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

Kovaleva, Marina; Ferguson, Laura; Steven, John; Porter, A.J.; Barelle, Caroline

doi:10.1517/14712598.2014.937701

Cited by 74 publications

(73 citation statements)

References 100 publications

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“…An extension of the monkey study also confirmed that this product could be administered subcutaneously as well as intravenously with both routes of administration leading to rapid bioavailability and half-life extension values of over 6 days. Extrapolation of these data, predicts that the half-life of an E06 fusion in man would be approximately 19 days, mirroring that of human albumin [44].…”

Section: E06-fit For Purposementioning

confidence: 93%

“…Both antibody-related and novel scaffolds are being progressed towards the clinic in the hope that these new formats will overcome the shortfalls of mAbs, and improve patient outcomes [44].…”

Section: Biologics Are Leading the Waymentioning

confidence: 99%

“…In depth descriptions of the different types of VNAR domains have been reviewed recently however for completeness, Figure 2 illustrates the main family members [44,45]. Unlike classical VH domains which consist of nine beta strands, VNAR domains are smaller due to the absence of C' and C'' strands [45][46][47].…”

Section: Small Size But Large Diversitymentioning

confidence: 99%

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VNARs: An Ancient and Unique Repertoire of Molecules That Deliver Small, Soluble, Stable and High Affinity Binders of Proteins

Barelle¹,

Porter²

2015

Antibodies

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At 420 million years, the variable domain of New Antigen Receptors or VNARs are undoubtedly the oldest (and smallest) antigen binding single domains identified in the vertebrate kingdom. Their role as an integral part of the adaptive immune system of sharks has been well established and has served to provide a greater understanding of the evolution of humoral immunity; their cellular components and processes as well as the underlying genetic organization and molecular control mechanisms. Intriguingly, unlike the variable domain of the camelid heavy chain antibodies or VHH, VNARs do not conform to all of the characteristic properties of classical antibodies with an ancestral origin that clearly distinguishes them from true immunoglobulin antibodies. However, this uniqueness of their origin only adds to their potential as next generation therapeutic biologics with their structural and functional attributes and commercial freedom all enhancing their profile and current success. In fact their small size, remarkable stability, molecular flexibility and solubility, together with their high affinity and selectivity for target, all reinforce the potential of these domains as drug candidates. The purpose of this review is to provide an overview of the existing basic biology of these unique domains, to highlight the drug-like properties of VNARs and describe current progress in their journey towards the clinic.

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Section: E06-fit For Purposementioning

confidence: 93%

Section: Biologics Are Leading the Waymentioning

confidence: 99%

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VNARs: An Ancient and Unique Repertoire of Molecules That Deliver Small, Soluble, Stable and High Affinity Binders of Proteins

Barelle¹,

Porter²

2015

Antibodies

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“…A shark vNAR domain against human serum albumin (HAS) was engineered by converting more than half of the framework amino acids to those of the human germline IgL kappa variable sequence DPK9 [91 ]. This humanized molecule lost very little affinity over the product of the parental construct, and the humanized IgNARV displayed negligible immunogenicity in dendritic cell assays [104].…”

Section: Libraries and Engineeringmentioning

confidence: 99%

“…A shark IgNAR was also shown to be an effective 'intrabody' against the hepatitis B virus precore protein in the endoplasmic reticulum [106]. A list of notable IgNARV binders to relevant targets is shown in Supplementary Table 1 (adapted from [94,104]). …”

Section: Libraries and Engineeringmentioning

confidence: 99%

Structural and genetic diversity in antibody repertoires from diverse species

Rios¹,

Criscitiello

Smider

2015

Current Opinion in Structural Biology

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The antibody repertoire is the fundamental unit that enables development of antigen specific adaptive immune responses against pathogens. Different species have developed diverse genetic and structural strategies to create their respective antibody repertoires. Here we review the shark, chicken, camel, and cow repertoires as unique examples of structural and genetic diversity. Given the enormous importance of antibodies in medicine and biological research, the novel properties of these antibody repertoires may enable discovery or engineering of antibodies from these non-human species against difficult or important epitopes.

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A simplified procedure for antibody engineering by yeast surface display: Coupling display levels and target binding by ribosomal skipping

Grzeschik

Hinz

Könning

et al. 2016

Biotechnology Journal

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Yeast surface display is a valuable, widely used method for protein engineering. However, current yeast display applications rely on the staining of epitope tags in order to verify full-length presentation of the protein of interest on the cell surface. We aimed at developing a modified yeast display approach that relies on ribosomal skipping, thereby enabling the translation of two proteins from one open reading frame and, in that manner, generating an intracellular fluorescence signal. This improved setup is based on a 2A sequence that is encoded between the protein to be displayed and a gene for green fluorescent protein (GFP). The intracellular GFP fluorescence signal of yeast cells correlates with full-length protein presentation and omits the need for the immunofluorescence detection of epitope tags. For method validation, shark-derived IgNAR variable domains (vNAR) were subjected to affinity maturation using the 2A-GFP system. Yeast library screening of full-length vNAR variants which were detected via GFP expression yielded the same high-affinity binder that had previously been isolated by our group using the conventional epitope tag-based display format. The presented method obviates the need for additional immunofluorescence cell staining, offering an easy and cost-friendly alternative to conventional epitope tag detections.

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

Cited by 74 publications

References 100 publications

VNARs: An Ancient and Unique Repertoire of Molecules That Deliver Small, Soluble, Stable and High Affinity Binders of Proteins

VNARs: An Ancient and Unique Repertoire of Molecules That Deliver Small, Soluble, Stable and High Affinity Binders of Proteins

Structural and genetic diversity in antibody repertoires from diverse species

A simplified procedure for antibody engineering by yeast surface display: Coupling display levels and target binding by ribosomal skipping

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