Figure 2 from Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors

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GEN1046 therapeutic efficacy and antitumor immune responses in MC38-hPD-L1 tumor–bearing hPD-L1/h4-1BB dKI mice. A, MC38-hPD-L1 cells (1 × 106 tumor cells) were injected s.c. in the right flank of hPD-L1/h4-1BB dKI mice. After tumor establishment (average tumor volume, ∼80 mm3), mice were randomized and treated with GEN1046 or isotype control antibody (each 5 mg/kg intravenous) at the indicated time points (n = 9 per group). B, Tumor growth of individual mice in each group, with CR defined as number of animals with CR. C, Progression-free survival, defined as the percentage of mice with tumor volume smaller than 500 mm3, is shown as a Kaplan–Meier curve. Mantel–Cox analysis was used to compare survival between treatment groups. ****, P < 0.0001. D, Mice with CR after treatment with GEN1046 (shown in B) were rechallenged by s.c. injection of 1 × 106 MC38-hPD-L1 tumor cells in the left flank on day 164. As a control group, a second cohort of naïve dKI animals was inoculated with 1 × 106 MC38-hPD-L1 tumor cells. Tumor growth of individual mice in each group is shown. E–I, MC38-hPD-L1 or MC38-WT cells (1 × 106 tumor cells) were injected s.c. in the right flank of hPD-L1/h4-1BB dKI mice. After tumor establishment (mean tumor volume, ∼75 mm3), mice were randomized and treated with GEN1046, a durvalumab analogue, or isotype control antibody (all 5 mg/kg intravenous) at the indicated time points. The mice were sacrificed 2 days after the last treatment (n = 5 per treatment group), and the tumors and spleens were excised. F, Sections of resected tumors (4 µm) were stained using anti-CD3, anti-CD8, or anti-FoxP3 antibodies by IHC. The number of positive cells was quantified per mm2. Mann–Whitney U statistical analysis was performed to compare the number of cellular subsets between treatment groups in MC38-hPD-L1 or MC38-WT tumor–bearing mice. *, P < 0.05. G and H, Flow cytometry analysis of dissociated splenocytes. Data from individual mice are shown as well as group mean ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001, Wilcoxon rank sum test. I, Peripheral blood samples were taken 1 day before treatment (d−1) and 2 days after each treatment. Cytokine analysis was performed by electrochemiluminescence immunoassay. s.c., subcutaneous; Treg, regulatory T cell.

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