CAR-J cells for antibody discovery and lead optimization of TCR-like immunoglobulins

mAbs

Alexander Bujotzek¹  Diana Darowski¹  Vesna Pulko¹  Pablo Umana¹  Wei Xu¹  Christian Klein¹  Lydia J Hanisch²  John Challier²  Stefan Klostermann²  Ekkehard Mössner²  Roland E. Kontermann²  Christian Jost² 

[1] Early Development, Schlieren, Switzerland;;Roche Innovation Center Zurich, Roche Pharma Research &

关键词: Lead identification;    T-cell receptor (TCR);    T-cell bispecific antibodies (TCB);    TCR-like antibodies (TCRL);    chimeric antigen receptor (CAR);    major histocompatibility complex (MHC);   

DOI  :  10.1080/19420862.2020.1840709

来源: DOAJ

【 摘 要 】

T-cell bispecific antibodies (TCBs) are a novel class of engineered immunoglobulins that unite monovalent binding to the T-cell receptor (TCR) CD3e chain and bivalent binding to tumor-associated antigens in order to recruit and activate T-cells for tumor cell killing. In vivo, T-cell activation is usually initiated via the interaction of the TCR with the peptide-HLA complex formed by the human leukocyte antigen (HLA) and peptides derived from intracellular proteins. TCR-like antibodies (TCRLs) that recognize pHLA-epitopes extend the target space of TCBs to peptides derived from intracellular proteins, such as those overexpressed during oncogenesis or created via mutations found in cancer. One challenge during lead identification of TCRL-TCBs is to identify TCRLs that specifically, and ideally exclusively, recognize the desired pHLA, but not unrelated pHLAs. In order to identify TCRLs suitable for TCRL-TCBs, large numbers of TCRLs have to be tested in the TCB format. Here, we propose a novel approach using chimeric antigen receptors (CARs) to facilitate the identification of highly selective TCRLs. In this new so-called TCRL-CAR-J approach, TCRL-candidates are transduced as CARs into Jurkat reporter-cells, and subsequently assessed for their specificity profile. This work demonstrates that the CAR-J reporter-cell assay can be applied to predict the profile of TCRL-TCBs without the need to produce each candidate in the final TCB format. It is therefore useful in streamlining the identification of TCRL-TCBs.

【 授权许可】

Unknown