eBook: Breakthroughs and Innovations in Immunology Research - 21

CAR molecule design
CAR is a modified fusion protein derived from the
T cell receptor comprising an antigen binding domain
and various intracellular signaling domains.
The CAR molecule is crucial for therapeutic success
as it targets CAR-T cells to attack cancer cells. To be
effective, the CAR molecule must have several essential
features, such as high specificity for the target
antigen to ensure that CAR-T cells only attack
cancer cells and not healthy ones. Additionally, it
should efficiently activate CAR-T cells to ensure a
robust immune response and minimize off-target
effects to limit the risk of unintended damage to
healthy tissues. Thus, extensive research efforts
have focused on optimizing the CAR molecule's efficiency,
specificity, and safety, making CAR-T cell
therapy a more effective and reliable treatment option
for cancer patients.
CARs comprise three major components: an extracellular
domain, a transmembrane domain,
and an intracellular signaling domain. The extracellular
domain includes the signal peptide and
the antigen-recognition domain, composed of a
single-chain fragment variant (scFV). The transmembrane
domain is usually an alpha helix that
spans the cell membrane, essential for maintaining
the receptor's surface expression and stability.
The intracellular domain undergoes conformational
changes upon antigen binding to recruit and
phosphorylate downstream signaling proteins. Although
it can include multiple functional units, the
T cell co-receptor CD3ζ's intracellular domain is the
primary component of most CARs. It includes three
immunoreceptor tyrosine-based activation motifs
(ITAMs), which are crucial for signal transduction
(Figure 2A).
There are five generations of CARs, with different
structures and compositions. The first contained
only a CD3ζ intracellular domain, which resulted in
low cytotoxicity and proliferation. The second generation
added a costimulatory domain to enhance
T cell proliferation and cytotoxicity, and the third
included an additional costimulatory domain. The
fourth generation, known as TRUCKs, included a
protein constitutively or inducibly expressed upon
CAR activation, such as IL-12. The fifth generation,
currently under development, contains a truncated
Figure 2. Structure of different chimeric antigen receptor (CAR) generations. Source: adapted from Tokarew, N, et al. 2019
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https://www.sinobiological.com/resource/antibody-technical/scfv-antibody-production https://www.sinobiological.com/search?keywords=CD3%CE%B6 https://www.sinobiological.com/areas/signal-transduction/itim/itam-immunoreceptors-and-related-molecules https://www.sinobiological.com/category/il-12

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