Localization of radiolabeled anti-CEA antibody in subcutaneous and intrahepatic colorectal xenografts: influence of tumor size and location within host organ on antibody uptake

Dearling, Jason; Flynn, AA; Qureshi, Uzma; Whiting, Stephen; Boxer, G. M.; Green, Alan; Begent, R. H. J.; Pedley, R. Barbara

doi:10.1016/j.nucmedbio.2009.07.003

Cited by 16 publications

(18 citation statements)

References 30 publications

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“…Observations of another antibody, A33, in a well-differentiated model also showed early uptake around blood vessels resulting in homogeneous tumor uptake by 48 h after injection (15). Anti-CEA antibodies had penetrated well-vascularized intrahepatic xenografts effectively at 24 h after injection (18)(19)(20), which is more in agreement with our results, compared with subcutaneous tumors of the same cell line (17,32). Lower-affinity antibodies (e.g., anti-HER2) penetrate tumors more efficiently (9), and modeling predicts that binding-site barrier effects are unlikely for mAbs with a K d greater than 1 nM (33), such as BR96 (K d 5 4 nM).…”

Section: Discussionmentioning

confidence: 88%

“…Although the methods of analysis differ, differences in antigen expression, vascularization, and immune response between the animals used are also likely to have been a factor (17). The increased variance in tumor activity uptake after 48 h after injection was attributed to variations in tumor growth or reduction, as has been observed elsewhere (19). The new cell populations present in several tumors had little activity uptake, probably because of a lower antibody concentration in the blood.…”

Section: Discussionmentioning

confidence: 90%

“…Several preclinical studies have been performed on the intratumoral distribution of antibodies, primarily targeting carcinoembryonic antigen (CEA) in immune-deficient mice bearing subcutaneous xenografts of human colorectal cancers (15)(16)(17)(18)(19)(20). However, such xenografts are artificial tumor models with little interaction with the host-for example, with a low probability of metastasizing-and with stromal and vascular interactions not similar to human cancers (21).…”

Section: Discussionmentioning

confidence: 99%

“…Two studies have reported uptake of 125 I-labeled anti-CEA antibody in necrotic areas at 48 h after injection and onward, although this finding is most likely an effect of free antibody or iodine pooling in blood (16,19). Studies of anti-CEA antibodies in subcutaneous xenografts of well-differentiated and regularly vascularized tumors exhibited a similar pattern of uptake to that in our model, whereas the antibody never penetrated very far from the blood vessels in poorly differentiated and vascularized tumors (17).…”

Section: Discussionmentioning

confidence: 99%

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The Intratumoral Distribution of Radiolabeled ¹⁷⁷Lu-BR96 Monoclonal Antibodies Changes in Relation to Tumor Histology over Time in a Syngeneic Rat Colon Carcinoma Model

et al. 2013

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The therapeutic effect of radioimmunotherapy depends on the distribution of the absorbed dose in relation to viable cancer cells within the tumor, which in turn is a function of the activity distribution. The aim of this study was to investigate the distribution of 177 Lu-DOTA-BR96 monoclonal antibodies targeting the Lewis Y antigen over 7 d using a syngeneic rat model of colon carcinoma. Methods: Thirty-eight tumor-bearing rats were intravenously given 25 or 50 MBq of 177 Lu-DOTA-BR96 per kilogram of body weight and were sacrificed 2,8,24, 48, 72, 96, 120, or 168 h after injection, with activity measured in blood and tumor samples. Adjacent cryosections of each tumor were analyzed in 3 ways: imaging using a silicon-strip detector for digital autoradiography, staining for histologic characterization, or staining to determine the distribution of the antigen, vasculature, and proliferating cells using immunohistochemistry. Absorbed-dose rate distribution images at the moment of sacrifice were calculated using the activity distribution and a point-dose kernel. The correlations between antigen expression and both activity uptake and absorbed-dose rate were calculated for several regions of interest in each tumor. Nine additional animals with tumors were given unlabeled antibody to evaluate possible immunologic effects. Results: At 2-8 h after injection, activity was found in the tumor margins; at 24 h, in viable antigen-expressing areas within the tumor; and at 48 h and later, increasingly in antigen-negative areas of granulation tissue. The correlation between antigen expression and both the mean activity and the absorbed-dose rate in regions of interest changed from positive to negative after 24 h after injection. Antigennegative areas also increased over time in animals injected with unlabeled BR96, compared with untreated tumors. Conclusion:The results indicate that viable Lewis Y-expressing tumor cells are most efficiently treated during the initial uptake period. The activity then seems to remain in these initial uptake regions after the elimination of tumor cells and formation of granulation tissue. Further studies using these techniques could aid in determining the effects of the intratumoral activity distribution on overall therapeutic efficacy. Thel imited success of radioimmunotherapy against solid tumors can be partly attributed to the difficulty in achieving high tumor uptake and penetration of radiolabeled monoclonal antibodies (mAbs) (1,2). Aspects of the microenvironment of solid tumors that limit the distribution of antibodies throughout viable regions include abnormal vasculature, high interstitial fluid pressure, and impaired lymphatic drainage (3-5), as well as the composition of the extracellular matrix (6,7). The antibody characteristics are also important for the microdistribution; for example, highaffinity antibodies risk entrapment in perivascular regions at a binding site barrier (8,9), and those targeting an intracellular antigen preferentially collect in necrotic areas (10,11). Additional...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The Intratumoral Distribution of Radiolabeled ¹⁷⁷Lu-BR96 Monoclonal Antibodies Changes in Relation to Tumor Histology over Time in a Syngeneic Rat Colon Carcinoma Model

