89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors: CEA-mediated tumor accumulation and role of IL-2 receptor-binding

Emilie M.J. van Brummelen, Marc C. Huisman, Linda J. de Wit-van der Veen, Tapan K. Nayak, Marcel P.M. Stokkel, Emma R. Mulder, Otto S. Hoekstra, Danielle J. Vugts, Guus A.M.S. Van Dongen, Henk M. Verheul, Stefan Evers, Jean J.L. Tessier, Jose Saro, Jan H.M. Schellens, C. Willemien Menke-van der Houven van Oordt

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Cergutuzumab amunaleukin (CEA-IL2v) is an immunocytokine directed against carcinoembryonic antigen (CEA) containing an IL2v-moiety with abolished IL-2 receptor (IL-2R) a binding. We describe the biodistribution and tumor accumulation of 89Zr-labeled CEA-IL2v. Twenty-four patients with advanced solid CEA positive (CEA+) or negative (CEA-) tumors received CEA-IL2v 6 mg (4 CEA+; 3 CEA-), 20 mg (9 CEA+), or 30 mg (4 CEA+; 4 CEA-) biweekly. In cycle 1, 2 mg of the total dose comprised 89Zr-CEA-IL2v (50 MBq) and serial 89Zr-PET imaging was conducted. Four CEA+ patients with visually confirmed 89Zr-CEA-IL2v tumor accumulation at 20 mg had repeated 89Zr-PET imaging during cycle 4. 89Zr-CEA-IL2v immuno-PET demonstrated preferential drug accumulation in CEA+ tumors (%ID/mLpeak CEA- 3.6 × 10-3 vs. CEA+ 6.7 ×·10-3). There was a non-significant trend towards dose-dependent tumor uptake, with higher uptake at doses ≥20 mg. Biodistribution was dose- and CEA-independent with major accumulation in lymphoid tissue compatible with IL-2R binding. Reduced exposure and reduced tumor accumulation (%ID/mLpeak 57% lower) on cycle 4 vs. cycle 1 was consistent with peripheral expansion of immune cells. The findings of this immune PET imaging study with 89Zr-CEA-IL2v support the therapeutic concept of CEA-IL2v, confirming selective and targeted tumor accumulation with this novel immunocytokine.

LanguageEnglish
Pages24737-24749
Number of pages13
JournalOncotarget
Volume9
Issue number37
DOIs
StatePublished - 15 May 2018

Cite this

van Brummelen, Emilie M.J. ; Huisman, Marc C. ; de Wit-van der Veen, Linda J. ; Nayak, Tapan K. ; Stokkel, Marcel P.M. ; Mulder, Emma R. ; Hoekstra, Otto S. ; Vugts, Danielle J. ; Van Dongen, Guus A.M.S. ; Verheul, Henk M. ; Evers, Stefan ; Tessier, Jean J.L. ; Saro, Jose ; Schellens, Jan H.M. ; Menke-van der Houven van Oordt, C. Willemien. / 89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors : CEA-mediated tumor accumulation and role of IL-2 receptor-binding. In: Oncotarget. 2018 ; Vol. 9, No. 37. pp. 24737-24749
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title = "89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors: CEA-mediated tumor accumulation and role of IL-2 receptor-binding",
abstract = "Cergutuzumab amunaleukin (CEA-IL2v) is an immunocytokine directed against carcinoembryonic antigen (CEA) containing an IL2v-moiety with abolished IL-2 receptor (IL-2R) a binding. We describe the biodistribution and tumor accumulation of 89Zr-labeled CEA-IL2v. Twenty-four patients with advanced solid CEA positive (CEA+) or negative (CEA-) tumors received CEA-IL2v 6 mg (4 CEA+; 3 CEA-), 20 mg (9 CEA+), or 30 mg (4 CEA+; 4 CEA-) biweekly. In cycle 1, 2 mg of the total dose comprised 89Zr-CEA-IL2v (50 MBq) and serial 89Zr-PET imaging was conducted. Four CEA+ patients with visually confirmed 89Zr-CEA-IL2v tumor accumulation at 20 mg had repeated 89Zr-PET imaging during cycle 4. 89Zr-CEA-IL2v immuno-PET demonstrated preferential drug accumulation in CEA+ tumors ({\%}ID/mLpeak CEA- 3.6 × 10-3 vs. CEA+ 6.7 ×·10-3). There was a non-significant trend towards dose-dependent tumor uptake, with higher uptake at doses ≥20 mg. Biodistribution was dose- and CEA-independent with major accumulation in lymphoid tissue compatible with IL-2R binding. Reduced exposure and reduced tumor accumulation ({\%}ID/mLpeak 57{\%} lower) on cycle 4 vs. cycle 1 was consistent with peripheral expansion of immune cells. The findings of this immune PET imaging study with 89Zr-CEA-IL2v support the therapeutic concept of CEA-IL2v, confirming selective and targeted tumor accumulation with this novel immunocytokine.",
keywords = "Zr, Biodistribution, Immuno-PET, Immunocytokine, Interleukin-2",
author = "{van Brummelen}, {Emilie M.J.} and Huisman, {Marc C.} and {de Wit-van der Veen}, {Linda J.} and Nayak, {Tapan K.} and Stokkel, {Marcel P.M.} and Mulder, {Emma R.} and Hoekstra, {Otto S.} and Vugts, {Danielle J.} and {Van Dongen}, {Guus A.M.S.} and Verheul, {Henk M.} and Stefan Evers and Tessier, {Jean J.L.} and Jose Saro and Schellens, {Jan H.M.} and {Menke-van der Houven van Oordt}, {C. Willemien}",
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89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors : CEA-mediated tumor accumulation and role of IL-2 receptor-binding. / van Brummelen, Emilie M.J.; Huisman, Marc C.; de Wit-van der Veen, Linda J.; Nayak, Tapan K.; Stokkel, Marcel P.M.; Mulder, Emma R.; Hoekstra, Otto S.; Vugts, Danielle J.; Van Dongen, Guus A.M.S.; Verheul, Henk M.; Evers, Stefan; Tessier, Jean J.L.; Saro, Jose; Schellens, Jan H.M.; Menke-van der Houven van Oordt, C. Willemien.

