European Journal of Cancer and Clinical Oncology

1991

DOI: 10.1016/0277-5379(91)90010-b

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Ablation of human choriocarcinoma xenografts in nude mice by antibody-directed enzyme prodrug therapy (ADEPT) with three novel compounds

Caroline J. Springer

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,

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Surinder K. Sharma

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et al.

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Cited by 109 publications

(35 citation statements)

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“…ZD2767P bisiodophenol was synthesized as previously published (Springer et al, 1991a). The F(ab′)2 fragment of A5B7 was conjugated to the bacterial enzyme CPG2 as described previously .…”

Section: Methodsmentioning

confidence: 99%

“…Animal models and previous clinical studies have demonstrated that ADEPT can be used to selectively deliver an antibodyenzyme conjugate to a tumour and produce significant regression (Springer et al, 1991a;Eccles et al, 1994). These effects have not, however, been correlated directly with production of the prodrug.…”

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confidence: 99%

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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

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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.

“…ZD2767P bisiodophenol was synthesized as previously published (Springer et al, 1991a). The F(ab′)2 fragment of A5B7 was conjugated to the bacterial enzyme CPG2 as described previously .…”

Section: Methodsmentioning

confidence: 99%

“…Animal models and previous clinical studies have demonstrated that ADEPT can be used to selectively deliver an antibodyenzyme conjugate to a tumour and produce significant regression (Springer et al, 1991a;Eccles et al, 1994). These effects have not, however, been correlated directly with production of the prodrug.…”

mentioning

confidence: 99%

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

¹

,

²

,

³

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.

“…Although the preliminary studies reported here are limited -using a single treatment and the same doxorubicin dose as used for the pharmacokinetic studies (10 mg kg) -they verify activity of the PDEPT combination in both the B16F10 and COR-L23 tumour models. Previous studies using the ADEPT system in a CC3 human choriocarcinoma xenograft (Springer et al, 1991) clearly showed that antitumour activity improved dramatically following optimisation of both schedule and dose of the antibody-enzyme conjugate and the prodrug. Future experiments with the HPMA copolymer-cathepsin B and PK1 model combination will optimise both HPMA copolymer-enzyme and PK1 doses and also the length of the repeated cycle of administration.…”

mentioning

confidence: 99%

PDEPT: polymer-directed enzyme prodrug therapy

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2001

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Summary Polymer-directed enzyme prodrug therapy (PDEPT) is a novel two-step antitumour approach using a combination of a polymeric prodrug and polymer-enzyme conjugate to generate cytotoxic drug selectively at the tumour site. In this study the polymeric prodrug N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-Gly-Phe-Leu-Gly-doxorubicin conjugate PK1 (currently under Phase II clinical evaluation) was selected as the model prodrug, and HPMA copolymer-cathepsin B as a model for the activating enzyme conjugate. Following polymer conjugation (yield of 30-35%) HPMA copolymer-cathepsin B retained ~20-25% enzymatic activity in vitro. To investigate pharmacokinetics in vivo, 125 I-labelled HPMA copolymer-cathepsin B was administered intravenously (i.v.) to B16F10 tumour-bearing mice. HPMA copolymercathespin B exhibited a longer plasma half-life (free cathepsin B t 1/2α = 2.8 h; bound cathepsin B t 1/2α = 3.2 h) and a 4.2-fold increase in tumour accumulation compared to the free enzyme. When PK1 (10 mg kg -1 dox-equiv.) was injected i.v. into C57 mice bearing subcutaneously (s.c.) palpable B16F10 tumours followed after 5 h by HPMA copolymer-cathepsin B there was a rapid increase in the rate of dox release within the tumour (3.6-fold increase in the AUC compared to that seen for PK1 alone). When PK1 and the PDEPT combination were used to treat established B16F10 melanoma tumour (single dose; 10 mg kg -1 dox-equiv.), the antitumour activity (T/C%) seen for the combination PDEPT was 168% compared to 152% seen for PK1 alone, and 144% for free dox. Also, the PDEPT combination showed activity against a COR-L23 xenograft whereas PK1 did not. PDEPT has certain advantages compared to ADEPT and GDEPT. The relatively short plasma residence time of the polymeric prodrug allows subsequent administration of polymer-enzyme without fear of prodrug activation in the circulation and polymer-enzyme conjugates have reduced immunogenicity. This study proves the concept of PDEPT and further optimisation is warranted. PDEPT concept using PK1 and HPMA copolymer-cathepsin B as a model combination. PK1 has proven ability to target solid tumours by the EPR effect (Seymour et al, 1994) with concomitant renal elimination resulting in low blood levels within 1-5 h in animals and man (Seymour et al, 1990;Vasey et al, 1999). HPMA copolymer-cathepsin B ( Figure 2B) was selected for PK1 activation as the PK1 Gly-Phe-Leu-Gly polymer-dox linker was designed to permit intralysosomal dox liberation due to action of the lysosomal cysteine proteases (Duncan et al, 1984). First it was necessary to prepare an HPMA copolymer-cathepsin B conjugate that would retain sufficient enzyme activity after conjugation. Activity was monitored in vitro using a low molecular weight substrate N-Benzoyl-Phe-Val-Arg-p-nitroanilide hydrochloride (Bz-Phe-Val-Arg-NAp) and the polymeric substrate PK1. The biodistribution of 125 I-labelled HPMA copolymer-cathepsin B and 125 I-labelled cathepsin B was assessed in mice bearing subcutaneous (s.c.) B16F10 tumours and this model wa...

“…Due to the selective localization of the antibody-enzyme conjugate, the prodrug is cleaved by the enzyme into active drug mainly in the tumor tissue. Although successful in several models (3,4) and clinical trials (5,6), the overall success of this approach is limited by several factors. First, the tumor must express a suitable tumor-associated antigen (TAA), and this is not always the case.…”

Section: Introductionmentioning

confidence: 99%

PTD-mediated Loading of Tumor-Seeking Lymphocytes with Prodrug-Activating Enzymes

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et al. 2008

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Abstract. Using the approach of peptide transduction domain (PTD)-mediated loading of interleukin-2 (IL-2)-activated natural killer (A-NK) cells, tumor-seeking lymphocytes, with prodrug-activating enzymes, we primarily aim to generate a cytotoxic drug selectively within tumors and minimize damage to normal tissues. A-NK cells are able to accumulate selectively at tumor sites. While these cells by themselves possess significant antitumor effect in vivo, we suggest that they can also serve as Trojan horses, by bringing anticancer agents, such as prodrug-activating enzymes, selectively to tumors. We have successfully demonstrated in a mouse model that A-NK cells can be rapidly loaded with prodrugactivating enzymes, such as alkaline phosphatase (AP) and beta-galactosidase (beta-gal), in vitro using enzyme-conjugated peptide PTD5. Upon adoptive transfer into lung-tumor-bearing animals, the loaded A-NK cells are able to bring their cargo of the prodrug-activating enzymes selectively to pulmonary metastases. The targeting of the AP to the tumor tissues is highly specific, since more than a fivefold higher concentration of AP was found in the tumor tissues compared to the surrounding normal lung tissue at 24 h after injection. The approach of transporting prodrug-activating enzymes selectively into tumors clearly shows potential for future targeted chemotherapy. Ongoing studies in our laboratory are evaluating the antitumor efficacy of cellular-dependent enzyme prodrug therapy.KEY WORDS: activated natural killer cells; delivery; metastases in vivo; prodrug enzymes; protein transduction domain.

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