UniCAR T-Cell Potency-A Matter of Affinity between Adaptor Molecules and Adaptor CAR T-Cells?

被引：0

作者：

Boutier, Hugo ^{[1
]}

Loureiro, Liliana R. ^{[1
]}

Hoffmann, Lydia ^{[1
]}

Arndt, Claudia ^{[1
,2
]}

Bartsch, Tabea ^{[1
]}

Feldmann, Anja ^{[1
,3
,4
,5
,6
,7
]}

Bachmann, Michael P. ^{[1
,3
,4
,5
,6
,7
]}

机构：

[1] Helmholtz Zentrum Dresden Rossendorf HZDR, Inst Radiopharmaceut Canc Res, Dept Radioimmunol, D-01328 Dresden, Germany

[2] Tech Univ Dresden, Fac Med Carl Gustav Carus, Mildred Scheel Early Career Ctr, D-01307 Dresden, Germany

[3] Natl Ctr Tumor Dis Dresden NCT UCC, German Canc Res Ctr DKFZ, D-69120 Heidelberg, Germany

[4] Tech Univ Dresden, Fac Med, D-01307 Dresden, Germany

[5] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, D-01307 Dresden, Germany

[6] German Canc Consortium DKTK, Partner Site Dresden, D-69120 Heidelberg, Germany

[7] German Canc Res Ctr, D-69120 Heidelberg, Germany

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2024年 / 25卷 / 13期

关键词：

adaptor CAR platform; UniCAR T-cells; cancer immunotherapy; Fibroblast Activation Protein (FAP); AUTOANTIGEN; LA; IDENTIFICATION; SPECIFICITY; RECEPTORS; UNIVERSAL; LA/SSB;

D O I：

10.3390/ijms25137242

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Although Chimeric Antigen Receptor (CAR) T-cells have shown high efficacy in hematologic malignancies, they can cause severe to life-threatening side effects. To address these safety concerns, we have developed adaptor CAR platforms, like the UniCAR system. The redirection of UniCAR T-cells to target cells relies on a Target Module (TM), containing the E5B9 epitope and a tumor-specific binding moiety. Appropriate UniCAR-T activation thus involves two interactions: between the TM and the CAR T-cell, and the TM and the target cell. Here, we investigate if and how alterations of the amino acid sequence of the E5B9 UniCAR epitope impact the interaction between TMs and the UniCAR. We identify the new epitope E5B9L, for which the monoclonal antibody 5B9 has the greatest affinity. We then integrate the E5B9L peptide in previously established TMs directed to Fibroblast Activation Protein (FAP) and assess if such changes in the UniCAR epitope of the TMs affect UniCAR T-cell potency. Binding properties of the newly generated anti-FAP-E5B9L TMs to UniCAR and their ability to redirect UniCAR T-cells were compared side-by-side with the ones of anti-FAP-E5B9 TMs. Despite a substantial variation in the affinity of the different TMs to the UniCAR, no significant differences were observed in the cytotoxic and cytokine-release profiles of the redirected T-cells. Overall, our work indicates that increasing affinity of the UniCAR to the TM does not play a crucial role in such adaptor CAR system, as it does not significantly impact the potency of the UniCAR T-cells.

引用

页数：16