Antibody and radionuclide characteristics and the enhancement of the effectiveness of radioimmunotherapy by selective dose delivery to radiosensitive areas of tumour

Flynn, AA; Pedley, RB; Green, A J; Boxer, G. M.; Boden, R.; Bhatia, J; Morris, Richard W; Begent, R. H. J.

doi:10.1080/09553000110117818

Cited by 17 publications

(16 citation statements)

References 20 publications

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“…Monovalent antibodies have faster circulatory clearance and weaker antigen binding than IgGs, resulting in lower tumor uptake and therapeutic potential but reduced systemic toxicity. It has also been suggested that they have the ability to localize more rapidly into tumor deposits (37,38). However, our results show that there was no physical barrier to localization and penetration of IgG (MW 150 kDa) into and through hepatic tumor deposits of all sizes.…”

Section: Discussioncontrasting

confidence: 50%

“…Indeed, some a particles and low-energy h particles may be more suitable for tackling small tumor deposits and adjuvant disease. We have previously used phosphor images of radioantibody localization to model dose distribution for a range of isotopes (18,19,37). However, the novel microscopy in the current study has provided a far more accurate picture of antibody distribution in relation to tumor microenvironment and will now inform models of energy deposition for antibody-bound radionuclides to determine optimal pairings of antibody and radionuclide for different situations.…”

Section: Discussionmentioning

confidence: 95%

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Microdistribution of Targeted, Fluorescently Labeled Anti–Carcinoembryonic Antigen Antibody in Metastatic Colorectal Cancer: Implications for Radioimmunotherapy

Fidarova

El-Emir²,

Boxer³

et al. 2008

Clinical Cancer Research

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Purpose: Most radioimmunotherapy studies on radiolabeled antibody distribution are based on autoradiographic and radioluminographic data, which provide a lack of detailed information due to low resolution. We used fluorescently labeled anti^carcinoembryonic antigen (CEA) antibody (A5B7) to investigate quantitatively the kinetics and microdistribution of antibody in a clinically relevant orthotopic colorectal cancer model (LS174T) using high-resolution digital microscopy. Experimental Design: Nude mice bearing LS174T liver orthotopic tumors received a single i.v. injection of fluorescently labeled A5B7 and were sacrificed at 10 minutes, 1hour, or 24 hours postinjection. Before sacrifice, mice were injected with the perfusion marker Hoechst 33342. An anti-CD31 antibody was used to detect blood vessel distribution. Cryostat sections were processed with immunofluorescence procedures and analyzed with fluorescence microscopy and image analysis techniques. The fluorescence images were related to morphologic images of the same or adjacent tumor sections. Results: Fluorescently labeled antibody showed rapid, selective uptake into tumor deposits, with a strong negative correlation with tumor size at 10 minutes and 1 hour (P V 0.01). By 24 hours, the correlation was no longer significant. The study showed movement of antibody across the tumor with time and a tendency to localize more uniformly by later time points (24 hours).The rate of antibody motility was similar in small and large tumor metastases, but small deposits showed more rapid antibody localization. Intratumoral vessels were positively related to tumor size (P V 0.001). Conclusion: The obtained data suggest that radioimmunotherapy can be highly efficient in an adjuvant or minimal residual disease setting.

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Section: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 95%

Microdistribution of Targeted, Fluorescently Labeled Anti–Carcinoembryonic Antigen Antibody in Metastatic Colorectal Cancer: Implications for Radioimmunotherapy

Fidarova

El-Emir²,

Boxer³

et al. 2008

Clinical Cancer Research

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“…Data from the current and previous studies (10,42) indicate similar localization of fluorescently and radiolabeled A5B7, and suggest that dose deposition from 131 I will treat most of the SW1222 tumor, but leave regions of LS174T untreated. Future studies will use the high-resolution images of antibody distribution for more accurate dosimetry modeling of therapeutic radionuclides, including dose to normoxic and hypoxic regions of viable tumor.…”

Section: Discussionmentioning

confidence: 72%

“…In previous articles, we have discussed how properties related to the antibody and radionuclide effect on therapeutic outcome, and how these may be optimized for therapy (8)(9)(10)(11). We have also shown that radioimmunotherapy can significantly enhance other therapies such as vascular-disrupting agents without increasing toxicity (12)(13)(14), and this is currently in clinical trial within our department.…”

