Antibody responses, consequences

In a separate line of research, the majority of 129 strain mice were shown to be resistant to a primary infection with 5. japonicum (Mitchell et al., 1984). Moreover, these mice had a dominant antibody response to a 26 kDa antigen from adult worms that was also strongly reactive with sera from rabbits multiply immunized with adult worm extract (Beall and Mitchell, 1986). This allowed the cDNA to be cloned from an expression library and identified as a GST (Smith et al., 1 986). The native protein was easily purified on a glutathione affinity column and used for protection experiments, with mostly negative results except for >50% on one occasion in C57BL/6 mice (Mitchell et al., 1988). The natural resistance of 129 strain mice for S. mansoni was also demonstrated (Tiu et al., 1 986) but unfortunately proved to be the result of a defective portal vasculature rather than acquired immunity (Cox, 1990). This finding undermined the whole concept of immunity induced by GST in 129 strain mice and as a consequence vaccine work with the Philippines strain of S. japonicum largely petered out. 

Immunogenicity assays for investigating the frequency and consequences of antibody development against a protein therapeutic agent are typically based on an immunoassay technique (mostly ELIS As of various types). However, other assay formats are available such as radioimmunoprecipitation assay, surface plasmon resonance, and electrochemiluminescence [3]. Assays for measuring antibody response should be established in the early preclinical stage of development to estimate the value of the applied animal models (see Chapters 16 and 20). 

The pattern of proinflammatory cytokines produced has implications for the character of the adaptive immune response, which will occur if the host is exposed to a foreign antigen. A T-helper type 1 (Thl) cytokine profde polarizes the immune response towards a cellular immune response, whereas a T-helper type 2 (Th2) profde favors antibody responses (Mos-mann and Coffman, 1987). IFN-y is a marker of a Thl response, and lL-4 is indicative of a Th2 response. There is evidence that morphine given in vivo biases the immune response toward a Th2 response (Roy et al., 2004). The consequences of this apparent shift toward Th2-type immunity are not clear, since other studies show that antibody production is suppressed in animals treated simUarly with morphine (Bus-siere et al., 1993). These results wUl be discussed in greater detaU below. 

The development of antibodies to therapeutic proteins can have direct safety consequences in addition to the impact on pharmacokinetics as addressed in this chapter. Provided the antibody response itself does not have direct safety issues, in some cases it is possible to continue dosing the therapeutic protein in the presence of antibody, provided efficacious levels of the therapeutic protein can be maintained. In this case, it is important to fully understand how the antibody response impacts active concentrations of the therapeutic protein so that it is possible to design dosing regimens that minimize the impact of the antibody response. In the... 

Biologies are sufficiently large and complex as to elicit immune responses directed to the protein. For the most part, the principal response elicited is a T cell-dependent humoral response. The development of an antibody response to a biologic in most cases has no adverse consequences (Schellekens 2002a Shankar et al. 2006). An antibody response is not an adverse event in itself. However, an antibody response to a biologic can have consequences that fall into three main categories hypersensitivity reactions, reduction in efficacy, and the induction of autoimmune disease (Schellekens 2002b). 

Anti-human recombinant protein antibody response may alter pharmacokinetics, neutralise biological effects, cause immune-complex lesions, or have no relevant consequence in animals. 

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