GITR inhibitors(Glucocorticoid-induced tumor necrosis factor receptor-related protein inhibitors), PD-1 inhibitors(Programmed cell death protein 1 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

AbbVie Biotherapeutics, Inc.

Active Organization

AbbVie Biotherapeutics, Inc.

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with PD-1/GITR Targeted Fc Fusion protein(AbbVie)

100 Translational Medicine associated with PD-1/GITR Targeted Fc Fusion protein(AbbVie)

100 Patents (Medical) associated with PD-1/GITR Targeted Fc Fusion protein(AbbVie)

Literatures (Medical) associated with PD-1/GITR Targeted Fc Fusion protein(AbbVie)

17 Feb 2022·Computational and Mathematical Methods in MedicineQ4 · ENGINEERING & TECHNOLOGY

OX40-Fc Fusion Protein Alleviates PD-1-Fc-Aggravated Rheumatoid Arthritis by Inhibiting Inflammatory Response

Q4 · ENGINEERING & TECHNOLOGY

ArticleOA

Author: Lin, Shudian ; Xiao, Lu ; Zhan, Yuwei ; Huang, Yanyan ; Wang, Ru ; Zhan, Feng

Background. Researches have confirmed that the abnormal signals of OX40 and PD-1 lead to the changes of T cell biological behavior, thus participating the immunopathological process of RA. However, the pathogenesis of RA immunopathological process has not been clarified yet. Methods. 30 DBA/1 mice were randomly divided into 5 groups (6 mice per group): control group, collagen-induced arthritis (CIA) group, PD-1-Fc/CIA group, OX40-Fc/CIA group, and PD-1-Fc + OX40-Fc/CIA group. The pathological changes in mice joints were observed by H&E staining. The proportion of CD4+ T, CD8+ T, CD28+, and CD19+ cells in peripheral blood mononuclear cells (PBMCs) was detected by flow cytometry. Serum inflammatory factors (CRP, IL-2, IL-4, IL-1β, INF-γ) and bone metabolism-related genes (CTX-I, TRACP-5b, BALP) were detected by ELISA assay. Western blotting was applied to measure the NF-κB signaling pathway-related protein (p-IKKβ, p-IκBα, p50) expression in synovial tissue of mice joint. Results. Compared with the control group, CIA mice showed significant increases in arthritis score and pathological score. In the CIA group, a marked decrease was identified in the proportion of CD8+ T, CD19+, and CD68+ cells. Additionally, the CIA group was associated with upregulation of secretion of inflammatory factors in serum and expression of bone metabolism-related genes and NF-κB pathway-related proteins. Compared with the CIA group, the same indexes above showed a further aggravation in the PD-1-Fc group while all indexes improved in the OX40-Fc group. Besides, OX40-Fc fusion protein slowed down significantly the further deterioration of CIA mouse pathological process caused by PD-1-Fc fusion protein. Conclusion. OX40-Fc fusion protein alleviates PD-1-Fc-aggravated RA by inhibiting inflammatory response. This research provides biological markers with clinical significance for diagnosis and prognosis of RA, as well as offers theoretical and experimental foundation to the new targets for immune intervention.

01 Dec 2014·Journal of Translational MedicineQ2 · MEDICINE

Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs

Q2 · MEDICINE

ArticleOA

Author: Rongsheng Zhang ; Hongzan Ji ; Xuan Wang ; Bin Zhang ; Xiaobing Xu ; Lei Lu

