Potentiating the activity of rituximab against mantle cell lymphoma in mice by targeting interleukin-2 to the neovasculature.
There is increasing interest in the site-directed pharmacodelivery of therapeutic payloads to the tumor site using antibodies as transport vehicles. Here, we investigated the efficacy of L19-IL2, an antibody-cytokine fusion protein that specifically delivers IL-2 to the tumor site by homing to the extra-domain B of fibronectin (EDB-Fn) expressed on tumor-associated blood vessels, against mantle cell lymphoma (MCL) in mice. L19-IL2 was shown to selectively localize at lymphoma lesions in vivo and to mediate significant lymphoma growth retardation, which was potentiated by co-administration of the anti-CD20 antibody rituximab. When co-injected with rituximab, L19-IL2 induced complete remissions of localized MCL xenografts in 6/8 mice (75%), whereas the combination of rituximab and equivalent doses of non-targeted IL-2 only slightly delayed tumor growth. In disseminated MCL, combination therapy with L19-IL2 and rituximab exhibited a significant survival benefit over treatment with IL-2 and rituximab and completely eradicated the disease in 2/7 cases (28.6%). Mechanistically, histological analyses of post-therapeutic lymphoma tissues revealed a strong intratumoral accumulation of macrophages and natural killer cells after a single dose of the immunocytokine, whereas L19-IL2 had no significant impact on microvessel density or on tissue penetration of co-injected rituximab. Collectively, these results provide the scientific rationale for the clinical evaluation of L19-IL2 in combination with anti-CD20 immunotherapy in patients with MCL.
Department of Medicine A, University Hospital Muenster, Muenster, Germany.
Niklas
N
Börschel
Department of Medicine A, University Hospital Muenster, Muenster, Germany.
Christian
C
Schwöppe
Department of Medicine A, University Hospital Muenster, Muenster, Germany.
Caroline
C
Zerbst
Department of Medicine A, University Hospital Muenster, Muenster, Germany.
Linus
L
Angenendt
Department of Medicine A, University Hospital Muenster, Muenster, Germany.
Torsten
T
Kessler
Institute of Hematopathology, University Hospital Schleswig-Holstein, Kiel, Germany.
Wolfram
W
Klapper
Philogen S.p.A., Siena, Italy.
Leonardo
L
Giovannoni
Philochem AG, Otelfingen, Switzerland.
Giuliano
G
Elia
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
Dario
D
Neri
Department of Medicine A, University Hospital Muenster, Muenster, Germany.
Wolfgang E
WE
Berdel
Department of Medicine A, University Hospital Muenster, Muenster, Germany.
Rolf M
RM
Mesters
Department of Medicine A, University Hospital Muenster, Muenster, Germany. Electronic address: christoph.schliemann@ukmuenster.de.
Christoph
C
Schliemann
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D007376:Interleukin-2 / Q000494:pharmacology / Q000627:therapeutic use*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000069283:Rituximab
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D007376:Interleukin-2; D000069283:Rituximab
Immunocytokine; Interleukin-2; Mantle cell lymphoma; Rituximab; Vascular targeting