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An affibody-adalimu...
An affibody-adalimumab hybrid blocks combined IL-6 and TNF-triggered serum amyloid A secretion in vivo
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- Yu, Feifan (författare)
- KTH,Proteinteknologi
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Gudmundsdotter, Lindvi (författare)
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- Akal, Anastassja (författare)
- KTH,Proteinteknologi
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Gunneriusson, Elin (författare)
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- Frejd, Fredrik (författare)
- Uppsala universitet,Institutionen för radiologi, onkologi och strålningsvetenskap
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- Nygren, Per-Åke (författare)
- KTH,Proteinteknologi
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(creator_code:org_t)
- 2014-11
- 2014
- Engelska.
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Ingår i: mAbs. - : Informa UK Limited. - 1942-0862 .- 1942-0870. ; 6:6, s. 1598-1607
- Relaterad länk:
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https://www.tandfonl...
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https://urn.kb.se/re...
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https://doi.org/10.4...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- In inflammatory disease conditions, the regulation of the cytokine system is impaired, leading to tissue damages. Here, we used protein engineering to develop biologicals suitable for blocking a combination of inflammation driving cytokines by a single construct. From a set of interleukin (IL)-6-binding affibody molecules selected by phage display, five variants with a capability of blocking the interaction between complexes of soluble IL-6 receptor a (sIL-6R alpha) and IL6 and the co-receptor gp130 were identified. In cell assays designed to analyze any blocking capacity of the classical or the alternative (trans) signaling IL-6 pathways, one variant, Z(IL-6_13) with an affinity (K-D) for IL-6 of similar to 500 pM, showed the best performance. To construct fusion proteins ("AffiMabs") with dual cytokine specificities, Z(IL-6_13) was fused to either the N-or C-terminus of both the heavy and light chains of the anti-tumor necrosis factor (TNF) monoclonal antibody adalimumab (Humira (R)). One AffiMab construct with Z(IL-6_13) positioned at the N-terminus of the heavy chain, denoted Z(IL-6_13)-HCAda, was determined to be the most optimal, and it was subsequently evaluated in an acute Serum Amyloid A (SAA) model in mice. Administration of the AffiMab or adalimumab prior to challenge with a mix of IL-6 and TNF reduced the levels of serum SAA in a dose-dependent manner. Interestingly, the highest dose (70 mg/kg body weight) of adalimumab only resulted in a 50% reduction of SAA-levels, whereas the corresponding dose of the Z(IL-6_13)-HCAda AffiMab with combined IL-6/TNF specificity, resulted in SAA levels below the detection limit.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Annan medicin och hälsovetenskap -- Övrig annan medicin och hälsovetenskap (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Other Medical and Health Sciences -- Other Medical and Health Sciences not elsewhere specified (hsv//eng)
Nyckelord
- AffiMab
- Antibody
- IL-6
- TNF
- adalimumab
- affibody
- affinity
- fusion
- inflammation
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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