Protease-activation using anti-idiotypic masks enables tumor specificity of a folate receptor 1-T cell bispecific antibody.

摘要: T-cell bispecific antibodies (TCBs) crosslink tumor and T-cells to induce cell killing. While TCBs are very potent, on-target off-tumor toxicity remains a challenge when selecting targets. Here, we describe protease-activated anti-folate receptor 1 TCB (Prot-FOLR1-TCB) equipped with an anti-idiotypic anti-CD3 mask connected the Fab through protease-cleavable linker. The potency of this Prot- FOLR1-TCB is recovered following protease-cleavage linker releasing scFv. In vivo, Prot-FOLR1-TCB mediates antitumor efficacy comparable parental whereas noncleavable control inactive. contrast, killing bronchial epithelial renal cortical cells low FOLR1 expression prevented compared FOLR1-TCB. findings confirmed for mesothelin as alternative antigen. Thus, masking fragment cleavage by tumor-specific proteases can be applied enhance specificity safety TCBs. clinical application T often limited lack tumour-specific antigens. study, authors present strategy increase TCB tumour-selectivity adding moiety that specifically activated specific in microenvironment.