Patent application EP16169237A (EP), filed 2016-05-11
Publication number: EP3243836A1
Title: C-TERMINALLY FUSED TNF FAMILY LIGAND TRIMER-CONTAINING ANTIGEN BINDING MOLECULES
Abstract: [0001]    The invention relates to novel TNF family ligand trimer-containing antigen binding molecules comprising (a) a Fab domain capable of specific binding to a target cell antigen, (b) a Fc domain composed of a first and a second subunit capable of stable association, and (c) a first polypeptide comprising two ectodomains of a TNF ligand family member or fragments thereof that are connected to each other by a peptide linker and a second polypeptide comprising one ectodomain of said TNF ligand family member or a fragment thereof, wherein the first polypeptide is fused at its N-terminus to the C-terminus of one of the subunits of the Fc domain and wherein the second polypeptide is fused at its N-terminus to the C-terminus of the other subunit of the Fc domain.
IPC codes: A61K  39/   395            A I
C07K  14/   705            A I
C07K  14/   715            A I
C07K  16/    14            A I
C07K  16/    24            A I
C07K  16/    28            A I
Claims: number: 1
text: 1. A TNF family ligand trimer-containing antigen binding molecule comprising
number: 2
text: 2. The TNF family ligand trimer-containing antigen binding molecule of claim 1, wherein the TNF ligand family member costimulates human T-cell activation.
number: 3
text: 3. The TNF family ligand trimer-containing antigen binding molecule of claims 1 or 2, wherein the TNF ligand family member is selected from 4-1BBL and OX40L.
number: 4
text: 4. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 3, wherein the ectodomain of a TNF ligand family member comprises the amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, particularly the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:5.
number: 5
text: 6. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 3, wherein the ectodomain of a TNF ligand family member comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 11 and SEQ ID NO:12.
number: 6
text: 7. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 8, wherein TNF family ligand trimer-containing antigen binding molecule is monovalent for the binding to the target cell antigen.
number: 7
text: 8. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 7, wherein the target cell antigen is selected from the group consisting of Fibroblast Activation Protein (FAP), Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP), Epidermal Growth Factor Receptor (EGFR), Carcinoembryonic Antigen (CEA), CD19, CD20 and CD33.
number: 8
text: 9. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 8, wherein the target cell antigen is Fibroblast Activation Protein (FAP).
number: 9
text: 10. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 8, wherein the target cell antigen is CD 19.
number: 10
text: 11. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 8, wherein the target cell antigen is CEA.
number: 11
text: 12. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 21, wherein the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (numbering according to Kabat EU index) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, L368A and Y407V (numbering according to Kabat EU index).
number: 12
text: 13. The TNF family ligand trimer-containing antigen binding molecule of any one of claim 12, wherein the first polypeptide comprising two ectodomains of a TNF ligand family member or fragments thereof that are connected to each other by a peptide linker is fused at its N-terminus to the C-terminus of the second subunit of the Fc domain and the second polypeptide comprising one ectodomain of said TNF ligand family member or a fragment thereof is fused at its N-terminus to the C-terminus of the first subunit of the Fc domain.
number: 13
text: 14. The TNF family ligand trimer-containing antigen binding molecule of any one of claim 12, wherein the first polypeptide comprising two ectodomains of a TNF ligand family member or fragments thereof that are connected to each other by a peptide linker is fused at its N-terminus to the C-terminus of the first subunit of the Fc domain and the second polypeptide comprising one ectodomain of said TNF ligand family member or a fragment thereof is fused at its N-terminus to the C-terminus of the second subunit of the Fc domain.
