Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):5944–5951

    PubMed  CAS  Google Scholar 

  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):771–781

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):8093–8101

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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):4194–4213

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):3007

    Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):29–43

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):2937–2942

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  27. Lesterhuis WJ, Haanen JB, Punt CJ (2011) Cancer immunotherapy—revisited. Nat Rev Drug Discov 10(8):591–600. doi:10.1038/nrd3500

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):104–113

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):4859–4868

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):613–621

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Oncology Research Unit, Pfizer Inc., 10724 Science Center Drive, San Diego, CA, 92121, USA

    Timothy S. Fisher, Victoria A. Love, Paul D. Lira, Simon Bergqvist, Sangita M. Baxi, Allison Rohner & Leslie L. Sharp

  2. Immunotoxicology Center of Emphasis, Drug Safety Research and Development, Pfizer Inc., Groton, CT, USA

    Cris Kamperschroer

  3. Biomarkers Flow Cytometry Core Facility, Drug Safety Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA

    Amy C. Shen, Chunli Huang & Sharon A. Sokolowski

  4. Genetically Engineered Models Center of Emphasis, Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA

    Regis Doyonnas

  5. Protein Therapeutics Center of Emphasis, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, MO, 63017, USA

    Theodore Oliphant

Authors
  1. Timothy S. Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cris Kamperschroer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Theodore Oliphant
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Victoria A. Love
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul D. Lira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Regis Doyonnas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Simon Bergqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sangita M. Baxi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Allison Rohner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Amy C. Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chunli Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sharon A. Sokolowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Leslie L. Sharp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leslie L. Sharp.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 2005 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fisher, T.S., Kamperschroer, C., Oliphant, T. et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol Immunother 61, 1721–1733 (2012). https://doi.org/10.1007/s00262-012-1237-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-012-1237-1

Keywords

Search

Navigation