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35 results on '"Begent, RHJ"'

1. HSAbodies: A new class of engineered antibody-based molecules for targeting cancer

Author

UCL - Autre, Huhalov, A, Graff, C, Wittrup, KD, Tolner, B, Pedley, RB, Vervecken, W, Contreras, R., Begent, RHJ, Chester, KA, British Cancer Research Meeting 2004, UCL - Autre, Huhalov, A, Graff, C, Wittrup, KD, Tolner, B, Pedley, RB, Vervecken, W, Contreras, R., Begent, RHJ, Chester, KA, and British Cancer Research Meeting 2004

Published
2004

11. Radioimmunotherapy of metastatic colorectal tumours with iodine-131-labelled antibody to carcinoembryonic antigen: phase I/II study with comparative biodistribution of intact and F(ab')2 antibodies

Author

Lane, DM, primary, Eagle, KF, additional, Begent, RHJ, additional, Hope-Stone, LD, additional, Green, AJ, additional, Casey, JL, additional, Keep, PA, additional, Kelly, AMB, additional, Ledermann, JA, additional, Glaser, MG, additional, and Hilson, AJW, additional

Published
1994
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24. Modifying an immunogenic epitope on a therapeutic protein: a step towards an improved system for antibody-directed enzyme prodrug therapy (ADEPT).

Author

A Mayer, Sharma, Sk, Tolner, B, Minton, Np, Purdy, D, Amlot, P, Tharakan, G, Begent, Rhj, and Chester, Ka

Subjects
IMMUNOTHERAPY, TUMORS, ANTIBODY-directed enzyme prodrug therapy, CANCER treatment, CARBOXYPEPTIDASES, PRODRUGS, EPITOPES, THERAPEUTICS
Abstract

Carboxypeptidase G2 (CP) is a bacterial enzyme, which is targeted to tumours by an antitumour antibody for local prodrug activation in antibody-directed enzyme prodrug therapy (ADEPT). Repeated cycles of ADEPT are desirable but are hampered by human antibody response to CP (HACA). To address this, we aimed to identify and modify clinically important immunogenic sites on MFECP, a recombinant fusion protein of CP with MFE-23, a single chain Fv (scFv) antibody. A discontinuous conformational epitope at the C-terminus of the CP previously identified by the CM79 scFv antibody (CM79-identified epitope) was chosen for study. Modification of MFECP was achieved by mutations of the CM79-identified epitope or by addition of a hexahistidine tag (His-tag) to the C-terminus of MFECP, which forms part of the epitope. Murine immunisation experiments with modified MFECP showed no significant antibody response to the CM79-identified epitope compared to A5CP, an unmodified version of CP chemically conjugated to an F(ab)2 antibody. Success of modification was also demonstrated in humans because patients treated with His-tagged MFECP had a significantly reduced antibody response to the CM79-identified epitope, compared to patients given A5CP. Moreover, the polyclonal antibody response to CP was delayed in both mice and patients given modified MFECP. This increases the prospect of repeated treatment with ADEPT for effective cancer treatment.British Journal of Cancer (2004) 90, 2402-2410. doi:10.1038/sj.bjc.6601888 www.bjcancer.com Published online 25 May 2004 [ABSTRACT FROM AUTHOR]

Published
2004
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33. Galactosylated streptavidin for improved clearance of biotinylated intact and F(ab')2fragments of an anti-tumour antibody

