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
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 activat...
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| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2395499 |
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| author | 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 |
| author_facet | 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 |
| author_sort | John S. Schardt |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-60b9a30240a24440876eea62946b972e |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-60b9a30240a24440876eea62946b972e2025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2395499IL-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 releaseJohn S. Schardt0Even Walseng1Kim Le2Chunning Yang3Pooja Shah4Ying Fu5Kausar Alam6Cathryn R. Kelton7Yu Gu8Fengying Huang9Jia Lin10Wenhai Liu11Andrew Dippel12Hanzhi Zhang13Kathy Mulgrew14Stacy Pryts15Vijaykumar Chennupati16Hung-Chang Chen17Jessica Denham18Xiaoru Chen19Pallab Pradhan20Yuling Wu21Colin Hardman22Chihao Zhao23Michael Kierny24Yang Song25Simon J. Dovedi26Saso Cemerski27Yariv Mazor28R&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAOncology ICC, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAOncology ICC, AstraZeneca, Gaithersburg, MD, USAOncology ICC, AstraZeneca, Gaithersburg, MD, USAData Science and Advanced Analytics, AstraZeneca, Gaithersburg, MD, USAData Science and Advanced Analytics, AstraZeneca, Gaithersburg, MD, USAOncology ICC, AstraZeneca, Cambridge, UKOncology ICC, AstraZeneca, Cambridge, UKOncology ICC, AstraZeneca, Cambridge, UKOncology ICC, AstraZeneca, Cambridge, UKDiscovery Bioanalysis, Clinical Pharmacology & Safety Sciences (CPSS), R&D, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAData Science and Advanced Analytics, AstraZeneca, Gaithersburg, MD, USAOncology ICC, AstraZeneca, Gaithersburg, MD, USAR&D Biologics Engineering, AstraZeneca, Gaithersburg, MD, USAT 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.https://www.tandfonline.com/doi/10.1080/19420862.2024.2395499Antibodyantibody engineeringbispecificcancerCRScytokine release syndrome |
| spellingShingle | 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 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 mAbs Antibody antibody engineering bispecific cancer CRS cytokine release syndrome |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Antibody antibody engineering bispecific cancer CRS cytokine release syndrome |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2395499 |
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