Biomedical Engineering Reference
In-Depth Information
been engineered to exhibit picomolar levels without com-
promising specificity. These high-affinity mTCRs have
been fused to a range of effector function polypeptides
including protein toxins, cytokines, or single chain anti-
bodies (scFv) to enable highly selective targeted killing of
malignant cells.
Furthermore, TCRs can be developed against peptides
derived from almost any intracellular antigen. Therefore,
this strategy could open up a new therapeutic platform, address-
ing, by a very wide margin, the largest class of specific targets
that the biology of cancer cells can afford. Cancer vaccines
have attempted to use this class of targets but are limited by
activating only naturally selected T cells that have low or, in
many cases, no sensitivity against the low copy number of
antigens presented on cancer cells. Therefore, ImmTACs, by
means of their exquisite antigen sensitivity and high potency,
may offer the first opportunity to address the huge spectrum of
cancer relevant targets presented as peptide-MHC complexes.
A gp100-targeting ImmTAC, IMCgp100, has entered
Phase I clinical trials in October 2010 for metastatic mela-
noma in both the United States and the United Kingdom.
More cancer-specific ImmTACs are being developed. Addi-
tionally, mTCRs are being assessed for therapeutic appli-
cations against viral diseases and autoimmune diseases, such
as type I diabetes. Experimentation has shown that the
mTCR platform can be used to generate fusion constructs
with a wide spectrum of effector moieties so that specific
requirements can be addressed in different cancers, viral,
and autoimmune diseases.
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ACKNOWLEDGMENTS
We thank Karen Pulford for help and suggestions in prepar-
ing figures and chapter and our colleagues at Immunocore
for help and comments.
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