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Nanocarriers as an Emerging Platform for Cancer Therapy
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Dan Peer, Jeffrey M. Karp, Seungpyo Hong, Omid C. Farokhzad, Rimona Margalit, Robert Langer
Although using genomics and proteomics technology to choose appropriate targets is an active area of research, to date no clinically effective targets have been identified. Creating new technologies to enhance selectivity and targeting efficacy with existing targets seem more promising. For example, fusion proteins can be created by combining two or more genes to produce a new protein with desired properties. Antibodies can be engineered so they bind to their target with high affinity, and using molecular biology techniques, it is possible to design protein-based ligand mimetics based on the structure of a receptor. Dimerization of proteins or peptides can increase ligand affinity through divalency—two simultaneous binding events, usually involving concurrent binding of a protein or a peptide to the two Fc domains of an antibody (Fig. 2.2b). For example, dimerization of a low-affinity scFv (also known as diabody) against the ErbB2, led to enhanced tumour localization in a mouse tumour model [37].
The science of biotechnology
Published in Ronald P. Evens, Biotechnology, 2020
The concept with fusion molecules is to structurally combine two compounds, a mix of proteins, peptides, a mab fragment (Fab or nanobody), toxins, vaccines, or a chemical. Twenty-nine such molecules were commercially available as of the end of 2019. Goals have been to alter pharmacokinetics, result in combined properties for the full molecule, serve as a carrier to the site of action, or enhance absorption of the large biological molecules. Several examples have been achieved and marketed, for example, denileukin, a protein (Interleukin-2) and a protein toxin, diphtheria proteins, for renal cell carcinoma; abatacept, the CTL4-A protein extracellular domain (T-cell antigen protein) and a fragment of IgG1 for rheumatoid arthritis; the protein albumin bound to a drug, paclitaxel, for breast cancer; Pneumococcal vaccine, a conjugate of the polysaccharide of Streptococcus pneumoniae bound to diphtheria protein, preventing Pneumococcal pneumonia; and etanercept, combining IgG1 Fc fragment with tumor necrosis factor, a mediator responsible for inflammation in arthritides, colitis, and psoriasis. Table 5.3 further elaborates on the types of fusion proteins and examples.
Selective Drug Delivery Using Targeted Enzymes For Prodrug Activation
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Nathan O. Siemers, Peter D. Senter
Recombinant DNA technology has been used for the preparation of fusion proteins having well defined characteristics. A single-chain sFv antibody-/Mactamase fusion protein was constructed and expressed using the L6 antitumor antibody and Bacillus cereus β-lactamase (Goshorn et al., 1993). The fusion protein was expressed in soluble form in Escherichia coli and purified by affinity chromatography with an anti-idiotypic mAb column. The L6-β-lactamase fusion protein retained enzymatic activity, and was able to effect prodrug activation in vitro.
Mass spectrometry-based multi-attribute method in protein therapeutics product quality monitoring and quality control
Published in mAbs, 2023
Feng Yang, Jennifer Zhang, Alexander Buettner, Eva Vosika, Monica Sadek, Zhiqi Hao, Dietmar Reusch, Maximiliane Koenig, Wayman Chan, Anja Bathke, Hilary Pallat, Victor Lundin, Jochen Felix Kepert, Patrick Bulau, Galahad Deperalta, Christopher Yu, Richard Beardsley, Tura Camilli, Reed Harris, John Stults
MAM can provide both targeted quantitation of multiple covalent modifications in one method, and new peak detection (NPD) through differential data analysis of LC-MS chromatograms in good manufacturing practice (GMP) batches compared to a reference standard.2–8−12 Standard, peptide-based MAM can be a platform method with several easy-to-execute options, such as trypsin, Lys-C digest, or non-reduced sample13 alternatives. Other protease of choice depends on the type of biotherapeutic proteins to be analyzed and, in certain cases, multi-enzyme digestion is required to achieve full sequence coverage and a reliable post-translational modification (PTM) assessment. For example, trypsin was used in combination with Glu-C14 or AspN15 for certain fusion proteins. It is also known that trypsin is not effective in digesting adeno-associated virus capsid proteins.16
R-spondin family biology and emerging linkages to cancer
Published in Annals of Medicine, 2023
Zhimin He, Jialin Zhang, Jianzhong Ma, Lei Zhao, Xiaodong Jin, Hongbin Li
Gene fusions have been considered to be driver mutations in tumors, and the findings of numerous studies have aided us in developing a better knowledge of the carcinogenic process [22]. Gene fusions involving RSPOs have been proven to induce the genesis of Wnt-dependent cancers in a variety of malignancies. Based on recent research reports, the authors identified five previously unreported RSPO fusion events (e.g. IFNGR1-RSPO3) [23]. Seshagiri et al. used RNA-SEQ to analyze 70 pairs of colon cancer tumors and their adjacent non-cancer tissues and identified a plurality of fusion transcripts involving RSPO2 and RSPO3, where the two transcriptions appeared together in patients with colon cancer in colon cancer. After fusion with EIF3E or PTPRK exon 1, the expression of RSPO2 or RSPO3 increased, which activated the Wnt pathway accordingly [24]. Zhang et al. studied the regulation of specific candidate fusion genes in the HCT116 colon cancer cell line by utilizing the brother of the regulator of imprinted sites (BORIS). It was found that BORIS inhibited the expressions of EIF3E, RSPO2, PTPRK, RSPO3, TADA2A, and CD4 in HCT116 cells and the expression of fusion transcripts [25]. A more detailed understanding of fusion proteins in terms of their regulatory mechanisms and the downstream biological effects in cellular processes can facilitate the development of new therapeutic methods in tumor treatment.
International nonproprietary names for monoclonal antibodies: an evolving nomenclature system
Published in mAbs, 2022
Sofia S. Guimaraes Koch, Robin Thorpe, Nana Kawasaki, Marie-Paule Lefranc, Sarel Malan, Andrew C.R. Martin, Gilles Mignot, Andreas Plückthun, Menico Rizzi, Stephanie Shubat, Karin Weisser, Raffaella Balocco
The INN Programme defines a fusion protein as “a multifunctional protein derived from a single nucleotide sequence which may contain two or more genes or portions of genes with or without amino acid linker sequences. The genes should originally code for separate proteins, with at least two of them endowed with pharmacological action (e.g., action and targeting)”. Such substances can be made up of a great variety of different component structures and can be used for a large array of clinical indications. The suffix -fusp for fusion protein was adopted in 2017. A detailed description of the INN scheme for fusion proteins is beyond the remit of this publication. For further information, see ref. 19. Full-length monoclonal antibodies or antibody fragments/related substances often comprise parts of fusion proteins. Initially, these were given an INN using the -mab stem, but this was soon considered unsatisfactory and replaced by the -fusp stem when it was adopted. In the current scheme, fusion proteins containing a monoclonal antibody component as the targeting moiety are given an -a- infix (e.g., tebentafusp, bintrafusp alfa). Other infixes are used for other components of the fusion protein. Fusion proteins containing IgG Fc are commonly produced to enhance the half-life of the non-IgG component. These substances are given an INN with the ef- prefix to indicate the non-targeting Fc component (e.g., eftrenonacog alfa).