Fig 1: XMT-1660 activity across a panel of breast cancer PDX. A, Waterfall plot of MBR among n = 3 per PDX model. Pink bars, TNBC. Green bars, ER+ breast cancer. B, The data from part A shown with B7-H4 IHC score in each model. Inset, responsive (MBR ≤ −0.3) and nonresponsive tumors when categorized by B7-H4 IHC as low TPS (< 75) or high TPS (≥75). C, Representative B7-H4 IHC images from pink (TNBC) and green (ER+) PDX models with low TPS (<75) and high TPS (≥75).
Fig 2: In vivo profile comparison of B7-H4 ADCs. A, Antitumor activity of B7-H4 ADCs in HBCx-24 PDX model. Inset, B7-H4 IHC. B, Antitumor activity of B7-H4 ADCs in MX-1 breast cancer cell line model. Inset, B7-H4 IHC. C, Plasma levels of conjugated drug in MX-1 tumor-bearing animals following a single administration of ADC at 0.15 mg/kg payload. Refer to legend in part B. D, Plasma levels of three analytes in cynomolgus monkeys following a single administration of ADC at 0.09 mg/kg payload. Blue, XMT-1660 DAR 6 DS; purple, DAR 2 DS.
Fig 3: In vitro characterization of B7-H4 ADCs. A, The anti–B7-H4 antibody does not block the functional activity of B7-H4 ligand. HEK293 or HEK293-B7-H4 cells were incubated with 10 nmol/L antibody (B7-H4 or nonbinding control) prior to the addition of CellTrace Violet-labeled CD3+ T cells and CD3/CD28 T-cell Activator. T cell proliferation was determined after 4-day incubation. Data represent the mean (± standard deviation) of triplicate samples. B, Schematics of the B7-H4–targeted ADCs evaluated in this study: site-specific DS DAR 2 and DAR 6, and DF DAR 12. C, Binding of ADCs to HEK293-B7-H4 cells and MX-1 breast cancer cells. Flow cytometry analysis was performed with B7-H4 ADCs, unconjugated antibody, and nonbinding control ADCs. D, Binding of ADCs to recombinant human B7-H4 protein. ELISA was performed with B7-H4 ADCs, unconjugated antibody, and non-binding control ADCs. E, B7-H4 ADCs elicit target-dependent cytotoxicity. HEK293-B7-H4 cells were incubated with test article for 3 days, and viability was measured with CellTiter-Glo.
Fig 4: XMT-1660 activity in ovarian tumors and PD-1 refractory breast tumor. A, Antitumor activity of XMT-1660 in OV2423 ovarian cancer PDX. Inset, B7-H4 IHC. B, Antitumor activity of XMT-1660 in CTG-1692 ovarian cancer PDX. Inset, B7-H4 IHC. C, Antitumor activity of XMT-1660 in mBR9013 MMTV-ERBB2-derived syngeneic tumor in FVB/NJ. Anti–PD-1 immune checkpoint inhibitor was also evaluated (dosed BIWx3 (IP)). Inset, B7-H4 (top) and PD-L1 (bottom) IHC.
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