Engineered Human Antibodies for Breast Cancer

The HER2 (c-erbB-2) proto-oncogene is over-expressed in approximately 30% of the>160,000/yr new cases of breast and ovarian cancer, and correlates inversely with prognosis. Whileanti-erbB-2 antibodies and immunoconjugates show much promise for breast cancer therapy, a fullyhuman high-affinity anti-erbB2 antibody is currently not available. Phage display libraries of antibodyvariable region repertoires have opened a novel route for the isolation of recombinant human monoclonalantibodies. What is lacking is a reliable means for completing the affinity maturation process in vitro.To accomplish, this we have developed a computer-assisted method, called Parsimonious Mutagenesis(PM), for scanning antibody CDR for mutations which improve affinity (Balint and Larrick, 1993). Thismethod facilitates the construction of "scanning" libraries which can "probe" the surface of an antigena few residues at a time with a wide selection of preselected amino acid side chains to search out andidentify new high-affinity contacts. These libraries are made with special low-redundancy "doping"codons and nucleotide mixtures designed to maximize the abundance of combining sites withpredetermined proportions of altered sites. In Phase I, we will use the method to "mature" the affinityin vitro of an anti-erbB-2 antibody which was isolated from a "naive" human repertoire library. In PhaseII, we will conduct pre-clinical evaluation of the highest affinity antibodies from Phase I.