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 111In-IMP288, patients were treated with a bsMAb/177Lu-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 177Lu-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 177Lu-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.

Pretargeted Dual-Modality Immuno-SPECT and Near-Infrared Fluorescence Imaging for Image-Guided Surgery of Prostate Cancer

“…The toxicity of IMP288 was investigated in mice: high doses were administered without any signs of toxicity. We have applied the IMP288 peptide labeled with In-111 in patients (100 mg/patient), without any toxicity (17). The toxicity of IRDye800CW has been studied extensively in rats (18).…”

MIRD Pamphlet No. 26: Joint EANM/MIRD Guidelines for Quantitative 177Lu SPECT Applied for Dosimetry of Radiopharmaceutical Therapy

“…The PRRT use in treatment of neuroendocrine tumors (NETs) is motivated by the fact that the carrier peptide, octreotate, shows highaffinity binding to somatostatin receptors, which are overexpressed on the cell surface of many NETs (2)(3)(4)(5)(6). Furthermore, 177 Lu has been used in radioimmunotherapy clinical trials to label different kinds of monoclonal antibodies (7)(8)(9)(10)(11)(12)(13)(14)(15).…”

Immuno-PET Using Anticarcinoembryonic Antigen Bispecific Antibody and 68Ga-Labeled Peptide in Metastatic Medullary Thyroid Carcinoma: Clinical Optimization of the Pretargeting Parameters in a First-in-Human Trial

“…Today, new pretargeting reagents have been designed (11)(12)(13)(14)(15). TF2 is an engineered trivalent BsMAb composed of a humanized anti-histamine-succinyl-glycine Fab fragment derived from the murine 679 antibody and 2 humanized anti-CEA Fab fragments derived from the hMN-14 antibody, formed into a 157-kD protein by the dock-andlock procedure (11).…”

“…IMP288 is a bivalent histamine-succinyl-glycine hapten that can be labeled with a variety of radionuclides for therapy ( 90 Y and 177 Lu), scintigraphy ( 111 In), or PET ( 124 I, 68 Ga, and 18 F). The clinical implementation of pretargeting requires a first phase to optimize the BsMAb and peptide molar doses and the delay between the 2 injections (14)(15)(16)(17). The first clinical results were reported using TF2/ 177 Lu-IMP288 in colorectal carcinoma patients, showing fast tumor uptake and high tumor-to-background activity ratios within a few hours (14).…”