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 | 
Jan 10, 2013
 |  BC Innovations  |  Cover Story

mAb about FGF21

Amgen Inc. has developed an antibody that mimics fibroblast growth factor 21 and has antidiabetic effects in monkeys.1 The findings cap a year of advances that have greatly increased understanding of the protein's tissue-specific actions, and work from groups including Eli Lilly and Co. and Roche's Genentech Inc. unit is informing drug development by at least six companies.

Fibroblast growth factor 21 (FGF21) is a secreted metabolic regulator that improves insulin sensitivity, induces weight loss and lowers levels of blood glucose, triglycerides and low-density lipoproteins (LDLs) when injected in mice and monkeys.

Eli Lilly scientists were the first to describe these functions in 2005 for the protein,2 and the results prompted widespread industry interest in the therapeutic potential of targeting the FGF21 pathway to treat type 2 diabetes and obesity.

David Moller, VP of endocrine and cardiovascular research and clinical investigation at Eli Lilly, told SciBX that the potential to simultaneously treat multiple type 2 diabetes symptoms is the driving force behind pharma interest in FGF21.

"One of our major strategic goals is to find a way to treat the underlying disease pathophysiology in a way that can yield multiple beneficial effects. That's what is exciting about the FGF21 pathway-there is nothing else, practically speaking, that has the same effect."

Despite the enticing functions, multiple hurdles have slowed the development of drugs targeting the FGF21 pathway.3 Native FGF21 is not suitable as a drug because of its short half-life. Development of drugs that mimic FGF21 function has been difficult because the precise receptors, cell types and downstream mechanisms responsible for the protein's beneficial effects need to be worked out.

Junichiro Sonoda, a scientist at Genentech, told SciBX that these unanswered questions spurred intense industry and academic study of the pathway. "One thing that really excites people about FGF21 is this novel biology. Nobody knows exactly how FGF21 does all these fantastic things," he said.

A breakthrough in understanding came in 2007, when a team at The University of Texas Southwestern Medical Center identified the transmembrane protein klotho-b (KLB) as a co-receptor required for FGF21 function.4 However, KLB pairs with multiple fibroblast growth factor receptors (FGFRs), and it was unclear which receptor complex was required for FGF21's antidiabetic effects.

Now, Amgen and Genentech have built the case that FGFR 1c isoform (FGFR1c) and KLB is the key complex and have shown antibodies...

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