Efficient and Selective Gene Transfer into Primary Human Brain Tumors by Using Single-Chain Antibody-Targeted Adenoviral Vectors with Native Tropism Abolished

Beusechem, Victor W. van; Grill, Jacques; Mastenbroek, D C J; Wickham, Thomas J.; Roelvink, Peter W.; Haisma, Hidde J.; Lamfers, Martine L.M.; Dirven, Clemens; Pinedo, H.M.; Gerritsen, Winald R.

doi:10.1128/jvi.76.6.2753-2762.2002

Cited by 76 publications

(44 citation statements)

References 37 publications

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“…Previously, we have shown that the bispecific scFv 425-S11, which targets adenoviruses towards the EGFR, enhances transduction of CAR-deficient cancer cells with AdV. 6,7,17,26 Here, we investigated if EGFR targeting using 425-S11 could also enhance the oncolytic potency of a CRAd. To provide the CRAd with constant EGFRtargeting properties during replication, 425-S11 was produced from a stable expression cassette inserted into the CRAd genome.…”

Section: Discussionmentioning

confidence: 99%

“…For example, AdV targeted towards the epithelial cell adhesion molecule were already made in this way and shown to provide efficient and selective transduction of cancer cells. 26,38 Thus, this versatile targeting approach allows tailored construction of CRAds with binding affinity for other molecules expressed on cancer cells using analogous procedures. In addition, the S11 moiety of the bispecific scFv binds not only to native adenovirus fiber knobs, but also to knobs that were made CAR-binding deficient by specific amino-acid deletions.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the S11 moiety of the bispecific scFv binds not only to native adenovirus fiber knobs, but also to knobs that were made CAR-binding deficient by specific amino-acid deletions. 26,39 Selective transduction of cancer cells using bispecific scFv together with AdV deficient in CAR and/or integrin binding was already demonstrated. 26,38 Hence, the strategy described herein, where a bispecific scFv targeting-antibody is expressed from the CRAd genome, could perhaps be combined with mutations in the CRAd genome that abolish CAR …”

Section: Discussionmentioning

confidence: 99%

“…Since primary high-grade malignant gliomas are often CAR-deficient but EGFR-positive, 5,6,26 we evaluated the utility of AdD24-425S11 in this context. Eight glioblastoma multiforme (GBM) specimens were obtained from patients undergoing surgery and short-term cultures were established.…”

Section: Egfr-targeted Crad Exhibits Enhanced Replication On Primary mentioning

confidence: 99%

“…The targeting moiety is the bispecific single-chain (scFv) antibody 425-S11 consisting of the anti-epidermal growth factor receptor (EGFR) scFv 425 and anti-adenovirus fiber knob scFv S11 that targets adenovirus entry via EGFR. 17,26 In contrast to CAR, EGFR is commonly overexpressed in many tumor types. 27 Here, we show that the novel EGFR-targeted CRAd produced its own bispecific scFvtargeting moiety, while replicating in CAR-deficient cancer cells, providing its progeny with CAR-independent infectivity.…”

Section: Introductionmentioning

confidence: 99%

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Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors

Beusechem¹,

Mastenbroek²,

Doel³

et al. 2003

Gene Ther

128

169

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Egfr-targeted Crad Exhibits Enhanced Replication On Primary mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors

Beusechem¹,

Mastenbroek²,

Doel³

et al. 2003

Gene Ther

128

169

View full text Add to dashboard Cite

The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade

Diamond

Winters

Smith

et al. 2001

Cancer

178

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Leuchtend: Eine von einem G‐Quartett inspirierte Fluoreszenzsonde (APD), die aus zwei acetylenverbrückten Purinen besteht, wurde synthetisiert. APD leuchtet in Gegenwart paralleler DNA‐ (z. B. c‐MYC) oder RNA‐G‐Quadruplexe, während es keine Fluoreszenzverstärkung in Gegenwart von doppelsträngiger DNA, antiparallelen oder gemischten (z. B. h‐Telo) G‐Quadruplexen zeigt. APD wurde auch zur bevorzugten Anfärbung von G‐Quadruplexen verwendet.

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Retargeting of adenoviral infection to melanoma: Combining genetic ablation of native tropism with a recombinant bispecific single‐chain diabody (scDb) adapter that binds to fiber knob and HMWMAA

Nettelbeck

Rivera

Kupsch

et al. 2003

Intl Journal of Cancer

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Gene therapy is an emerging and promising modality for the treatment of malignant melanoma and other neoplasms for which conventional therapies are inadequate. Various therapeutic genes have shown promise for tumor cell killing. However, successful gene therapy depends on the development of efficient and targeted gene transfer vectors. Here we describe a novel strategy for targeting of adenovirus-mediated gene transfer to melanoma cells. This strategy combines genetic ablation of native adenoviral tropism with redirected viral binding to melanoma cells via a bispecific adapter molecule, a bacterially expressed single-chain diabody, scDb MelAd, that binds to both the adenoviral fiber protein and to the high molecular weight melanoma-associated antigen (HMWMAA). This antigen is widely and specifically expressed on the surface of melanoma cells and its expression is associated with tumor development and progression. Our results showed specific and strong binding of the anti-HMWMAA scFv RAFT3 and the bispecific adapter scDb MelAd to melanoma cells. In adenoviral infection experiments, we demonstrated i) substantially (>50-fold) reduced infectivity of capsid mutant adenoviruses, ii) restored (up to 367-fold increase), CAR-independent and HMWMAAmediated infectivity of these mutant viruses by scDb MelAd specifically in melanoma cells, and iii) higher levels of transgene expression in melanoma cells by fiber mutant virus complexed with scDbMelAd, relative to a vector with wildtype fibers. We confirmed the utility of this targeting strategy with human primary melanoma cells that represent clinically relevant substrates. These experiments established that the retargeting strategy mediates up to 54-fold increased adenoviral gene transfer to CAR-negative melanoma cells compared to the vector with native tropism. Hence, the HMWMAA-targeted adenoviral vector lacking native tropism exhibits both enhanced specificity and augmented infectivity of gene transfer to melanoma cells, suggesting that it is feasible to use this vector to improve gene therapy for malignant melanoma.

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Efficient and Selective Gene Transfer into Primary Human Brain Tumors by Using Single-Chain Antibody-Targeted Adenoviral Vectors with Native Tropism Abolished

Cited by 76 publications

References 37 publications

Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors

Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors

The antiosteoporotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade

Retargeting of adenoviral infection to melanoma: Combining genetic ablation of native tropism with a recombinant bispecific single‐chain diabody (scDb) adapter that binds to fiber knob and HMWMAA

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