Combination anti-CD74 (milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma
Open Access
- 28 April 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 117 (17), 4530-4541
- https://doi.org/10.1182/blood-2010-08-303354
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.Keywords
This publication has 51 references indexed in Scilit:
- Milatuzumab immunoliposomes induce cell death in CLL by promoting accumulation of CD74 on the surface of B cellsBlood, 2010
- CD19 targeting of chronic lymphocytic leukemia with a novel Fc-domain–engineered monoclonal antibodyBlood, 2010
- Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cellsJCI Insight, 2009
- Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibodyBlood, 2009
- Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma GroupBlood, 2008
- Immunotherapy in mantle cell lymphoma: Anti‐CD20‐based therapy and beyondAmerican Journal of Hematology, 2007
- IL-8 secreted in a macrophage migration-inhibitory factor- and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survivalProceedings of the National Academy of Sciences of the United States of America, 2007
- Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphomaBlood, 2006
- Cholesterol depletion inhibits src family kinase‐dependent calcium mobilization and apoptosis induced by rituximab crosslinkingImmunology, 2005
- Invariant Chain Induces B Cell Maturation by Activating a TAFII105-NF-κB-dependent Transcription ProgramJournal of Biological Chemistry, 2001