From esoteric theory to therapeutic antibodies.

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.