Protective monoclonal antibodies

Parasitism by T. spiralis has been a subject of scientific interest for over 150 years. Recently, considerable attention has been paid to the parasite by immunologists interested in immunity to nematodes in general, and mucosal immunity in particular. It has been shown that glycan-specific antibodies are highly effective mediators of host defence against intestinal 7. spiralis infection. Protective monoclonal antibodies have been used to elucidate mechanisms of worm expulsion, as well as to identify molecules that the parasite uses to create its niche. In the future, detailed characterization of these molecules and their functions should afford additional insights into parasitism by Trichinella spiralis, and possibly also by other types of pathogen. 

Bickle, Q.D., Andrews, B.J. and Taylor, M.G. (1 986) Schistosoma mansoni characterization of two protective monoclonal antibodies. Parasite Immunology 8, 95-107. 

Harn, D.A., Cu, W., Oligino, L.D., Mitsuyama, M., Gebremichael, A. and Richter, D. (1992) A protective monoclonal antibody specifically recognizes and alters the catalytic activity of schistosome triose-phosphate isomerase. The Journal of Immunology 148, 562-567. 

Hazdai, R.T., Levi-Schaffer, F., Brenner, V., Horowitz, S., Eshhar, Z. and Arnon, R. (1985) Protective monoclonal antibody against Schistosoma mansoni antigen isolation, characterization, and suitability for active immunization. The Journal of Immunology 1 35, 2772-2779. 

Ko, A.I., Drager, U.C. and Harn, D.A. (1990) A Schistosoma mansoni epitope recognized by a protective monoclonal antibody is identical to the stage-specific embryonic antigen 1. Proceedings of the National Academy of Sciences of the United States of America 87, 4159—41 63. 

Di Padova, F., Brade, H., Barclay, G.R., Poxton, I.R., Liehl, E., Schuetze, E., Kocher, H.P., Ramsay, G., Schreier, M.H., McClelland, D.B.L., Rietschel, E.T. A broadly cross-protective monoclonal antibody binding to Escherichia coli and Salmonella lipopolysaccharide. Infect Immun 61 (1993) 3863-3872. 

Muller-Loennies, S., Brade, L., MacKenzie, C.R., DiPadova, F.E., Brade, H. Identification of a cross-reactive epitope widely present in lipopolysaccharide from enterobacteria and recognized by the cross-protective monoclonal antibody WN1 222-5. J Biol Chem 278 (2003) 25618-25627. 

Riggs M W, Stone A F, Yonnt P A, et al. (1997). Protective monoclonal antibody defines a circnmsporozoite-like glycoprotein exoantigen of Cryptosporidium parvum sporozoites and merozoites. J. Immunol. 158 1787-1795. 

Nonspecific immunosuppressive therapy in an adult patient is usually through cyclosporin (35), started intravenously at the time of transplantation, and given orally once feeding is tolerated. Typically, methylprednisone is started also at the time of transplantation, then reduced to a maintenance dose. A athioprine (31) may also be used in conjunction with the prednisone to achieve adequate immunosuppression. Whereas the objective of immunosuppression is to protect the transplant, general or excessive immunosuppression may lead to undesirable compHcations, eg, opportunistic infections and potential malignancies. These adverse effects could be avoided if selective immunosuppression could be achieved. Suspected rejection episodes are treated with intravenous corticosteroids. Steroid-resistant rejection may be treated with monoclonal antibodies (78,79) such as Muromonab-CD3, specific for the T3-receptor on human T-ceUs. Alternatively, antithymocyte globulin (ATG) may be used against both B- and T-ceUs. 

Whereas epidermal growth factor (EGF) enhances the radiosensitivity of human squamous ceU carcinoma cells in vitro (197), addition of EGF to hormone-deprived MCE-7 breast cancer cells prior to irradiation results ia iacreased radioresistance (198). An anti-EGE-receptor monoclonal antibody blocks the abiUty of EGE to enhance growth and radioresistance. Tumor cells, the growth of which is stimulated by EGE, appear to be protected those where growth is iohibited are sensitized (198). 

Rituxan (anti-CD20 monoclonal antibody) Liquid for IV injection Store at 2-8°C protect from light lOOmg or 500mg vial 9.0mg/mL NaCl, 7.35mg/mL Na-citrate, 0.7 mg/mL polysorbate 80... 

Monoclonal Antibodies. HA-1 A is a human monoclonal IgM antibody that binds to LPS and lipid A. The initial phase 3 trial demonstrated no overall benifit of HA-1 A compared with placebo (Z5). However, HA-1A appeared to afford significant protection to a subgroup of patients with gram-negative bacteremia (Z5). A second large-scale trial documented a lack of overall clinical benefit of HA-1A (W11). 

Starnes, H. F Pearee, M. K., Tewari, A., Yim, H. H., Zou, J. C., and Ambrams, J. S., Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-a challenge in mice. J. Immunol. 145,4185-4191 (1990). 

Ellis, L.A., Reason, A.J., Morris, H.R., Dell, A., Iglesias, R., Ubeira, F.M. and Appleton, J.A. (1994) Glycans as targets for monoclonal antibodies that protect rats against Trichinella spiralis. Glycobiology 4, 585—592. 

The in vivo manipulation of specific type 2 cytokines using anticytokine monoclonal antibodies, or mouse strains with targeted deletions in cytokine and/or cytokine receptor genes, has proved a fruitful approach in identifying the importance of individual cytokines and the responses that they control in contributing to host resistance. These studies have identified important roles for IL-4, IL-9 and IL-13 in host protection against nematode infection, though the relative importance of each cytokine appears to be nematode-species dependent. 

A cardinal role for IL-4 in host protection against intestinal nematode infection was first shown in the H. polygyrus challenge model. Worm expulsion was delayed following treatment with anti-IL-4 or anti-IL-4 receptor monoclonal antibodies, while control treated animals successfully cleared infection (Urban et al., 1991b). Blockade of the IL-4 receptor effectively prevents the in vivo function of IL-4 and IL-13, as these two cytokines share the IL-4 receptor a-chain for signalling functions (Lin et al, 1995). In... 

The involvement of mast cells in host protection against nematode infection is well characterized in T. spiralis infection. W/Wv mice exhibited a significant delay in worm expulsion, and treatment with either anti-SCF or anti-SCF receptor monoclonal antibody dramatically inhibited mast cell responses and expulsion of T. spiralis for the duration of treatment (Donaldson et al., 1996). W/Wv mice also lack interstitial cells of cajal and intraepithelial y T cells (Maeda et al., 1992 Puddington et al., 1994), which may contribute to the impaired response in these animals (see below). However, supporting evidence of a role for mast cells in protection against T. spiralis comes from studies in which overexpression of IL-9 in mice (which is known to influence the mast cell responses see above) resulted in an extremely rapid mast cell-dependent expulsion of T. spiralis (Faulkner et al., 1997). 

Thus, the tetravalency, anti-inflammatory properties and molecular stability of slgA make it particularly suitable for protective passive immunity when applied to mucosal surfaces. To date, the clinical evaluation of slgA protection in humans and animal models has been very limited. Indeed most studies have employed monomeric IgA monoclonal antibodies [3,15]. Hence, differences in IgA and IgG protective activities at the mucosal level have often not been observed [15]. Only a few studies have demonstrated the superior activity of polymeric IgA or slgA compared with monomeric IgG or IgA [16]. In order to determine the efficacy of slgA, future animal experiments and clinical trials are needed to compare the activities of IgG monoclonal antibodies and their slgA counterparts. The ability to engineer slgAs in plants will allow these comparisons to be made [17]. 

For other plant-derived antibodies, stability was shown to be similar to mammalian counterparts. For instance, a humanized anti-herpes simplex virus monoclonal antibody (IgGl) was expressed in soybean and showed stability in human semen and cervical mucus over 24 h similar to the antibody obtained from mammalian cell culture. In addition, the plant-derived and mammalian antibodies were tested in a standard neutralization assay with no apparent differences in their ability to neutralize HSV-2. As glycans may play a role in immune exclusion mechanisms in mucus, the diffusion of these monoclonal antibodies in human cerival mucus was tested. No differences were found in terms of the prevention of vaginal HSV-2 transmission in a mouse model, i.e. the plant-derived antibody provided efficient protection against a vaginal inoculum of HSV-2 [58]. This shows that glycosylation differences do not necessarily affect efficacy. 

Siegel, S.A. et al., The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo, Cytokine, 7, 26, 1995. 

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