Christian Itin

Selective inhibition of Plasmodium falciparum aldolase by a tubulin derived peptide and identification of the binding site

Aldolase of the human malaria parasite Plasmodium falciparum (PfAldo) may be a potential target for the development of novel antimalarial drugs. Using in vitro mutagenesis we analyzed the function of the carboxy-terminus of the recombinant enzyme. Deletion of the carboxy-terminus of PfAldo confirmed its critical role in catalysis; exchange of conserved residues minimally affected enzyme activity. We exchanged a pair of parasite specific lysine residues with corresponding amino acids of the host. These mutant enzymes exhibited an increased catalytic activity and reduced binding to erythrocyte band 3 protein. Homologous peptides of human band 3 protein and P. falciparum alpha-tubulin were competitive inhibitors of PfAldo. Selective inhibition of PfAldo by the alpha-tubulin peptide depends on the presence of tandem lysine residues and the fine structure of the inhibitor peptide. Our data support the concept of a matrix organisation of glycolytic enzymes in Plasmodium falciparum.

Clinical Experience with Gene Therapy and Bispecific Antibodies for T Cell-based Therapy of Cancer

Unlike any other cell type, T cells have a unique potential to eliminate cancer cells and to eventually cure cancer patients. As a result, researchers have made extensive efforts over the past three decades to develop therapeutics with the potential to mount T cell responses against cancer cells. One way in which such T cell responses can be triggered is by vaccines and adjuvants, potentially leading to tumor-specific T cell clones and lasting immunity. Alternatively, they can be induced with the help of recombinant proteins that either are expressed in patients’ T cells by gene therapeutic means, or are delivered to patients as pharmaceuticals for temporary engagement of T cells. With both recombinant technologies, cytotoxic T cells can be engaged for cancer cell lysis regardless of T cell receptor specificity and with the prospect of bypassing both complex T cell regulation and frequent immune escape mechanisms of tumor cells. In this review, we will focus on recombinant approaches for T cell engagement that currently are in clinical development. Approaches transfecting patient T cells with genes encoding recombinant T cell receptors or antibody fusion proteins will be compared to those temporarily engaging T cells by infused recombinant bispecific proteins. Initial experience has recently been gained in the clinic with both technologies such that their fundamental differences can now be discussed on the basis of patient data.