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Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope.

ABSTRACT: Affinity maturation selects B cells expressing somatically mutated antibody variants with improved antigen-binding properties to protect from invading pathogens. We determined the molecular mechanism underlying the clonal selection and affinity maturation of human B cells expressing protective antibodies against the circumsporozoite protein of the malaria parasite Plasmodium falciparum (PfCSP). We show in molecular detail that the repetitive nature of PfCSP facilitates direct homotypic interactions between two PfCSP repeat-bound monoclonal antibodies, thereby improving antigen affinity and B cell activation. These data provide a mechanistic explanation for the strong selection of somatic mutations that mediate homotypic antibody interactions after repeated parasite exposure in humans. Our findings demonstrate a different mode of antigen-mediated affinity maturation to improve antibody responses to PfCSP and presumably other repetitive antigens.

SUBMITTER: Imkeller K

PROVIDER: S-EPMC6420115 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope.

Imkeller Katharina K Scally Stephen W SW Bosch Alexandre A Martí Gemma Pidelaserra GP Costa Giulia G Triller Gianna G Murugan Rajagopal R Renna Valerio V Jumaa Hassan H Kremsner Peter G PG Sim B Kim Lee BKL Hoffman Stephen L SL Mordmüller Benjamin B Levashina Elena A EA Julien Jean-Philippe JP Wardemann Hedda H

Science (New York, N.Y.) 20180607 6395

Affinity maturation selects B cells expressing somatically mutated antibody variants with improved antigen-binding properties to protect from invading pathogens. We determined the molecular mechanism underlying the clonal selection and affinity maturation of human B cells expressing protective antibodies against the circumsporozoite protein of the malaria parasite <i>Plasmodium falciparum</i> (PfCSP). We show in molecular detail that the repetitive nature of PfCSP facilitates direct homotypic in ...[more]

PMID: 29880723

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Project description:Antibodies isolated from human donors are increasingly being developed for anti-infective therapeutics. These antibodies undergo affinity maturation in vivo, minimizing the need for engineering of therapeutic leads for affinity. However, the affinities required for some therapeutic applications may be higher than the affinities of the leads obtained, requiring further affinity maturation in vitro. To improve the neutralization potency of natural human antibody MSL-109 targeting human cytomegalovirus (CMV), we affinity matured the antibody against the gH/gL glycoprotein complex. A phage display library where most of the six complementary-determining regions (CDRs) were allowed to vary in only one amino acid residue at a time was used to scan for mutations that improve binding affinity. A T55R mutation and multiple mutations in position 53 of the heavy chain were identified that, when present individually or in combination, resulted in higher apparent affinities to gH/gL and improved CMV neutralization potency of Fab fragments expressed in bacterial cells. Three of these mutations in position 53 introduced glycosylation sites in heavy chain CDR 2 (CDR H2) that impaired binding of antibodies expressed in mammalian cells. One high affinity (KD<10 pM) variant was identified that combined the D53N and T55R mutations while avoiding glycosylation of CDR H2. However, all the amino acid substitutions identified by phage display that improved binding affinity without introducing glycosylation sites required between two and four simultaneous nucleotide mutations to avoid glycosylation. These results indicate that the natural human antibody MSL-109 is close to a local affinity optimum. We show that affinity maturation by phage display can be used to identify and bypass barriers to in vivo affinity maturation of antibodies imposed by glycosylation and codon usage. These constraints may be relatively prevalent in human antibodies due to the codon usage and the amino acid sequence encoded by the natural human repertoire.

Dataset Information

Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope.

Publications

Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope.

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