Localisation of monoclonal antibodies reacting with different epitopes on carcinoembryonic antigen (CEA) – implications for targeted therapy

Boxer, G. M.; Abassi, A. M.; Pedley, RB; Begent, R. H. J.

doi:10.1038/bjc.1994.56

Cited by 11 publications

(8 citation statements)

References 22 publications

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“…Other studies have not found consistent relationships between degree of vascularity and antibody uptake in tumours [3-5,8,9,27]. Given the avascular nature of the necrotic tumour centre, we conclude that huA33 can penetrate long distances from blood vessels before binding to tumour cells.…”

Section: Discussionsupporting

confidence: 48%

Quantitative intratumoural microdistribution and kinetics of 131I-huA33 antibody in patients with colorectal carcinoma

et al. 2014

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BackgroundThe ability of recombinant antibodies to adequately penetrate into tumours is a key factor in achieving therapeutic effect; however, the behaviour of antibodies at a cellular level in tumours is poorly understood. The purpose of this study was to investigate those factors that influence the macroscopic and microscopic intratumoural distribution of an IgG1-humanized antibody, huA33, in colorectal tumours.MethodsTwelve patients were infused with radiolabelled huA33 at 7 days prior to elective surgery for colorectal carcinoma. Macroscopic huA33 uptake was determined by both gamma well counter and autoradiography measurements of the resected tumour specimens. Microscopic uptake was then quantitated at a cellular level and compared to vascular penetrance. The impact of variation in tumour antigen (GPA33) expression, tumour size, specimen type (primary vs metastatic), presence of macroscopic necrosis, and tumour vasculature on huA33 uptake were examined.ResultsThe I-huA33 uptake in whole tumour sections was (mean ± SD) 5.13 ± 2.71 × 10−3% injected dose per gram (ID/g). GPA33 was expressed in all viable tumour cells, and huA33 uptake was excellent regardless of tumour size and specimen type. In tumours with macroscopically evident central necrosis (n = 5), huA33 uptake in tumour necrotic centres was lower than in viable peripheries (0.606 ± 0.493 vs 2.98 ± 2.17 × 10−3%ID, p = 0.06). However, when corrected for low cell viability in necrotic centres, uptake of huA33 at the cellular level was highly comparable to that in the more viable tumour periphery (7.10 ± 5.10 × 10−9 vs 3.82 ± 3.67 × 10−9%ID/cell, p = 0.4). In the five patients who exhibited macroscopic necrosis in their tumours, huA33 showed excellent tissue penetration, with a maximum penetration distance of 26 μm in peripheral tumour regions and 118 μm in central regions. No correlation was observed between 131I-huA33 uptake in tumour on a cellular basis and tumour vascularity.ConclusionsIn patients with colorectal carcinoma, monoclonal antibody huA33 effectively targets viable tumour cells in all cellular milieus examined, including effective penetration into necrotic tumour centres, a novel and therapeutically important finding.

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Section: Discussionsupporting

confidence: 48%

Quantitative intratumoural microdistribution and kinetics of 131I-huA33 antibody in patients with colorectal carcinoma

et al. 2014

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“…A number of these criteria are determined not only by the morphology and properties of the tumour itself but also by the properties of the chosen antibody and its antigen distribution and expression. (Boxer et al, 1994). The difference in the distribution of the two antibodies within the tumour is quite distinct in spite of the fact that immunohistochemistry has shown a similar pattern of reactivity between A5B7 and A33 in colon cancer tissue (Boxer et al, 1994).…”

Section: Discussionmentioning

confidence: 95%

“…(Boxer et al, 1994). The difference in the distribution of the two antibodies within the tumour is quite distinct in spite of the fact that immunohistochemistry has shown a similar pattern of reactivity between A5B7 and A33 in colon cancer tissue (Boxer et al, 1994). B72.3 also demonstrated only limited penetration into the xenograft tumour tissue.…”

Section: Discussionmentioning

confidence: 97%

Radioimmunotherapy of colorectal carcinoma xenografts in nude mice with yttrium-90 A33 IgG and Tri-Fab (TFM)

Antoniw

Farnsworth²,

Turner³

et al. 1996

Br J Cancer

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“…After PEG modification the tumour levels were significantly raised, though they never reached ---30 I3 h those achieved by the intact A5B7 (Figures 1, 2 and 3). However, fragments do show deeper tumour penetration, thereby enhancing the range of cell kill at an early stage after administration when the intact antibody is still accumulated around the blood vessels (Boxer et al, 1994). Although we have still to determine whether PEG-modified fragments show altered tumour penetration, their use for therapy thus has the potential for increasing the tumour dose when compared with parent fragments, while possibly also improving the range of tumour cell kill over intact antibody.…”

Section: Discussionmentioning

confidence: 99%

The potential for enhanced tumour localisation by poly(ethylene glycol) modification of anti-CEA antibody

Pedley

Boden²,

Boden³

et al. 1994

Br J Cancer

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Attachment of poly(ethylene glycol) (PEG) to proteins can greatly alter their pharmacological properties, including extending the plasma half-life and reducing immunogenicity, both of which are potentially beneficial to tumour targeting. IgG, F(ab')2 and Fab' fragments of the anti-CEA antibody A5B7 were chemically modified with PEG (M(r) 5,000), labelled with 125I and their pharmacokinetics compared with the unmodified forms in the LS174T colonic xenograft in nude mice. PEG modification of the intact antibody had little effect on biodistribution, although tumour localisation was slightly reduced. In contrast, similar modification of F(ab')2 and Fab'A5B7 significantly prolonged plasma half-life and increased radioantibody accumulation in the tumour and to a lesser extent in normal tissues, but reduced tissue to blood ratios. Prior to modification, Fab' A5B7 (M(r) 50,000) cleared more rapidly from the circulation than F(ab')2 (M(r) 100,000), but after PEG attachment their biodistributions converged, while the tumour to blood ratios were reduced and resembled that of the intact antibody. The enhanced tumour accumulation, reduced normal tissue to blood ratios and potentially reduced immunogenicity of fragments after PEG attachment may therefore prove superior to either unmodified fragments or intact antibody for antibody-targeted therapy, although the increased plasma half-life may necessitate the use of a clearance mechanism.

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Localisation of monoclonal antibodies reacting with different epitopes on carcinoembryonic antigen (CEA) – implications for targeted therapy

Cited by 11 publications

References 22 publications

Quantitative intratumoural microdistribution and kinetics of 131I-huA33 antibody in patients with colorectal carcinoma

Quantitative intratumoural microdistribution and kinetics of 131I-huA33 antibody in patients with colorectal carcinoma

Radioimmunotherapy of colorectal carcinoma xenografts in nude mice with yttrium-90 A33 IgG and Tri-Fab (TFM)

The potential for enhanced tumour localisation by poly(ethylene glycol) modification of anti-CEA antibody

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