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) α 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.

Engineering IL-2 to Give New Life to T Cell Immunotherapy

“…Indeed, in human CEA-transgenic C57BL/6 mice, CA demonstrated superior PK and tumor targeting compared with a wild-type IL-2-based CEA immunocytokine, strongly expanded NK and CD8 + T cells in the blood and tumor tissue, and demonstrated increased survival in syngeneic MC38-CEA and PancO2-CEA models, without preferentially activating Tregs (76). Selective and targeted tumor accumulation was confirmed in a recent positron emission tomography imaging study (77). Preliminary phase I data in patients with CEA-positive advanced/metastatic solid tumors confirmed the expansion of CD8 + T cells and NK cells and the intratumoral accumulation of CA (78).…”

A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells

“…There has been substantial effort in the field to create mutations in the rhIL-2 protein which disrupt binding to the IL-2Rα subunit to avoid preferential binding to the high-affinity trimeric IL-2 receptor and overcome these unwanted side effects 24 , 25 , 28 . While achieving the desired function, these mutant proteins have also been shown to be immunogenic and must be further conjugated to a larger molecule to confer a longer in vivo half-life 30 , 31 , 44 .…”

“…Mutated cytokines have also been fused to antibodies or Fc domains to increase the in vivo half-life of the molecules and localize the cytokine to the site of the tumor 18,27,28 . While some of these engineered proteins have the desired functional activity, many of them suffer from high levels of immunogenicity in vivo and present challenges with in vivo stability and manufacturing 24,[29][30][31][32] . Therefore, creating an anti-tumor agonist of the IL-2 pathway with the desired biological activity, safety profile, and ideal drug-like properties remains an unmet need in the field.…”

89Zr-PET imaging in humans: a systematic review

“…Aiming to provide new insights into the mechanisms of immunotherapy, Pandit-Taskar et al successfully imaged tumor-infiltrating CD8-positive (CD8 +) T lymphocytes through 89 Zr-IAB22M2C, a radiolabeled minibody against CD8 + T cells in six patients with solid malignancies [49]. In 2018, van Brummelen et al conducted an immuno-PET imaging study to assess biodistribution and tumor accumulation of 89 Zr-labeled cergutuzumab amunaleukin (CEA-IL2v), an immunocytokine directed against carcinoembryonic antigen (CEA), in twenty-four patients with advanced solid tumors, confirming selective and targeted tumor accumulation of this novel immunocytokine [61]. Similarly, Menke-van der Houven van Oordt et al investigated biodistribution and tumor uptake of the 89 Zrlabeled anti-HER3, mAb GSK2849330, and demonstrated a dose-dependent inhibition of tumor uptake by unlabeled mAb confirming target engagement to the HER3 receptor [36].…”