Acquired Immunity
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal in Principles of Physiology for the Anaesthetist, 2020
B lymphocytes are normally dormant in the lymphoid tissues. After exposure to an antigen, there is an interval of about 2 weeks before antibodies can be found in the blood. The invading antigen (microorganism) is first localized and phagocytosed by macrophages that present it to adjacent B lymphocytes. The antigen also activates helper T lymphocytes. The B lymphocytes then proliferate and differentiate into lymphoblasts that become plasma cells in the lymph gland. The plasma cells release antibodies into the lymph to be carried to the blood. These antibodies do not reach a high concentration and do not persist. This is the primary immune response (Figure 56.3). In the primary response, B lymphocytes produce IgM and then undergo the following changes: (i) class switching – changing, (ii) affinity maturation – antibody binds more tightly to antigen and (iii) memory cell formation.
Potential of Antibody Therapy for Respiratory Virus Infections
Sunit K. Singh in Human Respiratory Viral Infections, 2014
Once lead antibodies have been validated, alterations to either the variable or constant antibody domains may be made to improve the affinity for target antigen and to improve pharmacological activity of the antibody (see Figure 10.7). Improvements to first-generation antibodies may be achieved through humanization of regions flanking the CDR domains or affinity maturation of the CDR domains, yielding second-generation antibodies with higher affinity for target antigen. These are then succeeded by third-generation antibodies, which have improved Fc functions in addition to improved variable domains. Many of these next-generation antibodies have been developed for use in noninfectious immune conditions with varying degrees of success and have been reviewed elsewhere [126]. We focus our discussion on the development of next-generation Palivizumab as an example of both the potential and challenges of antibody-based therapy for respiratory viruses.
The Immunoglobulin Variable-Region Gene Repertoire and Its Analysis
Cliburn Chan, Michael G. Hudgens, Shein-Chung Chow in Quantitative Methods for HIV/AIDS Research, 2017
Immunoglobulin (Ig) is a protein that binds to molecular determinants (antigens) on pathogenic microbes, infected cells, and dysregulated self. It serves as the recognition element of the B-cell receptor (BCR) and as secreted antibody, one of the key effectors of immunity. The domain of the Ig gene responsible for these functions is called the immunoglobulin variable region gene (IgVRG). The IgVRG repertoire—the collection of all IgVRGs simultaneously present in an individual organism—is diverse and dynamic. This diversity is due to the assembly of IgVRG by stochastic recombination of gene-segment libraries early in B-cell ontogeny and to somatic hypermutation subsequent to antigen exposure. B cells are activated by engagement of their BCR and proliferate, forming clones that undergo affinity maturation by somatic hypermutation and differentiate into long-lived plasma or memory cells. Affinity maturation is essential to effective humoral immunity; its induction is a primary goal of much vaccine design and in particular of vaccine design against human immunodeficiency virus 1 (HIV-1) disease.
Fast-tracking antibody maturation using a B cell-based display system
Published in mAbs, 2022
Hitomi Masuda, Atsushi Sawada, Shu-ichi Hashimoto, Kanako Tamai, Ke-Yi Lin, Naoto Harigai, Kohei Kurosawa, Kunihiro Ohta, Hidetaka Seo, Hiroshi Itou
Monoclonal antibodies are becoming an indispensable therapeutic modality owing to their remarkable clinical benefits.1,2 Advances in antibody discovery and engineering technologies have allowed for highly rapid and efficient therapeutic antibody generation.3 Affinity maturation is a key step for developing antibodies exhibiting therapeutic properties. Many techniques, including in vitro display-based approaches combined with random- or targeted-mutagenesis and chain shuffling and in silico computational approaches, have been established and widely adopted.4 These well-researched techniques, however, require in-depth knowledge of antibody engineering for artificial mutation library design and involve complicated experimental procedures, including reformatting of antibody fragments into full-length antibodies. Thus, these techniques are usually unsuccessful at processing multiple antibodies simultaneously. The limitations of these approaches can potentially delay further downstream processes of drug development.
Anti-EGF antibodies as surrogate biomarkers of clinical efficacy in stage IIIB/IV non-small-cell lung cancer patients treated with an optimized CIMAvax-EGF vaccination schedule
Published in OncoImmunology, 2020
Xitlally Popa, Beatriz García, Karla P. Fuentes, Vivian Huerta, Karen Alvarez, Carmen E. Viada, Elia Neninger, Pedro C. Rodríguez, Zuyen González, Amnely González, Tania Crombet, Zaima Mazorra
Antibody affinity maturation is an antigen-dependent process24. To our knowledge, no previous studies have addressed affinity maturation of antibody response generated by cancer vaccines. This characterization could provide a quantitative analysis regarding the contribution of affinity maturation to the clinical outcome of treated patients. The EGF-specific antibody response developed in NSCLC patients during CIMAvax-EGF administration was characterized by an early and significant increment in antibody concentration and by discrete but continuous decrease in the dissociation rates. These results evidence that long-term maturation of antibody response elicited by CIMAvax-EGF vaccine increases the average affinity of antibody population due to lower dissociation rates of EGF-antibody complexes. Considering the high heterogeneity on affinity maturation among individuals found in human response against protein antigens, larger sample number would be also necessary to identify the relationship between the affinity of anti-EGF antibodies and the clinical outcome of patients. Interestingly, according to a theoretical model, the increase in the affinity seems to be related to IgG4 switch42 which is in line with the aforementioned switch in IgG subclass.
Affinity maturation of antibodies by combinatorial codon mutagenesis versus error-prone PCR
Published in mAbs, 2020
Jan Fredrik Simons, Yoong Wearn Lim, Kyle P. Carter, Ellen K. Wagner, Nicholas Wayham, Adam S. Adler, David S. Johnson
Ultimately, the goal of an antibody affinity maturation campaign is to identify functionally improved molecules. We therefore compared the function of several clones using cell-surface binding and in vitro efficacy assays. rOX40.24.2For example, the anti-PD-1 and anti-PD-L1 antibodies had between 4.8- to 9.6-fold stronger binding to cells than to corresponding soluble antigens. We speculate that the increased affinity of the antibodies to cell-surface antigens may be a result of conformational differences between the soluble and surface- expressed antigens, post-translational modifications, or an avidity effect caused by the close proximity of target antigens on the cell surface.30 In contrast, for the anti-CTLA-4 antibodies, cell surface EC50 values were comparable to the BLI affinity constants (Figure 5a; Table 4).
Related Knowledge Centers
- Antibody
- B Cell
- Germinal Center
- Immunology
- Somatic Hypermutation
- Antigen
- Follicular B Helper T Cells
- Immune Response
- Complementarity-Determining Region
- Activation-Induced Cytidine Deaminase