Method for production of monoclonal antibodies in chimeric mice or rats having xenogeneic antibody-producing cells

A method for the production of a monoclonal antibody which specifically binds a predetermined antigen, comprising:

• (a) immunizing a chimeric non-human mouse or rat M4 having xenogeneic hematopoietic cells with the predetermined antigen such that xenogeneic antibody-producing cells are produced in said chimeric mouse or rat, wherein said mouse or rat M4 is a mouse or rat M1, the hematopoietic cells of which have been substantially destroyed, said mouse or rat M1 having transplanted therein cells or tissue from at least two different sources, at least one of said sources being hematopoietic cells from a mouse M2 having a T and/or B cell immunodeficiency, and at least a second of said sources being xenogeneic hematopoietic cells obtained from a mammal M3 of a species other than that of mouse or rat M1 and mouse M2, wherein said xenogeneic hematopoietic cells comprise cells which are or give rise to antibody-producing cells and said T and/or B cell immunodeficiency of said mouse M2 is such that the T and/or B cell immunodeficiency can be reconstituted with xenogeneic hematopoietic cells;
• (b) removing and immortalizing said antibody-producing cells;
• (c) selecting and cloning the immortalized antibody producing cells producing the desired antibody;
• and
• (d) isolating the antibodies produced by the selected, cloned immortalized antibody producing cells.