Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism

Changhao He; Rachana R Maniyar; Yahel Avraham; Roberta Zappasodi; Radda Rusinova; Walter Newman; Heidi Heath; Jedd D Wolchok; Rony Dahan; Taha Merghoub; Joel Meyerson

doi:10.1126/sciadv.abm4552

Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism

Changhao He
, Rachana R Maniyar
, Yahel Avraham
, Roberta Zappasodi
, Radda Rusinova
, Walter Newman
, Heidi Heath
, Jedd D Wolchok
, Rony Dahan
, Taha Merghoub
, Joel Meyerson

Department of Systems Immunology

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

9 Citations (Scopus)

Abstract

GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology.

Original language	English
Article number	eabm4552
Number of pages	11
Journal	Science advances
Volume	8
Issue number	8
DOIs	https://doi.org/10.1126/sciadv.abm4552
Publication status	Published - 25 Feb 2022

Funding

This work was supported by Parker Institute for Cancer Immunotherapy scholar and bridge scholar awards (to R.Z.), Melanoma Research Alliance (MRA) grant (to R.D.), NIH/NCI Cancer Center Support Grants P30 CA008748/NCI R01 CA056821 (to T.M.) and R01 CA056821 (to T.M.), Swim Across America (to T.M.), Ludwig Institute for Cancer Research (to T.M.), Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering (to T.M.), Cancer Research Institute (to T.M.), Parker Institute for Cancer Immunotherapy (to T.M.), Leap Therapeutics (to T.M.), and STARR Cancer Consortium grant (to J.R.M.)

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title = "Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism",

abstract = "GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology.",

author = "Changhao He and Maniyar, \{Rachana R\} and Yahel Avraham and Roberta Zappasodi and Radda Rusinova and Walter Newman and Heidi Heath and Wolchok, \{Jedd D\} and Rony Dahan and Taha Merghoub and Joel Meyerson",

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AU - He, Changhao

AU - Maniyar, Rachana R

AU - Avraham, Yahel

AU - Zappasodi, Roberta

AU - Rusinova, Radda

AU - Newman, Walter

AU - Heath, Heidi

AU - Wolchok, Jedd D

AU - Dahan, Rony

AU - Merghoub, Taha

AU - Meyerson, Joel

PY - 2022/2/25

Y1 - 2022/2/25

N2 - GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology.

AB - GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology.

UR - https://www.scopus.com/pages/publications/85125348457

U2 - 10.1126/sciadv.abm4552

DO - 10.1126/sciadv.abm4552

M3 - Article

SN - 2375-2548

VL - 8

JO - Science advances

JF - Science advances

IS - 8

M1 - eabm4552

ER -

Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism

Abstract

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