Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results

Abstract

Background: Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC).

Methods: Different dose schedules were studied in four cohorts of five patients: (1) shortening the interval between the bsMAb and peptide administration (5 days vs 1 day), (2) escalating the TF2 dose (from 75 to 150 mg), and (3) reducing the peptide dose (from 100 to 25 μg). After confirmation of tumour targeting by (111)In-IMP288, patients were treated with a bsMAb/(177)Lu-IMP288 cycle.

Results: Rapid and selective tumour targeting of the radiolabelled peptide was visualised within 1 h, with high tumour-to-tissue ratios (>20 at 24 h). Improved tumour targeting was achieved with a 1-day interval between the administration of the bsMAb and the peptide and with the 25-μg peptide dose. High (177)Lu-IMP288 doses (2.5-7.4 GBq) were well tolerated, with some manageable TF2 infusion reactions, and transient grades 3-4 thrombocytopaenia in 10% of the patients who received (177)Lu-IMP288.

Conclusion: This phase I study demonstrates for the first time that pretargeting with bsMAb TF2 and radiolabelled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted.

Figure 1

Treatment schedule. Patients received an imaging cycle with TF2 and ¹¹¹In-IMP288 to determine the pharmacokinetics and radiation dose to the red bone marrow and kidneys. A safe, cumulative ¹⁷⁷Lu-activity dose was estimated, and one-fourth of this amount was administered in the first therapy cycle.

Figure 2

Schematic representation of the pretargeting agents. The trivalent bispecific antibody construct, TF2, binds divalently to CEACAM5, the tumour-associated antigen that is overexpressed on the cell surface of colorectal tumour cells. After the bsMAb has localised the tumour and cleared from the blood, a radiolabelled divalent peptide is given, substituted with the hapten, histamine-succinyl-glycine (HSG). This is rapidly targeted to the tumours and bound by high affinity to the anti-HSG Fab fragment of the bsMAb. Due to its bivalency, it has the ability to crosslink the bsMAbs at the tumour surface, forming a stable complex. The peptide is conjugated with the chelator, DOTA that can be labelled with a variety of radionuclides.

Figure 3

Pharmacokinetics. (A) Serum clearance of TF2 determined by ELISA in cohorts 1, 2, and 4 that received 75 mg of TF2, and in cohort 3, 150 mg (mean±standard deviation; N=5 per cohort). TF2 cleared rapidly from the serum, with cohort 3 having twice as high serum concentrations. (B) ¹¹¹In-IMP288 blood clearance per cohort (mean±standard deviation; N=5 per cohort). In all cohorts, >98% ID was cleared at 24 h p.i., although peptide blood clearance was somewhat delayed by shortening the interval between bsMAb and peptide administration, and to a lesser extent due to a higher antibody and a lower peptide doses.

Figure 4

Scintigraphic images. The SPECT/CT image (A), acquired 24 h after injection of ¹¹¹In-IMP288 (185 MBq, 25 μg), pretargeted with 75 mg TF2 (1-day interval), in a 38-year-old patient (cohort 4), shows very clear tumour targeting of an axillary lymph-node metastasis, with very low concentrations of radioactivity in normal tissues. This patient had a CEA level of 17 μg l⁻¹ and the concentration of ¹¹¹In-IMP288 in the tumour was 6.3% ID kg⁻¹, with a tumour-to-normal tissue ratio of 33. Corresponding contrast-enhanced CT scan and a fused FDG-PET/CT scan are shown (B and C, respectively). The primary colon tumour (50 cm ab ano) also shows highly specific tumour targeting in the SPECT image (D), confirmed by the CT scan and FDG-PET/CT (E and F, respectively), with non-specific FDG uptake in the ascending colon.