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Last update 23 Jan 2025

IL-2Rβ x CD19

Last update 23 Jan 2025

Basic Info

Related Targets

IL-2RβCD19

Drugs associated with IL-2Rβ x CD19

SYNCAR-001+STK-009(Synthekine)

Target

CD19 x IL-2Rβ

Mechanism

CD19 inhibitors [+1]

Active Org.

Synthekine, Inc.Startup

Originator Org.

Synthekine, Inc.Startup

Active Indication

Lupus Nephritis [+7]

Inactive Indication-

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with IL-2Rβ x CD19

NCT06544330

/ RecruitingPhase 1

A Phase 1, Open-Label Study to Evaluate the Safety and Tolerability of a Combination Autologous CD19 CAR T Cell Therapy (SYNCAR-001 + STK-009) in Subjects With Severe, Refractory Systemic Lupus Erythematosus

This is a phase 1 study of SYNCAR-001 + STK-009 in patients with severe, refractory systemic lupus erythematosus.

Start Date01 Mar 2025

Sponsor / Collaborator

Synthekine, Inc.Startup

NCT05665062

/ RecruitingPhase 1

A Phase 1 Study to Evaluate the Safety and Tolerability of a Combination Autologous CD19 CAR T Cell Therapy (SYNCAR-001 + STK-009) in Subjects With Relapsed or Refractory CD19+ Hematologic Malignancies

This is a first-in-human phase 1 study of SYNCAR-001 + STK-009 in patients with CD19+ hematologic malignancies.

Start Date24 Jun 2022

Sponsor / Collaborator

Synthekine, Inc.Startup

100 Clinical Results associated with IL-2Rβ x CD19

100 Translational Medicine associated with IL-2Rβ x CD19

0 Patents (Medical) associated with IL-2Rβ x CD19

Literatures (Medical) associated with IL-2Rβ x CD19

01 Aug 2023·Molecular Therapy

A chemically inducible IL-2 receptor signaling complex allows for effective in vitro and in vivo selection of engineered CD4+ T cells

Article

Author: Uenishi, Gene I ; Dahl, Noelle P ; Yang, Su Jung ; Wang, Li-Jie ; Sommer, Karen ; Grimm, Annaiz ; Cook, Peter J ; Repele, Andrea ; Drow, Travis ; West, Samuel E ; Scharenberg, Andrew M ; Jacobs, Chester ; Rawlings, David J ; Boukhris, Ahmad

Engineered T cells represent an emerging therapeutic modality. However, complex engineering strategies can present a challenge for enriching and expanding therapeutic cells at clinical scale. In addition, lack of in vivo cytokine support can lead to poor engraftment of transferred T cells, including regulatory T cells (T_reg). Here, we establish a cell-intrinsic selection system that leverages the dependency of primary T cells on IL-2 signaling. FRB-IL2RB and FKBP-IL2RG fusion proteins were identified permitting selective expansion of primary CD4+ T cells in rapamycin supplemented medium. This chemically inducible signaling complex (CISC) was subsequently incorporated into HDR donor templates designed to drive expression of the T_reg master regulator FOXP3. Following editing of CD4+ T cells, CISC+ engineered T_reg (CISC EngTreg) were selectively expanded using rapamycin and maintained T_reg activity. Following transfer into immunodeficient mice treated with rapamycin, CISC EngTreg exhibited sustained engraftment in the absence of IL-2. Furthermore, in vivo CISC engagement increased the therapeutic activity of CISC EngTreg. Finally, an editing strategy targeting the TRAC locus permitted generation and selective enrichment of CISC+ functional CD19-CAR-T cells. Together, CISC provides a robust platform to achieve both in vitro enrichment and in vivo engraftment and activation, features likely beneficial across multiple gene-edited T cell applications.

01 Jan 2022·American Journal of Transplantation

Engineering IL-2 to steer immune responses

Author: Li, Xian C.

