From Site-Specific Conjugation to Linker−Payload Presentation: Lessons from AJICAP and Exo-Linker for Antibody−Drug Conjugate Pharmaceutical Design

Abstract The therapeutic activity and pharmacokinetics of antibody−drug conjugates (ADCs) depend on antibody specificity, payload potency, and the attachment and surface presentation of the linker−payload. Linker−payload presentation denotes the spatial arrangement and local chemical environment of the linker−payload on the antibody. Conjugation site, drug-to-antibody ratio (DAR), release chemistry, and manufacturability are therefore interdependent design variables. This perspective examines AJICAP second-generation site-specific conjugation and Exo-Linker chemistry as approaches to controlling linker−payload presentation. AJICAP enables control of the conjugation site on native immunoglobulin G (IgG) antibodies without antibody sequence engineering, whereas Exo-Linker chemistry illustrates how linker−payload reconfiguration can alter hydrophobic exposure and off-target enzymatic processing. The central argument is that the conjugation site and linker−payload presentation should be evaluated together using orthogonal analytical, pharmacokinetic, stability, and manufacturability readouts. We propose matched site-by-linker comparisons to distinguish these contributions and guide the balance between systemic stability, intracellular release, and manufacturability.