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mouse light and heavy chain variable regions. Their half-life in human
patients can be around two weeks, and may exert their biological
effectiveness during that period. One of the first approved therapeutic
antibodies of this type is an anti-CD20 antibody, designed to treat low grade
B cell lymphoma. CD20 is a surface molecule present in most B cells.
Various pharmaceutical companies are developing other chimeric antibodies
of hybrid mouse and human origin to treat cancers and viral infections.
HUMANIZING MOUSE ANTIBODIES
Chimeric antibodies make use of V L and V H of mouse antibodies containing
the CDR's selected for certain specificities. In addition they also contain the
framework regions (FR's) of the original mouse antibodies. Some of these
FR's can be antigenic, thus reducing their half-lives in human patients, even
though several FR amino acid sequences are conserved among human,
mouse and rabbit. At the gene level, it is possible to cut out the segments
coding for CDR's from mouse antibody genes. These segments can then be
grafted onto gene segments coding for human FR's. The resulting antibody
is known as humanized mouse antibody. The major question in
manufacturing such antibodies is which human FR's should be used.
Ideally, in order to maintain the avidity of a humanized mouse antibody, the
mouse FR's should be matched against all known human FR's. The most
similar human FR's should then be used. This can preserve the overall
three-dimensional folding of the resulting antibody molecule. To achieve
this, a special program for sequence matching has been included in our
website, <http://immuno.bme.nwu.edu>. An example is illustrated in Fig. 1-
15. On opening our website, click on SeqhuntII. A new window will open
up. Pick Match. In the third window, pick amino acid and choose HUMAN
IG HEAVY chain variable region, for example. Then, type in the required
amino acid sequence in single letter abbreviation. The example shows the
match of a mouse heavy chain FRH1 sequence of V11, i.e.
EVKLVESGGGLVQPGGSLRLSCATSGFTFT
There are four best matches for human heavy chain FRH1 with two amino
acid residue differences. One of them is mAB55 as shown in Fig. 1-15.
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