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Pharmaceuticals and Nutraceuticals from Fish and Their Activities
Published in Ramasamy Santhanam, Santhanam Ramesh, Subramanian Nivedhitha, Subbiah Balasundari, Pharmaceuticals and Nutraceuticals from Fish and Fish Wastes, 2022
Ramasamy Santhanam, Santhanam Ramesh, Subramanian Nivedhitha, Subbiah Balasundari
Brain therapy: Lampreys have been reported to help boost brain therapies. The molecules derived from the lampreys’ immune system called “variable lymphocyte receptors” have been reported to carry drugs to the brain, boosting the effectiveness of treatments for brain cancer, brain trauma, or stroke (Cohut, 2019).
Immunology
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
The immunization with the phage f2 led to discovery of the immunoglobulins in the primary immune response of the bullfrog Rana catesbiana, which paved the way for the further studies on the phylogenetic origins and evolution of the antibody structure (Marchalonis and Edelman 1966). In this study, the molecular mass and amino acid composition of the amphibian γM and γG type immunoglobulins were determined. Furthermore, the sea lamprey Petromyzon marinus was found to produce specific antibodies after immunization with the phage f2 (Marchalonis and Edelman 1968). It was shown therefore that the amphibian and jawless fish antibodies revealed the same chain structures as those of their counterparts in higher animal species. However, it is noteworthy that the results on lamprey still remained unexplained in the absence of immunoglobulins in these species of fish (Matsunaga and Rahman 1998). The latter review proposed that these results were attributable to the binding activities of activated C3 and C4 component for foreign cells and molecules. Later, the dual nature of the adaptive immune system in lampreys was discovered (Guo et al. 2009). It appeared that the jawless vertebrates use so-called variable lymphocyte receptors (VLRs), comprised of leucine-rich-repeat segments as counterparts of the immunoglobulin-based receptors that jawed vertebrates use for the antigen recognition. The highly diverse VLR genes were somatically assembled by the insertion of variable leucine-rich-repeat sequences into the incomplete germline VLRA and VLRB genes. The VLRA(+) and VLRB(+) lymphocytes resembled those of the mammalian T and B cells, and the VLRB lymphocytes bound native antigens and differentiated into the VLR antibody-secreting cells. Therefore, the early work of Marchalonis and Edelman (1968), together with further finding of the T-like and B-like lymphocytes in lampreys, offered new insight into the evolution of the adaptive immunity.
Phylogeny of the mucosal immune system
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Robert D. Miller, Irene Salinas
In the hagfish and lamprey, diversity occurs at a gene cluster encoding a class of receptors called the variable lymphocyte receptors (VLRs). The VLRs are the functional equivalent to the antibodies in jawed vertebrates. However, instead of being based on immunoglobulin protein domains, they are composed of leucine-rich repeat (LRR) domains similar to toll-like receptors. Both hagfish and lampreys have two sets of VLR genes, VLRA and VLRB, which define the distinct VLRA+ and VLRB+ lymphocyte lineages. VLRA+ cells express a nonsecreted cell-surface receptor and produce cytokines and chemokines. VLRB+ cells express a cell-surface receptor that, upon cell activation, is secreted either as tetramers or pentamers, much like IgM in gnathostomes, and functions as an antibody. VLRs differ from Igs and TCRs not only in the protein structure that is being used but also in the genetic mechanisms used to generate diversity. Ig and TCR diversity is generated via the assembly of an exon encoding the variable domain from the V, D, and J gene segments by means of the cutting and splicing of DNA using site-specific endonucleases and DNA repair mechanisms. In contrast, the VLR gene system in lampreys and hagfish generates diversity using a gene conversion mechanism that is dependent on DNA damage induced by cytidine deaminase. The cytidine deaminases expressed in agnathan lymphocytes are related to the activation-induced cytidine deaminases (AIDs) that participate in primary antibody diversification, affinity maturation, and isotype switching in birds, mammals, and other gnathostomes. Therefore, the involvement of such deaminases in antigen receptor genetics is also ancient in the vertebrate lineage (see Table 2.1). Through gene conversion, a variable number and combination of LRR domains are added to the expressed locus. As with V(D)J recombination, the VLR system is capable of generating many (in the order of 1014) possible receptors.
Development of chimeric antigen receptors targeting T-cell malignancies using two structurally different anti-CD5 antigen binding domains in NK and CRISPR-edited T cell lines
Published in OncoImmunology, 2018
Sunil S. Raikar, Lauren C. Fleischer, Robert Moot, Andrew Fedanov, Na Yoon Paik, Kristopher A. Knight, Christopher B. Doering, H. Trent Spencer
We have previously shown that a variable lymphocyte receptor (VLR) can be used for CAR-mediated antigen recognition instead of the more traditional immunoglobulin-based single chain variable fragment (scFv).24 VLRs represent the functional unit of the adaptive immune system in jawless vertebrates (lamprey and hagfish), and are analogous, but not homologous to immunoglobulins.25,26 VLRs have a fundamentally different structure and geometry than immunoglobulin-based antibodies, while still demonstrating high degrees of specificity and avidity. Importantly for the production of CAR-based therapeutics, they exist naturally as single chain crescent-shaped proteins with their variable region consisting of multiple assembled repeating sequences, termed leucine rich repeats (LRRs).25-28 VLRs function as avidity-based antibodies with the individual monomeric VLR units exhibiting lower affinity towards their target compared to their multimeric form.29,30 The unique single chain structure of VLRs allows for rapid insertion into a CAR scaffold, compared to the corresponding use of an immunoglobulin, in which the variable heavy and light chains need further engineering for adapting to CAR technologies. We hypothesized that a CD5-directed VLR-CAR would have equal or superior efficacy compared to a corresponding scFv-CAR.
