The humanized CD40 antibody SGN-40 demonstrates pre-clinical activity that is enhanced by lenalidomide in chronic lymphocytic leukaemia

Br J Haematol. 2009 Mar;144(6):848-55. doi: 10.1111/j.1365-2141.2008.07548.x. Epub 2009 Jan 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • B-Lymphocytes / immunology
  • CD40 Antigens / immunology*
  • Cytotoxicity Tests, Immunologic
  • Flow Cytometry
  • Humans
  • Killer Cells, Natural / immunology
  • Lenalidomide
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Thalidomide / analogs & derivatives*
  • Thalidomide / therapeutic use
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • CD40 Antigens
  • Thalidomide
  • Lenalidomide