Cow antibodies are super infection-fighters
Antibodies from cows may provide a new source of drugs for human diseases such as AIDS, according to a study led by Scripps Research Institute scientists.
Bovines produce unusual antibodies that are very efficient in grabbing onto molecular targets, such as proteins from disease-causing microbes, said the study, published Thursday in the journal Cell. Vaughn V. Smider was the paper’s senior author, Feng Wang the first author; both are of Scripps. Smider is a co-founder of Fabrus, a La Jolla company working on antibody therapies.
The antibodies contain what appears to be a singular feature not found in other animals, the scientists say. They’re not even sure just how it works. Scientists not involved in the work say the discovery is surprising and promising.
Cow antibodies could be effective in neutralizing microbes such as HIV that have proven resistant to human antibodies, Smider said. The study included AIDS researcher Ian A. Wilson of Scripps, who has been working on AIDS and influenza vaccines for years.
“This cow antibody structure is just so unusual that we think it could be used to develop antibodies against targets that are relatively difficult for standard antibodies that normally would come from a human,” Smider said.
Antibodies form a Y shape; at the ends of the two arms are loops of protein that latch onto the molecular target, called an antigen. These loops are called complementarity-determining regions, or CDRs. These regions can occur in astronomical numbers of configurations. When one configuration complements the structure of an antigen and fits, the immune system makes more of these antibodies.
An antibody region called CDR H3 is far longer in cows than in humans, which provides a greater reach to find the right molecular complement, such as in a deep indentation. A human antibody that neutralizes a broad range of HIV strains has an exceptionally long CDR H3 region, but is still much shorter than that in cows, the paper said.
“These cow antibodies were very interesting as they had the longest CDRs known by far,” Wilson said. “We are still trying to understand how cow antibodies recognize foreign antigens and wonder whether they could be used for neutralizing HIV-1 and other viruses by inserting its long CDR H3 into deep pockets in the virus structure.”
These deep pockets contain areas of HIV that remain mostly unchanged across many strains. HIV is famous for its ability to mutate away from antibody attacks, but certain parts of the virus can’t change much, or it loses the ability to infect.
The longest loop of the CDR area in humans is built of about 30 amino acids, the building blocks of proteins, Wilson said. The same region in cows has 60 of these amino acids. A graduate student of Wilson’s, Damian Ekiert, determined the region’s structure, and likened it to a ball-and-chain configuration.
“Bizarre,” is how Shane Crotty, a professor at the La Jolla Institute for Allergy & Immunology, described the structure, which Crotty said he hadn’t seen in any other animal. The structure resembles a screwdriver more than a ball-and-chain, said Crotty, in the institute’s vaccine discovery division.
The CDR H3 region is different from any other animal antibody, said Robert Rickert, director of the inflammatory disease program at the Sanford-Burnham Medical Research Institute. While bovine antibodies have been studied before, the difference in this region and its implications hadn’t been reported.
“I’m a bit surprised it’s been overlooked until now, because people have spent a lot of time comparing how antibodies are made in vertebrates from sharks to humans, Rickert said.
“One of the things that was brought out in the paper is not just the unusual length of the CDRs, but the amino acid sequence,” Rickert said. The sequence contains more of the amino acid cysteine, which can form chemical bonds within the CDR between each cysteine’s sulfur atoms.
These disulfide bridges give rigidity to the CDRs, “so they’re not just flapping around,” Rickert said.
Unlike Wilson and colleagues, Fabrus is not seeking to turn these antibodies into vaccines, indeed, the human immune system may not be capable of making them. Instead, they are researching how to make the antibodies as human therapeutics.
Antibody production is one of biotechnology’s oldest feats. An immune cell that makes the desired antibody is fused with an “immortalized” animal cell that grows indefinitely. The fused cells, called hybridomas, are grown in fermentation tanks, and they churn out exact clones of the antibody. Hence the name, monoclonal antibodies. Examples of monoclonal antibody medicines include Rituxan, for non-Hodgkin’s lymphoma and rheumatoid arthritis; and Avastin, for cancer.
However, antibodies made from cows or other animals can’t be just injected into people; the human immune system would recognize them as foreign and reject them. This happened with some of the first antibody drugs, derived from mice. It took years of effort to learn which parts of the antibodies provoked immune reactions. The rejection-causing parts of the antibody were swapped out with human The result was “chimeric” antibodies, named after the mythical chimera, part human and part animal.
Making humanized or chimeric antibodies from mice is now well understood, and cows have been genetically engineered to make human antibodies. However, tailoring cow antibodies to work in humans hasn’t been done before. Smider said his team now has a fairly good idea of how cows make these antibodies, so he’s optimistic that their properties can be grafted onto antibodies the human immune system will accept.
“It’s a very good idea,” Crotty said. “I certainly assume there’ll be some technical challenges. But even if they were only able to do it for a specific application, it would still be worthwhile.”
Rickert said prospects are good for making a chimeric antibody with the HD3 feature that works in humans. The CDR regions in chimeric antibodies are grafted onto a human base structure, this is done by swapping in human genes that control production of the antibody base.
“The nature of the binding (to antigens) will be very different, it won’t be the same as in mouse or human-based antibodies,” Rickert said. “I think the opportunity to have antibodies with enhanced diversity may be greater.”
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