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

Molecular Therapy: Oncolytics

Hyeon-Seok Eom¹  Beom K. Choi²  Bomi Park²  Young H. Kim²  Tetsuya Kitaguchi³  Chungyong Han⁴  Seon-Hee Kim⁴  Seongeun Han⁴  Su-Jung Sim⁴  Masaki Takahashi⁵  Yohei Tsuchiya⁶  Byoung S. Kwon⁷  Hiroshi Ueda⁷ 

[1] Eutilex Institute for Biomedical Research, Eutilex, Seoul, Republic of Korea;Biomedicine Production Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea;Center for Hematologic Malignancy, Hospital, National Cancer Center, Goyang, Republic of Korea;Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea;Graduate School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan;Interdisciplinary Graduate School of Science and Engineering, Tokyo Institute of Technology, Yokohama, Japan;Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan;

关键词: antibody;    affinity;    HLA-DR;    polymorphism;    T cell;    chimeric antigen receptor;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown