Humans immunogenicity

Immunogenicity is a substantial complication for preclinical safety assessment studies. Antibodies can invalidate the animal model species. Antibody production alone, however, should not necessarily prohibit the conduct of these studies. The effect on pharmacokinetics and pharmcodynamics needs to be measured and evaluated. The potential consequences of the antibodies on endogenous molecules also needs to be evaluated. Secondary effects, such as antibody deposition, should be measured. The lack of ability to predict absolute human immunogenicity does not preclude the use of animals to assess the relative potential for an immune response. 

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]. 

Amino acid substitutions on the native y52 8sKIpeptide, coiled-coil domain of human fibrin were able to stabilize the coiled-coil formation. These substitutions were targeted to the positions that compose the interface between coiled-coil strands while the solvent-exposed residues were left unperturbed. This strategy aimed at reducing the likelihood of immunogenicity for future in vivo apphcafion of these materials. In contrast to PEG block copolymers with end blocks that are not used for directed assembly, PEG copolymers with coiled-coil protein motives aim to enhance intermolecular interactions and control over the assembly conditions [85, 173]. 

Mammalian cells Get export of proteins Get desired post-translational modifications and products not likely to be immunogenic to humans Good expression systems available Large-scale growth of animal cells costly Great care needed to avoid contamination of cultures... 

In the early 1900s, a balanced mixture of diphtheria toxin and antitoxin was found to produce active immunity in both animals and humans. This preparation gained widespread acceptance and protected approximately 85% of recipients. Several years later, diphtheria toxoid was developed by treating the toxin with small amounts of formalin. This process caused the toxin to lose its toxic properties while maintaining its immunogenic properties. In the mid-1920s, the addition of an alum precipitate enhanced the immunogenic properties of the toxoid. 

The discovery of monoclonal antibodies and combining them with polymeric prodrugs is the newest approach to overcome the lack of selectivity for disposition in target tissue (23). Recently the selectivity of antibody-targeted polymeric anthracycline antibiotics to T lymphocytes was accomplished (25). In addition decreased immunogenicity of proteinaceous conjugates with IgG and human transferrin has been reported (26). 

Kosten T., Rosen M., Bond J. et al. Human therapeutic cocaine vaccine safety and immunogenicity. Vaccine. 20 1196, 2002. 

Human immunodeficiency virus (HIV) type 1 ELDKWA epitope Potato virus X in tobacco leaf Sera from normal and hu-PBL-SCID mice showed anti-HIV-1 neutralizing activity. Immunogenic in mice when delivered parenterally or nasally. 18... 

Human rhinovirus type 14 VP1 epitope Epitope display on cowpea mosaic virus in cowpea leaf Immunogenic in rabbits when delivered parenterally. 81... 

Rabies virus glycoprotein (G)and nucleo-protein (N) Alfala mosaic virus and tobacco mosaic vims in tobacco and spinach leaf Elicited specific virus-neutralizing antibodies in mice. Immunogenic in mice when delivered orally and parenterally immunogenic in humans when delivered orally. Moderately protective against lethal challenge infection in mice. 16, 71... 

Enterotoxigenic E. coli B subunits of the heat labile toxin (LTB) Maize seed Elicited neutralizing antibodies. Immunogenic when administered orally. Serum and secretory immune responses in humans. Partially protective in mouse gut fluid assay. 27-29, 89, unpublished data... 

Hepatitis B surface antigen (HBsAg) Lettuce leaf Immunogenic in humans when administered orally 2 of 3 human subjects developed very modest semm antibody response titers in primary immunization. 70... 

Human immunodeficiency virus (HIV) type 1 p24 protein Tomato bushy stunt virus in tobacco leaf No immunogenicity assays performed. 97, 98... 

Human papilloma virus type 11 major capsid protein LI Tobacco leaf, potato tuber Reacted well with assembled capsids and isolated LI capsomers. Immunogenic in mice when administered parenterally with subsequent oral boosting. 99... 

Human papilloma virus (HPV) type 16 oncoprotein E7 Potato virus X in tobacco leaf (complete reading frame) Immunogenic in mice when administered parenterally. Mice protected moderately when challenged with surrogate (C3 cells). 100... 

Human papilloma virus (HPV) type 16 major capsid protein LI Tobacco and potato Weak, transient anti LI antibody response in 3 of 24 mice when administered orally. Immunogenic when administered orally after parenteral boost. 102... 

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