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Published on: May 16, 2020

Ligand-Blocking and Agonist Antibodies Targeting TNFR2 Use Distinct Modes of Action to Induce Antitumor Immunity

Linda Mårtensson1, Petra Holmkvist1, Kirstie L Cleary2

  • 1BioInvent International AB, Lund, Sweden.

Cancer Research
|July 17, 2026
PubMed

Insights

Two novel TNFR2 antibodies, a ligand-blocking and an agonist type, demonstrate potent anti-tumor efficacy alone and with PD-1 blockade. Both antibody types activate tumor-specific CD8+ T cells, offering new cancer immunotherapy strategies.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Immunotherapy

Background:

  • Checkpoint inhibitors targeting CTLA-4 and PD-(L)1 have advanced cancer treatment.
  • Tumor Necrosis Factor Receptor 2 (TNFR2) is a promising target for cancer therapy.
  • Understanding the role of TNFR2 agonists versus blockers and FcγR interactions is crucial for therapeutic development.

Purpose of the Study:

  • To engineer and evaluate two distinct types of alpha-TNFR2 antibodies: ligand-blocking and agonist.
  • To assess the anti-tumor efficacy of these antibodies in preclinical models, both as monotherapy and in combination with anti-PD-1 therapy.
  • To elucidate the mechanisms of action, including FcγR interactions and effects on immune cell populations.

Main Methods:

  • Engineering of ligand-blocking, FcγR-engaging, and non-ligand-blocking agonist alpha-TNFR2 antibodies.
  • Evaluation of anti-tumor efficacy in multiple syngeneic mouse tumor models.
  • Analysis of immune cell populations, including Tregs, myeloid cells, T cells, and NK cells, using flow cytometry and other techniques.
  • Assessment of FcγR-dependent and -independent mechanisms.

Main Results:

  • Both engineered alpha-TNFR2 antibodies demonstrated potent anti-tumor efficacy in preclinical models.
  • The ligand-blocking antibody depleted intratumoral Tregs and modulated myeloid cells towards a pro-inflammatory phenotype, dependent on FcγR interactions.
  • The agonist antibody co-stimulated T and NK cells via FcγR-independent mechanisms.
  • Both antibody types converged on activating tumor-specific CD8+ T cells, leading to tumor rejection.
  • Combination therapy with alpha-PD-1 enhanced anti-tumor responses.

Conclusions:

  • Both ligand-blocking and agonist TNFR2 antibodies are effective in promoting anti-tumor immunity.
  • TNFR2-targeted therapies, engaging distinct mechanisms, hold significant promise for cancer treatment.
  • Ongoing clinical trials are evaluating these ligand-blocking (BI-1808) and agonist (BI-1910) alpha-TNFR2 antibodies.

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