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PMID: 10963674 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Virus neutralization by germ-line vs. hypermutated antibodies.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 18 ·2000-08-29 ·Pages 10126-31

Kalinke U, Oxenius A, Lopez-Macias C, Zinkernagel RM, Hengartner H

Abstract

Mice infected with vesicular stomatitis virus (VSV), a cytopathic virus closely related to rabies virus, mount a virus-neutralizing antibody response protecting against lethal disease. VSVneutralizing monoclonal IgGs isolated from primary immune responses were devoid of somatic mutations, whereas most secondary and all hyperimmune response IgGs tested were hypermutated. A comparative analysis of recombinant single-chain antibody fragments (scFv-Ckappa) revealed that even the germ-line precursor of one hypermutated antibody bound and neutralized VSV. Four somatic amino acid substitutions in V(H) increased by 300-fold the binding strength of monovalent scFv-Ckappa. The multivalent binding avidity of germ-line scFv-Ckappa was increased by more than 10-fold compared with the monovalent binding strength. In contrast, hypermutated scFv-Ckappa did not show such avidity effects. Thus the overall binding difference between the germ-line and the hypermutated VSV-neutralizing antibody was only 10- to 15-fold. This may explain why primary germ-line antibodies and secondary hypermutated antibodies directed against pathogens such as viruses and bacteria expressing repetitive antibody determinants show rather similar binding qualities, whereas monovalently binding hapten-specific antibodies can show "affinity maturation" effects of up to 1000-fold.

MeSH Terms
Animals Antibodies, Monoclonal/genetics,immunology Antibodies, Viral/genetics,immunology Antibody Specificity Base Sequence Germ-Line Mutation Immunoglobulin G/genetics,immunology Immunoglobulin Heavy Chains/genetics,immunology Immunoglobulin Light Chains/genetics,immunology Immunoglobulin Variable Region/genetics,immunology Mice Mice, SCID Mites/immunology,virology Mutagenesis, Site-Directed Neutralization Tests Recombinant Proteins/immunology Vesicular stomatitis Indiana virus/immunology
Chemicals
Antibodies, Monoclonal Antibodies, Viral Immunoglobulin G Immunoglobulin Heavy Chains Immunoglobulin Light Chains Immunoglobulin Variable Region Recombinant Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Kalinke U
Institute of Experimental Immunology, 8091 Zurich, Switzerland. kalinke@embl-monterotondo.it
Oxenius A
Lopez-Macias C
Zinkernagel R M
Hengartner H
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.97.18.10126
Email
kalinke@embl-monterotondo.it
Published
2000-08-29
Pages
10126-31
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC27744
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.97.18.10126 PMC Full Text View journal details
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