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Abstract Number: 0087

SYNCAR: An Engineered IL-2/IL-2R-system That Selectively Enhances CD19 CAR T Cells to Deplete B Cells and Provide Therapeutic Benefit in SLE and RA Mouse Models Without Lymphodepletion

Ethan Jung1, Marie semana1, Ivan Cheng1, Helena Silva1, Sandro Vivona1, Somya Singh1, Michele Bauer1, Mohammed Ali1, Henry Rosas1, Woei Chang1, Deepti Rokkam1, Patrick Lupardus1, Martin Oft1 and Paul-Joseph Aspuria2, 1Synthekine, Menlo Park, 2Sythekine, Menlo Park, CA

Meeting: ACR Convergence 2024

Keywords: Animal Model, autoimmune diseases, rheumatoid arthritis, Systemic lupus erythematosus (SLE), T Cell

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Session Information

Date: Saturday, November 16, 2024

Title: SLE – Animal Models Poster

Session Type: Poster Session A

Session Time: 10:30AM-12:30PM

Background/Purpose: CD19 CAR-T therapy has demonstrated efficacy in autoimmune (AI) diseases like systemic lupus erythematosus (SLE) and lupus nephritis (LN), showing its potential beyond oncology. Its application in other B cell-related AI conditions, such as rheumatoid arthritis (RA), could expand its therapeutic impact. Lymphodepleting (LD) chemotherapy, essential for T cell engraftment and efficacy, also carries risks like cytokine release syndrome, cytopenia, infections, genotoxic risk, and secondary malignancies. To fully utilize CD19 CAR-T therapy, strategies to reduce LD while maintaining efficacy are needed.

IL-2 can stimulate T cell proliferation but causes systemic toxicities due to widespread immune activation. An orthogonal oIL-2/oIL-2R system was developed, consisting of a pegylated IL-2 mutein (STK-009) that doesn’t significantly activate the wild-type (WT) receptor and a mutated IL-2 Receptor Beta (oRβ) that doesn’t respond to WT IL-2. This system provides a “private IL-2 signal” to engineered oRβ-expressing cells, reducing toxicities. STK-009 selectively expands oRβ-expressing CD19 CAR T cells (SYNCAR-001), enhancing anti-tumor control and durable responses in lymphoma models.

Methods: To explore the orthogonal IL-2/IL-2R system’s potential, CD19 CAR T cells were used in autoimmune mouse models without LD whereby murine T cells co-expressing mCD19 CAR and moRβ (mSYNCAR-001) were administered alone or with mSTK-009, the murine surrogate of STK-009. Two AI mouse models, SLE and RA, were employed. In the SLE model, aged NZB/NZWF1 mice with elevated anti-dsDNA/nuclear antibodies and kidney dysfunction were used. For RA, a non-lymphodepleted collagen-induced arthritis model was utilized. The impact on CD19+ B cell depletion, autoantibody production, kidney function, and arthritis symptoms were assessed in the relevant model. Rituximab mouse surrogate (anti-CD20 mAb) was also administered for comparison.

 

Results: Co-administration of mSTK-009 and mSYNCAR-001 effectively depleted CD19+ B cells in both SLE and RA models. mSTK-009 was essential for significant expansion of mSYNCAR-001 and subsequent CD19+ B cell depletion. In non-lymphodepleted NZB/NZWF1 mice, mSTK-009 enabled mSYNCAR-001 to significantly reduce autoantibody production, improving kidney function. In the RA model, mSTK-009 promoted mSYNCAR-001 to reverse arthritis, evidenced by the normalization of swollen paws and toes. The combination of mSTK-009 and mSYNCAR-001 showed superior efficacy compared to the rituximab surrogate, which achieved incomplete B cell depletion and minimal therapeutic benefit, highlighting the enhanced potential of the orthogonal IL-2/IL-2R system in AI models.

Conclusion: These findings support clinical exploration of SYNCAR-001 + STK-009 in AI diseases like SLE and RA to achieve CD19 CAR T expansion and significant B cell aplasia without genotoxic, lymphodepleting agents. SYNCAR-001 + STK-009 is in Phase I trials for heme malignancies (NCT05665062), with LN and SLE patient enrollment expected later this year.


Disclosures: E. Jung: Synthekine, 3; M. semana: Synthekine, 3; I. Cheng: Synthekine, 3; H. Silva: Synthekine, 3; S. Vivona: Synthekine, 3; S. Singh: Synthekine, 3; M. Bauer: Synthekine, 3; M. Ali: Synthekine, 3; H. Rosas: Synthekine, 3; W. Chang: Synthekine, 3; D. Rokkam: Synthekine, 3; P. Lupardus: Synthekine, 3; M. Oft: Synthekine, 3, 4; P. Aspuria: Synthekine, 3.

To cite this abstract in AMA style:

Jung E, semana M, Cheng I, Silva H, Vivona S, Singh S, Bauer M, Ali M, Rosas H, Chang W, Rokkam D, Lupardus P, Oft M, Aspuria P. SYNCAR: An Engineered IL-2/IL-2R-system That Selectively Enhances CD19 CAR T Cells to Deplete B Cells and Provide Therapeutic Benefit in SLE and RA Mouse Models Without Lymphodepletion [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/syncar-an-engineered-il-2-il-2r-system-that-selectively-enhances-cd19-car-t-cells-to-deplete-b-cells-and-provide-therapeutic-benefit-in-sle-and-ra-mouse-models-without-lymphodepletion/. Accessed .
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