Antibody, humanized

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). 

Riechmann, L., et al. Reshaping human antibodies for therapy. Nature 332 323-327, 1988. 

A number of chimerized, humanized, and one human mAb have now been approved for therapeutic use in humans in the treatment of autoimmunity, malignancy, infection and cardiovascular disease (Table 1). Some of the currently licensed mAb will be discussed here. A much larger number of mAb are currently being evaluated in Phase I, II and III trials. In general, chimeric, humanized and human mAb are very well tolerated with few side effects. Chimeric or humanized mAb still have the potential to evoke host immune response to the variable domains or CDRs of the antibody so-called HACA (human anti-chimeric antibody) or HAHA (human anti-human antibody) responses, although these responses are uncommon. Short-lived and occasionally severe infusion-related acute hypersensitivity reactions such as fever, skin itching, shivering, respiratory compromise and low blood pressure sometimes occur-. Such effects may... 

Adalimumab Complete human antibody against TNF-a with similar properties as infliximab. 

ADCC. Cetuximab is approved for treatment of metastatic colorectal cancer (CRC) and squamous cell carcinoma of the head and neck (SCCHN). Interestingly, an adverse event, acneiform rash seems to correlate with a better response to cetuximab, while there is no such correlation with expression levels of EGFR assessed by immunohistochemistry. Further side effects are rare infusion reactions and hypomagnesia. Two other anti-EGFR antibodies approved for clinical use are the fully human antibody panitumumab (Vectibix)... 

Trastuzumab (Herceptin) Humanized antibody, IgGi ErbB2/Her-2 Receptor down-regulation Breast cancer... 

Panitumumab (Vectibix) Fully human antibody, lgG2 EGFR Ligand competition CRC... 

Nimotuzumab (TheraCIM) Humanized antibody, IgGi EGFR Ligand competition SSCHN... 

Bevacizumab (Avastin) Humanized antibody, lgG1 VEGF Inhibition of ligand binding CRC NSCLC... 

Ranibizumab (Lucentis) Humanized antibody fragment, IgG-) VEGF-A Inhibition of ligand binding AMD... 

Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA (1998) Structure of an HIV gpl20 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393 648-659... 

Basiliximab and daclizumab are considered monoclonal antibodies. Daclizumab is a humanized antibody that is approximately 10% murine and 90% human, whereas basiliximab is a chimeric antibody that is approximately 30% murine and 70% human.9,11 These agents bind with high affinity to the IL-2 receptor, where they act as CD25 receptor antagonists. These receptors are present on almost all activated T cells. Their role in induction therapy involves inhibiting IL-2-mediated activation of lymphocytes, which is an important step for the clonal expansion of T cells. 

Ditzel HI, Rosenkilde MM, Garred P, et al. The CCR5 receptor acts as an alloantigen in CCR5Delta32 homozygous individuals identification of chemokine and HIV-1-blocking human antibodies. Proc Natl Acad Sci U S A 1998 95 5241-5245. 

Two types of antibody libraries can be constructed, immune or non-immune. Immune libraries are constructed by immunizing the animal of interest with an antigen(s). In the case of humans, the source can be volunteers with the disease or condition under study (Persson et al., 1991). Human antibodies have also been obtained from severe combined immunodeficiency mice populated with human peripheral blood... 

Marks, J. D., Hoogenboom, H. R., Bonnert, T. P., McCafferty, J., Griffiths, D., and Winter, G. (1991). By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J. Mol. Biol. 222, 581-597. 

Vaughan, T. J., Williams, A. J., Pritchard, K., Osbourn, J. K., Pope, A. R., Eamshaw, J. C., McCafferty, J., Hodits, R. A., Wilton, J., and Johnson, K. S. (1996). Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library. Nat. Biotechnol. 14, 309-314. 

Many primate studies are on human antibodies that cannot be tested with other species due to problems of antigenicity. 

Fig. 24. Cyclic peptide vaccine candidate bearing the minimally epitopic D1 branch of the Man9 G1cNAc2 antigen of HIV-1 gpl20 recognized by the protective human antibody 2G12.191...

FIG. 49. Oligomannoside-ending azides used in cUck-chemistry toward HIV-1 gpl20 mimetics recognized by human antibody 2G12 and DC-SIGN.325... 

Fig. 61. Crystal structure of the FIIV-l neutralizing human antibody 2G12 bound to the oligomannoside MaiiyGlcNAc i present on the silent face of the gpl20 envelope glycoprotein (PDB 10P5).

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