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

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 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.

SUBMITTER: Schroeder KM

PROVIDER: S-EPMC4617399 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Schroeder Krista M KM Beyer Thomas P TP Hansen Ryan J RJ Han Bomie B Pickard Richard T RT Wroblewski Victor J VJ Kowala Mark C MC Eacho Patrick I PI

Journal of lipid research 20150920 11

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 degrad ...[more]

PMID: 26392590

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Project description:BackgroundAnti-drug antibodies (ADAs) to bococizumab were detected in > 40% of subjects in the SPIRE lipid-lowering trials. The risk of cross-reactivity between anti-bococizumab antibodies and other approved anti-proprotein convertase subtilisin/kexin type-9 (PCSK9) monoclonal antibodies (mAbs) was investigated using a single-assay approach.MethodsBococizumab immunogenicity was assessed in SPIRE-HR, a 52-week study. The highest ADA titer sample from each ADA-positive subject (n = 155) was tested in vitro for cross-reactivity to alirocumab and evolocumab using a novel ADA assay approach. Additional specificity tiers within the bococizumab ADA assay against each drug were validated using recombinant PCSK9 as a surrogate cross-reactive positive control. If the highest ADA titer sample showed cross-reactivity, additional samples from that subject were analyzed. Cross-reactivity was determined by the ability of alirocumab or evolocumab to inhibit the sample signal greater than or equal to the cross-reactivity cut-points.ResultsADAs were detected in 44.0% (155/352) of bococizumab-treated subjects, and 27.0% also developed neutralizing antibodies (NAbs). Median ADA and NAb titers ranged from 276 to 526 and 8 to 12 over the course of the study, respectively. From 155 ADA-positive subjects tested for cross-reactivity, one (0.6%) subject showed weak cross-reactivity to both alirocumab and evolocumab. This cross-reactivity signal was transient (from Days 337 to 373) and undetectable at the last ADA-positive timepoint (Day 407).ConclusionA novel, single-assay approach was validated to assess the potential cross-reactivity of anti-bococizumab antibodies to alirocumab and evolocumab. In subjects who developed ADAs to bococizumab, the likelihood of clinically relevant cross-reactivity to marketed anti-PCSK9 mAbs is remote, based on the low frequency of cross-reactivity observed, which was weak in signal inhibition and transient in nature.Clinical trial registrationThe SPIRE-HR study is registered on ClinicalTrials.gov under the identifier NCT01968954.

Dataset Information

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

Publications

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

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