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The Journal of Immunology, 2007, 178: 48.28.
Copyright © 2007 by The American Association of Immunologists, Inc.
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48.28

Engineering T cell receptors for potential therapeutic applications

S A Richman1, D H Aggen1, J D Stone1, K S Weber1, M L Dossett2,3, D L Donermeyer4, R A Mariuzza5, P M Allen4, P D Greenberg2,3 and D M Kranz1

1 Biochemistry, U of Illinois at Urbana-Champaign, RAL, Urbana, IL, 61801, 2 Immunology, U of Washington, 1959 NE Pacific St, Seattle, WA, 98109, 3 Fred Hutchinson Cancer Research Center, Fairview Ave N, Seattle, WA, 98109, 4 Pathology and Immunology, Washington U, School of Medicine, St. Louis, MO, 63110, 5 CARB, U of Maryland, Biotechnology Institute, Rockville, MD, 20850

Abstract

Using T cell receptors (TCRs) for potential therapeutic applications provides an opportunity to target an expanded array of antigens, compared to those now targeted with monoclonal antibodies. Relative to antibodies, TCRs typically exhibit reduced solubility and lower affinity, properties that hamper their production and efficacy. To improve these parameters, we have developed strategies using yeast display engineering. Several different TCRs were cloned as single chain (sc) TCRs and V{alpha}C{alpha}/VbetaCbeta heterodimers, as each of these display scaffolds has unique advantages for engineering and potential applications. Display of scTCRs, unlike that of scFv fragments, required mutagenesis and selection. Analysis of a collection of mutants revealed distinct regions of the scTCR that require mutations to allow yeast surface display, as well as solubility of purified protein. Although the sc format has several potential advantages such as increased tissue penetration, mutagenesis and selection of displayed mutants can present a technical challenge. To overcome this obstacle, we have recently explored the role of the C domains in driving heterodimer association. In addition, we have developed mutagenic strategies to improve the association of engineered, full {lambda}{varepsilon}{tau} {gamma}{eta} {alpha} and beta chains.

Supported by grants from NIH.





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