Document Detail

Combination anti-CD74 (milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma.
MedLine Citation:
PMID:  21228331     Owner:  NLM     Status:  MEDLINE    
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.
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
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-01-12
Journal Detail:
Title:  Blood     Volume:  117     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-04-29     Completed Date:  2011-06-30     Revised Date:  2013-09-25    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4530-41     Citation Subset:  AIM; IM    
Division of Hematology, Department of Medicine, College of Medicine, The Ohio State University, Columbus, USA.
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MeSH Terms
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
Lymphoma, Mantle-Cell / drug therapy*,  pathology
Membrane Potential, Mitochondrial / drug effects,  immunology
NF-kappa B / antagonists & inhibitors,  immunology
Reactive Oxygen Species / metabolism
Grant Support
Reg. No./Substance:
0/Antibodies, Immobilized; 0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Antibodies, Monoclonal, Murine-Derived; 0/Antigens, CD20; 0/Antigens, Differentiation, B-Lymphocyte; 0/Antineoplastic Agents; 0/Histocompatibility Antigens Class II; 0/NF-kappa B; 0/Reactive Oxygen Species; 0/invariant chain; 0/milatuzumab; 0/rituximab

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