China
Africa
Explore chapters and articles related to this topic
The Inducible Defense System: Antibody Molecules and Antigen-Antibody Reactions
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The ability of the antibody molecule to bind to a single epitope is created by the “shape” produced by the interaction of the VL and VH domains (Figure 7.6A). Within the V region of the L and H chains there are areas that are quite constant from molecule to molecule in amino acid composition. These regions are “conserved” so the molecule can fold properly into the lg-superfamily domain configuration, and are therefore called the framework regions (Figure 7.6B). Within the V region of the L and H chains, (Figure 7.6B) there are also three regions that are highly variable and are therefore called the hypervariable regions. Each such region is five to ten amino acids in length. When the molecule folds together, the three VH and three VL hypervariable regions become located near each other on the outer surface of the antibody molecule (Figure 7.6B). These regions give the antibody molecule its “unique” shape. Because one or more of these regions makes contact with the epitope on the antigen, they are also known as the complementarity determining regions (CDR). Differences in amino acid sequences in the CDRs are responsible for the large number of unique antigen-binding sites which exist. Because the three-dimensional shape of the variable region is “unique.” the shape is referred to as the idiotype (idio means unique to each individual), and the binding site is the idiotypic region. Since the variable region itself has a unique shape, it may serve as an antigen in some situations.
Immunoglobulins
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
The parts of antibody which contact antigen are called complementarity-determining regions (CDRs, see below). The CDRs 1 and 2 are encoded by the 5’ regions of VH genes and they reflect predominantly germline-encoded sequence diversity. All of the rearrangement mechanisms described above create diversity within the most 3’ CDR3, made up of the 3’ end of VH D, (one or more genes, some possibly inverted, with imprecise joining, with or without N sequences, and possibly having undergone gene conversion), and the 5’ end of JH. One analysis estimates the overall number of potential CDR3 sequences to be on the order of 1014!
Immunoglobulins: Structure and diversity
Published in Gabriel Virella, Medical Immunology, 2019
Actually, certain sequence stretches of the variable regions vary widely from protein to protein, even among proteins sharing the same type of variable regions. For this reason, these highly variable stretches have been designated as hypervariable regions (Figure 5.10). The structure of hypervariable regions is believed to play a critical role in determining antibody specificity, since these regions are believed to be folded in such a way that they determine the three-dimensional structure of the “pouch” where a given epitope of an antigen will fit. In other words, the hypervariable regions will interact to create a paratope whose configuration is complementary to that of a given epitope. Thus, these regions can be also designated as complementarity-determining regions (CDRs). A paratope is determined by three CDR regions (1, 2, 3). CD1 and CD2 are mainly formed by hypervariable regions, while CDR3, the most variable of them, is formed by hypervariable regions but also by other regions of light- and heavy-chain molecules known as diversity and joining regions, described in detail in Chapter 7.
Challenges in antibody structure prediction
Published in mAbs, 2023
Monica L. Fernández-Quintero, Janik Kokot, Franz Waibl, Anna-Lena M. Fischer, Patrick K. Quoika, Charlotte M. Deane, Klaus R. Liedl
Antibodies are crucial components of the adaptive immune response.15 Genetic recombination and somatic hypermutation events enable the adaptive immune system to produce a vast number of antibodies against a variety of pathogens.14 To understand and optimize antigen recognition and to enable rational design of antibodies, accurate structure models are essential.16 Despite these recent advances, accurate structure prediction of antibodies remains challenging and still needs to be extensively validated. In particular, the flexible loops involved in recognizing the antigen pose a major challenge.17,18 In comparison to other protein superfamilies, the fold of antibodies is generally highly conserved.19–21 In particular, the framework of the antigen-binding fragment (Fab) is structurally almost identical for all antibodies.22,23 However, the area hardest to predict accurately is the six hypervariable loops that can form, together with several framework residues, the antigen-binding site, engaging with the respective epitope. These loops are also known as the complementarity-determining region (CDR) and provide the sequence and structure diversity essential to recognize a wide range of antigens. Five of the six loops tend to adopt canonical cluster folds based on their length and sequence composition. However, the third CDR loop of the heavy chain, the CDR-H3 loop, is the most diverse in length, sequence and structure and therefore is the most challenging loop to predict accurately.
Restoring the biological activity of crizanlizumab at physiological conditions through a pH-dependent aspartic acid isomerization reaction
Published in mAbs, 2023
Fabian Bickel, François Griaud, Wolfram Kern, Frieder Kroener, Manuela Gritsch, Jérôme Dayer, Samuel Barteau, Blandine Denefeld, Chi-Ya Kao-Scharf, Manuel Lang, Izabela Slupska-Muanza, Carla Schmidt, Matthias Berg, Jürgen Sigg, Lina Boado, Dirk Chelius
Biologics technical development integrates developability assessment as a major project selection milestone to minimize late-stage development issues, building on in silico scoring tools for the prediction of degradation hotspots, such as aspartic acid in the DG motif prone to isomerization. If chemical modifications exist in the antibody’s complementarity-determining regions (CDR), an effect on the binding activity is possible. The influence on the binding activity by the presence of succinimide in the CDR has already been reported.17–20 Iso-aspartic acid as isomerization variant has also been shown to result in a decreased binding activity, if present in the CDR.18,21,22 Degradation hotspots, such as the DG isomerization site, are scored negatively during the developability assessment using in silico prediction tools.
Time-spatial analysis of T cell receptor repertoire in esophageal squamous cell carcinoma patients treated with combined radiotherapy and PD-1 blockade
Published in OncoImmunology, 2022
Cihui Yan, Xiaoxue Ma, Zhoubo Guo, Xiaoying Wei, Dong Han, Tian Zhang, Xi Chen, Fuliang Cao, Jie Dong, Gang Zhao, Xuan Gao, Tao Wang, Yao Jiang, Ping Wang, Qingsong Pang, Wencheng Zhang
Each T cell clones express a unique T cell receptor (TCR) that recognizes antigen in a unique cognate peptide, namely major histocompatibility complex (MHC). About 90–95% TCRs are composed of α- and β-subunits that are encoded by recombinant genes generated from somatic variable (V), diversity (D) and joining (J) segments (VJ rearrangement for α; V[D]J rearrangement for β), which results in the high diversities of complementarity determining region 3 (CDR3) and antigen-specific T cell repertoire. Recent studies have shown that deep sequencing of the TCR variable beta (Vβ) (TCRB) CDR3 region could monitor the dynamics of T-cell repertoire response to treatment.8,9 Moreover, TCR clonality and diversity showed association in response to a broad range of tumor-associated antigens.10,11 Nonetheless, the TCR profiling response to immunotherapy in ESCC is relatively sparse.