Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity

Shelley E. Ackerman; Cecelia I. Pearson; Joshua D. Gregorio; Joseph C. Gonzalez; Justin A. Kenkel; Felix J. Hartmann; Angela Luo; Po Y. Ho; Heidi LeBlanc; Lisa K. Blum; Samuel C. Kimmey; Andrew Luo; Murray L. Nguyen; Jason C. Paik; Lauren Y. Sheu; Benjamin Ackerman; Arthur Lee; Hai Li; Jennifer Melrose; Richard P. Laura; Vishnu C. Ramani; Karla A. Henning; David Y. Jackson; Brian S. Safina; Grant Yonehiro; Bruce H. Devens; Yaron Carmi; Steven J. Chapin; Sean C. Bendall; Marcin Kowanetz; David Dornan; Edgar G. Engleman; Michael N. Alonso

doi:10.1038/s43018-020-00136-x

Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity

Shelley E. Ackerman, Cecelia I. Pearson, Joshua D. Gregorio, Joseph C. Gonzalez, Justin A. Kenkel, Felix J. Hartmann, Angela Luo, Po Y. Ho, Heidi LeBlanc, Lisa K. Blum, Samuel C. Kimmey, Andrew Luo, Murray L. Nguyen, Jason C. Paik, Lauren Y. Sheu, Benjamin Ackerman, Arthur Lee, Hai Li, Jennifer Melrose, Richard P. LauraVishnu C. Ramani, Karla A. Henning, David Y. Jackson, Brian S. Safina, Grant Yonehiro, Bruce H. Devens, Yaron Carmi, Steven J. Chapin, Sean C. Bendall, Marcin Kowanetz, David Dornan, Edgar G. Engleman, Michael N. Alonso^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

125 Scopus citations

Abstract

Innate pattern recognition receptor agonists, including Toll-like receptors (TLRs), alter the tumor microenvironment and prime adaptive antitumor immunity. However, TLR agonists present toxicities associated with widespread immune activation after systemic administration. To design a TLR-based therapeutic suitable for systemic delivery and capable of safely eliciting tumor-targeted responses, we developed immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 dual agonist conjugated to tumor-targeting antibodies. Systemically administered human epidermal growth factor receptor 2 (HER2)-targeted ISACs were well tolerated and triggered a localized immune response in the tumor microenvironment that resulted in tumor clearance and immunological memory. Mechanistically, ISACs required tumor antigen recognition, Fcγ-receptor-dependent phagocytosis and TLR-mediated activation to drive tumor killing by myeloid cells and subsequent T-cell-mediated antitumor immunity. ISAC-mediated immunological memory was not limited to the HER2 ISAC target antigen since ISAC-treated mice were protected from rechallenge with the HER2⁻ parental tumor. These results provide a strong rationale for the clinical development of ISACs.

Original language	English
Pages (from-to)	18-33
Number of pages	16
Journal	Nature Cancer
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/s43018-020-00136-x
State	Published - Jan 2021

Funding

Funders	Funder number
Stanford BioX
European Molecular Biology Organization	ALTF 1141-2017
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	171741, P2ZHP3-171741
National Institutes of Health	T32GM007276, CA209971, CA222969, 1DP2OD022550-01

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Ackerman, S. E., Pearson, C. I., Gregorio, J. D., Gonzalez, J. C., Kenkel, J. A., Hartmann, F. J., Luo, A., Ho, P. Y., LeBlanc, H., Blum, L. K., Kimmey, S. C., Luo, A., Nguyen, M. L., Paik, J. C., Sheu, L. Y., Ackerman, B., Lee, A., Li, H., Melrose, J., ... Alonso, M. N. (2021). Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nature Cancer, 2(1), 18-33. https://doi.org/10.1038/s43018-020-00136-x

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title = "Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity",

abstract = "Innate pattern recognition receptor agonists, including Toll-like receptors (TLRs), alter the tumor microenvironment and prime adaptive antitumor immunity. However, TLR agonists present toxicities associated with widespread immune activation after systemic administration. To design a TLR-based therapeutic suitable for systemic delivery and capable of safely eliciting tumor-targeted responses, we developed immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 dual agonist conjugated to tumor-targeting antibodies. Systemically administered human epidermal growth factor receptor 2 (HER2)-targeted ISACs were well tolerated and triggered a localized immune response in the tumor microenvironment that resulted in tumor clearance and immunological memory. Mechanistically, ISACs required tumor antigen recognition, Fcγ-receptor-dependent phagocytosis and TLR-mediated activation to drive tumor killing by myeloid cells and subsequent T-cell-mediated antitumor immunity. ISAC-mediated immunological memory was not limited to the HER2 ISAC target antigen since ISAC-treated mice were protected from rechallenge with the HER2− parental tumor. These results provide a strong rationale for the clinical development of ISACs.",

