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.

• Authors: R Schoffelen, O C Boerman, D M Goldenberg, R M Sharkey, C M L van Herpen, G M Franssen, W J McBride, C-H Chang, E A Rossi, W T A van der Graaf, W J G Oyen
• Journal: British journal of cancer (Br J Cancer) Vol. 109 Issue 4 Pg. 934-42 (Aug 20 2013) ISSN: 1532-1827 [Electronic] England
• PMID: 23860529 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific
• CEACAM5 protein, human
• Carcinoembryonic Antigen
• DOTA-tyrosyl-lysyl(histaminyl-succinyl-glycyl)-glutamyl-lysyl(histaminyl-succinyl-glycyl)amide
• GPI-Linked Proteins
• Haptens
• Heterocyclic Compounds, 1-Ring
• Oligopeptides

Topics

• Adult
• Aged
• Antibodies, Bispecific (therapeutic use)
• Carcinoembryonic Antigen (immunology)
• Cohort Studies
• Colorectal Neoplasms (pathology, radiotherapy)
• Female
• GPI-Linked Proteins (immunology)
• Haptens (immunology)
• Heterocyclic Compounds, 1-Ring (therapeutic use)
• Humans
• Male
• Middle Aged
• Oligopeptides (therapeutic use)
• Radioimmunotherapy (methods)