number: 14
text: 15. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 14, wherein the Fab domain capable of specific binding to a target cell antigen is fused at the C-terminus to the N-terminus of the first subunit of the Fc domain.
number: 15
text: 16. The TNF family ligand trimer-containing antigen binding molecule of any one of claims 1 to 26 further comprising
Office action: search_report, dated 2017-11-15
Rejection reasons: novelty_epc_54
inventive_step_epc_56
Prior art cited: ref_id: WO2010010051A1
ref_type: patent
severity: background
ref_id: WO0220565A2
ref_type: patent
severity: background
ref_id: WO9316185A2
ref_type: patent
severity: background
ref_id: US5571894A
ref_type: patent
severity: background
ref_id: US5587458A
ref_type: patent
severity: background
ref_id: US5869046A
ref_type: patent
severity: background
ref_id: EP0404097A2
ref_type: patent
severity: background
ref_id: WO9301161A1
ref_type: patent
severity: background
ref_id: US6248516B1
ref_type: patent
severity: background
ref_id: WO2012020006A2
ref_type: patent
severity: background
ref_id: US5821333A
ref_type: patent
severity: background
ref_id: US5731168A
ref_type: patent
severity: background
ref_id: US7695936B2
ref_type: patent
severity: background
ref_id: US2003157108A1
ref_type: patent
severity: background
ref_id: US2004093621A1
ref_type: patent
severity: background
ref_id: WO03011878A2
ref_type: patent
severity: background
ref_id: US6602684B1
ref_type: patent
severity: background
ref_id: US2005123546A1
ref_type: patent
severity: background
ref_id: WO9730087A1
ref_type: patent
severity: background
ref_id: WO9858964A1
ref_type: patent
severity: background
ref_id: WO9922764A1
ref_type: patent
severity: background
ref_id: US7521541B2
ref_type: patent
severity: background
ref_id: WO2012130831A1
ref_type: patent
severity: background
ref_id: US6737056B1
ref_type: patent
severity: background
ref_id: US7332581B2
ref_type: patent
severity: background
ref_id: US5500362A
ref_type: patent
severity: background
ref_id: US5821337A
ref_type: patent
severity: background
ref_id: WO2006029879A2
ref_type: patent
severity: background
ref_id: WO2005100402A1
ref_type: patent
severity: background
ref_id: WO2009089004A1
ref_type: patent
severity: background
ref_id: US5959177A
ref_type: patent
severity: background
ref_id: US6040498A
ref_type: patent
severity: background
ref_id: US6420548B1
ref_type: patent
severity: background
ref_id: US7125978B1
ref_type: patent
severity: background
ref_id: US6417429B1
ref_type: patent
severity: background
ref_id: US4186567A
ref_type: patent
severity: background
ref_id: US5969108A
ref_type: patent
severity: background
ref_id: US5565332A
ref_type: patent
severity: background
ref_id: US7527791B2
ref_type: patent
severity: background
ref_id: US6982321B2
ref_type: patent
severity: background
ref_id: US7087409B2
ref_type: patent
severity: background
ref_id: US2004132066A1
ref_type: patent
severity: background
ref_id: US2005260186A1
ref_type: patent
severity: background
ref_id: US2006104968A1
ref_type: patent
severity: background
ref_id: US6267958B1
ref_type: patent
severity: background
ref_id: US6171586B1
ref_type: patent
severity: background
ref_id: WO2006044908A2
ref_type: patent
severity: background
ref_id: WO2011147834A1
ref_type: patent
severity: background
ref_id: WO2010145792A1
ref_type: patent
severity: background
ref_id: US6054297A
ref_type: patent
severity: background
ref_id: - HUDSON ET AL., NAT MED, vol. 9, 2003, pages 129 - 134
ref_type: npl
severity: background
ref_id: - PLUCKTHUN: "The Pharmacology of Monoclonal Antibodies", vol. 113, 1994, SPRINGER-VERLAG, pages: 269 - 315
ref_type: npl
severity: background
ref_id: - HOLLINGER ET AL., PROC NATL ACAD SCI USA, vol. 90, 1993, pages 6444 - 6448
ref_type: npl
severity: background
ref_id: - HOUSTON, J.S., METHODS IN ENZYMOL., vol. 203, 1991, pages 46 - 96
ref_type: npl
severity: background
ref_id: - GEBAUER; SKERRA: "Engineered protein scaffolds as next-generation antibody therapeutics", CURR OPIN CHEM BIOL, vol. 13, 2009, pages 245 - 255
ref_type: npl
severity: background
ref_id: - STUMPP ET AL.: "Darpins: A new generation of protein therapeutics", DRUG DISCOVERY TODAY, vol. 13, 2008, pages 695 - 701, XP023440383, DOI: doi:10.1016/j.drudis.2008.04.013
ref_type: npl
severity: background
ref_id: - LILJEBLAD ET AL., GLYCO J, vol. 17, 2000, pages 323 - 329
