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Pfizer Taps FivePrime to Use Cell-Based Screens in Protein Rx Discovery Alliance

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Protein therapeutics discovery and development shop FivePrime and Pfizer this week announced a collaborative research and licensing agreement to discover antibody targets and novel therapeutic proteins to treat certain types of cancer and diabetes.  
 
Pfizer, through its new Biotherapeutics and Bioinnovation Center, is in search of novel targets for drug development, and FivePrime’s role in the alliance is to use in vivo and in vitro cell-based assays to provide Pfizer with targets it can turn into biologic drugs — either antibody targets or protein therapeutics — according to FivePrime CEO Gail Maderis.
 
Pfizer and FivePrime will jointly validate the hits that come out of those screens, she added.
 
Under the terms of the agreement, FivePrime will receive an undisclosed up-front payment and equity investment from Pfizer, in addition to three years of committed research funding, Maderis said.
 
In exchange, Pfizer will gain exclusive worldwide rights to develop and commercialize certain products and targets discovered under the agreement. The companies will share the rights to other compounds, Maderis said, without elaborating.
 
Additional details of the agreement were not disclosed.
 
Maderis said that at the core of the agreement is FivePrime’s protein discovery system. “Essentially, we have collected all of the secreted proteins and all of the extracellular domains of the membrane proteins that could be either protein therapeutics or targets for antibody therapy,” she said.
 
“Cell-based assays are one of our core competencies,” said Maderis, adding that the company focuses on high-content screens, and, whenever possible, uses human primary cells. 
 
FivePrime can run very complex primary screens because, as Maderis explained, “our comprehensive protein library contains about 5,000 proteins, compared to millions of compounds in a pharmaceutical company’s small-molecule library.”
 
FivePrime’s scientists will often look at dozens of readouts, all in the same assay, said Maderis. These readouts include intracellular molecular markers, cytokines or other proteins excreted from cells, and morphological changes in the cells, such as proliferation or survival and clustering.  
 
“We are very focused on the medical utility of a protein,” Maderis said. Oftentimes, FivePrime researchers will do a set of assays and counterassays that, in combination, will identify and profile a drug that they think will be useful in drug discovery.    
 
“By setting up a suite of assays, we are able to set up a very specific system to ask, ‘Is there a protein in the human body that has the desired product attributes?’” said Maderis.
 
That question can sometimes be answered using a single cell type and looking at multiple readouts from that cell type, Maderis said. However, in certain cases, such as diabetes, “we use different cell types and look for overall effect.”
 
It usually takes FivePrime six to nine months to set up an assay, depending on its complexity and the number of assays involved in going after a particular indication, said Maderis. The screening then “takes another three months or so on top of that.”
 
The whole process from start to finish, with confirmed hits identified using the system, “is 12 to 15 months for in vitro” research, said Maderis, adding that the in vivo process is shorter, and that the hit validation process “is very idiosyncratic by molecule.”
 

“Cell-based assays are one of our core competencies.”

Pfizer did not respond to a request for comment before deadline. However, in a statement, Pfizer Biotherapeutics and Bioinnovation Center President Corey Goodman said the company is “very excited about this research collaboration, as it will fill a core need for Pfizer's new biologics enterprise, the Biotherapeutics and Bioinnovation Center. …
 
“The investment and partnership with FivePrime represents a key milestone in our efforts, as we are confident it will generate therapeutic proteins and antibodies that will ultimately lead to innovative medicines for patients worldwide."  
 
Cell-based assays comprise the majority of FivePrime’s business, said Maderis. “It was our primary discovery system for the first part of our history, and now we are using the same protein library and primary in vivo screens.”
 
Maderis said that about two-thirds of FivePrime’s business is on the in vitro side and one third is on the in vivo side.
 
She said the company has collaborations with Boehringer Ingelheim and the Centocor division of Johnson & Johnson in immunology that are “exclusively cell-based assay programs.”
 
In April 2006 the company and Boehringer Ingelheim entered into a two-year research collaboration to discover novel drugs for rheumatoid arthritis and other diseases. Eight months later, FivePrime penned a deal with Centocor to discover novel drugs for osteoarthritis and pulmonary fibrosis. 
 
Prime of Life
 
Founded in 2002 in San Francisco, FivePrime employs 88 people. The firm spent its first three years building its discovery platform, which it started by collecting and building its cDNA library “from which we extracted all of the proteins in our protein screening collection,” said Maderis.
 
The process established a full-length human cDNA library comprising more than 300,000 clones, she said. It is from that library that FivePrime derived its protein screening set.
 
“We have spent a tremendous amount of time working on protein production so that we can now produce proteins at a rate of about 2,000 proteins per week for screening,” said Maderis.
 
These proteins, which are derived from mammalian cells, are in individual wells so “we get proper folding, functional proteins out of the system.”
 
Over the same three years, FivePrime honed its cell-based assay chops, Maderis said. “We started screening in our third year,” she said. “The first hits came out of the library during that time.”
 
FivePrime’s research focuses on cancer, diabetes, immunology, and regenerative medicine because “these are all areas where antibody targets and protein therapeutics have high value,” said Maderis. She added that the company is not looking to expand into other indications.
 
FivePrime is privately held and has raised about $135 million in private equity since it was founded, Maderis said. The company’s current investors include Advanced Technology Ventures, DBL Investors, DNAform, Domain Associates, HealthCap, Johnson and Johnson, Kleiner Perkins Caulfield and Byers, Mitsubishi UFJ Capital, Pfizer, Singapore BioInnovations, TPG Ventures, Versant Ventures, and The Wellcome Trust.
 
FivePrime may be looking to enter into other alliances, though “the Pfizer collaboration is very big for us, and we still have the BI and Centocor collaborations ongoing,” said Maderis. “Our focus over the next several months is getting the Pfizer collaboration started on a strong note, but we may seek collaborations, particularly in the area of immunology.”
 
Cytokine Discovery
 
FivePrime’s platform was described in a May 9 Science paper by Haishan Lin of FivePrime and colleagues. In that paper, the researchers produced recombinant secreted proteins from 3,400 cDNAs that encode secreted proteins and extracellular domains of transmembrane proteins.
 
Each cDNA was individually transfected into 293T cells in high throughput. A parallel set of cDNAs that encode the proteins in tagged form was similarly transfected into 293T.
 
To identify the functional and potential therapeutic applications of the human secreted proteins and their receptors, the investigators chose a wide range of cells that represent different tissue types. Each protein was tested in a suite of assays that measured metabolic, growth, or transcriptional responses in these diverse cell types.
 
The pattern of responses across the suite of assays was analyzed to assess the degree of functional selectivity of each protein. One of the highly selective proteins identified was interleukin-34, a previously undescribed ligand that stimulates monocyte viability, but does not affect responses in a wide spectrum of other assays.
 
In a separate screen, the researchers used a collection of extracellular domains of transmembrane proteins to identify the receptor for IL-34, colony-stimulating factor-1.
 
The investigators used the ACEA RT-CES system to screen cells for factors affecting cell impedence and Promega Cell Titer-Glo assay kits to screen cells for factors affecting their viability. They concluded that their approach is useful for identifying new ligands and receptors, and evaluating the functional selectivity of extracellular regulatory proteins.  

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