AbbVie Symposium "Development of a Scalable Route for the Drug-Linker of Immunology ADC ABBV-154"

A scalable route has been developed to the bromoacetamide glucocorticoid drug-linker used in conjugation with the monoclonal antibody (mAb) adalimumab to produce antibody-drug conjugate ABBV-154. Optimization and insights will be discussed into the key transformations and isolations including a challenging acetal deprotection, amide coupling between an aniline and dipeptide, phosphate formation via a phosphoramidite displacement and oxidation, Fmoc cleavage with a continuous extraction, bromoacetic acid coupling, and a global acidic deprotection. Notably, the final deprotection of three t-butyl protecting groups proceeds through several intermediates and is complicated by acetal epimerization. This complex reaction was initially optimized in a batch setup, but scaling issues prompted the development of a flow process with an impinging jet mixing element.