Immunogenicity of proteins

The above mentioned effects were observed with different inert polymeric carriers. The results obtained with HPMA copolymer-drug conjugates are discussed in Sect. 5.3., the decrease of the immunogenicity of proteins after PEG modification in Sec. 2.1.1.1. 

TABLE 5.6. Immunogenicity of protein pharmaceuticals and clinical consequences... 

Immunogenicity may be affected by the route of administration. Extravascular injection has been shown to stimulate antibody formation more than IV application, but this is most likely due to the increased immunogenicity of protein aggregates and precipitates formed at the injection site [44]. A recent study investigated the effect of the route of administration of INF-P preparations on inducing anti-INF-P antibodies in multiple sclerosis patients. The results indicate that IM injections appear less immunogenic compared to SC injections, resulting in both a lower serum level of anti-INF-P antibodies as well as a delay in their appearance [45]. 

For biotechnologically derived products the acceptable levels of foreign proteins should be based on the sensitivity/selectivity of the test method, the dose to be given to a patient, the frequency of administration of the drug, the source, and the potential immunogenicity of protein contaminants [10]. Levels of specific foreign proteins range from 4 ppm to 1000 ppm. 

Stewart HPG, Hollingshead PG, Pitts SL, Chang R, Martin LE, Oakley H. Transgenic mice as a model to test the immunogenicity of proteins altered by site-specific mutagenesis. Mol Biol Med 1989 6 275-81. 

Chirino AJ, Ary ML, Marshall SA. Minimizing the immunogenicity of protein therapeutics. Drug Discov Today 2004 9 82-90. 

Table 3.6. Factors determining the immunogenicity of protein drugs...

Konrad, M. (1989). Immunogenicity of proteins administered to humans for therapeutic purposes. TIBTECH 7, 175 179. 

Lees, A., et al.. Enhanced immunogenicity of protein-dextran conjugates I. Rapid stimulation of enhanced antibody responses to poorly immunogenic molecules. Vaccine, 1994, 12, 1160-1166. 

As mentioned above, several product-related factors can influence the immunogenicity of protein therapeutics. The impact of trace impurities and excipients used... 

Despite the progress in explaining the immunogenicity of protein drugs, unfortunately rather often immunogenicity cannot be assigned to the above listed factors, and the underlying mechanism(s) remain unknown. 

Extravascular injection is known to stimulate antibody formation more than intravenous application, most likely due to the increased immunogenicity of protein aggregates and precipitates formed... 

Up to a certain degree, an increase in the dose (weight) of antigen will increase antibody titer however, this may also increase crossreactivity. Adjuvants also increase the immunogenicity of proteins. Haptens should be labeled with carrier proteins to elicit an immune response. The carrier protein should be foreign to the host to be recognized by the T-cells. For most immunogens, the interaction of T- and B-cells is essential for antibody production. 

Flanagan PA, Duncan R, Rihova B, Subr V, Kopecek J. Immunogenicity of protein-N-(2-hydro rpropyl)methacryla-mide copolymer conjugates measured in A/J and BIO mice. J Bioact Compat Polym 1990 5 151-166. 

Baker MP, Reynolds HM, Lumicisi B, Bryson CJ. Immunogenicity of protein therapeutics the key causes, consequences and challenges. Self/Nonself—Immune Recognition and Signaling. 2010 l(4) 314-22. 

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