From esoteric theory to therapeutic antibodies |
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Authors: | Tai Te Wu |
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Institution: | (1) Departments of Biochemistry, Molecular Biology and Cell Biology, of Biomedical Engineering, Northwestern University, 60208 Evanston, IL;(2) Departments of Engineering Sciences and Applied Mathematics, Northwestern University, 60208 Evanston, IL |
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Abstract: | Theoretical analyses of amino acid and nucleotide sequences of immunoglobulins have provided a unique approach to the understanding
of structure and function of antibodies. Variability plots unambiguously identified that the antibody-combining site is formed
by six short complementarity determining regions (CDRs), three each from light and heavy chains. Since three-dimensional (3-D)
foldings of framework regions (FRs) are similar among different antibodies, the 3-D configurations of CDRs from a specific
antibody can be predicted based on their amino acid sequences. The resulting structure forms a compact surface that fits the
antigen molecule tightly. The third CDR of the heavy chain (CDRH3), which is coded by the D-minigene together with the N-
and/or P-segments, appears to play a unique role in fine fitting between antibody and antigen molecules. In order to maintain
biological activities, the grafting of mouse CDRs onto human FRs should closely match the human FR amino acid sequences with
the original mouse antibody. Similarities between human and mouse FR sequences that have been preserved for over 20 million
years of evolution can be a useful tool in humanizing mouse antibodies. |
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Keywords: | Antibodies amino acid sequences nucleotide sequences |
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