Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia.
BACKGROUND
C-type lectin-like molecule-1 is a transmembrane receptor expressed on myeloid cells, acute myeloid leukemia blasts and leukemic stem cells. To validate the potential of this receptor as a therapeutic target in acute myeloid leukemia, we generated a series of monoclonal antibodies against the extracellular domain of C-type lectin-like molecule-1 and used them to extend the expression profile analysis of acute myeloid leukemia cells and to select cytotoxic monoclonal antibodies against acute myeloid leukemia cells in preclinical models.


METHODS
C-type lectin-like molecule-1 expression was analyzed in acute myeloid leukemia cell lines, and in myeloid derived cells from patients with acute myeloid leukemia and healthy donors. Anti-C-type lectin-like molecule-1 antibody-mediated in vitro cytotoxic activity against acute myeloid leukemia blasts/cell lines and in vivo anti-cancer activity in a mouse xenograft model were assessed. Internalization of C-type lectin-like molecule-1 monoclonal antibodies upon receptor ligation was also investigated.


RESULTS
C-type lectin-like molecule-1 was expressed in 86.5% (45/52) of cases of acute myeloid leukemia, in 54.5% (12/22) of acute myeloid leukemia CD34(+)/CD38(-) stem cells, but not in acute lymphoblastic leukemia blasts (n=5). Selected anti-C-type lectin-like molecule-1 monoclonal antibodies mediated dose-dependent complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity specifically against acute myeloid leukemia-derived cell lines. Exogenous expression of the transmembrane receptor in HEK293 cells rendered the cells susceptible to antibody-mediated killing by monoclonal antibodies to the receptor. Furthermore, these monoclonal antibodies demonstrated strong complement-dependent cytotoxicity against freshly isolated acute myeloid leukemia blasts (15/16 cases; 94%). The monoclonal antibodies were efficiently internalized upon binding to C-type lectin-like molecule-1 in HL-60 cells. Moreover, a lead chimeric C-type lectin-like molecule-1 monoclonal antibody reduced the tumor size in xenograft mice implanted with HL-60 cells. Conclusions Our results demonstrate that targeting C-type lectin-like molecule-1 with specific cytotoxic monoclonal antibodies is an attractive approach which could lead to novel therapies for acute myeloid leukemia.
Zhao
Xiaoxian
X
Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH, USA.
Singh
Shweta
S
Pardoux
Cecile
C
Zhao
Jingsong
J
Hsi
Eric D
ED
Abo
Arie
A
Korver
Wouter
W
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000627:therapeutic use* / Q000633:toxicity; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018922:HL-60 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D021381:Protein Transport / Q000276:immunology; D011975:Receptors, Mitogen; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000911:Antibodies, Monoclonal; C529398:CLEC12A protein, mouse; D037181:Lectins, C-Type; D011975:Receptors, Mitogen