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377 AGEN2373 is a CD137 agonist antibody designed to leverage optimal CD137 and FcγR co-targeting to promote antitumor immunologic effects
  1. Claire Galand1,
  2. Vignesh Venkatraman1,
  3. Marilyn Marques1,
  4. James Strauss2,
  5. Richard Carvajal3,
  6. Min Lim1,
  7. Benjamin Morin1,
  8. Olga Ignatovich1,
  9. Mark Findeis1,
  10. Dennis Underwood1,
  11. Marc Van Dijk4,
  12. Irina Shapiro1,
  13. Lernik Ohanjanian1,
  14. Anna Wijatyk1,
  15. Nicholas Wilson5,
  16. Jennifer Buell1,
  17. Dhan Chand1,
  18. David Savitsky1 and
  19. Anthony Tolcher6
  1. 1Agenus Inc., Lexington, MA, USA
  2. 2Mary Crowley Cancer Research Center, Dallas, TX, USA
  3. 3Columbia University Medical Center, New York, NY, USA
  4. 4AgenTus Therapeutics, Inc., Cambridge, UK
  5. 5Gilead Sciences, San Carlos, CA, USA
  6. 6Next Onoclogy, San Antonio, TX, USA


Background CD137 (4-1BB) represents a costimulatory pathway that promotes T, NK, and dendritic cell effector functions favorable for antitumor immunity. The extracellular domain of CD137, comprised of four cysteine-rich domains (CRD-I, CRD-II, CRD-III, CRD-IV), trimerizes upon binding to CD137 ligand (CD137L) to induce cell stimulatory transcriptional and epigenetic changes.1 2 The investigation of CD137-targeting agonist antibody, urelumab (CRD-I-binding, IgG4), in human subjects showed immunologic and pharmacodynamic effects, but poor efficacy due to dose-limiting liver toxicity.3 Preclinical studies using a murine surrogate antibody, clone 3H3 (CRD-I-binding, rIgG2a), also demonstrated hepatotoxicity that correlated with activation of CD137-expressing myeloid cells and memory CD8+ T cells.4 5 In contrast, utomilumab (CRD-II/III-binding, IgG2) showed acceptable tolerability, but limited clinical efficacy.6 7 These and more recent findings implicate epitope and Fc gamma receptor (FcγR)-dependent antibody cross-linking as critical factors for CD137 therapeutic antibody design.

Methods We investigated the molecular and cellular effects of AGEN2373 (CRD-IV-binding, IgG1), a conditionally active CD137-targeting agonist antibody designed to bind and induce CD137 signaling upon FcγR cross-linking while permitting ligand binding to CD137. The role of epitope and FcγR binding as critical factors for anti-CD137 therapeutic activity were elucidated in primary cell-based assays and syngeneic tumor-bearing mouse models using anti-mouse antibody clones S3B1 (CRD-IV-binding) and 3H3, surrogates of AGEN2373 and urelumab, respectively. In an ongoing phase 1 trial (NCT04121676), we evaluated the safety and tolerability of AGEN2373.

Results AGEN2373 bound with high-affinity to CD137 CRD-IV and promoted potent agonist activity of CD137 that was conditionally dependent on Fc-dependent antibody cross-linking. AGEN2373 surrogate, S3B1, showed comparable binding and cross-link dependent agonist activity. In CT26 tumor-bearing mice, S3B1 and 3H3 demonstrated complete tumor control that was not reproducible with a Fc-silent S3B1 antibody. The Fc-dependent activity of S3B1 correlated with induced immunologic changes in the TME including CD8 T cell expansion, NK cell activation, and Treg depletion. Patients with advanced solid cancers, treated with AGEN2373 up to 1 mg/kg every 4 weeks, demonstrate clinical activity with no evidence of hepatotoxicity.

Conclusions Conditional and potent agonist activity of AGEN2373 is dependent on binding to CD137 CRD-IV and FcγR. Preclinically, our data demonstrate that AGEN2373-like murine surrogate antibodies promote potent immune activation and anti-tumor immunity. Phase 1 clinical trials investigating the safety and efficacy of AGEN2373, alone or combination with balstilimab (anti-PD-1), are underway.

Trial Registration NCT04121676


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  2. Bitra A, et al. Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. J Biol Chem 2018;293(26): p. 9958–9969.

  3. Segal NH, et al., Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 2017;23(8): p. 1929–1936.

  4. Bartkowiak T, et al., Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27-dependent pathway. Clin Cancer Res 2018;24(5): p. 1138–1151.

  5. Lin GH, et al., GITR-dependent regulation of 4-1BB expression: implications for T cell memory and anti-4-1BB-induced pathology. J Immunol 2013;190(9): p. 4627–39.

  6. Segal, N.H., et al., Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res 2018;24(8): p. 1816–1823.

  7. Li Y, et al., Limited Cross-Linking of 4-1BB by 4-1BB ligand and the agonist monoclonal antibody utomilumab. Cell Rep 2018;25(4): p. 909–920 e4.

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