Radioimmunotherapy: Is avidin-biotin pretargeting the preferred choice among pretargeting methods?

Goldenberg, David M.; Chang, Chien-Hsing; Sharkey, Robert M.; Rossi, Edmund A.; Karacay, Habibe; McBride, William J.; Hansen, Hans J.; Chatal, Jean‐François; Barbet, Jacques

doi:10.1007/s00259-002-1089-6

Cited by 40 publications

(20 citation statements)

References 16 publications

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“…An alternative approach using DNAs was first proposed by Kuijpers et al [3] and is now being developed using DNA analogues. Each approach has its own advantages and disadvantages [4,5].…”

Section: Introductionmentioning

confidence: 99%

Predicting the biodistribution of radiolabeled cMORF effector in MORF-pretargeted mice

Liu

Dou

et al. 2006

Eur J Nucl Med Mol Imaging

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Pretargeting with phosphorodiamidate morpholino oligomers (MORFs) involves a MORFconjugated anti-tumor antibody such as MN14 as pretargeting agent administered before that of the radiolabeled complementary MORF (cMORF) as the effector. The dosages of the pretargeting agent and effector, the pretargeting interval, and the detection time are the four pretargeting variables. The goal of this study was to develop a semiempirical description capable of predicting the biodistribution of the radiolabeled effector in pretargeted mice and then compare predictions with experimental results from pretargeting studies in tumored animals in which the pretargeting interval and the detection time were both fixed but the dosages of both the effector and pretargeting agent were separately varied.Methods-Pretargeting studies in LS174T tumored mice were performed using the anti-CEA antibody MN14 conjugated with MORF and the cMORF radiolabeled with 99m Tc. A description was developed based on our previous observations in the same mouse model of the blood and tumor levels of MORF-MN14, accessibility of MORF-MN14 to labeled cMORF, the tumor accumulation of labeled cMORF relative to MORF-MN14 levels therein, and the kidney accumulation of labeled cMORF. The predicted values were then compared with the experimental values.Results-The predicted biodistribution of the radiolabeled effector and the experimental data were in gratifying agreement in normal organs, suggesting that the description of the pretargeting process was reliable. The tumor accumulations occasionally fell outside two standard deviations of that predicted, but after tumor size correction, good agreement between prediction and experimental values was observed as well.Conclusion-A semiempirical description of the biodistribution of labeled cMORF was capable of predicting the biodistribution of the radiolabeled effector in the pretargeted tumored mouse model, demonstrating that the underlying pretargeting concepts are correct. We believe that the approach described herein may be applied to any of the alternative pretargeting approaches and animal tumor models currently under investigation. Furthermore, appreciation of the concepts may provide a rationale for selecting dosages and timings in human pretargeting studies as an alternative to pure empirical means.

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“…An alternative approach using DNAs was first proposed by Kuijpers et al [3] and is now being developed using DNA analogues. Each approach has its own advantages and disadvantages [4,5].…”

Section: Introductionmentioning

confidence: 99%

Predicting the biodistribution of radiolabeled cMORF effector in MORF-pretargeted mice

Liu

Dou

et al. 2006

Eur J Nucl Med Mol Imaging

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“…The SA-biotin approach has been widely tested and demonstrates striking efficacy, but has been criticized because SA is a highly immunogenic bacterial protein that may limit the ability to administer repeated cycles of therapy. (18, 41, 42) This potential limitation may be mitigated, however, in patients with hematologic malignancies, since their immunocompromised status may render them incapable of responding to foreign immunogens. A second potential limitation of SA-biotin PRIT is the presence of endogenous biotin in the blood and tissues of patients, which theoretically could occupy SA binding sites, blocking binding of subsequently administered radio-biotin compounds.…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers

et al. 2016

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Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7) with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hrs. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared to 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (p<0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (p<0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression and superior efficacy.

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“…Although the same Ramos tumor model used by Press et al 6 was studied here, it is premature to draw comparisons between these pretargeting procedures. The merits of each type of pretargeting method have been debated, 16,17 and each clearly improves the treatment response compared to the directly radiolabeled IgG, which should encourage more studies utilizing pretargeting approaches for cancer radioimmunotherapy. Earlier studies have shown the antitumor effects afforded by the unlabeled IMMU-106 IgG, but at higher doses than used in this report.…”

Section: Discussionmentioning

confidence: 99%

Improved therapy of non-Hodgkin's lymphoma xenografts using radionuclides pretargeted with a new anti-CD20 bispecific antibody

Karacay

et al. 2005

Leukemia

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A comparison of the therapeutic efficacy of a new bispecific monoclonal antibody (bsMAb)-pretargeting system vs the conventional direct targeting modality was undertaken. A bsMAb was made by coupling the Fab 0 of a humanized anti-CD20 antibody to the Fab 0 of a murine antibody directed against the peptide histamine-succinyl-glycine (HSG). The tumor targeting of the bsMAb was separated from the subsequent delivery of the radionuclide-bearing HSG peptide conjugated with 111 In or 90 Y. Nude mice bearing s.c. Ramos human B-cell lymphomas were injected with the bsMAb and then, 48 h later, 111In/ 90 Y-HSG peptide was given. At 3 h postinjection, tumor/ blood ratios for pretargeted 111 In-HSG-peptide were similar to that observed with the directly conjugated 111 In-anti-CD20 IgG at its highest level on day 7, but by day 1, tumor/blood ratios were about 10-fold higher than the IgG. Tumors progressed rapidly in animals given 800 lCi of 90 Y-HSG peptide alone, whereas 5/10 animals in the group pretargeted by the anti-CD20 bsMAb were tumor-free 18 weeks later. The antitumor response in animals administered the pretargeted 90 Y-HSG peptide was also significantly superior to treatment with the directly radiolabeled 90 Y-anti-CD20 IgG, whether given as a single injection (Po0.007) or as a divided dose (P ¼ 0.016). This bsMAb-pretargeting procedure significantly improves the therapeutic response of targeted radionuclides in non-Hodgkin's lymphoma, warranting further development of this method of radioimmunotherapy.

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Radioimmunotherapy: Is avidin-biotin pretargeting the preferred choice among pretargeting methods?

Cited by 40 publications

References 16 publications

Predicting the biodistribution of radiolabeled cMORF effector in MORF-pretargeted mice

Predicting the biodistribution of radiolabeled cMORF effector in MORF-pretargeted mice

Comparative Analysis of Bispecific Antibody and Streptavidin-Targeted Radioimmunotherapy for B-cell Cancers

Improved therapy of non-Hodgkin's lymphoma xenografts using radionuclides pretargeted with a new anti-CD20 bispecific antibody

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