Supplementary Figures 1-3 and Tables 1-6 from MMAE Delivery Using the Bicycle Toxin Conjugate BT5528

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Supplementary data are provided to further understand the pharmacokinetics and efficacy of BT5528 and EphA2 expression in tumors. Figure S1: Plasma concentration-time curves of BT5528 and MMAE following IV dosing of BT5528 1 in mouse, rat, and cynomolgus Monkey at 1 mg/kg (n=3 per species). Related to in vivo PK. Figure S2: EphA2 expression and tumour growth inhibition in CDX and PDX xenograft models are correlated. BT5528 3 mg/kg qw dosing has a range of anti-tumour activities across different cell-line derived and patient-derived xenograft models (*p<0.05, **p<0.01, ***p<0.001 2way ANOVA from D0 to last day of vehicle tumour measurement).Data used to generate Figure 3. Figure S3: EphA2 Immunohistochemistry staining of CDX and PDX xenograft models. A range of EphA2 expression is observed in stained tumour tissue from mouse xenograft models. Related to figure 3. Table T1: Ki values for BT5528, 1C1-mcMMAF and control compounds binding to human, mouse and rat Epha2 receptor. Ki values for Bicycle, BTC and DOTA analogues used to generate data in Figures 1, 4 and 5. Table T2: Binding affinities for BT5528 binding to EphA and EphB tyrosine kinases receptors determined by Surface Plasmon Resonance. Data defining BTC and Bicycle KD values for EphA2 orthologues. Table T3: In vitro ADME properties of BT5528 in mouse, rat, NHP and human: plasma protein binding, plasma stability and metabolic stability in hepatocytes. Related to in vitro ADME properties of BT5528. Table T4: Summary of experimentally determined and calculated PK Parameters for BT5528 and MMAE Following IV Dosing of 1 mg/kg BT5528 in Mouse, Rat and Cynomolgus Monkey. Related to in vivo PK Table T5a: Anti-Human EphA2 Antibody Binding Sites on CDX Cell Lines. Expression data used to generate Figure 3. Table T5b:Anti-Human EphA2 Antibody Binding Sites on PDX Cell Lines. Expression data used to generate Figure 3. Table T6: Doses of BT5528 and corresponding toxin (MMAE) used in preclinical toxicology studies compared with the clinical dose of MED-547 and corresponding toxin (MMAF)1. Related to the discussion (ADC versus BTC toxicology responses).

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.