{
  "abstract": "Background IL-2 is a clinically validated immunotherapy. However, toxicity limits its use and despite years of research, the optimal approach to deliver IL-2 has yet to be achieved. AZD6750 applies cis-guiding to deliver a modified IL-2 mutein preferentially to CD8 + T cells and is comprised of two CD8 binding domains and two IL-2 mutein domains. AZD6750 has been designed with high affinity binding to CD8α and the CD122/CD132 IL-2R complex and lowered affinity binding to CD25 (IL-2Rα). Pre-clinical studies indicate this design results in preferential delivery of IL-2 to CD8+ T cells. In addition, the IL-2 mutein biases the IL-2 towards effector immune subsets while mitigating preferential activation of Tregs. This approach potentially limits the side effects of Aldesleukin, typically attributed to the broad effects of IL-2R signalling, which should result in a safer, more effective IL-2 that has the potential to provide benefit to larger numbers of patients.Methods In vitro, proliferation of human PBMCs and antigen-specific tumor cytolysis were evaluated after treatment with AZD6750, Aldesleukin or an unguided-IL-2 mutein. Ex vivo, patient-derived tumor samples were treated with AZD6750, and the activity evaluated by IFN-γ secretion. In vivo, NSG mice were implanted subcutaneously with pp65 antigen-expressing tumors, engrafted with expanded human PBMCs containing enriched pp65-specific CD8 + T cells, and treated with a dose range of AZD6750 or an isotype control. Tumor growth and CD8+ T cell expansion in the blood and tumor were monitored.Results AZD6750 preferentially proliferated CD8 + T cells and drove improved antigen-specific cytolysis of tumors when compared to an unguided IL-2 mutein or Aldesleukin. Importantly, the enhanced CD8 T cell activity (proliferation and cytolysis) observed with AZD6750 did not increase cytokine release from PBMCs when compared with an unguided IL-2 mutein in vitro. In addition, AZD6750 treatment of primary tumors drove an increase in IFN-γ secretion, highlighting the potential of AZD6750 to generate productive responses in tumor infiltrating lymphocytes. In vivo, AZD6750 treatment resulted in robust dose-dependent tumor growth inhibition and CD8+ T cell expansion in an antigen-specific humanized tumor model.Conclusions Our data demonstrate that cis-(CD8) guiding of an IL-2 mutein may improve the therapeutic index of IL-2 by maintaining the superior potency attributed to Aldesleukin treatment without compromising on the improved safety (as measured by cytokine release) observed with IL-2 mutein approaches.Ethics Approval All procedures were ethically approved by the Animal Welfare and Ethical Review Body. Studies were performed in accordance with the UK Animal (Scientific Procedures) Act 1986 and the EU Directive 86/609, under a UK Home Office Project License, using guidelines outlined by Workman and colleagues and the UKCCR guidance. All patient samples were obtained with written informed consent and studies were conducted in accordance with recognized ethical guidelines (Declaration of Helsinki) and were approved by the East of England - Cambridge East Research Ethics Committee (HTA license number 12109).",
  "authors": [
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Matthew J Elder"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Aidan H Riley"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Sin Lih Tan"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Jerome Mastio"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Bruno Frederico"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Fabien Garçon"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Frederick B Sherlock"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Hung-Chang Chen"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Adam Holberry-Brown"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Julien Fleurence"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Carolina T Orozco"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Andie Collinson"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Anna Sigurdardottir"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Liam V Brown"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Mark S Penney"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Nicholas M Durham"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Erin E Karski"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Christopher Lloyd"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Francisca Wollerton"
    },
    {
      "affiliations": [
        "AstraZeneca, Waltham, MA, USA"
      ],
      "name": "Mark Cobbold"
    },
    {
      "affiliations": [
        "AstraZeneca, Gaithersburg, MD, USA"
      ],
      "name": "Saso Cemerski"
    },
    {
      "affiliations": [
        "AstraZeneca, Cambridge, Cambridgeshire, UK"
      ],
      "name": "Simon J Dovedi"
    },
    {
      "affiliations": [
        "AstraZeneca, Waltham, MA, USA"
      ],
      "name": "Jonathan B Fitzgerald"
    }
  ],
  "title": "852 AZD6750: design and efficacy of a CD8-guided IL-2 that enhances CD8+ T cell function",
  "uid": "60859406-7e8a-5a48-8c0e-5e7fab726f59"
}