January 15, 2008 (Vol. 28, No. 2)

CBAS and MBAS Approaches Generate Drugs for Collaborations and In-house Pipeline

Antibodies now account for about one-quarter of the biopharmaceutical market and the sector is growing at 30–35% per annum. Meanwhile, there has been a recent wave of mergers and acquisitions of antibody companies by big pharma and biotech firms (e.g., Cambridge Antibody Technology’s and MedImmune’s acquisition by AstraZeneca as well as Tanox’ acquisition by Genentech).

Affitech (http://www.affitech.com) is a well-established biotech company based in Oslo, specializing in the discovery and development of fully human recombinant therapeutic antibodies for cancer and other potential applications,” says Rathin Das, Ph.D., svp, CBO, and president.

Affitech uses a number of technologies for antibody discovery and development with collaborators and for its internal oncology program, including its CBAS™ (cell-based antibody selection) platform. It is unusual in that it generates an unlimited supply of both antibodies and their targets.

Affitech was established in 1997 by a group of Norwegian and German researchers in the field of phage display and antibody engineering. The company was founded on the original, worldwide, exclusive license on the phagemid antibody display system, which had been acquired from the German Cancer Research Center in Heidelberg.

In 2000, Affitech acquired Actigen from Active Biotech, which gave the company rights to Protein L, an affinity purification reagent for antibodies and antibody fragments that has huge potential in this growing market. The company also acquired a license on bacterial protein expression to help with high cell density production of antibodies and other biological molecules.

Affitech has a strong IP position, with freedom to operate in all aspects of phage display technology as well as the capability for global export of human antibody drugs. In 2001, the company set up a wholly owned U.S. subsidiary in the San Francisco Bay Area, which is the focus of its global business development and marketing. “Affitech was one of the few Norwegian companies to establish a U.S. presence early on,” says Dr. Das.

Antibody Platforms

The firm’s antibody technology platforms encompass two approaches: molecule-based antibody screening (MBAS) and CBAS. MBAS involves the conventional phagemid display of human antibody libraries covering IgM, IgD, and IgG repertoires as well as a newer technology called AffiScreeN™, which is a high-throughput screening technology for validated targets.

AffiScreeN allows the direct isolation of human antibodies from libraries made from the samples of patients or vaccines without the need for preselection on the basis of their binding characteristics. It uses automation by robot filter screening, which leads to faster output than conventional antibody screening methods, says Dr. Das.

The combination of the conventional phagemid screening and the AffiScreeN gives an improved selection of new antibodies for known or unknown targets from pure proteins, peptides, cell membranes, or cell lysates, and provides Affitech with a competitive edge in discovering antibodies against various targets, according to the company.

CBAS is an in vitro reverse-screening approach starting with cells and tissues for the discovery of both antibodies and their targets from disease-specific cells, which generates results faster than by more traditional genomic- or proteomic-based systems. In the latter, going from target identification through antibody identification and validation and into clinical development would take, typically, four to five years. The CBAS approach, starting from cells and including target and antibody identification and validation, will take two to three years to reach clinical development, reports Dr. Das.

In CBAS, the use of intact disease cells for antibody and target discovery enables the generation of antibodies having high affinity for targets in their normal membrane-bound configuration. Subtractive screening leads to the identification of cell-type/disease-specific cell-surface antigens. CBAS, therefore, offers obvious advantages at a time when the discovery of novel targets is one of the most difficult aspects of early-stage antibody research.

Affitech has applied CBAS to many human cancer cell types including breast, bladder, pancreatic, colon, lung, and prostate. The resulting antibodies tend to show a high level of antibody-mediated cancer-cell killing activity alone and also when tested as an immunotoxin. They also demonstrate excellent immunohistochemistry data on nanomolar affinity, Dr. Das claims.

Both the MBAS and CBAS systems have significant quality, time, safety, and cost advantages over other antibody discovery technologies, reports Affitech. Currently, the company has used these approaches to generate three antibodies that are in preclinical R&D for cancer and has several more in the pipeline coming from their in-house research as well as various collaborations.

Present and Potential Products

Affitech’s lead collaborative product candidate involves the antibody R84, which selectively blocks vascular endothelial growth factor (VEGF) by binding only to VEGF receptor 2 (VEGFR2), the receptor primarily responsible for tumor angiogenesis. This differs from Avastin and other drugs in development that block VEGF from binding to both VEGFR2 and VEGFR1. Selective blocking of VEGF binding to VEGFR2 may ultimately offer safety or efficacy benefits over nonselective approaches.

“We are delighted with the in vivo results and Peregrine’s decision to evaluate R84 as a candidate for further preclinical studies and potential clinical development,” comments Martin Welschof, Ph.D., Affitech’s CEO. “The studies demonstrated that the selective blocking of VEGF binding to VEGFR2 is as effective as Avastin in preclinical models. R84 is one of several fully human antibodies we have been able to successfully discover for Peregrine and other collaborators using our antibody library and screening technologies.”

Affitech also generates revenues from its Protein L technology. Protein L is an affinity protein that can bind to certain antibodies where the standard Protein A cannot be used. This applies to the upcoming third-generation antibody fragments or domain antibodies, where Protein L will become an essential tool for purification, reports the company. Affitech has developed a production process for Protein L, which is ready for scale-up, and owns all the related IP.

Protein L is currently being produced and sold to the research market, and the company has just signed its first nonexclusive research license. It is now ready to expand into the commercial antibody separation market, with or without a major partner.

Meanwhile, Affitech has also developed new expression vectors that are optimized for the production of antibody fragments and other proteins in high-density fermentation conditions. They are compatible with common E. coli strains, allowing production in defined media with yields of more than 1 g/L of antibody fragments and more than 5 g/L of Protein L.

Collaborative and In-house Efforts

Affitech has a number of strategic collaborations and partnerships with both academic and commercial organizations that have generated short-term revenues. In the future, the company hopes that royalties on marketed products will lead to long-term value generation. In addition to Peregrine, partners and collaborators include Roche, Viventia, NatImmune, Pharmexa, Micromet, and Xoma.

The company has cross-licensing deals with Dyax and XOMA and has in-licensed diabody IP from Pharmexa and scFv IP from Micromet. The recently signed Roche deal is for the discovery and development of fully human mAbs against an undisclosed oncology target. The company also has a long-term partnering and licensing relationship with the Norwegian Radium Hospital that includes an exclusive product in-licensing deal.

The company currently has a strong focus on the development of its internal pipeline, with three candidates in early-stage preclinical research and proof-of-concept studies in Norway, the U.S., and Australia, adds Dr. Welschof.

“While we are working with our partners to move the Affitech-discovered antibodies into the clinic as quickly as possible, in the next five years we would like to build our own product pipeline for out-licensing some candidates after significant animal studies are carried out, while moving others further up into the development process ourselves.”

Susan Aldridge, Ph.D., is a freelance science and medical writer specializing in biotechnology, pharmaceuticals, chemistry, medicine, and health. E-mail: [email protected].

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