A2B543 is based on the A2 Bio Tmod™ platform providing selective killing of tumor cells while protecting normal cells

A2 Biotherapeutics, Inc. (A2 Bio), a clinical-stage immunotherapy company developing first-in-class logic-gated therapies for solid tumors, today announced the first patient dosed with A2B543, initiating the second arm of the Phase 1/2 EVEREST-2 study (NCT06051695).

A2B543 is an autologous CAR T cell therapy that builds upon A2 Bio’s proprietary Tmod™ platform. A2B543 adds an inducible, membrane-tethered IL-12 booster, augmenting the platform's core ability to selectively kill tumor cells while protecting normal tissue. Designed to activate only when the Tmod™ cell engages a tumor antigen, the booster aims to enhance the potency and persistence of Tmod™ cells within the immunosuppressive solid tumor microenvironment while avoiding systemic toxicity.

“Dosing the first patient with A2B543 is a significant step forward in the evolution of the Tmod™ platform,” said John Welch, M.D., Ph.D., chief medical officer of A2 Bio. “While systemic IL-12 induces a potent antitumor immune response, its use has been limited by severe toxicity. With A2B543, we are arming our Tmod™ cells with a membrane-tethered, inducible IL-12 component. This design allows us to localize the impact of IL-12 to the tumor microenvironment, boosting the persistence and potency of Tmod™ without the systemic side effects.”

Enabling Efficient Patient Identification for A2 Bio Precision Medicine Studies

The A2 Bio clinical programs include A2B543, A2B694, A2B395, and the BASECAMP-1 prescreening study, as well as several preclinical programs exploring additional pipeline expansion opportunities using the proprietary Tmod™ technology platform. The Tmod™ platform comprises a suite of technologies that can be used in isolation or in combination, and in both autologous and allogeneic settings, to create novel therapies for cancers and other grievous diseases.

The BASECAMP-1 (NCT04981119) master prescreening study enables efficient identification of patients for all A2 Bio precision medicine studies. Patients are enrolled in EVEREST-2 through BASECAMP-1, which identifies patients with HLA loss of heterozygosity (LOH) at any time in the course of their disease via next-generation sequencing. Upon disease progression, the patients may screen for enrollment in EVEREST-2. There is no time requirement between the studies, and patients may go directly from BASECAMP-1 to EVEREST-2 based on their own disease course. BASECAMP-1 utilizes artificial intelligence (AI)-enabled precision diagnostics as a cost-effective, high-yield approach to identify eligible patients for all A2 Bio clinical studies.^1,2

For more information about A2 Bio clinical studies and how to enroll, visit www.a2bioclinicaltrials.com.

About A2B543

A2B543 is designed for the treatment of germline heterozygous HLA-A*02 adults with recurrent unresectable, locally advanced, or metastatic solid tumors that express MSLN and have lost HLA-A*02 expression. A2B543 is comprised of autologous Tmod™ cells transduced with two lentiviral vectors: one expressing both the HLA-A*02-targeted blocker and the MSLN-targeted CAR activator; and a second expressing an inducible, membrane-tethered IL-12 (mem-IL-12) booster. The inducible mem-IL-12 booster, which activates only upon engagement with tumor antigens, is designed to reduce toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod™.³

About EVEREST-2

The EVEREST-2 master protocol (NCT06051695) is a seamless Phase 1/2 study evaluating the safety and efficacy of A2B694 (Arm 1) and A2B543 (Arm 2), autologous logic-gated investigational cell therapies developed from the A2 Bio proprietary Tmod™ platform. The Tmod™ platform provides selective killing of tumor cells and protection of normal cells via a dual-receptor design consisting of an activator that targets tumor cells and a blocker that protects normal cells. A2B694 consists of an activator that targets MSLN and a blocker that targets HLA-A*02. HLA-A*02 is lost in tumor cells and present in normal cells in the eligible patient population. A2B543 contains the same Tmod™ construct as A2B694 with an added mem-IL-12 booster. The EVEREST-2 study is recruiting patients with colorectal cancer, pancreatic cancer, non-small cell lung cancer, ovarian cancer, mesothelioma, and other solid tumors that express MSLN and have lost HLA-A*02 expression.

About the Tmod™ Platform

Invented at A2 Bio, the Tmod^TM platform is a precision-targeting cellular system, designed with logic-gate technology to enable immune cells to unequivocally differentiate tumors from normal tissues. The system consists of activator and blocker receptors. The activator recognizes antigens on tumor cells and triggers their destruction, while the blocker recognizes antigens on normal cells and protects them. This novel blocker technology enables precise, personalized, and effective T-cell targeting specifically against tumors.

About A2 Bio

A2 Biotherapeutics, Inc. (A2 Bio) is a clinical-stage biotech company developing first-in-class logic-gated cell therapies to address the high unmet need in cancers. A2 Bio invented the proprietary Tmod™ cell therapy platform to tackle the fundamental challenge in cancer treatment—the ability of cancer medicines to distinguish between tumor and normal cells. For more information, visit the company’s website at www.a2bio.com.

References

¹ Smith CJ, Simeone DM, Grierson PM, et al. Improving ethnic and racial diversity in biomarker-driven clinical trials: a proof of concept with the BASECAMP-1 master prescreening study of patients with high-risk solid tumors with human leukocyte antigen-A*02 (HLA-A*02) loss of heterozygosity (LOH). ASCO Annual Meeting 2024. Available at: https://www.a2bio.com/wp-content/uploads/ASCO-2024_Improving-Trial-Diversity.pdf

² Lozac’hmeur A, Danek T, Yang Q, et al. Detecting HLA loss of heterozygosity within a standard diagnostic sequencing workflow for prognostic and therapeutic opportunities. NPJ Precis Oncol. 2024;8(1):174. Available at: https://www.a2bio.com/wp-content/uploads/Detecting-HLA-LOH-Within-Diagnostic-Sequencing-npj-Precision-Oncology.pdf

³ Zhang JA, Imboden S, Lee D, et al. Onboard, tethered IL-12 boosts potency of the Tmod NOT gate and preserves selectivity. J Immunother Cancer. 2025;13(5):e010976. Available at: https://www.a2bio.com/wp-content/uploads/Onboard-tethered-IL-12-boosts-potency-of-the-Tmod-NOT-gate-and-preserves-selectivity.pdf

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"With A2B543, we are arming our Tmod™ cells with a membrane-tethered, inducible IL-12 component. This design allows us to localize the impact of IL-12 to the tumor microenvironment." John Welch, M.D., Ph.D., Chief Medical Officer, A2 Bio