Surface immunoglobulins as a target for antibody therapy

Abdul-Ahad, Ayad Kamil (1983) Surface immunoglobulins as a target for antibody therapy. University of Southampton, Doctoral Thesis.

Abstract

This thesis relates to the therapeutic use of antibody in the treatment of chronic lymphocytic leukaemia. The antibody was raised in sheep and directed against idiotypic determinants (Id) on the surface immunoglobulins of the neoplastic lymphocytes. Three patients received the therapy. The author's contributions to this work were to characterise Fab fragments prepared from the surface immunoglobulin, to investigate the catabolism of infused xenogeneic antibody, and to assist in the clinical trials.The work is divided into three sections. The first section deals with the proteolytic cleavage of surface and secreted immunoglobulins, the second with the catabolic rates of immunoglobulins in xenogeneic animals, the third with the clinical trials. In the first section, papain was used to cleave surface immunoglobulins on the neoplastic lymphocytes from chronic lymphocytic leukaemia patients. The immunoglobulins were cleaved in situ, releasing Fab fragments that carry idiotypic determinants specific to the particular neoplastic clone of cells. Sheep were immunised with the Fabµ fragments to produce anti-Id antibodies. The cleavage of surface IgM with papain released Fabµ fragments and another molecule which we termed fragment X. Fragment X contains Fabµ determinants which are not present on Fabµ prepared from serum IgM. These non-Fabµ determinants were highly immunogenic in sheep, and antibodies produced against them are of no use in antibody therapy. Fragment X probably results from the cleavage of membrane-bound IgM at a site C-terminal to the Cµ3 domain. Fragment X was detected in small amounts in the papain digest of serum IgM. The fragments released by the cleavage of surface IgD with papain were also studied. In the second section, the catabolic rates of rabbit IgG and its fragments in strain two guinea pigs were studied. This was to determine the feasibility of using the monovalent fragment Fab/c and whole IgG in antibody therapy. Whole IgG and Fab/c had similar survival times in guinea pigs, with a half life of around 8 days. Faby fragments were catabolised very rapidly with a half life of a few hours. In the third section, three patients with chronic lymphocytic leukaemia were treated with sheep antibodies directed against the Id on the surface immunoglobulin of their neoplastic cells. In each instance there was partial destruction of the tumour, the extent of which varied from one patient to the other. The effectiveness of they antibody therapy probably depends on many factors including the tumour load, antigenic modulation and the levels of circulating immunoglobulins that carry the tumour Id. The survival time of sheep IgG was determined in each patient.

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