Data from Glucuronide-Linked Antibody–Tubulysin Conjugates Display Activity in MDR<sup>+</sup> and Heterogeneous Tumor Models

Abstract

<div>Abstract<p>Although antibody–drug conjugates (ADCs) find increasing applications in cancer treatment, <i>de novo</i> or treatment-emergent resistance mechanisms may impair clinical benefit. Two resistance mechanisms that emerge under prolonged exposure include upregulation of transporter proteins that confer multidrug resistance (MDR<sup>+</sup>) and loss of cognate antigen expression. New technologies that circumvent these resistance mechanisms may serve to extend the utility of next-generation ADCs. Recently, we developed the quaternary ammonium linker system to expand the scope of conjugatable payloads to include tertiary amines and applied the linker to tubulysins, a highly potent class of tubulin binders that maintain activity in MDR<sup>+</sup> cell lines. In this work, tubulysin M, which contains an unstable acetate susceptible to enzymatic hydrolysis, and two stabilized tubulysin analogues were prepared as quaternary ammonium-linked glucuronide-linkers and assessed as ADC payloads in preclinical models. The conjugates were potent across a panel of cancer cell lines and active in tumor xenografts, including those displaying the MDR<sup>+</sup> phenotype. The ADCs also demonstrated potent bystander activity in a coculture model comprised of a mixture of antigen-positive and -negative cell lines, and in an antigen-heterogeneous tumor model. Thus, the glucuronide–tubulysin drug-linkers represent a promising ADC payload class, combining conjugate potency in the presence of the MDR<sup>+</sup> phenotype and robust activity in models of tumor heterogeneity in a structure-dependent manner. <i>Mol Cancer Ther; 17(8); 1752–60. ©2018 AACR</i>.</p></div>