Identification of antibody-drug conjugate payloads which are substrates of ATP-binding cassette drug efflux transporters
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Aim
Antibody-drug conjugates (ADCs) are a form of targeted chemotherapy featuring an antibody recognizing a specific protein on cancer cells joined to a potent toxic payload. Numerous antibody-drug conjugates have received FDA approval; however, clinical resistance arises commonly in tumors. Resistance mechanisms include decreased expression or mutation of the antibody target, failure to release the payload from the ADC, or increased expression of ATP-binding cassette (ABC) efflux transporters associated with multidrug resistance. We therefore sought to characterize the interactions of ABC multidrug transporters with ADC payloads.
Methods
We performed a high-throughput screen with 27 common ADC payloads using cells lines expressing ABC transporters P-glycoprotein (P-gp, encoded by ABCB1 ) or ABCG2 (encoded by ABCG2 ). Confirmatory assays were also performed using cells transfected to express P-gp, ABCG2, or MRP1 (encoded by ABCC1 ).
Results
Several commonly used ADC payloads were found to be avid substrates of P-gp, including calicheamicin gamma1, monomethyl auristatin E, DM1, and DM4. All the pyrrolobenzodiazepines tested - SJG136, SGD-1882, SG2057, and SG3199 - were substrates of P-gp, ABCG2, and MRP1. The modified anthracyclines nemorubicin and its metabolite PNU-159682 were poorly transported by both ABCB1 and ABCG2 and displayed nanomolar to picomolar toxicity. Further, we found that the efficacy of the recently FDA-approved ADC mirvetuximab soravtansine, which has DM4 as the toxic payload, was decreased in cell lines with overexpression of P-gp.
Conclusion
Several commonly used ADC payloads can be effluxed from cells by ABC transporters which may lead to transporter-mediated drug resistance in patients. Future ADCs should be developed using payloads that are not substrates of ABC transporters.
