An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes

Zhang, Liwen; McCabe, Timothy J.; Condra, Jon H.; Yan, Ni; Peterson, Laurence B.; Wang, Weirong; Strack, Alison M.; Wang, Fubao; Pandit, Shilpa; Hammond, Holly A.; Wood, Dana D.; Lewis, Dale; Rosa, Ray; Mendoza, Vivienne; Cumiskey, Anne Marie; Johns, Douglas G.; Hansen, Barbara C.; Shen, Xun; Geoghagen, Neil S.; Jensen, Kristian K.; Zhu, Lei; Wietecha, Karol; Wisniewski, Douglas; Huang, Lingyi; Zhao, Jing; Ernst, Robin; Hampton, Richard; Haytko, Peter; Ansbro, Frances; Chilewski, Shannon D; Chin, Jayne; Mitnaul, Lyndon J.; Pellacani, Andrea; Sparrow, Carl P.; An, Zhiqiang; Strohl, William R.; Hubbard, Brian K.; Plump, Andrew S.; Blom, Daniël; Sitlani, Ayesha

doi:10.7150/ijbs.3524

Cited by 94 publications

(87 citation statements)

References 46 publications

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“…Moreover, treatment with the 1B20 antiPCSK9 monoclonal antibody in mice and rhesus monkeys led to robust LDL-cholesterol lowering in plasma decreased liver PCSK9 and LDL mRNAs, and transient increases in total plasma levels of PCSK9 [61].…”

Section: In the Proprotein Convertase Subtilisin Kexine Type 9 Genementioning

confidence: 98%

“…A recent study showed that antibody 1B20, which binds to PCSK9 with high affinity, disrupts the PCSK9-LDL receptor interaction, and inhibits the effect of PCSK9 on cellular LDL uptake [61]. Moreover, treatment with the 1B20 antiPCSK9 monoclonal antibody in mice and rhesus monkeys led to robust LDL-cholesterol lowering in plasma decreased liver PCSK9 and LDL mRNAs, and transient increases in total plasma levels of PCSK9 [61].…”

Section: In the Proprotein Convertase Subtilisin Kexine Type 9 Genementioning

confidence: 99%

See 1 more Smart Citation

Autosomal Dominant Hypercholesterolemia: Needs for Early Diagnosis and Cascade Screening in the Tunisian Population

Jelassi¹,

Najah²,

Slimani³

et al. 2013

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Abstract:Autosomal dominant hypercholesterolemia (ADH) is characterized by an isolated elevation of plasmatic lowdensity lipoprotein (LDL), which predisposes to premature coronary artery disease (CAD) and early death. ADH is largely due to mutations in the low-density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), or the proprotein convertase subtilisin/kexin type 9 (PCSK9). Early diagnosis and initiation of treatment can modify the disease progression and its outcomes. Therefore, cascade screening protocol with a combination of plasmatic lipid measurements and DNA testing is used to identify relatives of index cases with a clinical diagnosis of ADH. In Tunisia, an attenuated phenotypic expression of ADH was previously reported, indicating that the establishment of a special screening protocol is necessary for this population.

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Section: In the Proprotein Convertase Subtilisin Kexine Type 9 Genementioning

confidence: 98%

Section: In the Proprotein Convertase Subtilisin Kexine Type 9 Genementioning

confidence: 99%

Autosomal Dominant Hypercholesterolemia: Needs for Early Diagnosis and Cascade Screening in the Tunisian Population

Jelassi¹,

Najah²,

Slimani³

et al. 2013

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“…The LLOQ was selected close to the concentration of endogenous sPD-1 levels in normal human sera (~100 pg/mL). This assay was designed and proven to measure sPD-1 in the presence of nivolumab (see last section of Results), the levels of total sPD-1 post drug treatment may increase significantly since the clearance of analyte-antibody complex were expected to be slower based on our experience with other circulating proteins (18). Therefore, the ULOQ was selected at 10,000 pg/mL so that the calibration curve covers a wide range of concentrations.…”

Section: Standard Curve and Assay Rangementioning

confidence: 99%

Development and Fit-for-Purpose Validation of a Soluble Human Programmed Death-1 Protein Assay

Yan

Yuan

Newitt

et al. 2015

AAPS J

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Abstract. Programmed death-1 (PD-1) protein is a co-inhibitory receptor which negatively regulates immune cell activation and permits tumors to evade normal immune defense. Anti-PD-1 antibodies have been shown to restore immune cell activation and effector function-an exciting breakthrough in cancer immunotherapy. Recent reports have documented a soluble form of PD-1 (sPD-1) in the circulation of normal and disease state individuals. A clinical assay to quantify sPD-1 would contribute to the understanding of sPD-1-function and facilitate the development of anti-PD-1 drugs. Here, we report the development and validation of a sPD-1 protein assay. The assay validation followed the framework for full validation of a biotherapeutic pharmacokinetic assay. A purified recombinant human PD-1 protein was characterized extensively and was identified as the assay reference material which mimics the endogenous analyte in structure and function. The lower limit of quantitation (LLOQ) was determined to be 100 pg/mL, with a dynamic range spanning three logs to 10,000 pg/mL. The intra-and inter-assay imprecision were ≤15%, and the assay bias (percent deviation) was ≤10%. Potential matrix effects were investigated in sera from both normal healthy volunteers and selected cancer patients. Bulk-prepared frozen standards and pre-coated Streptavidin plates were used in the assay to ensure consistency in assay performance over time. This assay appears to specifically measure total sPD-1 protein since the human anti-PD-1 antibody, nivolumab, and the endogenous ligands of PD-1 protein, PDL-1 and PDL-2, do not interfere with the assay.

