Abstract 2276: Preclinical development and mechanism of action studies of NM21-1480, a PD-L1/4-1BB/HSA trispecific MATCH3 therapeutic clinical candidate

Abstract

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 a novel 4-1BB/PD-L1/HSA trispecific MATCH3 immunomodulatory drug candidate (NM21-1480) that agonizes 4-1BB conditionally upon PD-L1 binding / blockade. Here we show the preclinical development data package for NM21-1480 demonstrating exquisite tumour-specific T cell activation associated with both 4-1BB agonism as well as PD-L1/PD-1 antagonism. We also demonstrate tumour specific localisation and accumulation of NM21-1480 in a mouse xenograft model. We report on the toxicity profile and pharmacokinetic properties of the molecule in non-human primates. We plan to initiate a first-in-human clinical study in the second half of 2020 to determine the safety, tolerability and first signs of clinical activity of the molecule. Citation Format: Daniel Snell, Tea Gunde, Stefan Warmuth, Peter Lichtlen, Julia Tietz, Matthias Brock, Alexandre Simonin, Christian Hess, Weinert Christopher, Robin Heiz, Naomi Flueckiger, Julia Zeberer, Dania Diem, Dana Mahler, Diego Morenzoni, Belinda Wickihalder, Simone Muntwiler, Antonia Poelderl, Benjamin Kuettner, Sandro Wagen, Sebastian Meyer, Timothy Egan, David Urech. Preclinical development and mechanism of action studies of NM21-1480, a PD-L1/4-1BB/HSA trispecific MATCH3 therapeutic clinical candidate [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2276.

Emerging new therapeutic antibody derivatives for cancer treatment

“…[162][163][164][165] To prevent potential toxic side effects due to unspecific overactivation, a monovalent trispecific antibody NM21-1480 comprising three scFvs (αPD-L1, α4-1BB and αHSA) fused in a single chain was designed to restrict 4-1BB signaling upon PD-L1 blockage. 166 A similar immunomodulatory design strategy was used to construct GNC-038, a tetraspecific IgG-scFvconjugated antibody (αCD19/CD3/4-1BB/PD-L1), now in phase I clinical trial (NCT04606433).…”

The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy

“…Most molecules still display an antibody framework or include antibody-derived binding domains, such as scFv (ABL503/TJ-L14B, ABL111/Tj-CD4B, ABL105/YH32367, ATG-101/YN051, LBL-024), 64 , 65 , 71 , 77 , 78 VH (CB307), 67 VH/VL (ND021/NM21-1480), 58 sdAb (INBRIX-105/ES101) 43 or VHH (PM1003, PM1032). 49 In contrast, FAP-4-1BBL (RG7827) and CD19-4-1BBL (RG6076) are antibody fusion proteins based on human 4–1BBL ectodomains fused to an IgG1 framework 32 and DSP107 is a trimeric fusion protein without the implementation of antibody components.…”

“…For example, for ND021/NM21-1480, targeting the N-terminal (membrane distal) 4–1BB-epitope lead to improved functionality compared to membrane-proximal epitopes. 58 An optimal synapse space of 140 Å has also been predicted, potentially giving smaller molecules an advantage. 72 …”