Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2

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Blood First Edition Paper, prepublished online November 12, 2008; DOI

10.1182/blood-2008-05-160747.

Complete eradication of human B-cell lymphoma xenografts using rituximab in

combination with the immunocytokine L19-IL2

Christoph Schliemann, Alessandro Palumbo, Kathrin Zuberbuhler, Alessandra Villa,

a Kaspar, Eveline Trachsel, Wolfram Klapper, Hans Dietrich Menssen, and

Dario Neri*

Institute of Pharmaceutical Sciences, Department of Chemistry and Applied

Biosciences, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland

Philochem AG, Zurich, Switzerland

Department of Pathology, Haematopathology and Lymph Node Registry, University

Hospital Schleswig-Holstein, Kiel, Germany

Bayer Schering Pharma AG, Berlin, Germany

* Corresponding author; email: neri@... .

The antibody-mediated delivery of therapeutic agents to sites of angiogenesis is

an attractive strategy for anti-cancer therapy, but is largely unexplored in

hematologic malignancies. In the present study, we show that the extra domain B

(EDB) of fibronectin, a marker of angiogenesis, is expressed in B-cell

non-Hodgkin lymphomas (NHLs), and that the human monoclonal anti-EDB antibody

L19 can selectively localize to the lymphoma-associated sub-endothelial

extracellular matrix. In vivo, the preferential accumulation of the antibody at

the tumor site was confirmed by quantitative biodistribution analyses with

radioiodinated antibody preparations. The fusion protein L19-IL2, which mediates

the delivery of interleukin-2 (IL-2) to the neovasculature, displayed a superior

anti-lymphoma activity compared to unconjugated IL-2 in localized and systemic

xenograft models of NHL. When co-administered with rituximab, L19-IL2 induced

complete remissions of established localized lymphomas and provided long-lasting

protection from disseminated lymphoma. The combined use of rituximab and

L19-IL2, which dramatically increases the infiltration of immune effector cells

in lymphomas, may deserve clinical investigations, facilitated by the fact that

L19-IL2 is currently being studied in phase II clinical trials in patients with

solid tumors.