Abstract 56: Antibody-drug conjugates containing glucuronide-tubulysin payloads display activity in MDR+ and heterogeneous tumor models

Abstract

While antibody-drug conjugates (ADCs) find increasing application in cancer treatment regimens, de novo or treatment-emergent resistance mechanisms could impair clinical benefit. Two resistance mechanisms that emerge under continuous ADC exposure in vitro include upregulation of transporters that confer multidrug resistance (MDR+) 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 amine-containing compounds and applied the linker to tubulysins, a highly potent class of microtubule disrupting agents that maintain activity in MDR+ cell lines. Quaternary ammonium-linked glucuronide-tubulysin drug-linkers were synthesized and evaluated as ADCs. The resulting conjugates were potent and immunologically specific across a panel of cancer cell lines, including those displaying the MDR phenotype. The ADCs also demonstrate potent bystander activity in a co-culture model containing a mixture of antigen-positive and -negative cell lines. Incorporation of a PEG12 side chain in the linker enabled loading at 8-drugs/Ab for increased in vivo potency while maintaining suitable ADC pharmacokinetic properties. In vivo, the glucuronide-tubulysin conjugates displayed activity in MDR+ xenograft models and bystander activity in an admixed Ag+/Ag- heterogeneous tumor model. Thus, the glucuronide-tubulysin drug-linkers represent a promising new payload for ADCs, combining conjugate potency in the presence of the MDR phenotype with robust activity in models of tumor antigen heterogeneity. Citation Format: Patrick J. Burke, Joseph Z. Hamilton, Joshua H. Hunter, Julia H. Cochran, Thomas A. Pires, Christopher I. Leiske, Kim K. Emmerton, Peter D. Senter, Robert P. Lyon, Scott C. Jeffrey. Antibody-drug conjugates containing glucuronide-tubulysin payloads display activity in MDR+ and heterogeneous tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 56. doi:10.1158/1538-7445.AM2017-56

DNA damaging agent-based antibody-drug conjugates for cancer therapy

“…Emerging new payloads have shown promising pre-clinical/clinical data. Here are a few examples: new tubulysin payloads [display pM potency [81–83] or retain potency against multidrug-resistant cancer cells [84]], PM050489 [one β-tubulin binder originally isolated from marine sponge [85]], new cryptophycin [a microtubule binder at the vinca site [86]], new CPIs [DNA alkylator that can generate toxic interstrand crosslinks [87]], D211 (an isoquinolidinobenzodiazepine payload that belongs to the PBD dimer family), kinesin spindle protein inhibitors [88], FGX-2-62 (pyridinobenzodiazepines, sequence-selective DNA mono-alkylating agent), bicyclic octapeptide amanitins (an RNA polymerase II inhibitor) [89], spliceostatins and thailanstatins (RNA spliceosome inhibitors) [90–92] and PNU-159682 (an anthracycline which is three orders of magnitude more potent than doxorubicin) [93]. …”