Dulaglutide (revision 4)

Dulaglutide is a GLP-1 receptor agonist constructed as a covalent fusion protein: two modified GLP-1(7–37) analogues joined by a peptide linker to the Fc fragment of a human IgG4 antibody. At about 60 kDa it is an order of magnitude larger than the acylated peptide agonists and is properly a biologic rather than a synthetic peptide.^[1]

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.^[1]

The GLP-1 portion carries three substitutions — Aib at position 8 for 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.^[2]

Fusion to Fc is a different engineering philosophy from acylation. Acylation leaves a small peptide with a reversible carrier attachment; fusion produces a permanently large molecule. The trade-offs run in both directions.

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 synthesis, which scales differently.

Against it: subcutaneous bioavailability is lower — roughly half, compared with about 89% for 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.^[1]