Anti-serum albumin domain antibodies for extending the half-lives of short lived drugs

Abstract

We have used phage display to isolate a range of human domain antibodies (dAbs) that bind to mouse, rat and/or human serum albumin (SA) and can be expressed at very high levels in bacterial, yeast or mammalian cell culture. In contrast to non-SA-binding dAbs, which have terminal half-lives of less than 45 min, the half-lives of these 12 kDa 'AlbudAbs' can match the half-life of SA itself. To demonstrate the use of AlbudAbs for extending the half-lives of therapeutic drugs, we created a fusion of the interleukin-1 receptor antagonist (IL-1ra) with an AlbudAb. Soluble IL-1ra is potent inhibitor of IL-1 signalling that is approved for the treatment of rheumatoid arthritis but has a relatively short in vivo half-life. Here we show that although the AlbudAb/IL-1ra fusion has a similar in vitro potency, its in vivo efficacy can be dramatically improved due to its extended serum half-life. AlbudAbs could potentially be used to generate a range of long half-life versions of many different drugs in order to improve their dosing regimen and/or clinical effect.

Single-Domain Antibody–Based and Linker-Free Bispecific Antibodies Targeting FcγRIII Induce Potent Antitumor Activity without Recruiting Regulatory T Cells

“…As shown in Fig. 5A, the cytotoxic activity triggered by sdAb C17-Fc was lower than that of bsFab C21, both in terms of EC 50 (values in the nmol/L range) and of maximal lysis (< 50%), despite its bivalent binding to CEA. This result is likely due to the weaker interaction of the Fc portion of sdAb C17-Fc with FcgRIIIa, as compared with bsFab C21.…”

“…Nevertheless, the bsFab format authorizes the linker-free addition of single-domain antibodies at the C-terminus of CH1 or Ck domains (data not shown). It can therefore be envisaged to construct trispecific formats by adding an anti-human serum albumin sdAb, a method that has been shown to significantly increase tumor retention and half-life (50,51).…”

A Monovalent Anti-Human CD28 Domain Antibody Antagonist: Preclinical Efficacy and Safety

“…Phage particles from a large synthetic Vk dAb repertoire (24) based on a fully human scaffold encoded by germline k L chain genes O12/O2/DPK9 and Jk1 with the side chain diversity incorporated at positions in the Ag binding site were prepared and purified as described (25). This library was selected against recombinant biotinylated monomeric human CD28 fragment in solution, matured, and expressed as previously described (26). Surface plasmon resonance method for affinity measurements.…”

Shark variable new antigen receptor biologics – a novel technology platform for therapeutic drug development

“…One interesting programme is the fusion of an anti-HSA dAb (GSK2374697) to GLP-1 for the possible treatment of diabetes. The inclusion of an anti-HSA dAb as part of this drug formulation has validated the approach of 'piggybacking' on the long-lived serum protein as a method of increasing the half-life of biologically active but short-lived peptides in the body [89,90].…”