China
Africa
Explore chapters and articles related to this topic
Order Sepolyvirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
As described earlier, the great DNA packaging and delivery potential of the SV40 VLPs was established first in late 1990s (Sandalon et al. 1997). The in vitro packaging methodology that was elaborated by Kimchi-Sarfaty et al. (2003) overcame restrictions of the other SV40 systems such as the requirement for SV40 sequences and the limitation in size of DNA that can be packaged. The in vitro packaging system used the four SV40 proteins VP1, VP2, VP3, and agno or VP1 only. The packaged plasmids ranged in size from 4.2–17.6 kb, did not require any SV40 sequence, and only slightly affected particle size. Furthermore, Kimchi-Sarfaty et al. (2005) demonstrated the first use of the SV40 pseudovirions to deliver into human cells both principal types of RNAi effector molecules: plasmid-expressed short hairpin RNAs (shRNAs) and synthetic siRNAs. Kimchi-Sarfaty et al. (2006) delivered a toxin to treat human adenocarcinomas in mice when a truncated Pseudomonas exotoxin gene was transferred by the SV40 pseudovirions. Later, Lund et al. (2010) and Kimchi-Sarfaty and Gottesman (2012) published the detailed procedure on how to generate the SV40 pseudovirions and deliver the packaged genes.
Recombinant Antibodies
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Melvyn Little, Sergey M. Kipriyanov
This approach used by Benhar et al. (1994) for humanization of carcinoma-specific mAb B3 combines, with some differences, the principles of CDR grafting and resurfacing. The variable domains of the heavy and light chain were aligned with their best human homologues to identify framework residues that differ. Six VH and five VL residues that differ were not changed because they were buried in the interdomain interface, or found to result in decreased affinity when mutated. This basic design resulted in 20-fold loss of activity. Changing VL residues at the interdomain interfacial position 100 and at the buried position 104 to the human sequence increased the activity 8-fold. Changing a VH residue at position 82b from the human sequence back to that of the mouse restored the activity 2- to 3-fold. As a result, humanized B3(Fv) fused to the Pseudomonas exotoxin PE38 retained antigen-binding activity but lost immunogenic epitopes recognized by sera from monkeys that had been immunized with B3(Fv)-PE38 (Benhar et al., 1994).
Bacteria and Bioactive Peptides
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Ameer Khusro, Chirom Aarti, Paul Agastian
Diphtheria toxin (DT) is known to bind with the surface of cells, expressing the heparin-binding epidermal growth factor (HB-EGF) precursor, forming a DT-HB-EGF complex. DT undergoes post-translational modifications, forming DT fragment A. This catalytically ribosylates elongation factor-2 (EF-2) leading to inhibition of protein synthesis with subsequent cell lysis and/or induction of apoptosis (Lanzerin et al. 1996; Louie et al. 1997; Falnes et al. 2000; Frankel et al. 2002). Likewise, Pseudomonas exotoxin A is also known to inhibit protein synthesis.
Antibody-drug conjugates: Design and development for therapy and imaging in and beyond cancer, LabEx MAbImprove industrial workshop, July 27–28, 2017, Tours, France
Published in mAbs, 2018
Camille Martin, Claire Kizlik-Masson, André Pèlegrin, Hervé Watier, Marie-Claude Viaud-Massuard, Nicolas Joubert
Dr. Mathieu Cinier (Affilogic, Nantes, France) followed with his talk on Nanofitins® as tunable targeting agents for both imaging and therapy. Nanofitins® are very small binding proteins designed for therapeutic application with low predicted immunogenicity, as well as good tissue and tumor penetration. Their fast clearance profile can be easily modulated to match the requirements of their application via a proprietary half-life extension domain. Nanofitins® are naturally highly stable to temperature (Tm > 70 °C) and to various chemical conditions such as high and low pH (0–12). All these different features make them attractive bioconjugate formats. Protein engineering, genetic fusion or chemical reactions can be performed at either the C-terminus or N-terminus, giving the opportunity to pair Nanofitins® with radioelements, toxins, enzymes, nanoparticles, mAbs or half-life extension modules. A case study with anti-epidermal growth factor receptor (EGFR) Nanofitins® was presented with demonstration of their selectivity for both murine and human EGFR (affinities in the nM range). Internalizing Nanofitins® were identified using a truncated portion of Pseudomonas exotoxin A (Pe38) toxin-based assay. Upon 18F labelling, an anti-EGFR Nanofitin® allowed fast and high contrast imaging of tumors in vivo with no accumulation in healthy organs.14,15
Moxetumomab pasudotox for the treatment of hairy cell leukemia
Published in Expert Opinion on Biological Therapy, 2019
Agnieszka Janus, Tadeusz Robak
The Pseudomonas exotoxin is composed of three domains: Ia – the cell binding domain, Ib of unknown significance, II – used to release domain III from Ia, and domain III – the ADP-ribosylating domain which inactivates elongation factor 2 (EF2) [35]. CD22 is a 140 kDa type I membrane protein, a member of the Siglec family (sialic-acid-binding immunoglobulin-like lectin), that negatively regulates B-cell receptor Ca++ signaling. Its exclusive expression on the B-cell surface, and the absence of expression on B-cell precursors and normal tissues, makes it a perfect pharmacological target [36].
MAPPs for the identification of immunogenic hotspots of biotherapeutics; an overview of the technology and its application to the biopharmaceutical arena
Published in Expert Review of Proteomics, 2018
Valerie Quarmby, Qui T Phung, Jennie R Lill
Recombinant immunotoxins (RITs) have tremendous therapeutic potential, but their efficacy can be limited by immunogenicity. Drivers of unwanted immune responses to Pseudomonas exotoxin A (PE38)-based RITs have been studied extensively by Pastan, Mazor, and colleagues. They employed risk-ranking tools to engineer less immunogenic PE38 RITs. This has been accomplished by introducing point mutations to eliminate potential T- and B-cell epitopes. As mentioned above, this is a difficult balancing act, as changes that are intended to help with ‘de-immunization’ cannot be allowed to impair toxin potency [92].