Humanized antibodies examples

Another example of vims clearance is for IgM human antibodies derived from human B lymphocyte cell lines where the steps are precipitation, size exclusion using nucleases, and anion-exchange chromatography (24). A second sequence consists of cation-exchange, hydroxylapatite, and immunoaffinity chromatographies. Each three-step sequence utilizes steps based on different properties. The first sequence employs solubiUty, size, and anion selectivity the second sequence is based on cation selectivity, adsorption, and selective recognition based on an anti-u chain IgG (24). 

The majority of the proteins in clinical trials in August 1991 were monoclonal antibodies for treatment of sepsis or neoplasia (see Immunotherapeutic agents). Monoclonal antibodies are derived in most cases from mouse cell lines. This leads to the problem that the antibodies are recognized as foreign by the human immune system. Research efforts are directed toward humanizing antibodies so that these molecules can escape immune surveillance, for example, by the systematic replacement of murine-specific peptide sequences with human homologues while still maintaining the... 

The first and the second approaches have provided some positive results but, unfortunately, they depend upon the structure of the protein. Typical examples of sequence modifications to improve stability and pharmacokinetics are the preparation of humanized antibodies, where part of the mouse sequence is substituted by the human form, and the granulocyte colony-stimulating factor muteins, where up to seven amino acids are substituted. Examples of truncated sequence proteins with improved characteristic are the 7-36 analogues of glucagon-like peptides or the 1-29 sequence growth hormone-releasing factor [1, 2]. 

The processing sequence can be varied with complete freedom in order to accomplish different purposes in an assay (i.e., for either RIA or ELISA for either antigen or antibody detection by either the direct or the indirect techniques). As an example, the following sequence of steps is appropriate for ELISA detection of human antibody to a specific viral antigen, by the indirect (labeled second antibody) technique (Fig. 5A shows diagrammatically how this can be accomplished). 

For example, trastuzumab can be parsed as follows tras-tu-zu-mab. The -zu- denotes a humanized antibody and the -tu- a tumor target. If you wanted to show that it targets the breast specifically, you could call it tramazumab. 

After the antibodies have demonstrated acceptable sensitivity, one should proceed to testing for specificity (cross-reactivity) with structurally similar compounds or compounds that are most likely to be present in the assay matrix. The assay specificity was determined by running the cotinine assay in the presence of compounds structurally similar to cotinine or likely to be present in human samples. Examples included caffeine, nicotinic acid, nicotinamide, and aspirin. Protocol (Number 4) provides testing for assay specificity with the following steps ... 

Although the advent of technologies that can provide fully human antibodies (see Section 2.3) would appear to have solved the problem of immunogenicity, it is to be expected that the solution to this problem is not complete. Some human antibodies are known to be immunogenic, typically through anti-idiotypic or anti-allotypic effects. For example, the fully human antibody adahmumab (Humira), which was... 

Therapeutic antibodies, especially the latest generation platforms (humanized and fully human), have a potentially superior specificity due, for example, to the high number of variants in the selection process (more than 10 °) that cannot be matched by small-molecule libraries that show diversities in the range of 10 (see also Part V, Chapter 2). This often leads to better side-effect profiles shown in the better overall clinical survival rates, especially for humanized and fully human antibodies (e.g. [23]) (see also Part IV, Chapter 3). In addition, monoclonal antibodies have specific capabilities that are entirely unique (e.g., activation of immune response). 

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