TY - JOUR
T1 - A novel antibody-drug conjugate targeting SAIL for the treatment of hematologic malignancies
AU - Kim, S. Y.
AU - Theunissen, J. W.
AU - Balibalos, J.
AU - Liao-Chan, S.
AU - Babcock, M. C.
AU - Wong, T.
AU - Cairns, B.
AU - Gonzalez, D.
AU - Van Der Horst, E. H.
AU - Perez, M.
AU - Levashova, Z.
AU - Chinn, L.
AU - D'Alessio, J. A.
AU - Flory, M.
AU - Bermudez, A.
AU - Jackson, D. Y.
AU - Ha, E.
AU - Monteon, J.
AU - Bruhns, M. F.
AU - Chen, G.
AU - Migone, T. S.
N1 - Funding Information:
Procedures to obtain specimens were conducted under institutional review board approval with all patients signing informed consent. Fresh specimens from acute myeloid leukemia (AML) and multiple myeloma (MM) patients and normal peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) from nondiseased donors were acquired from AllCells (Emeryville, CA, USA). Fresh chronic lymphocytic leukemia (CLL) specimens were from Billings Clinic (Billings, MT, USA) and the University of Florida. Additional frozen AML and CLL patient specimens for flow analysis were from AllCells and the University of California San Diego, respectively. Primary solid tumors and normal adjacent control samples were from CHTN (The Cooperative Human Tissue Network) or the National Disease Research Interchange. CHTN is funded by the National Cancer Institute.
PY - 2015/5/29
Y1 - 2015/5/29
N2 - Although several new therapeutic approaches have improved outcomes in the treatment of hematologic malignancies, unmet need persists in acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin's lymphoma. Here we describe the proteomic identification of a novel cancer target, SAIL (Surface Antigen In Leukemia), whose expression is observed in AML, MM, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). While SAIL is widely expressed in CLL, AML, MM, DLBCL and FL patient samples, expression in cancer cell lines is mostly limited to cells of AML origin. We evaluated the antitumor activity of anti-SAIL monoclonal antibodies, 7-1C and 67-7A, conjugated to monomethyl auristatin F. Following internalization, anti-SAIL antibody-drug conjugates (ADCs) exhibited subnanomolar IC50 values against AML cell lines in vitro. In pharmacology studies employing AML cell line xenografts, anti-SAIL ADCs resulted in significant tumor growth inhibition. The restricted expression profile of this target in normal tissues, the high prevalence in different types of hematologic cancers and the observed preclinical activity support the clinical development of SAIL-targeted ADCs.
AB - Although several new therapeutic approaches have improved outcomes in the treatment of hematologic malignancies, unmet need persists in acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin's lymphoma. Here we describe the proteomic identification of a novel cancer target, SAIL (Surface Antigen In Leukemia), whose expression is observed in AML, MM, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). While SAIL is widely expressed in CLL, AML, MM, DLBCL and FL patient samples, expression in cancer cell lines is mostly limited to cells of AML origin. We evaluated the antitumor activity of anti-SAIL monoclonal antibodies, 7-1C and 67-7A, conjugated to monomethyl auristatin F. Following internalization, anti-SAIL antibody-drug conjugates (ADCs) exhibited subnanomolar IC50 values against AML cell lines in vitro. In pharmacology studies employing AML cell line xenografts, anti-SAIL ADCs resulted in significant tumor growth inhibition. The restricted expression profile of this target in normal tissues, the high prevalence in different types of hematologic cancers and the observed preclinical activity support the clinical development of SAIL-targeted ADCs.
UR - http://www.scopus.com/inward/record.url?scp=84989325782&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84989325782&partnerID=8YFLogxK
U2 - 10.1038/bcj.2015.39
DO - 10.1038/bcj.2015.39
M3 - Article
C2 - 26024286
AN - SCOPUS:84989325782
SN - 2044-5385
VL - 5
JO - Blood cancer journal
JF - Blood cancer journal
IS - 5
M1 - e316
ER -