Generation of a novel agonist of the human CD137 costimulatory pathway for cancer immunotherapy

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B208
Abstract ID: 4949

Presenting Author:
Christa D. Jackson , Postdoctoral Fellow at Univ. of Missouri Sch. of Med.

Abstract:

The use of immune checkpoint stimulators is an increasingly attractive therapeutic approach against cancer, and costimulatory pathway agonists are being developed for clinical use. Our laboratory has focused on the 4-1BB (CD137) pathway because of its critical role in CD8⁺ T cell expansion, survival, acquisition of effector function, and establishment of long-term memory. We previously reported the generation of a recombinant oligomeric form of the mouse ligand, muSA-4-1BBL, which, unlike the natural 4-1BB ligand, demonstrated robust costimulatory activity in soluble form. muSA-4-1BBL showed therapeutic efficacy as the immune adjuvant component of subunit vaccines in various mouse transplantable tumor models. In this study, we generated a human version of this ligand, huSA-4-1BBL, and characterized its structure and function. The molecule binds to 4-1BB on LPS-activated human THP-1 monocytes, but not ConA-stimulated mouse T cells expressing the 4-1BB receptor. Conversely, muSA-4-1BBL binds to ConA-stimulated mouse T cells, but not LPS-activated human THP-1 cells, demonstrating species-specific binding for both molecules. To assess the cancer immunotherapeutic efficacy of huSA-4-1BBL, we generated a transgenic mouse model where mouse 4-1BB was replaced with the human ortholog. The assessment of huSA-4-1BBL anti-tumor efficacy in this model will serve as a prelude for further development and translation of this novel agonist to the clinic for cancer immunotherapy.