Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2.
The antibody-mediated delivery of therapeutic agents to sites of angiogenesis is an attractive strategy for anticancer 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 lymphoma (NHL) and that the human monoclonal anti-EDB antibody L19 can selectively localize to the lymphoma-associated subendothelial 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 antilymphoma activity compared with unconjugated IL-2 in localized and systemic xenograft models of NHL. When coadministered 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.
Schliemann
Christoph
C
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology Zürich, Zürich, Switzerland.
Palumbo
Alessandro
A
Zuberbühler
Kathrin
K
Villa
Alessandra
A
Kaspar
Manuela
M
Trachsel
Eveline
E
Klapper
Wolfram
W
Menssen
Hans Dietrich
HD
Neri
Dario
D
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000008:administration & dosage*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D000069283:Rituximab; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C067625:FN1 protein, human; D005353:Fibronectins; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C513931:SIP(L19) fusion protein; D000069283:Rituximab