A2 Biotherapeutics Receives FDA Clearance for A2B543 CAR-T Therapy with IL-12 Booster for Advanced Solid Tumors
核心洞察
A2 Biotherapeutics (搜索) received FDA clearance for its IND application for A2B543 (搜索), a novel CAR-T therapy enhanced with a membrane-tethered IL-12 (搜索) booster designed to treat adults with advanced solid tumors (搜索).
The therapy targets patients with germline heterozygous HLA-A*02 (搜索) who have recurrent unresectable, locally advanced, or metastatic solid tumors (搜索) expressing mesothelin and showing HLA-A*02 loss.
A2B543 (搜索) will be evaluated as the second arm of the EVEREST-2 Phase 1/2 master protocol, recruiting patients with colorectal, pancreatic, lung, ovarian cancers, mesothelioma (搜索), and other solid tumors (搜索).
A2 Biotherapeutics (搜索) announced that the U.S. Food and Drug Administration has cleared the company's Investigational New Drug application for A2B543 (搜索), a novel CAR-T cell therapy enhanced with a membrane-tethered IL-12 (搜索) booster. The therapy is designed for treatment of germline heterozygous HLA-A02 adults with recurrent unresectable, locally advanced, or metastatic solid tumors (搜索) that express mesothelin and have lost HLA-A02 expression.
Enhanced CAR-T Design Addresses Tumor Microenvironment
A2B543 (搜索) represents an advancement in CAR-T cell therapy design, incorporating a membrane-tethered IL-12 (搜索) booster intended to enhance potency and persistence of Tmod™ cells while addressing the immunosuppressive tumor microenvironment. The therapy is comprised of autologous Tmod™ cells transduced with two lentiviral vectors: one expressing both the HLA-A*02 (搜索)-targeted blocker and the MSLN-targeted CAR activator, and a second expressing the membrane-tethered IL-12 booster.
The inducible membrane-tethered IL-12 (搜索) booster activates only upon engagement with tumor antigens, designed to reduce toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod™ cells.
"FDA clearance of our IND for A2B543 (搜索) is an important milestone for A2 Bio. Our ability to launch four clinical programs in just four years highlights the adaptability and robustness of the Tmod™ platform and the promising clinical pipeline of Tmod™-based cell therapies," said Jim Robinson, chief executive officer of A2 Bio.
EVEREST-2 Master Protocol Evaluation
A2B543 (搜索) will be evaluated as the second arm of the EVEREST-2 master protocol (NCT06051695), a seamless Phase 1/2 study assessing the safety and efficacy of autologous logic-gated investigational cell therapies. The study is recruiting participants with colorectal cancer (搜索), pancreatic cancer (搜索), non-small cell lung cancer (搜索), ovarian cancer (搜索), mesothelioma (搜索), and other solid tumors (搜索) that express mesothelin and have lost HLA-A*02 (搜索) expression.
The EVEREST-2 protocol also evaluates A2B694 in its first arm, which contains the same Tmod™ construct as A2B543 (搜索) but without the added membrane-tethered IL-12 (搜索) booster. Both therapies utilize the Tmod™ platform's dual-receptor design consisting of an activator that targets tumor cells and a blocker that protects normal cells.
Precision Patient Identification Strategy
Patient enrollment for EVEREST-2 occurs through the BASECAMP-1 master prescreening study (NCT04981119), which enables efficient identification of patients for all A2 Bio precision medicine studies. BASECAMP-1 identifies patients with HLA loss of heterozygosity at any time during their disease course via next-generation sequencing.
The prescreening study utilizes artificial intelligence-enabled precision diagnostics as a cost-effective, high-yield approach to identify eligible patients. Upon disease progression, participants may screen for enrollment in EVEREST-2 with no time requirement between studies, allowing patients to transition directly from BASECAMP-1 to EVEREST-2 based on their disease course.
Tmod™ Platform Technology
The Tmod™ platform represents a precision-targeting cellular system that incorporates two receptors—an activator and a blocker—to direct immune cell activity specifically at tumors while protecting normal tissues. The activator recognizes antigens on tumor cells that trigger their destruction, while the blocker recognizes antigens on normal cells to protect them.
This dual-receptor approach enables the platform to unequivocally differentiate tumors from normal tissues, addressing the fundamental challenge in cancer treatment of distinguishing between malignant and healthy cells. The platform comprises a suite of technologies that can be used individually or in combination, in both autologous and allogeneic settings.