Site‐directed delivery of anthracyclines for treatment of cancer

Trail, Pamela A.; Willner, David; Hellström, Karl Erik

doi:10.1002/ddr.430340209

Cited by 17 publications

(23 citation statements)

References 52 publications

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“…With 10/1 substitution of this photosensitizer on the anti-ICAM (anti-intracellular adhesion molecule) MAb, the cytotoxic mechanisms appeared to be qualitatively similar; however, the IC conferred a 2-log increase in efficiency with respect to photosensitizer concentration. This finding confirms the theoretical assumption that targeted therapy can effectively lower required drug concentrations [Trail et al, 1995].…”

Section: Immunophototherapysupporting

confidence: 85%

“…Several methods of establishing linkers on antibodies or antibody fragments have been reported for a variety of investigational, clinical, and diagnostic endpoints; however, this methodology is beyond the scope of the article and has been recently reviewed [Trail et al, 1995]. For immunophototherapy, the key issue in the generation of an immunoconjugate is retention of photopotentiation by the photosensitizer moiety, as well as the immunoreactivity of the targeting functional group.…”

Section: Formulation Of Immunoconjugatesmentioning

confidence: 99%

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Immunophotodynamic therapy: Current developments and future prospects

Miller

Lown

1997

Drug Dev. Res.

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Photodynamic therapy (PDT) may offer an enhanced therapeutic index via one or more of the following modalities: a) preferential photosensitizer uptake by the target tissue, b) specific illumination of target tissue to excite the photosensitizer, c) strategic timing of light application to minimize toxicity to normal tissues, d) topical application of the photosensitizer restricted to the target tissue, infusion of the photosensitizer to the vasculature immediately upstream of the target, and intra‐target administration. While each photosensitizer has inherent properties of biodistribution, it is generally accepted that few provide a significant therapeutic index and that the desired effect is far from universal with respect to tumor types. Moreover, the optical properties of tumor and normal tissues vary dramatically and precision dosimetry remains an elusive goal in most clinical situations. Certain tumors, particularly those of the reticuloendothelial system, will usually be surrounded by normal stroma with greater concentrations of photosensitizer than are present in the tumor at a given post‐administration interval, presenting a major obstacle to practical therapy. Deep‐seated or large solid malignancies are not amenable to topical application of the photosensitizer and single tumor masses are frequently served by multiple arterial sources, rendering major dosimetric obstacles for photosensitizers administered via the upstream vasculature. One approach to specific photosensitizer delivery is via covalently bound immunoconjugates of photosensitizer and antibodies or antibody fragments to unique tumor markers. This approach is the subject of several clinical trials and provides encouragement for successful application in a wide variety of neoplastic diseases. In addition to therapeutic endpoints, this approach is capable of facilitating detection of subclinical lesions through the fluorescent properties of photosensitizers. Drug Dev. Res. 42:182–197, 1997. © 1997 Wiley‐Liss, Inc.

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Section: Immunophototherapysupporting

confidence: 85%

Section: Formulation Of Immunoconjugatesmentioning

confidence: 99%

Immunophotodynamic therapy: Current developments and future prospects

Miller

Lown

1997

Drug Dev. Res.

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“…A number of specific mechanisms focusing on DNA damaging agents to induce cell death have been and are being evaluated for ADCs both clinically and preclinically. These include double-strand DNA cleavage via the natural product calicheamicin, DNA intercalation via anthracylines such as doxorubicin, as well as DNA alkylation via duocarmycins and pyrrolobenzenodiazepine dimers …”

Section: Discussionmentioning

confidence: 99%

Natural Product Splicing Inhibitors: A New Class of Antibody–Drug Conjugate (ADC) Payloads

Puthenveetil¹,

Loganzo

He³

et al. 2016

Bioconjugate Chem.

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There is a considerable ongoing work to identify new cytotoxic payloads that are appropriate for antibody-based delivery, acting via mechanisms beyond DNA damage and microtubule disruption, highlighting their importance to the field of cancer therapeutics. New modes of action will allow a more diverse set of tumor types to be targeted and will allow for possible mechanisms to evade the drug resistance that will invariably develop to existing payloads. Spliceosome inhibitors are known to be potent antiproliferative agents capable of targeting both actively dividing and quiescent cells. A series of thailanstatin-antibody conjugates were prepared in order to evaluate their potential utility in the treatment of cancer. After exploring a variety of linkers, we found that the most potent antibody-drug conjugates (ADCs) were derived from direct conjugation of the carboxylic acid-containing payload to surface lysines of the antibody (a "linker-less" conjugate). Activity of these lysine conjugates was correlated to drug-loading, a feature not typically observed for other payload classes. The thailanstatin-conjugates were potent in high target expressing cells, including multidrug-resistant lines, and inactive in nontarget expressing cells. Moreover, these ADCs were shown to promote altered splicing products in N87 cells in vitro, consistent with their putative mechanism of action. In addition, the exposure of the ADCs was sufficient to result in excellent potency in a gastric cancer xenograft model at doses as low as 1.5 mg/kg that was superior to the clinically approved ADC T-DM1. The results presented herein therefore open the door to further exploring splicing inhibition as a potential new mode-of-action for novel ADCs.

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“…Bio-Beads SM-2 chromatographic support was supplied by Bio-Rad Laboratories. 1 H NMR and 13 C NMR spectra were obtained at Internal referencing was used and chemical shifts are reported in ppm. FTIR's were obtained as KBr pellets.…”

Section: Methodsmentioning

confidence: 99%

“…Monoclonal antibody conjugates have been shown to be effective targeting vehicles for cytotoxic drugs such as doxorubicin (1). We have previously demonstrated the antitumor activity of BR96-DOX conjugates in the treatment of human tumor xenografts in mice and rats (2,3).…”

mentioning

confidence: 99%

Monoclonal Antibody Conjugates of Doxorubicin Prepared with Branched Linkers: A Novel Method for Increasing the Potency of Doxorubicin Immunoconjugates

Yurgaitis

Willner

et al. 1999

Bioconjugate Chem.

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Immunoconjugates of monoclonal antibody BR96 and Doxorubicin have been prepared using a novel series of branched hydrazone linkers. Since each linker bound to the mAb carries two DOX molecules, the DOX/mAb molar ratios of these conjugates were approximately 16, twice that of those previously prepared with single-chain hydrazone linkers. The conjugates were stable at a physiological pH of 7, but released DOX rapidly at lysosomal pH 5. The branched series of BR96 conjugates demonstrated antigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both a DOX (4-14-fold) and mAb (7-23-fold) basis. The results suggest that, by using the branched linker methodology, it is possible to significantly reduce the amount of mAb required to achieve antigen-specific cytotoxic activity. In this paper, the synthesis and in vitro biology of branched chain immunoconjugates are described.

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Site‐directed delivery of anthracyclines for treatment of cancer

Cited by 17 publications

References 52 publications

Immunophotodynamic therapy: Current developments and future prospects

Immunophotodynamic therapy: Current developments and future prospects

Natural Product Splicing Inhibitors: A New Class of Antibody–Drug Conjugate (ADC) Payloads

Monoclonal Antibody Conjugates of Doxorubicin Prepared with Branched Linkers: A Novel Method for Increasing the Potency of Doxorubicin Immunoconjugates

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