IL-2-armored peptide-major histocompatibility class I bispecific antibodies redirect antiviral effector memory CD8+ T cells to induce potent anti-cancer cytotoxic activity with limited cytokine release
John S. Schardt,
Even Walseng,
Kim Le,
Chunning Yang,
Pooja Shah,
Ying Fu,
Kausar Alam,
Cathryn R. Kelton,
Yu Gu,
Fengying Huang,
Jia Lin,
Wenhai Liu,
Andrew Dippel,
Hanzhi Zhang,
Kathy Mulgrew,
Stacy Pryts,
Vijaykumar Chennupati,
Hung-Chang Chen,
Jessica Denham,
Xiaoru Chen,
Pallab Pradhan,
Yuling Wu,
Colin Hardman,
Chihao Zhao,
Michael Kierny,
Yang Song,
Simon J. Dovedi,
Saso Cemerski,
Yariv Mazor
Affiliations
John S. Schardt
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Even Walseng
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Kim Le
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Chunning Yang
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Pooja Shah
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Ying Fu
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Kausar Alam
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Cathryn R. Kelton
Oncology ICC, AstraZeneca, Gaithersburg, MD, USA
Yu Gu
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Fengying Huang
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Jia Lin
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Wenhai Liu
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Andrew Dippel
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Hanzhi Zhang
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Kathy Mulgrew
Oncology ICC, AstraZeneca, Gaithersburg, MD, USA
Stacy Pryts
Oncology ICC, AstraZeneca, Gaithersburg, MD, USA
Vijaykumar Chennupati
Data Science and Advanced Analytics, AstraZeneca, Gaithersburg, MD, USA
Hung-Chang Chen
Data Science and Advanced Analytics, AstraZeneca, Gaithersburg, MD, USA
Jessica Denham
Oncology ICC, AstraZeneca, Cambridge, UK
Xiaoru Chen
Oncology ICC, AstraZeneca, Cambridge, UK
Pallab Pradhan
Oncology ICC, AstraZeneca, Cambridge, UK
Yuling Wu
Oncology ICC, AstraZeneca, Cambridge, UK
Colin Hardman
Discovery Bioanalysis, Clinical Pharmacology & Safety Sciences (CPSS), R&D, AstraZeneca, Gaithersburg, MD, USA
Chihao Zhao
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Michael Kierny
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Yang Song
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
Simon J. Dovedi
Data Science and Advanced Analytics, AstraZeneca, Gaithersburg, MD, USA
Saso Cemerski
Oncology ICC, AstraZeneca, Gaithersburg, MD, USA
Yariv Mazor
R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USA
T cell engagers (TCEs) are becoming an integral class of biological therapeutic owing to their highly potent ability to eradicate cancer cells. Nevertheless, the widespread utility of classical CD3-targeted TCEs has been limited by narrow therapeutic index (TI) linked to systemic CD4+ T cell activation and aberrant cytokine release. One attractive approach to circumvent the systemic activation of pan CD3+ T cells and reduce the risk of cytokine release syndrome is to redirect specific subsets of T cells. A promising strategy is the use of peptide-major histocompatibility class I bispecific antibodies (pMHC-IgGs), which have emerged as an intriguing modality of TCE, based on their ability to selectively redirect highly reactive viral-specific effector memory cytotoxic CD8+ T cells to eliminate cancer cells. However, the relatively low frequency of these effector memory cells in human peripheral blood mononuclear cells (PBMCs) may hamper their redirection as effector cells for clinical applications. To mitigate this potential limitation, we report here the generation of a pMHC-IgG derivative known as guided-pMHC-staging (GPS) carrying a covalent fusion of a monovalent interleukin-2 (IL-2) mutein (H16A, F42A). Using an anti-epidermal growth factor receptor (EGFR) arm as a proof-of-concept, tumor-associated antigen paired with a single-chain HLA-A *02:01/CMVpp65 pMHC fusion moiety, we demonstrate in vitro that the IL-2-armored GPS modality robustly expands CMVpp65-specific CD8+ effector memory T cells and induces potent cytotoxic activity against target cancer cells. Similar to GPS, IL-2-armored GPS molecules induce modulated T cell activation and reduced cytokine release profile compared to an analogous CD3-targeted TCE. In vivo we show that IL-2-armored GPS, but not the corresponding GPS, effectively expands grafted CMVpp65 CD8+ T cells from unstimulated human PBMCs in an NSG mouse model. Lastly, we demonstrate that the IL-2-armored GPS modality exhibits a favorable developability profile and monoclonal antibody-like pharmacokinetic properties in human neonatal Fc receptor transgenic mice. Overall, IL-2-armored GPS represents an attractive approach for treating cancer with the potential for inducing vaccine-like antiviral T cell expansion, immune cell redirection as a TCE, and significantly widened TI due to reduced cytokine release.
