Combination anti-CD74 (milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma.

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL.

• Authors: Lapo Alinari, Bo Yu, Beth A Christian, Fengting Yan, Jungook Shin, Rosa Lapalombella, Erin Hertlein, Mark E Lustberg, Carl Quinion, Xiaoli Zhang, Gerard Lozanski, Natarajan Muthusamy, Mette Prætorius-Ibba, Owen A O'Connor, David M Goldenberg, John C Byrd, Kristie A Blum, Robert A Baiocchi
• Journal: Blood (Blood) Vol. 117 Issue 17 Pg. 4530-41 (Apr 28 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21228331 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Immobilized
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD20
• Antigens, Differentiation, B-Lymphocyte
• Antineoplastic Agents
• Histocompatibility Antigens Class II
• NF-kappa B
• Reactive Oxygen Species
• invariant chain
• milatuzumab
• Rituximab

Topics

• Antibodies, Immobilized (immunology)
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Antibodies, Monoclonal, Murine-Derived (pharmacology)
• Antigens, CD20 (immunology, metabolism)
• Antigens, Differentiation, B-Lymphocyte (immunology, metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Death (drug effects, immunology)
• Cell Line, Tumor
• Cytoskeleton (drug effects, immunology, metabolism)
• Drug Therapy, Combination
• Flow Cytometry
• Histocompatibility Antigens Class II (immunology, metabolism)
• Humans
• In Vitro Techniques
• Lymphoma, Mantle-Cell (drug therapy, pathology)
• Membrane Potential, Mitochondrial (drug effects, immunology)
• NF-kappa B (antagonists & inhibitors, immunology)
• Reactive Oxygen Species (metabolism)
• Rituximab