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Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Antibodies or immunoglobulins (Ig) are the important members of immune system that neutralize the antigens by recognizing their epitopes. Antigen binding site is located in hypervariable regions or complementarity determining regions (CDRs) that mainly involve first 110 amino acids of heavy and light chains of antibodies. Arrangement of variable regions results in diversity among the antibodies (Owen et al., 2012). Several methods have been developed to engineer antibodies with high specificity and affinity (He and Zhu, 2015). Regions including fragments of antigen binding (Fab) comprising VH, VL, CH1, and CL domains and Fragment of crystallization (Fc region) consisting of hinge, CH2, and CH3 domains are the main targets to engineer novel antibodies. Several strategies are also being employed to increase the in vivo half- life of antibodies. Eculizumab is the first antibody with engineered Fc region that was approved in 2007 (Czajkowsky et al., 2012; Wang et al., 2018). In several cases, monoclonal antibodies are not as effective as therapeutic agents, hence, antibody scaffolds are being used to incorporate the specific activity to develop them as successful therapeutic candidates (Gebauer and Skerra, 2009).
Plant-Based Production of Biosimilar Drug Products
Published in Laszlo Endrenyi, Paul Jules Declerck, Shein-Chung Chow, Biosimilar Drug Product Development, 2017
Kenny K. Y. So, Michael R. Marit, Michael D. McLean, J. Christopher Hall
In mAbs, two potential structural domains contribute to its potential immunogenicity. Both foreign complementarity-determining regions (CDRs) on humanized antibodies and glycans that contain xenogeneic sugars, such as β1,2-xylose and α1,3-fucose, can elicit a host immune response (van de Weert and Møller, 2008). Although the humanization of murine mAbs by replacement of framework regions can result in clinically safe mAbs, as in the case of trastuzumab, the small proportion of murine sequences in the CDRs that can remain may still be sufficient to induce immunogenicity. Such is the case reported for natalizumab, a humanized mAb of murine origin prescribed for the treatment of multiple sclerosis. Antinatalizumab antibodies with affinity to the CDR regions of natalizumab were discovered in the serum of treated patients, and the levels of circulating natalizumab were depleted (Subramanyam, 2008).
Cytoplasmic and periplasmic expression of recombinant shark VNAR antibody in Escherichia coli
Published in Preparative Biochemistry and Biotechnology, 2019
Herng C. Leow, Katja Fischer, Yee C. Leow, Katleen Braet, Qin Cheng, James McCarthy
In contrast to camelids, immunoglobulin new antigen receptor (IgNAR) is an intra-domain disulfide bond immunoglobulin superfamily protein that provided additional stability without adversely affecting antigen binding efficiency. This protein was naturally discovered from nurse shark (Ginglymostoma cirratum)[5] and wobbegong shark (Orectolobus maculates).[6] Unlike immunoglobulin (Ig) isotypes found in higher mammals, the variable domains of shark IgNAR (VNAR) is an unusual single domain antibody that contains only a single H-chain homodimer and lacks a light chain.[7] According to molecular analysis, the deletion of a large portion of framework region 2-complementarity determining region 2 (FR2-CDR2) has made VNAR the smallest variable domain with a size of ∼12 kDa in the animal kingdom.[7] It may be due to VNARs have evolved from separate lineage from immunoglobulins and thus have never had a CDR2.[8,9]Moreover, VNAR domains possess an extraordinary CDR3 domain which is much longer than that of conventional antibodies. The inter- or intra-loop of CDR3 is typically influenced by the numbers of cysteine residues and the penetration capability into the cleft region of the target antigen.[10,11] Owing to peculiar structure, the excellent solubility and thermostability of these natural single domain fragments may be due to the substitutions of amino acid at heavy and light variable domains (VH-VL) interface, resulting to be more hydrophilicity rather than a hydrophobic interface as exhibited in conventional antibodies.[7,12]