A2B543: First Patient Dosed in Arm 2 of EVEREST-2 Study for Solid Tumors

The first patient has been dosed in the second arm of the phase 1/2 EVEREST-2 study (NCT06051695) evaluating A2B543, a first-in-class, logic-gated autologous chimeric antigen receptor (CAR) T cell therapy designed to treat solid tumors including colorectal cancer, pancreatic cancer, non–small cell lung cancer, ovarian cancer, mesothelioma, and other solid tumors that express mesothelin (MSLN) and have lost HLA-A*02 expression.¹

EVEREST-2 is a phase 1/2 trial evaluating the safety and efficacy of 2 Tmod™ therapies. The primary innovation of A2B543 lies in its dual-mechanism design: it utilizes the proprietary Tmod™ platform to distinguish between cancerous and healthy cells, and is enhanced with an inducible, membrane-tethered IL-12 (mem-IL-12) booster. This booster is engineered to increase the potency and persistence of the therapy within the immunosuppressive tumor microenvironment while strictly avoiding the severe toxicity historically associated with systemic IL-12 delivery.

Arm 1 of the study is evaluatinga logic-gated therapy targeting MSLN and HLA-A*02; arm 2 evaluates the same Tmod™ construct as arm 1, but with the added mem-IL-12 booster.

The FDA cleared the investigational new drug application for A2B543 in early 2026, leading to the current initiation of dosing in arm 2 of the EVEREST-2 study.²

The Tmod™ Platform: Logic-Gated Precision

The foundation of A2 Biotherapeutics’ clinical pipeline is the Tmod™ platform, a cellular system designed to solve the fundamental challenge of cancer therapy: the ability to distinguish tumor cells from normal tissue.¹

The platform utilizes a "logic-gate" technology consisting of 2 distinct receptors:

• The activator: Recognizes specific antigens on tumor cells and triggers their destruction.
• The blocker: Recognizes antigens present on normal cells but lost in tumor cells. When the blocker engages a normal cell, it protects that cell from the activator, preventing "off-target" damage.

This "NOT gate" logic allows for precise, personalized T-cell targeting, enabling the destruction of tumors that were previously difficult to target without damaging healthy organs.

A2B543 represents an evolution of the Tmod™ platform by incorporating a biological "booster" to enhance efficacy in solid tumors.

A2B543 is comprised of autologous T-cells transduced with 2 lentiviral vectors:

1. Vector 1: Expresses the MSLN-targeted CAR activator and the HLA-A*02-targeted blocker.
2. Vector 2: Expresses the inducible, membrane-tethered IL-12 (mem-IL-12) booster.

The A2B543 program targets a specific genetic profile: germline heterozygous HLA-A*02adults with recurrent unresectable, locally advanced, or metastatic solid tumors that express MSLN and have lost HLA-A*02 expression.

The Role of the mem-IL-12 Booster

Interleukin-12 (IL-12) is known to induce a potent antitumor immune response, but its clinical utility has been hampered by extreme systemic toxicity. A2B543 addresses this via:

• Localization: The IL-12 is tethered to the T-cell membrane, ensuring its effects are confined to the immediate tumor microenvironment.
• Inducible activation: The booster only activates when the Tmod™ cell engages with a tumor antigen.
• Enhanced persistence: The booster is designed to improve the long-term survival and potency of the CAR T cells within the harsh environment of a solid tumor.

The BASECAMP-1 Study

The BASECAMP-1 study (NCT04981119)serves as a "feeder" for EVEREST-2. It utilizes AI-enabled precision diagnostics and next-generation sequencing to identify patients who exhibit HLA loss of heterozygosity (LOH).

• LOH identification: The study identifies patients who have lost HLA-A*02 expression in their tumors but retain it in their healthy tissue.
• Proactive screening: Patients are identified early in their disease course. Upon disease progression, they can transition directly into the EVEREST-2 therapeutic study.
• Efficiency: This high-yield approach is designed to be a cost-effective method for identifying eligible candidates for precision medicine.

“Dosing the first patient with A2B543 is a significant step forward in the evolution of the Tmod™ platform,” said John Welch, MD, PhD, chief medical officer of A2 Biotherapeutics, in a news release. “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 [adverse] effects.”

REFERENCES

1.A2 Biotherapeutics doses first patient in EVEREST-2 study with A2B543, a logic-gated CAR T cell therapy enhanced with a membrane-tethered IL-12 booster. News release. A2 Biotherapeutics. Published February 26, 2026. Accessed March 3, 2026. https://tinyurl.com/4whmznbn

2.A2 Biotherapeutics announces FDA clearance of IND for A2B543 for treatment of adults with recurrent unresectable, locally advanced, or metastatic solid tumors that express mesothelin and have lost HLA-A*02 expression. News release. Published January 8, 2026. Accessed March 3, 2026. https://tinyurl.com/yc3f4pda