author = "Ackerman, {Shelley E.} and Pearson, {Cecelia I.} and Gregorio, {Joshua D.} and Gonzalez, {Joseph C.} and Kenkel, {Justin A.} and Hartmann, {Felix J.} and Angela Luo and Ho, {Po Y.} and Heidi LeBlanc and Blum, {Lisa K.} and Kimmey, {Samuel C.} and Andrew Luo and Nguyen, {Murray L.} and Paik, {Jason C.} and Sheu, {Lauren Y.} and Benjamin Ackerman and Arthur Lee and Hai Li and Jennifer Melrose and Laura, {Richard P.} and Ramani, {Vishnu C.} and Henning, {Karla A.} and Jackson, {David Y.} and Safina, {Brian S.} and Grant Yonehiro and Devens, {Bruce H.} and Yaron Carmi and Chapin, {Steven J.} and Bendall, {Sean C.} and Marcin Kowanetz and David Dornan and Engleman, {Edgar G.} and Alonso, {Michael N.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature.",

year = "2021",

month = jan,

doi = "10.1038/s43018-020-00136-x",

language = "אנגלית",

volume = "2",

pages = "18--33",

journal = "Nature Cancer",

issn = "2662-1347",

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Ackerman, SE, Pearson, CI, Gregorio, JD, Gonzalez, JC, Kenkel, JA, Hartmann, FJ, Luo, A, Ho, PY, LeBlanc, H, Blum, LK, Kimmey, SC, Luo, A, Nguyen, ML, Paik, JC, Sheu, LY, Ackerman, B, Lee, A, Li, H, Melrose, J, Laura, RP, Ramani, VC, Henning, KA, Jackson, DY, Safina, BS, Yonehiro, G, Devens, BH, Carmi, Y, Chapin, SJ, Bendall, SC, Kowanetz, M, Dornan, D, Engleman, EG & Alonso, MN 2021, 'Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity', Nature Cancer, vol. 2, no. 1, pp. 18-33. https://doi.org/10.1038/s43018-020-00136-x

TY - JOUR

T1 - Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity

AU - Ackerman, Shelley E.

AU - Pearson, Cecelia I.

AU - Gregorio, Joshua D.

AU - Gonzalez, Joseph C.

AU - Kenkel, Justin A.

AU - Hartmann, Felix J.

AU - Luo, Angela

AU - Ho, Po Y.

AU - LeBlanc, Heidi

AU - Blum, Lisa K.

AU - Kimmey, Samuel C.

AU - Luo, Andrew

AU - Nguyen, Murray L.

AU - Paik, Jason C.

AU - Sheu, Lauren Y.

AU - Ackerman, Benjamin

AU - Lee, Arthur

AU - Li, Hai

AU - Melrose, Jennifer

AU - Laura, Richard P.

AU - Ramani, Vishnu C.

AU - Henning, Karla A.

AU - Jackson, David Y.

AU - Safina, Brian S.

AU - Yonehiro, Grant

AU - Devens, Bruce H.

AU - Carmi, Yaron

AU - Chapin, Steven J.

AU - Bendall, Sean C.

AU - Kowanetz, Marcin

AU - Dornan, David

AU - Engleman, Edgar G.

AU - Alonso, Michael N.

PY - 2021/1

Y1 - 2021/1

N2 - Innate pattern recognition receptor agonists, including Toll-like receptors (TLRs), alter the tumor microenvironment and prime adaptive antitumor immunity. However, TLR agonists present toxicities associated with widespread immune activation after systemic administration. To design a TLR-based therapeutic suitable for systemic delivery and capable of safely eliciting tumor-targeted responses, we developed immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 dual agonist conjugated to tumor-targeting antibodies. Systemically administered human epidermal growth factor receptor 2 (HER2)-targeted ISACs were well tolerated and triggered a localized immune response in the tumor microenvironment that resulted in tumor clearance and immunological memory. Mechanistically, ISACs required tumor antigen recognition, Fcγ-receptor-dependent phagocytosis and TLR-mediated activation to drive tumor killing by myeloid cells and subsequent T-cell-mediated antitumor immunity. ISAC-mediated immunological memory was not limited to the HER2 ISAC target antigen since ISAC-treated mice were protected from rechallenge with the HER2− parental tumor. These results provide a strong rationale for the clinical development of ISACs.

AB - Innate pattern recognition receptor agonists, including Toll-like receptors (TLRs), alter the tumor microenvironment and prime adaptive antitumor immunity. However, TLR agonists present toxicities associated with widespread immune activation after systemic administration. To design a TLR-based therapeutic suitable for systemic delivery and capable of safely eliciting tumor-targeted responses, we developed immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 dual agonist conjugated to tumor-targeting antibodies. Systemically administered human epidermal growth factor receptor 2 (HER2)-targeted ISACs were well tolerated and triggered a localized immune response in the tumor microenvironment that resulted in tumor clearance and immunological memory. Mechanistically, ISACs required tumor antigen recognition, Fcγ-receptor-dependent phagocytosis and TLR-mediated activation to drive tumor killing by myeloid cells and subsequent T-cell-mediated antitumor immunity. ISAC-mediated immunological memory was not limited to the HER2 ISAC target antigen since ISAC-treated mice were protected from rechallenge with the HER2− parental tumor. These results provide a strong rationale for the clinical development of ISACs.

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JO - Nature Cancer

JF - Nature Cancer

IS - 1

ER -

Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity

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