Antibody drug conjugates (ADCs) have shown significant clinical success, with 11 FDA approvals for solid tumors. However, translating preclinical findings to the clinic remains challenging due to differences in tumor biology and drug response between mice and humans. This study shows that ADCs approved for solid tumors can achieve substantial efficacy in mouse models when administered at similar weight-based dosing (mg/kg) as the maximum tolerated dose (MTD) in humans. This is due to similar drug concentrations in tumors and tissue penetration, which are influenced by ADC delivery features. Computational models can help predict clinical efficacy by accounting for complex tumor microenvironment dynamics. The study analyzed preclinical efficacy data of six FDA-approved ADCs in solid tumors, finding that all showed efficacy in mouse models at doses similar to the clinical MTD. However, many discontinued ADCs required higher doses in mice than the clinical MTD to achieve efficacy. This highlights the importance of matching mg/kg dosing in mice to the clinical MTD for accurate preclinical evaluation. Tissue penetration and payload concentration are key factors in ADC efficacy, with higher tissue penetration leading to better clinical outcomes. ADCs with lower drug-to-antibody ratios (DAR) can achieve higher tissue penetration, improving efficacy. The study also found that ADCs with higher payload concentrations in tumors showed better clinical outcomes. However, the concentration of drug in a tumor is influenced by factors such as vascular permeability and surface area, leading to similar total uptake in mice and humans when dosed at similar mg/kg levels. This suggests that preclinical studies using similar mg/kg dosing can provide a reliable estimate of clinical efficacy. The study also examined the tolerability of clinical ADCs, finding that toxicity is often due to the cytotoxic payload rather than the antibody itself. Mouse models often have higher MTDs than humans due to differences in payload potency and antibody target expression. This highlights the need for careful dose estimation based on clinical data and non-human primate (NHP) studies to ensure safe and effective ADC development. In conclusion, matching mg/kg dosing in mice to the clinical MTD is crucial for accurate preclinical evaluation of ADCs. This approach helps predict clinical efficacy and informs the design of more effective ADCs. The study emphasizes the importance of considering factors such as tissue penetration, payload concentration, and toxicity when developing ADCs for clinical use.Antibody drug conjugates (ADCs) have shown significant clinical success, with 11 FDA approvals for solid tumors. However, translating preclinical findings to the clinic remains challenging due to differences in tumor biology and drug response between mice and humans. This study shows that ADCs approved for solid tumors can achieve substantial efficacy in mouse models when administered at similar weight-based dosing (mg/kg) as the maximum tolerated dose (MTD) in humans. This is due to similar drug concentrations in tumors and tissue penetration, which are influenced by ADC delivery features. Computational models can help predict clinical efficacy by accounting for complex tumor microenvironment dynamics. The study analyzed preclinical efficacy data of six FDA-approved ADCs in solid tumors, finding that all showed efficacy in mouse models at doses similar to the clinical MTD. However, many discontinued ADCs required higher doses in mice than the clinical MTD to achieve efficacy. This highlights the importance of matching mg/kg dosing in mice to the clinical MTD for accurate preclinical evaluation. Tissue penetration and payload concentration are key factors in ADC efficacy, with higher tissue penetration leading to better clinical outcomes. ADCs with lower drug-to-antibody ratios (DAR) can achieve higher tissue penetration, improving efficacy. The study also found that ADCs with higher payload concentrations in tumors showed better clinical outcomes. However, the concentration of drug in a tumor is influenced by factors such as vascular permeability and surface area, leading to similar total uptake in mice and humans when dosed at similar mg/kg levels. This suggests that preclinical studies using similar mg/kg dosing can provide a reliable estimate of clinical efficacy. The study also examined the tolerability of clinical ADCs, finding that toxicity is often due to the cytotoxic payload rather than the antibody itself. Mouse models often have higher MTDs than humans due to differences in payload potency and antibody target expression. This highlights the need for careful dose estimation based on clinical data and non-human primate (NHP) studies to ensure safe and effective ADC development. In conclusion, matching mg/kg dosing in mice to the clinical MTD is crucial for accurate preclinical evaluation of ADCs. This approach helps predict clinical efficacy and informs the design of more effective ADCs. The study emphasizes the importance of considering factors such as tissue penetration, payload concentration, and toxicity when developing ADCs for clinical use.