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Driving CARs with alternative navigation tools - the potential of engineered binding scaffolds.

ABSTRACT: T cells that are genetically engineered to express chimeric antigen receptors (CAR T cells) have shown impressive clinical efficacy against B-cell malignancies. In contrast to these highly potent CD19-targeting CAR T cells, many of those directed against other tumor entities and antigens currently suffer from several limitations. For example, it has been demonstrated that many scFvs used as antigen-binding domains in CARs show some degree of oligomerization, which leads to tonic signaling, T cell exhaustion, and poor performance in vivo. Therefore, in many cases alternatives to scFvs would be beneficial. Fortunately, due to the development of powerful protein engineering technologies, also non-immunoglobulin-based scaffolds can be engineered to specifically recognize antigens, thus eliminating the historical dependence on antibody-based binding domains. Here, we discuss the advantages and disadvantages of such engineered binding scaffolds, in particular with respect to their application in CARs. We review recent studies, collectively showing that there is no functional or biochemical aspect that necessitates the use of scFvs in CARs. Instead, antigen recognition can also be mediated efficiently by engineered binding scaffolds, as well as natural ligands or receptors fused to the CAR backbone. Finally, we critically discuss the risk of immunogenicity and show that the extent of nonhuman amino acid stretches in engineered scaffolds-even in those based on nonhuman proteins-is more similar to humanized scFvs than might be anticipated. Together, we expect that engineered binding scaffolds and natural ligands and receptors will be increasingly used for the design of CAR T cells.

SUBMITTER: Zajc CU

PROVIDER: S-EPMC8048499 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Passenger cars are an important source of air pollution, especially in urban areas. Recently, real-driving emissions (RDE) test procedures have been introduced in the EU aiming to evaluate nitrogen oxides (NOx) and particulate number (PN) emissions from passenger cars during on-road operation. Although RDE accounts for a large variety of real-world driving, it excludes certain driving situations by setting boundary conditions (e.g., in relation to altitude, temperature or dynamic driving). The present work investigates the on-road emissions of NOx, NO2, CO, particle number (PN) and CO2 from a fleet of 19 Euro 6b, 6c and 6d-TEMP vehicles, including diesel, gasoline (GDI and PFI) and compressed natural gas (CNG) vehicles. The vehicles were tested under different on-road driving conditions outside boundaries. These included 'baseline' tests, but also testing conditions beyond the RDE boundary conditions to investigate the performance of the emissions control devices in demanding situations. Consistently low average emission rates of PN and CO were measured from all diesel vehicles tested under most conditions. Moreover, the tested Euro 6d-TEMP and Euro 6c diesel vehicles met the NOx emission limits applicable to Euro 6d-TEMP diesel vehicles during RDE tests (168 mg/km). The Euro 6b GDI vehicle equipped with a gasoline particulate filter (GPF) presented PN emissions < 6 × 1011 #/km. These results, in contrast with previous on-road measurements from earlier Euro 6 vehicles, indicate more efficient emission control technologies are currently being used in diesel and gasoline vehicles. At the same time, the results suggest that particular attention should be given to CO and PN emissions of certain types of vehicles when driven under dynamic conditions, and possibly additional work is necessary. In particular, the emissions of CO (measured in this study during the regulated RDE test, but without an emission limit associated to it) or PN from PFI vehicles (presently not covered by the Euro 6 standard) showed elevated results in some occasions. Emissions of CO were up to 7.5 times higher when the more dynamic tests were conducted and the highest PN emissions were measured from a PFI gasoline vehicle during dynamic driving. Although based on a limited sample of cars, our work points to the relevance of a technology- and fuel-neutral approach to vehicle emission standards, whereby all vehicles must comply with the same emission limits for all pollutants.

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Driving CARs with alternative navigation tools - the potential of engineered binding scaffolds.

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