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.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

CONCLUSION:

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.

• Authors: John F DiJoseph, Maureen M Dougher, Lyka B Kalyandrug, Douglas C Armellino, Erwin R Boghaert, Philip R Hamann, Justin K Moran, Nitin K Damle
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 1 Pg. 242-9 (Jan 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16397048 (Publication Type: Journal Article)

Chemical References

• Aminoglycosides
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antibodies, Monoclonal, Murine-Derived
• Immunoconjugates
• Immunologic Factors
• Sialic Acid Binding Ig-like Lectin 2
• Rituximab
• Inotuzumab Ozogamicin

Topics

• Aminoglycosides (chemistry, immunology)
• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antibodies, Monoclonal, Humanized
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cell Line, Tumor
• Cytotoxicity, Immunologic (drug effects)
• Female
• Flow Cytometry
• Humans
• Immunoconjugates (pharmacology)
• Immunologic Factors (administration & dosage)
• Inotuzumab Ozogamicin
• Lymphoma, B-Cell (drug therapy)
• Male
• Mice
• Mice, Nude
• Mice, SCID
• Neoplasms, Experimental (drug therapy)
• Rituximab
• Sialic Acid Binding Ig-like Lectin 2 (drug effects, immunology)
• Xenograft Model Antitumor Assays