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“…This function of APLP2 PCSK9 remains intact and accumulates in the circulation, which reduces the duration of action of anti-PCSK9 mAbs (discussed below). Accumulation of circulating PCSK9 was observed in animal studies in multiple anti-PCSK9 mAbs ( 31,32 ), including an increase of >20-fold in monkeys. A signifi cant accumulation of total PCSK9 was also observed in humans treated with an anti-PCSK9 mAb ( 23 ).…”

Section: Proteolytic Cleavage Of Pcsk9 Slows the CL Of Ly From Serummentioning

confidence: 99%

“…The serum concentration of PCSK9, which included the antibody-bound and free forms of both intact and truncated PCSK9, was measured in the monkeys as an index of target engagement. Previous studies in anti-PCSK9 mAbs in mice, monkeys and humans have demonstrated as much as 20-fold accumulation of circulating PCSK9 ( 23,31,32 ), due to slower PCSK9 clearance (CL) when bound to a therapeutic antibody. However, serum PCSK9 concentration did not increase in monkeys treated with LY, similar to monkeys treated with a control IgG4 ( Fig.…”

Section: Binding and Effi Cacy Of Lymentioning

confidence: 99%

Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody

Schroeder

Beyer

Hansen

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org atherosclerosis ( 7,8 ). Conversely, loss-of-function mutations are associated with reduced LDL-C and reduced risk of cardiovascular diseases ( 9-11 ).PCSK9 is expressed in multiple tissues, including liver, intestine, kidney, and cerebellum, of which the liver appears to be the major source of the circulating protein (12)(13)(14). It is synthesized as a 74 kDa proprotein, which is activated prior to secretion by the autocatalytic cleavage of its N-terminal prodomain ( 15 ). PCSK9 that is secreted from cells is comprised of the 14 kDa prodomain associated noncovalently with a 60 kDa mature domain, the latter consisting of an N-terminal catalytic domain and a cysteine-and histidine-rich C-terminal domain. In addition to this 74 kDa form (intact PCSK9), a smaller form (truncated PCSK9) is found in serum in which the N terminus of the catalytic domain is truncated by 7-8 kDa. This truncated PCSK9 represents up to 40% of the total circulating PCSK9 in humans (16)(17)(18). The site of cleavage in PCSK9 was identifi ed as Arg218 of the catalytic domain ( 16,17 ). Furin appears to be responsible for most of the cleavage in vivo, based on studies in mice with hepatocytespecifi c inactivation of the protease ( 18 ). The observation of reduced plasma levels of the truncated PCSK9 in humans heterozygous for the R218S gain-of-function mutation is also consistent with furin-mediated cleavage, as this mutation disrupts the RXXR sequence recognized by furin ( 18 ).Several reports have addressed the question of whether the truncated PCSK9 is active in the regulation of LDL-C. Studies in furin knockout mice found reduced circulating levels of truncated PCSK9 and less hepatic LDLR than in Abstract Lilly PCSK9 antibody LY3015014 (LY) is a monoclonal antibody (mAb) that neutralizes proprotein convertase subtilisin-kexin type 9 (PCSK9). LY decreases LDL cholesterol in monkeys and, unlike other PCSK9 mAbs, does not cause an accumulation of intact PCSK9 in serum. Comparing the epitope of LY with other clinically tested PCSK9 mAbs, it was noted that the LY epitope excludes the furin cleavage site in PCSK9, whereas other mAbs span this site. In vitro exposure of PCSK9 to furin resulted in degradation of PCSK9 bound to LY, whereas cleavage was blocked by other mAbs. These other mAbs caused a signifi cant accumulation of serum PCSK9 and displayed a shorter duration of LDL-cholesterol lowering than LY when administered to mice expressing the WT human PCSK9. In mice expressing a noncleavable variant of human PCSK9, LY behaved like a cleavage-blocking mAb, in that it caused signifi cant PCSK9 accumulation, its duration of LDL lowering was reduced, and its clearance (CL) from serum was accelerated. Thus, LY neutralizes PCSK9 and allows its proteolytic degradation to proceed, which limits PCSK9 accumulation, reduces the CL rate of LY, and extends its duration of action.PCSK9 mAbs with this property are likely to achieve longer durability and require lower doses than mAbs that cause antigen...

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An Anti-PCSK9 Antibody Reduces LDL-Cholesterol On Top Of A Statin And Suppresses Hepatocyte SREBP-Regulated Genes

Cited by 94 publications

References 46 publications

Autosomal Dominant Hypercholesterolemia: Needs for Early Diagnosis and Cascade Screening in the Tunisian Population

Autosomal Dominant Hypercholesterolemia: Needs for Early Diagnosis and Cascade Screening in the Tunisian Population

Development and Fit-for-Purpose Validation of a Soluble Human Programmed Death-1 Protein Assay

Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody

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