AstraZeneca's AZD5863 Demonstrates Promising Anti-Tumor Activity with Reduced Cytokine Release

Strategic Insights -

A recent study published in the Journal for ImmunoTherapy of Cancer has revealed that AstraZeneca's AZD5863, a bispecific T-cell engager (TCE), shows potent anti-tumor activity while inducing limited levels of cytokines. This breakthrough in cancer therapy has significant implications for the treatment of gastric, pancreatic, and esophageal adenocarcinomas.

Key Takeaways:

  • AZD5863 is a bispecific TCE with high affinity to CLDN18.2 and low affinity to CD3, designed to decrease its peripheral cytokine release potential and improve the therapeutic index.
  • The study evaluated AZD5863's affinities, specificity, potency, and bystander killing activity using CLDN18.2-expressing human cell lines alone or in co-cultures with human or cynomolgus monkey peripheral blood mononuclear cells.
  • In vitro and in vivo studies demonstrated that AZD5863 mediates potent anti-tumor activity, while inducing lower levels of cytokines compared to a CLDN18.2 TCE with higher affinity for CD3.
  • AZD5863 was shown to bind specifically to human and cynomolgus monkey CLDN18.2 and CD3, with CLDN18.2 binding also conserved against the murine protein.
  • The research was conducted by a team of scientists from AstraZeneca, led by D Gareth Rees, and included Yun He, Scott A Hammond, Mark Cobbold, Nicolas Giraldo, and others.
  • AZD5863 has been designed to target Claudin 18.2, a protein overexpressed in various types of cancer, and has shown promise in preclinical studies, warranting further investigation in phase 1 clinical trials.

Statistics:

  • AZD5863 was evaluated in humanized mice and human CD3 transgenic mice implanted with CLDN18.2-expressing cancer cell lines.
  • The study demonstrated that AZD5863 mediated T cell-dependent anti-tumor activity against CLDN18.2-expressing lines, with potency significantly correlating with CLDN18.2 receptor density.
  • Cytokine secretion induced by AZD5863, in vitro and in vivo, was lower compared with a CLDN18.2 TCE with higher affinity for CD3.
  • In vivo, AZD5863 treatment resulted in potent tumor control in pancreatic, gastric, and esophageal models and enhanced engraftment of immune populations in a humanized model.

Sources:

  • Journal for ImmunoTherapy of Cancer, 2025,13(8).
  • AstraZeneca's press release on AZD5863 (https://www.astrazeneca.com/our-company/research-development.html).
  • NewsRx report on the study (NewsRx. Reports Summarize Cancer Therapy Study Results from AstraZeneca (An affinity-modulated T cell engager targeting Claudin 18.2 shows potent anti-tumor activity with limited cytokine release)). Cancer Weekly. August 19, 2025; p 121.