Kohler and Milstein demonstrated the “hybridoma technology” of producing MoAb capable of binding to tumor antigen with remarkable specificity and stability about 30 years ago. Many early trials using MoAbs revealed obstacles to successful therapy. Unfortunately, these trials did not establish MoAb therapy as the “magic bullet” as some had previously hoped. Treatment with murine MoAb induced human anti-mouse antibody (HAMA) responses. Once an immune response occurs, administered MoAb can be rapidly cleared from the circulation. Until recently, progress of MoAb treatment has been frustratingly slow for this obstacle. In the past five years, however, the situation has changed dramatically, with some MoAbs now showing clinical potential. The development of genetic engineering has pushed forward the clinical use of MoAbs. This technology has allowed the conversion of existing murine MoAbs into mouse-human chimeric MoAbs, and humanized MoAbs where only the MoAb conaplementarity-determining regions(CDR) are of murine MoAb. More recently, the production of fully humanized MoAb has been made routinely, using either phage technology or transgenic mice. MoAb therapy is beginning at last. Now, with the approval and widespread use of rituximab (Rituxan) for B-cell non Hodgkin's lymphoma and trastuzumab (Herceptin)for advanced breast cancer, MoAb therapy has significant success.

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The historical aspects of the development of cancer therapy using antibodies were considered. And cancer treatment trials using antibody conducted in USA were introduced. At present the key antibody in the treatment of cancers is herceptin that bound to HER-2/neu. Many kinds of chemotherapeutic regimen had been combined with antibody therapy. Also some unique antibodies other than herceptin had been developed and clinical studies were conducted. The number of clinical study using antibody in Japan is still very small.

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The CD 20 antigen is expressed consistently on nearly all human B-cells and B-lymphoma cells. Rituximab is a chimeric IgG 1 kappa monoclonal antibody (mAb) with mouse variable and human constant regions that recognizes the CD 20 antigen. In vitro experiments have revealed that rituximab lyses human B-cells through complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. The toxicities of rituximab are mainly non-hematological grade 1 or 2 episodes. Hematological toxicities are not severe. In the phase I/II study in the USA, an overall response rate (ORR) of 50% was obtained in relapsed low-grade B-cell lymphoma. The median time to progression (TTP) of the responders was 10.2 months. The good response rate and fairly long TTP were reproduced in a subsequent pivotal trial, which enrolled 166 patients with low-grade or follicular B-cell lymphoma. In the phase I study in Japan, 12 patients with relapsed CD 20⁺B-cell lymphoma were enrolled : 4 at 250 mg/m² and 8 at 375 mg/m², once a week for 4 weeks. Of the 11 eligible pts, 2 showed CR and 5 showed PR. 90 relapsed pts were enrolled in the subsequent phase II study and treated with rituximab at 375 mg/m² × 4 weekly infusions. The ORR in indolent B-dell lymphoma and MCL were 61% (37/61) and 46% (6/13), respectively. Several trials of rituximab in combination with chemotherapy have revealed promising results not only for indolent B-cell lymphoma but also for aggressive B-cell lymphoma. Particularly, rituximab plus CHOP therapy might become a new standard regimen for untreated aggressive B-cell lymphoma.

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Tumor necrosis factor-alpha (TNFalpha), a proinflammatory cytokine, plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Biotechnology agents including a chimeric monoclonal anti-TNF antibody (infliximab), a humanized monoclonal anti-TNF antibody (CDP 571), and a recombinant TNF receptor fusion protein (etanercept) have been used to inhibit TNFalpha activity. Controlled trials have demonstrated efficacy for infliximab in moderately to severely active Crohn's disease (CD) and fistulizing CD sufficient to justify recent U. S. Food and Drug Administration (FDA) approval. Additional trials have been completed in rheumatoid arthritis(RA). Similarly, preliminary controlled trials have suggested efficacy for CDP 571 in active CD. And etanercept is effective in patients with active CD similar to RA. Toxicities observed with anti-TNF therapies have included formation of human antichimeric antibodies (HACA) with associated acute and delayed hypersensitivity infusion reactions, human antihuman antibodies (HAHAs), and formation of autoantibodies with rare instances of drug-induced lupus. Several cases of non-Hodgkin's lymphoma also has been described. Future studies should evaluate optimal timing and duration of anti-TNF therapy, the utility of adjuvant medical treatments during anti-TNF therapy, and evaluate long-term safety and efficacy of the various anti-TNF agents.

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Rheumatoid arthritis is a chronic inflammatory disease of joints with the potential to cause substantial joint damage and disability. Proinflammatory cytokines(TNFα, IL-6, IL-1) have recently been shown to play important roles in the pathogenesis of rheumatoid arthritis. In addition, advances in the field of genetic engineering have made possible therapies using monoclonal antibody targeting specific inflammatory mediators. Infliximab is a chimeric anti-TNFα monoclonal antibody that is already available for rheumatoid arthritis patients in the United States and European countries following the results of multiple double-blinded placebo-controlled trials. Infliximab has been demonstrated to improve symptoms and signs of synovitis, and to prevent radiographic evidence of progeressive joint damage in a majority of patients with rheumatoid arthritis. However, increased susceptibility to infection is a potential concern with agents inhibiting TNFα as the cytokine plays a central role in host defense. In fact, several kinds of infection, including tuberculosis, have been reported as adverse events following anti-TNFα blockade therapy. Physicians are therefore recommended to screen patients for latent tuberculosis infection or disease before initiating such therapies. IL-6 is likely to be involved in the pathogenesis of rheumatoid arthritis in addition to TNFα. Clinical trials into IL-6 blockade therapy using complementarity determining regions (CDR)-grafted anti-human IL-6 receptor monoclonal antibody have therefore started. In the near future, these anti-cytokine therapies will become part of the standard armamentarium for the treatment of rheumatoid arthritis in Japan.

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Different sialic acid-linked glycoprotein-conjuagted liposomes were prepared. N-acetyl-glacosaminylated (GlcNAc) human albumin (HSA)-coupled iposomes (GlcNAc-HSA-Lip) were enzymatically galactosylated at 4-position, and fucosylated at 3-position of GlcNAc to prepare LX. Galactose of LX was enzymatically sialylated at 3-position to do SLX. GlcNAc of GlcNAc-HSA-Lip was modified with 3'-sialyated galactose, or 6'-sialyated galactose at 4-position, to prepare 3 SLN and 6 SLN, respectively. The reticuloendotherial system (RES) uptake of these conjugates was investigated in Ehrlich-solid tumor-bearing mice. Sialic acid linked with a terminal sugar chain of SLX increased the uptake by RES, such as liver and spleen. Whereas, sialic acid of 3 SLN and 6 SLN reduced the RES uptake. Besides, uptake of liposomes by tumor tissues was closely correlated with a long blood circulating character of these conjugates. These results suggest that sialic acid residue increases the RES uptake of glycoprotein-conjugated liposomes in presence of fucose-residue nearby, while it reduces the uptake via masking galactose-residue in absence of fucose-residue. Thus, modification of glycoprotein-conjugated liposomes with sialic acid may lead to be development of a useful carrier for drug delivery system (DDS).

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