A Phase 1a Open-Label, Dose Escalation Study of the Safety and Pharmacokinetics of OMP-336B11 Administered as a Single Agent to Subjects With Locally Advanced or Metastatic Solid Tumors

The purpose of this study is to test the safety and efficacy of OMP-336B11. OMP-336B11 is an engineered human protein that was designed to bind to the GITR receptor on T cells and activate the immune system to recognize and eliminate cancer cells.

开始日期2017-09-12

申办/合作机构

Mereo BioPharma 5, Inc.

100 项与 Efaprinermin alfa 相关的临床结果

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100 项与 Efaprinermin alfa 相关的转化医学

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100 项与 Efaprinermin alfa 相关的专利（医药）

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项与 Efaprinermin alfa 相关的文献（医药）

2024-09-01·Arthritis & Rheumatology

A GITRL‐mTORC1‐GM‐CSF Positive Loop Promotes Pathogenic Th17 Response in Primary Sjögren Syndrome

Article

作者: Gan, Yuzhou ; Li, Zijun ; Zhao, Xiaozhen ; Liu, Hongjiang ; Wang, Qingwen ; Han, Qimao ; Zhu, Huaqun ; Li, Zhanguo ; He, Jing ; Guo, Yixue ; Ye, Hua ; Huang, Bo ; Wang, Ziye ; Sun, Xiaolin ; Zhou, Haotian

ObjectiveGlucocorticoid‐induced tumor necrosis factor receptor superfamily–related protein (GITR), with its ligand (GITRL), plays an important role in CD4+ T cell–mediated autoimmunity. This study aimed to investigate the underlying mechanisms of GITRL in primary Sjögren syndrome (pSS).MethodsPatients with pSS and healthy controls were recruited. Serum GITRL and Th17‐related cytokines were determined. RNA sequencing was performed to decipher key signal pathways. Nonobese diabetes (NOD) mice were adopted as experimental Sjögren models and recombinant adeno‐associated virus (rAAV) transduction was conducted to verify the therapeutic potentials of targeting GITRL in vivo.ResultsSerum GITRL was significantly higher in patients with pSS and showed a positive correlation with leukopenia, thrombocytopenia, autoantibodies, lung involvement, and disease activity. Serum GITRL was correlated with Th17‐related cytokines. GITRL promoted the expansion of Th17 and Th17.1 cells. Expansion of granulocyte‐macrophage colony‐stimulating factor positive (GM‐CSF+) CD4+ T cells induced by GITRL could be inhibited by blockade of GITRL. Moreover, GM‐CSF could stimulate GITRL expression on monocytes. RNA sequencing revealed mammalian target of rapamycin complexes 1 (mTORC1) might be the key modulator. The increased phosphorylation of S6 and STAT3 and the expansion of Th17 and Th17.1 cells induced by GITRL were effectively inhibited by rapamycin, suggesting a GITRL–mTORC1–GM‐CSF positive loop in pathogenic Th17 response in pSS. Administration of an rAAV vector expressing short hairpin RNA targeting GITRL alleviated disease progression in NOD mice.ConclusionOur results identified the pathogenic role of GITRL in exacerbating disease activity and promoting pathogenic Th17 response in pSS through a GITRL–mTORC1–GM‐CSF loop. These findings suggest GITRL might be a promising therapeutic target in the treatment of pSS.

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2024-07-23·Journal of Virology

Flt3 agonist enhances immunogenicity of arenavirus vector-based simian immunodeficiency virus vaccine in macaques

Article

作者: Boopathy, Archana Vidya ; Sung, Janette ; Suthram, Silpa ; Nekkalapudi, Anurag ; Wimmer, Raphaela ; Callebaut, Christian ; Geleziunas, Romas ; Sharma, Bhawna ; Schulha, Sophie ; Orlinger, Klaus K ; Ng, Sarah ; Hung, Magdeleine ; Schmidt, Sarah ; Falkard, Brie ; Kuhne, Michelle ; Carr, Brian ; Jin, Debi ; Lauterbach, Henning ; Lu, Sabrina ; Ahmadi-Erber, Sarah

