使用新型同类最佳CD3结合物扩展强效双特异性PD-L1:CD3 T细胞衔接器的治疗窗口

Introduction: Bispecific T cell engagers (TCE) are potent, off-the-shelf immune modulators that have been hugely successful against hematologic malignancies and are beginning to demonstrate utility in solid tumors. PD-L1 targeting bispecific TCE with an SP34 variant CD3 binder showed exceptionally potent activity against intracranial tumor models in mice. To further expand the potential therapeutic index, we engineered SCRI-6, a novel, high-affinity, non-polyreactive CD3 binder, into a next generation PD-L1 TCE and compared the SP34 and SCRI-6 versions for efficacy and tolerability. Methods: The efficacious dose range of systemically administered PD-L1:CD3 TCE was interrogated using SP34 or SCRI-6 CD3 binders against intracranially implanted NCI-H1975-GFP/ffLuc, modeling metastatic lung cancer. Activity of SP34 or SCRI-6 TCE with a murine PD-L1 binder was evaluated in mice transgenic for human CD3ε. Results: Bioluminescent tumor burden of mice treated with the SP34 TCE was eliminated in 85-100% of mice across the entire dose range of 0.3 to 8.5 mg/kg. However, despite the loss of luminescent signal at 2.1, 4.2, and 8.4 mg/kg, 28-85% of these mice met humane end point criteria and were removed from study early, suggesting that these doses exceeded the maximum tolerated dose. SCRI-6 TCE eliminated bioluminescent tumor signal and 100% of mice remained healthy at doses from 0.03 to 2.12 mg/kg (the highest dose tested). Doses of 0.0005-0.008 mg/kg did not alter tumor growth, and the median survival was similar to the negative control group, establishing the lower limit of efficacy for this TCE. A dose titration from 0.01 to 5 mg/kg of both the SP34 and SCRI-6 TCE in human CD3ε transgenic mice showed pharmacodynamic responses with similar, modest, and transient loss of body weight and transient depletion of circulating lymphocytes at doses of 0.4-5mg/kg. Cytokines associated with cytokine release syndrome (IL-6, IFNgamma and TNFalpha) were found to be elevated at higher levels in SP34 TCE treated mice compared to those in SCRI-6 TCE mice. INFgamma was significantly higher in the SP34 TCE at 5, 2.5, and 0.1mg/kg (p=0.03, 0.05, and 0.01 respectively), TNFalpha at 5mg/kg (p=0.003), and IL-6 at 1.3mg/kg (p=0.03), suggesting a higher tolerated threshold for the SCRI-6-based TCE. In the NCI-H1975 brain metastases model, the SCRI-6 TCE induced complete and durable remissions for the entirety of the study, whereas remissions tended to be variable and transient with the SP34 version. Conclusion: Incorporation of the novel SCRI-6 CD3 binder into a potent PD-L1 targeted TCE showed superior efficacy with lower cytokine secretion, demonstrating potential to expand the therapeutic index.