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Antibody blood-brain barrier efflux is modulated by glycan modification.

ABSTRACT: Drug delivery to the brain is a major roadblock to treatment of Alzheimer's disease. Recent results of the PRIME study indicate that increasing brain penetration of antibody drugs improves Alzheimer's treatment outcomes. New approaches are needed to better accomplish this goal. Based on prior evidence, the hypothesis that glycan modification alters antibody blood-brain barrier permeability was tested here.The blood-brain barrier permeability coefficient Pe of different glycosylated states of anti-amyloid IgG was measured using in vitro models of brain microvascular endothelial cells. Monoclonal antibodies 4G8, with sialic acid, and 6E10, lacking sialic acid, were studied. The amount of sialic acid was determined using quantitative and semi-quantitative surface plasmon resonance methods.Influx of IgG was not saturable and was largely insensitive to IgG species and glycosylation state. By contrast, efflux of 4G8 efflux was significantly lower than both albumin controls and 6E10. Removal of ?2,6-linked sialic acid group present on 12% of 4G8 completely restored efflux to that of 6E10 but increasing the ?2,6-sialylated fraction to 15% resulted in no change. Removal of the Fc glycan from 4G8 partially restored efflux. Alternate sialic acid groups with ?2,3 and ?2,8 linkages, nor on the Fc glycan, were not detected at significant levels on either 4G8 or 6E10.These results support a model in which surface-sialylated 4G8 inhibits its own efflux and that of asialylated 4G8.Glycan modification has the potential to increase antibody drug penetration into the brain through efflux inhibition.

SUBMITTER: Finke JM

PROVIDER: S-EPMC5557653 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Antibody blood-brain barrier efflux is modulated by glycan modification.

Finke John M JM Ayres Kari R KR Brisbin Ryan P RP Hill Hali A HA Wing Emily E EE Banks William A WA

Biochimica et biophysica acta. General subjects 20170615 9

<h4>Background</h4>Drug delivery to the brain is a major roadblock to treatment of Alzheimer's disease. Recent results of the PRIME study indicate that increasing brain penetration of antibody drugs improves Alzheimer's treatment outcomes. New approaches are needed to better accomplish this goal. Based on prior evidence, the hypothesis that glycan modification alters antibody blood-brain barrier permeability was tested here.<h4>Methods</h4>The blood-brain barrier permeability coefficient Pe of d ...[more]

PMID: 28624473

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Project description:Antipsychotic (AP)-induced adverse drug reactions (ADRs) are a current problem of biological and clinical psychiatry. Despite the development of new generations of APs, the problem of AP-induced ADRs has not been solved and continues to be actively studied. One of the important mechanisms for the development of AP-induced ADRs is a genetically-determined impairment of AP efflux across the blood-brain barrier (BBB). We present a narrative review of publications in databases (PubMed, Springer, Scopus, Web of Science E-Library) and online resources: The Human Protein Atlas; GeneCards: The Human Gene Database; US National Library of Medicine; SNPedia; OMIM Online Mendelian Inheritance in Man; The PharmGKB. The role of 15 transport proteins involved in the efflux of drugs and other xenobiotics across cell membranes (P-gp, TAP1, TAP2, MDR3, BSEP, MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8, MRP9, BCRP) was analyzed. The important role of three transporter proteins (P-gp, BCRP, MRP1) in the efflux of APs through the BBB was shown, as well as the association of the functional activity and expression of these transport proteins with low-functional and non-functional single nucleotide variants (SNVs)/polymorphisms of the ABCB1, ABCG2, ABCC1 genes, encoding these transport proteins, respectively, in patients with schizophrenia spectrum disorders (SSDs). The authors propose a new pharmacogenetic panel "Transporter protein (PT)-Antipsychotic (AP) Pharmacogenetic test (PGx)" (PTAP-PGx), which allows the evaluation of the cumulative contribution of the studied genetic biomarkers of the impairment of AP efflux through the BBB. The authors also propose a riskometer for PTAP-PGx and a decision-making algorithm for psychiatrists. Conclusions: Understanding the role of the transportation of impaired APs across the BBB and the use of genetic biomarkers for its disruption may make it possible to reduce the frequency and severity of AP-induced ADRs, since this risk can be partially modified by the personalized selection of APs and their dosing rates, taking into account the genetic predisposition of the patient with SSD.

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Antibody blood-brain barrier efflux is modulated by glycan modification.

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Antibody blood-brain barrier efflux is modulated by glycan modification.

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