Biparatopic CAR T-cells for Enhanced Efficacy Against FLT3-Positive Leukemia

A novel cell-based immunotherapy utilizes engineered immune cells expressing a biparatopic Chimeric Antigen Receptor (CAR) designed to enhance the treatment of blood cancers. This next-generation CAR is uniquely designed to simultaneously bind to two distinct epitopes on the CD135 (FLT3) polypeptide, offering a potent strategy to circumvent tumor escape and treat CD135-positive blood malignancies.

Description

This cell therapy introduces a biparatopic Chimeric Antigen Receptor (CAR) designed to enhance the durability and efficacy of treatment against FLT3-positive malignancies. Unlike single-target CARs, this construct incorporates two distinct antigen binding domains that simultaneously recognize two discrete epitopes on the FLT3 (CD135) polypeptide. This dual recognition is the core innovation, providing a crucial mechanism to circumvent a common cause of treatment failure: tumor-mediated antigen loss or alternative splicing. The CAR can be expressed on engineered immune cells, such as T cells and Natural Killer (NK) cells, which are then activated upon dual-epitope binding to specifically target and destroy the cancer cells. The CAR structure includes a robust intracellular signaling cascade (e.g., 4-1BB and CD3ζ) to ensure potent immune cell activation and cytotoxic activity against the tumor.

Applications

- Acute Myeloid Leukemia (AML) treatment, particularly for FLT3-positive subtypes.
- Acute Lymphocytic Leukemia (ALL) treatment for CD135-positive disease.
- Adoptive Cell Therapy (ACT) platform utilizing engineered T cells or Natural Killer (NK) cells.
- Development of novel viral vectors and nucleic acid therapeutics for CAR gene delivery.
- Combination therapies with existing anti-cancer agents, such as chemotherapy or immune-checkpoint inhibitors.

Advantages

- Potentially circumvents tumor escape and relapse by targeting two discrete epitopes simultaneously, thus mitigating single-antigen loss.
- Offers enhanced cytotoxic activity and cytokine secretion compared to single-domain CARs.
- Provides a novel therapeutic option for the treatment of CD135-positive blood cancers, including Acute Myeloid Leukemia (AML) and Acute Lymphocytic Leukemia (ALL).
- Potentially targets a broader spectrum of tumor subtypes by accommodating different splicing isoforms of the antigen.
- Demonstrated ability to mediate in vivo tumor clearance in multiple xenograft AML models.

Invention Readiness

The biparatopic CAR technology is currently at a pre-clinical stage of development. Proof-of-of-concept has been successfully demonstrated, including the design and synthesis of the CAR constructs, cloning into lentiviral vectors, and expression on engineered immune cells. Compelling functional data has been generated, showing increased cytotoxic activity and cytokine secretion in vitro, which translated to effective in vivo tumor clearance in multiple mouse models of Acute Myeloid Leukemia (AML). Moving forward, large animal efficacy and safety studies are needed to further validate the platform prior to pursuing regulatory clearance and advancing to human clinical trials.

IP Status

Patent Pending