ref_type: npl
severity: background
ref_id: - HEELEY, ENDOCR RES, vol. 28, 2002, pages 217 - 229
ref_type: npl
severity: background
ref_id: - GOLD; FREEDMAN, J EXP MED., vol. 121, 1965, pages 439 - 462
ref_type: npl
severity: background
ref_id: - BERINSTEIN N. L., J CLIN ONCOL., vol. 20, 2002, pages 2197 - 2207
ref_type: npl
severity: background
ref_id: - NAP ET AL., TUMOUR BIOL., vol. 9, no. 2-3, 1988, pages 145 - 153
ref_type: npl
severity: background
ref_id: - NAP ET AL., CANCER RES., vol. 52, no. 8, 1992, pages 2329 - 2339
ref_type: npl
severity: background
ref_id: - HAMMARSTROM S., SEMIN CANCER BIOL., vol. 9, no. 2, 1999, pages 67 - 81
ref_type: npl
severity: background
ref_id: - MARSHALL J., SEMIN ONCOL., vol. 30, no. 8, 2003, pages 30 - 36
ref_type: npl
severity: background
ref_id: - GOLDENBERG D M., THE INTERNATIONAL JOURNAL OF BIOLOGICAL MARKERS, vol. 7, 1992, pages 183 - 188
ref_type: npl
severity: background
ref_id: - CHAU I. ET AL., J CLIN ONCOL., vol. 22, 2004, pages 1420 - 1429
ref_type: npl
severity: background
ref_id: - FLAMINI ET AL., CLIN CANCER RES, vol. 12, no. 23, 2006, pages 6985 - 6988
ref_type: npl
severity: background
ref_id: - KINDT ET AL.: "Kuby Immunology", 2007, W.H. FREEMAN AND CO., pages: 91
ref_type: npl
severity: background
ref_id: - CHOTHIA; LESK, J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
ref_type: npl
severity: background
ref_id: - KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, NATIONAL INSTITUTES OF HEALTH
ref_type: npl
severity: background
ref_id: - KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1983
ref_type: npl
severity: background
ref_id: - CHOTHIA ET AL., J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
ref_type: npl
severity: background
ref_id: - KABAT ET AL.: "Sequence of Proteins of Immunological Interest", 1983
ref_type: npl
severity: background
ref_id: - ALMAGRO; FRANSSON, FRONT. BIOSCI., vol. 13, 2008, pages 1619 - 1633
ref_type: npl
severity: background
ref_id: - RIDGWAY ET AL., PROT ENG, vol. 9, 1996, pages 617 - 621
ref_type: npl
severity: background
ref_id: - CARTER, J IMMUNOL METH, vol. 248, 2001, pages 7 - 15
ref_type: npl
severity: background
ref_id: - CARTER, J IMMUNOL METHODS, vol. 248, 2001, pages 7 - 15
ref_type: npl
severity: background
ref_id: - BOWIE, J. U. ET AL., SCIENCE, vol. 247, 1990, pages 1306 - 1310
ref_type: npl
severity: background
ref_id: - CUNNINGHAM; WELLS, SCIENCE, vol. 244, 1989, pages 1081 - 1085
ref_type: npl
severity: background
ref_id: - WRIGHT ET AL., TIBTECH, vol. 15, 1997, pages 26 - 32
ref_type: npl
severity: background
ref_id: - KAM, N.W. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 102, 2005, pages 11600 - 11605
ref_type: npl
severity: background
ref_id: - HELLSTROM ET AL., PROC NATL ACAD SCI USA, vol. 83, 1986, pages 7059 - 7063
ref_type: npl
severity: background
ref_id: - HELLSTROM ET AL., PROC NATL ACAD SCI USA, vol. 82, 1985, pages 1499 - 1502
ref_type: npl
severity: background
ref_id: - BRUGGEMANN ET AL., J EXP MED, vol. 166, 1987, pages 1351 - 1361
ref_type: npl
severity: background
ref_id: - CLYNES ET AL., PROC NATL ACAD SCI USA, vol. 95, 1998, pages 652 - 656
ref_type: npl
severity: background
ref_id: - GAZZANO-SANTORO ET AL., J IMMUNOL METHODS, vol. 202, 1996, pages 163
ref_type: npl
severity: background
ref_id: - CRAGG ET AL., BLOOD, vol. 101, 2003, pages 1045 - 1052
ref_type: npl
severity: background
ref_id: - CRAGG; GLENNIE, BLOOD, vol. 103, 2004, pages 2738 - 2743
ref_type: npl
severity: background
ref_id: - MANIATIS ET AL.: "MOLECULAR CLONING: A LABORATORY MANUAL", 1989, COLD SPRING HARBOR LABORATORY
ref_type: npl
severity: background
ref_id: - AUSUBEL ET AL.: "CURRENT PROTOCOLS IN MOLECULAR BIOLOGY", 1989, GREENE PUBLISHING ASSOCIATES AND WILEY INTERSCIENCE
ref_type: npl
severity: background
ref_id: - GERNGROSS, NAT BIOTECH, vol. 22, 2004, pages 1409 - 1414
ref_type: npl
severity: background
ref_id: - LI ET AL., NAT BIOTECH, vol. 24, 2006, pages 210 - 215
ref_type: npl
severity: background
ref_id: - GRAHAM ET AL., J GEN VIROL, vol. 36, 1977, pages 59
ref_type: npl
severity: background
ref_id: - MATHER, BIOL REPROD, vol. 23, 1980, pages 243 - 251
ref_type: npl
severity: background
ref_id: - MATHER ET AL., ANNALS N.Y. ACAD SCI, vol. 383, 1982, pages 44 - 68
ref_type: npl
severity: background
ref_id: - URLAUB ET AL., PROC NATL ACAD SCI USA, vol. 77, 1980, pages 4216
