Protein used to treat cancer modified to boost potency reduce toxicity

London March 19 ANI Scientists have improved potency and reduced side effects of a naturally occurring protein used to treat cancers

The utility of the protein known as interleukin2 or IL2 given as a drug to treat advanced cancers is limited by the severe side effects it sometimes causes

But a Stanford University School of Medicine scientist has generated a mutant version of the protein whose modified shape renders it substantially more potent than the natural protein while reducing its toxicity

IL2 is a master regulator of the immune system It acts as a growth factor for many different kinds of immune cells including an allimportant class called T cells These cells can both recognize and organize attacks against pathogens or tumors

The protein stimulates T cells proliferation in response to these threats That makes it a potent anticancer drug When injected into a patient it spurs fierce antitumor activity

In a substantial subset about 7 percent of patients with advanced metastatic melanomas or kidney cancers IL2 treatment actually cures the disease said Christopher Garcia professor of molecular and cellular physiology and of structural biology and the studys senior author

Thats an impressive result considering the failure of most treatments at such a late stage of cancer

IL2 is also used offlabel for various other cancers and a wide range of other indications including HIV But its use is restricted because it can cause severe toxic side effects such as difficulty in breathing due to pulmonary edema or swelling of the lung caused by the buildup of fluid in that organ

This in turn is the result of leakage from the copious capillaries that permeate lung tissue the better to carry away oxygenated blood to distant tissues

The cells that cause these toxic effects appear to express different levels and types of IL2 receptors than do the cells that produce the therapeutic effects Garcia said

For this study Garcias group produced a vast variety of mutated versions of the protein and then in a testtube competition compared the strength of these mutant proteins binding to a particular cellsurface receptor a process that is crucial to the Tcell activation needed to treat cancer

The researchers eventually obtained a mutant that Garcia dubbed Super2 which had more than 300 times the receptorbinding strength of natural IL2 In subsequent tests designed to assess Super2s ability to impede tumor growth the new molecule outperformed natural IL2 by a significant margin

The researchers also tested Super2 to determine the extent of the side effects it would cause To do this they collaborated with a coauthor of the study Onur Boyman MD of University Hospital Zurich in Switzerland who had previously found that the type of cells in the lung that are responsible for capillary leakage have receptors for IL2

Boyman developed an assay for IL2s most doselimiting side effect pulmonary edema This assay compares the weight of lungs from mice treated with a test compound versus lungs that are not thusly treated The greater the weight difference the more fluid buildup has occurred

Boyman and a member of his group Carsten Krieg PhD carried out all the animal research used for the study By this assay pulmonary edema caused by Super2 was significantly and substantially less than by natural IL2

What makes Super2 so effective said Garcia is its altered shape A Tcells IL2 receptor complex consists of three separate protein components sitting on the cells surface

But the mutations Garcias team induced lock Super2 into a configuration whose optimized shape lets it bind directly to beta bypassing alpha The threedimensional structure of Super2 together with computer simulations from the laboratory of associate professor of chemistry Vijay Pande PhD suggested this was because the mutant form of IL2 was less floppy than the natural form so that it presented a tighter binding surface to the beta receptor

This soupedup form of the protein was several times as potent as the naturally occurring form of IL2 at slowing tumor growth as measured by assays employing three different tumor types in culture

Major pharmaceutical companies have expressed an interest in Super2 according to Garcia who said he suspects that a licensing agreement from one of them may be in the offing Stanford has applied for a patent on Super2

However he said a group at the National Institutes of Health including some of the heavyweight scientific experts who originally put IL2 through its clinical paces some years ago is now testing Super2 from Garcias lab in a large number of tumor models in the hope of fasttracking its development as a new therapy for additional cancer indications

I hope it goes this route because that would mean human trials would get started more quickly Garcia said

The findings appeared online in Nature ANI

Date : 27 Mar, 2012
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