Matrix metalloproteinase (MMP) family members are extremely important proteinases able to precisely control a wide variety of physiological and pathological processes. Among them, MMP-12/-24 are promising pharmacological targets as their inhibitors have great potential in being valuable drugs in multiple pathologies. Particularly, MMP-12, mainly produced by macrophages is a potent elastase and inflammatory mediator associated with cardiovascular and destructive lung diseases like arterial stiffness and emphysema. And MMP-24, chiefly expressed in the nervous system and playing critical roles in brain pathophysiology, is a crucial mediator of peripheral thermal nociception and inflammatory hyperalgesia. However, small molecule inhibitors of MMPs in recent efforts have all failed in clinical trials due to lack of specificity. Our hypothesis is that antibody-based inhibitors can render the therapy needed specificity. In this study, we combined three novel technologies - PROSS (protein repair one-stop shop) algorithm for MMP design, convex paratope antibody library construction, and function-based genetic selection. As the results, highly potent monoclonal antibodies inhibitors with high selectivity targeting MMP-12/-24 were successfully discovered. Generated Fabs exhibited nanomolar range binding affinity, inhibition potency, and decent inhibition selectivity over MMP-1/-7/-9/-14. We expect that the combination of these three novel technologies will be able to facilitate the generation of functional mAbs for many additional proteases, most of whom are difficult for active expression in <i>E</i>. <i>coli</i>or have active sites which are not easily accessible by the conventional paratope design.

Generation of functional monoclonal antibodies inhibiting matrix metalloproteinases

2019 Spring National Meeting

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