Intratumoral Payload Concentration Correlates with the Activity of Antibody-Drug Conjugates.

Donglu Zhang,Peter S Dragovich,Cornelis E.C.A Hop,Thomas H Pillow,Yong Ma,Andrew G Polson,Keyang Xu,Dian Su,S Cyrus Khojasteh,Jack D Sadowsky,Shang-Fan Yu,Katherine R Kozak

doi:10.1158/1535-7163.mct-17-0697

Donglu Zhang, Peter S Dragovich + Show 10 more

Open Access

https://doi.org/10.1158/1535-7163.mct-17-0697

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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. Mol Cancer Ther; 17(3); 677-85. ©2018 AACR.

Highlights

Antibody–drug conjugates (ADC) consist of an antibody that targets disease antigen(s) and a payload that is connected to the antibody via a linker
Our previous study established that the number of PBD molecules per 106 base pair that was covalently bound to DNA at the site of action can be determined, and the majority of PBD delivered intracellularly via an ADC preferentially forms
The payload concentration Ctumor was widely separated at Day 18 even at Day 10, Ctumor at Day 4 seemed to be similar between these four ADCs (A1, A2, A3, and A4), which supports that a threshold PBD concentration (Ctumor) was achieved for ADCs A2 and A3 to sustain the corresponding Tumor growth inhibition (TGI)

Summary

Introduction

Antibody–drug conjugates (ADC) consist of an antibody that targets disease antigen(s) and a payload that is connected to the antibody via a linker. Such payloads are often potent antimitotic cytotoxins such as the maytansinoid present in ado-trastuzumab emtansine (Kadcyla, T-DM1) and the auristatin contained in brentuximab vedotin An ADC can be viewed as a prodrug in which the circulating ADC as a reservoir slowly releases the active payload drug in tissues. Following internalization of an ADC, the payload is released into cells at a site of action to exert its biological activities (e.g., in tumor cells).

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