Abstract 4129: Preclinical assessment of GlycoConnect™ ADCs with potency-modulated derivatives of PNU-159,682

Abstract

Abstract PNU-159,682 is an oxidized secondary metabolite of nemorubicin (MMDX), and substantially more potent (2100-6400-fold) than the commonly used chemotherapeutic anthracycline doxorubicin/adriamycin, but without the dose-limiting cardiotoxicity. Based on these beneficial features, PNU-159,682 is currently being clinically evaluated (phase 1) for solid tumor indications as a payload in various antibody-drug conjugates (NBE-002, SO-N102). It must be noted, however, that the HNSTD of current PNU-based ADCs in non-human primates (~1 mg/kg) may end up in a clinical dose that is sub-optimal to achieve high tumor uptake, due to putative target-mediated drug disposition in healthy tissue. We embarked on a program to develop a set of 2nd-generation PNU-159,682 analogues with attenuated potency, to enable the generation of ADCs with a potentially improved pharmacokinetic profile. Moreover, we reasoned that the adaptation of the new PNU analogues to our proprietary best-in-class ADC technology (GlycoConnect™)1, in combination with our polar spacer technology (HydraSpace™)2 might enable PNU-based ADCs with significantly expanded therapeutic index (TI). We here exhibit the chemical synthesis of a panel of PNU-analogues with attenuated potency and enhanced tolerability, based on specific tailoring of the aminosugar morpholino group. Homogeneous and stable GlycoConnect™/HydraSpace™ ADCs were subsequently generated and evaluated in vitro and in vivo to assess efficacy and tolerability. These studies demonstrate the potential of attenuated PNU derivatives for application in stable and site-specific ADCs with anticipated higher clinic dose and potentially improved therapeutic index. 1 Wijdeven et al., Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering. mAbs 2022, 14. 2 Verkade et al. A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody-Drug Conjugates. Antibodies 2018, 7, 12, doi:10.3390/antib7010012. Citation Format: Floris L. van Delft, Remon van Geel. Preclinical assessment of GlycoConnect™ ADCs with potency-modulated derivatives of PNU-159,682. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4129.