A cytotoxic agent can be generated selectively at cancer sites

Bagshawe, K. D.; Cj, Springer; Searle, F.; Antoniw, Pari; Sharma, SK; Melton, R. G.; Sherwood, R.F.

doi:10.1038/bjc.1988.293

Cited by 249 publications

(134 citation statements)

References 15 publications

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“…When the antibody -enzyme has cleared from the circulation, a prodrug is given and is converted to active drug in the tumour by the targeted enzyme (Bagshawe et al, 1988). An illustration of the ADEPT concept is shown in Figure 1.…”

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confidence: 99%

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

et al. 2004

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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.

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

et al. 2004

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“…ADEPT represents a potentially valuable means of effectively destroying tumours without causing systemic toxicities (Sherwood, 1996;Bagshawe et al, 1998). The key element in this strategy is tumour specificity; tumours are selectively targeted through the antigens they express.…”

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Measurement of the critical DNA lesions produced by antibody-directed enzyme prodrug therapy (ADEPT) in vitro, in vivo and in clinical material

et al. 2001

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Summary An antibody-directed enzyme prodrug therapy (ADEPT) system against CEA-positive tumours is currently in phase I clinical trials. It consists of a prodrug, 4-[N,N-bis(2-iodoethyl) amino] phenoxycarbonyl L-glutamic acid (ZD2767P) and a conjugate of the F(ab') 2 anti-CEA antibody A5B7 and the bacterial enzyme carboxypeptidase G2 (CPG2). ZD2767P is converted by antibody-targeted CPG2 into an active bifunctional alkylating drug (ZD2767) at the tumour site. The IC 50 value of the prodrug against the human colorectal tumour LS174T cell line was 55 ± 9 µM following a 1 h exposure. In contrast, co-incubation of ZD2767P with CPG2 resulted in 229-fold increase in activity. Using a modified comet assay, DNA interstrand cross links (ISC) were detected within 1 h of ZD2767P + CPG2 treatment and were repaired by 24 h. A clear dose-response was seen between the level of ISC, growth inhibition and ZD2767 concentration. Administration of a therapeutic dose of ZD2767P 72 h after the F(ab′) 2 A5B7 conjugate to mice bearing LS147T xenografts resulted in extensive ISC in the tumour after 1 h; repair was seen at 24 h. Tumour biopsies and peripheral lymphocytes were studied in 5 patients on the ADEPT phase I clinical trial. In 4 patients no ISC were detected. These patients also demonstrated poor localization of conjugate and no tumour response was seen. However a significant level of ISC was detected in one tumour biopsy, which also showed evidence of conjugate localization and clinical response. These studies demonstrate the application of the comet assay in the measurement of ISC in vitro and in clinical material and confirm that activation of ZD2767P results in the formation of DNA crosslinks.

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“…His interests included nitroreductase and microsomal activation of cyclophosphamide; however, targeting an enzyme to the tumour did not become feasible until the 1980s when Ken Bagshawe's CRC laboratories at Charing Cross Hospital described antibody-directed enzyme prodrug therapy (ADEPT) (Bagshawe, 1987;Bagshawe et al, 1988). The Phase I/II Committee chaired by Tom, encouraged clinical trials of ADEPT on the mechanism of action of the components to show whether conditions for effective therapy were being achieved.…”

Section: Antibody Enzyme Prodrug Therapy -Caroline Springer and Richamentioning

confidence: 99%

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

et al. 2003

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A cytotoxic agent can be generated selectively at cancer sites

Cited by 249 publications

References 15 publications

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

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

Measurement of the critical DNA lesions produced by antibody-directed enzyme prodrug therapy (ADEPT) in vitro, in vivo and in clinical material

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

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