Potentiating the activity of rituximab against mantle cell lymphoma in mice by targeting interleukin-2 to the neovasculature
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Potentiating the activity of rituximab against mantle cell lymphoma in mice by targeting interleukin-2 to the neovasculature. / Börschel, Niklas; Schwöppe, Christian; Zerbst, Caroline; Angenendt, Linus; Kessler, Torsten; Klapper, Wolfram; Giovannoni, Leonardo; Elia, Giuliano; Neri, Dario; Berdel, Wolfgang E; Mesters, Rolf M; Schliemann, Christoph.
In: Leukemia research, Vol. 39, No. 7, 07.2015, p. 739-48.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research
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TY - JOUR
T1 - Potentiating the activity of rituximab against mantle cell lymphoma in mice by targeting interleukin-2 to the neovasculature
AU - Börschel, Niklas
AU - Schwöppe, Christian
AU - Zerbst, Caroline
AU - Angenendt, Linus
AU - Kessler, Torsten
AU - Klapper, Wolfram
AU - Giovannoni, Leonardo
AU - Elia, Giuliano
AU - Neri, Dario
AU - Berdel, Wolfgang E
AU - Mesters, Rolf M
AU - Schliemann, Christoph
N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.
PY - 2015/7
Y1 - 2015/7
N2 - 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.
AB - 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.
KW - Animals
KW - Antibodies, Monoclonal, Murine-Derived
KW - Antineoplastic Agents
KW - Female
KW - Interleukin-2
KW - Lymphoma, Mantle-Cell
KW - Mice
KW - Mice, SCID
KW - Neovascularization, Pathologic
KW - Rituximab
U2 - 10.1016/j.leukres.2015.04.005
DO - 10.1016/j.leukres.2015.04.005
M3 - SCORING: Journal article
C2 - 25934049
VL - 39
SP - 739
EP - 748
JO - LEUKEMIA RES
JF - LEUKEMIA RES
SN - 0145-2126
IS - 7
ER -
