Cathepsin B-sensitive dipeptide prodrugs. 1. A model study of structural requirements for efficient release of doxorubicin

Dubowchik, Gene M.; Firestone, Raymond A.

doi:10.1016/s0960-894x(98)00609-x

Cited by 171 publications

(154 citation statements)

References 13 publications

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“…MMAE was then additionally modified with maleimidocaproyl-vc to result in vcMMAE, which contained a p-aminobenzylcarbamate spacer between the MMAE and the linker. Similarly, Dox was modified to result in vcDox containing a p-aminobenzylcarbamate spacer between Dox and the linker (30). The resulting structures of drug derivatives used in these studies are shown appended to mAb-SH in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Subsequent to proteolytic cleavage, residual linker between the peptide and the drug undergoes fragmentation, leading to release of fully active MMAE (26) or Dox (30).…”

Section: Resultsmentioning

confidence: 99%

“…3 and 4B). The lysosomally cleaved vc linker offers a significant stability advantage over acid-cleaved linkers (26,30). CD20 modulation may occur slowly compared with other internalizing antigens such as CD33; thus, successful drug delivery via CD20 may require a stable, highly potent antibody-drug conjugate and stable cell surface binding.…”

Section: Discussionmentioning

confidence: 99%

“…The synthesis of MMAE and the activated vc linker used in both the auristatin and Dox syntheses was as described previously (26). The synthesis of Dox with the vc linker has been described previously (30).…”

Section: Methodsmentioning

confidence: 99%

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Efficient Elimination of B-Lineage Lymphomas by Anti-CD20–Auristatin Conjugates

Law

Cerveny

Gordon

et al. 2004

Clinical Cancer Research

107

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The anti-CD20 antibody rituximab is useful in the treatment of certain B-cell malignancies, most notably nonHodgkin's lymphoma. Its efficacy has been increased when used in combination with chemotherapy, yet anti-CD20 monoclonal antibodies (mAbs) directly conjugated with drugs such as doxorubicin (Dox) have failed to deliver drug or to demonstrate antitumor activity. We have produced anti-CD20 antibody-drug conjugates that possess potent antitumor activity by using the anti-mitotic agent, monomethyl auristatin E (MMAE), linked via the lysosomally cleavable dipeptide, valine-citrulline (vc). Two anti-CD20 conjugates, rituximab-vcMMAE and 1F5-vcMMAE, were selectively cytotoxic against CD20؉ B-lymphoma cell lines, with IC 50 values ranging from 50 ng/mL to 1 g/mL. Unlike rituximab, which showed diffuse surface localization, rituximabvcMMAE capped and was internalized within 4 hours after binding to CD20 ؉ B cells. Internalization of rituximabvcMMAE was followed by rapid G 2 -M phase arrest and onset of apoptosis. Anti-CD20 antibody-drug conjugates prepared with Dox were internalized and localized as with rituximab-vcMMAE, yet these were not effective for drug delivery (IC 50 > 50 g/mL). Consistent with in vitro activity, rituximab-vcMMAE showed antitumor efficacy in xenograft models of CD20-positive lymphoma at doses where rituximab or rituximab-Dox conjugates were ineffective. These data indicate that anti-CD20 -based antibody-drug conjugates are effective antitumor agents when prepared with a stable, enzyme-cleavable peptide linkage to highly potent cytotoxic agents such as MMAE.

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Section: Resultsmentioning

confidence: 99%

“…Subsequent to proteolytic cleavage, residual linker between the peptide and the drug undergoes fragmentation, leading to release of fully active MMAE (26) or Dox (30).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Efficient Elimination of B-Lineage Lymphomas by Anti-CD20–Auristatin Conjugates

Law

Cerveny

Gordon

et al. 2004

Clinical Cancer Research

107

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“…Although several disulfide-linked ADCs are currently under clinical investigation (Table 1), more stable cleavable linkers are engineered in the form of lysosomal protease substrates, e.g. containing a valine-citrulline dipeptide bond, which is specifically cleaved by cathepsin B [26][27][28] .…”

Section: Linker Chemistriesmentioning

confidence: 99%

Antibody–Drug Conjugates for Tumor Targeting—Novel Conjugation Chemistries and the Promise of non-IgG Binding Proteins

et al. 2015

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Antibody-drug conjugates (ADCs) have emerged as a promising class of anti-cancer agents, combining the specificity of antibodies for tumor targeting and the destructive potential of highly potent drugs as payload. An essential component of these immunoconjugates is a bifunctional linker capable of reacting with the antibody and the payload to assemble a functional entity. Linker design is fundamental, as it must provide high stability in the circulation to prevent premature drug release, but be capable of releasing the active drug inside the target cell upon receptor-mediated endocytosis. Although ADCs have demonstrated an increased therapeutic window, compared to conventional chemotherapy in recent clinical trials, therapeutic success rates are still far from optimal. To explore other regimes of half-life variation and drug conjugation stoichiometries, it is necessary to investigate additional binding proteins which offer access to a wide range of formats, all with molecularly defined drug conjugation. Here, we delineate recent progress with site-specific and biorthogonal conjugation chemistries, and discuss alternative, biophysically more stable protein scaffolds like Designed Ankyrin Repeat Proteins (DARPins), which may provide such additional engineering opportunities for drug conjugates with improved pharmacological performance.3

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Synthesis and Evaluation of New Elastase Substrates as Tripartate Prodrugs

Achilles

2002

Arch. Pharm. Pharm. Med. Chem.

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Cathepsin B-sensitive dipeptide prodrugs. 1. A model study of structural requirements for efficient release of doxorubicin

Cited by 171 publications

References 13 publications

Efficient Elimination of B-Lineage Lymphomas by Anti-CD20–Auristatin Conjugates

Efficient Elimination of B-Lineage Lymphomas by Anti-CD20–Auristatin Conjugates

Antibody–Drug Conjugates for Tumor Targeting—Novel Conjugation Chemistries and the Promise of non-IgG Binding Proteins

Synthesis and Evaluation of New Elastase Substrates as Tripartate Prodrugs

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