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Potential of Antibody Therapy for Respiratory Virus Infections
Published in Sunit K. Singh, Human Respiratory Viral Infections, 2014
Tze-Minn Mak, Ruisi Hazel Lin, Yee-Joo Tan
However, considerable difficulty was found in displaying large proteins on the terminal end of the outer membrane of E. coli as the recombinant protein has to traverse across both the inner and outer membranes of Gram-negative bacteria. This was eventually alleviated by the autotransporter display systems, which use the serine protease EspP autotransporter on E. coli to secrete fusion protein through the inner membrane and subsequently out of the cell. This procedure also involves engineering a type of binding protein called anticalin, to be specific for the desired antigen and to easily pass through the inner and outer membranes to reach the bacterial cell surface for display [67].
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Lipocalins are the family of 160–180 amino acid residue proteins that share high structural similarity. Lipocalins are mainly involved in transfer of molecules such as hormones, vitamins, steroids, and other metabolic products. Structurally, lipocalins contain eight antiparallel β-strands that are packed in cylindrical manner. At the N-terminus, the β-sheet region is extended by a coiled polypeptide whereas at the C-terminus it is packed against C-terminal helix and a stretch of amino acids in the extended conformation. On the broader side of the β-barrel, the β-strands are connected by the loops that are variable, which can be mutagenized for binding target proteins (Schlehuber and Skerra, 2005). The binding pocket of Lipocalin protein from Pieris brassicae was reengineered to bind to fluorescein. Fluorescein binding lipocalins were designed by mutating the 16 residues at the binding site formed by the four external loops. The fluorescein binding lipocalin variants were selected by bacterial phage display method. Variants showed the nano-molar binding affinity to fluorescein (Beste et al., 1999). Anticalin with picomolar binding affinity for prostate–specific membrane protein (PSMA) was engineered to diagnose the prostate carcinoma or neovasculature of solid tumors (Barinka et al., 2016). Anticalin specific for binding VEGF-A was engineered using the human tear lipocalin. The anticalin PRS-050 variant showed pico-molar binding affinity to VEGF-A, and blocked its functional activities, including the mitogenic signaling and proliferation of human endothelial cells. The plasma half-life of anticalin was further extended by PEGylation. As blockage of VEGF-A is advantageous in numerous neovascular diseases, anticalin can serve as future potential therapeutic (Gille et al., 2016).
Anticalin® proteins: from bench to bedside
Published in Expert Opinion on Biological Therapy, 2021
Friedrich-Christian Deuschle, Elena Ilyukhina, Arne Skerra
Natural lipocalins prefer small to mid-size ligands of the hapten type while tight complex formation with a protein ligand is only seen in a few instances. One of these rare examples is the Ornithodoros moubata Complement Inhibitor (OmCI), whose recombinant form is in advanced clinical studies (initially under the name Coversin, now Nomacopan) for the treatment of acute and chronic inflammatory diseases [45,46]. However, this tick salivary lipocalin binds its target, the complement component C5, not by involving the structurally variable loop region but via one side of the β-barrel and part of the conserved α-helix [47]. In so far it is remarkable that the Anticalin technology based on the structural principles described above also turned out to be useful for the high-affinity binding of disease-relevant proteins with extended tertiary structure. The proof of concept was the selection of an Lcn2-based Anticalin with antagonistic properties against the cytotoxic T-lymphocyte-associated protein 4 (CTLA4, also known as CD152), the prototypic immune checkpoint receptor [48,49]. X-ray crystallographic analysis of an Anticalin candidate with picomolar affinity both in complex with the extracellular region of CTLA-4 and in the ligand-free state revealed remarkable plasticity of the lipocalin binding site, thus further confirming the structural analogy with Igs. Subsequently, Anticalins – based on both Lcn2 and Lcn1 as human lipocalin scaffolds – were developed against a series of relevant therapeutic protein targets [20] including VEGF-A, PSMA, ED-B, Hsp70, VEGF-R3, cMET, PCSK9, 4-1BB (CD137) and CD98hc, among others (see below and Table 1).