Tuning the potency and selectivity of ImmTAC molecules by affinity modulation

Clin Exp Immunol. 2023 Nov 1:uxad120. doi: 10.1093/cei/uxad120. Online ahead of print.ABSTRACTT cell engaging bispecifics have great clinical potential for the treatment of cancer and infectious diseases. The binding affinity and kinetics of a bispecific molecule for both target and T cell CD3 have substantial effects on potency and specificity, but the rules governing these relationships are not fully understood. Using ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules as a model, we explored the impact of altering affinity for target and CD3 on the potency and specificity of the re-directed T cell response. This class of bispecifics, exemplified by tebentafusp which has recently shown survival benefit in a randomized phase 3 clinical trial1, bind specific target peptides presented by human leukocyte antigen (HLA) on the cell surface via an affinity-enhanced T cell receptor and can redirect T cell activation with an anti-CD3 effector moiety. The data reveal that combining a strong affinity TCR with an intermediate affinity anti-CD3 results in optimal T cell activation, while strong affinity of both targeting and effector domains significantly reduces maximum cytokine release. Moreover, by optimising the affinity of both parts of the molecule, it is possible to improve the selectivity. These results could be effectively modelled based on kinetic proof-reading with limited signalling. This model explained the experimental observation that strong binding at bot...
Source: Clinical and Developmental Immunology - Category: Allergy & Immunology Authors: Source Type: research