Harnessing the Power of Amanitin-based ADCs: HDP-102's Potential in Non-Hodgkin's Lymphoma Therapy

Antibody-drug conjugates (ADCs) are increasingly significant in cancer treatment. While traditional ADCs target proliferating cells with cytotoxic agents, HDP's proprietary ATAC platform uses amatoxins, which are potent inhibitors of RNA polymerase II in eukaryotes. These compounds are unique as they do not restrict their cytotoxic effects to rapidly dividing cells and there are no known resistance mechanisms against them in mammalian cells, suggesting a promising new category of ADCs.

We report on HDP-102, an anti-CD37 ATAC, where CD37 is a transmembrane protein primarily found on immune cells, notably mature B-cells, and is also present in many B-cell malignancies, such as Non-Hodgkin’s Lymphoma (NHL). HDP-102 is an ADC that employs a cysteine-reactive, site-specific amatoxin-linker construct.

The in vitro cytotoxicity of HDP-102 was evident, with low nanomolar EC50 values in all CD37-positive cell lines, yet it showed no toxicity to CD37-negative cells. In NHL disseminated CDX models, HDP-102 demonstrated remarkable anti-tumor effects, with a single dose of 0.5 mg/kg leading to complete remission in a Raji-luc model and a 60% survival rate at day 100 in a MEC-2 model. In a tolerability study with Cynomolgus monkeys, HDP-102 was administered intravenously up to 2.5 mg/kg without significant clinical toxicity, with the main microscopic finding being decreased cellularity in lymphoid tissue, attributed to HDP-102's targeted impact on CD37-positive cells.

The high non-toxic starting dose (HNSTD) of 2.5 mg/kg, combined with the potent anti-tumor efficacy of HDP-102, indicates a therapeutic window of approximately 200 for HDP-102. Given its prevalence in B-cell malignancies and limited presence in healthy cells, CD37 is an ideal target for ADCs. HDP-102 has shown to be a promising drug candidate for NHL treatment, with excellent anti-tumor efficacy in CDX models even after a single dose, and pharmacological activity in Cynomolgus monkeys, evidenced by the depletion of B-cells in lymphoid organs. Furthermore, HDP-102 was well tolerated in monkeys, suggesting it is a potential new treatment option for NHL patients, offering a favorable safety profile with robust anti-tumor effects.

The study included cytotoxicity assays using the CellTiter Glo 2.0 method on CD37-positive cell lines MEC-2, Raji-luc, Ramos, and CD37-negative Nalm-6 cells. Efficacy was assessed in disseminated MEC-2 and Raji-Luc mouse xenograft tumor models through single dose experiments. A tolerability study in Cynomolgus monkeys involved intravenous HDP-102 treatment on days 1 and 22, with blood sampling for pharmacokinetic analysis and necropsy and histopathology conducted on days 28 and 64.