Geoffrey Allan Pietersz

Crystal structure of a non-canonical low-affinity peptide complexed with MHC class I: a new approach for vaccine design.

Peptides bind with high affinity to MHC class I molecules by anchoring certain side-chains (anchors) into specificity pockets in the MHC peptide-binding groove. Peptides that do not contain these canonical anchor residues normally have low affinity, resulting in impaired pMHC stability and loss of immunogenicity. Here, we report the crystal structure at 1.6 A resolution of an immunogenic, low-affinity peptide from the tumor-associated antigen MUC1, bound to H-2Kb. Stable binding is still achieved despite small, non-canonical residues in the C and F anchor pockets. This structure reveals how low-affinity peptides can be utilized in the design of novel peptide-based tumor vaccines. The molecular interactions elucidated in this non-canonical low-affinity peptide MHC complex should help uncover additional immunogenic peptides from primary protein sequences and aid in the design of alternative approaches for T-cell vaccines.

The Use of Drug-Monoclonal Antibody Conjugates for the Treatment of Cancer

As we reflect on the use of antibodies for immunotherapy, several important points emerge. Firstly, the polyclonal antibody (PAb) response to infectious agents such as tetanus is entirely satisfactory. This polyclonal response is often present with low amounts of high-affinity IgM and IgG antibodies and is accompanied by the appropriate T- and B-cell memory so that large amounts of high affinity/avidity antibodies can be produced at short notice. On the basis of such a successful immune response, how can the immune response be used to treat cancer? Clearly the antigens are endogenous and not intrinsically immunogenic. Thus, the first problem has been to make an appropriate immune response to a nonimmunogenic antigen: a nonsequeter. However, human tumors are immunogenic in other species leading to monoclonal antibodies (MAbs) produced in the mouse. However, these antibodies are monoclonal and react with one specificity as opposed to PAbs, which react with multiple specificities; thus for MAbs there will be less antibody molecules bound to a tumor cell. In addition, for mouse MAbs the Fc piece functions poorly in humans and does not adequately mobilize various elements of an inflammatory response (by Fc and complement receptors). Thus for the most part, mouse antibodies alone have not proven useful for either the detection or treatment of solid tumors. It is clear that the antibodies had to made more potent and Paul Ehrlich’s suggestion of converting them to “magic bullets” was reintroduced when MAbs began to appear in the 1980s for the treatment of cancer.