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01.12.2018 | Original research | Ausgabe 1/2018 Open Access

EJNMMI Research 1/2018

Assessment of target-mediated uptake with immuno-PET: analysis of a phase I clinical trial with an anti-CD44 antibody

Zeitschrift:
EJNMMI Research > Ausgabe 1/2018
Autoren:
Yvonne W. S. Jauw, Marc C. Huisman, Tapan K. Nayak, Danielle J. Vugts, Randolph Christen, Valerie Meresse Naegelen, Dominik Ruettinger, Florian Heil, Adriaan A. Lammertsma, Henk M. W. Verheul, Otto S. Hoekstra, Guus A. M. S. van Dongen, C. Willemien Menke-van der Houven van Oordt
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13550-018-0358-8) contains supplementary material, which is available to authorized users.

Abstract

Background

Ideally, monoclonal antibodies provide selective treatment by targeting the tumour, without affecting normal tissues. Therefore, antibody imaging is of interest, preferably in early stages of drug development. However, the imaging signal consists of specific, as well as non-specific, uptake. The aim of this study was to assess specific, target-mediated uptake in normal tissues, with immuno-PET in a phase I dose escalation study, using the anti-CD44 antibody RG7356 as example.

Results

Data from thirteen patients with CD44-expressing solid tumours included in an imaging sub-study of a phase I dose escalation clinical trial using the anti-CD44 antibody RG7356 was analysed. 89Zirconium-labelled RG7356 (1 mg; 37 MBq) was administered after a variable dose of unlabelled RG7356 (0 to 675 mg). Tracer uptake in normal tissues (liver, spleen, kidney, lung, bone marrow, brain and blood pool) was used to calculate the area under the time antibody concentration curve (AUC) and expressed as tissue-to-blood AUC ratios.
Within the dose range of 1 to 450 mg, tissue-to-blood AUC ratios decreased from 10.6 to 0.75 ± 0.16 for the spleen, 7.5 to 0.86 ± 0.18 for the liver, 3.6 to 0.48 ± 0.13 for the bone marrow, 0.69 to 0.26 ± 0.1 for the lung and 1.29 to 0.56 ± 0.14 for the kidney, indicating dose-dependent uptake. In all patients receiving ≥ 450 mg (n = 7), tumour uptake of the antibody was observed.

Conclusions

This study demonstrates how immuno-PET in a dose escalation study provides a non-invasive technique to quantify dose-dependent uptake in normal tissues, indicating specific, target-mediated uptake.
Zusatzmaterial
Additional file 1: Table S1. Specific scoring criteria for CD44 expression in patient samples. (DOCX 14 kb)
13550_2018_358_MOESM1_ESM.docx
Additional file 2: Supplementary Data. Information on the quality control of the radiolabelled tracer. (DOCX 16 kb)
13550_2018_358_MOESM2_ESM.docx
Additional file 3: Figure S1. Example of immunohistochemistry staining for CD44 for (a) patient 9, rectum carcinoma, biopsy of a liver metastasis CD44 score: 2+; (b) patient 8, squamous cell carcinoma of the head and neck, biopsy of a neck metastasis, CD44 score: 3+. (TIFF 4368 kb)
13550_2018_358_MOESM3_ESM.tif
Additional file 5: Figure S3. Additional examples of focal tumour uptake of 89Zr-RG7356 at 96 h p.i.. From left to right: low dose CT, attenuation-corrected PET and fused image. (a) Tumour lesion: left side of the skull (patient 8, 450 mg cohort). (b) Tumour lesion: sacrum (patient 13, 675 mg cohort). (TIFF 6335 kb)
13550_2018_358_MOESM5_ESM.tif
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