Systemic adverse effects of chemotherapy can be reduced by improving concentration of the agents at their site of action, a characteristic of antibody–drug conjugates (ADCs). Prostate-specific membrane antigen (PSMA)-binding single-domain ADCs were studied to determine the effect of tissue penetration on efficacy in vitro and in vivo. Interestingly, ADCs that demonstrated low potency in vitro had higher in vivo efficacy than high-potency ADCs. Smaller size of ADC and slower internalization rate improved tissue penetration and increased efficacy in vivo. Addition of an albumin-binding domain was also beneficial, as those lacking this domain were rapidly cleared, reducing cellular uptake. Thus, maximizing the number of cells that receive a lethal dose correlates with efficacy more strongly than total tumour uptake or in vitro potency. Modelling and protein engineering could be used to custom design ADCs for controlling these variables and maximizing outcomes.
Nessler, I. et al. Increased tumor penetration of single-domain antibody drug conjugates improves in vivo efficacy in prostate cancer models. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-19-2295 (2020)
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Fenner, A. Tissue penetration to optimize PSMA ADCs. Nat Rev Urol 17, 132 (2020). https://doi.org/10.1038/s41585-020-0291-2