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Genetically Engineering Longer-Lasting Antibodies Could Lead To Better Therapeutic Drugs

Date:
July 28, 1997
Source:
UT Southwestern Medical Center At Dallas
Summary:
Delivering drugs to fetuses and fighting such diseases as cancer and autoimmunity may be greatly enhanced by altering a common antibody so that it stays in the blood stream longer, according to researchers at UT Southwestern Medical Center at Dallas.

DALLAS -- July 25, 1997 -- Delivering drugs to fetuses andfighting such diseases as cancer and autoimmunity may be greatlyenhanced by altering a common antibody so that it stays in theblood stream longer, according to researchers at UT SouthwesternMedical Center at Dallas.

By taking a portion of the natural antibody IgG and usingprotein engineering techniques, the scientists found they couldisolate fragments that bound with higher affinity or force to the Fcreceptor, FcRn. This receptor is involved in regulating the levelof gamma globulin, the part of the blood containing mostantibodies, in many mammals. In rodents and humans, it also isbelieved to be part of the pathway that transfers antibodies acrossthe placenta from mother to child. The research, published in arecent issue of Nature Biotechnology, showed that manipulatingthe antibody extended its half-life in the circulation of mice.

"We thought if we could increase the binding affinity of anIgG fragment for FcRn, then it would have a longer serumhalf-life than the endogenous (naturally occurring) IgGs," said Dr.E. Sally Ward, associate professor of microbiology and CancerImmunobiology Center researcher. "We mutated antibodyfragments called Fc fragments and selected ones that bound betterto FcRn."

Antibodies are Y-shaped proteins with IgG being the mostcommon type. The long arm of IgG is the Fc fragment, which isthe non-antigen binding portion of the molecule and carries outtasks called effector functions.

Because a very similar Fc receptor is found in humans,Ward said their research could be applicable to people. Since thealtered antibodies are more persistent in the blood, smalleramounts of therapeutic antibodies made with this technologywould be needed. Therefore, the necessity for repeated doseswould be reduced. This approach also could be used to isolatesmaller molecules that have high affinity for bonding to FcRn.These molecules could then be used to tag drugs.

"If the drugs have a longer serum persistence, then it willbe cheaper and more economically attractive for patients," Wardsaid. "We also believe this tighter binding of the IgG fragment toFcRn will transfer antibody across the placenta moreefficiently."

This means it may be possible to deliver therapeuticantibodies or drugs to fetuses in cases where the mothers have adisease such as AIDS, she said.

The UT Southwestern investigators found that the mutantantibody fragment had a binding affinity for FcRn that is 3.5 timeshigher than the unaltered Fc fragment from which it was derived.In one strain of laboratory mouse, the amount of mutated antibodystill effectively circulating in the blood 20 days after injection ofIgG was four times greater than with the parent antibody. It wastwice as much in another strain.

Other researchers involved in this study were Dr. VictorGhetie, associate professor of microbiology; Dr. Sergei Popov,assistant instructor of pharmacology; research fellows, JozefBorvak and Dr. Corneliu Medesan; former UT Southwesternresearch fellows Caius Radu and Diana Matesoi; and Dr.Raimund Ober, a collaborator from The University of Texas atDallas.

The study was funded by grants from the National Institutesof Health, the Welch Foundation and the Texas AdvancedResearch Program.

###

This news release is available on our World Wide Web homepage at http://www.swmed.edu/news/newspubs.htm/


Story Source:

The above story is based on materials provided by UT Southwestern Medical Center At Dallas. Note: Materials may be edited for content and length.


Cite This Page:

UT Southwestern Medical Center At Dallas. "Genetically Engineering Longer-Lasting Antibodies Could Lead To Better Therapeutic Drugs." ScienceDaily. ScienceDaily, 28 July 1997. <www.sciencedaily.com/releases/1997/07/970728215147.htm>.
UT Southwestern Medical Center At Dallas. (1997, July 28). Genetically Engineering Longer-Lasting Antibodies Could Lead To Better Therapeutic Drugs. ScienceDaily. Retrieved September 16, 2014 from www.sciencedaily.com/releases/1997/07/970728215147.htm
UT Southwestern Medical Center At Dallas. "Genetically Engineering Longer-Lasting Antibodies Could Lead To Better Therapeutic Drugs." ScienceDaily. www.sciencedaily.com/releases/1997/07/970728215147.htm (accessed September 16, 2014).

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