Spontaneous antibodies

Binding proteins such as antibodies, receptors, and lectins may spontaneously aggregate in presence of bi- or multivalent specific ligands. This process, however, often results in assemblies that lack well-defined morphological and structural elements. 

HDV and is the most accurate diagnostic test. The presence of IgM antibodies to HDV Ag (IgM anti-HD) indicates active disease, and IgG anti-HD also becomes detectable if the infection does not resolve spontaneously. Unlike the antibodies developed against HAV, HDV antibodies do not confer immunity. 

Khan, W.I., Abe, T., Ishikawa, N., Nawa, Y. and Yoshimura, K. (1995) Reduced amount of intestinal mucus after treatment with anti-CD4 antibody interferes with the spontaneous cure of Nippostrongylus brasiliensis infection in mice. Parasite Immunology 17, 485-491. 

It has already been noted that the phenotype of an acquired immune response is considered to reflect the early cytokine environment in which naive CD4+ T cells interact with antigen. Again, it has been suggested, for example, that early exposure to IL-4 can push an immune response in a Th-2 direction (Swain et al., 1990). We therefore investigated (by ELISA) whether ES-62 was able spontaneously to induce IL-4 secretion in naive murine spleen cells (48 h exposure). Ironically, given that the molecule induces a Th-2 antibody response and seems to be able to induce the release of a number of other cytokines, IL-4 was not detected (Harnett et al., 1999a). It was noted, however, that IL-4 was produced by spleen cells from mice that had been pre-exposed to ES-62. This established Th-2 phenotype is consistent with the antibody data. 

Wiessner, C., Bareyre, F. M., Allegrini, P. R. etal. Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats. J. Cereb. Blood Flow Metab. 23 154-165, 2003. 

Monestier, M., Novick, K.E., and Losman, M.J., D-penicillamine- and quinidine-induced antinuclear antibodies in A.SW (H-2s) mice Similarities with autoantibodies in spontaneous and heavy metal-induced autoimmunity. Eur. J. Immunol., 24, 723, 1994. 

Mercuric chloride in the BN rat gives a lymphoproliferation in spleen and lymph nodes, including B and T helper cells, an increase in the number of Ig containing cells resulting in a rise in all serum Ig isotypes and an early thymic atrophy [196]. The kinetics of the increase in the serum level of various Ig isotypes were similar to that observed for IgE, suggesting spontaneous autoregulation, which could involve suppressor T cells [ 197, 198] and/or auto-anti-idiotypic antibodies [ 199]. 

Table 1 Kinetic and thermodynamic parameters for the spontaneous, enzyme-catalysed and antibody-catalysed conversion of chorismic acid [23] into prephenic acid [24],...

Fig. 12 The Diels-Alder cycloaddition of TCTD [27] and [28] proceeds through an unstable intermediate [29] which spontaneously extrudes S02 to give the dihydro-phthalimide adduct [30], Hapten [31] was designed as a stable mimic of [29] that would be sufficiently different from product [30] to avoid product inhibition of the antibody...

A number of further examples of Diels-Alder catalytic antibodies have been described (Appendix entries 17.2-17.5) and they must needs benefit from the same entropic advantage over spontaneous reactions, albeit without Hilvert s ingenious approach to avoiding product inhibition. Their success in achieving control of regio- and stereo-chemistry will be discussed later (Section 6). 

Fig. 25 The monoclonal antibody 26D9, generated to the jV-oxide hapten [67], catalysed the 6-exo-tet ring closure of [65] regioselectively to yield the disfavoured tetrahydropyran product [68]. This is a formal violation of Baldwin s rules, which predicts a 5-exo-tet spontaneous process to generate tetrahydrofuran derivative [66].

As exponents of catalytic antibodies have become more confident of the power of abzymes, their attention has turned from reactions of moderate to good feasibility to more demanding processes. Their work has on the one hand tackled more adventurous stereochemical problems and on the other hand is attempting to catalyse reactions whose spontaneous rates are very slow indeed. Examples of both of these areas are discussed in this section. 

On the other hand, abzymes are generally able to accelerate reactions by at most 107 times the rate of the spontaneous process. It has to be said that scientists at large are looking for a major step forward in antibody catalysis to achieve rate accelerations up to 109 that would establish abzymes as a feature of synthetically useful biotransformations. At the same time, it is essential to demonstrate that product inhibition is not an obstacle to the scaled-up use of abzymes. 

Fig. 8.17. Mechanism of bioactivation of self-immolative carbamate prodrugs of cytotoxic amines. A bacterial nitroreductase coupled to a tumor-directed antibody reduces the prodrug to a hydroxylamine (Reaction a), which breaks down spontaneously to liberate the antitumor...

In order to generate antibodies which catalyse the hydrolysis of carbonates (6, 10), carboxylic esters (9) and amides with a certain degree of specificity, the phosphates (7a. lOai and phosphonates 9a were used as haptens that mimic the tetrahedral negatively charged transition state of the spontaneous hydrolysis reaction (see Scheme 11.3) [27] [29]. 

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