Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function

Research output: Contribution to journalArticle

Abstract

The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcγR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcγR-dependent Treg cell depleting capacity and FcγR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic.

Details

Authors
  • Sarah L. Buchan
  • Lang Dou
  • Marcus Remer
  • Steven G. Booth
  • Stuart N. Dunn
  • Chester Lai
  • Monika Semmrich
  • Ingrid Teige
  • Linda Mårtensson
  • Christine A. Penfold
  • H. T.Claude Chan
  • Jane E. Willoughby
  • C. Ian Mockridge
  • Lekh N. Dahal
  • Kirstie L.S. Cleary
  • Sonya James
  • Anne Rogel
  • Mats Jernetz
  • Emily L. Williams
  • Eugene Healy
  • J. Sjef Verbeek
  • Peter W.M. Johnson
  • Björn Frendéus
  • Mark S. Cragg
  • Martin J. Glennie
  • Juliet C. Gray
  • Aymen Al-Shamkhani
  • Stephen A. Beers
External organisations
  • University Hospital Southampton
  • BioInvent International AB
  • Skåne University Hospital
  • Leiden University Medical Centre
  • University of Southampton
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
  • Cancer and Oncology

Keywords

  • 4-1BB, agonism, cancer, combination, depletion, immunotherapy, PD-1, TNFR, Treg cell, tumor
Original languageEnglish
Pages (from-to)958-970
Number of pages13
JournalImmunity
Volume49
Issue number5
Publication statusPublished - 2018
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes