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A pretargeting system for tumor PET imaging and radioimmunotherapy.

Kraeber-Bodéré F, Rousseau C, Bodet-Milin C, Frampas E, Faivre-Chauvet A, Rauscher A, Sharkey RM, Goldenberg DM, Chatal JF, Barbet J - Front Pharmacol (2015)

Bottom Line: It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios.Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency.The results of recent evaluation of pretargeting in PET imaging also are discussed.

View Article: PubMed Central - PubMed

Affiliation: Nuclear Medicine Department, Nantes University Hospital Nantes, France ; Nuclear Medicine Department, Institut de Cancérologie de l'Ouest René Gauducheau Nantes, France ; Cancer Research Center, University of Nantes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Nantes, France.

ABSTRACT
Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed.

No MeSH data available.


Related in: MedlinePlus

Pretargeted immuno-PET recorded after injection of 120 nmol of TF2 and 3 nmol of 68Ga-IMP-288 at 30 h in a patient with metastatic breast carcinoma. Immuno-PET (A,C) shows a high tumor uptake and a higher number of lesions as compared to FDG-PET (B,D).
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Figure 4: Pretargeted immuno-PET recorded after injection of 120 nmol of TF2 and 3 nmol of 68Ga-IMP-288 at 30 h in a patient with metastatic breast carcinoma. Immuno-PET (A,C) shows a high tumor uptake and a higher number of lesions as compared to FDG-PET (B,D).

Mentions: PET, with its improved sensitivity and better resolution, as compared to scintigraphy and SPECT in humans, is indeed expected to provide useful clinical information. PET imaging with IgG antibodies labeled with long-lived positron-emitting radionuclides, such as zirconium-89, has been shown to be quite effective for in vivo tumor detection and to demonstrate antigen expression (Vugts et al., 2013). However, PET must be recorded days after activity injection for optimal contrast, and these long-lived radionuclides that emit, in addition to a positron, gamma rays of high energy have an unfavorable dosimetry. Pretargeting makes possible the use of short-lived radionuclides, such as gallium-68, but also fluorine-18. The PET images may be recorded only a few hours after activity injection. This has already been shown in preclinical studies (McBride et al., 2006; Schoffelen et al., 2010a, 2012), and clinical trials are in progress that show very promising sensitivity and specificity (Schuhmacher et al., 2001). Two clinical trials are on-going in France, aiming at optimizing and assessing pretargeted immuno-PET, using anti-CEA TF2 and 68Ga-IMP288 in patients with relapsed MTC and HER2-negative breast cancer. In each study, four or five cohorts of three patients are compared to determine the best TF2/IMP-288 molar dose ratio and the best pretargeted delay. Figure 2 illustrates the high tumor uptake obtained with this approach in a MTC patient with bone marrow lesions, injected with 120 nmol of TF2 and 6 nmol of 68Ga-IMP-288 30 h later. In some cases, immuno-PET allowed detection of lesions not detected by F-DOPA-PET, considered as reference PET imaging in MTC (Figure 3). Promising results were also obtained in a CEA-positive breast cancer patients (Figure 4).


A pretargeting system for tumor PET imaging and radioimmunotherapy.

Kraeber-Bodéré F, Rousseau C, Bodet-Milin C, Frampas E, Faivre-Chauvet A, Rauscher A, Sharkey RM, Goldenberg DM, Chatal JF, Barbet J - Front Pharmacol (2015)

Pretargeted immuno-PET recorded after injection of 120 nmol of TF2 and 3 nmol of 68Ga-IMP-288 at 30 h in a patient with metastatic breast carcinoma. Immuno-PET (A,C) shows a high tumor uptake and a higher number of lesions as compared to FDG-PET (B,D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4379897&req=5

Figure 4: Pretargeted immuno-PET recorded after injection of 120 nmol of TF2 and 3 nmol of 68Ga-IMP-288 at 30 h in a patient with metastatic breast carcinoma. Immuno-PET (A,C) shows a high tumor uptake and a higher number of lesions as compared to FDG-PET (B,D).
Mentions: PET, with its improved sensitivity and better resolution, as compared to scintigraphy and SPECT in humans, is indeed expected to provide useful clinical information. PET imaging with IgG antibodies labeled with long-lived positron-emitting radionuclides, such as zirconium-89, has been shown to be quite effective for in vivo tumor detection and to demonstrate antigen expression (Vugts et al., 2013). However, PET must be recorded days after activity injection for optimal contrast, and these long-lived radionuclides that emit, in addition to a positron, gamma rays of high energy have an unfavorable dosimetry. Pretargeting makes possible the use of short-lived radionuclides, such as gallium-68, but also fluorine-18. The PET images may be recorded only a few hours after activity injection. This has already been shown in preclinical studies (McBride et al., 2006; Schoffelen et al., 2010a, 2012), and clinical trials are in progress that show very promising sensitivity and specificity (Schuhmacher et al., 2001). Two clinical trials are on-going in France, aiming at optimizing and assessing pretargeted immuno-PET, using anti-CEA TF2 and 68Ga-IMP288 in patients with relapsed MTC and HER2-negative breast cancer. In each study, four or five cohorts of three patients are compared to determine the best TF2/IMP-288 molar dose ratio and the best pretargeted delay. Figure 2 illustrates the high tumor uptake obtained with this approach in a MTC patient with bone marrow lesions, injected with 120 nmol of TF2 and 6 nmol of 68Ga-IMP-288 30 h later. In some cases, immuno-PET allowed detection of lesions not detected by F-DOPA-PET, considered as reference PET imaging in MTC (Figure 3). Promising results were also obtained in a CEA-positive breast cancer patients (Figure 4).

Bottom Line: It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios.Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency.The results of recent evaluation of pretargeting in PET imaging also are discussed.

View Article: PubMed Central - PubMed

Affiliation: Nuclear Medicine Department, Nantes University Hospital Nantes, France ; Nuclear Medicine Department, Institut de Cancérologie de l'Ouest René Gauducheau Nantes, France ; Cancer Research Center, University of Nantes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Nantes, France.

ABSTRACT
Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed.

No MeSH data available.


Related in: MedlinePlus