BACKGROUNDThe coinhibitory receptor Programmed Death-1 (PD-1) inhibits effector functions of activated T cells and prevents autoimmunity, however, cancer hijack this pathway to escape from immune attack. The costimulatory receptor glucocorticoid-induced TNFR related protein (GITR) is up-regulated on activated T cells and increases their proliferation, activation and cytokine production. We hypothesize that concomitant PD-1 blockade and GITR triggering would synergistically improve the effector functions of tumor-infiltrating T cells and increase the antitumor immunity. In present study, we evaluated the antitumor effects and mechanisms of combined PD-1 blockade and GITR triggering in a clinically highly relevant murine ID8 ovarian cancer model.METHODSMice with 7 days-established peritoneal ID8 ovarian cancer were treated intraperitoneally (i.p.) with either control, anti-PD-1, anti-GITR or anti-PD-1/GITR monoclonal antibody (mAb) and their survival was evaluated; the phenotype and function of tumor-associated immune cells in peritoneal cavity of treated mice was analyzed by flow cytometry, and systemic antigen-specific immune response was evaluated by ELISA and cytotoxicity assay.RESULTSCombined anti-PD-1/GITR mAb treatment remarkably inhibited peritoneal ID8 tumor growth with 20% of mice tumor free 90 days after tumor challenge while treatment with either anti-PD-1 or anti-GITR mAb alone exhibited little antitumor effect. The durable antitumor effect was associated with a memory immune response and conferred by CD4⁺ cells and CD8⁺ T cells. The treatment of anti-PD-1/GITR mAb increased the frequencies of interferon-γ-producing effector T cells and decreased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, shifting an immunosuppressive tumor milieu to an immunostimulatory state in peritoneal cavity. In addition, combined treatment of anti-PD-1/GITR mAb mounted an antigen-specific immune response as evidenced by antigen-specific IFN-γ production and cytolytic activity of spleen cells from treated mice. More importantly, combined treatment of anti-PD-1/GITR mAb and chemotherapeutic drugs (cisplatin or paclitaxel) further increased the antitumor efficacy with 80% of mice obtaining tumor-free long-term survival in murine ID8 ovarian cancer and 4 T1 breast cancer models.CONCLUSIONSCombined anti-PD-1/GITR mAb treatment induces a potent antitumor immunity, which can be further promoted by chemotherapeutic drugs. A combined strategy of anti-PD-1/GITR mAb plus cisplatin or paclitaxel should be considered translation into clinic.

15 Dec 2013·The Journal of ImmunologyQ2 · MEDICINE

In Vivo Blockade of the Programmed Cell Death-1 Pathway Using Soluble Recombinant PD-1-Fc Enhances CD4+ and CD8+ T Cell Responses but Has Limited Clinical Benefit

Q2 · MEDICINE

Article

Author: Ansari, Aftab A. ; Villinger, Francois ; Rogers, Kenneth ; Amancha, Praveen K. ; Hong, Jung Joo

AbstractThe programmed cell death-1 (PD-1)/programmed cell death ligand-1 pathway has been shown to limit cell-mediated effector functions during chronic viral infections impeding clearance of pathogens. As a strategy to reverse this exhaustion and increase T cell polyfunctionality, PD-1 ligands were blocked in vivo using a recombinant macaque PD-1 fused to a macaque Ig-Fc (rPD-1-Fc) in SIVmac239–infected rhesus macaques during the early chronic phase of infection, either alone or in combination with antiretroviral therapy. In vitro blockade showed improvement of Ag-specific CD4+ and CD8+ T cells from monkeys chronically infected with SIV. Of note, a prolonged 5-d blockade in culture was beneficial for both gag-specific CD4+ and CD8+ T cells based on proliferation and dual cytokine production. Although the in vivo administration of rPD-1-Fc induced enhanced SIV-specific CD4 and CD8 T cell proliferation both in the blood and gut, it failed to alter plasma viremia. However, rPD-1-Fc administration in the context of antiretroviral therapy interruption induced a significant delay of viral load rebound. In addition, rPD-1-Fc administration in MamuA*001+ monkeys led to both an increase in the frequencies and Ki67 expression of GagCM9+ CD8+ T cells in the blood and rectal mucosa and polyfunctionality of GagCM9+ CD8+ T cells in blood. In conclusion, however, our data suggest that PD-1/programmed cell death ligand-1 blockade using soluble rPD-1-Fc instead of anti–PD-1 mAb, although effective in rescuing the effector function of SIV-specific CD4+ and CD8+ T cells during the early chronic phase of infection, has limited clinical benefit.

100 Deals associated with PD-1/GITR Targeted Fc Fusion protein(AbbVie)

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	AbbVie Biotherapeutics, Inc.	28 Feb 2022

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