Immunopaleontology reveals how affinity enhancement is achieved during affinity maturation of antibodies to influenza virus

Therapeutic Monoclonal Antibodies for Ebola Virus Infection Derived from Vaccinated Humans

“…In these examples, the great majority of therapeutic antibodies were isolated from animals or humans after multiple or prolonged exposures to the EBOV glycoprotein. These levels of exposure are thought to select for high-affinity antibodies through the acquisition of multiple adaptive somatic mutations after repeated rounds of competitive selection of B cells in the germinal centers of lymph nodes during affinity maturation; reviewed in (Eisen and Chakraborty, 2013;Oropallo and Cerutti, 2014). Structural analysis of human monoclonal antibodies to influenza hemagglutinin, isolated from each stage of this process, suggests that the useful mutations pre-configure the tertiary structure of the binding loops of the antibody to minimize the energy cost of binding.…”

Antibody Engineering and Therapeutics

“…This process has been analyzed in detail by the combination of cellular immunology and x-ray structure determination of progressively matured antibodies for a given lineage. 119 , 120 These data revealed that the long CDR-H3 in the given B-cell lineage becomes increasingly more rigid as the binding site achieves higher affinities with greater specificity. Recent studies 121 , 122 were noted that describe results of a statistical analysis of the 200 distinct antigen-antibody crystal structures in the Protein Data Base.…”

“…Their maturation in the immune system is directed in specific ways, governed by antigen interactions with a given lineage of B-cell receptors to progressively improve antigen-binding properties of the displayed antibody binding site. This process has been analyzed in detail by the combination of cellular immunology and x-ray structure determination of progressively matured antibodies for a given lineage 119 , 120 . These data revealed that the long CDR-H3 in the given B-cell lineage becomes increasingly more rigid as the binding site achieves higher affinities with greater specificity.…”

To dream the impossible dream: universal influenza vaccination

“…While affinity maturation is clearly a central feature of Ab responses, it is possible that other factors contribute to B cell selection. Indeed, as we approach the 50 th anniversary of the discovery of affinity maturation [44,45], much remains to be learned regarding its workings in the context of primary vs. memory responses. How can affinity maturing B cells sense essentially minute differences in Ab affinity if antigen is presented in multivalent form on viruses, creating enormously avid interactions between virions and B cells [46]?…”