Abstract 1865: HDP-102 - a CD37-targeting Amanitin-based-ADC for the treatment of NHL - non-clinical data package

Abstract

Abstract Background: Antibody-drug conjugates (ADC) are gaining importance as anti-cancer therapy. Most ADCs are based on cytotoxic warheads targeting only proliferating cells. In contrast, HDP´s proprietary ATAC platform utilizes amatoxins as payload. Amatoxins are specific inhibitors of eukaryotic RNA polymerase II, suppressing a key function in the protein metabolism not limiting their cytotoxicity to proliferating cells. Furthermore, there are no known resistance mechanisms against amatoxins in mammalian cells (i.e. multi drug resistance transporters), making ATACs a promising new class of anti-cancer ADCs. Here we present pre-clinical data on the anti-CD37 ATAC HDP-102. CD37 is a transmembrane protein expressed exclusively on immune cells, mainly mature B-cells, and in many B-cell malignancies, including Non-Hodgkin’s Lymphoma (NHL). Material and Methods: HDP-102: anti-CD37 ADC based on cysteine-reactive, site-specific amatoxin-linker constructs produced by HDP Cytotoxicity assays: CellTiter Glo 2.0 (Promega) assays on CD37pos cell lines MEC-2, Raji-luc, Ramos and CD37neg Nalm-6 cells Efficacy studies: Disseminated MEC-2 and Raji-Luc mouse xenograft tumor models in single dose experiments Tolerability study in Cynomolgus monkeys: i.v. HDP-102 treatment on days 1 and 22; blood sampling for PK analysis; necropsy and histopathology on days 28 and 64 Results: HDP-102 showed full-blown cytotoxicity with EC50 values in the low nanomolar range in all CD37pos cell lines in vitro but no cytotoxicity on CD37neg cells. In vivo, the anti-tumor efficacy of HDP-102 was evaluated in disseminated CDX models of NHL. A single dose of 0.5 mg/kg HDP-102 already led to complete tumor remission in all animals in a Raji-luc model and 60% survival on day 100 in a MEC-2 model, demonstrating the high potency of HDP-102 in NHL models. In a tolerability study in Cynomolgus monkeys, i.v. administration of HDP-102 was well tolerated up to 2.5 mg/kg without clinical signs of toxicity. Microscopically, decreased cellularity in lymphoid tissue was the main finding, caused by the targeted effect of HDP-102 on CD37pos cells. The HNSTD of 2.5 mg/kg together with the potent anti-tumor efficacy of HDP-102 leads to a therapeutic window of ~200 for HDP-102. Conclusion: CD37 is an ideal target for ADCs due to its high prevalence in B-cell malignancies and limited expression on healthy cells. We have demonstrated that the anti-CD37 ATAC HDP-102 is a promising drug candidate for the treatment of NHL. HDP-102 showed excellent anti-tumor efficacy in CDX models even after single doses. Pharmacological activity of HDP-102 was also seen in Cynomolgus monkeys as evidenced by depletion of B-cells in lymphoid organs. Furthermore, HDP-102 was well tolerated in monkeys. Taken together, based on pre-clinical data, HDP-102 is a promising new treatment option for NHL patients combining a good safety profile with strong anti-tumor efficacy. Citation Format: Sarah-Jane Neuberth, Kristin Decker, Christian Orlik, Irina Dranova, Anikó Pálfi, Torsten Hechler, Andreas Pahl, Michael Kulke. HDP-102 - a CD37-targeting Amanitin-based-ADC for the treatment of NHL - non-clinical data package [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1865.