Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers

Abstract

Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSCs), early progenitor cells, immature thymocytes and steady-state dendritic cells (DCs) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood and lymphoid organs. CDX-301 has an identical amino-acid sequence and comparable biological activity to the previously tested rhuFlt3L, which ceased clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1-75 μg/kg/day) over 5-10 days. One event of Grade 3 community-acquired pneumonia occurred. There were no other infections, dose-limiting toxicities or serious adverse events. CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and plasmacytoid DCs, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations.

Figure 1

CDX-301 serum concentrations are shown as a function of time following the first dose of CDX-301. CDX-301 concentrations were determined by immunoassay and mean values (± standard deviations) for each study day are plotted for the cohorts as indicated in the legend.

Figure 2

CDX-301 increases WBC and monocyte counts in the peripheral blood. WBC (Figure 2A) and monocyte (Figure 2B) counts are plotted as mean values (± standard error) for the cohorts as indicated in the legend.

Figure 3

CDX-301 increases the number of CD34 high cells in the peripheral blood. Graphs show the kinetics of cell number per ml of blood over 21 days.. The absolute numbers per milliliter of blood were obtained by multiplying the number of cells (obtained by flow cytometry) by the total number of PBMCs per milliliter of blood. CD34 high cells numbers are plotted as mean values (± standard error) for the cohorts as indicated in the legend.

Figure 4

CDX-301 increases the number of myeloid dendritic cells in the peripheral blood. Graphs show the kinetics of cell number per ml of blood over 21 days. The absolute numbers per milliliter of blood were obtained by multiplying the number of cells (obtained by flow cytometry) by the total number of PBMCs per milliliter of blood. The numbers of BDCA-1+ myeloid DCs in Figure 4A and BDCA-3 high myeloid DCs in Figure 4B are plotted as mean values (± standard error) for the cohorts as indicated in the legend.

Figure 5

CDX-301 increases the number of plasmacytoid dendritic cells in the peripheral blood. Graphs show the kinetics of cell number per ml of blood over 21 days. The absolute numbers per milliliter of blood were obtained by multiplying the number of cells (obtained by flow cytometry) by the total number of PBMCs per milliliter of blood. The numbers of BDCA-2+ plasmacytoid DCs are plotted as mean values (± standard error) for the cohorts as indicated in the legend.

Figure 6

The CDX-301 dosing regimens studied did not markedly alter the numbers of regulatory T cells (Treg) in the peripheral blood. Graphs show the kinetics of cell number per ml of blood over 21 days. The absolute numbers per milliliter of blood were obtained by multiplying the number of cells (obtained by flow cytometry) by the total number of PBMCs per milliliter of blood. The numbers of Treg (CD3+ CD8- CD4+ CD25+ CD127− FoxP3+ cells) are plotted as mean values (± standard error) for the cohorts as indicated in the legend.