Abstract
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.
Highlights
Monoclonal antibodies are useful agents for various applications
The study investigated the consequence of MVR chimeric antigen receptor (CAR) transduction in the human leukocyte antigen (HLA)-DR-expressing T cells
Without any knowledge on the binding epitope, we found that weak affinity CAR-T was desensitized through an “autotuning” process and could sense the antigen levels on the target cell surface
Summary
Antibodies generally bind to target antigens with high affinity (KD in the nM range) to elicit target-specific activities. In the case of T cellengaging strategies, this high affinity is often accompanied by serious on-target off-tumor side effects, since these strategies redirect cytotoxic T cells that mediate massive immune responses.[4,5,6] Recent studies have suggested that on-target off-tumor side effects can be reduced by adjusting the affinity of bispecific antibodies and CARs.[7,8,9,10] an optimal affinity range, in which the T cells mediate maximal therapeutic effects while minimizing side effects, has not been fully investigated because of the lack of antibody-antigen pairs with a broad affinity range
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