A Semiempirical Model of Tumor Pretargeting

Liu, Guozheng; Hnatowich, Donald J.

doi:10.1021/bc8002748

Cited by 28 publications

(44 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We recently reported an evaluation of this same pretargeting system for PET using 68 Ga-and 18 F-labeled peptides (18) and found, as in that study, that 5 nmol (800 mg) of TF2 saturated the amount of antigen in LS174T tumors. Thus, this amount of bsmAb is the upper limit that should be used in this pretargeting setting (28). Using 5 nmol of TF2, we next determined the optimal IMP288 dose: 0.28 nmol of IMP288 essentially saturated the amount of bsMAb-binding sites.…”

Section: Discussionmentioning

confidence: 99%

Pretargeted ¹⁷⁷Lu Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colonic Tumors in Mice

Schoffelen¹,

Graaf²,

Franssen³

et al. 2010

J Nucl Med

View full text Add to dashboard Cite

Pretargeted radioimmunotherapy (PRIT) with bispecific antibodies in combination with a radiolabeled peptide reduces the radiation dose to normal tissues, especially the bone marrow. In this study, the optimization, therapeutic efficacy, and toxicity of PRIT of colon cancer with a 177 Lu-labeled peptide was determined in mice with carcinoembryonic antigen (CEA)-expressing human tumors. Methods: To obtain the optimal therapeutic efficacy, several strategies were evaluated to increase the total amount of radioactivity targeted to subcutaneous LS174T colon cancer tumors in BALB/c nude mice. First, the maximum amount of bispecific anti-CEA and antihapten antibody TF2 and the peptide IMP288 that could be targeted was determined. Second, the tumor targeting of repeated administrations of radiolabeled IMP288 was investigated. Mice received 1 TF2 injection, followed by multiple IMP288 injections (3-h interval) or multiple cycles, with each IMP288 administration preceded by a new TF2 injection (72-h interval). PRIT was administered at maximum doses of TF2 and 177 Lu-labeled IMP288 in groups of 9 mice with subcutaneous LS174T tumors. Mice received 1, 2, or 3 successive cycles of treatment (26 MBq/mouse/cycle) or carrier only. The primary endpoint was survival; secondary endpoints were tumor growth, body weight, bone marrow, and renal toxicity. Results: The highest amount of radioactivity delivered to a subcutaneous colon tumor was achieved by the administration of 5.0 nmol of TF2 and 0.28 nmol of IMP288 in 3 successive cycles, with each IMP288 preceded by a new TF2 injection (72-h interval). PRIT effectively delayed tumor growth and prolonged survival significantly. Higher activity doses, administered in successive cycles, correlated with longer survival: the median survival of untreated mice was 13 d (range, 6-20 d), whereas that of mice treated with 1, 2, or 3 cycles of PRIT was 24 (range, 24-31 d), 45 (range, 38 $ 130 d), and 65 (range, 48 $ 130 d) days, respectively. Toxicity was limited: no significant changes in mean body weight were measured. Minimal changes in leukocyte counts were measured at 2 and 3 wk after injection, with full recovery within 7 wk after treatment. Platelet counts were unaffected. Serum creatinine levels were not increased significantly; thus, there was no indication of acute renal toxicity. Conclusion: This study indicates that PRIT in mice is an effective treatment modality against colon cancer, with limited toxicity.

show abstract

Section: Discussionmentioning

confidence: 99%

Pretargeted ¹⁷⁷Lu Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colonic Tumors in Mice

Schoffelen¹,

Graaf²,

Franssen³

et al. 2010

J Nucl Med

View full text Add to dashboard Cite

show abstract

“…8 The results of the present investigation confirm the prediction that tumor accumulation of the effector will be unaffected as long as its dosage is below that required to saturate the accessible antibody in tumor. 21 Mirallie et al used avidin as a clearing agent in a pretargeting strategy using bispecific antibodies and also did not observe a decrease in tumor accumulation of the effector. 8 Although there are other literature reports on changes in percentage of tumor accumulations when clearing agents are used, 3,4,6 these tumor accumulations may not have been at their MPTAs.…”

Section: Discussionmentioning

confidence: 99%

“…21 As always, any convenient dosage of the pretargeting antibody may be selected, as long as it does not saturate the tumor antigen. It has been shown for the LS174T tumor model that a 30 mg dosage of MORF-CC49-biotin satisfies this condition.…”

Section: Clearance Study In Normal Micementioning

confidence: 99%

“…It has been previously shown that the MPTA of any effector is equal to the product of the fraction (f) of cardiac output (F) to tumor, the reciprocal of the tumor weight (W À1 ), the tumor trapping fraction of the effector (E), and the area under the blood curve of the effector 21 :…”

Section: Clearance Studies In Tumored Micementioning

confidence: 99%

“…21 However, as the tumor accumulation of MORF-CC49-biotin may be slightly altered by the biotin modification, to guarantee that the effector accumulation in tumor does not exceed saturation, about half of the calculated saturating dosage (1.2 mg) was used.…”

Section: Clearance Studies In Tumored Micementioning

confidence: 99%

See 2 more Smart Citations

Adding a Clearing Agent to Pretargeting Does Not Lower the Tumor Accumulation of the Effector as Predicted

Liu

Dou

Chen

et al. 2010

Cancer Biotherapy and Radiopharmaceuticals

Self Cite

View full text Add to dashboard Cite

Clearing agents are often used in pretargeting despite the potential for decreased tumor accumulation of the effector. However, according to the authors' semiempirical model, a clearing agent should not necessarily decrease tumor accumulation. In this study, the authors have added a clearing step to their model-morpholino phosphorodiamidate oligomer (MORF)/complement MORF (cMORF) pretargeting system-to confirm this prediction. The CC49 antibody was conjugated with both biotin and an 18 mer MORF. The influence of avidin on antibody clearance was first evaluated in normal mice in which each animal received 30 mg of MORF-CC49-biotin, 0-70 mg of avidin 1 day later, and 1.2 mg of 99m Tc-cMORF 3 hours later, with sacrifice at 3 hours. Thereafter, a pretargeting study in mice bearing an LS174T tumor was performed at a 34 mg avidin dosage. In normal mice, the blood level of 99m Tc-cMORF fell by 60% at an avidin dosage of 10 mg or higher. In tumored mice, avidin produced a similar reduction in blood but had no influence on tumor level, which remained at 6.30% ID/g as predicted. In conclusion, in addition to the expected reduced effector levels in blood and normal tissues, a reduction in tumor accumulation was avoided when adding a clearing agent as predicted.

show abstract

Use of Morpholino Oligomers for Pretargeting

Liu

2017

Morpholino Oligomers

View full text Add to dashboard Cite

Differing from the conventional direct-targeting strategy in which a probe or payload is directly loaded onto a targeting molecule that binds to the native target, pretargeting is an improved targeting strategy. It converts the native target to an artificial target specific for a secondary targeting molecule loaded with the probe or payload (effector). The effector is small and does not accumulate in normal tissues, which accelerates the targeting process and generates high target to nontarget ratios. DNA/cDNA analogs can serve as the recognition pair, i.e., the artificial target and the secondary targeting effector. Morpholino oligomers are so far the most investigated and the most successful DNA/cDNA analog recognition pairs for pretargeting. Herein, we describe the pretargeting principles, the pretargeting strategy using Morpholino oligomers, and the preclinical success so far achieved.

show abstract

A Semiempirical Model of Tumor Pretargeting

Cited by 28 publications

References 64 publications

Pretargeted ¹⁷⁷Lu Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colonic Tumors in Mice

Pretargeted ¹⁷⁷Lu Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colonic Tumors in Mice

Adding a Clearing Agent to Pretargeting Does Not Lower the Tumor Accumulation of the Effector as Predicted

Use of Morpholino Oligomers for Pretargeting

Contact Info

Product

Resources

About

A Semiempirical Model of Tumor Pretargeting

Cited by 28 publications

References 64 publications

Pretargeted 177Lu Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colonic Tumors in Mice

Pretargeted 177Lu Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colonic Tumors in Mice

Adding a Clearing Agent to Pretargeting Does Not Lower the Tumor Accumulation of the Effector as Predicted

Use of Morpholino Oligomers for Pretargeting

Contact Info

Product

Resources

About

Pretargeted ¹⁷⁷Lu Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colonic Tumors in Mice

Pretargeted ¹⁷⁷Lu Radioimmunotherapy of Carcinoembryonic Antigen–Expressing Human Colonic Tumors in Mice