title: Human monoclonal antibodies to HIV-1 gp140 from mice bearing YAC-based human immunoglobulin transloci.
abstract: Mice carrying human immunoglobulin transloci were immunised with HIV-1 gp140 antigen to gain insight into the range and nature of human monoclonal antibodies (mAbs) that can be elicited from such humanised mice. Using five-feature mice that harbour YAC-based germline-configuration human IgM, Igκ and Igλ transloci in a mouse background disrupted for endogenous mouse IgH and Igκ expression, gp140-specific human IgM mAbs were readily elicited following serial immunisation. These mAbs were converted to human IgG1 format and were found to bind diverse epitopes within gp140, exhibiting high functional affinity for the antigen-typically in the nanomolar or sub-nanomolar range. The number of specific, stable hybridomas per mouse was, however, low (typically around five) with the hybridomas within individual mice often being clonally related. Nevertheless, different mice used B cell clones expressing varied V(D)J combinations, with affinity maturation through somatic hypermutation making a critical contribution. Thus, a wide range of distinct high-affinity mAbs can be obtained by immunising multiple animals. The results confirm the utility of the translocus-mouse approach and give insight into strategies for possible future improvement.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Pruzina
authors.forename: Gareth T
authors.initials: GT
authors.lastname: Williams
authors.forename: Galina
authors.initials: G
authors.lastname: Kaneva
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Davies
authors.forename: Alicia
authors.initials: A
authors.lastname: Martín-López
authors.forename: Marianne
authors.initials: M
authors.lastname: Brüggemann
authors.forename: Sueli M
authors.initials: SM
authors.lastname: Vieira
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jeffs
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Sattentau
authors.forename: Michael S
authors.initials: MS
authors.lastname: Neuberger
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D005803:Genes, Immunoglobulin; D006801:Humans; D006825:Hybridomas / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007075:Immunoglobulin M / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D014178:Translocation, Genetic / Q000235:genetics*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1