Anti-ldiotype Antibodies: Novel Therapeutic Approach to Cancer Therapy
Ronald H. Goldfarb, Theresa L. Whiteside in Tumor Immunology and Cancer Therapy, 2020
Immunoglobulin (Ig) molecules possess variable regions specific for antigen recognition. The variable region is encoded by VH, D and JH genes for the heavy chains and VL and JL chains for the light chain (1). The variable region contains determinants known as idiotypes (Ids), which are themselves immunogenic. Antibodies can be made to many structures in the variable region associated with the light chain, heavy chain, or a combination of both chains (2,3). Early studies by Oudin and Michel (3) and Kunkel and co-workers (2) indicated that an Id was unique to a small set of antibody molecules. However, the idiotypic determinants may show a continuum of specificity from more or less private to semi-public (4,5), e.g., if different antibodies are coded by the same VH gene segment, a shared or semi-public Id may be found. The Id is often defined by the antibody made against it known as anti-Id antibody.
The Lymphatic/Immune System and Its Disorders
Walter F. Stanaszek, Mary J. Stanaszek, Robert J. Holt, Steven Strauss in Understanding Medical Terms, 2020
Each Y-shaped antibody or immunoglobulin is made up of two light peptide chains and two heavy chains. The arms of the Y form the variableregion, which differs for each specific antibody; the variable region contains the combining site(antigen-binding site) specific for the antigens to which they attach and can be split chemically to yield the Fab fragment(antigen-binding fragment). There are five different kinds of heavy chains providing the classification of immunoglobulins: IgA (or gA), IgG, IgD, IgE, and IgM.
Fluorescence In Situ Hybridization and Polymerase Chain Reaction
Wojciech Gorczyca in Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
The immunoglobulin molecule is made up of two heavy chains and two light chains, joined by disulfide bonds. Both heavy and light chains have variable and constant regions corresponding to the V and Cμ genes. The genes encoding heavy chains are located on chromosome 14, and the genes encoding light chains are located on chromosomes 2 (kappa) and 22 (lambda). During the maturation of lymphocytes, B cells rearrange their genes producing fusion gene composed of variable (V), diversity (D), joining (J), and constant (C) segments, which encode an antigen receptor that is expressed on the surface of B cells and become secreted when B cells differentiate into plasma cells. All maturing B cells rearrange their genes differently by splicing out and deleting a portion of the IGH gene, in which 1 of 30 D regions is juxtaposed first with 1 of 6 J regions, followed by joining of 1 of ~200 V regions. Antibody type (IgA, IgM, IgD, IgE, and IgG) depends on which C region (Cα, Cμ, Cδ, Cε, or Cγ) joins the rearranged VDJ genes. The heavy-chain protein (IGH) joins either kappa (κ) or lambda (λ) light-chain proteins (which are encoded by genes rearranged in a similar manner) to produce antibody. The unique coding sequence for both heavy- and light-chain genes ensures the diversity of antibody production by the plasma cells. Normal B-cell population, therefore, consists of polyclonal IG gene rearrangements.
SPLICELECT™: an adaptable cell surface display technology based on alternative splicing allowing the qualitative and quantitative prediction of secreted product at a single-cell level
Published in mAbs, 2020
Christel Aebischer-Gumy, Pierre Moretti, Romain Ollier, Christelle Ries Fecourt, François Rousseau, Martin Bertschinger
Here, we describe a method of cell surface display based on alternative splicing using the chicken cardiac troponin intron 4, which is located upstream of the alternative exon 5 in the chicken genome.49,58 This intron is around 0.5 kbs long, and therefore more convenient for use in plasmids. In order to modulate the fractions of secreted and displayed antibody, the intron consensus sequences can be modified. We also show that the transmembrane domain added at the C-term of the heavy chain has a huge impact on the proportion of displayed antibody. This alternative splicing construct can, for example, be used as a screening or sorting tool in cell line development or in antibody discovery, allowing not only screening for the highest producers, but also for the desired product quality attributes, such as the heterodimerization level of a bispecific antibody or binding affinity to a target molecule.
Inter-assay variability in automated serum free light chain assays and their use in the clinical laboratory
Published in Critical Reviews in Clinical Laboratory Sciences, 2020
Laura Caponi, Nadia Romiti, Elona Koni, Annarita Di Fiore, Aldo Paolicchi, Maria Franzini
The five types of heavy chains (α, δ, ε, γ, μ) correspond to the five immunoglobulin (Ig) classes (IgA, IgD, IgE, IgG, IgM). The two light chains are kappa (κ) and lambda (λ), the latter consisting of peptides of about 220 amino acids, with a molecular weight of 22–25 kDa. In humans, about 60% of antibodies contain the κ chain and 40%, the λ chain, irrespective of the Ig class [2]. Both the light and heavy chains display structural regions called immunoglobulin domains, which are named constant (when shared by all immunoglobulins of the same class), or variable (when specific for each antibody). The paired variable domains of the heavy and light chains form the antigen-binding site. Although most of the heterogeneity between different Igs exists in the variable domains, a certain degree of heterogeneity also exists in the constant domains of the light chains; at least four functional isotypes of the λ chain [3,4] and three allotypes of the κ chain have been reported [4]. Plasma cells produce more light chains (10–40%) than heavy chains [5–7], and excess light chains secreted in the blood are known as free light chains (FLC). It is estimated that healthy subjects release 500 mg/day of FLC into the bloodstream [6,8].
Human-likeness of antibody biologics determined by back-translation and comparison with large antibody variable gene repertoires
Published in mAbs, 2020
Samuel Schmitz, Cinque Soto, James E. Crowe, Jens Meiler
To further investigate the role of public and private repertoires on the eligibility of Abs as drugs, we calculated PGSSMVJ scores using each of the three individual immunome repertoires. The majority of staged antibodies exhibit a cutoff of −2 or greater (Figure 6). Hence, we roughly defined any of the three scores as human-like as long as the Z-Score of the PGSSMVJ was greater or equal to −2. Figure 7 depicts the number of human-like scores for non-human (orange), human GenBank Abs (blue), and biologics (green), separated by light chains (a) and heavy chains (b). We observed high agreement between the three scores for human and therapeutic Abs. We also observed high agreement rates between all three repertoires, including 70.0% of all biologics and 92.3% of all human GenBank heavy chain sequences and 81.8% of all biologics and 94.6% of all human GenBank light chain sequences. In contrast only 8.8% light chain and 8.8% heavy chain sequences of biologics and 1.3% of light chain biologics and 2.6% of heavy chain human GenBank sequences were scored as non-human in all three cases.
Related Knowledge Centers
- Antibody
- Immunoglobulin A
- Immunoglobulin D
- Immunoglobulin Domain
- Immunoglobulin Light Chain
- Immunoglobulin M
- Isotype
- Protein Domain
- Immunoglobulin G
- Antigen