Polymorphic Region-Specific Antibody for Evaluation of Affinity-Associated Profile of Chimeric Antigen Receptor

• Main Authors: Chungyong Han, Beom K. Choi, Seon-Hee Kim, Su-Jung Sim, Seongeun Han, Bomi Park, Yohei Tsuchiya, Masaki Takahashi, Young H. Kim, Hyeon-Seok Eom, Tetsuya Kitaguchi, Hiroshi Ueda, Byoung S. Kwon
• Format: Article
• Language: English
• Published: Elsevier 2020-06-01
• Series: Molecular Therapy: Oncolytics
• Subjects: antibody; affinity; HLA-DR; polymorphism; T cell; chimeric antigen receptor
• Online Access: http://www.sciencedirect.com/science/article/pii/S2372770520300541

Antibody applications in cancer immunotherapy involve diverse strategies, some of which redirect T cell-mediated immunity via engineered antibodies. Affinity is a trait that is crucial for these strategies, as optimal affinity reduces unwanted side effects while retaining therapeutic function. Antibody-antigen pairs possessing a broad affinity range are required to define optimal affinity and to investigate the affinity-associated functional profiles of T cell-engaging strategies such as bispecific antibodies and chimeric antigen receptor-engineered T cells. Here, we demonstrate the unique binding characteristic of the developed antibody clone MVR, which exhibits robust binding to B-lymphoid cell lines. Intriguingly, MVR specifically recognizes the highly polymorphic human leukocyte antigen (HLA)-DR complex and exhibits varying affinities that are dependent upon the HLA-DRB1 allele type. Remarkably, MVR binds to the conformational epitope that consists of two hypervariable regions. As an application of MVR, we demonstrate an MVR-engineered chimeric antigen receptor (CAR) that elicits affinity-dependent function in response to a panel of target cell lines that express different HLA-DRB1 alleles. This tool evaluates the effect of affinity on cytotoxic killing, polyfunctionality, and activation-induced cell death of CAR-engineered T cells. Collectively, MVR exhibits huge potential for the evaluation of the affinity-associated profile of T cells that are redirected by engineered antibodies.