Irreversibly binding anti-metal chelate antibodies: Artificial receptors for pretargeting

Corneillie, Todd M.; Whetstone, Paul A.; Meares, Claude F.

doi:10.1016/j.jinorgbio.2006.01.004

Cited by 19 publications

(26 citation statements)

References 83 publications

(98 reference statements)

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“…To radiolabel, 50 AL 99m Tc-pertechnetate generator eluate was introduced into a combined solution consisting of 30 AL (>0.5 Ag) of MAG 3 -MORF in NH 4 OAc buffer (pH 5.2), 10 AL of 50 Ag/AL Na 2 tartrateÁ2H 2 O in a pH 9.2 buffer, and 3 AL of 4 Ag/AL SnCl 2 Á2H 2 O in ascorbate-HCl solution (1 Ag/AL sodium ascorbate in 10 mmol/L HCl). The solution was heated at 100jC for 20 min.…”

Section: Methodsmentioning

confidence: 99%

An experimental and theoretical evaluation of the influence of pretargeting antibody on the tumor accumulation of effector

Liu

Dou

Rusckowski

et al. 2008

Molecular Cancer Therapeutics

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In treating tumors by pretargeting, the antitumor antibody and the cytotoxic effector (e.g., toxins and radioactivity) are separately administered. Therefore, pretargeting is more complicated with many variables. We are conducting studies to understand the influence of each variable using a novel recognition pair of mutually complementary phosphorodiamidate morpholino oligomers (MORF/ cMORF). Earlier we developed a semi-empirical model capable of accurately predicting the behavior of a radiolabeled cMORF effector with variations in dosages and timing. We have now extended the model to predict the effector behavior, in particular, its maximum percent tumor accumulation (MPTA) in mice pretargeted with three different MORF-conjugated antibodies (MN14, B72.3, and CC49). The MN14 and the CC49 target different antigens in the same tumor, whereas the CC49 and the B72.3 target the same antigen but with very different tumor accumulation. By comparing the pretargeting results of these three antibodies with our prediction, we confirmed that the MPTA of the radiolabeled cMORF effector in the LS174T tumor is independent of the antibodies. In conclusion, the MPTA cannot be improved through the use of different pretargeting antibodies, although different antibodies may improve the maximum absolute tumor accumulation, the heterogeneity, and/or the tumor-to-normal tissue ratios of the effector. This conclusion will apply equally well to effectors carrying a fluorescent probe, an anticancer agent, or a radioactive imaging agent.

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Section: Methodsmentioning

confidence: 99%

An experimental and theoretical evaluation of the influence of pretargeting antibody on the tumor accumulation of effector

Liu

Dou

Rusckowski

et al. 2008

Molecular Cancer Therapeutics

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“…Similar improvements have also been made in parallel in the pretargeting of solid tumors both for imaging and therapy (1-10) such that encouraging results are now increasingly being reported in clinical trials of pretargeting (11). Pretargeting is popularly considered as a means of separating tumor targeting and radionuclide delivery and thus differs from conventional targeting in which the two are bound and administered together (2, 3), (12-18).…”

Section: Introductionmentioning

confidence: 92%

A Semiempirical Model of Tumor Pretargeting

Liu

Hnatowich

2008

Bioconjugate Chem.

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This article provides an overview of a semiempirical pretargeting model now under development. After a brief review of the pretargeting concept, the strategies available, and the complexities of optimizing the dosage and timing, a semiempirical model is described that is not only capable of optimizing dosage and timing but also capable of predicting the results of pretargeting as a function of most pretargeting variables. The model requires knowledge of the pharmacokinetics of both the pretargeting agent (usually an antibody) and the effector, the accessibility of the pretargeting antibody for the effector, and their quantitative relationships in vivo. Several misconceptions that often surround pretargeting are also clarified.

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“…PRIT, a concept that separates the delivery of the targeting antibody to tumor from the delivery of the radioactivity, was initially developed by Reardan, Goodwin, and Meares using anti-radiometal chelate antibodies [11–13], Initial uptakes documented proof of principle for this approach, showing improved tumor targeting compared to conventional RIT, but TIs were still suboptimal, partly because of the insufficient retention (on the order of several hours) of the radioactivity when carried by anti-chelate antibodies of only nanomolar (nM) affinity [14, 15]. …”

Section: Introductionmentioning

confidence: 99%

Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity 86Y- or 177Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

Cheal

Guo

et al. 2015

Eur J Nucl Med Mol Imaging

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Purpose GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pre-targeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn (radiolanthanide metal) complex. Methods PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent (CA), and the C825-haptens 177Lu-or 86Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Results Using optimized PRIT, therapeutic indices (TIs) for tumor radiation absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI: 73), 6.3 (TI: 10), 6.6 (TI: 10), and 5.3 (TI: 12), respectively. Two cycles of PRIT treatment (66.6 or 111 MBq 177Lu-DOTA-Bn) were safe and effective, with 9/9 complete responses of established s.c. tumors (100–700 mm3) and 2/9 alive without recurrence >140 d. Tumor log kill in this model was estimated to be 2.1–3.0 based time to 500-mm3 tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA-hapten 86Y-DOTA-Bn. Conclusions We have developed anti-GPA33 PRIT, as a triple-step theranostic strategy for pre-clinical detection, dosimetry and safe targeted radiotherapy of established human colorectal mouse xenografts.

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Irreversibly binding anti-metal chelate antibodies: Artificial receptors for pretargeting

Cited by 19 publications

References 83 publications

An experimental and theoretical evaluation of the influence of pretargeting antibody on the tumor accumulation of effector

An experimental and theoretical evaluation of the influence of pretargeting antibody on the tumor accumulation of effector

A Semiempirical Model of Tumor Pretargeting

Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity 86Y- or 177Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

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