Docking site decoy, antibody fragment wed.

Docking site decoy, antibody fragment wed

Researchers this week reported engineering a new class of hybrid molecules they say may significantly improve a promising, experimental AIDS therapy. The antibody-like molecules, dubbed immunoadhesins, not only sop up criculating AIDs viruses but also contain protein fragments with the potential to trigger an immune response against the virus, HIV.

The approach adds an offensive component to an essentially passive form of AIDS protection now under investigation by the National Cancer Institute in Bethesda, Md. In those trials, researchers inject patients with a soluble variety of CD4, the "docking site" molecule on the surface of cells to which HIV normally binds. Preliminary results suggest soluble CD4 can slow or prevent infection by saturating the CD4 binding sites of circulating HIV before the virusues can attach to and infect immune system cells (SN: 8/20/88, p.124).

Daniel J. Capon of genentech, Inc., a South San Francisco biotechnology company, and his colleagues sought to add a one-two punch to soluble CD4. They engineered the genetic machinery inside cultured huamn kidney cells to mass produce a new product --a CD4 molecule fused with a string of amino acids common to many antibody molecules. In intact antibodies, that amino acid portion -- called the Fc fragment -- normally mediates two powerful immune responses: It helps killer white blood cells recognize and ingest antibody-bound foreign invaders and it triggers a process known as complement activation that destroys those invaders by chemical dissolution. The reserachers tested immunoadhesins' ability to protect cultured cells exposed to HIV. They report in the Feb. 9 NATIRe that the Fc fragment, when linked to CD4, loses its ability to activate complement. But the novel molecule appears to retain its ability to rally immune cells against sopped-up HIV.

The researchers say further tinkering may produce an "optimal molecule" that passively attracts and more actively attacks HIV. Significantly, they add, animal experiments indicate immunoadhesins will remain in the human body nearly 200 times longer than run-of-the-mill CD4, which can disappear from circulation within a few hours. Moreover, the molecule's structure suggests it can cross the plancenta from mother to fetus, suggesting immunoadhesins may prove useful in preventing perinatally acquired HIV infection.