Biomedical Engineering Reference
In-Depth Information
32
HIGH-AFFINITY MONOCLONAL T-CELL
RECEPTOR (mTCR) FUSIONS
N
IKOLAI
M. L
ISSIN
,N
AMIR
J. H
ASSAN
,
AND
B
ENT
K. J
AKOBSEN
Immunocore Ltd, Abingdon, UK
32.1 Introduction: the T cell receptor (TCR) as a targeting
molecule
32.2 Engineered high-affinity monoclonal TCRs (mTCR)
32.3 mTCR-based fusion proteins for therapeutic applications
32.4 Immune-mobilizing monoclonal TCRs against cancer
(ImmTAC)
32.5 Conclusions and future perspectives
Acknowledgments
References
the expression of hugely diverse
ab
combinations, each one
unique to a particular T-cell clone. Selection in the thymus,
however, limits the repertoire, such that the estimated number
of naturally occurring T-cell variants is
10
7
per indi-
vidual [1,2]. The T cells that are released into the peripheral
lymphoid system have very low affinities for their relevant
peptide-HLA antigens, this being a necessary feature to avoid
autoimmune reactions. However, the low antigen affinities of
naturally occurring T cells lead to immune escape by cancer
cells, which achieve a selective advantage by presenting
reduced peptide-MHC antigen levels [3]. Moreover, TCRs
specific for cancer antigens are generally of particularly low
affinity because the majority of tumor-associated peptide
antigens (TAPAs) are self-antigens that are either over-repre-
sented or, in some cases, mutated. The close relationship to
self-antigens, which are subject to negative T-cell selection in
the thymus, means that only T cells with very low affinity
TCRs are available to recognize most TAPAs. This stands in
contrast to viral peptide antigens, which are generally
quite distinct from self-peptide antigens and therefore can
attract T cells with higher affinity TCRs. Significantly,
antiviral T-cell responses are far more efficacious than
anticancer ones, and at least some of this difference is
associated with unequal TCR affinities for the two classes
of antigen.
T-cell repertoires are governed (restricted) by each indi-
vidual's particular types of MHC molecules (class I and II,
with their corresponding subclasses) in the context of which
antigenic peptides are presented; a restriction which will
equally apply in the use of TCR-based therapeutics. MHC
class I present 8-11 (typically 9) amino acid residue-long
peptides, which are surveyed by CD8
2.5
32.1 INTRODUCTION: THE T CELL RECEPTOR
(TCR) AS A TARGETING MOLECULE
Monoclonal antibodies, notwithstanding the extremely
broad range of uses for which they can be applied, cannot
be employed to target intracellular proteins (Figure 32.1).
For cancer, in particular, this constitutes a severe limitation
because secreted or cell surface-bound proteins represent
only a fraction, probably 10-15%, of malignant state-asso-
ciated antigens. T-cell receptors (TCRs) are antibody-like
molecules comprising either the alpha/beta (
ab
) or gam-
ma/delta (
gd
) heterodimers, expressed on the surface of
T cells. While the functions of the
gd
receptor are still
debated, the
ab
type of TCR, which is expressed on the
vast majority of T cells, recognizes antigenic peptides derived
from cellular proteins and presented on the cell surface as
peptide-major histocompatibility complex (MHC) complexes
(in humans also called peptide-human leukocyte antigen
[HLA]). Similarly to antibodies, the TCR chains are encoded
in the germ line by an array of rearranging genes, resulting in
cytotoxic T cells.
Longer peptides (typically 15-24 amino acid residues long)
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