| Popis: |
Antagonistic molecules targeting the PD-1/PD-L1 axis have shown excellent activity in the clinic. However, the majority of patients do not respond to the therapy due to multifaceted reasons implicating a non-effective activation of the immune system in those patients. The co-stimulatory molecule 4-1BB has been shown to be a key signalling component of T cells and the combination of 4-1BB activation and PD-1/PD-L1 antagonism has been shown to be highly active in preclinical models. Systemic application of first-generation anti-4-1BB antibodies however have resulted in dose limiting hepatic toxicities. We have generated and are currently clinically investigating a novel 4-1BB/PD-L1/HSA trispecific MATCH3 immunomodulatory drug candidate (NM21-1480) that agonizes 4-1BB conditionally upon PD-L1 binding and concomitantly blocks the interaction between PD-1 and PD-L1. Here we investigate the impact of dose dependency in vitro and the translation of this to in vivo studies to aid the selection of optimal doses for our ongoing clinical study of NM21-1480 in cancer patients. In human PD-L1 tumor bearing mice, triple knock-in for human PD-1, human PD-L1 and human 4-1BB, we have investigated the impact of dose titrations of NM21-1480. We observe a dose dependent effect of NM21-1480 on tumor growth, systemic exposure, tumor exposure and pharmacodynamic biomarkers of immune cell activation. We also demonstrate the formation of a memory response in treated mice through rechallenge of the mice with tumor. We also investigate the effect of combination therapy of NM21-1480 with immune-oncology targeted therapeutics both in vitro and in vivo. In particular, we demonstrate that the combination of NM21-1480 with anti-CD3 T cell engagers is highly effective in T cell activation and tumor control. These data highlight the potential of NM21-1480 for the treatment of cancer patients and enable greater understanding of the relationship between dose, tumor exposure, immune activation and tumor growth inhibition. Citation Format: Daniel Snell, Tea Gunde, Stefan Warmuth, Peter Lichtlen, Linlin Liu, Shu-wen Teng, Lan Zhang, ChaoHsuan Pan, Peiqi Li, Julia Tietz, Matthias Brock, Alexandre Simonim, Christian Hess, Christopher Weinert, Maria Johansson, Bithi Chatterjeee, Nicole Bassler, Niels Kirk, Catia Mendes, Robin Heiz, Naomi Flueckiger, Dania Diem, Dana Mahler, Belinda Wickihalder, Simone Muntwiler, Sandro Wagen, Elmar vom Baur, Archie N. Tse, David Urech. Dose selection investigations and combination strategies of NM21-1480, a PD-L1/4-1BB/HSA trispecific MATCH3 therapeutic clinical candidate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2870. |
