Mannose receptor contributes to preferential oligomannosidic glycoform clearance in a murine pharmacokinetics model

The pharmacokinetic profile of therapeutic antibodies, which affects the dosing frequency, efficacy, and cost of the products, is influenced by several molecular features, including N- glycosylation. While the accelerated clearance of antibodies carrying non-complex type glycans is well established, the mechanism behind this phenomenon is poorly understood. Though there have been indirect indications before, we provide the first direct evidence for the involvement of the mannose receptor in the clearance of therapeutic antibodies. Wild-type (WT) mice showed accelerated clearance of an oligomannose enriched antibody, and this effect was reduced in mannose receptor (MRC1) knockout (KO) mice. Subsequent glycoform-resolved analysis by mass spectrometry showed in WT an accelerated clearance of oligomannosidic compared to complex glycoforms. This accelerated clearance was also observed in MRC1 KO mice, but to a lesser extent. Interestingly, the glycoform distribution of total circulating mouse antibodies, which do not contain oligomannosidic glycoforms, was not affected by MRC1 KO. Hence, we show that the mannose receptor is involved in, but not exclusively responsible for, preferential clearance of oligomannosidic glycoforms of antibodies. This points toward a role for additional, glycan-targeting receptors for therapeutic antibody clearance. In addition, we observed a preferential clearance of complex afucosylated glycoforms, unique to the mouse model, which was MRC1-independent.