Monoclonal anti-T cell antibodies

Antilymphocyte globulin and monoclonal anti-T cell antibodies 1,2, 3... 

Wofsy, D., Ledbetter, J.A., Hendler, P.L. and Seaman, W.E. (1985). Treatment of murine lupus with monoclonal anti-T cell antibody. ]. Immunol, 134, 852—857... 

Waid TH, Lucas BA, Amlot P, Janossy G, Yacoub M, Cammisuli S, Jezek D, Rhoades J, Brown S,Thompson JS.T10B9.1A-31 anti-T-cell monoclonal antibody preclinical studies and clinical treatment of solid organ allograft rejection. Am J Kidney Dis 1989 14 61-70. 

Chatenoud L, Ferran C, Reuter A, Legendre C, Gevaert Y, Kreis H, Franchimont P, Bach JF. Systemic reaction to the anti-T-cell monoclonal antibody OKT3 in relation to serum levels of tumor necrosis factor and interferon-y. N Engl J Med 1989 320(21) 1420-1421. 

The first mouse monoclonal antibody specific for human CD3 was produced in 1979 and named orthoclone OKT3. Aside from its use in the laboratory, OKT3 became the first anti-CD3 antibody to be utilized in transplantation medicine, but its wider application was hampered by its immunogenic and mitogenic properties (reviewed in [6]). Consequently, humanized and engineered anti-CD3 antibodies were developed to circumvent these limitations (Table 1). Since T cells and the TCR are involved in many immunological diseases, it is not surprising that the application of CD3 antibodies is not restricted to the field of transplantation. For example, CD3 antibodies are tested in clinical studies of diseases such as autoimmune diabetes (type 1 diabetes), immune-mediated inflammatory arthritis and inflammatory bowel disease [7]. 

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). 

Priliximab (cM-T412) is an anti-CD4 chimeric monoclonal antibody that was evaluated in the clinic for the treatment of autoimmune diseases. Priliximab binds to CD4 on the surface of T cells and leads to a profound and sustained decrease in circulating CD4+ T cells decreased counts have been reported to be below normal levels at 18 and 30 months following single- and multiple-infusions.81 Similar findings were observed in preclinical studies in chimpanzees.82 The administration of priliximab was also associated with a cytokine-release syndrome that caused transient fever, myalgia, chills, headache, nausea, and/or hypotension that was accompanied by an increase in serum IL-6. Although evidence of efficacy was observed in clinical trials for CD, the... 

Tumor Necrosis Factor There are two types of tumor necrosis factor TNF-a and TNF- 8. Of the two, TNF-a has been studied in more detail. TNF-a is a 157 amino acid polypeptide. It is a mediator of immune regulation, including the activation of macrophages and induction of the proliferation of T cells. Another TNF-a function is its cytotoxic effects on a number of tumor cells. Recent research, however, concentrates on its property in the stimulation of inflammation, particularly in the case of rheumatoid arthritis. Clinical trials are being conducted with drugs to block TNF-a with anti-TNF-a monoclonal antibodies. These antibodies target the excessive levels of TNF-a in the synovial fluid of joints and provide relief to sufferers of rheumatoid arthritis (Exhibit 4.10). 

Figure 7 Immunopotentiating reconstituted influenza virosomes (IRIV) mediated adjuvance in cytotoxic T-cell induction requires CD4+ T cells. CD8+ and CD14+ cells were cultured in the presence of autologous intact or irradiated CD4+ cells. These cultures were stimulated with influenza matrix (IM)58 66 (1 Pg/mL) alone (A) or supplemented with IRIV (1 50) (B). After seven days of incubation both cocultures were restimulated with irradiated IMss-ee pulsed CD14+ cells and cultured for six further days in the presence of interleukin-2 [see Materials and Methods ]. Six days after restimulation, cultures were stained with HLA-A0201 /IM58-66 PE-specilic tetramers and anti-CD8 fluorescein isothiocyanate monoclonal antibodies. Source. From Ref 6.

Table 11 lists the reactivity of antibodies to various lymphoreticular neoplasms in formalin- or B5-fixed tissues. Many of the monoclonal antibodies available to B- or T-cell lymphomas are not strictly lineage specific (MBl, MB2, LNl, MTl). CD20 (L26) (45) for B-cells and CD45RO (UCHL-1) (46) for T-cells has been shown to be fairly specific. UCHL-1 is not present on all T-cells, therefore one may want to include another T-cell marker to detect T-cell lymphomas. (3-FI (47), which recognizes a framework epitope on the T-cell P chain antigen receptor, and anti-CD3 (48) may be particularly promising in specifically detecting T-cell lymphomas. 

Adalimumab is a fully human IgGi anti-TNF monoclonal antibody. This compound complexes with soluble TNF-ct and prevents its interaction with p55 and p75 cell surface receptors. This results in down-regulation of macrophage and T cell function. 

The effect of CVS is T-cell mediated, since no effect was observed in athymic nu/nu mice of BALB/c background which were hereditarily T cell deficient (data not shown). Therefore, we examined the participation of T-cell subsets in the antitumor effect of CVS following their in vivo depletion with monoclonal antibodies in the Meth A and BALB/c system, Fig. (6)-Protocol B. CVS was injected i.t. 3 times from day 2, and tumor i.v. rechallenging was performed on day 9. Anti-CD3 treatment completely inhibited the antitumor effect of CVS (data not shown). Anti-CD4 and anti-CD8 treatment partially inhibited the effect of CVS. Less than 1.0% of the CD3-, CD4-, or CD8-positive cells were detected in the spleen or lymph nodes following in vivo treatment with the corresponding antibodies by flow-cytometric analysis using FACS (Becton Dickinson, USA). 

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