In-Vitro Generation of T-Cell Clones to Difluorophenylglyoxal: Implications for Understanding the Immunogenicity of MK-3207.

MK-3207 was withdrawn from development because of drug-induced liver injury. Metabolic studies identified bioactivation to a protein-reactive 3,5-difluorophenylglyoxal (DFPG) intermediate. Although phenylglyoxal metabolites readily form protein adducts, their immunogenic potential has been poorly understood. We compared the immunogenicity of three DFPG isomers (3,5-, 2,4-, and 3,4-DFPG) using T-cell clones generated from treated healthy donor PBMCs. Reactive clones were detected against isomers with 3,5-DFPG inducing the strongest responses. Activation required antigen processing, and no cross-reactivity with MK-3207 was observed. These findings demonstrate the immunogenicity of 3,5-DFPG and show that structural differences among phenylglyoxal isomers influence T cell activation.