CEA-IL2v (cergutuzumab amunaleukin, RG7813) is an engineered IL-2 variant (IL-2v) antibody directed against Carcinoembryonic Antigen (CEA) with abolished IL-2 receptor (IL-2R) α (CD25) binding. The molecule was designed to improve the pharmacological and safety profile of IL-2 and direct local accumulation in CEA-positive (CEA+) tumors. To demonstrate selective and specific tumor targeting, CEA-IL-2v was labeled with 89Zr. Biodistribution and tumor accumulation was assessed at varying doses in tumors with different CEA status.
Patients (pts) with advanced and/or metastatic solid CEA+ or CEA-negative (CEA-) tumors were eligible for this sub-study of a phase I trial. CEA-IL2v was administered intravenously q2W at total doses of 6 mg, 20 mg and 30 mg (incl 50 MBq/2mg 89Zr-CEA-IL2v). All pts underwent up to 3 89Zr-PET assessments during cycle 1. In the 20 mg cohort, pts with initial tumor uptake at cycle 1 underwent additional 89Zr-PET assessments in cycle 4.
Patients were treated with 6 mg (4 pts CEA + ; 3 pts CEA-), 20 mg (8 pts CEA+) or 30 mg CEA-IL2v (4 pts CEA + ; 4 pts CEA-). Accumulation of 89Zr-CEA-IL-2v (at day 5 post injection) was observed independent of CEA status in lymphoid tissues like spleen (SUVmean 10.0 ± 3.1) and non-pathological lymph nodes (SUVmean 2.0 ± 1.2) at all doses; this was considered IL-2 receptor-mediated uptake. Intratumoral accumulation of 89Zr-CEA-IL-2v in cycle 1 was observed in CEA+ patients: 1/4 pts at 6 mg (SUVpeak 5.4), 6/8 pts at 20 mg (SUVpeak 5.2 ± 2.7) and 4/4 pts at 30 mg (SUVpeak 5.8 ± 4.4). At cycle 4, 89Zr-CEA-IL-2v accumulation in tumor lesions (SUVpeak 4.0 ± 1.1) decreased, possibly due to anti-drug antibodies or expansion of IL-2R expressing T-cells. In tumors with high accumulation of 89Zr- CEA-IL-2v at cycle 1, there was a trend towards decreased metabolic activity at early FDG-PET evaluation.
At all doses, 89Zr- CEA-IL-2v accumulated in spleen and secondary lymphoid tissues, due to IL-2R mediated uptake. CEA-mediated tumor accumulation was observed in a dose-dependent manner with consistent targeting starting at 20 mg CEA-IL2v; a phase I study as monotherapy and with atezolizumab is ongoing.
Clinical trial identification
ClinicalTrials.gov Identifier:NCT02004106 EUDRACT NUMBER: 2013-003041-41
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd
T. Nayak: Employement and stock/ownership Hoffman LaRoche. H.M. Verheul: Honoraria and consulting/advisory role for Boehringer Ingelheim- recipient: Institution. Reserach Funding of AMGEN, VHS, ImmunonovoBV, Roche - recipient: Institution. M. Feilke: Consulting/advisory role for Roche Diagnostics GmbH Travel/ accomodation expenses received from Roche Diagnostics GmbH. C. Guizani: Employement of Hoffmann-LaRoche Stock/ownership Hoffmann-LaRoche. E. Guarin: Employment Hoffmann-LaRoche. S. Evers: Employment Roche Glycart Leadership Roche Glycart Stock/ownership F Hoffmann-LaRoche. J. Saro: Employment Roche Glycart Stock/ownership Roche and BMS. All other authors have declared no conflicts of interest.