In: Oncotarget, Vol. 9, No. 37, 15.05.2018, p. 24737-24749.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - 89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors

T2 - Oncotarget

AU - van Brummelen,Emilie M.J.

AU - Huisman,Marc C.

AU - de Wit-van der Veen,Linda J.

AU - Nayak,Tapan K.

AU - Stokkel,Marcel P.M.

AU - Mulder,Emma R.

AU - Hoekstra,Otto S.

AU - Vugts,Danielle J.

AU - Van Dongen,Guus A.M.S.

AU - Verheul,Henk M.

AU - Evers,Stefan

AU - Tessier,Jean J.L.

AU - Saro,Jose

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AU - Menke-van der Houven van Oordt,C. Willemien

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N2 - Cergutuzumab amunaleukin (CEA-IL2v) is an immunocytokine directed against carcinoembryonic antigen (CEA) containing an IL2v-moiety with abolished IL-2 receptor (IL-2R) a binding. We describe the biodistribution and tumor accumulation of 89Zr-labeled CEA-IL2v. Twenty-four patients with advanced solid CEA positive (CEA+) or negative (CEA-) tumors received CEA-IL2v 6 mg (4 CEA+; 3 CEA-), 20 mg (9 CEA+), or 30 mg (4 CEA+; 4 CEA-) biweekly. In cycle 1, 2 mg of the total dose comprised 89Zr-CEA-IL2v (50 MBq) and serial 89Zr-PET imaging was conducted. Four CEA+ patients with visually confirmed 89Zr-CEA-IL2v tumor accumulation at 20 mg had repeated 89Zr-PET imaging during cycle 4. 89Zr-CEA-IL2v immuno-PET demonstrated preferential drug accumulation in CEA+ tumors (%ID/mLpeak CEA- 3.6 × 10-3 vs. CEA+ 6.7 ×·10-3). There was a non-significant trend towards dose-dependent tumor uptake, with higher uptake at doses ≥20 mg. Biodistribution was dose- and CEA-independent with major accumulation in lymphoid tissue compatible with IL-2R binding. Reduced exposure and reduced tumor accumulation (%ID/mLpeak 57% lower) on cycle 4 vs. cycle 1 was consistent with peripheral expansion of immune cells. The findings of this immune PET imaging study with 89Zr-CEA-IL2v support the therapeutic concept of CEA-IL2v, confirming selective and targeted tumor accumulation with this novel immunocytokine.

AB - Cergutuzumab amunaleukin (CEA-IL2v) is an immunocytokine directed against carcinoembryonic antigen (CEA) containing an IL2v-moiety with abolished IL-2 receptor (IL-2R) a binding. We describe the biodistribution and tumor accumulation of 89Zr-labeled CEA-IL2v. Twenty-four patients with advanced solid CEA positive (CEA+) or negative (CEA-) tumors received CEA-IL2v 6 mg (4 CEA+; 3 CEA-), 20 mg (9 CEA+), or 30 mg (4 CEA+; 4 CEA-) biweekly. In cycle 1, 2 mg of the total dose comprised 89Zr-CEA-IL2v (50 MBq) and serial 89Zr-PET imaging was conducted. Four CEA+ patients with visually confirmed 89Zr-CEA-IL2v tumor accumulation at 20 mg had repeated 89Zr-PET imaging during cycle 4. 89Zr-CEA-IL2v immuno-PET demonstrated preferential drug accumulation in CEA+ tumors (%ID/mLpeak CEA- 3.6 × 10-3 vs. CEA+ 6.7 ×·10-3). There was a non-significant trend towards dose-dependent tumor uptake, with higher uptake at doses ≥20 mg. Biodistribution was dose- and CEA-independent with major accumulation in lymphoid tissue compatible with IL-2R binding. Reduced exposure and reduced tumor accumulation (%ID/mLpeak 57% lower) on cycle 4 vs. cycle 1 was consistent with peripheral expansion of immune cells. The findings of this immune PET imaging study with 89Zr-CEA-IL2v support the therapeutic concept of CEA-IL2v, confirming selective and targeted tumor accumulation with this novel immunocytokine.

KW - Zr

KW - Biodistribution

KW - Immuno-PET

KW - Immunocytokine

KW - Interleukin-2

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van Brummelen EMJ, Huisman MC, de Wit-van der Veen LJ, Nayak TK, Stokkel MPM, Mulder ER et al. 89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors: CEA-mediated tumor accumulation and role of IL-2 receptor-binding. Oncotarget. 2018 May 15;9(37):24737-24749. Available from, DOI: 10.18632/oncotarget.25343