Unusual cow antibodies suggest new human therapies

Unusual cow antibodies suggest new human therapies

A NEW study led by researchers at The Scripps Research Institute (TSRI) that focused on an extraordinary family of cow antibodies points to new ways to make human medicines.

"These antibodies' structure and their mechanism for creating diversity haven't been seen before in other animals' antibodies," Vaughn V. Smider, assistant professor of cell and molecular biology at TSRI and principal investigator for the study, said.

The study appears as the cover story in the June 6 issue of the journal Cell.

Antibodies are large proteins that have a tail and two identical arms for grabbing specific targets. At the end of each arm is a small set of protein loops called complementarity-determining regions (CDRs), which actually do the grabbing.

By rearranging and mutating the genes that code for CDRs, an animal's immune system can generate a vast and diverse population of antibodies that collectively can bind to nearly any of the body's foreign invaders.

In people and many other mammals, most of an antibody's specificity for a target is governed by the largest region: CDR H3. Researchers have been finding hints that an unusually long version of this domain can sometimes be the key to a successful defense against a dangerous infection.

Waithaka Mwangi, assistant professor in the Texas A&M College of Veterinary Medicine & Biomedical Sciences and an author on the Cell paper, suggests thinking of these long CDRs as a probe on a thin, extended scaffold that can fit into narrow crevices to reach and bind unique hidden pathogen determinants that ordinary antibodies cannot.

Reports on these antibodies recently caught the interest of Smider, whose area of research includes finding new ways to generate therapeutic antibody proteins.

"We started thinking about how we could make these long (CDR H3s) that are so rare in humans, and we knew from the literature that cows make even longer ones all the time," he said.

First author Feng Wang, at the time a postdoctoral research associate at TSRI, led the effort to purify long CDR H3 cow antibodies — which represent about 10% of the cow antibody repertoire — and analyze their corresponding gene sequences.

Co-first author Damien C. Ekiert, at the time a graduate student at TSRI, was able to crystallize the long CDR H3 antibody samples and determine the 3-D atomic structures of two representative antibodies by X-ray crystallography.

The researchers found that the structure of the CDR H3 antibodies in the cow samples turned out to be unique: a long "stalk" element topped by an antigen-binding "knob." Sequencing the DNA that codes for the knob region revealed an unusual abundance of cysteine, a sulfur-containing amino acid that is apt to bond to a nearby cysteine on the same protein chain, thus forming a loop.

Analyses of these DNA sequences also indicated that, in the cow's B cells where these antibodies are made, the knob-coding gene segments are extraordinarily likely to develop point mutations that either add or subtract cysteine molecules.

"This is a very efficient way to evolve new protein folds," Wang said, noting that it seems to be the principal way in which the cow's immune system creates a diverse set of these long CDR H3 antibodies.

The researchers hope to harness the potential power of long CDR H3 antibodies for a wide variety of human — and, perhaps, veterinary — medical applications.

Volume:85 Issue:24

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