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Hematopoietic Cell Collection

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.

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Acknowledgements

We are grateful to Ralph M Steinman for his mentorship, wisdom and passion for clinical translation. We also thank the study volunteers; the Rockefeller CTSA, hospital and pharmacy staff; the support of Dr James Krueger, Dr Barry Coller and Dr Michelle Lowes; and Renee Riggs for clinical trial management. The study was funded by Celldex Therapeutics, Inc. The Rockefeller University Center for Clinical and Translational Science is supported, in part, by a Clinical and Translational Science Award (CTSA) and the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health. NA was supported, in part, by grant UL1TR000043/KL2TR000151 from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, the Dermatology Foundation, the Klarman Family Foundation and supported by NIAMS AR063461-01A1 (to NA). Research reported in this publication was supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number U19AI111825. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. GB was supported by Iris and Junming Le Foundation.

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Correspondence to N Anandasabapathy.

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JG, TH, HCM, MY, TD and TK are employed by and hold stock options in Celldex Therapeutics, Inc. SS is on the board of directors and holds stock in Ariad. The remaining authors declare no conflict of interest.

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Anandasabapathy, N., Breton, G., Hurley, A. et al. Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers. Bone Marrow Transplant 50, 924–930 (2015). https://doi.org/10.1038/bmt.2015.74

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