HUMAN MONOCLONAL-ANTIBODIES SPECIFIC TO HEPATITIS-B VIRUS GENERATED IN A HUMAN MOUSE RADIATION CHIMERA - THE TRIMERA SYSTEM/

An approach to develop fully human monoclonal antibodies in a human/mo use radiation chimera, the Trimera system, is described, In this syste m, functional human lymphocytes are engrafted in normal strains of mic e which are rendered immune-incompetent by lethal total body irradiati on followed by radioprotection with severe combined immunodeficient (S CID) mouse bone marrow. Following transplantation, human lymphocytes c olonize murine lymphatic organs and secrete human immunoglobulins. We have established this system as a tool to develop fully human monoclon al antibodies, and applied it for the generation of monoclonal antibod ies specific for hepatitis B virus surface antigen. A strong memory re sponse to hepatitis B surface antigen was elicited in Trimera engrafte d with lymphocytes from human donors positive for antibodies to hepati tis B surface antigen, The human specific antibody fraction in the Tri mera was 10(2)-10(3)-fold higher as compared with that found in the do nors. Spleens were harvested from Trimera mice showing high specific-a ntibody titres and cells were fused to a human-mouse heteromyeloma fus ion partner. Several stable hybridoma clones were isolated and charact erized. These hybridomas produce high-affinity. IgG, anti-hepatitis B surface antigen antibodies demonstrating the potential of the Trimera system for generating Fully human monoclonal antibodies. The biologica l function and the neutralizing activity of these antibodies are curre ntly being tested.