Abstract:
Novel hypoxia-selective antibody-drug conjugates could reduce toxicity and increase tumour selectivity, thereby increasing the therapeutic window. We conjugated a nitroCBI hypoxia-activated prodrug to trastuzumab and cetuximab at a DAR of 2.7 and 2.9 with minimal aggregation. Exposing cells that express the bacterial nitroreductase NsfB to our ADC showed increased cytotoxicity compared to trastuzumab alone. A549 tumour spheroids showed an increased growth delay after treatment with our hypoxia-selective ADC compared to antibody alone. To our knowledge, this is the first example of a dual antigen- and hypoxia-targeting ADC, with potential for improved tumour selectivity.
