GPNMB and neoplasm: These hurdles align with the aforementioned issues seen in major drug classes: GPNMB is not exclusive to tumor tissues, as its expression in normal tissues raises the risk of severe side effects, echoing the off-target toxicity concerns of ADCs stemming from non-cancer-specific antigen binding; additionally, GPNMB’s ECD segment is shed from tumor cells under the action of ADAM10, and this shed ECD binds to targeted drugs to block their anti-tumor activity, a problem analogous to how resistance mechanisms (like target mutations for small-molecule inhibitors) undermine drug efficacy.