Recombinant Human Flt-3 Ligand/FLT3L-Fc (F176-GRP)

Dendritic cells are professional antigen-presenting cells that function in priming T lymphocytes during the immune response1. When an immune response is initiated, DCs present antigen, via cross-presentation or direct transfection, and upregulate costimulatory molecules, resulting in T lymphocyte priming. In the immune-oncology setting, DCs can be used to boost the efficacy of cancer vaccines. Relative to other leukocyte populations, DCs are rare in vivo1, 2. Consequently, DCs must be generated in vitro to obtain clinically or experimentally useful amounts. FLT3L is a DC-poietin used to stimulate DC proliferation1, 2 and is a hematopoietic growth factor that stimulates the proliferation of hematopoietic stem and progenitor cells in bone marrow, peripheral blood, and spleen3. Administration in mice leads to the generation of functionally mature DCs in multiple organs. Additionally, FLT3L generates bone marrow cultured DCs that are similar in morphology, surface marker expression, and production of inflammatory mediators to freshly isolated DCs from normal mice. In FLT3L-Fc, the pharmacokinetics of mouse FLT3L have been enhanced by cytokine fusion to human immunoglobulin Fc2. The half-life of engineered chimeric mouse FLT3L-Fc is ~16-fold greater than unmodified FLT3L. When combined with hydrodynamic gene transfer, FLT3L-Fc protein accumulation and cytokine exposure are vastly higher than with unmodified FLT3L protein. Post-injection in mice, FLT3L-Fc generates a robust expansion of functionally active DCs in vivo, with DCs able to secrete cytokines and stimulate T-cell proliferation. The quaternary structure of engineered FLT3L-Fc allows for spontaneous assembly into covalently linked stabilized Fc-disulfide-Fc homodimers via its cysteine residues. In contrast, endogenous FLT3L is a non-covalently linked homodimer. A mouse FLT3L-Fc (murine IgG2A Fc) has been successfully used as an adjuvant for anti-cancer DNA vaccines to mobilize DCs and enhance T cell responses to a target tumor antigen1. Human FLT3L-Fc has been successfully used to expand DC populations in mouse models4.