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

被引：89

作者：

Anandasabapathy, N. ^{[1
,2
]}

Breton, G. ^{[1
]}

Hurley, A. ^{[1
]}

Caskey, M. ^{[1
]}

Trumpfheller, C. ^{[1
]}

Sarma, P. ^{[1
]}

Pring, J. ^{[1
]}

Pack, M. ^{[1
]}

Buckley, N. ^{[1
]}

Matei, I. ^{[3
]}

Lyden, D. ^{[3
]}

Green, J. ^{[4
]}

Hawthorne, T. ^{[4
]}

Marsh, H. C. ^{[4
]}

Yellin, M. ^{[4
]}

Davis, T. ^{[4
]}

Keler, T. ^{[4
]}

Schlesinger, S. J. ^{[1
]}

机构：

[1] Rockefeller Univ, Lab Cellular Physiol & Immunol, New York, NY 10021 USA

[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA USA

[3] Weill Cornell Med Coll, Dept Pediat, New York, NY USA

[4] Celldex Therapeut Inc, Needham, MA USA

来源：

BONE MARROW TRANSPLANTATION | 2015年 / 50卷 / 07期

基金：

美国国家卫生研究院;

关键词：

IN-VIVO; LIGAND; MOBILIZATION; GENERATION; PROLIFERATION; PROGENITORS; FLT3-LIGAND; EXPRESSION; EXPANSION; SUBSETS;

D O I：

10.1038/bmt.2015.74

中图分类号：

Q6 [生物物理学];

学科分类号：

071011 [生物物理学];

摘要：

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 mu g/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.

引用

页码：924 / 930

页数：7

共 24 条

[1]

Bertho JM, 2000, SCAND J IMMUNOL, V52, P53

[2]

Generation of functional human dendritic cells from adherent peripheral blood monocytes by CD40 ligation in the absence of granulocyte-macrophage colony-stimulating factor [J].