ref_type: npl
severity: background
ref_id: - YAZAKI; WU: "Methods in Molecular Biology", vol. 248, 2003, HUMANA PRESS, pages: 255 - 268
ref_type: npl
severity: background
ref_id: - HARLOW; LANE: "Antibodies, a laboratory manual", 1988, COLD SPRING HARBOR LABORATORY
ref_type: npl
severity: background
ref_id: - ALMAGRO; FRANSSON, FRONT BIOSCI, vol. 13, 2008, pages 1619 - 1633
ref_type: npl
severity: background
ref_id: - RIECHMANN ET AL., NATURE, vol. 332, 1988, pages 323 - 329
ref_type: npl
severity: background
ref_id: - QUEEN ET AL., PROC NATL ACAD SCI USA, vol. 86, 1989, pages 10029 - 10033
ref_type: npl
severity: background
ref_id: - JONES ET AL., NATURE, vol. 321, 1986, pages 522 - 525
ref_type: npl
severity: background
ref_id: - MORRISON ET AL., PROC NATL ACAD SCI, vol. 81, 1984, pages 6851 - 6855
ref_type: npl
severity: background
ref_id: - MORRISON; OI, ADV IMMUNOL, vol. 44, 1988, pages 65 - 92
ref_type: npl
severity: background
ref_id: - VERHOEYEN ET AL., SCIENCE, vol. 239, 1988, pages 1534 - 1536
ref_type: npl
severity: background
ref_id: - PADLAN, MOLEC IMMUN, vol. 31, no. 3, 1994, pages 169 - 217
ref_type: npl
severity: background
ref_id: - KASHMIRI ET AL., METHODS, vol. 36, 2005, pages 25 - 34
ref_type: npl
severity: background
ref_id: - PADLAN, MOL IMMUNOL, vol. 28, 1991, pages 489 - 498
ref_type: npl
severity: background
ref_id: - DALL'ACQUA ET AL., METHODS, vol. 36, 2005, pages 43 - 60
ref_type: npl
severity: background
ref_id: - OSBOURN ET AL., METHODS, vol. 36, 2005, pages 61 - 68
ref_type: npl
severity: background
ref_id: - KLIMKA ET AL., BR J CANCER, vol. 83, 2000, pages 252 - 260
ref_type: npl
severity: background
ref_id: - VAN DIJK; VAN DE WINKEL, CURR OPIN PHARMACOL, vol. 5, 2001, pages 368 - 374
ref_type: npl
severity: background
ref_id: - LONBERG, CURR OPIN IMMUNOL, vol. 20, 2008, pages 450 - 459
ref_type: npl
severity: background
ref_id: - "Monoclonal Antibody Production Techniques and Applications", 1987, MARCEL DEKKER, INC., pages: 51 - 63
ref_type: npl
severity: background
ref_id: - LONBERG, NAT BIOTECH, vol. 23, 2005, pages 1117 - 1125
ref_type: npl
severity: background
ref_id: - HOOGENBOOM ET AL.: "Methods in Molecular Biology", vol. 178, 2001, HUMAN PRESS, pages: 1 - 37
ref_type: npl
severity: background
ref_id: - MCCAFFERTY ET AL., NATURE, vol. 348, pages 552 - 554
ref_type: npl
severity: background
ref_id: - CLACKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
ref_type: npl
severity: background
ref_id: - MORRIS: "Methods in Molecular Biology", vol. 66, 1996, HUMANA PRESS, article "Epitope Mapping Protocols"
ref_type: npl
severity: background
ref_id: - HARLOW; LANE: "Antibodies: A Laboratory Manual", 1988, COLD SPRING HARBOR LABORATORY
ref_type: npl
severity: background
ref_id: - "Remington's Pharmaceutical Sciences", 1990, MACK PRINTING COMPANY
ref_type: npl
severity: background
ref_id: - SAMBROOK ET AL.: "Molecular cloning: A laboratory manual", 1989, COLD SPRING HARBOR LABORATORY PRESS
ref_type: npl
severity: background
ref_id: - KABAT, E.A. ET AL.: "Sequences of Proteins of Immunological Interest", 1991, NIH PUBLICATION NO 91-3242
ref_type: npl
severity: background
ref_id: - "Current Protocols in Cell Biology", 2000, JOHN WILEY & SONS, INC.
ref_type: npl
severity: background
ref_id: - MOREA, V. ET AL., METHODS, vol. 20, no. 3, 2000, pages 267 - 279
ref_type: npl
severity: background
ref_id: - JENDEBERG L. ET AL., J. IMMUNOLOGICAL METHODS, 1997
ref_type: npl
severity: background
ref_id: - WAGENER ET AL., J IMMUNOL, vol. 130, 1983, pages 2308
ref_type: npl
severity: background
ref_id: - NEUMAIER ET AL., J IMMUNOL, vol. 135, 1985, pages 3604
ref_type: npl
severity: background
ref_id: - VAN MUIJEN GN; JANSEN KF; CORNELISSEN IM; SMEETS DF; BECK JL; RUITER DJ: "Establishment and characterization of a human melanoma cell line (MV3) which is highly metastatic in nude mice", INT J CANCER, vol. 48, no. 1, 22 April 1991 (1991-04-22), pages 85 - 91
ref_type: npl
severity: background
ref_id: - RODRIGUES ET AL., INT J CANCER, 1992, pages 45 - 50
ref_type: npl
severity: background
ref_id: - ASCIERTO, P. A.; E. SIMEONE; M. SZNOL; Y. X. FU; I. MELERO: "Clinical experiences with anti-CD137 and anti-PDl therapeutic antibodies", SEMIN ONCOL, vol. 37, 2010, pages 508 - 516, XP008175440, DOI: doi:10.1053/j.seminoncol.2010.09.008
ref_type: npl
severity: background
