Summary:

The National Cancer Institute is seeking research co-development partners and licensing collaborators to accelerate the development and commercialization of innovative bifunctional antibody fusion molecules designed to activate and expand engineered TCR-expressing cells, advancing next-generation cancer immunotherapies.

Description of Technology:

T cell receptor (TCR)-T cell technologies equip a patient’s immune system with engineered receptors designed to recognize specific disease targets. They harness the power of adoptive cell therapy (ACT). The engineered receptors often comprise mouse constant regions to improve the expression, stability, and safety of the receptor when expressed in human T cells. While clinically effective against several human malignancies, the future of ACT lies in maximizing efficacy while minimizing patient burden. Current protocols often rely on high-dose cytokine regimens, such as aldesleukin (IL-2). These expand T cells non-specifically and are associated with substantial toxicities – including capillary leak syndrome, high fevers, and hypotension. There is a critical need for technologies that increase the purity and potency of T cell products and enable the selective expansion of engineered TCR-T cells without significant systemic side effects.

To address this need, inventors at the National Cancer Institute (NCI) have designed novel bifunctional antibody fusion molecules. These molecules comprise a single-chain variable fragment (scFv) or a fragment antigen-binding (Fab) region derived from the H57-597 antibody fused to a native IL-2 molecule and a fragment crystallizable (Fc) domain. The resulting molecules, named H57scFv_IL2 and H57Fab_IL2, recognize an epitope in the constant region of the mouse TCRβ chain and deliver IL-2 specifically to engineered TCR-T cells. This potentially improves T cell product manufacturing, patient safety, and therapeutic efficacy. The inventors have assessed the function of H57scFv_IL2 and H57Fab_IL2 in engineered T cells expressing HPV16 E7-targeting TCRs or NY-ESO-1-targeting TCRs. These in vitro studies demonstrate enhanced cytotoxic activity compared to untreated TCR-T cells and the H57-597 antibody alone.

The NCI is seeking research co-development partners and/or licensees to advance the bifunctional antibody fusion molecules for use in adoptive cell therapy. These molecules have the potential to be used during cell manufacturing and/or as adjuvant immunotherapy following administration of the TCR-T cell product. The benefits include selective activation and expansion of engineered TCR-T cells ex vivo or in patients.

Potential Commercial Applications:

• Metastatic, relapsed or refractory cancers.
• Autoimmune diseases.
• Certain rare diseases.
• Bifunctional molecules may be applicable to the treatment of a variety of diseases that is addressed by ACT.

Competitive Advantages:

• Bifunctional molecules support and enhance adoptive cell therapy (ACT), in particular, engineered TCR-based therapies.
• Bifunctional antibody-fusion molecules specifically expand T cells engineered to express TCRs – compared to non-specific CD3/CD28 agonizing antibodies and IL-2.
• Expected to be safer and more effective than high-dose IL-2.
• Single step approach for targeted delivery of cytokines into engineered TCR-T cells.