Antigen recognition by single-domain antibodies: structural latitudes and constraints
Published in mAbs, 2018
Kevin A. Henry, C. Roger MacKenzie
Fully synthetic sdAbs, derived from VHHs, VNARs or from rare human and murine VH and VL domains that remain stable and soluble outside the context of the natural VH:VL pairing, can be engineered to bind antigens using in vitro methods (e.g., phage display). More recently, technologies have been developed for generating semi-synthetic sdAbs using engineered cell lines capable of inducible V(D)J recombination121 and transgenic mice bearing either hybrid llama-human or fully human igh loci;122 in both cases, a limited set of VH, D and JH genes (some of which are in non-germline configurations to promote autonomous folding) are rearranged in a foreign cellular or in vivo system. Limited numbers of synthetic sdAbs have been described and fewer still have been studied structurally in complex with antigens. Nevertheless, the available data suggests that some synthetic sdAbs have cleft-binding properties akin to those of VHHs and VNARs51 while others employ unusual mechanisms to interact with planar protein epitopes (e.g., dramatic CDR3 restructuring of a MDM4-specific VH domain to accommodate packing against a hydrophobic helix;123 significant involvement of FRs in binding of VHs to vascular endothelial growth factor124,125 and CD40126 using distinct mechanisms). Even less is known regarding the paratope structures and binding modes of non-Ig-based antibodies such as variable lymphocyte receptors127 and non-antibody scaffolds (based on monomeric non-Ig domains such as fibronectin type III and SRC homology 3 domains), and their synthetic origin may imply that they follow no general patterns. If so, restrictions on the binding specificities of naturally-occurring sdAbs may not equally affect synthetic sdAbs and non-antibody scaffolds, although fundamental structural constraints on the amino acid sequences that can be tolerated by stable Ig folds would still apply.
Preclinical studies of chimeric antigen receptor-modified natural killer cells in cancer immunotherapy: a review
Published in Expert Opinion on Biological Therapy, 2022
Mina Hosseini, Zahra Habibi, Narges Hosseini, Sina Abdoli, Nima Rezaei
Utilizing surrogate affinity components instead of scFvs holds a number of advantages, including lower possibility of Human Anti-Mouse Antibodies (HAMA) induction in case of using scFvs with murine elements. In a study by Raikar et al., anti-CD5, scFv- and Variable Lymphocyte Receptor (VLR)-basedsecond-generation CAR-modified NK-cells were used for targeting T-cell malignancies. VLR is a component of intrinsic immunity in jawless vertebrates that can be used as an alternative to scFv in CAR structures. Although both types of CAR-NK-cells exerted similar levels of cytotoxic effects in vitro, scFv-CARs proved more effective than VLR-CARs in reducing disease severity in vivo, probably due to lower persistence of VLR-based CARs [135]. As another approach to lessen the immunogenicity associated with murine scFvs, human fibronectin type III (Fn3) was used as Ag-binding domain. The CAR structure was composed of a specific VEGFR2-binding Fn3 domain, along with CD3ζ and CD28 signaling domains. The resulting CAR-NK-cells demonstrated enhanced cytotoxicity and specific IFN-γ release upon encounter with VEGFR2+ targets in vitro. Such FnCARs also offer the advantage of multiple-Ag binding due to their small size [136]. As another alternative to scFvs, Hambach et al. investigated the use of nanobodies in CAR structures to target CD38 in multiple myeloma and Burkitt lymphoma. Nanobodies (Nbs), as single-variable domains derived from heavy-chain antibodies of camelids, harbor favorable stability, solubility, and affinity, thus serving as a good option for use in the structure of fusion proteins. The proposed CAR structure, consisting of IgG4-derived hinge, CD28 transmembrane, and CD3ζ, CD28, and 4–1BB signaling domains, rendered the resulting CAR-NK-cells effective in lysing CD38-expressing cells in cell lines and human bone marrow samples in a time- and dose-dependent manner, compared to control cells. The anti-tumor function of Nb-CARs is dependent upon specific binding to the defined epitopes of CD38 mainly inaccessible to scFvs, thereby activating the respective signaling cascade of CAR and inducing NK-mediated cytotoxicity via releasing perforin and granzyme. Some Nbs were also able to block the enzymatic function of CD38 [137]. A significant advantage offered by Nbs is their easily modifiable affinity to control off-target effects associated with conventional CARs. In general, scFv-substituting Ag-binding domains, e.g. VLRs, Nbs, and proteins with specific-binding properties, might present an alternative to scFvs, due to better safety profile, facile modulation, and the possibility of multiple-Ag targeting.