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2017 ; 8
(ä): 1001
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Therapeutic Antibodies against Intracellular Tumor Antigens
#MMPMID28868054
Trenevska I
; Li D
; Banham AH
Front Immunol
2017[]; 8
(ä): 1001
PMID28868054
show ga
Monoclonal antibodies are among the most clinically effective drugs used to treat
cancer. However, their target repertoire is limited as there are relatively few
tumor-specific or tumor-associated cell surface or soluble antigens.
Intracellular molecules represent nearly half of the human proteome and provide
an untapped reservoir of potential therapeutic targets. Antibodies have been
developed to target externalized antigens, have also been engineered to enter
into cells or may be expressed intracellularly with the aim of binding
intracellular antigens. Furthermore, intracellular proteins can be degraded by
the proteasome into short, commonly 8-10 amino acid long, peptides that are
presented on the cell surface in the context of major histocompatibility complex
class I (MHC-I) molecules. These tumor-associated peptide-MHC-I complexes can
then be targeted by antibodies known as T-cell receptor mimic (TCRm) or T-cell
receptor (TCR)-like antibodies, which recognize epitopes comprising both the
peptide and the MHC-I molecule, similar to the recognition of such complexes by
the TCR on T cells. Advances in the production of TCRm antibodies have enabled
the generation of multiple TCRm antibodies, which have been tested in vitro and
in vivo, expanding our understanding of their mechanisms of action and the
importance of target epitope selection and expression. This review will summarize
multiple approaches to targeting intracellular antigens with therapeutic
antibodies, in particular describing the production and characterization of TCRm
antibodies, the factors influencing their target identification, their advantages
and disadvantages in the context of TCR therapies, and the potential to advance
TCRm-based therapies into the clinic.
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