Bovine epiphany

Cows inspire TSRI researchers to create therapy that fuses hormones and antibodies

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LA JOLLA, Calif.—Scientists at The Scripps Research Institute (TSRI) have made progress toward a new therapy that could be used to treat a range of conditions involving hormone deficiencies—and they have cows to thank for it.
A new study from TSRI suggests that the therapeutic approach has the potential to significantly improve quality of life for people who currently take daily injections of human growth hormone to treat their conditions. TSRI research associate Tao Liu, a co-author of the study, tells DDNews that researchers were inspired by the immune system of cows to develop a compound that fuses hormones with antibodies. “We’ve previously found that immune molecules in cows have a structure that is quite different from humans,” says Liu. “We were inspired by this unique structure to assemble an antibody with the potential to treat a range of conditions in humans.”
Current treatments for conditions that feature hormone deficiencies often involve injections of human growth hormone (HGH). While this course of treatment can be highly effective, it is usually necessary for patients to receive injections with great frequency due to the quickness with which the body breaks down HGH. In some cases, the body degrades HGH within 30 minutes.
“A major disadvantage of hormones as a treatment is the need for frequent injections,” says Liu. “Children with growth hormone deficiency, for example, have to receive injections of growth hormone every day, and that can be very painful for a little kid.”
TSRI’s study suggests it may be possible to develop hormone-based treatments that remain active in the human body long enough to be administered much less frequently—perhaps weekly or monthly. This could be accomplished by fusing hormones with antibodies, which can survive for weeks in the body.
An older TSRI study from 2013 showed that compounds providing a potential model for fusing hormones and antibodies exist in the immune system of cows. The 2013 study of the bovine antibody revealed an unusual structure that features a round base with a long amino-acid stalk extending outwards. On the top of the stalk is a “knob region” that was believed to bind to pathogens.
Researchers designed the new TSRI study to test whether it is possible to switch the knob region of the bovine antibody with DNA from a human hormone, such as HGH. They first pursued this theory by using recombinant DNA technology to fuse HGH to a coiled version of the bovine antibody’s stalks. The results were promising: the fusion proved stable and did not prevent HGH from retaining its normal function.
The next step of the study involved an attempt to create a fully humanized version of the antibody to test whether it was possible for the molecules to be applied in human therapy. Researchers used the humanized anticancer drug Herceptin as the antibody base to develop an antibody-hormone molecule without any cow DNA.
“We used Herceptin because it has already been used as a drug to treat cancer and it has a well-established profile,” says Liu. “We modified it so it didn’t have anything to do with treating cancer and its only function was to help the growth hormone grow correctly and to improve the half life of the compound.”
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,” according to Liu. “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.” The study ultimately demonstrated that human hormones and antibodies can be fused together in a way that mimics the long, stalk-like cow antibodies.
The senior authors of the new study, which was published in the journal Proceedings of the National Academy of Sciences, were Peter Schultz of TSRI and Feng Wang of the California Institute for Biomedical Research.
The researchers are continuing to explore how this new therapeutic approach could provide longer-lasting doses of HGH that would improve treatments for people with conditions ranging from Turner Syndrome, which causes short stature in females, to low birth weight. Liu believes the therapy could eventually improve treatments for an even wider spectrum of individuals, including those who require insulin to treat type 2 diabetes. Reducing the frequency of injections for all these conditions, he says, has the potential to improve patient compliance and quality of life.

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