Scientists engineer human T cell receptors against cancer antigens

Schematic representation of the design approach developed by Smith and Kranz that allows a human T cell receptor to be changed from one specificity (Target A) to another specificity (Target B), using a method called directed evolution.

Graduate student Sheena Smith and Professor David Kranz of the Department of Biochemistry have developed an approach to discover T cell receptors that could be therapeutically useful against different cancers. In collaboration with graduate students Yuhang Wang and Javier Baylor and Professor Emad Tajkhorshid, molecular dynamics simulations revealed plausible mechanisms for the “switch” in specificities.

T cell receptors are found on the surface of T cells, where they bind to antigens such as those on cancer cells. After activation by the binding of the receptor, the T cell destroys the cancer cell. One of the problems associated with cancer is that a patient’s own T cells may not have the proper T cell receptors that can bind to such antigens. Over the past 15 years, the Kranz group has developed various strategies to attempt to engineer receptors that can serve these purposes, by taking a single receptor from a known T cell clone and improving its affinity for an antigen. In the present study, published in the journal Nature Communications , the scientists showed that it was possible to take a T cell receptor against one antigen (Figure) and using entirely in vitro, directed evolution techniques, to convert this receptor to a completely different specificity. The strategy could thus allow the development of specific receptors, at will, against a large array of known cancer antigens.

The approach involved computational analyses to guide the design of “libraries” that contain millions of mutated T cell receptors. The mutants are each displayed on the surface of a yeast cell, and then high-speed instruments called fluorescence activated cell sorters could be used to select only those yeast cells displaying a T cell receptor that binds to the antigen of interest. In the present study, the antigen of interest was derived from human melanoma (Target B in Figure), and the original T cell receptor had been derived from a T cell clone that recognized a viral antigen (Target A in Figure). Various mutational approaches, and molecular dynamics simulations by the Tajkhorshid group, provided insight into how the specific mutations found in the selected T cell receptors allowed binding only to the melanoma antigen.

A major implication of the study is that the design approach could be extended to other target antigens providing a platform to rapidly discover T cell receptors against many antigens. Current methods have required that each engineered T cell receptor be generated from human T cell clone, which can take years to produce. Engineered T cell receptors have already reached clinical trials in various therapeutic formats. The present approach provides an additional discovery strategy for their use in the treatment and detection of cancer, viral diseases, and autoimmune diseases, depending on the target antigen chosen for the specific T cell receptor.

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November 07, 2014.