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We used protein engineering, glycan optimization, and a novel biomanufacturing platform to enhance potency by using a three\u2010prong strategy. First, we added new N\u2010glycans to ENPP1; second, we optimized pH\u2010dependent cellular recycling by protein engineering of the Fc neonatal receptor; finally, we used a two\u2010step process to improve sialylation by first producing ENPP1\u2010Fc in cells stably transfected with human \u03b1\u20102,6\u2010sialyltransferase (ST6) and further enhanced terminal sialylation by supplementing production with 1,3,4\u2010<jats:italic>O<\/jats:italic>\u2010Bu<jats:sub>3<\/jats:sub>ManNAc. These steps sequentially increased the half\u2010life of the parent compound in rodents from 37\u00a0hours to ~\u00a067\u00a0hours with an added N\u2010glycan, to ~\u00a096\u00a0hours with optimized pH\u2010dependent Fc recycling, to ~\u00a0204\u00a0hours when the therapeutic was produced in ST6\u2010overexpressing cells with 1,3,4\u2010<jats:italic>O<\/jats:italic>\u2010Bu<jats:sub>3<\/jats:sub>ManNAc supplementation. The alterations were demonstrated to increase drug potency by maintaining efficacious levels of plasma phosphoanhydride pyrophosphate in ENPP1\u2010deficient mice when the optimized biologic was administered at a 10\u2010fold lower mass dose less frequently than the parent compound\u2014once every 10\u00a0days vs. 3 times a week. 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