Intratumoral Payload Concentration Correlates with the Activity of Antibody–Drug Conjugates

Abstract

Antibody-drug conjugates (ADC) have become important scaffolds for targeted cancer therapies. However, ADC exposure-response correlation is not well characterized. We demonstrated that intratumor payload exposures correlated well with the corresponding efficacies of several disulfide-linked ADCs, bearing an DNA alkylating agent, pyrrolo[2,1-c][1,4]benzodiazepine-dimer (PBD), in HER2-expressing xenograft models. The correlation suggests that a threshold concentration of intratumor payload is required to support sustained efficacy and an ADC can deliver an excessive level of payload to tumors that does not enhance efficacy ("Plateau" effect). In contrast to tumor PBD concentrations, related assessments of systemic exposures, plasma stability, and drug-to-antibody ratio changes of related ADCs did not consistently rationalize the observed ADC efficacies. A minimal efficacious dose could be determined by ADC dose-fractionation studies in the xenograft models. Mechanistic investigations revealed that both linker immolation and linker disulfide stability are the key factors that determine intratumor PBD concentrations. Overall, this study demonstrates how a linker design can impact ADC efficacy and that the intratumor exposure of a payload drug as the molecular mechanism quantitatively correlate with and predict the antitumor efficacy of ADCs. .

Catalytic Cleavage of Disulfide Bonds in Small Molecules and Linkers of Antibody–Drug Conjugates

“…Intermediate 15 could also lead to formation of 16 through the intramolecular disulfide formation. The immolation of the less substituted b-mercaptoethyl-carbamate linker in 15 might be slower than that of b-mercaptoisopropyl-carbamate linker in 14 (Zhang et al, 2018), which would allow sufficient time to form intramolecular disulfide 16.…”

Antibody drug conjugates (ADCs) charged with HDAC inhibitor for targeted epigenetic modulation

“…This result demonstrates the ability of ADCs to be internalized and to acts as a HDAC inhibitor, due to the presence of compound 2 indeed. 27 …”

Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule–Related Therapeutic Modalities

“…Figure 5 illustrates hypothetical ADC payload concentration-time profiles in tumors, liver, and blood, in which tumor payload concentration is much greater than that in livers with very low concentration in plasma. The tumor growth inhibition correlated with intratumor PBD exposures, but not with systemic exposures of ADCs or the payload after administration of HER2disulfide-PBD conjugates in xenograft mice (Zhang et al, 2018). These results indicate that analysis of ADC species in circulation is insufficient to explain or predict ADC efficacy and suggested that payload/catabolite identification and quantitation in the tumors of xenograft mice are important to understand the ADC efficacy.…”