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Human antibody repertoires in transgenic mice: generation, developmental regulation and therapeutic application of high affinity human antibodies

Objective



Monoclonal antibodies have received much attention because of their potential application to therapy in man. However, in order to reduce the immunogenicity of these reagents, it is very desirable that the administered monoclonal antibodies are of human origin.
Major problems have been encountered in preparing monoclonal antibodies of human origin. In particular, it will be difficult to circumvent the ethical and humane hurdles implicit in immunizing human volunteers.
Two major alternative approaches to the isolation of human monoclonal antibodies have been put forward:the phage display and transgenic mouse approaches, each of which has their particular advantages. At present, neither approach is fully developed but we anticipate that the two approaches might ultimately prove complementary.
It is the object of this application to finalize the development and application of the transgenic mouse approach. The advantage of this approach is that once the creation of the suitable mouse strain is finalized, it should be possible to isolate high affinity human antibodies to human antigens using entirely conventional and user-friendly technology.
The engineered mouse strain will contain human immunoglobulin heavy and light chain gene loci in germline configuration. These loci can undergo gene rearrangement yielding a population of mouse lymphocytes expressing a diverse array of human immunoglobulin molecules; antigen challenge of these mice in the conventional way can then lead to the establishment of antigen-specific hybridomas that secrete human monoclonal antibodies. The mouse immunoglobulin loci in these animals will carry targeted disruptions to facilitate human antibody isolation.
The creation of a suitable mouse strain is in its near final stages and the data obtained so far are extremely encouraging. The object of the work described in this application is - as part of an intra-European collaboration to finalize the creation of and evaluate the first line of mice from which high affinity human antibodies can be isolated, to obtain and test human monoclonals of potential therapeutic benefit and to initiate further experiments on antibody selection and diversification so as to facilitate the development of further, improved strains of transgenic mice.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

MRC Laboratory of Molecular Biology
Address
Hills Road
CB2 2QH Cambridge
United Kingdom

Participants (4)

HOSPITAL UNIVERSITARIO CLINICA PUERTA DE HIERRO
Spain
Address
4,San Martin De Porres 4 Clínica Puerta De Hierro
28035 Madrid
The Babraham Institute
United Kingdom
Address
Babraham Hall
CB2 4AT Cambridge
Universidad de Vigo
Spain
Address
S/n,calle Lagoas-marcosende
36200 Pontevedra Vigo
Universidade do Porto
Portugal
Address
823,Rua Do Campo Alegre
4150 Porto