Waldmann H

REMISSION INDUCTION IN NON-HODGKIN LYMPHOMA WITH RESHAPED HUMAN MONOCLONAL ANTIBODY CAMPATH-1H

A genetically reshaped human IgG1 monoclonal antibody (CAMPATH-1H) was used to treat two patients with non-Hodgkin lymphoma. Doses of 1-20 mg daily were given intravenously for up to 43 days. In both patients lymphoma cells were cleared from the blood and bone marrow and splenomegaly resolved. One patient had lymphadenopathy which also resolved. These effects were achieved without myelosuppression, and normal haemopoeisis was restored during the course of treatment, partially in one patient and completely in the other. No antiglobulin response was detected in either patient. CAMPATH-1H is a potent lympholytic antibody which might have an important use in the treatment of lymphoproliferative disorders and additionally as an immunosuppressive agent.

PRELIMINARY EVIDENCE FROM MAGNETIC-RESONANCE-IMAGING FOR REDUCTION IN DISEASE-ACTIVITY AFTER LYMPHOCYTE DEPLETION IN MULTIPLE-SCLEROSIS

The central nervous system lesions of multiple sclerosis (MS) can be detected by magnetic resonance imaging (MRI) and the initial perivascular inflammatory component is distinguished by the presence of gadolinium enhancement. To assess the effect of systemic lymphocyte depletion on disease activity, seven patients with MS received a 10-day intravenous course of the humanised monoclonal antibody CAMPATH-1H (anti-CDw52). With some variations in the protocol, enhanced cerebral MR images were obtained monthly for 3-4 months before and at least 6 months after treatment. 28 enhancing areas were detected on the first series of 7 scans; 51 additional active lesions were identified on 18 scans before treatment; 15 were detected on 20 scans done over the next 3 months, but only 2 active lesions were seen on 23 scans during follow-up beyond 3 months. The difference in lesion incidence rate before and after treatment varied and the rate ratio was significantly reduced in only three patients. Collectively, in a meta-analysis, the rate ratios were 0.15 [corrected] (95% CI 0.09-0.24) for all seven patients and 0.24 (0.14-0.42; p < 0.001) with exclusion of the patient whose scanning schedule differed. The effect of CAMPATH-1H on disease activity provides direct, but preliminary, evidence that disease activity in MS depends on the availability of circulating lymphocytes and can be prevented by lymphocyte depletion. It is too early to say anything about the clinical results of treatment with this agent.

T cell depletion with CAMPATH-1 in allogeneic bone marrow transplantation.

A total of 282 patients with leukemia have been treated by transplantation from HLA-matched siblings using marrow depleted of T cells with CAMPATH-1 and autologous complement. The incidence of graft-versushost disease (GVHD) of grades 2–4 was only 12% but the maximum incidence of graft failure was 15%. A significant increase in relapse cannot yet be detected in acute leukemia but relapse in chronic granulocytic leukemia (CGL) was substantially above that reported before T cell depletion. The most important predictive factor for relapse in CGL appeared to be slow engraftment. This finding suggests an alternative explanation for the graft-versus-leukemia effect other than a direct attack on leukemia cells. This is that donor T cells may affect the balance of competition between donor and recipient haemopoesis by preventing a rejection reaction to donor stem cells. Recipient leukemic cells would benefit (i.e. relapse) if recipient hemopoiesis gained an advantage. If this explanation were true we would expect extra immunosuppressive preconditioning of recipients to reduce the incidence of relapse, as well as preventing graft rejection.

Isolation of low-frequency class-switch variants from rat hybrid myelomás

Class-switch variants have been isolated from rat-rat hybrid myelomas by sib selection using a simple assay based on red cell-labelled antiglobulins. The variants detected are consistent with the gene order deduced from molecular cloning. They appear to arise spontaneously at a rate approximately ten-fold lower than for mouse cell lines but the rate of switching back to the parental isotype is substantial in comparison. An IgG2b variant antibody having the same specificity as CAMPATH-1 for human lymphocytes and monocytes is active in antibody-dependent cell-mediated killing (unlike the parental IgG2a) and may prove to be a valuable therapeutic antibody for immunosuppression and treatment of leukaemia and lymphoma.

Advantages of rat monoclonal antibodies

During the past three years the pages of this journal have witnessed the explosion of interest in monoclonal antibodies and particularly in their applications for diagnosis and therapy of disease. For reasons of history and, we suspect, of tradition, virtually all investigators now use one of the various mouse myeloma lines to construct their hybrid myelomas. We are often tantalized by reports of human myeloma lines which are said to be suitable for fusions to produce human monoclonal antibodies, but so far none of them has been particularly fruitful. During this time we have been using the rat myeloma line Y3/Ag 1.2.3 (Ref. 1) in rat x rat fusions to make antibodies against cell-surface antigens of mouse and human leukocytes and have noticed several advantages of this system, some of which may not be widely appreciated. One of the main reasons for the development of a rat myeloma line was to enable larger amounts of antibody to be made as ascitic fluid in vivo and this remains a technical advantage, especially when gram quantities of antibody are required, for example for clinical trials. It is unlikely that most large-scale production of antibody will ultimately be by culture of cells in vitro but even then rat hybrids may offer advantages of more favourable growth requirements. An immediate application of the rat system was for production of antibodies against monomorphic differentiation antigens of the mouse 23 or polymorphic antigens in the rat 4. Previously, these types of specificity were available only from fusions of rat spleen cells with mouse myeloma lines with their attendant disadvantages.

Monoclonal antibody therapy of chronic intraocular inflammation using Campath-1H.

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Prevention of immune-mediated corneal graft destruction with the anti-lymphocyte monoclonal antibody, CAMPATH-1H.

We report a patient with peripheral rheumatoid corneal melting who developed a corneal perforation in one eye requiring tectonic keratoplasty. Nine consecutive corneal grafts were rapidly destroyed despite systemic immunosuppression with corticosteroid, cyclophosphamide, azathioprine and cyclosporin A. A rejection episode was observed in one graft before it melted and allograft rejection may have contributed to the destruction of other grafts. Corneal graft survival was ultimately achieved by systemic immunosuppression with the anti-lymphocyte monoclonal antibody, CAM-PATH-1H. A single episode of rejection developed in the early post-operative period which was easily reversed by topical corticosteroid. Corneal melting has not recurred and the graft has now remained intact and clear for 24 months. Anti-lymphocyte monoclonal antibodies may therefore provide effective immunosuppression in the treatment of refractory ocular disorders.