Anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia.
Despite therapeutic advances, the long-term survival rates for acute myeloid leukemia (AML) are estimated to be 10% or less, pointing to the need for better treatment options. AML cells express the myeloid marker CD33, making it amenable to CD33-targeted therapy. Thus, the in vitro and in vivo anti-tumor activities of lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, were investigated. In vitro assays were used to assess the ability of lintuzumab to mediate effector functions and to decrease the production of growth factors from AML cells. SCID mice models of disseminated AML with the multi-drug resistance (MDR)-negative HL60 and the MDR(+), HEL9217 and TF1-alpha, cell lines were developed and applied to examine the in vivo antitumor activity. In vitro, lintuzumab significantly reduced the production of TNFalpha-induced pro-inflammatory cytokines and chemokines by AML cells. Lintuzumab promoted tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) activities against MDR(-) and MDR(+) AML cell lines and primary AML patient samples. At doses from 3 to 30 mg/kg, lintuzumab significantly enhanced survival and reduced tumor burden in vivo, regardless of MDR status. Survival of the mice was dependent upon the activity of resident macrophages and neutrophils. The results suggest that lintuzumab may exert its therapeutic effects by modulating the cytokine milieu in the tumor microenvironment and through effector mediated cell killing. Given that lintuzumab induced meaningful responses in a phase 1 clinical trial, the preclinical antitumor activities defined in this study may underlie its observed therapeutic efficacy in AML patients.
Sutherland
May Kung
MK
Department of Pre-Clinical Therapeutics, Seattle Genetics, Inc., Bothell, WA, USA. msutherland@seagen.com
Yu
Changpu
C
Lewis
Timothy S
TS
Miyamoto
Jamie B
JB
Morris-Tilden
Carol A
CA
Jonas
Mechthild
M
Sutherland
Jennifer
J
Nesterova
Albina
A
Gerber
Hans-Peter
HP
Sievers
Eric L
EL
Grewal
Iqbal S
IS
Law
Che-Leung
CL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010587:Phagocytosis; D063268:Sialic Acid Binding Ig-like Lectin 3; D016896:Treatment Outcome; D020298:U937 Cells
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D016207:Cytokines; D063268:Sialic Acid Binding Ig-like Lectin 3; C477390:lintuzumab