HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 A and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 A. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.

Allelic variation in the DR subregion of the human major histocompatibility complex has been analyzed by nucleic acid sequencing of cDNA clones obtained from cell lines homozygous by consanguinity for all the common serological types DR1-9. Two expressed loci were identified in the haplotypes DR2, -3, -4, -7, and -9; one locus being present at a much lower frequency (4-7%) than the other. The low-frequency allele was highly conserved between each of the DRw53 (DR4, -7, -9) and the DRw52 (DR3, -5, -6) haplotypes. Analysis of the variation between alleles confirms the presence of three allelic hypervariable regions. At each variable residue, a limited range of amino acid substitutions are found, distinguishing them from immunoglobulin hypervariable regions. Dinucleotide substitutions are extremely common. Individual hypervariable regions are often shared between haplotypes. Much of the variation in these alleles can be attributed to the shuffling of these regions between haplotypes, possibly by the mechanism of gene conversion.

This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study.