A review.Interleukin-2 (IL-2) was discovered as a T cell growth factor and initially believed to support just T cell proliferation.Engineering IL-2 variants to modulate the binding affinity to its receptor and consequently the functional status of immune cells represents another emerging approach.This review discuss about creation of an interesting IL-2 variant in which a point mutation was introduced into IL-2 to specifically replace the glutamine 126 with threonine (i.e., the H9T variant).This H9T variant seems to have an altered interaction with the IL-2R complex specifically at the IL-2γc interface, and therefore, functions as a partial agonist.The in vitro assays were performed for comparing the Effects on expansion of mouse CD8+ T cells of wild-type IL-2, which typically signals through the trimeric high-affinity IL-2R (i.e., the αβγc), an IL-2 mutant (H9) that binds the IL-2Rβ and signals in the absence of IL-2Rα, and the newly created H9T variant.However, in contrast to IL-2 and H9, the H9T-expanded T cells showed a markedly reduced expression of exhaustion markers(including programmed cell death 1 [PD-1] and T cell Ig and mucin domain-containing protein 3 ([TIM-3]), and reduced levels of perforin, granzyme B and interferon γ (IFN-γ).Specifically, IL-2 and H9 induced prominent expression of genes encoding checkpoint inhibitors including Prdm1 (encoding PD-1) and Havcr2 (encoding TIM-3) and effector mols. such as Prf1, Gzmb and Il10, whereas H9T upregulated the expression of Ccr7, Cxcr3 and Tcf7 (encoding T cell factor 1 [TCF-1]), a gene expression profile of T cell stemness.In H9T-expanded CD8+ T cells, glycolysis was reduced compared with those expanded by IL-2 or H9, as evidenced by reduced glucose uptake, lower levels of acetate and a lower rate of basal extracellular acidification.H9T triggered a reduced signal transducer and activator of transcription 5 (STAT5) activation in CD8+ T cells, while activation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) was maintained at levels comparable to those in IL-2- and H9-activated cells.In two different tumor models (melanoma and acute lymphoblastic leukemia) involving T cell receptor (TCR) transgenic and CD19 chimeric antigen receptor CD8+ T cells, adoptive transfer of H9T-expanded T cells eliminated tumor cells in vivo and markedly improved survival of tumor-bearing mice.Clearly, these findings demonstrate that new IL-2 variants can be engineered with unique properties and therapeutic potentials.

01 Mar 2018·Nature MedicineQ1 · MEDICINE

A novel chimeric antigen receptor containing a JAK–STAT signaling domain mediates superior antitumor effects

Q1 · MEDICINE

Article

Author: Tanaka, Shinya ; Kagoya, Yuki ; Wang, Chung-Hsi ; Butler, Marcus O ; Anczurowski, Mark ; Saso, Kayoko ; Guo, Tingxi ; Minden, Mark D ; Hirano, Naoto

The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit. Although inefficient tumor trafficking and various immunosuppressive mechanisms can impede CAR-T cell effector responses, the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions. Optimal T cell activation and proliferation requires multiple signals, including T cell receptor (TCR) engagement (signal 1), co-stimulation (signal 2) and cytokine engagement (signal 3). However, CAR constructs currently being tested in the clinic contain a CD3z (TCR signaling) domain and co-stimulatory domain(s) but not a domain that transmits signal 3 (refs. 13, 14, 15, 16, 17, 18). Here we have developed a novel CAR construct capable of inducing cytokine signaling after antigen stimulation. This new-generation CD19 CAR encodes a truncated cytoplasmic domain from the interleukin (IL)-2 receptor β-chain (IL-2Rβ) and a STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif, together with the TCR signaling (CD3z) and co-stimulatory (CD28) domains (hereafter referred to as 28-ΔIL2RB-z(YXXQ)). The 28-ΔIL2RB-z(YXXQ) CAR-T cells showed antigen-dependent activation of the JAK kinase and of the STAT3 and STAT5 transcription factors signaling pathways, which promoted their proliferation and prevented terminal differentiation in vitro. The 28-ΔIL2RB-z(YXXQ) CAR-T cells demonstrated superior in vivo persistence and antitumor effects in models of liquid and solid tumors as compared with CAR-T cells expressing a CD28 or 4-1BB co-stimulatory domain alone. Taken together, these results suggest that our new-generation CAR has the potential to demonstrate superior antitumor effects with minimal toxicity in the clinic and that clinical translation of this novel CAR is warranted.

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