An anti-CD30 chimeric receptor that mediates CD3-zeta-independent T-cell activation against Hodgkin's lymphoma cells in the presence of soluble CD30.
Hodgkin's lymphoma patients fail to establish an efficient cellular response against CD30+ Hodgkin/Reed-Sternberg cells. An impaired T-cell receptor/CD3-zeta-mediated activation of T cells is thought to be involved in this situation. We here present a chimeric anti-CD30 receptor that mediates MHC and T-cell receptor/CD3-zeta-independent T-cell activation against CD30+ lymphoma cells even in the presence of soluble CD30. The receptor consists of the binding domain of the monoclonal antibody HRS3 and the signaling unit of the Fc epsilonRI-receptor gamma-chain. After expression in MD45 T cells, receptor cross-linking with immobilized anti-idiotypic monoclonal antibody and CD30+ cells, respectively, results in increased interleukin 2 secretion and specific cytolysis of CD30+ Hodgkin's lymphoma cells. Soluble CD30 in concentrations up to 6000 units/ml did not interfere with cellular activation induced by membrane-bound antigen. This demonstrates the feasibility of the chimeric anti-CD30-scFv-gamma receptor in CD30+ lymphoma cell targeting, even in the presence of as high concentrations of soluble CD30 as are found in patients during progression of the disease.
Hombach
A
A
Klinik I für Innere Medizin, Universität zu Köln, Germany.
Heuser
C
C
Sircar
R
R
Tillmann
T
T
Diehl
V
V
Pohl
C
C
Abken
H
H
D017252:CD3 Complex / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D004306:Dose-Response Relationship, Immunologic; D006689:Hodgkin Disease / Q000276:immunology*; D006801:Humans; D007128:Immunoglobulin Fragments; D017730:Ki-1 Antigen / Q000737:chemistry / Q000276:immunology*; D008213:Lymphocyte Activation; D011993:Recombinant Fusion Proteins; D012995:Solubility; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D017252:CD3 Complex; D007128:Immunoglobulin Fragments; D017730:Ki-1 Antigen; D011993:Recombinant Fusion Proteins