Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of calicheamicin, and rituximab against non-Hodgkin's B-cell lymphoma.
OBJECTIVE
CMC-544 is a CD22-targeted cytotoxic immunoconjugate, currently being evaluated in B-cell non-Hodgkin's lymphoma (B-NHL) patients. Rituximab is a CD20-targeted antibody commonly used in B-NHL therapy. Here, we describe antitumor efficacy of a combination of CMC-544 and rituximab against B-cell lymphoma (BCL) in preclinical models.


METHODS
BCLs were cultured in vitro with CMC-544, rituximab, or their combination. BCLs were injected either s.c. or i.v. to establish localized s.c. BCL in nude mice or disseminated BCL in severe combined immunodeficient mice, respectively. I.p. treatment with CMC-544 or rituximab was initiated at various times either alone or in combination and its effect on s.c. BCL growth or survival of mice with disseminated BCL was monitored.


RESULTS
In vitro growth-inhibitory activity of CMC-544 combined with rituximab was additive. Rituximab but not CMC-544 exhibited effector functions, such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Rituximab was less effective in inhibiting growth of established BCL xenografts than developing xenografts. In contrast, CMC-544 was equally effective against both developing and established BCL xenografts. Although CMC-544 and rituximab individually caused partial inhibition of the growth of BCL xenografts at suboptimal doses examined, their combination suppressed xenograft growth by >90%. In a disseminated BCL model, 60% of CMC-544-treated mice and 20% of rituximab-treated mice survived for 125 days. In contrast, 90% of mice treated with the combination of CMC-544 and rituximab survived for longer than 125 days.


CONCLUSIONS
The demonstration of superior antitumor activity of a combination of CMC-544 and rituximab described here provides the preclinical basis for its clinical evaluation as a treatment option for B-NHL.
DiJoseph
John F
JF
Oncology Discovery Research, Wyeth Research, Pearl River, New York 10965, USA.
Dougher
Maureen M
MM
Kalyandrug
Lyka B
LB
Armellino
Douglas C
DC
Boghaert
Erwin R
ER
Hamann
Philip R
PR
Moran
Justin K
JK
Damle
Nitin K
NK
D000617:Aminoglycosides / Q000737:chemistry / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007155:Immunologic Factors / Q000008:administration & dosage; D000080045:Inotuzumab Ozogamicin; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D000069283:Rituximab; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000617:Aminoglycosides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018796:Immunoconjugates; D007155:Immunologic Factors; D051918:Sialic Acid Binding Ig-like Lectin 2; D000069283:Rituximab; D000080045:Inotuzumab Ozogamicin