title: The humanized CD40 antibody SGN-40 demonstrates pre-clinical activity that is enhanced by lenalidomide in chronic lymphocytic leukaemia.
abstract: Antibody-based therapies, such as rituximab and alemtuzumab, have contributed significantly to the treatment of Chronic Lymphocytic leukaemia (CLL). The CD40 antigen is expressed predominantly on B-cells and represents a potential target for immune-based therapies. SGN-40 is a humanized IgG1 monoclonal antibody currently in Phase I/II clinical trials for indolent lymphomas, diffuse large B cell lymphomas and Multiple Myeloma. Its biological effect on CLL cells has not been studied. The present study demonstrated that SGN-40 mediated modest apoptosis in a subset of patients with secondary cross-linking but did not mediate complement-dependent cytotoxicity. SGN-40 also mediated antibody-dependent cellular cytotoxicity (ADCC) predominantly through natural killer (NK) cells. Previous studies by our group and others have demonstrated that lenalidomide upregulates CD40 expression on primary B CLL cells and activates NK-cells. We therefore examined for the combinatorial effect of lenalidomide and SGN-40 and demonstrated that both enhanced direct apoptosis and ADCC against primary CLL B cells. These data together provide justification for clinical trials of SGN-40 and lenalidomide in combination for CLL therapy.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Lapalombella
authors.forename: Aruna
authors.initials: A
authors.lastname: Gowda
authors.forename: Trupti
authors.initials: T
authors.lastname: Joshi
authors.forename: Najma
authors.initials: N
authors.lastname: Mehter
authors.forename: Carolyn
authors.initials: C
authors.lastname: Cheney
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: Natarajan
authors.initials: N
authors.lastname: Muthusamy
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D013792:Thalidomide; D000077269:Lenalidomide