains 4 mg mifamurtide*. After reconstitution, each mL of suspension in the vial contains 0.08 mg mifamurtide. *fully synthetic analogue of a component of Mycobacterium sp. cell wall. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for concentrate for dispersion for infusion White to off-white homogeneous cake or powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications MEPACT is indicated in children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection. It is used in combination with post-operative multi-agent chemotherapy. Safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis (see section 5.1). 4.2 Posology and method of administration Mifamurtide treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of osteosarcoma. Posology The recommended dose of mifamurtide for all patients is 2 mg/m2 body surface area. It should be administered as adjuvant therapy following resection: twice weekly at least 3 days apart for 12 weeks, followed by once-weekly treatments for an additional 24 weeks for a total of 48 infusions in 36 weeks. Special populations Adults > 30 years None of the patients treated in the osteosarcoma studies were 65 years or older and in the phase III randomised study, only patients up to the age of 30 years were included.
    [Show full text]
  • Advances and Limitations of Antibody Drug Conjugates for Cancer
    biomedicines Review Advances and Limitations of Antibody Drug Conjugates for Cancer Candice Maria Mckertish and Veysel Kayser * Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia; [email protected] * Correspondence: [email protected]; Tel.: +61-2-9351-3391 Abstract: The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful devel- opment of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation. Keywords: antibody drug conjugates; drug resistance; linkers; payloads; therapeutic index; target specific; ADC clearance; protein aggregation Citation: Mckertish, C.M.; Kayser, V. Advances and Limitations of Antibody Drug Conjugates for 1. Introduction Cancer. Biomedicines 2021, 9, 872. Conventional cancer therapy often entails a low therapeutic window and non-specificity https://doi.org/10.3390/ of chemotherapeutic agents that consequently affects normal cells with high mitotic rates biomedicines9080872 and provokes an array of adverse effects, and in some cases leads to drug resistance [1].
    [Show full text]
  • 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
    [Show full text]
  • Phenotype Microarrays Panels PM-M1 to PM-M14
    Phenotype MicroArrays™ Panels PM-M1 to PM-M14 for Phenotypic Characterization of Mammalian Cells Assays: Energy Metabolism Pathways Ion and Hormone Effects on Cells Sensitivity to Anti-Cancer Agents and for Optimizing Culture Conditions for Mammalian Cells PRODUCT DESCRIPTIONS AND INSTRUCTIONS FOR USE PM-M1 Cat. #13101 PM-M2 Cat. #13102 PM-M3 Cat. #13103 PM-M4 Cat. #13104 PM-M5 Cat. #13105 PM-M6 Cat. #13106 PM-M7 Cat. #13107 PM-M8 Cat. #13108 PM-M11 Cat. #13111 PM-M12 Cat. #13112 PM-M13 Cat. #13113 PM-M14 Cat. #13114 © 2016 Biolog, Inc. All rights reserved Printed in the United States of America 00P 134 Rev F February 2020 - 1 - CONTENTS I. Introduction ...................................................................................................... 2 a. Overview ................................................................................................... 2 b. Background ............................................................................................... 2 c. Uses ........................................................................................................... 2 d. Advantages ................................................................................................ 3 II. Product Description, PM-M1 to M4 ................................................................ 3 III. Protocols, PM-M1 to M4 ................................................................................. 7 a. Materials Required .................................................................................... 7 b. Determination
    [Show full text]
  • Chemical Properties Biological Description Solubility
    Data Sheet (Cat.No.T4412) Roquinimex Chemical Properties CAS No.: 84088-42-6 Formula： C18H16N2O3 Molecular Weight： 308.34 Appearance： N/A Storage： 0-4℃ for short term (days to weeks), or -20℃ for long term (months). Biological Description Description Roquinimex (Linomide) is a quinoline derivative immunostimulant which increases NK cell activity and macrophage cytotoxicity; inhibits angiogenesis and reduces the secretion of TNF alpha. Targets(IC50) Others: None In vivo Prophylactic administration of DSS-treated mice with roquinimex significantly reduced clinical signs of colitis, MDS and the CH-reduction. Moreover, in roquinimex treated animals, the MPO activity was significantly reduced by more than 50% compared to DSS control mice. Notably, therapeutic administration of roquinimex in DSS-treated mice also significantly inhibited the MDS, CH-reduction and MPO activity. Linomide, a synthetic immunomodulator, at concentrations effective in vivo reduces the number of MBP-reactive TNF-alpha and increases MBP-reactive IL-10 and TGF-beta mRNA expressing MNC from MS patients' blood when analysed in vitro. Compared to dexamethasone, Linomide up-regulated levels of blood MNC expressing mRNA of TGF-beta after culture in presence of MBP Solubility Information Solubility DMSO: 83.3 mg/mL (270.17 mM) (< 1 mg/ml refers to the product slightly soluble or insoluble) Preparing Stock Solutions 1mg 5mg 10mg 1 mM 3.243 mL 16.216 mL 32.432 mL 5 mM 0.649 mL 3.243 mL 6.486 mL 10 mM 0.324 mL 1.622 mL 3.243 mL 50 mM 0.065 mL 0.324 mL 0.649 mL Please select the appropriate solvent to prepare the stock solution, according to the solubility of the product in different solvents.
    [Show full text]
  • Encapsulation of Nedaplatin in Novel Pegylated Liposomes Increases Its Cytotoxicity and Genotoxicity Against A549 and U2OS Human Cancer Cells
    pharmaceutics Article Encapsulation of Nedaplatin in Novel PEGylated Liposomes Increases Its Cytotoxicity and Genotoxicity against A549 and U2OS Human Cancer Cells 1, 2, 1 1 2, Salma El-Shafie y, Sherif Ashraf Fahmy y , Laila Ziko , Nada Elzahed , Tamer Shoeib * and Andreas Kakarougkas 1,* 1 Department of Biology, School of Sciences and Engineering, The American University in Cairo, Cairo 11835, Egypt; [email protected] (S.E.-S.); [email protected] (L.Z.); [email protected] (N.E.) 2 Department of Chemistry, School of Sciences and Engineering, The American University in Cairo, Cairo 11835 Egypt; sheriff[email protected] * Correspondence: [email protected] (T.S.); [email protected] (A.K.) These authors contribute equally to this paper. y Received: 7 April 2020; Accepted: 25 August 2020; Published: 10 September 2020 Abstract: Following the discovery of cisplatin over 50 years ago, platinum-based drugs have been a widely used and effective form of cancer therapy, primarily causing cell death by inducing DNA damage and triggering apoptosis. However, the dose-limiting toxicity of these drugs has led to the development of second and third generation platinum-based drugs that maintain the cytotoxicity of cisplatin but have a more acceptable side-effect profile. In addition to the creation of new analogs, tumor delivery systems such as liposome encapsulated platinum drugs have been developed and are currently in clinical trials. In this study, we have created the first PEGylated liposomal form of nedaplatin using thin film hydration. Nedaplatin, the main focus of this study, has been exclusively used in Japan for the treatment of non-small cell lung cancer, head and neck, esophageal, bladder, ovarian and cervical cancer.
    [Show full text]