Low Density Lipoprotein Cholesterol Reduction and Safety With Lib003, an Anti-Proprotein Convertase Subtilisin/Kexin Type 9 Fusion Protein: Results of a Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study

Stein, Evan A.; Turner, Traci; Biernat, Lukasz; Dimova, Dessy; Zhou, Rong; Mei, Dai; Daniels, Christopher; Mitchell, Tracy

doi:10.1016/s0735-1097(19)32320-4

Cited by 8 publications

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“…In a similar application, and to further improve efficacy, a serum albumin domain was also fused to the Adnectin-anti-PCSK9 construct to improve circulation half-life to match that of antibodies ( Figure 3E) [79]. This resulted in comparable pharmacokinetics and cholesterol reduction to evolocumab [84], with a phase 2 study presenting similar efficacy with a 70% decrease in cholesterol 8 weeks after treatment, closely mimicking the effects of comparable antibodies [85].…”

Section: Fusion To Extend Half-lifementioning

confidence: 99%

Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain

Chandler

Buckle

2020

Cells

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As a non-antibody scaffold, monobodies based on the fibronectin type III (FN3) domain overcome antibody size and complexity while maintaining analogous binding loops. However, antibodies and their derivatives remain the gold standard for the design of new therapeutics. In response, clinical-stage therapeutic proteins based on the FN3 domain are beginning to use native fibronectin function as a point of differentiation. The small and simple structure of monomeric monobodies confers increased tissue distribution and reduced half-life, whilst the absence of disulphide bonds improves stability in cytosolic environments. Where multi-specificity is challenging with an antibody format that is prone to mis-pairing between chains, multiple FN3 domains in the fibronectin assembly already interact with a large number of molecules. As such, multiple monobodies engineered for interaction with therapeutic targets are being combined in a similar beads-on-a-string assembly which improves both efficacy and pharmacokinetics. Furthermore, full length fibronectin is able to fold into multiple conformations as part of its natural function and a greater understanding of how mechanical forces allow for the transition between states will lead to advanced applications that truly differentiate the FN3 domain as a therapeutic scaffold.

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Section: Fusion To Extend Half-lifementioning

confidence: 99%