GITR Immune Checkpoint Molecule for Drug Development

Overview of GITR

Glucocorticoid-induced TNFR-related (GITR), also known as TNFRS18 or CD257, is a gene coding for a member of the tumor necrosis factor (TNF) receptor superfamily, displaying a delayed upregulation at around 24 to 72 hours after T cell activation. GITR is expressed at low levels on resting responder T lymphocytes. Its delayed expression suggests that GITR does not play a significant role in T cell priming but instead acts shortly after that. GITR is also constitutively expressed on T regulatory cells (Tregs) at high levels and impairs Tregs ingress into tumors. The upregulation co-stimulatory signal to T cells of GITR agonists induces suppression that reverts Treg proliferation, which is possible to enhance immunity in response to infection and tumor immunity. Therefore, GITR is an attractive target for immunotherapy, owing to its capacity to promote effector T cell functions and hamper regulatory T cell suppression.

Model for GITR modulation of antitumor immunity. Fig.1 Model for GITR modulation of antitumor immunity. (Knee, 2016)

GITR Signaling and Function

GITR represents a class of targets referred to as costimulatory receptors, including OX40 and 4-1BB, among others. GITR signaling and function are contexts and cell type-dependent. In the thymus, GITR is expressed during T cell development and plays an important role in thymic Treg differentiation and expansion. In the periphery, engagement of GITR on T cells with agonist antibodies, recombinant GITRL or GITRL transfectants, following suboptimal TCR stimulation, enhances T cell activation by upregulating CD25. GITR and GITRL signaling is mediated through the activation of NF-kB and members of the MAPK pathway. While high GITR expression is a marker for Tregs, its function on Tregs is more complex. In general, GITR modulation induces Treg expansion, inhibits Treg suppressive function, and promotes effector T cells (Teffs) resistance to Treg suppression.

Clinical Studies of Anti-GITR Biologics

A growing number of clinical studies showed the favorable prognostic importance of CD8+ CD45RO+ memory cell infiltrates in various cancer types. Based on preclinical data, the emerging hypothesis is that a GITR agonist antibody with the ability to bind activating FcγR should shift the balance in the CD8+ Teff/Treg ratio to impart robust antitumor immunity. The clinical utility of anti-GITR antibodies as single agents may vary depending upon the pretreatment balance of Tregs to Teffs, the presence of natural killer (NK) cells, and macrophages capable of ADCC or ADCP respectively.

Current immune checkpoint-modulating agents have demonstrated clinical efficacy in certain tumor types, particularly those with a high burden of tumor-specific neoantigens, high tumor-mutational burden, and abundant tumor-infiltrating T cells. GITR is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule. Creative Biolabs offers a wide range of services for drug development projects of diverse immune checkpoints. Our seasoned scientists provide a series of custom services for immune checkpoint GITR, including but not limited to:

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  1. Knee, D.A.; et al. Rationale for anti-GITR cancer immunotherapy. European journal of cancer. 2016, 67:1-0.

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