TRANSGENIC NON-HUMAN ANIMALS CAPABLE OF PRODUCING HETEROLOGOUS ANTIBODIES

摘要

The invention relates transgenic non-human animals capable of producing heterologous antibodies and transgenic non--human animals having inactivated endogenous immunoglobulin genes. In one aspect of the invention, endogenous immunoglob-ulin genes are suppresed by antisense polynucleotides and/or by antiserum directed against endogenous immunoglobulins. He-terologous antibodies are encoded by immunoglobulin genes not normally found in the genome of that species of non-human animal. In one aspect of the invention, one or more transgenes containing sequences of unrearranged heterogolous human immu-noglobulin heavy chains are introduced into a non-human animal thereby forming a transgenic animal capable of functionally rearranging transgenic immunoglobulin sequences and producing a repertoire of antibodies of various isotypes encoded by hu-man immunoglobulin genes. Such heterologous human antibodies are produced in B-cells which are thereafter immortalized, e.g., by fusing with an immortalizing cell line such as a myeloma or by manipulating such B-cells by other techniques to perpetuate a cell line capable of producing a monoclonal heterologous antibody. The invention also relates to heavy and light chain immunog-lobulin transgenes for making such transgenic non-human animals as well as methods and vectors for disrupting endogenous im-munogiobulin loci in the transgenic animal.