Improved Radioimmunodetection of Tumours Using Second Antibody

Bradwell, Arthur R.; Vaughan, Andrew T M; Fairweather, D.S.; Dykes, P.W.

doi:10.1016/s0140-6736(83)92626-0

Cited by 21 publications

(6 citation statements)

References 4 publications

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“…The pentameric structure of AGP3 combined with the presence of multiple PEG chains on each βG tetramer may have promoted the formation of large immune complexes, which are cleared more rapidly than small immune complexes (Roitt et al, 1989). AGP3 appears to produce more rapid and complete clearance than other antibodies previously employed for clearance, which have been limited to IgG fractions of polyclonal antiserum (Bradwell et al, 1983;Sharkey et al, 1984;Pedley et al, 1989;Begent et al, 1989) or monoclonal IgG antibodies (Sharma et al, 1990;Kerr et al, 1993;Haisma et al, 1995;Wallace et al, 1994). Polyclonal IgG antibodies reduced radioimmunoconjugate levels in serum from around 10-fold (Bradwell et al, 1983;Sharkey et al, 1984;Begent et al, 1989) to 130-fold (Pedley et al, 1989) in 24 h whereas monoclonal IgG antibodies reduced the serum levels of antibody-enzyme conjugates from 3-10fold in a few hours (Sharma et al, 1990;Haisma et al, 1995) to 40-60-fold in 24 h (Kerr et al, 1993;Wallace et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Accelerated Clearance of Polyethylene Glycol-Modified Proteins by Anti-Polyethylene Glycol IgM

Cheng

Wu²,

Wu³

et al. 1999

Bioconjugate Chem.

143

128

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Tumor therapy by the preferential activation of a prodrug at tumor cells targeted with an antibody-enzyme conjugate may allow improved treatment efficacy with reduced side effects. We examined antibody-mediated clearance of poly(ethylene glycol)-modified beta-glucuronidase (betaG-sPEG) as a method to reduce serum concentrations of enzyme and minimize systemic prodrug activation. Enzyme-linked immunosorbent assay and immunoblot analysis of two monoclonal antibodies generated by immunization of BALB/c mice with an antibody-betaG-sPEG conjugate showed that mAb 1E8 (IgG1) bound betaG and betaG-sPEG whereas mAb AGP3 (IgM) bound poly(ethylene glycol). Neither antibody affected the betaG activity. mAb 1E8 and AGP3 were modified with 36 and 208 galactose residues (1E8-36G and AGP3-208G) with retention of 72 and 48% antigen-binding activity, respectively, to target immune complexes to the asialoglycoprotein receptor on liver cells. mAb 1E8 and AGP3 cleared betaG-PEG from the circulation of mice as effectively as 1E8-36G and AGP3-208G, respectively. mAb AGP3, however, cleared betaG-sPEG more completely and rapidly than 1E8, reducing the serum concentration of betaG-sPEG by 38-fold in 8 h. AGP3 also reduced the concentration of an antibody-betaG-sPEG conjugate in blood by 280-fold in 2 h and 940-fold in 24 h. AGP3-mediated clearance did not produce obvious damage to liver, spleen, or kidney tissues. In addition, AGP3 clearance of betaG-sPEG before administration of BHAMG, a glucuronide prodrug of p-hydroxyaniline mustard, prevented toxicity associated with systemic activation of the prodrug based on mouse weight and blood cell numbers. AGP3 should be generally useful for accelerating the clearance of PEG-modified proteins as well as for improving the tumor/blood ratios of antibody-betaG-PEG conjugates for glucuronide prodrug therapy of cancer.

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Section: Discussionmentioning

confidence: 99%

Accelerated Clearance of Polyethylene Glycol-Modified Proteins by Anti-Polyethylene Glycol IgM

Cheng

Wu²,

Wu³

et al. 1999

Bioconjugate Chem.

143

128

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“…Second antibody was initially incorporated into liposomes? leaving the variable region available at the surface to bind to the anti-tumor antibody (Begent et al, 1982;Barratt et al, 19831, but free second antibody is equally efficient for doses can be used (Bradwell et al, 1983;Sharkey et al, 1984;Chester al.9 1984;Pedley et al, 1986).…”

Section: ~~I~l S D I E Smentioning

confidence: 99%

The effect of second antibody clearance on the distribution and dosimetry of radiolabelled anti‐cea antibody in a human colonic tumor xenograft model

Pedley

Dale

Boden

et al. 1989

Intl Journal of Cancer

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Radioimmunotherapy in humans is limited by toxicity to normal tissues, caused by circulating radio-antibody. Second antibody directed against the first (anti-tumor) antibody accelerates clearance of first antibody from normal tissues, and may thus improve the therapeutic ratio. The effect of second antibody both on anti-tumor antibody distribution and on tumor and normal tissue radiation doses, has been investigated in nude mice bearing colonic tumor xenografts. Second antibody, given either 6 or 24 hr after the first, rapidly cleared circulating activity and reduced the calculated radiation dose to all tissues except the spleen, where it rose by 11 and 43% respectively. The dose received by the blood fell by 87% and 71%, while that to the tumor was reduced by 81% and 58%, after 6 or 24 hr second antibody. Administration of second antibody therefore improved the tumor to blood ratios. Tumor identification by gamma camera was greatly facilitated by the use of second antibody, and required no background subtraction. Results obtained from this system demonstrate the utility of second antibody in protecting normal tissues from prolonged circulating radioactivity during radioimmunotherapy.

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“…Several groups have reported enhanced clearance of primary antibody by injection of antispecies antisera [1,4,11,12]. The problem with this approach is that the antiserum itself is not of human origin and therefore will be immunogenic in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Production of a human monoclonal antibody recognising a determinant on mouse IgG2b from a patient receiving mouse monoclonal antibody for diagnostic imaging

Durrant

Robins

Ballantyne

et al. 1990

Cancer Immunol Immunother

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The development of human antibodies recognising mouse immunoglobulins represents an obstacle to effective antibody therapy. This study shows that patients produce modest titres of antibodies (predominantly anti-mouse rather than anti-idiotypic) after a single low-dose injection for immunoscintigraphy, suggesting that repeated imaging with the same or a different antibody could be a problem. Fusion of the lymphocytes from a patient who had been imaged twice previously resulted in a monoclonal antibody that specifically binds to an IgG2b isotypic determinant. Anti-IgG2b antibodies predominated in this patient's serum. Production of human monoclonal antibodies from patients given mouse monoclonal antibodies not only allows a finer dissection of the immune repertoire but also provides possible reagents for controlling the human anti-(mouse Ig) response, for selection of class-switch variants of mouse monoclonal antibodies and enhancing tumour imaging.

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Improved Radioimmunodetection of Tumours Using Second Antibody

Cited by 21 publications

References 4 publications

Accelerated Clearance of Polyethylene Glycol-Modified Proteins by Anti-Polyethylene Glycol IgM

Accelerated Clearance of Polyethylene Glycol-Modified Proteins by Anti-Polyethylene Glycol IgM

The effect of second antibody clearance on the distribution and dosimetry of radiolabelled anti‐cea antibody in a human colonic tumor xenograft model

Production of a human monoclonal antibody recognising a determinant on mouse IgG2b from a patient receiving mouse monoclonal antibody for diagnostic imaging

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