Albumin-binding domain from Streptococcus zooepidemicus protein Zag as a novel strategy to improve the half-life of therapeutic proteins

Cantante, Cátia; Lourenço, Sara; Morais, Maurício; Leandro, João; Gano, Lurdes; Silva, Nuno; Leandro, Paula; Serrano, Mònica; Henriques, Adriano O.; André, A; Cunha-Santos, Catarina; Fontes, Carlos M. G. A.; Correia, João D. G.; Aires-da-Silva, Frederico; Gonçalves, João

doi:10.1016/j.jbiotec.2017.05.017

Cited by 16 publications

(14 citation statements)

References 18 publications

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“…Recently, the design of small FcRnbinding sequences has shown successful competition with IgG, 38 pH-dependent FcRn binding, engagement with FcRnmediated recycling in cell models, 39 and significantly prolonged the in vivo half-lives of these rapidly cleared moieties. The saturation mutagenesis strategies used in this study may also be adaptable to serum albumin fusions, due to its similar pH-dependent interaction with FcRn, [40][41] as an alternative for the applications where longer half-life but no other Fc functions are desired.…”

Section: Discussionmentioning

confidence: 99%

Antibody Fc engineering for enhanced neonatal Fc receptor binding and prolonged circulation half-life

Mackness¹,

Jaworski²,

Boudanova³

et al. 2019

mAbs

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The neonatal Fc receptor (FcRn) promotes antibody recycling through rescue from normal lysosomal degradation. The binding interaction is pH-dependent with high affinity at low pH, but not under physiological pH conditions. Here, we combined rational design and saturation mutagenesis to generate novel antibody variants with prolonged half-life and acceptable development profiles. First, a panel of saturation point mutations was created at 11 key FcRn-interacting sites on the Fc region of an antibody. Multiple variants with slower FcRn dissociation kinetics than the wildtype (WT) antibody at pH 6.0 were successfully identified. The mutations were further combined and characterized for pH-dependent FcRn binding properties, thermal stability and the FcγRIIIa and rheumatoid factor binding. The most promising variants, YD (M252Y/T256D), DQ (T256D/T307Q) and DW (T256D/T307W), exhibited significantly improved binding to FcRn at pH 6.0 and retained similar binding properties as WT at pH 7.4. The pharmacokinetics in human FcRn transgenic mice and cynomolgus monkeys demonstrated that these properties translated to significantly prolonged plasma elimination half-life compared to the WT control. The novel variants exhibited thermal stability and binding to FcγRIIIa in the range comparable to clinically validated YTE and LS variants, and showed no enhanced binding to rheumatoid factor compared to the WT control. These engineered Fc mutants are promising new variants that are widely applicable to therapeutic antibodies, to extend their circulation half-life with obvious benefits of increased efficacy, and reduced dose and administration frequency.

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Section: Discussionmentioning

confidence: 99%

Antibody Fc engineering for enhanced neonatal Fc receptor binding and prolonged circulation half-life

Mackness¹,

Jaworski²,

Boudanova³

et al. 2019

mAbs

View full text Add to dashboard Cite

show abstract

“…Another ABD consisting of 52 amino acid residues from protein Zag was also reported to bind human, rat, mouse, horse and dog serum albumin 66 . Cantante et al 67 has developed a Zag ABD fused with an anti-TNF α VHH camelid derived sdAb. The fusion protein showed specific binding to human, rat and mouse serum albumins and exhibited a strong increase in circulating half-life in mice to approximately 39-fold compared with the parental sdAb.…”

Section: Natural Proteins As Carriers For Drug Delivery and Tissue Enmentioning

confidence: 99%

Biomacromolecules as carriers in drug delivery and tissue engineering

Zhang

Sun

Jiang

2018

Acta Pharmaceutica Sinica B

332

178

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Natural biomacromolecules have attracted increased attention as carriers in biomedicine in recent years because of their inherent biochemical and biophysical properties including renewability, nontoxicity, biocompatibility, biodegradability, long blood circulation time and targeting ability. Recent advances in our understanding of the biological functions of natural-origin biomacromolecules and the progress in the study of biological drug carriers indicate that such carriers may have advantages over synthetic material-based carriers in terms of half-life, stability, safety and ease of manufacture. In this review, we give a brief introduction to the biochemical properties of the widely used biomacromolecule-based carriers such as albumin, lipoproteins and polysaccharides. Then examples from the clinic and in recent laboratory development are summarized. Finally the current challenges and future prospects of present biological carriers are discussed.

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“…Fusion to albumin targeting nanobodies ( 44 – 46 ) or even albumin itself ( 47 ) has proven to be successful for the half-life extension of nanobodies and scFvs. As an alternative, and with the intention to keep the size of the targeting moiety the smallest possible, fusion to albumin-binding peptides ( 48 ) or albumin-binding domains of streptococcal proteins have been used ( 49 , 50 ).…”

Section: The Thiele Modulus and Systemic Clearancementioning

confidence: 99%

Antibody or Antibody Fragments: Implications for Molecular Imaging and Targeted Therapy of Solid Tumors

2017

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The use of antibody-based therapeutics has proven very promising for clinical applications in cancer patients, with multiple examples of antibodies and antibody–drug conjugates successfully applied for the treatment of solid tumors and lymphomas. Given reported recurrence rates, improvements are clearly still necessary. A major factor limiting the efficacy of antibody-targeted cancer therapies may be the incomplete penetration of the antibody or antibody–drug conjugate into the tumor. Incomplete tumor penetration also affects the outcome of molecular imaging, when using such targeting agents. From the injection site until they arrive inside the tumor, targeting molecules are faced with several barriers that impact intratumoral distribution. The primary means of antibody transport inside tumors is based on diffusion. The diffusive penetration inside the tumor is influenced by both antibody properties, such as size and binding affinity, as well as tumor properties, such as microenvironment, vascularization, and targeted antigen availability. Engineering smaller antibody fragments has shown to improve the rate of tumor uptake and intratumoral distribution. However, it is often accompanied by more rapid clearance from the body and in several cases also by inherent destabilization and reduction of the binding affinity of the antibody. In this perspective, we discuss different cancer targeting approaches based on antibodies or their fragments. We carefully consider how their size and binding properties influence their intratumoral uptake and distribution, and how this may affect cancer imaging and therapy of solid tumors.

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Albumin-binding domain from Streptococcus zooepidemicus protein Zag as a novel strategy to improve the half-life of therapeutic proteins

Cited by 16 publications

References 18 publications

Antibody Fc engineering for enhanced neonatal Fc receptor binding and prolonged circulation half-life

Antibody Fc engineering for enhanced neonatal Fc receptor binding and prolonged circulation half-life

Biomacromolecules as carriers in drug delivery and tissue engineering

Antibody or Antibody Fragments: Implications for Molecular Imaging and Targeted Therapy of Solid Tumors

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