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. 2021 May 24;42(1):306–342. doi: 10.1002/med.21818

Table 1.

Pros and contras of different antigen‐binding moieties in a CAR

CAR ectodomain type CAR ectodomain subtype Advantages Disadvantages Clinically tested
scFv CARs
  • •
    Proven clinically effective
  • •
    Clinically validated mAbs available against a variety of TAAs
  • •
    Instability
  • •
    Tonic signaling
  • •
    Risk of antigen loss
  • •
    Trial‐and‐error research
  • •
    Limited availability of parent mAbs and scFv libraries
  • •
    Risk of domain swapping
  • •
    Immunogenic (humanized/human scFvs under investigation)
 Yes
NanoCARs
  • •
    Stable monomers
  • •
    Immune libraries allow candidate screening
  • •
    Compact binding domain
  • •
    Risk of antigen loss
  • •
    Trial‐and‐error research
  • •
    Immunogenic (humanization protocols available/human VH under investigation)
 Yes
Receptor‐ligand CARs
  • •
    Non‐immunogenic
  • •
    Toxicity can be assessed via murine homologs
  • •
    Increased risk of on‐target/off‐tumor toxicity
Receptor‐based CARs
  • •
    Not cancer type‐restricted
  • •
    Multiple tumor‐associated ligands
  • •
    Reduced risk of antigen escape
 Yes
Ligand‐based CARs
  • •
    Variety of possible ligand classes
  • •
    APRIL‐based CAR failed in clinic
 Yes
uCARs
  • •
    Flexible antigen targeting
  • •
    Patient‐adjustable
  • •
    Less concerns about antigen loss
  • •
    Elegant therapy termination
  • •
    Suboptimal cell‐to‐cell distance
  • •
    Individual optimization required
  • •
    Multiple drug administrations required
  • •
    Difficult to combine with clinically approved mAbs
Biotin‐based
  • •
    High specificity
  • •
    Immunogenic
  • •
    Anti‐biotin mAbs potentially present
  • •
    Soluble biotin in patient plasma
 No
SUPRA CAR
  • •
    Tunable Zipper affinity
  • •
    Possibility to spare cells expressing a “safety protein”
  • •
    Low immunogenicity
  • •
    scFv‐based
  • •
    Few data available
 No
Anti‐FITC CAR
  • •
    Positioning of FITC molecule can be designed to optimize signaling
  • •
    Immunogenic
 No
FcγRIII CAR
  • •
    Low immunogenicity
  • •
    Combinations with clinical‐grade mAbs
  • •
    Unspecific due to IgG presence in patients
  • •
    Several trials (temporarily) halted due to safety concerns
 Yes
Peptide‐specific CAR
  • •
    Positioning of peptide can be designed to optimize signaling
  • •
    Immunogenic peptide
 Yes
Convertible CAR
  • •
    Natural receptor‐ligand‐based
  • •
    Low immunogenicity
  • •
    Few data available
 No
SpyTag/SpyCatcher CAR
  • •
    Pre‐arming uCARs possible
  • •
    Few data available
  • •
    Formation of a covalent bond: loss of controllability
  • •
    Immunogenic
 No
SNAP CAR
  • •
    Low immunogenicity
  • •
    Pre‐arming uCARs possible
  • •
    Few data available
  • •
    Formation of a covalent bond: loss of controllability
 No
Co‐LOCKR CAR
  • •
    AND/OR/NOT‐gate combinations possible to improve safety and specificity
  • •
    Few data available
  • •
    Complex
  • •
    Immunogenic
 No
CARs targeting more than 1 antigen
Pooled CARs
  • •
    OR‐gate: anticipates antigen loss
  • •
    Adjustable per patient
  • •
    One population outnumbers the other
  • •
    Multiple genetic modifications required
  • •
    Double antigen loss possible
 Yes
MultiCARs
  • •
    OR‐gate: anticipates antigen loss
  • •
    >1 genetic modification or large transgene = inefficient
  • •
    Double antigen loss possible
 Yes
TandemCARs
  • •
    OR‐gate: anticipates antigen loss
  • •
    Suboptimal binding for different targeting domains
  • •
    Double antigen loss possible
 Yes
SplitCARs
  • •
    AND‐gate: safety mechanism to spare healthy tissue
  • •
    Requires equal receptor triggering
  • •
    > 1 genetic modification or large transgene = inefficient
  • •
    Risk of antigen loss
 No
SynNotch CARs
  • •
    AND‐gate: safety mechanism to spare healthy tissue
  • •
    >1 genetic modification or large transgene = inefficient
  • •
    Risk of antigen loss
 No
Others
  • •
    Few studies
  • •
    Early development
  • •
    Risk of antigen loss
Protein scaffolds
  • •
    Small, stable, monomeric
  • •
    Derived from synthetic libraries
  • •
    Few are well‐characterized in patients
 No
dcCARs
  • •
    No artificial linkers
  • •
    Stability of the targeting domain
  • •
    Complex and large transgene
  • •
    Bulky ectodomain
 No
TRuCs
  • •
    More natural signaling
  • •
    Possibility to include different targeting moieties
  • •
    Complex and large transgene
 No