Section: Introductionmentioning

confidence: 99%

Predicting Response to Radioimmunotherapy from the Tumor Microenvironment of Colorectal Carcinomas

Emir¹,

Qureshi²,

Dearling³

et al. 2007

Cancer Research

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Solid tumors have a heterogeneous pathophysiology, which directly affects antibody-targeted therapies. Here, we consider the influence of selected tumor parameters on radioimmunotherapy, by comparing the gross biodistribution, microdistribution, and therapeutic efficacy of either radiolabeled or fluorescently labeled antibodies (A5B7 anti-carcinoembryonic antigen antibody and a nonspecific control) after i.v. injection in two contrasting human colorectal xenografts in MF1 nude mice. The LS174T is moderately/poorly differentiated, whereas SW1222 has a well-differentiated glandular structure. Biodistribution studies (1.8 MBq 131 I-labeled A5B7, four mice per group) showed similar gross tumor uptake at 48 h in the two models (25.1% and 24.0% injected dose per gram, respectively). However, in therapy studies (six mice per group), LS174T required a 3-fold increase in dose (18 versus 6 MBq) to equal SW1222 growth inhibition (f55 versus f60 days, respectively). To investigate the basis of this discrepancy, highresolution multifluorescence microscopy was used to study antibody localization in relation to tumor parameters (5 min, 1 and 24 h, four mice per time point). Three-dimensional microvascular corrosion casting and transmission electron microscopy showed further structural differences between xenografts. Vascular supply, overall antigen distribution, and tumor structure varied greatly between models, and were principally responsible for major differences in antibody localization and subsequent therapeutic efficacy. The study shows that multiparameter, high-resolution imaging of both therapeutic and tumor microenvironment is required to comprehend complex antibody-tumor interactions, and to determine which tumor regions are being successfully treated. This will inform the design of optimized clinical trials of single and combined agents, and aid individual patient selection for antibody-targeted therapies. [Cancer Res 2007;67(24):11896-905]

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“…2a). Antibodies localize most efficiently in the periphery of the tumor [9]; this provides a therapeutic advantage, because the targeted therapy is fre- Fig. 1.…”

Section: Tumor Pathophysiology and Targetsmentioning

confidence: 99%

Engineering Antibodies for Clinical Applications in Cancer

Chester¹,

Pedley²,

Tolner³

et al. 2004

Tumor Biol

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The ‘magic bullet’ concept predicted over a century ago that antibodies would be used to target cancer therapy. Since then initial problems that were related to specificity, purity and immungenicity of antibody-based reagents have slowly been overcome due to developments in technology and increased knowledge. As a result, antibodies are in use for many clinical applications and now comprise the second largest category of medicines in clinical development after vaccines. For antibody-based cancer therapeutics the last 20 years have met with an explosion of knowledge about the biology of the disease and potential targets as well as new technology which allows cloning and manipulation of multifunctional antibody-based molecules. However, the focus still remains on developing therapeutics that will have potential for treating cancer in people and this is efficiently assessed in mechanistic clinical trials that feed back to the laboratory for further development. This review illustrates the mechanistic approach to making new molecules for antibody imaging and therapy of cancer. It is illustrated by examples of radioimmunotherapy and antibody-directed enzyme prodrug therapy developed by the authors.

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Antibody and radionuclide characteristics and the enhancement of the effectiveness of radioimmunotherapy by selective dose delivery to radiosensitive areas of tumour

Abstract: The extent of heterogeneity of dose deposition in tumour is highly dependent on the antibody characteristics and radionuclide properties, and can enhance therapeutic efficacy through the selective dose delivery to the radiosensitive areas of tumour.

Cited by 17 publications

References 20 publications

Microdistribution of Targeted, Fluorescently Labeled Anti–Carcinoembryonic Antigen Antibody in Metastatic Colorectal Cancer: Implications for Radioimmunotherapy

Microdistribution of Targeted, Fluorescently Labeled Anti–Carcinoembryonic Antigen Antibody in Metastatic Colorectal Cancer: Implications for Radioimmunotherapy

Predicting Response to Radioimmunotherapy from the Tumor Microenvironment of Colorectal Carcinomas

Engineering Antibodies for Clinical Applications in Cancer

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