Drug targeting can be achieved by coupling drugs or their carriers to affinity molecules, mostly antibodies (Abs), which recognise specific protein targets. However, most proteins are not expressed in an exclusive configuration but as various isoforms. Hence, selected targeting molecules may fail to target with enough efficiency in clinical trials, which is overlooked. We illustrate this by targeting intercellular adhesion molecule 1 (ICAM-1), a cell-surface protein overexpressed in many pathologies. Most ICAM-1 targeting studies used Ab R6.5, which binds ICAM-1 domain 2 (D2). Yet, literature and our data show that D2 is frequently absent among ICAM-1 isoforms. We thus produced a battery of five new Abs (B4, B6, B11, C12 and G2) and tested their ability to recognise both full-length and -D2 ICAM-1. In solution, all Abs recognised both ICAM-1 forms (from 5.3 × 10