Antibodies in therapy

CAMPATH-1 antibodies have been used in a variety of clinical trials. The IgM antibody, CAMPATH-1M, was developed for prevention of graft-versus-host disease by depletion of donor T cells from bone marrow. This was very effective, but resulted in an increased risk of graft rejection and of leukemia relapse. Now CAMPATH-1 G or CAMPATH-1 H are being tested for simultaneous control of both donor and host T cells, with a proportion of donor T cells being kept for later administration in the event of leukemia recurrence. CAMPATH-1H has been used for treatment of lymphoid malignancies and was very effective in patients with certain leukemias (T cell prolymphocytic leukemia and B chronic lymphocytic leukemia), but less so in patients with solid tumor masses (Figure 3). It has also been used as an immunosuppressive agent for treatment of transplant rejection and autoimmune diseases, including rheumatoid arthritis, vasculitis and multiple sclerosis (Figure 4). Treatment resulted in longlasting lymphopenia, particularly of CD4+ cells, which may not

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Figure 4 Treatment of Wegener's granulomatosis with CAMPATH-1 H. This patient suffered from severe erosion of sinus passages due to leukocyte infiltration, as shown by whole body scanning after injection of '"In-labeled leukocytes (area circled). Antibody treatment depleted the T cells which were driving the inflammatory process and this resulted in a normal leukocyte scan and disease stabilization for at least 12 months. (Reproduced with permission from Reuter et al. (1995).)

MAb ThCfiipy

Figure 4 Treatment of Wegener's granulomatosis with CAMPATH-1 H. This patient suffered from severe erosion of sinus passages due to leukocyte infiltration, as shown by whole body scanning after injection of '"In-labeled leukocytes (area circled). Antibody treatment depleted the T cells which were driving the inflammatory process and this resulted in a normal leukocyte scan and disease stabilization for at least 12 months. (Reproduced with permission from Reuter et al. (1995).)

return to normal blood levels for several years. The immunological significance of this is not obvious as few, if any, of the patients appear to suffer any long-term immunodeficiency. The majority of patients experienced an improvement in symptoms (in the case of multiple sclerosis, a decline in the frequency of new lesions) which lasted from 2 months to over a year. In the event of relapse, retreatment was possible and only infrequently limited by an antiidiotype response.

In a minority of patients, the first lymphocytes to regenerate lacked GPI-anchored proteins. This is characteristic of cells in paroxysmal nocturnal hemoglobinuria (PNH) and probably results from a somatic mutation in the X-linked PIG-A gene which codes for a critical step in GPI biosynthesis. Considering the frequency and time course of appearance of these cells, it seems unlikely that a mutation was induced by therapy, rather that it selected GPI-deficient cells already present at low numbers. So far, these cells appear to have normal functions and may even mediate graft rejection. Patients do not appear to suffer any adverse effect and in due course they are replaced by normal lymphocytes.

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