title: 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.affiliation: Division of Hematology, Department of Medicine, College of Medicine, The Ohio State University, Columbus, USA.
authors.forename: Lapo
authors.initials: L
authors.lastname: Alinari
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.forename: Beth A
authors.initials: BA
authors.lastname: Christian
authors.forename: Fengting
authors.initials: F
authors.lastname: Yan
authors.forename: Jungook
authors.initials: J
authors.lastname: Shin
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
authors.forename: Erin
authors.initials: E
authors.lastname: Hertlein
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lustberg
authors.forename: Carl
authors.initials: C
authors.lastname: Quinion
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.forename: Mette
authors.initials: M
authors.lastname: Prætorius-Ibba
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Kristie A
authors.initials: KA
authors.lastname: Blum
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
mesh_terms: D055910:Antibodies, Immobilized / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000069283:Rituximab
chemical_list: D055910:Antibodies, Immobilized; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000944:Antigens, Differentiation, B-Lymphocyte; D000970:Antineoplastic Agents; D000949:Histocompatibility Antigens Class II; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C045084:invariant chain; C540932:milatuzumab; D000069283:Rituximab