Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia.
CMC-544 (inotuzumab ozogamicin) is a CD22-specific cytotoxic immunoconjugate of calicheamicin intended for the treatment of B-lymphoid malignancies. This preclinical study investigated antitumor activity of CMC-544 against CD22+ acute lymphoblastic leukemia (ALL). CMC-544 inhibited in vitro growth of ALL cell lines more potently than that of Ramos B-lymphoma cells. When administered to nude mice with established sc xenografts of REH ALL, CMC-544 caused dose-dependent inhibition of xenograft growth producing complete tumor regression and cures in tumor-bearing mice at the highest dose of 160 microg/kg of conjugated calicheamicin. In contrast, a nonbinding control conjugate was 16-fold less effective than CMC-544 in inhibiting growth of REH ALL xenografts. When REH cells were injected intravenously in scid mice and allowed to disseminate systemically, mice developed hind-limb paralysis that was effectively prevented by treatment with CMC-544. Flow cytometric analysis of cells recovered from the bone marrow from mice with disseminated disease verified the presence of engrafted ALL cells. Significantly reduced numbers of ALL cells were recovered from the bone marrow of CMC-544-treated mice than from vehicle-treated mice with disseminated disease. The anti-leukemia activity of CMC-544 demonstrated here further supports clinical evaluation of CMC-544 for the treatment of CD22+ leukemia.
Oncology Discovery Research, Wyeth Research, Pearl River, NY 10965, USA.
J F
JF
Dijoseph
M M
MM
Dougher
D C
DC
Armellino
D Y
DY
Evans
N K
NK
Damle
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000295:instrumentation* / Q000379:methods; D000080045:Inotuzumab Ozogamicin; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000737:chemistry* / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051918:Sialic Acid Binding Ig-like Lectin 2; D000080045:Inotuzumab Ozogamicin