Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody[S]
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 o...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-11-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S002222752035481X |
| _version_ | 1818384320831684608 |
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| author | Krista M. Schroeder Thomas P. Beyer Ryan J. Hansen Bomie Han Richard T. Pickard Victor J. Wroblewski Mark C. Kowala Patrick I. Eacho |
| author_facet | Krista M. Schroeder Thomas P. Beyer Ryan J. Hansen Bomie Han Richard T. Pickard Victor J. Wroblewski Mark C. Kowala Patrick I. Eacho |
| author_sort | Krista M. Schroeder |
| collection | DOAJ |
| description | 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 significant 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 significant 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 to accumulate. |
| first_indexed | 2024-12-14T03:20:24Z |
| format | Article |
| id | doaj.art-f9915123339b461b9a86c49a1bb6065e |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-14T03:20:24Z |
| publishDate | 2015-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-f9915123339b461b9a86c49a1bb6065e2022-12-21T23:19:03ZengElsevierJournal of Lipid Research0022-22752015-11-01561121242132Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody[S]Krista M. Schroeder0Thomas P. Beyer1Ryan J. Hansen2Bomie Han3Richard T. Pickard4Victor J. Wroblewski5Mark C. Kowala6Patrick I. Eacho7To whom correspondence should be addressed; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285Lilly 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 significant 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 significant 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 to accumulate.http://www.sciencedirect.com/science/article/pii/S002222752035481Xproprotein convertase subtilisin-kexin type 9pharmacologypharmacokineticslow density lipoprotein/metabolismdrug therapydyslipidemias |
| spellingShingle | Krista M. Schroeder Thomas P. Beyer Ryan J. Hansen Bomie Han Richard T. Pickard Victor J. Wroblewski Mark C. Kowala Patrick I. Eacho Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody[S] Journal of Lipid Research proprotein convertase subtilisin-kexin type 9 pharmacology pharmacokinetics low density lipoprotein/metabolism drug therapy dyslipidemias |
| title | Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody[S] |
| title_full | Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody[S] |
| title_fullStr | Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody[S] |
| title_full_unstemmed | Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody[S] |
| title_short | Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody[S] |
| title_sort | proteolytic cleavage of antigen extends the durability of an anti pcsk9 monoclonal antibody s |
| topic | proprotein convertase subtilisin-kexin type 9 pharmacology pharmacokinetics low density lipoprotein/metabolism drug therapy dyslipidemias |
| url | http://www.sciencedirect.com/science/article/pii/S002222752035481X |
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