ABSTRACT Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens are capable of inducing efficacious humoral and cellular immune responses in nonhuman primates. Several studies have evaluated the use of immune modulators to further enhance vaccine-induced T-cell responses. The hematopoietic growth factor Flt3L drives the expansion of various bone marrow progenitor populations, and administration of Flt3L was shown to promote expansion of dendritic cell populations in spleen and blood, which are targets of arenaviral vectors. Therefore, we evaluated the potential of Flt3 signaling to enhance the immunogenicity of arenaviral vaccines encoding SIV immunogens (SIV SME543 Gag, Env, and Pol) in rhesus macaques, with a rhesus-specific engineered Flt3L-Fc fusion protein. In healthy animals, administration of Flt3L-Fc led to a 10- to 100-fold increase in type 1 dendritic cells 7 days after dosing, with no antidrug antibody (ADA) generation after repeated dosing. We observed that administration of Flt3L-Fc fusion protein 7 days before arenaviral vaccine increased the frequency and activation of innate immune cells and enhanced T-cell activation with no treatment-related adverse events. Flt3L-Fc administration induced early innate immune activation, leading to a significant enhancement in magnitude, breadth, and polyfunctionality of vaccine-induced T-cell responses. The Flt3L-Fc enhancement in vaccine immunogenicity was comparable to a combination with αCTLA-4 and supports the use of safe and effective variants of Flt3L to augment therapeutic vaccine-induced T-cell responses. IMPORTANCE Induction of a robust human immunodeficiency virus (HIV)-specific CD4 + and CD8 + T-cell response through therapeutic vaccination is considered essential for HIV cure. Arenaviral vaccine vectors encoding simian immunodeficiency virus (SIV) immunogens have demonstrated strong immunogenicity and efficacy in nonhuman primates. Here, we demonstrate that the immunogenicity of arenaviral vectors encoding SIV immunogens can be enhanced by administration of Flt3L-Fc fusion protein 7 days before vaccination. Flt3L-Fc-mediated increase in dendritic cells led to robust improvements in vaccine-induced T- and B-cell responses compared with vaccine alone, and Flt3L-Fc dosing was not associated with any treatment-related adverse events. Importantly, immune modulation by either Flt3L-Fc or αCTLA-4 led to comparable enhancement in vaccine response. These results indicate that the addition of Flt3L-Fc fusion protein before vaccine administration can significantly enhance vaccine immunogenicity. Thus, safe and effective Flt3L variants could be utilized as part of a combination therapy for HIV cure.

2024-02-01·Toxicology and Applied Pharmacology

Nonclinical pharmacokinetics, pharmacodynamics and safety assessment of a FLT3L-Fc molecule for cancer immunotherapy

Article

作者: Chilton, Jennifer A ; Getz, Jennifer A ; Hosseini, Iraj ; Nguyen, Tien ; Bainbridge, Travis W ; Moussion, Christine C ; Zabka, Tanja S ; Wu, Kai Connie ; Kenkre, Radhika ; Rao, Gautham K ; Decalf, Jérémie ; Adedeji, Adeyemi O

FLT3L-Fc is a cytokine-Fc fusion agonizing receptor-type tyrosine-protein kinase FLT3 (fms-related tyrosine kinase 3; CD135). FLT3 is expressed on dendritic cells (DCs) as well as myeloid and lymphoid progenitors. Nonclinical pharmacokinetics, pharmacodynamics and safety of FLT3L-Fc were investigated in rats and cynomolgus monkeys. FLT3L-Fc induced robust pharmacodynamic responses, evidenced by marked expansion of peripheral blood cDC1s, cDC2s, and pDCs (up to 301-fold in rats and 378-fold in monkeys), peaking at 8-10 days after the first dose. FLT3L-Fc was well tolerated with no adverse findings at doses up to 10 mg/kg administered intravenously twice three weeks apart. In both species, major clinical pathology findings consisted of expansion of white blood cell (WBC) populations including lymphocytes, monocytes, neutrophils, basophils, and large unstained cells, which were pronounced after the first dose. The WBC findings were associated microscopically with histiocytic and mononuclear cell infiltrates in multiple organs. Tissue immunohistochemistry in monkeys showed that the leukocyte infiltrates consisted of hematopoietic progenitor cells and histiocytes with a reactive morphology and were associated with a slight stimulation of regional T and B cell populations. Additional FLT3L-Fc-associated changes included decreases in red blood cell (RBC) mass, increases in RBC distribution width, variable changes in reticulocytes, and transient alterations in platelet counts (rats only). The RBC and WBC findings were associated microscopically with increased hematopoietic cellularity of the bone marrow in both species and increased splenic megakaryocytic extramedullary hematopoiesis in rats. The totality of nonclinical safety data support the clinical development of FLT3L-Fc.

100 项与 Efaprinermin alfa 相关的药物交易

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