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Preclinical positivity for Prothena
May 2016
by Kelsey Kaustinen  |  Email the author
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DUBLIN, Ireland—Clinical biotechnology company Prothena Corporation plc recently published preclinical data showing that its conformation-specific antibodies developed against misfolded transthyretin (TTR) bind to and facilitate in-vitro cellular uptake of amyloidogenic forms of TTR. The paper, titled “Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin,” appeared online in the journal Amyloid.
 
Transthyretin-mediated amyloidosis (ATTR amyloidosis) is a rare, progressive disease characterized by the deposit of aggregates of misfolded protein, or amyloid. There are three types of ATTR amyloidosis: familial amyloid polyneuropathy, familial amyloid cardiomyopathy and wild-type (or senile systemic) ATTR. The first two types are hereditary and can occur concurrently, but wild-type ATTR is not hereditary.
 
TTR protein is produced primarily in the liver. In its normal tetrameric form, it serves as a carrier for thyroxin and vitamin A. In hereditary familial amyloid polyneuropathy and familial amyloid cardiomyopathy, the body produces a mutant form of the TTR protein. Wild-type ATTR is similar to hereditary ATTR, except that the deposited protein is a misfolded, non-mutated transthyretin protein.
 
“One of the fundamental challenges of developing an effective treatment for many amyloid diseases, including ATTR amyloidosis, is creating a therapeutic that not only reduces circulating levels of the misfolded protein, but one that can also prevent the formation of new fibrils and facilitate the elimination of fibrils that have deposited in tissue and cause progressive organ failure,” Dr. Gene Kinney, chief scientific officer and head of research and development at Prothena, remarked in a press release. “Our preclinical data demonstrate that these antibodies are highly selective for the misfolded form of TTR, can prevent fibril formation and can potentially recruit immune cells to clear amyloid fibrils from tissue. This could offer an important complement to other therapies for TTR amyloidosis in development.”
 
The work focuses on monoclonal antibodies that specifically bind to misfolded forms of the TTR protein but don’t affect the normal form. The antibodies interrupt the in-vitro formation of TTR fibrils and recognize TTR amyloid deposits in cardiac tissue from ATTR patients. Once bonded to the misfolded proteins, the antibodies’ ability to promote the clearance of misfolded TTR suggests it could have in-vivo potential to prompt the immune system to remove misfolded TTR amyloid deposits from tissue.
 
As described in the paper’s abstract, “Antibody clones were generated by immunizing mice with an antigenic peptide comprising a cryptotope within the TTR sequence and screened for specific binding to non-native TTR conformations, suppression of in-vitro TTR fibrillogenesis, promotion of antibody-dependent phagocytic uptake of mis-folded TTR and specific immunolabeling of ATTR amyloidosis patient-derived tissue.” In all, the researchers characterized four identified monoclonal antibodies.
 
Kinney notes that there are no FDA-approved medical treatments for ATTR, though common unapproved options “include use of the nonsteroidal anti-inflammatory drug Diflunisal, supportive care that addresses organ damage and/or, in some cases, liver transplant. Tafamidis (trade name Vyndaqel) is approved for use in Europe and Japan, but not the United States, for the treatment of TTR amyloidosis with polyneuropathy involvement (known as FAP).”
 
“Antibodies that specifically target the amyloid, such as those described by Prothena, are not yet in clinical development, but could be envisioned to be used to directly target amyloid and clear these accumulated forms of the protein either as a single agent treatment or in combination with therapies designed to reduce new production of the TTR protein. There are no currently approved treatments that target amyloid to clear the accumulated forms of TTR,” he adds.
 
According to the Amyloidosis Foundation, more than 125 different TTR mutations have been identified in ATTR. ATTR and non-TTR are generally considered rare diseases, as current estimates place the disease incidence rate at one in 100,000. Wild-type ATTR almost exclusively affects men, with rough estimates that it is present in some 80 percent of men over 80 years of age, though some experts believe the disease is underdiagnosed, the Amyloidosis Foundation notes. Traditionally, it used to be “reported in those age of 80 and over. As research continues, wild-type ATTR has been increasingly found in individuals in their early 60s. It is often overlooked as an amyloidosis disease because so many people experience heart problems in their later years.”
 
Code: E051613

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