ref_id: - AGGARWAL B.B.: "Signalling pathways of the TNF superfamily: a double-edged sword", NAT. REV. IMMUNOL., vol. 3, no. 9, 2003, pages 745 - 756
ref_type: npl
severity: background
ref_id: - BANNER D. ET AL.: "Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation", CELL, vol. 73, 1993, pages 431 - 445
ref_type: npl
severity: background
ref_id: - BODMER J.; SCHNEIDER P.; TSCHOPP, J.: "The molecular architecture of the TNF superfamily", TRENDS IN BIOCHEMICAL SCIENCES, vol. 27, no. 1, 2002, pages 19 - 26, XP004332356, DOI: doi:10.1016/S0968-0004(01)01995-8
ref_type: npl
severity: background
ref_id: - BROIL, K.; RICHTER, G.; PAULY, S.; HOFSTAEDTER, F.; SCHWARZ, H.: "CD137 expression in tumor vessel walls. High correlation with malignant tumors", AM J CLIN PATHOL, vol. 115, 2001, pages 543 - 549, XP009028982, DOI: doi:10.1309/E343-KMYX-W3Y2-10KY
ref_type: npl
severity: background
ref_id: - BUECHELE, C.; BAESSLER, T.; SCHMIEDEL, B.J.; SCHUMACHER, C.E.; GROSSE-HOVEST, L.; RITTIG, K.; SALIH, H.R.: "4-1BB ligand modulates direct and Rituximab-induced NK-cell reactivity in chronic lymphocytic leukemia", EUR J IMMUNOL, vol. 42, 2012, pages 737 - 748
ref_type: npl
severity: background
ref_id: - CHOI, B.K.; KIM, Y.H.; KWON, P.M.; LEE, S.C.; KANG, S.W.; KIM, M.S.; LEE, M.J.; KWON, B.S.: "4-1BB functions as a survival factor in dendritic cells", J IMMUNOL, vol. 182, 2009, pages 4107 - 4115
ref_type: npl
severity: background
ref_id: - CUADROS, C.; DOMINGUEZ, A.L.; LOLLINI, P.L.; CROFT, M.; MITTLER, R.S.; BORGSTROM, P.; LUSTGARTEN, J.: "Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice", INT J CANCER, vol. 116, 2005, pages 934 - 943
ref_type: npl
severity: background
ref_id: - CURRAN, M.A.; KIM, M.; MONTALVO, W.; AL-SHAMKHANI, A.; ALLISON, J.P.: "Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production", PLOS ONE, vol. 6, 2011, pages E19499
ref_type: npl
severity: background
ref_id: - DIEHL, L.; VAN MIERLO, G.J.; DEN BOER, A.T.; VAN DER VOORT, E.; FRANSEN, M.; VAN BOSTELEN, L.; KRIMPENFORT, P.; MELIEF, C.J.; MITT: "In vivo triggering through 4-1BB enables Th-independent priming of CTL in the presence of an intact CD28 costimulatory pathway", J IMMUNOL, vol. 168, 2002, pages 3755 - 3762, XP002238986
ref_type: npl
severity: background
ref_id: - DUBROT, J.; MILHEIRO, F.; ALFARO, C.; PALAZON, A.; MARTINEZ-FORERO, I.; PEREZ-GRACIA, J.L.; MORALES-KASTRESANA, A.; ROMERO-TREVEJO: "Treatment with anti-CD 137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ", CANCER IMMUNOL IMMUNOTHER, vol. 59, 2010, pages 1223 - 1233, XP019842192
ref_type: npl
severity: background
ref_id: - FUTAGAWA, T.; AKIBA, H.; KODAMA, T.; TAKEDA, K.; HOSODA, Y.; YAGITA, H.; OKUMURA, K.: "Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells", INT IMMUNOL, vol. 14, 2002, pages 275 - 286, XP002486148, DOI: doi:10.1093/intimm/14.3.275
ref_type: npl
severity: background
ref_id: - GUO, Z.; CHENG, D.; XIA, Z.; LUAN, M.; WU, L.; WANG, G.; ZHANG, S.: "Combined TIM-3 blockade and CD 137 activation affords the long-term protection in a murine model of ovarian cancer", J TRANSL MED, vol. 11, 2013, pages 215, XP021164386, DOI: doi:10.1186/1479-5876-11-215
ref_type: npl
severity: background
ref_id: - HEINISCH, I.V.; DAIGLE, I.; KNOPFLI, B.; SIMON, H.U.: "CD137 activation abrogates granulocyte-macrophage colony-stimulating factor-mediated anti-apoptosis in neutrophils", EUR J IMMUNOL, vol. 30, 2000, pages 3441 - 3446
ref_type: npl
severity: background
ref_id: - HORNIG, N.; KERMER, V.; FREY, K.; DIEBOLDER, P.; KONTERMANN, R.E.; MUELLER, D.: "Combination of a bispecific antibody and costimulatory antibody-ligand fusion proteins for targeted cancer immunotherapy", J. IMMUNOTHER, vol. 35, 2012, pages 418 - 429, XP009163394, DOI: doi:10.1097/CJI.0b013e3182594387
ref_type: npl
severity: background
ref_id: - JU, S.A.; CHEON, S.H.; PARK, S.M.; TAM, N.Q.; KIM, Y.M.; AN, W.G.; KIM, B.S.: "Eradication of established renal cell carcinoma by a combination of 5-fluorouracil and anti-4-1BB monoclonal antibody in mice", INT J CANCER, vol. 122, 2008, pages 2784 - 2790
ref_type: npl
severity: background
ref_id: - KIENZLE, G.; VON KEMPIS, J.: "CD137 (ILA/4-1BB), expressed by primary human monocytes, induces monocyte activation and apoptosis of B lymphocytes", INT IMMUNOL, vol. 12, 2000, pages 73 - 82
ref_type: npl
severity: background
