The novel chimeric anti-NCAM (neural cell adhesion molecule) antibody ch.MK1 displays antitumor activity in SCID mice but does not activate complement-dependent cytolysis (CDC).
A monoclonal chimeric antibody ch.MK1 was generated by immunizing F004 mice expressing human instead of murine IgG1/kappa immunoglobulin constant regions. The novel antibody specifically binds cell surface-expressed human neural cell adhesion molecule (NCAM) as shown by immunoprecipitation, flow cytometry and cytospins. Functional analysis revealed nearly complete absence of complement-dependent cytolysis in ch.MK1 and in all other anti-NCAM antibodies tested for reference (UJ13a, ERIC1, 123C3, ch.5A2, B159), indicating an unexpected and group-specific property of anti-NCAM antibodies. As a most plausible mechanism, posttranslational modification of NCAM by complement-inhibiting polysialic acid is discussed. The antibody ch.MK1 demonstrated significant in vivo activity against NCAM-positive neuroblastoma in SCID mice in presence of human peripheral blood mononuclear cell. In absence of human peripheral blood mononuclear cell no distinct antitumor activity of the antibody alone was observed. In ch.MK1 the cellular component of the immune system seems to be the dominant effector mechanism, whereas complement-dependent cytolysis seems not to be necessarily required for antitumor activity. These observations help us to understand immunotherapeutic mechanisms of native anti-NCAM antibodies and may additionally contribute to the understanding of results of currently ongoing clinical studies with conjugated anti-NCAM antibodies.
Klehr
Martin
M
Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany.
Koehl
Ulrike
U
Mühlenhoff
Martina
M
Tawadros
Samir
S
Fischer
Thomas
T
Schomäcker
Klaus
K
Heuckmann
Johannes M
JM
Bochennek
Konrad
K
Jensen
Markus
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000276:immunology*; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007167:Immunotherapy; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D019006:Neural Cell Adhesion Molecules / Q000276:immunology*; D009447:Neuroblastoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D007127:Immunoglobulin Constant Regions; D019006:Neural Cell Adhesion Molecules; D011993:Recombinant Fusion Proteins; D003165:Complement System Proteins