Biology Reference
In-Depth Information
We are now applying the method to study the interactions between
TCRs and cancer-related p-MHC systems, like, for instance, the histo-
compatibility leukocyte antigen (HLA)-A2 tumor epitope NY-ESO-1.
NY-ESO-1 is a cancer testis antigen peptide expressed not only in
melanoma, but also in several other types of cancers. It has been observed
at high frequencies in melanoma patients with unusually positive clinical
outcome and, therefore, represents an interesting target for cancer
immunotherapy using adoptive transfer with modified TCRs. As explained
in the previous section, the MM-GBSA approach not only allows decom-
position of the calculated binding free energy between two proteins into
contributions coming from the different residues, but also provides infor-
mation about which energy terms are responsible for a residue's contri-
bution, in terms of van der Waals or electrostatic interactions, for
instance. Therefore, the results of the MM-GBSA approach identify
those TCR residues that are more or less important for the association
process with p-MHC, and those that could be mutated. It also helps
in designing sequence modifications that are expected to increase the
affinity and selectivity of the protein-protein binding.
Sequence mutations of TCRs potentially increasing the affinity for
this epitope have been proposed based on this theoretical approach and
tested experimentally. A large number was found experimentally to
increase the affinity of the TCR for this p-MHC, showing a qualitative
agreement between the theory and experiments, and opening the way to
adoptive transfer immunotherapy. Successfully predicted mutations
include drastic changes like, for instance, mutations from alanine to glu-
tamate, illustrating the efficiency of the approach. In addition, a signifi-
cant quantitative agreement was also found between the binding free
energy change upon mutation calculated using the theoretical approach,
and the change in affinity between TCR and p-MHC measured using an
ELISA experiment for the different mutations, with a correlation of
about 0.80 (see Fig. 7). The predictive ability of our approach shows that
a rational fine-tuning of the TCR sequence can be obtained.
5.2. Drug Design
The heme-containing enzyme indoleamine 2,3-dioxygenase (IDO;
EC 1.13.11.52) has been implicated in the establishment of pathological