et al. 2013

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“…Briefly, 2 · 10 6 cells were injected into the spleen, followed by a splenectomy after 10 min (21,22). Hepatic tumor growth was monitored by bioluminescence imaging using the IVIS system (Xenogen/Caliper Life Sciences) as previously described (23).…”

Section: Cell Linesmentioning

confidence: 99%

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer

et al. 2015

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Despite extensive efforts to improve the clinical management of patients with colorectal cancer, approved treatments for advanced disease offer limited survival benefit. Therefore, the identification of novel treatment strategies is essential. We evaluated the preclinical efficacy of combination radioimmunotherapy, using a humanized 131 Ilabeled anti-carcinoembryonic antigen antibody ( 131 I-huA5B7), with cetuximab in colorectal cancer (CRC). Methods: Three human CRC cell lines-SW1222, LoVo, and LS174T-were used to generate subcutaneous xenografts, and stably luciferase-transfected SW1222 cells were used to establish a model of hepatic metastases in immunocompromised mice. Imaging and biodistribution studies were conducted to confirm the selective tumor localization of 131 I-huA5B7. Efficacy was evaluated on the basis of tumor growth delay and survival, along with markers of DNA damage response, cell cycle, proliferation, and apoptosis. Results: Selective tumor targeting was achieved with 131 IhuA5B7 alone or in combination with cetuximab without observable toxicity. Compared with monotherapy, combining cetuximab with radioimmunotherapy significantly and synergistically reduced tumor growth and prolonged survival of mice in 2 of the subcutaneous and in the metastatic tumor model. Evidence of DNA damage, G2/M arrest, significantly decreased proliferation, and increased apoptosis were observed with radioimmunotherapy and the combination therapy. However, a significant decrease in DNA-protein kinase expression with the combination regimen suggests that the addition of cetuximab suppressed DNA repair. Conclusion: Our results demonstrate enhanced therapeutic efficacy with the combination of cetuximab and radioimmunotherapy in CRC, which could potentially translate into successful clinical outcomes. This strategy could improve the treatment of residual disease postoperatively and ultimately prevent or delay recurrence. Furthermore, other carcinoembryonic antigen-expressing malignancies could also benefit from this approach.

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One‐Pot Synthesis of an ¹²⁵I‐Labeled Trifunctional Reagent for Multiscale Imaging with Optical and Nuclear Techniques

et al. 2011

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Localization of radiolabeled anti-CEA antibody in subcutaneous and intrahepatic colorectal xenografts: influence of tumor size and location within host organ on antibody uptake

Cited by 16 publications

References 30 publications

The Intratumoral Distribution of Radiolabeled ¹⁷⁷Lu-BR96 Monoclonal Antibodies Changes in Relation to Tumor Histology over Time in a Syngeneic Rat Colon Carcinoma Model

The Intratumoral Distribution of Radiolabeled ¹⁷⁷Lu-BR96 Monoclonal Antibodies Changes in Relation to Tumor Histology over Time in a Syngeneic Rat Colon Carcinoma Model

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer

One‐Pot Synthesis of an ¹²⁵I‐Labeled Trifunctional Reagent for Multiscale Imaging with Optical and Nuclear Techniques

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Localization of radiolabeled anti-CEA antibody in subcutaneous and intrahepatic colorectal xenografts: influence of tumor size and location within host organ on antibody uptake

Cited by 16 publications

References 30 publications

The Intratumoral Distribution of Radiolabeled 177Lu-BR96 Monoclonal Antibodies Changes in Relation to Tumor Histology over Time in a Syngeneic Rat Colon Carcinoma Model

The Intratumoral Distribution of Radiolabeled 177Lu-BR96 Monoclonal Antibodies Changes in Relation to Tumor Histology over Time in a Syngeneic Rat Colon Carcinoma Model

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer

One‐Pot Synthesis of an 125I‐Labeled Trifunctional Reagent for Multiscale Imaging with Optical and Nuclear Techniques

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The Intratumoral Distribution of Radiolabeled ¹⁷⁷Lu-BR96 Monoclonal Antibodies Changes in Relation to Tumor Histology over Time in a Syngeneic Rat Colon Carcinoma Model

The Intratumoral Distribution of Radiolabeled ¹⁷⁷Lu-BR96 Monoclonal Antibodies Changes in Relation to Tumor Histology over Time in a Syngeneic Rat Colon Carcinoma Model

One‐Pot Synthesis of an ¹²⁵I‐Labeled Trifunctional Reagent for Multiscale Imaging with Optical and Nuclear Techniques