MAbs therapy

An important demonstration of the efficacy of a MAb in minimal residual disease was achieved usiug MAb 17-lA (directed against the EGP-2 or EpCAM antigen as described previously) in patients with stage III colorectal cancer. Following surgical resection, MAb therapy reduced the overall death rate by 32% and the rate of recurrence by 23% [122]. 

Following the success of recombinant proteins such as insulin, therapeutic mAbs today represent the second wave of innovation created by the biotechnology industry during the past 20 years. The recent success of a number of new mAb therapies, for example rituximab (Rituxan ) and infliximab (Remicade ), suggests a resurgence of the biotech industry for the coming years. For serious chronic diseases such as cancer or rheumatoid arthritis, mAb therapy has indeed proven its clinical efficacy. 

Interestingly, anti-IL-6 mAb therapy has been suggested to be efficacious in RA in an open-label study (126). However, a controlled study has not been published as yet. Support for the potential of interfering with IL-6 activities also stems from a study of anti-IL-6 receptor mAbs in experimental arthritis (127). 

One of the earliest attempts to exploit hybridoma technology for cancer treatment was the work of Levy and co-workers, who produced mAbs reactive with the idiotype expressed on malignant B lymphocytes obtained from individual patients (157-158). Although the need to produce custom-made mAbs for each patient has severely limited the feasibility of this strategy, these pioneering studies did provide early and convincing evidence that mAb therapy could elicit durable antitumor responses. 

Fagerberg J, Frodin JE, Ragnhammar P, Steinitz M, Wigzell H, Mellstedt H. Induction of an immune network cascade in cancer patients treated with monoclonal antibodies (abl). II. Is induction of anti-idiotype reactive T cells (T3) of importance for tumor response to mAb therapy Cancer Immunol Immunother 1994 38 149-59. 

The exact mechanism of action of the anti-CD25 mAbs is not completely understood but likely results from the binding of the anti-CD25 mAbs to the IL-2 receptor on the surface of activated, but not resting, T cells. Significant depletion of T cells does not appear to play a major role in the mechanism of action of these mAbs. Therapy with the anti-IL-2R mAbs is thought to result in a relative decrease of the expression of the a chain, either from depletion of coated lymphocytes or modulation of the a chain secondary to decreased expression or increased shedding. 

There is no marker or test to monitor the effectiveness of anti-lL-2R therapy, as satmation of a chain on circulating lymphocytes during anti-lL-2R mAb therapy does not predict rejection. The duration of IL-2R blockade by basihximab was similar in patients with or without acute rejection episodes. 

Berkowitz S D, et al (1997). Acute profound thrombocytopenia after C7E3 Fab (abcixi-mab) therapy. Circulation. 95(4) 809-813. 

Cragg M, Walshe C, Ivanov A, Glennie M. The biology of CD20 and its potential as a target for mAb therapy. Current Directions in Autoimmunity 2005 8 140-174. 

Another route wherety tolerance regimens for mAb therapy may gain access into transplantation is by first establishing them in the treatment of auto-... 

Animal models of transplantation and mAb therapy defining the problem... 

Monoclonal antibodies have revolutionized our understanding of immunology but their impact on human transplantation remains limited. We have outlined many reasons for the low clinical impact that exists at present, however tolerance induction following a short course of mAb therapy still remains a realistic goal. Transplantation is still a relatively new field and it is perhaps salient that in the 1997 United Network for Organ Sharing report (1), which analysed the results of 97 000 transplants in the United States from 1988-1994, one of the major factors influencing survival was the centre where transplantation was undertaken. 

Anti-TNFa mAbs are powerful anti-inflammatoiy agents with proven efficacy in RA High dose intravenous treatment produces rapid disease improvement but repeated therapies can lead to significant inunimosuppression with the risk of infection. Frequent subcutaneous low dose treatment may be a safer alternative since the immune response can recover quickly once anti-TNFa mAb therapy is stopped. 

Reactions following initial infusions of antibody are common, but these can usually be handled by a cautious rate of infusion, appropriate hydration and diuresis, and, if necessary, praned-ication. Twenty six percent of initial reactions are reported to be mild, 48 % moderate, and 26 % severe. The initial infusion reaction to some mAbs, for example, rituximab (see below), may provoke tumor lysis syndrome, cytokine release syndrome, and systemic inflammatory response syndrome. Tumor lysis syndrome, noted particularly with rituximab, can occur following cancer treatment and sometimes without treatment. It is believed to be the result of breakdown products of cancer cells leading to increased levels of some metabolites and reflected in conditions such as hypercalcemia, hyperkalemia, hyperphosphatemia, acute uric acid nephropathy, and acute renal failure. The syndrome can occur in the early stages of mAb therapy and is potentially life-threatening. Cytokine release syndrome, also called cytokine storm, is commonly seen after... 

Perhaps the most astonishing aspect of this mAh is that it was used for the treatment of acute renal allograft rejection in patients only two years after being raised, on the basis of its ability to block CTLs in vitro, at a time when the structure of the T cell receptor complex was unknown (7). Although, even now it remains as an effective treatment for the reversal of steroid resistant acute allograft rejection, many of the compUcations associated with therapy were either underestimated or not anticipated. Nowadays extensive pre-clinical data is required, often involving primate studies, before a mAb can be used in clinical trials. It is likely that if mAbs to CDS were introduced today rather than in 1981 that they would not have gained a hcence for human use. Monoclonal antibodies to CDS in both human and animal studies have broadly similar effects and are of interest because they elicit many of the complications associated with mAb therapy. How these problems have been circumvented serves a framework for many other mAbs under development. 

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