Nanocarriers as an Emerging Platform for Cancer Therapy
Lajos P. Balogh in Nano-Enabled Medical Applications, 2020
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
Ronald P. Evens in 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.
Peptide vaccines
F. Y. Liew in Vaccination Strategies of Tropical Diseases, 2017
The reason for the enhanced response to the multiple copy construct is not clear. Whether it is the repetition of the antigenic determinant which is important, as suggested by Enea et al.,22 for the immunodominant sequence of the circumsporozoite antigen of malaria has not been determined. However, this explanation seems unlikely because keyhold limpet hemocyanin carrying 35 copies of the peptide does not give an enhanced response. A more likely explanation is the relative topography of the B cell epitope with the T cell epitopes of the β-galactosidase molecule, i.e., the configuration of the multiple copies of the peptide with respect to the T cell epitopes. Structural studies at the atomic level of the single and multiple copy fusion proteins could provide significant information on this problem.
GLP-1R agonists for the treatment of obesity: a patent review (2015-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Chunxia Liu, Yuxing Zou, Hai Qian
Fusion proteins are products of fusion genes, and can also be obtained by fusing one or two proteins through biological or chemical methods. Generally, in order to obtain an ideal drug, GLP-1 needs to select different proteins for fusion. To address the shortcomings of GLP-1 being rapidly cleared by DPP-4 in vivo and lack of effectiveness, one of the strategies is fusing GLP-1 analogues with antibody. Currently, the longest-acting of GLP-1 agonists dulaglutide which is a fusion of an IgG4-Fc fragment to the GLP-1 analogues can be administered once per week. The antibody used for fusion has the biological activity of specifically recognizing GLP-1 R without hindering the binding of GLP-1 receptor. Its high affinity and stability with the receptor can activate GLP-1 receptor for a long time, consequently, the effective time and potency of its binding to the receptor promote greatly.
An update on gene therapy for lysosomal storage disorders
Published in Expert Opinion on Biological Therapy, 2019
Murtaza S. Nagree, Simone Scalia, William M. McKillop, Jeffrey A. Medin
Modifications to improve delivery of every lysosomal enzyme may not be possible as some targets may lose their activity and/or stability. Resulting fusion proteins may also be uniquely immunogenic compared to the natural enzyme, reducing the efficacy of therapy [118]. Instead of targeting transgene-products to specific tissues, it may prove beneficial to develop tissue-targeting vectors, especially for in vivo gene therapy. Various methods are being explored to discover or engineer serotypes of AAV that confer tissue specificity [125]. A library of serotypes each capable of transducing specific tissue types can be envisioned. Progress is being made towards this goal. For example, peptides selected by phage-display technology were engineered into AAV2 capsids to make AAV-PFG, an AAV redirected from a predominantly liver tropism to that of the brain endothelium [126]. Systemic delivery of AAV-PFG has been used for the treatment of CNS manifestations in MPS VII mice [127]. Similarly, a serotype called AAVB1 was engineered from AAV9 to enhance transduction of neurons and muscles to treat Pompe disease. This novel serotype has been evaluated in mice wherein correction of respiratory dysfunction was achieved [128]. Alternatively, different formulations of vectors are being investigated to allow new routes of administration, such as AAV delivery by intranasal inhalation, which may facilitate vector crossing the BBB as seen in a MPS I mouse study [129]. While these technologies may prove to be useful, they are still in their infancy.
Antibody-mediated delivery of LIGHT to the tumor boosts natural killer cells and delays tumor progression
Published in mAbs, 2021
Marco Stringhini, Jacqueline Mock, Vanessa Fontana, Patrizia Murer, Dario Neri
A fusion of murine LIGHT with the F8 antibody (specific to the alternatively-spliced extra domain A (EDA) of fibronectin, a conserved tumor-associated antigen) has previously been described, using the antibody in single-chain variable fragment (scFv) format and relying on the ability of LIGHT to form stable non-covalent homotrimers.24 The resulting fusion protein was homogeneous in biochemical characterization assays and maintained binding ability in vitro. However, in contrast to the results obtained with fusions of the F8 antibody with both murine and human TNF (which showed selective uptake at the tumor site with excellent biodistribution results), the fusion of scFv(F8) and murine LIGHT exhibited poor uptake at the tumor site and rapid clearance from the body.24 It has previously been reported that members of the TNF superfamily may gain stability when expressed as a single polypeptide, with linkers connecting the three monomeric subunits.25,26
Related Knowledge Centers
- Chimera
- Chromosomal Translocation
- Fusion Gene
- Molecular Cloning
- Mutation
- Oncogene
- Peptide
- Protein Domain
- Gene
- Chronic Myelogenous Leukemia