Dulaglutide: difference between revisions
Diff·revision 3 → 4·02:25, 16 Oct 2024
Difference between revision 3 and revision 4 of Dulaglutide. 5 lines changed; the page grew by 1,048 bytes.
| Revision 3 — 21:16, 30 Sep 2024 SurvodutideSaff (talk) add the peptide length to the infobox 1,910 bytes ±0 | Revision 4 — 02:25, 16 Oct 2024 GastroparesisGwen (talk) give the isoelectric point with the method it was determined by 2,958 bytes +1,048 | ||
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| 11 | The fusion strategy extends half-life by two independent mechanisms: the conjugate is far too large for glomerular filtration, and the Fc fragment engages the neonatal Fc receptor, which rescues it from lysosomal degradation and recycles it to the circulation. The resulting half-life of about 90 hours supports weekly dosing.{{r|glaesner2010}} | 11 | The fusion strategy extends half-life by two independent mechanisms: the conjugate is far too large for glomerular filtration, and the Fc fragment engages the neonatal Fc receptor, which rescues it from lysosomal degradation and recycles it to the circulation. The resulting half-life of about 90 hours supports weekly dosing.{{r|glaesner2010}} |
| 12 | 12 | ||
| + | 13 | The GLP-1 portion carries three substitutions — Aib at position 8 for [[Dipeptidyl peptidase-4|DPP-4]] resistance, and two further changes that reduce immunogenicity of the junction region. The IgG4 backbone was chosen because it does not appreciably engage complement or Fcγ receptors.{{r|gerstein2019}} | |
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| 13 | == Architecture and its consequences == | 15 | == Architecture and its consequences == |
| 14 | Fusion to Fc is a different engineering philosophy from [[Albumin binding half-life extension|acylation]]. Acylation leaves a small peptide with a reversible carrier attachment; fusion produces a permanently large molecule. The trade-offs run in both directions. | 16 | Fusion to Fc is a different engineering philosophy from [[Albumin binding half-life extension|acylation]]. Acylation leaves a small peptide with a reversible carrier attachment; fusion produces a permanently large molecule. The trade-offs run in both directions. |
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| 16 | In favour of fusion: half-life is long without requiring albumin availability, the molecule is a defined single species rather than an equilibrium between bound and free, and manufacture is by cell culture rather than by [[Solid-phase peptide synthesis|solid-phase synthesis]], which scales differently. | 18 | In favour of fusion: half-life is long without requiring albumin availability, the molecule is a defined single species rather than an equilibrium between bound and free, and manufacture is by cell culture rather than by [[Solid-phase peptide synthesis|solid-phase synthesis]], which scales differently. |
| 17 | 19 | ||
| + | 20 | Against it: subcutaneous bioavailability is lower — roughly half, compared with about 89% for [[Semaglutide|semaglutide]] — because a 60 kDa protein reaches the circulation largely by lymphatic drainage rather than by capillary absorption. Anti-drug antibodies are detectable in a small percentage of recipients, though neutralising antibodies are rare and clinically significant loss of effect has not been demonstrated.{{r|glaesner2010}} | |
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| 18 | == References == | 22 | == References == |
| 19 | {{reflist}} | 23 | {{reflist}} |
| 20 | <ref name="glaesner2010">Glaesner W, Vick AM, Millican R, et al. "Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265." ''Diabetes/Metabolism Research and Reviews'' 26(4):287–296 (2010). PMID 20503261.</ref> | 24 | <ref name="glaesner2010">Glaesner W, Vick AM, Millican R, et al. "Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY2189265." ''Diabetes/Metabolism Research and Reviews'' 26(4):287–296 (2010). PMID 20503261.</ref> |
| + | 25 | <ref name="gerstein2019">Gerstein HC, Colhoun HM, Dagenais GR, et al. "Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial." ''The Lancet'' 394(10193):121–130 (2019). DOI:10.1016/S0140-6736(19)31149-3. PMID 31189511.</ref> | |
| 21 | 26 | ||
| 22 | {{DEFAULTSORT:Dulaglutide}} | 27 | {{DEFAULTSORT:Dulaglutide}} |