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Matrix metalloproteinase‐12 (MMP‐12), also known as macrophage elastase, is a potent inflammatory mediator and therefore an important pharmacological target. Clinical trial failures of broad‐spectrum compound MMP inhibitors suggested that specificity is the key for a successful therapy. To provide the required selectivity, monoclonal antibody (mAb)‐based inhibitors are on the rise. However, poor production of active recombinant human MMP‐12 catalytic domain (cdMMP‐12) presented a technical hurdle for its inhibitory mAb development. We hypothesized that this problem could be solved by designing an expression‐optimized cdMMP‐12 mutant without structural disruptions at its reaction cleft and surrounding area, and thus isolated active‐site inhibitory mAbs could maintain their binding and inhibition functions toward wild‐type MMP‐12. We combined three advances in the field—PROSS algorithm for cdMMP‐12 mutant design, convex paratope antibody library construction, and functional selection for inhibitory mAbs. As a result, isolated Fab inhibitors showed nanomolar affinity and potency toward cdMMP‐12 with high selectivity and high proteolytic stability. Particularly, Fab LH11 targeted the reaction cleft of wild‐type cdMMP‐12 with 75 nM bindingK_Dand 23 nM inhibition IC₅₀. We expect that our methods can promote the development of mAbs inhibiting important proteases, many of which are recalcitrant to functional production.