![]() Therefore the concept of a universal binding module was extended from antibodies to alternative protein frameworks referred to as scaffolds. High costs of goods, production and purification plants and often complex intellectual property issues are notable facts. mAbs have to be produced in mammalian cells in some cases post-translational modifications, such as specific glycosylation patterns, are required. Fragment crystallizable region (Fc)-mediated complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) can give rise to adverse effects. For example, due to their large size, tumor tissue penetration is a potential issue, and due to a planar binding interface, binding to grooves and catalytic sites of enzymes is difficult to achieve ( 8- 11). However, certain limitations regarding antibody-derived therapeutics have emerged. The latter are less hydrophobic, do not aggregate, are remarkably stable and can recognize hidden epitopes normally inaccessible to rodent and human antibodies. Among these formats are diabodies, multivalent, multispecific and multimodular antibodies, as well as heavy (H)-chain-based antibodies derived from camel or shark ( 8, 9). In addition, new antibody-based formats are presently undergoing preclinical and clinical evaluation ( 3- 7). Various monoclonal antibodies (mAbs) have been approved for the treatment of cancer, in most cases in combination with small-molecule anticancer drugs, and they are the gold standard with regard to antigen-specific protein therapeutics ( 1, 2). In addition, we also discuss the new molecular entities as imaging tools and outline their unique characteristics in the context of multimeric and multivalent binding. Accordingly, we discuss adnectins, lipocalins, Kunitz domain-based binders, avimers, knottins, fynomers, atrimers and cytotoxic T-lymphocyte associated protein-4 (CTLA4)-based binders which fall into the first category, while darpins, affibodies, affilins and armadillo repeat protein-based scaffolds are members of the second category. These entities can be placed into two categories: scaffolds which bind ligands via amino acids in exposed loops and those in which ligand binding is mediated by amino acids in secondary structures, such as β-sheet modules. In order to overcome limitations of monoclonal antibodies, new protein-based scaffolds have been designed and evaluated pre-clinically, and some of them are in clinical studies for the treatment of cancer.
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