ref_id: - KIM, D.H.; CHANG, W.S.; LEE, Y.S.; LEE, K.A.; KIM, Y.K.; KWON, B.S.; KANG, C.Y.: "4-1BB engagement costimulates NKT cell activation and exacerbates NKT cell ligand-induced airway hyperresponsiveness and inflammation", J IMMUNOL, vol. 180, 2008, pages 2062 - 2068
ref_type: npl
severity: background
ref_id: - KIM, Y.H.; CHOI, B.K.; OH, H.S.; KANG, W.J.; MITTLER, R.S.; KWON, B.S.: "Mechanisms involved in synergistic anticancer effects of anti-4-1BB and cyclophosphamide therapy", MOL CANCER THER, vol. 8, 2009, pages 469 - 478, XP008159721, DOI: doi:10.1158/1535-7163.MCT-08-0993
ref_type: npl
severity: background
ref_id: - KWON, B.S.; WEISSMAN, S.M.: "cDNA sequences of two inducible T-cell genes", PROC NATL ACAD SCI U S A, vol. 86, 1989, pages 1963 - 1967
ref_type: npl
severity: background
ref_id: - LEE, H.; PARK, H.J.; SOHN, H.J.; KIM, J.M.; KIM, S.J.: "Combinatorial therapy for liver metastatic colon cancer: dendritic cell vaccine and low-dose agonistic anti-4-IBB antibody co-stimulatory signal", J SURG RES, vol. 169, 2011, pages E43 - E50
ref_type: npl
severity: background
ref_id: - LEVITSKY, V.; DE CAMPOS-LIMA, P.O.; FRISAN, T.; MASUCCI, M.G.: "The clonal composition of a peptide-specific oligoclonal CTL repertoire selected in response to persistent EBV infection is stable over time", J IMMUNOL, vol. 161, 1998, pages 594 - 601
ref_type: npl
severity: background
ref_id: - LI, F.; RAVETCH, J.V.: "Inhibitory Fcgamma receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies", SCIENCE, vol. 333, 2011, pages 1030 - 1034, XP002720021, DOI: doi:10.1126/science.1206954
ref_type: npl
severity: background
ref_id: - LIN, W.; VOSKENS, C.J.; ZHANG, X.; SCHINDLER, D.G.; WOOD, A.; BURCH, E.; WEI, Y.; CHEN, L.; TIAN, G.; TAMADA, K. ET AL.: "Fc-dependent expression of CD137 on human NK cells: insights into ''agonistic'' effects of anti-CD137 monoclonal antibodies", BLOOD, vol. 112, 2008, pages 699 - 707, XP055037053, DOI: doi:10.1182/blood-2007-11-122465
ref_type: npl
severity: background
ref_id: - MELERO, I.; JOHNSTON, J.V.; SHUFFORD, W.W.; MITTLER, R.S.; CHEN, L.: "NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies", CELL IMMUNOL, vol. 190, 1998, pages 167 - 172
ref_type: npl
severity: background
ref_id: - MELERO, I.; SHUFORD, W.W.; NEWBY, S.A.; ARUFFO, A.; LEDBETTER, J.A.; HELLSTROM, K.E.; MITTLER, R.S.; CHEN, L.: "Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors", NAT MED, vol. 3, 1997, pages 682 - 685, XP002104261, DOI: doi:10.1038/nm0697-682
ref_type: npl
severity: background
ref_id: - MERCHANT, A.M.; ZHU, Z.; YUAN, J.Q.; GODDARD, A.; ADAMS, C.W.; PRESTA, L.G.; CARTER, P.: "An efficient route to human bispecific IgG", NAT BIOTECHNOL, vol. 16, 1998, pages 677 - 681, XP002141015, DOI: doi:10.1038/nbt0798-677
ref_type: npl
severity: background
ref_id: - MORALES-KASTRESANA, A.; SANMAMED, M.F.; RODRIGUEZ, I.; PALAZON, A.; MARTINEZ-FORERO, I.; LABIANO, S.; HERVAS-STUBBS, S.; SANGRO, B: "Combined immunostimulatory monoclonal antibodies extend survival in an aggressive transgenic hepatocellular carcinoma mouse model", CLIN CANCER RES, vol. 19, 2013, pages 6151 - 6162, XP055176308, DOI: doi:10.1158/1078-0432.CCR-13-1189
ref_type: npl
severity: background
ref_id: - MUELLER, D.; FREY, K.; KONTERMANN, R.E.: "A novel antibody-4-IBBI fusion protein for targeted costimulation in cancer immunotherapy", J. IMMUNOTHER, vol. 31, 2008, pages 714 - 722, XP009183889
ref_type: npl
severity: background
ref_id: - MURILLO, O.; DUBROT, J.; PALAZON, A.; ARINA, A.; AZPILIKUETA, A.; ALFARO, C.; SOLANO, S.; OCHOA, M.C.; BERASAIN, C.; GABARI, I. ET: "In vivo depletion of DC impairs the anti-tumor effect of agonistic anti-CD137 mAb", EUR J IMMUNOL, vol. 39, 2009, pages 2424 - 2436
ref_type: npl
severity: background
ref_id: - NARAZAKI, H.; ZHU, Y.; LUO, L.; ZHU, G.; CHEN, L.: "CD137 agonist antibody prevents cancer recurrence: contribution of CD 137 on both hematopoietic and nonhematopoietic cells", BLOOD, vol. 115, 2010, pages 1941 - 1948, XP055034669, DOI: doi:10.1182/blood-2008-12-192591
ref_type: npl
severity: background
ref_id: - NISHIMOTO, H.; LEE, S.W.; HONG, H.; POTTER, K.G.; MAEDA-YAMAMOTO, M.; KINOSHITA, T.; KAWAKAMI, Y.; MITTLER, R.S.; KWON, B.S.; WARE: "Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor", BLOOD, vol. 106, 2005, pages 4241 - 4248
ref_type: npl
severity: background
