Development of a mono‐specific anti‐VEGF bivalent nanobody with extended plasma half‐life for treatment of pathologic neovascularization

Needle-free uptake across mucosal barriers is a preferred route for delivery of biologics, but the efficiency of unassisted transmucosal transport is poor. To make administration and therapy efficient and convenient, strategies for the delivery of biologics must enhance both transcellular delivery and plasma half-life. We found that human albumin was transcytosed efficiently across polarized human epithelial cells by a mechanism that depends on the neonatal Fc receptor (FcRn). FcRn also transported immunoglobulin G, but twofold less than albumin. We therefore designed a human albumin variant, E505Q/T527M/K573P (QMP), with improved FcRn binding, resulting in enhanced transcellular transport upon intranasal delivery and extended plasma half-life of albumin in transgenic mice expressing human FcRn. When QMP was fused to recombinant activated coagulation factor VII, the half-life of the fusion molecule increased 3.6-fold compared with the wild-type human albumin fusion, without compromising the therapeutic properties of activated factor VII. Our findings highlight QMP as a suitable carrier of protein-based biologics that may enhance plasma half-life and delivery across mucosal barriers.

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Development and in vivo characterization of a novel peptide drug delivery system providing extended plasma half life

Journal of Controlled Release ◽

10.1016/j.jconrel.2011.09.092 ◽

2012 ◽

Vol 157 (3) ◽

pp. 375-382 ◽

Cited By ~ 17

Author(s):

Gul Shahnaz ◽

Javed Iqbal ◽

Deni Rahmat ◽

Glen Perera ◽

Flavia Laffleur ◽

...

Keyword(s):

Drug Delivery ◽

Drug Delivery System ◽

Delivery System ◽

Half Life ◽

Peptide Drug ◽

Extended Plasma ◽

In Vivo Characterization ◽

Plasma Half Life

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Covalent Complexes Between Low Molecular Weight Heparin Fragments and Antithrombin III – Inhibition Kinetics and Turnover Parameters

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657333 ◽

1983 ◽

Vol 49 (02) ◽

pp. 109-115 ◽

Cited By ~ 4

Author(s):

M Hoylaerts ◽

E Holmer ◽

M de Mol ◽

D Collen

Keyword(s):

Molecular Weight ◽

Half Life ◽

Low Molecular Weight Heparin ◽

Antithrombin Iii ◽

Factor Xa ◽

Life Time ◽

Low Molecular Weight ◽

High Affinity ◽

Plasma Half Life ◽

Covalent Complex

SummaryTwo high affinity heparin fragments (A/r 4,300 and M, 3,200) were covalently coupled to antithrombin III (J. Biol. Chem. 1982; 257: 3401-3408) with an apparent 1:1 stoichiometry and a 30-35% yield.The purified covalent complexes inhibited factor Xa with second order rate constants very similar to those obtained for antithrombin III saturated with these heparin fragments and to that obtained for the covalent complex between antithrombin III and native high affinity heparin.The disappearance rates from plasma in rabbits of both low molecular weight heparin fragments and their complexes could adequately be represented by two-compartment mammillary models. The plasma half-life (t'/j) of both low Afr-heparin fragments was approximately 2.4 hr. Covalent coupling of the fragments to antithrombin III increased this half-life about 3.5 fold (t1/2 ≃ 7.7 hr), approaching that of free antithrombin III (t1/2 ≃ 11 ± 0.4 hr) and resulting in a 30fold longer life time of factor Xa inhibitory activity in plasma as compared to that of free intact heparin (t1/2 ≃ 0.25 ± 0.04 hr).

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