Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers.
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.
1] The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, USA [2] Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
N
N
Anandasabapathy
The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, USA.
G
G
Breton
The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, USA.
A
A
Hurley
The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, USA.
M
M
Caskey
The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, USA.
C
C
Trumpfheller
The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, USA.
P
P
Sarma
The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, USA.
J
J
Pring
The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, USA.
M
M
Pack
The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, USA.
N
N
Buckley
Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA.
I
I
Matei
Department of Pediatrics, Weill Cornell Medical College, New York, NY, USA.
D
D
Lyden
Celldex Therapeutics, Inc., Needham, MA, USA.
J
J
Green
Celldex Therapeutics, Inc., Needham, MA, USA.
T
T
Hawthorne
Celldex Therapeutics, Inc., Needham, MA, USA.
H C
HC
Marsh
Celldex Therapeutics, Inc., Needham, MA, USA.
M
M
Yellin
Celldex Therapeutics, Inc., Needham, MA, USA.
T
T
Davis
Celldex Therapeutics, Inc., Needham, MA, USA.
T
T
Keler
The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY, USA.
S J
SJ
Schlesinger
D000293:Adolescent; D000328:Adult; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D064368:Healthy Volunteers; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019172:Transplantation Conditioning / Q000379:methods*; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism*
C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3