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Aug 14, 2008
 |  BC Innovations  |  Tools & Techniques

Surrogate Antibodies

A study by researchers at The Scripps Research Instituteand Sea Lane Biotechnologies LLC describes the generation of Surrobodies, or antibody-like molecules with high antigen-binding affinities, using phage display and combinatorial methods.1 The authors think the unique structural features of Surrobodies could produce molecules that have greater diversity and more functionality-perhaps including intracellular targeting-than antibodies.

The research, led by Richard Lerner, president and professor of chemistry and immunochemistry at Scripps, and Ramesh Bhatt, VP of research at Sea Lane, was published in the Proceedings of the National Academy of Sciences.

"We've done proof-of-concept to show that we can generate libraries of Surrobodies-and select from the library those with high binding affinity for the antigen-just as you can with classical antibodies," Lerner told SciBX.

Companies contacted by SciBX agreed that the team's approach could have advantages over existing methods of antibody generation, but they said it remains to be seen whether Surrobodies are more effective therapeutics than antibodies.

It's unclear how long it will take for such comparative efficacy data to emerge, as Sea Lane is not disclosing its plans for the Surrobody technology. The company focuses on therapeutic discovery using biologic platforms and technologies.

When a body meets a body

The Lerner-Bhatt team's work followed a 2007 report on the crystal structure of the pre-B cell receptor (pre-BCR) complex, which was solved by researchers at Stanford University School of Medicine.2 Surrobodies are modeled on the pre-BCR complex, which is an antibody precursor with a structure similar to that of an antibody.

Whereas an antibody contains a pair of identical variable light chains, the pre-BCR contains a pair of identical surrogate light chains that differ from antibody light chains in three ways:

First, whereas antibody light chains are composed of single, covalently bound peptide sequences, the surrogates are composed of two distinct peptide segments-VpreB1 (CD179A), which is coded by prelymphocyte gene 1 (VPREB1), and immunoglobulin l-5 polypeptide 1 (CD179B; l5)-which are bound to one another noncovalently.

Second, the peptide sequences of VpreB1 and l5 are invariant.

Third, both peptide segments have tails that extend beyond the noncovalent binding site between them (see "Classical antibody versus Surrobody").

The Lerner-Bhatt team hypothesized that variations could be introduced into the sequences of both VpreB1 and l5, thereby producing pre-BCR-like structures, the Surrobodies, with greater diversity than antibodies.

The team wrote in PNAS that Surrobody libraries could achieve greater size than antibody libraries, and therefore could provide greater diversity, because Surrobodies have three different components that can be varied: the heavy chain and each of the two peptide...

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