The friendly cow, said to be blown by all the winds that pass, and wet with all the showers, may soon share the quality of steadfastness with protein therapeutics, particularly growth hormone injections, which tend to last but briefly. Hormone injections, it now appears, could acquire some of the quiet persistence demonstrated by cow antibodies.

In general, therapeutic antibodies can last for weeks in the body. And so antibodies with agonist or antagonist activities have been sought, in hopes that they could assist the development of therapeutic proteins with long plasma half-lives. Cow antibodies may be particularly useful because it has recently been demonstrated that they can be fused with human hormones. The resulting molecules are called antibody–hormone chimeras, and they have the potential for long-lasting action.

In a new study, scientists at The Scripps Research Institute (TSRI) drew inspiration from the bovine antibody, which has an unusual structure—a round base with a long amino-acid “stalk” pointing out. On the top of the stalk is a “knob region” that presumably binds to pathogens. This knob region, the scientists supposed, could be switched with DNA from a human hormone, such as hGH. And so they decided to use recombinant DNA technology to fuse hGH to a coiled version of the bovine antibody's stalks.

This scientists described their approach February 3 in the Proceedings of the National Academy of Sciences, in an article entitled, “Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists.”

“Based on the structure of a natural bovine antibody with an ultralong, well-folded heavy-chain complementarity-determining region [CDR], we have developed a strategy for the generation of functional human antibody–hormone chimeras with biological activities comparable to native hormones and significantly enhanced pharmacological properties,” wrote the authors. “This approach likely provides a general, relatively straightforward platform for generating antibody agonists and antagonists for a range of therapeutic applications.”

After the scientists determined that their first attempt at fusion resulted in a stable and functional version of hGH, they took their approach one step farther.  They tried making an antibody-hormone molecule without any cow DNA, so that the molecules might someday be applied in human therapy. They used the humanized anti-cancer antibody Herceptin as the antibody base in the new treatment.

The researchers then tested their antibody-hGH molecule in rat models. They found that hGH-deficient rats that received the treatment grew normally. In fact, the treated rats only needed injections two times a week to grow, compared with daily injections for rats given hGH without the antibody base.

“It acts just like the normal growth hormone,” said TSRI research associate Tao Liu, co-first author of the new study with Yong Zhang, a researcher at the California Institute for Biomedical Research. “This means the treatment might only need to be injected once a week or even once a month in humans. It would be so much easier for patients.”

To further test their method, the researchers attached Herceptin to leptin, a hormone that regulates body weight. They showed that the antibody-leptin molecule was just as effective in mice as natural leptin—and it didn't have to be injected as often. Subsequent experiments showed no harmful side effects from the treatments.

“Pharmacological studies in rodents indicated a 20- to 100-fold increase in plasma circulating half-life for these antibody agonists and significantly extended in vivo activities in the GH-deficient rat model and leptin-deficient obese mouse model for the hGH and hLeptin antibody fusions, respectively,” noted the authors. “These results illustrate the utility of antibody CDR fusions as a general and versatile strategy for generating long-acting protein therapeutics.”

The research team is working to optimize the treatment for potential use in humans, and Liu hopes the method could someday deliver longer-lasting doses of hGH—or maybe even insulin to treat type 2 diabetes—to patients in need. And so protein therapeutics may emulate the cow—she who wanders here and there and yet cannot stray.








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