ref_id: - OLOFSSON, P.S.; SODERSTROM, L.A.; WAGSATER, D.; SHEIKINE, Y.; OCAYA, P.; LANG, F.; RABU, C.; CHEN, L.; RUDLING, M.; AUKRUST, P. ET: "CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice", CIRCULATION, vol. 117, 2008, pages 1292 - 1301, XP055052079, DOI: doi:10.1161/CIRCULATIONAHA.107.699173
ref_type: npl
severity: background
ref_id: - PALAZON, A.; TEIJEIRA, A.; MARTINEZ-FORERO, I.; HERVAS-STUBBS, S.; RONCAL, C.; PENUELAS, I.; DUBROT, J.; MORALES-KASTRESANA, A.; P: "Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes", CANCER RES, vol. 71, 2011, pages 801 - 811
ref_type: npl
severity: background
ref_id: - SCHWARZ, H.; VALBRACHT, J.; TUCKWELL, J.; KEMPIS, J.; LOTZ, M.: "ILA, the human 4-1BB homologue, is inducible in lymphoid and other cell lineages", BLOOD, vol. 85, 1995, pages 1043 - 1052
ref_type: npl
severity: background
ref_id: - SHAO, Z.; SCHWARZ, H.: "CD 137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction", J LEUKOC BIOL, vol. 89, 2011, pages 21 - 29
ref_type: npl
severity: background
ref_id: - SHI, W.; SIEMANN, D.W.: "Augmented antitumor effects of radiation therapy by 4-1BB antibody (BMS-469492) treatment", ANTICANCER RES, vol. 26, 2006, pages 3445 - 3453
ref_type: npl
severity: background
ref_id: - SIMEONE, E.; ASCIERTO, P.A.: "Immunomodulating antibodies in the treatment of metastatic melanoma: the experience with anti-CTLA-4, anti-CD 137, and anti-PD1", J IMMUNOTOXICOL, vol. 9, 2012, pages 241 - 247, XP009181173, DOI: doi:10.3109/1547691X.2012.678021
ref_type: npl
severity: background
ref_id: - SNELL, L.M.; LIN, G.H.; MCPHERSON, A.J.; MORAES, T.J.; WATTS, T.H.: "T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy", IMMUNOL REV, vol. 244, 2011, pages 197 - 217
ref_type: npl
severity: background
ref_id: - STAGG, J.; LOI, S.; DIVISEKERA, U.; NGIOW, S.F.; DURET, H.; YAGITA, H.; TENG, M.W.; SMYTH, M.J.: "Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy", PROC NATL ACAD SCI USA, vol. 108, 2011, pages 7142 - 7147, XP055079201, DOI: doi:10.1073/pnas.1016569108
ref_type: npl
severity: background
ref_id: - TENG, M.W.; SHARKEY, J.; MCLAUGHLIN, N.M.; EXLEY, M.A.; SMYTH, M.J.: "CDld-based combination therapy eradicates established tumors in mice", J IMMUNOL, vol. 183, 2009, pages 1911 - 1920
ref_type: npl
severity: background
ref_id: - KEMPIS, J.; SCHWARZ, H.; LOTZ, M.: "Differentiation-dependent and stimulus-specific expression of ILA, the human 4-1BB-homologue, in cells of mesenchymal origin", OSTEOARTHRITIS CARTILAGE, vol. 5, 1997, pages 394 - 406, XP009005285, DOI: doi:10.1016/S1063-4584(97)80044-1
ref_type: npl
severity: background
ref_id: - WEI, H.; ZHAO, L.; LI, W.; FAN, K.; QIAN, W.; HOU, S.; WANG, H.; DAI, M.; HELLSTROM, I.; HELLSTROM, K.E.: "Combinatorial PD-1 blockade and CD 137 activation has therapeutic efficacy in murine cancer models and synergizes with cisplatin", PLOS ONE, vol. 8, 2013, pages E84927
ref_type: npl
severity: background
ref_id: - WILCOX, R.A.; CHAPOVAL, A.I.; GORSKI, K.S.; OTSUJI, M.; SHIN, T.; FLIES, D.B.; TAMADA, K.; MITTLER, R.S.; TSUCHIYA, H.; PARDOLL, D: "Cutting edge: Expression of functional CD137 receptor by dendritic cells", J IMMUNOL, vol. 168, 2002, pages 4262 - 4267
ref_type: npl
severity: background
ref_id: - WILCOX, R.A.; TAMADA, K.; FLIES, D.B.; ZHU, G.; CHAPOVAL, A.I.; BLAZAR, B.R.; KAST, W.M.; CHEN, L.: "Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo", BLOOD, vol. 103, 2004, pages 177 - 184
ref_type: npl
severity: background
ref_id: - ZHANG, N.; SADUN, R.E.; ARIAS, R.S.; FLANAGAN, M.L.; SACHSMAN, S.M.; NIEN, Y; KHAWLI, L.A.; HU, P.; EPSTEIN, A.L.: "Targeted and untargeted CD137L fusion proteins for the immunotherapy of experimental solid tumors", CLIN. CANCER RES., vol. 13, 2007, pages 2758 - 2767, XP055186494, DOI: doi:10.1158/1078-0432.CCR-06-2343
ref_type: npl
severity: background
ref_id: - ZHANG, X; VOSKENS, C.J.; SALLIN, M.; MANIAR, A.; MONTES, C.L.; ZHANG, Y.; LIN, W.; LI, G.; BURCH, E.; TAN, M. ET AL.: "CD137 promotes proliferation and survival of human B cells", J IMMUNOL, vol. 184, 2010, pages 787 - 795
ref_type: npl
severity: background
ref_id: WO2015183902A1
ref_type: patent
severity: background
ref_id: WO2010010051A1
ref_type: patent
severity: background
ref_id: AU2011265482A1
ref_type: patent
severity: background
ref_id: WO2004039841A2
ref_type: patent
severity: background
ref_id: WO2012130471A1
ref_type: patent
