Interaction of anti-idiotype antibodies with the surface of neoplastic lymphocytes
Interaction of anti-idiotype antibodies with the surface of neoplastic lymphocytes
A panel of monoclonal anti-idiotype antibodies specific for cell surface immunoglobulin (Ig) of the L2C leukaemia of guinea pigs has been investigated. Equilibrium constants were established for reaction of the antibodies with surface Ig in situ. They ranged between 108 and 109M-1 for intact IgG antibodies, and 10' and 108M-1 for their Fab'γ fragments. Values at O^u and 37^u were similar. All antibodies were shown to bind bivalently at equilibrium but showed striking differences in their ability to clear Ig from the L_2C cell surface by antigenic modulation in vitro. Differences in the ability to induce antigenic modulation correlated with the readiness of different antibodies to cross-link neighbouring Ig molecules and evidence is presented for the existence of two distinct types of anti-idiotype antibody: 1) those which form intra-Ig bridges and do not favour modulation (monogamous binders), 2) those which form inter-Ig bridges and favour modulation (bigamous binders). Competitive binding assays showed that simultaneous access of more than one anti-idiotype antibody is generally not permitted. This approach therefore revealed no gross spatial separation of the target determinants of monogamously and bigamously binding antibodies. Fab' arms from two monoclonal antibodies have been used in the preparation of univalent antibodies (FabFc and FabIgG) where Fab' is joined to xenogeneic effector (IgG or Fc) via tandem thioether bonds. The effector capabilities (complement cytotoxicity and antibody dependent cellular cytotoxicity) of a number of chimeric univalent antibodies sharing the same monoclonal Fab' arm but with various effector moieties were investigated and shown to differ according to the species donating the Fc or IgG moiety. In general, those univalent antibodies which were efficient recruiters of effectors in vitro gave the best protection against L_2C leukaemia in therapeutic trials, though by 1) using univalent antibodies which were poor activators of complement and 2) running trials in congenitally C3 deficient guinea pigs, the role of complement in tumour combat would seem to be relatively unimportant. By preparing univalent antibodies which share the same effector region by carry Fab's of different affinity, the role of affinity in therapeutic efficacy was shown to be minimal, although the available range of affinities was narrow. (D72232/87)
University of Southampton
1986
Elliott, Timothy John
(1986)
Interaction of anti-idiotype antibodies with the surface of neoplastic lymphocytes.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
A panel of monoclonal anti-idiotype antibodies specific for cell surface immunoglobulin (Ig) of the L2C leukaemia of guinea pigs has been investigated. Equilibrium constants were established for reaction of the antibodies with surface Ig in situ. They ranged between 108 and 109M-1 for intact IgG antibodies, and 10' and 108M-1 for their Fab'γ fragments. Values at O^u and 37^u were similar. All antibodies were shown to bind bivalently at equilibrium but showed striking differences in their ability to clear Ig from the L_2C cell surface by antigenic modulation in vitro. Differences in the ability to induce antigenic modulation correlated with the readiness of different antibodies to cross-link neighbouring Ig molecules and evidence is presented for the existence of two distinct types of anti-idiotype antibody: 1) those which form intra-Ig bridges and do not favour modulation (monogamous binders), 2) those which form inter-Ig bridges and favour modulation (bigamous binders). Competitive binding assays showed that simultaneous access of more than one anti-idiotype antibody is generally not permitted. This approach therefore revealed no gross spatial separation of the target determinants of monogamously and bigamously binding antibodies. Fab' arms from two monoclonal antibodies have been used in the preparation of univalent antibodies (FabFc and FabIgG) where Fab' is joined to xenogeneic effector (IgG or Fc) via tandem thioether bonds. The effector capabilities (complement cytotoxicity and antibody dependent cellular cytotoxicity) of a number of chimeric univalent antibodies sharing the same monoclonal Fab' arm but with various effector moieties were investigated and shown to differ according to the species donating the Fc or IgG moiety. In general, those univalent antibodies which were efficient recruiters of effectors in vitro gave the best protection against L_2C leukaemia in therapeutic trials, though by 1) using univalent antibodies which were poor activators of complement and 2) running trials in congenitally C3 deficient guinea pigs, the role of complement in tumour combat would seem to be relatively unimportant. By preparing univalent antibodies which share the same effector region by carry Fab's of different affinity, the role of affinity in therapeutic efficacy was shown to be minimal, although the available range of affinities was narrow. (D72232/87)
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Published date: 1986
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Local EPrints ID: 460809
URI: http://eprints.soton.ac.uk/id/eprint/460809
PURE UUID: fe061da5-25c9-4381-bb47-1a7147560ca7
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Date deposited: 04 Jul 2022 18:30
Last modified: 04 Jul 2022 18:30
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Author:
Timothy John Elliott
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