LDL Cholesterol Reduction With BMS-962476, an Adnectin Inhibitor of Pcsk9: Results of a Single Ascending Dose Study

Stein, Evan A.; Kasichayanula, Sreeneeranj; Turner, Traci; Kranz, Therese; Arumugam, Uma; Biernat, Lukasz; Lee, John

doi:10.1016/s0735-1097(14)61372-3

Cited by 41 publications

(24 citation statements)

References 6 publications

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“…While the highly stable adnectin polypeptide scaffold allows incorporation of various PK enhancement modalities, the first-generation PCSK9 adnectin, BMS-962476, employed polyethylene glycol [29]. In a proof-ofconcept ascending single-dose study, the 0.3 mg/kg dose in statin-treated patients resulted in a LDL-C reduction of 48 % from baseline [30].…”

Section: Non-monoclonal Antibody Inhibitors Of Pcsk9mentioning

confidence: 99%

Lipid-Lowering Drug Therapy for CVD Prevention: Looking into the Future

Stein

Raal

2015

Curr Cardiol Rep

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Over the past three decades, statins have become first-line treatment for reducing LDL cholesterol (LDL-C) and cardiovascular disease (CVD). They have provided a clear, robust, and reproducible relationship between the absolute LDL-C reduction and the decrease in CVD; every 1 mmol/L (~40 mg/dL) in LDL-C reduction results in a 22 % decrease in CVD events. This relationship has recently been extended to reduction in LDL-C with a non-statin, ezetimibe, on top of statin therapy, further consolidating LDL-C as the cornerstone in CVD risk reduction. Despite these two effective and safe LDL-C-lowering drugs, there remains a need for additional drugs to reduce LDL-C, the focus of this review which covers agents which produce sufficient LDL-C reduction to potentially help address this unmet need and are either recently approved or currently in clinical trials.

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Section: Non-monoclonal Antibody Inhibitors Of Pcsk9mentioning

confidence: 99%

Lipid-Lowering Drug Therapy for CVD Prevention: Looking into the Future

Stein

Raal

2015

Curr Cardiol Rep

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“…Conjugation of PEG to an Adnectin monobody that inhibited PCSK9 activity resulted in a molecule that showed a marked cholesterol decrease in pre-clinical models while extending circulation time [81]. Unfortunately in humans this construct reduced LDL-C by only 47% at the highest intravenous dose, or by 48% as a subcutaneous dose in combination with statins [82], in stark contrast to the efficacy of approved antibodies such as Evolocumab which reduce cholesterol by 60% or more with similar doses [79]. Alongside this work, an affibody non-antibody domain which targeted PCSK9 was fused with serum albumin for longer half-life [79,83].…”

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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“…Conjugation of PEG to an Adnectin monobody that inhibited PCSK9 activity resulted in a molecule that showed a marked cholesterol decrease in pre-clinical models while extending circulation time [80]. Unfortunately this construct reduced LDL-C by only 47% at the highest intravenous dose, or by 48% as a subcutaneous dose in combination with statins [81], in stark contrast to the efficacy of approved antibodies such as Evolocumab which reduce cholesterol by 60% or more with similar doses [78]. Alongside this work, an affibody non-antibody domain which targeted PCSK9 was fused with serum albumin for longer half-life [78,82].…”

Section: Fusion To Extend Half-lifementioning

confidence: 99%

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

Chandler

Buckle

2020

Preprint

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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 design of new therapeutics. In response, clinical 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 of chains, 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.

show abstract

LDL Cholesterol Reduction With BMS-962476, an Adnectin Inhibitor of Pcsk9: Results of a Single Ascending Dose Study

Cited by 41 publications

References 6 publications

Lipid-Lowering Drug Therapy for CVD Prevention: Looking into the Future

Lipid-Lowering Drug Therapy for CVD Prevention: Looking into the Future

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

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

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