Non‐Antibody Scaffolds as Alternative Therapeutic Agents

Fiedler, Markus; Skerra, Arne

doi:10.1002/9783527682423.ch17

Cited by 6 publications

(10 citation statements)

References 174 publications

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“…a lipocalin or a Kunitz protease inhibitor-for details on the latter, see (Fiedler and Skerra 2014 ;Nixon et al 2014 )) or (2) a stably folded domain excised from a cell surface (e.g. protein A or fi bronectin) or cytoskeletal protein (e.g.…”

Section: The Concept Of Alternative Protein Scaffoldsmentioning

confidence: 99%

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Biobetters

2015

AAPS Advances in the Pharmaceutical Sciences Series

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Section: The Concept Of Alternative Protein Scaffoldsmentioning

confidence: 99%

“…ankyrin). Compared with antibodies or their recombinant fragments, such protein scaffolds promise practical advantages, in particular elevated stability and high production yield in microbial expression systems, together with an independent intellectual property situation (Fiedler and Skerra 2014 ).…”

Section: The Concept Of Alternative Protein Scaffoldsmentioning

confidence: 99%

Biobetters

2015

AAPS Advances in the Pharmaceutical Sciences Series

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“…Immunoglobulin (Ig) antibodies are the best‐studied examples of such recognition agents, and have been reviewed extensively . However, problems with stability, expense of expression, and specificity of interaction of Ig antibodies have led in recent years to the development of alternative binding scaffolds . Antibodies rely on disulfide bond formation for their stability, requiring difficult, expensive eukaryotic cell production; this also makes them unsuitable for applications in reducing conditions .…”

Section: Introductionmentioning

confidence: 99%

“…In the search for better recognition agents, many different scaffolds have emerged; some notable examples are peptide and DNA aptamers, affimers, and anticalins, among others. The motivation and results of this research have been extensively reviewed in recent years . among these scaffolds, repeat proteins such as designed ankyrin repeat proteins (DARPins) tetratricopeptide repeat proteins (TPRs), and armadillo repeats have emerged as a promising class of scaffolds.…”

Section: Introductionmentioning

confidence: 99%

“…Repeat proteins are comparatively simple to design and can have highly variable binding surfaces, and several examples of designed repeat proteins are remarkably stable . Repeat proteins can be expressed in Escherichia coli , can be engineered to be well‐folded and cysteine‐free, and have very large binding sites relative to the size of the protein, minimizing available surface for nonspecific binding . Additionally, their modular architecture makes them relatively simple to analyze and redesign .…”

Section: Introductionmentioning

confidence: 99%

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Engineering repeat proteins of the immune system

McCord

Grove

2020

Biopolymers

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Limitations associated with immunoglobulins have motivated the search for novel binding scaffolds. Repeat proteins have emerged as one promising class of scaffolds, but often are limited to binding protein and peptide targets. An exception is the repeat proteins of the immune system, which have in recent years served as an inspiration for binding scaffolds which can bind glycans and other classes of biomolecule.Like other repeat proteins, these proteins can be very stable and have a monomeric mode of binding, with elongated and highly variable binding surfaces. The ability to target glycans and glycoproteins fill an important gap in current tools for research and biomedical applications.

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Engineered Fn3 protein has targeted therapeutic effect on mesothelin‐expressing cancer cells and increases tumor cell sensitivity to chemotherapy

Sirois

Deny

et al. 2019

Biotech & Bioengineering

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Mesothelin is a protein expressed at high levels on the cell surface in a variety of cancers, with limited expression in healthy tissues. The presence of mesothelin on tumor tissue correlates with increased invasion and metastasis, and resistance to traditional chemotherapies, through mechanisms that remain poorly understood. Molecules that specifically recognize mesothelin and interrupt its contribution to tumor progression have significant potential for targeted therapy and targeted drug delivery applications. A number of mesothelin‐targeting therapies are in preclinical and clinical development, although none are currently approved for routine clinical use. In this work, we report the development of a mesothelin‐targeting protein based on the fibronectin type‐III non‐antibody protein scaffold, which offers opportunities for applications where antibodies have limitations. We engineered protein variants that bind mesothelin with high affinity and selectively initiate apoptosis in tumor cells expressing mesothelin. Interestingly, apoptosis does not occur through a caspase‐mediated pathway and does not require downregulation of cell‐surface mesothelin, suggesting a currently unknown pathway through which mesothelin contributes to cancer progression. Importantly, simultaneous treatment with mesothelin‐binding protein and chemotherapeutic mitomycin C had a greater cytotoxic effect on mesothelin‐positive cells compared to either molecule alone, underscoring the potential for combination therapy including biologics targeting mesothelin.

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Non‐Antibody Scaffolds as Alternative Therapeutic Agents

Cited by 6 publications

References 174 publications

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Engineering repeat proteins of the immune system

Engineered Fn3 protein has targeted therapeutic effect on mesothelin‐expressing cancer cells and increases tumor cell sensitivity to chemotherapy

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