Author

Marshall, D, Pedley, RB, Melton, RG, Boden, JA, Boden, R, and Begent, RHJ

Abstract

Persistence of high levels of radiolabelled antibody in the circulation is a major limitation of radioimmunotherapy. Biotinylation of the radiolabelled anti-tumour antibody followed by administration of streptavidin is known to give much improved tumour to blood ratios as the radioantibody is complexed and subsequently cleared via the reticuloendothelial system, although prolonged splenic uptake is a problem. We have investigated the effect on the clearance pattern and tumour localisation of a 125I-labelled biotinylated anti-CEA antibody (A5B7) after administration of a galactosylated form of streptavidin (gal-streptavidin) in nude mice bearing a human colon carcinoma xenograft. Fifteen minutes to 1 h after gal-streptavidin administration the complexes were cleared via the liver alone (as opposed to liver and spleen after native streptavidin). Twenty-four hours after administration of gal-streptavidin, the tumour to blood ratio for biotinylated A5B7 IgG increased from 2.9 to 13.2 and for biotinylated F(ab')2 fragments an increase from 4.9 to 33.2 was achieved. The reduction in tumour accumulation of F(ab')2 24 h after injection of the clearing agent was less than that seen with intact antibody. Injection of asialofetuin inhibited clearance, confirming that removal of the gal-streptavidin-biotinylated antibody complexes from the blood was via the asialoglycoprotein receptor on liver hepatocytes. Therefore, galactosylation of the streptavidin clearing agent allows rapid removal of radiolabelled biotinylated antibodies via the liver asialoglycoprotein receptor, as opposed to the reticuloendothelial system.

Published
1995
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34. Comparative radioimmunotherapy using intact or F(ab')2fragments of 131I anti-CEA antibody in a colonic xenograft model

Author

Pedley, RB, Boden, JA, Boden, R, Dale, R, and Begent, RHJ

Abstract

The therapeutic efficacy of intact and F(ab')2 fragments of a 131I anti-CEA antibody were compared in an established LS174T colonic xenograft model in nude mice. A single IV dose of either 0.5 mCi (18.5 MBq) intact or 1.0 mCi (37 MBq) F(ab')2 fragments significantly delayed tumour growth, and increased survival time to the same extent. Biodistribution studies showed that the more rapid clearance of the fragments from the circulation improved the tumour: normal tissue ratios found for the intact antibody, but reduced the duration and therefore absolute amount of radioantibody localisation (% injected dose/gram) at the tumour site. The tumours received a similar accumulated beta radiation dose, with 4,065 cGy from 0.5 mCi intact antibody and 4,500 cGy from 1.0 mCi F(ab')2 fragments. The dose rate to the tumour was initially higher for the fragments, but fell off more rapidly as clearance occurred. However, the rapid circulatory clearance resulted in a radiation dose of only 995 cGy to the blood, compared with 2,300 cGy for the intact antibody. This suggests that twice the radiation dose could be delivered to the tumour in the form of fragments for the same blood dose from the intact antibody. Fractionating the 1.0 mCi dose of F(ab')2 into three doses of 0.33 mCi (12.2 MBq), given on days 1, 3 and 5, significantly reduced the therapeutic effect of the treatment. The clinical relevance of these findings is discussed.

Published
1993
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35. The management of high-risk gestational trophoblastic tumours (GTT).

Author

Newlands ES, Bower M, Holden L, Short D, Brock C, Rustin GJS, Begent RHJ, and Bagshawe KD

Abstract

Between 1979 and 1995 we have treated 272 consecutive women with high-risk (GTT including 121 previously treated patients who were treated with the weekly EMA/CO (etoposide, methotrexate, actinomycin D alternating with cyclophosphamide and vincristine). The median follow-up is 4.5 years (range 1-16 years). The cumulative 5 year survival is 86.2% (95% confidence interval 81.9-90.5%). No deaths from GTT occurred later than 2 years after starting EMA/CO. In a multivariate analysis, adverse prognostic factors were the presence of liver metastases (p < 0.0001), interval from antecedent pregnancy > 24 months (p < 0.0001), brain metastases (p = 0.0008) and term delivery of antecedent pregnancy (p = 0.045). There were 11 (4%) early deaths while 213 (78%) achieved complete remission. 47 (17%) developed drug resistance to EMA/CO of whom 33 (70%) were salvaged by further cisplatinum based chemotherapy and sugery. 2 women developed acute myeloid leukaemia after treatment with EMA/CO. 56% of women who have been in remission for at least 2 years and had fertility conserving surgery have achieved pregnancy since completing EMA/CO and there have been 112 live births including 3 babies with congenital abnormalities. EMA/CO is an effective, easy to administer and well tolerated regimen for treating patient with high-risk GTT. More than half of these women will retain their fertility. However, there is a small but significant increase in second malignancies., (© 1998 International Federation of Gynecology and Obstetrics.)

Published
1998
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