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Structural Biology 2018
Volume: 4
Biochemistry & Molecular Biology Journal
Page 70
March 15-16 2018
Barcelona, Spain
10th Edition of International Conference on
Structural Biology
T he epidermal growth factor receptor (EGFR) is aberrantly
activatedbyvariousmechanisms like receptoroverexpression,
mutation, ligand-dependent receptor dimerization, ligand-
independent activation and is associated with development of
variety of tumors. Therefore, specific EGFR inhibition is one of
the key targets for cancer therapy. Two major approaches have
been developed and demonstrated benefits in clinical trials for
targeting EGFR; monoclonal antibodies (mAbs) and tyrosine
kinase inhibitors (TKIs). However, total cure of patients with
EGFR-related cancer is still a field of challenge. Although use of
bispecific T-cell engagers (BiTE) have previously been introduced
as interesting therapeutic platforms, patients with EGFR
overexpression/mutation do not still profit from treatment with
such antibodies. This might be because of the large size of BiTE
antibodies, and thereby, their adverse properties. In this project,
for the first time, trispecific Tcell engagers (TriTEs) consisting
of nanobodies 9G8 and anti-CD3 along with HLA-A*0201 fused
to Wilms’ tumor 1 (WT1) peptide epitope were designed for the
treatment of EGFR-related cancers utilizing various computational
approaches. In agreement with this approach, few reports have
also reported for design of trispecific killer engagers (TriKE) in
cancer immunotherapy implying an emerging perspective of
this strategy in cancer treatment. After analysis of HLA-A*0201
structure presenting WT1 peptide, the main residues involved
in interactions with T-cell receptors (TCR) were identified. To
generate HLA-A*0201-WT1 fusion, the WT1 peptide was inserted
in a region of this HLA-type that caused no significant change in
its 3D structures. Subsequently, the nanobodies and engineered
HLA-type were fused using optimal Glycine linkers. By using
optimal linkers, 3D structure of each nanobody and engineered
HLA-A*0201 was preserved. Biological activity of this TriTE
was validated in silico utilizing molecular docking studies and
molecular dynamics simulations carried out by Haddock and
Gromacs tools, respectively. This designed TriTE can be highly
capable of recruiting T-cells to the EGFR-related cancer cells and
subsequently activate their response against cancer cells.
Rational design of a trispecific T-cell engagers (TriTE)
consisting of nanobodies 9G8 and anti-CD3 along with HLA-
A*0201-WT1 fusion for treatment of EGFR-related cancers
Mansour Poorebrahim and Matin Asghari
Tehran University of Medical Sciences, Iran
Biochem Mol biol J, Volume 4
DOI: 10.21767/2471-8084-C1-009