![]() The evaluation of the pharmacological properties of the identified binding domain usually requires the production of milligram amounts of the properly folded peptide. The synthetic access to the screening hit can be achieved by either a biotechnological or chemical approach. In this regard, phage display-evolved miniature protein binders, which specifically target tumour-associated antigens, have substantial potential for radionuclide imaging and peptide receptor radiation therapy. These techniques facilitate the detection of pathophysiological processes at a curable stage and allow an optimised therapy plan as well as the detailed monitoring of its response. In clinical oncology, the combination of molecular imaging modalities with anatomic imaging techniques, such as computed tomography (CT) or magnetic resonance imaging (MRI), is of upmost significance. These modalities enable a non-invasive visualisation of biological processes at the molecular level. Recently, molecular imaging tools, such as single photon emission tomography (SPECT) or positron emission tomography (PET) have gained importance in the preclinical evaluation of pharmacokinetic properties of novel drugs. These aspects have already been addressed in a number of studies on the downsizing of antibodies and their engineered fragments to improve their therapeutic and diagnostic potential. The superb pharmacokinetic properties allow a rapid accumulation in the region of interest, provide a fast clearance from non-specific compartments and therefore enable precise targeting in vivo. The remarkable in vivo stability in combination with a high binding affinity and selectivity make these scaffolds excellent candidates for diagnostic applications. The key benefits of miniprotein binders are the pharmacokinetic properties that result from their small size. These so-called domain antibodies (dAbs) or nanobodies have already been designed to facilitate therapeutic as well as diagnostic applications. ![]() Several antibody fragments, such as the antigen-binding fragment (F ab) or the single-chain variable fragment (scFv), were engineered to act as non-immunogenic targeting proteins with improved biodistribution and blood clearance properties resulting from minimizing their size. Historically, this step helped to understand the relationship between protein size and pharmacological properties. Therefore, the continuous downsizing of antibodies, enzymes or other large proteins in order to accentuate the binding domain, give rise to a future-perspective approach for the design of alternative binding specificities ( Figure 1). In the context of conventional Ig, only a minor part of the molecule is involved in the binding interaction. Moreover, recent developments for therapeutic and especially diagnostic applications of miniproteins are reviewed.Ĭurrent research efforts are focused on the miniaturisation of antibodies into smaller formats, adapting the unique target specificity and exceeding their limited application at the same time. This review summarises the characteristics and the engineering of miniproteins as a novel class of scaffolds to generate of alternative binding agents using phage display screening. ![]() Owing to their high enzymatic resistance and structural stability, miniproteins are ideal templates to display binding epitopes for medical applications in vivo. These properties classify miniprotein scaffolds as promising tools for lead structure generation using phage display technologies. ![]() They are tolerant to multiple amino acid substitutions, which allow for the integration of a randomised affinity function into the stably folded framework. Miniproteins are rigid scaffolds that are stabilised by alpha-helices, beta-sheets and disulfide-constrained secondary structural elements. Miniproteins are currently developed as alternative, non-immunoglobin proteins for the generation of novel binding motifs.
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