Monoclonal antibodies against IREM-1: potential for targeted therapy of AML.
IREM-1 is an inhibitory cell surface receptor with an unknown function and is expressed on myeloid cell lineages, including cell lines derived from acute myeloid leukemia (AML) patients. We have generated a series of monoclonal antibodies (mAbs) against the extracellular domain of IREM-1 and further assessed its expression in normal and AML cells. IREM-1 was restricted to cells from myeloid origin and extensive expression analysis in primary cells obtained from AML patients showed IREM-1 expression in leukemic blasts of 72% (39/54) of samples. We therefore searched for specific IREM-1 mAbs with activity in functional complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Lead mAbs against IREM-1 showed specific cytotoxic activity against a variety of AML-derived cell lines and freshly isolated blasts from AML patients. Internalization of mAbs upon IREM-1 binding was also shown. In vivo anticancer activity of lead mAbs was observed in an established HL-60 xenograft model with a tumor growth delay of up to 40% and in a model using primary human AML cells, where treatment with anti-IREM-1 mAb resulted in a significant reduction of engrafted human cells. These results demonstrate IREM-1 as a potential novel target for immunotherapy of AML.
Korver
W
W
Discovery Research, Nuvelo Inc., San Carlos, CA 94080, USA. wouter.korver@takedasf.com
Zhao
X
X
Singh
S
S
Pardoux
C
C
Zhao
J
J
Guzman
M L
ML
Sen
S
S
Yonkovich
S
S
Liu
S
S
Zhan
X
X
Tomasevic
N
N
Zhou
C
C
Gros
D
D
Jordan
C T
CT
Gotlib
J
J
Hsi
E D
ED
Abo
A
A
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000627:therapeutic use*; D000915:Antibody Affinity; D000920:Antibody-Dependent Cell Cytotoxicity; D018952:Antigens, CD34 / Q000032:analysis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; C519443:CD300LF protein, human; D011971:Receptors, Immunologic; D051997:ADP-ribosyl Cyclase 1