severity: background
ref_id: WO2016156291A1
ref_type: patent
severity: background
ref_id: WO2016075278A1
ref_type: patent
severity: background
ref_id: - MÜLLER DAFNE ET AL: "A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy", JOURNAL OF IMMUNOTHERAPY, LIPPINCOTT WILLIAMS & WILKINS, USA, vol. 31, no. 8, 1 October 2008 (2008-10-01), pages 714 - 722, XP009183889, ISSN: 1537-4513
ref_type: npl
severity: background
ref_id: - HORNIG NORA ET AL: "Combination of a Bispecific Antibody and Costimulatory Antibody-Ligand Fusion Proteins for Targeted Cancer Immunotherapy", JOURNAL OF IMMUNOTHERAPY, LIPPINCOTT WILLIAMS & WILKINGS INC, US, vol. 35, no. 5, 1 June 2012 (2012-06-01), pages 418 - 429, XP009163394, ISSN: 1524-9557, DOI: 10.1097/CJI.0B013E3182594387
ref_type: npl
severity: background
ref_id: - V. KERMER ET AL: "Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy.", MOLECULAR CANCER THERAPEUTICS, vol. 13, no. 1, 6 November 2013 (2013-11-06), US, pages 112 - 121, XP055200723, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-13-0282
ref_type: npl
severity: background
ref_id: - NICOLE MÜLLER ET AL: "Activity of soluble OX40 ligand is enhanced by oligomerization and cell surface immobilization", FEBS JOURNAL, vol. 275, no. 9, 1 May 2008 (2008-05-01), pages 2296 - 2304, XP055015512, ISSN: 1742-464X, DOI: 10.1111/j.1742-4658.2008.06382.x
ref_type: npl
severity: background
ref_id: - BAUER: "Targeted bioactivity of membrane-anchored TNF by an antibody-derived TNF fusion protein", THE JOURNAL OF IMMUNOLOGY, vol. 172, no. 6, 1 January 2004 (2004-01-01), pages 3930, XP055005065, ISSN: 0022-1767
ref_type: npl
severity: background
ref_id: - EDWIN BREMER: "Targeting of the Tumor Necrosis Factor Receptor Superfamily for Cancer Immunotherapy", ISRN ONCOLOGY, vol. 176, no. 2, 1 January 2013 (2013-01-01), pages 974 - 25, XP055184622, ISSN: 2090-5661, DOI: 10.1186/1479-5876-9-204
ref_type: npl
severity: background
ref_id: WO2004039841
ref_type: patent
severity: obviousness
ref_id: WO2010010051
ref_type: patent
severity: obviousness
ref_id: AU2011265482
ref_type: patent
severity: obviousness
ref_id: WO2012130471
ref_type: patent
severity: obviousness
ref_id: WO2015183902
ref_type: patent
severity: obviousness
ref_id: WO2016075278
ref_type: patent
severity: novelty_destroying
ref_id: WO2016156291
ref_type: patent
severity: novelty_destroying
ref_id: - MÜLLER DAFNE ET AL, "A novel antibody-4-1BBL fusion protein for targeted costimulation in cancer immunotherapy", JOURNAL OF IMMUNOTHERAPY, LIPPINCOTT WILLIAMS & WILKINS, USA, (20081001), vol. 31, no. 8, ISSN 1537-4513, pages 714 - 722, XP009183889 [Y] 1-16 * the whole document *
ref_type: npl
severity: obviousness
ref_id: - HORNIG NORA ET AL, "Combination of a Bispecific Antibody and Costimulatory Antibody-Ligand Fusion Proteins for Targeted Cancer Immunotherapy", JOURNAL OF IMMUNOTHERAPY, LIPPINCOTT WILLIAMS & WILKINGS INC, US, (20120601), vol. 35, no. 5, doi:10.1097/CJI.0B013E3182594387, ISSN 1524-9557, pages 418 - 429, XP009163394 [Y] 1-16 * the whole document *
ref_type: npl
severity: obviousness
ref_id: - V. KERMER ET AL, "Combining antibody-directed presentation of IL-15 and 4-1BBL in a trifunctional fusion protein for cancer immunotherapy.", MOLECULAR CANCER THERAPEUTICS, US, (20131106), vol. 13, no. 1, doi:10.1158/1535-7163.MCT-13-0282, ISSN 1535-7163, pages 112 - 121, XP055200723 [Y] 1-16 * the whole document *
ref_type: npl
severity: obviousness
ref_id: - NICOLE MÜLLER ET AL, "Activity of soluble OX40 ligand is enhanced by oligomerization and cell surface immobilization", FEBS JOURNAL, (20080501), vol. 275, no. 9, doi:10.1111/j.1742-4658.2008.06382.x, ISSN 1742-464X, pages 2296 - 2304, XP055015512 [Y] 1-16 * the whole document *
ref_type: npl
severity: obviousness
ref_id: - BAUER, "Targeted bioactivity of membrane-anchored TNF by an antibody-derived TNF fusion protein", THE JOURNAL OF IMMUNOLOGY, (20040101), vol. 172, no. 6, ISSN 0022-1767, page 3930, XP055005065 [Y] 1-16 * the whole document *
ref_type: npl
severity: obviousness
ref_id: - EDWIN BREMER, "Targeting of the Tumor Necrosis Factor Receptor Superfamily for Cancer Immunotherapy", ISRN ONCOLOGY, (20130101), vol. 176, no. 2, doi:10.1186/1479-5876-9-204, ISSN 2090-5661, pages 974 - 25, XP055184622 [Y] 1-16 * the whole document *
ref_type: npl
severity: obviousness
Final disposition: pending (2017-11-15)