GIUSEPPE D'ALESSIO:  FRIDAY 31 MARCH 2006, 10:40

Human Antitumor Immunoagents

Giuseppe D’Alessio and Claudia De Lorenzo
Department of Structural and Functional Biology, University of Naples Federico II, Naples, Italy

Our aim has been to produce immunoagents of human origin, hence poorly, or no immunogenic, directed to one of the most convenient tumor-associated antigens, the TKR ErbB2 (Her2/neu).

First we isolated from a phage library, and characterized Erbicin, a single-chain human anti-ErbB2 immunoagent. Then we exploited and expanded the immuno-toxin concept to make an immunoRNase, i.e. an immuno-pro-toxin, in which the human scFv Erbicin is fused to a human, non-toxic RNase. The latter would become toxic only when tethered by the immuno moiety inside ErbB2-positive cells. An alternative approach was to fuse two Erbicin molecules with the CH2 and CH3 regions of a human IgG1. This led to the production of a fully human, compact (reduced size) antibody.

Erbicin, the immunoRNase (hErb-RNase) and the compact antibody (hErb-cAb), selectively bind ErbB2 with 1-4 nM affinity, and selectively kill ErbB2-positive carcinoma cells, which readily internalize the immunoagents. Both, hErb-RNase and hErb-cAb are effective as antitumor agents in vivo on tumor xenographts implanted in laboratory animals.

Recent data suggest that the immunoagents have different mechanisms of antitumor action. Monovalent Erbicin and hErb-RNase inhibit the hetero-dimerization of ErbB2 with other receptors of the ErbB family, thus engendering a favourable anti-oncogenic effect. Divalent hErb-cAb instead was found to induce the homodimerization of ErbB2, which leads to its down regulation and its depletion on ErbB2-positive cells. Binding competition data indicate that the ErbB2 epitope to which the immunoagents are directed is distinct from that of Herceptin, the humanized monoclonal currently used in clinical immunotherapy.

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