Cure of Xenografted Human Carcinomas by BR96-Doxorubicin Immunoconjugates

Trail, Pamela A.; Willner, David; Lasch, Shirley J.; Henderson, Arris J.; Hofstead, Sandra J.; Casazza, Anna Maria; Firestone, Raymond A.; Hellström, Ingegerd; Hellström, Karl Erik

doi:10.1126/science.8327892

Cited by 509 publications

(258 citation statements)

References 16 publications

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“…Monoclonal immunoglobulin fractions are frequently utilized for specific recognition and physical binding to antigens or receptor complexes uniquely overexpressed on the exterior surface membrane of neoplastic cell populations. 7,[26][27][28][29][30] Doxorubicin 28,29,[31][32][33] has been the most common anthracycline to date utilized to synthesize covalent immunochemotherapeutics in addition to the relatively limited utilization of daunorubicin [34][35][36] and epirubicin.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

Coyne

Jones²,

Bear³

2012

Cancer Biotherapy and Radiopharmaceuticals

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The C 3 -monoamine on the carbohydrate moiety (daunosamine -NH 2 -3¢) of epirubicin was reacted under anhydrous conditions with succinimidyl 4,4-azipentanoate to create a covalent UV-photoactivated epirubicin-(C 3 -amide) intermediate with primary amine-reactive properties. A synthetic covalent bond between the UV-photoactivated epirubicin-(C 3 -amide) intermediate and the e-amine of lysine residues within the amino acid sequence of anti-HER2/neu monoclonal immunoglobulin was subsequently created by exposure to UV light (354 nm) for 15 minutes. Size-separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis combined with immunodetection analysis and chemiluminescent autoradiographic imaging revealed a lack of IgG-IgG polymerization or degradative protein fragmentation of the covalent epirubicin-(C 3 -amide)-[anti-HER2/neu] immunochemotherapeutic. Retained binding-avidity of epirubicin-(C 3 -amide)-[anti-HER2/neu] was validated by cell-ELISA utilizing monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma SKBr-3 which highly overexpress membrane-associated HER2/neu complexes. Between epirubicin-equivalent concentrations of 10 -10 to 10 -6 M the covalent epirubicin-(C 3 -amide)-[anti-HER2/neu] immunochemotherapeutic consistently evoked levels of cytotoxic anti-neoplastic potency that were highly analogous to chemotherapeuticequivalent concentrations of epirubicin. Cytotoxic anti-neoplastic potency of epirubicin-(C 3 -amide)-[anti-HER2/ neu] against chemotherapeutic-resistant mammary adenocarcinoma SKBr-3 challenged with epirubicin-(C 3 -amide)-[anti-HER2/neu] at an epirubicin-equivalent concentration of 10 -6 M was 88.5% (e.g., 11.5% residual survival). Between final epirubicin-equivalent concentrations of 10 -8 and 10 -7 M there was a marked threshold increase in the mean cytotoxic anti-neoplastic activity for epirubicin-(C 3 -amide)-[anti-HER2/neu] from 9.9% to 66.9% (90.2% to 33.1% residual survival).

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Section: Introductionmentioning

confidence: 99%

Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

Coyne

Jones²,

Bear³

2012

Cancer Biotherapy and Radiopharmaceuticals

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“…? 248 has been reported to induce complete regressions and cures of xenografted human lung, breast, and colon carcinomas growing subcutaneously in athymic mice and rats (13). One schedules varying from once a week for 12 wk to a single dose ( 10,14).…”

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confidence: 99%

BR96-Doxorubicin Conjugate (BMS-182248) Versus Doxorubicin: A Comparative Toxicity Assessment in Rats

et al. 1994

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The toxicity of BMS-182248, an Additional effects noted with either drug included testicular atrophy, axonal degeneration of sciatic nerve and nerve tracts of brain and spinal cord, teeth (incisor) abnormalities, thymic atrophy, bone marrow hypocellularity, splenic lymphoid and red-pulp depletion, and increased extramedullary hematopoiesis in the spleen and liver. Also noted were altered chief cells in the stomach, vacuolation of adrenal gland and corpora lutea in the ovary, uterine and seminal vesicle atrophy, ulceration and myocyte regeneration/degeneration in the tongue, increased osteoclasts and osteoblasts in bone, and lymphoid hyperplasia of mandibular lymph node. In general, these effects were more severe in doxorubicin-treated rats.All changes observed with BMS-182248 were considered primarily due to the effects of doxorubicin and were substantially less severe (most notably cardiotoxicity) compared to those produced by an equivalent amount of doxorubicin.

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“…The serum stability of hydrazone linkers, however, is poor 21,22 . The low clinical efficacy and the safety concerns of gemtuzumab ozogamicin were mainly attributed to this linker instability and premature drug release in the circulation 5,16,23 .…”

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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Cure of Xenografted Human Carcinomas by BR96-Doxorubicin Immunoconjugates

Cited by 509 publications

References 16 publications

Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

BR96-Doxorubicin Conjugate (BMS-182248) Versus Doxorubicin: A Comparative Toxicity Assessment in Rats

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

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Cure of Xenografted Human Carcinomas by BR96-Doxorubicin Immunoconjugates

Cited by 509 publications

References 16 publications

Synthesis of a Covalent Epirubicin-(C3-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

Synthesis of a Covalent Epirubicin-(C3-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

BR96-Doxorubicin Conjugate (BMS-182248) Versus Doxorubicin: A Comparative Toxicity Assessment in Rats

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

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Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate