Advertisement

Cancer Immunology, Immunotherapy

, Volume 61, Issue 10, pp 1721–1733 | Cite as

Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity

  • Timothy S. Fisher
  • Cris Kamperschroer
  • Theodore Oliphant
  • Victoria A. Love
  • Paul D. Lira
  • Regis Doyonnas
  • Simon Bergqvist
  • Sangita M. Baxi
  • Allison Rohner
  • Amy C. Shen
  • Chunli Huang
  • Sharon A. Sokolowski
  • Leslie L. Sharp
Original article

Abstract

4-1BB (CD137, TNFRSF9) is a costimulatory receptor expressed on several subsets of activated immune cells. Numerous studies of mouse and human T cells indicate that 4-1BB promotes cellular proliferation, survival, and cytokine production. 4-1BB agonist mAbs have demonstrated efficacy in prophylactic and therapeutic settings in both monotherapy and combination therapy tumor models and have established durable anti-tumor protective T-cell memory responses. PF-05082566 is a fully human IgG2 that binds to the extracellular domain of human 4-1BB with high affinity and specificity. In preclinical studies, this agonist antibody demonstrated its ability to activate NF-κB and induce downstream cytokine production, promote leukocyte proliferation, and inhibit tumor growth in a human PBMC xenograft tumor model. The mechanism of action and robust anti-tumor efficacy of PF-05082566 support its clinical development for the treatment of a broad spectrum of human malignancies.

Keywords

CD137 TNFRSF9 Agonist monoclonal antibody Immunotherapy T cell Cancer 

Notes

Acknowledgments

We thank Pfizer La Jolla Comparative Medicine for animal support; Jerry Casperson, James Christensen and Steve Bender for project support; Bart Jessen, Robert Arch, Tim Paradis, Craig Davis, Karin Jooss and Mike Primiano for discussion of the manuscript.

Conflicts of interest

All authors are current or former employees of Pfizer Inc.

Supplementary material

262_2012_1237_MOESM1_ESM.docx (2 mb)
Supplementary material 1 (DOCX 2005 kb)

References

  1. 1.
    Wang C, Lin GH, McPherson AJ, Watts TH (2009) Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev 229(1):192–215. doi: 10.1111/j.1600-065X.2009.00765.x PubMedCrossRefGoogle Scholar
  2. 2.
    Broll K, Richter G, Pauly S, Hofstaedter F, Schwarz H (2001) CD137 expression in tumor vessel walls. High correlation with malignant tumors. Am J Clin Pathol 115(4):543–549. doi: 10.1309/6U88-357U-UKJ5-YPT3 PubMedCrossRefGoogle Scholar
  3. 3.
    Seaman S, Stevens J, Yang MY, Logsdon D, Graff-Cherry C, St Croix B (2007) Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 11(6):539–554. doi: 10.1016/j.ccr.2007.04.017 PubMedCrossRefGoogle Scholar
  4. 4.
    Olofsson PS, Soderstrom LA, Wagsater D, Sheikine Y, Ocaya P, Lang F, Rabu C, Chen L, Rudling M, Aukrust P, Hedin U, Paulsson-Berne G, Sirsjo A, Hansson GK (2008) CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation 117(10):1292–1301. doi: 10.1161/CIRCULATIONAHA.107.699173 PubMedCrossRefGoogle Scholar
  5. 5.
    Dawicki W, Bertram EM, Sharpe AH, Watts TH (2004) 4–1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses. J Immunol 173(10):5944–5951PubMedGoogle Scholar
  6. 6.
    Pollok KE, Kim YJ, Zhou Z, Hurtado J, Kim KK, Pickard RT, Kwon BS (1993) Inducible T cell antigen 4–1BB. Analysis of expression and function. J Immunol 150(3):771–781PubMedGoogle Scholar
  7. 7.
    Chan FK (2007) Three is better than one: pre-ligand receptor assembly in the regulation of TNF receptor signaling. Cytokine 37(2):101–107. doi: 10.1016/j.cyto.2007.03.005 PubMedCrossRefGoogle Scholar
  8. 8.
    Michel J, Langstein J, Hofstadter F, Schwarz H (1998) A soluble form of CD137 (ILA/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur J Immunol 28(1):290–295. doi: 10.1002/(SICI)1521-4141(199801)28:01<290:AID-IMMU290>3.0.CO;2-S PubMedCrossRefGoogle Scholar
  9. 9.
    Furtner M, Straub RH, Kruger S, Schwarz H (2005) Levels of soluble CD137 are enhanced in sera of leukemia and lymphoma patients and are strongly associated with chronic lymphocytic leukemia. Leukemia 19(5):883–885. doi: 10.1038/sj.leu.2403675 PubMedCrossRefGoogle Scholar
  10. 10.
    Hentschel N, Krusch M, Kiener PA, Kolb HJ, Salih HR, Schmetzer HM (2006) Serum levels of sCD137 (4–1BB) ligand are prognostic factors for progression in acute myeloid leukemia but not in non-Hodgkin’s lymphoma. Eur J Haematol 77(2):91–101. doi: 10.1111/j.1600-0609.2006.00679.x PubMedCrossRefGoogle Scholar
  11. 11.
    Sabbagh L, Pulle G, Liu Y, Tsitsikov EN, Watts TH (2008) ERK-dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo. J Immunol 180(12):8093–8101PubMedGoogle Scholar
  12. 12.
    Croft M (2009) The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 9(4):271–285. doi: 10.1038/nri2526 PubMedCrossRefGoogle Scholar
  13. 13.
    Wang S, Chen L (2011) Immunobiology of cancer therapies targeting CD137 and B7-H1/PD-1 cosignal pathways. Curr Top Microbiol Immunol 344:245–267. doi: 10.1007/82_2010_81 PubMedCrossRefGoogle Scholar
  14. 14.
    Lynch DH (2008) The promise of 4-1BB (CD137)-mediated immunomodulation and the immunotherapy of cancer. Immunol Rev 222:277–286. doi: 10.1111/j.1600-065X.2008.00621.x PubMedCrossRefGoogle Scholar
  15. 15.
    Palazon A, Teijeira A, Martinez-Forero I, Hervas-Stubbs S, Roncal C, Penuelas I, Dubrot J, Morales-Kastresana A, Perez-Gracia JL, Ochoa MC, Ochoa-Callejero L, Martinez A, Luque A, Dinchuk J, Rouzaut A, Jure-Kunkel M, Melero I (2011) Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes. Cancer Res 71(3):801–811. doi: 10.1158/0008-5472.CAN-10-1733 PubMedCrossRefGoogle Scholar
  16. 16.
    Vinay DS, Cha K, Kwon BS (2006) Dual immunoregulatory pathways of 4-1BB signaling. J Mol Med (Berl) 84(9):726–736. doi: 10.1007/s00109-006-0072-2 CrossRefGoogle Scholar
  17. 17.
    Niu L, Strahotin S, Hewes B, Zhang B, Zhang Y, Archer D, Spencer T, Dillehay D, Kwon B, Chen L, Vella AT, Mittler RS (2007) Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice. J Immunol 178(7):4194–4213PubMedGoogle Scholar
  18. 18.
    Dubrot J, Palazon A, Alfaro C, Azpilikueta A, Ochoa MC, Rouzaut A, Martinez-Forero I, Teijeira A, Berraondo P, Le Bon A, Hervas-Stubbs S, Melero I (2011) Intratumoral injection of interferon-alpha and systemic delivery of agonist anti-CD137 monoclonal antibodies synergize for immunotherapy. Int J Cancer 128(1):105–118. doi: 10.1002/ijc.25333 PubMedCrossRefGoogle Scholar
  19. 19.
    Sznol M, Hodi FS, Margolin K, McDermott DF, Ernestoff S, Kirkwood JM (2008) Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients with advanced cancer. J Clin Oncol 26(115S):3007Google Scholar
  20. 20.
    Ascierto PA, Simeone E, Sznol M, Fu YX, Melero I (2010) Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies. Semin Oncol 37(5):508–516. doi: 10.1053/j.seminoncol.2010.09.008 PubMedCrossRefGoogle Scholar
  21. 21.
    Chen SJ, Foster WR, Jure-Kunkel MN, Girit E, Abraham R, Hefta LJ, Gao S, Yonan CR, Lin JH, Dambach DM (2008) Cloning, expression and characterization of monkey (Macaca fascicularis) CD137. Vet Immunol Immunopathol 126(3–4):377–381. doi: 10.1016/j.vetimm.2008.07.009 PubMedCrossRefGoogle Scholar
  22. 22.
    King M, Pearson T, Shultz LD, Leif J, Bottino R, Trucco M, Atkinson MA, Wasserfall C, Herold KC, Woodland RT, Schmidt MR, Woda BA, Thompson MJ, Rossini AA, Greiner DL (2008) A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene. Clin Immunol 126(3):303–314. doi: 10.1016/j.clim.2007.11.001 PubMedCrossRefGoogle Scholar
  23. 23.
    Pitcher CJ, Hagen SI, Walker JM, Lum R, Mitchell BL, Maino VC, Axthelm MK, Picker LJ (2002) Development and homeostasis of T cell memory in rhesus macaque. J Immunol 168(1):29–43PubMedGoogle Scholar
  24. 24.
    Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7(2):118–130. doi: 10.1038/nri2017 PubMedCrossRefGoogle Scholar
  25. 25.
    Iwanuma Y, Chen FA, Egilmez NK, Takita H, Bankert RB (1997) Antitumor immune response of human peripheral blood lymphocytes coengrafted with tumor into severe combined immunodeficient mice. Cancer Res 57(14):2937–2942PubMedGoogle Scholar
  26. 26.
    Sondak VK, Smalley KS, Kudchadkar R, Grippon S, Kirkpatrick P (2011) Ipilimumab. Nat Rev Drug Discov 10(6):411–412. doi: 10.1038/nrd3463 PubMedCrossRefGoogle Scholar
  27. 27.
    Lesterhuis WJ, Haanen JB, Punt CJ (2011) Cancer immunotherapy—revisited. Nat Rev Drug Discov 10(8):591–600. doi: 10.1038/nrd3500 PubMedCrossRefGoogle Scholar
  28. 28.
    Cheever MA (2008) Twelve immunotherapy drugs that could cure cancers. Immunol Rev 222:357–368. doi: 10.1111/j.1600-065X.2008.00604.x PubMedCrossRefGoogle Scholar
  29. 29.
    Schabowsky RH, Elpek KG, Madireddi S, Sharma RK, Yolcu ES, Bandura-Morgan L, Miller R, MacLeod KJ, Mittler RS, Shirwan H (2009) A novel form of 4-1BBL has better immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated severe toxicity. Vaccine 28(2):512–522. doi: 10.1016/j.vaccine.2009.09.127 PubMedCrossRefGoogle Scholar
  30. 30.
    McNamara JO, Kolonias D, Pastor F, Mittler RS, Chen L, Giangrande PH, Sullenger B, Gilboa E (2008) Multivalent 4–1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice. J Clin Invest 118(1):376–386. doi: 10.1172/JCI33365 PubMedCrossRefGoogle Scholar
  31. 31.
    Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, Samanta M, Lakhal M, Gloss B, Danet-Desnoyers G, Campana D, Riley JL, Grupp SA, June CH (2009) Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17(8):1453–1464. doi: 10.1038/mt.2009.83 PubMedCrossRefGoogle Scholar
  32. 32.
    Song DG, Ye Q, Carpenito C, Poussin M, Wang LP, Ji C, Figini M, June CH, Coukos G, Powell DJ Jr (2011) In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Cancer Res 71(13):4617–4627. doi: 10.1158/0008-5472.CAN-11-0422 PubMedCrossRefGoogle Scholar
  33. 33.
    Finney HM, Akbar AN, Lawson AD (2004) Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol 172(1):104–113PubMedGoogle Scholar
  34. 34.
    Sadelain M, Brentjens R, Riviere I (2009) The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol 21(2):215–223. doi: 10.1016/j.coi.2009.02.009 PubMedCrossRefGoogle Scholar
  35. 35.
    Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3(95):95ra73. doi: 10.1126/scitranslmed.3002842 PubMedCrossRefGoogle Scholar
  36. 36.
    Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365(8):725–733. doi: 10.1056/NEJMoa1103849 PubMedCrossRefGoogle Scholar
  37. 37.
    Tan JT, Whitmire JK, Ahmed R, Pearson TC, Larsen CP (1999) 4–1BB ligand, a member of the TNF family, is important for the generation of antiviral CD8 T cell responses. J Immunol 163(9):4859–4868PubMedGoogle Scholar
  38. 38.
    Zhu Y, Zhu G, Luo L, Flies AS, Chen L (2007) CD137 stimulation delivers an antigen-independent growth signal for T lymphocytes with memory phenotype. Blood 109(11):4882–4889. doi: 10.1182/blood-2006-10-043463 PubMedCrossRefGoogle Scholar
  39. 39.
    Hong HJ, Lee JW, Park SS, Kang YJ, Chang SY, Kim KM, Kim JO, Murthy KK, Payne JS, Yoon SK, Park MJ, Kim IC, Kim JG, Kang CY (2000) A humanized anti-4-1BB monoclonal antibody suppresses antigen-induced humoral immune response in nonhuman primates. J Immunother 23(6):613–621PubMedCrossRefGoogle Scholar
  40. 40.
    Calarota SA, Hokey DA, Dai A, Jure-Kunkel MN, Balimane P, Weiner DB (2008) Augmentation of SIV DNA vaccine-induced cellular immunity by targeting the 4-1BB costimulatory molecule. Vaccine 26(25):3121–3134. doi: 10.1016/j.vaccine.2008.02.017 PubMedCrossRefGoogle Scholar
  41. 41.
    Hirao LA, Hokey DA, Morrow MP, Jure-Kunkel MN, Weiner DB (2011) Immune modulation through 4-1BB enhances SIV vaccine protection in non-human primates against SIVmac251 challenge. PLoS ONE 6(9):e24250. doi: 10.1371/journal.pone.0024250 PubMedCrossRefGoogle Scholar
  42. 42.
    Li F, Ravetch JV (2011) Inhibitory Fcgamma receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science 333(6045):1030–1034. doi: 10.1126/science.1206954 PubMedCrossRefGoogle Scholar
  43. 43.
    White AL, Chan HT, Roghanian A, French RR, Mockridge CI, Tutt AL, Dixon SV, Ajona D, Verbeek JS, Al-Shamkhani A, Cragg MS, Beers SA, Glennie MJ (2011) Interaction with FcgammaRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody. J Immunol 187(4):1754–1763. doi: 10.4049/jimmunol.1101135 PubMedCrossRefGoogle Scholar
  44. 44.
    Gladue RP, Paradis T, Cole SH, Donovan C, Nelson R, Alpert R, Gardner J, Natoli E, Elliott E, Shepard R, Bedian V (2011) The CD40 agonist antibody CP-870,893 enhances dendritic cell and B-cell activity and promotes anti-tumor efficacy in SCID-hu mice. Cancer Immunol Immunother 60(7):1009–1017. doi: 10.1007/s00262-011-1014-6 PubMedCrossRefGoogle Scholar
  45. 45.
    Hunter TB, Alsarraj M, Gladue RP, Bedian V, Antonia SJ (2007) An agonist antibody specific for CD40 induces dendritic cell maturation and promotes autologous anti-tumour T-cell responses in an in vitro mixed autologous tumour cell/lymph node cell model. Scand J Immunol 65(5):479–486. doi: 10.1111/j.1365-3083.2007.01927.x PubMedCrossRefGoogle Scholar
  46. 46.
    Carpenter EL, Mick R, Ruter J, Vonderheide RH (2009) Activation of human B cells by the agonist CD40 antibody CP-870,893 and augmentation with simultaneous toll-like receptor 9 stimulation. J Transl Med 7:93. doi: 10.1186/1479-5876-7-93 PubMedCrossRefGoogle Scholar
  47. 47.
    Ruter J, Antonia SJ, Burris HA, Huhn RD, Vonderheide RH (2010) Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. Cancer Biol Ther 10(10):983–993. doi: 10.4161/cbt.10.10.13251 PubMedCrossRefGoogle Scholar
  48. 48.
    Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, Torigian DA, O’Dwyer PJ, Vonderheide RH (2011) CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331(6024):1612–1616. doi: 10.1126/science.1198443 PubMedCrossRefGoogle Scholar
  49. 49.
    Fox BA, Schendel DJ, Butterfield LH, Aamdal S, Allison JP, Ascierto PA, Atkins MB, Bartunkova J, Bergmann L, Berinstein N, Bonorino CC, Borden E, Bramson JL, Britten CM, Cao X, Carson WE, Chang AE, Characiejus D, Choudhury AR, Coukos G, de Gruijl T, Dillman RO, Dolstra H, Dranoff G, Durrant LG, Finke JH, Galon J, Gollob JA, Gouttefangeas C, Grizzi F, Guida M, Hakansson L, Hege K, Herberman RB, Hodi FS, Hoos A, Huber C, Hwu P, Imai K, Jaffee EM, Janetzki S, June CH, Kalinski P, Kaufman HL, Kawakami K, Kawakami Y, Keilholtz U, Khleif SN, Kiessling R, Kotlan B, Kroemer G, Lapointe R, Levitsky HI, Lotze MT, Maccalli C, Maio M, Marschner JP, Mastrangelo MJ, Masucci G, Melero I, Nelief C, Murphy WJ, Nelson B, Nicolini A, Nishimura MI, Odunsi K, Ohashi PS, O’Donnell-Tormey J, Old LJ, Ottensmeier C, Papamichail M, Parmiani G, Pawelec G, Proietti E, Qin S, Rees R, Ribas A, Ridolfi R, Ritter G, Rivoltini L, Romero PJ, Salem ML, Scheper RJ, Seliger B, Sharma P, Shiku H, Singh-Jasuja H, Song W, Straten PT, Tahara H, Tian Z, van Der Burg SH, von Hoegen P, Wang E, Welters MJ, Winter H, Withington T, Wolchok JD, Xiao W, Zitvogel L, Zwierzina H, Marincola FM, Gajewski TF, Wigginton JM, Disis ML (2011) Defining the critical hurdles in cancer immunotherapy. J Transl Med 9(1):214. doi: 10.1186/1479-5876-9-214 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Timothy S. Fisher
    • 1
  • Cris Kamperschroer
    • 2
  • Theodore Oliphant
    • 5
  • Victoria A. Love
    • 1
  • Paul D. Lira
    • 1
  • Regis Doyonnas
    • 4
  • Simon Bergqvist
    • 1
  • Sangita M. Baxi
    • 1
  • Allison Rohner
    • 1
  • Amy C. Shen
    • 3
  • Chunli Huang
    • 3
  • Sharon A. Sokolowski
    • 3
  • Leslie L. Sharp
    • 1
  1. 1.Oncology Research UnitPfizer Inc.San DiegoUSA
  2. 2.Immunotoxicology Center of Emphasis, Drug Safety Research and DevelopmentPfizer Inc.GrotonUSA
  3. 3.Biomarkers Flow Cytometry Core Facility, Drug Safety Research and DevelopmentPfizer Inc.GrotonUSA
  4. 4.Genetically Engineered Models Center of EmphasisPfizer Inc.GrotonUSA
  5. 5.Protein Therapeutics Center of EmphasisPfizer Inc.ChesterfieldUSA

Personalised recommendations