Engineered mice make human antibodies.

For years, monoclonal antibodies have teased investors and researchers alike with their potential as the wonder products of biotechnology. Scientists had harnessed the mouse immune system to tailor antibodies to target specific substances, including those that cause disease in humans. But these mouse-derived molecules can cause allergic reactions in people.

Now, two biotechnology companies hope to sidestep this problem by creating mice that produce human antibodies. They have used cells from these mice to make antibodies against human proteins.

Aya Jakobovits and her colleagues at Cell Genesys in Foster City, Calif., first made two new mouse strains by inserting yeast artifical chromosomes (YACs) into very early mouse embryos (SN: 6/5/93, p.360). One strain's YAC got genes for key parts of a so-called heavy chain in human antibodies. The other strain's YAC carried genes for a human antibody light chain.

In general, cells mix and match various genes for these two chains to create many different antibodies. So the researchers bred these mice to create offspring with genes for both components of human antibodies. They mated the resulting generation of animals with mice whose genes for making mouse anibodies had been for making mouse antibodies had been disabled, they report in th May NATURE GENETICS.

In the resulting young, "the human genes are using the mouse machinery to [produce and] process the antibody," says Jakobovits.

At GenPharm International in Mountain View, Calif., Nils Lonberg and his colleagues developed their new strain of mice similarly, but they used a different genetic approach. Instead of YACs, they made artificial genes called minilocus transgenes. The researchers created one minilocus by joining pieces of human DNA involved in heavy-chain production and two more miniloci using DNA involved in light-chain production, Lonberg's group reports in the April 28 NATURE.

In both companies' mice, the immune system rearranges these human genes to create a variety of antibodies known as IgM immunoglobulins. The GenPharm mice also make second-generation antibodies known as IgG immunoglobulins, says GenPharm's Robert M. Kay.