AZD6750, a CD8alpha-guided IL-2 immunocytokine effectively combines with rilvegostomig, a PD-1/TIGIT bispecific antibody, to enhance endogenous immunity

Background: AZD6750 is a CD8alpha-guided IL-2 immunocytokine engineered to enhance the therapeutic index of IL‑2 by reducing aldesleukin‑associated toxicities, while preserving the efficacy that has been compromised with recent clinical IL‑2 mutein strategies. This should result in a safer, more effective IL-2 with the potential to benefit larger numbers of patients and allow for the utilization of IL-2 in synergistic combinations. Combinations of anti-PD-1 with IL-2 therapies are currently being explored in the clinic with both preliminary clinical and nonclinical evidence that this combination can generate improved responses. As such, a potentially effective therapy is the combination of AZD6750 plus rilvegostomig, a monovalent, Fc-reduced, bispecific IgG1 antibody against PD-1 and TIGIT receptors, to enhance IO activity. Methods: In vitro , antigen-specific tumor cell cytolysis was evaluated after treatment with AZD6750, rilvegostomig, or a combination of both therapies. Ex vivo , non-small cell lung cancer (NSCLC) patient-derived tumor samples were treated with AZD6750, rilvegostomig, or a combination of both therapies, and the activity evaluated by IFN-gamma secretion. In vivo , NSG mice were implanted subcutaneously with antigen-expressing tumors, engrafted with expanded human PBMCs containing enriched antigen-specific CD8 + T cells, and treated with AZD6750, rilvegostomig, a combination of both therapies, or an isotype control and tumor growth was monitored. Results: In vitro , AZD6750 in combination with rilvegostomig improved antigen-specific cytolysis of tumor cells compared with AZD6750 monotherapy (EC 50 p<0.01). In addition, ex vivo treatment of primary NSCLC tumors with rilvegostomig plus AZD6750 drove an increase in IFN-gamma secretion compared with either AZD6750 (2-fold) or rilvegostomig (6-fold) monotherapies, highlighting the potential of this combination to augment functional responses in tumor infiltrating lymphocytes. In vivo , AZD6750 plus rilvegostomig resulted in a statistically significant reduction in tumor growth rate when compared to an isotype IgG (all studies), rilvegostomig (all studies), or AZD6750 (in 2 out of 3 studies) in an antigen-specific humanized mouse tumor model. Conclusions: These preclinical data demonstrate that AZD6750 combined with rilvegostomig can enhance anti-tumor immune responses, leading to greater tumor cell killing. The Phase 1 study investigating AZD6750 in select advanced or metastatic solid tumors is currently ongoing (NCT07115043).