Because DARPins are engineered from consensus sequences of naturally occurring human ankyrin repeat proteins, they are designed to exhibit low intrinsic immunogenicity in clinical applications. Their compact, highly stable frameworks lack complex post-translational modifications like non-human glycosylation patterns found in other expression systems, which helps minimize unwanted immune system activation. However, like any foreign therapeutic protein administered repeatedly to humans, some level of anti-drug antibody formation can occasionally occur depending on the specific engineered sequence, dosage regimen, and patient population, making immunogenicity profiling an essential part of preclinical and clinical evaluation.