Durvalumab (PD-L1 Inhibitor)

Proposed Mechanism of Action

Durvalumab is an engineered human monoclonal antibody of the immunoglobulin G1 kappa subclass.1-3 In vitro studies have demonstrated that durvalumab inhibits binding of programmed death-ligand 1 (PD-L1) to programmed cell death protein 1 (PD-1) and CD80.3 Expression of PD-L1 is one mechanism through which tumor cells can evade the immune system response.4 PD-L1 activates its receptor, PD-1, which inhibits activity of T cells.4 Preclinical studies have shown that blocking the PD-1/PD-L1 pathway increases immune activation, anti-tumor immune functions, and may help restore T cell function.5,6

Durvalumab is under clinical development as an investigational product for the treatment of hematological malignancies.

Durvalumab Hypothesized Mechanism of Action

Targeting PD-1/PD-L1 interactions with durvalumab is hypothesized to restore T-cell antitumor function in acute myeloid leukemia and myelodysplastic syndromes.

Rationale for Clinical Development of Durvalumab With a Hypomethylating Agent in Hematologi Malignancies

Hypomethylating agents are epigenetic modifiers hypothesized to activate immune responses. Inhibition of the PD-1/PD-L1 pathway has been shown in vitro to potentially increase immune activation and anti-tumor immune functions.

Durvalumab by Disease State

Durvalumab in Acute Myeloid Leukemia

  • Phase 2 Acute Myeloid Leukemia

Rationale for Clinical Development

Compared with healthy volunteers, patients with acute myeloid leukemia (AML) have higher expression of PD-L1.7 Experiments using mouse models of AML have shown that mice lacking PD-1 demonstrated a lower frequency of leukemia cells compared with controls.8 PD-L1 blockade also resulted in the mitigation of decreased CD8+ T-cell proliferation and interferon gamma production observed in a mouse model of the graft-vs-leukemia effect.9 In addition, higher levels of regulatory T cells (Tregs) have been associated with poorer prognosis in patients with AML,10 and blockade of PD-L1 has demonstrated the potential to decrease transforming growth factor beta (TGF-β)–induced Treg generation in vitro.11

Durvalumab in Myelodysplastic Syndromes

  • Phase 2 Myelodysplastic Syndromes Post HMA failure
  • View Trials Investigating Durvalumab in Myelodysplastic Syndromes.

    Durvalumab in MDS

Rationale for Clinical Development

When compared with healthy volunteers, patients with myelodysplastic syndromes (MDS) have higher expression of PD-L1.7 In vitro experiments have demonstrated that PD-1–PD-L1 blockade may decrease apoptosis and increases proliferation of T cells in the presence of MDS cells.21 In addition, increased numbers of Tregs in patients with MDS are associated with less effective anti-tumor T-cell responses and are a poor prognostic indicator; however, in vitro experiments suggest that blockade of PD-L1 may decrease TFG-beta induced Treg generation.22

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

Durvalumab is owned by Medimmune Inc., a member of the AstraZeneca Group. Celgene entered into a partnering agreement with Medimmune to lead the development of this compound in hematological malignancies while Medimmune is leading the development of durvalumab in solid tumor indications.

References

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