Location Matters: Site of Conjugation Modulates Stability and Pharmacokinetics of Antibody Drug Conjugates

SummaryAntibody drug conjugates (ADCs) are a therapeutic class offering promise for cancer therapy. The attachment of cytotoxic drugs to antibodies can result in an effective therapy with better safety potential than nontargeted cytotoxics. To understand the role of conjugation site, we developed an enzymatic method for site-specific antibody drug conjugation using microbial transglutaminase. This allowed us to attach diverse compounds at multiple positions and investigate how the site influences stability, toxicity, and efficacy. We show that the conjugation site has significant impact on ADC stability and pharmacokinetics in a species-dependent manner. These differences can be directly attributed to the position of the linkage rather than the chemical instability, as was observed with a maleimide linkage. With this method, it is possible to produce homogeneous ADCs and tune their properties to maximize the therapeutic window.

Graphical AbstractFigure optionsDownload high-quality image (300 K)Download as PowerPoint slideHighlights
► Site-specific conjugation of diverse payloads can be achieved with transglutaminase
► Efficient conjugation was achieved at multiple positions throughout an antibody
► Site of conjugation has significant impact on ADC stability and pharmacokinetics
► Differences in ADC stability and pharmacokinetics are species dependent