Abstract：
:The safety and efficacy of anticancer antibody-drug conjugates (ADCs) depend on the selection of tumor-targeting monoclonal antibody (mAb), linker, and drug, as well as their specific chemical arrangement and linkage chemistry. In this study, we used a heterobifunctional cross-linker to conjugate docetaxel (DX) to cetuximab (CET) or panitumumab (PAN). The resulting ADCs were investigated for their in vitro EGFR-specific cytotoxicity and in vivo anticancer activity. Reaction conditions, such as reducing agent, time, temperature, and alkylation buffer, were optimized to yield potent and stable ADCs with consistent batch-to-batch drug-to-antibody ratios (DARs). ADCs were synthesized with DARs from 0.4 to 3.0, and all retained their EGFR affinity and specificity after modification. ADCs were sensitive to cell surface wildtype EGFR expression, demonstrating more cytotoxicity in EGFR-expressing A431 and MDA-MB-231 cell lines compared to U87MG cells. A431 tumor-bearing mice treated once weekly for four weeks with 100 mg/kg cetuximab-docetaxel ADC (C-SC-DX, DAR 2.5) showed durable anticancer responses and improved overall survival compared to the same treatment regimen with 1 mg/kg DX, 100 mg/kg CET, or a combination 1 mg/kg DX and 100 mg/kg CET. New treatment options are emerging for patients with both wild-type and mutated EGFR-overexpressing cancers, and these studies highlight the potential role of EGFR-targeted ADC therapies as a promising new treatment option.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Glatt DM,Beckford Vera DR,Prabhu SS,Mumper RJ,Luft JC,Benhabbour SR,Parrott MCdoi
10.1021/acs.molpharmaceut.8b00672subject
Has Abstractpub_date
2018-11-05 00:00:00pages
5089-5102issue
11eissn
1543-8384issn
1543-8392journal_volume
15pub_type
杂志文章abstract：:Cyclic RGD (cRGD) peptide-conjugated boronated albumin was developed to direct toward integrin αvβ3, which overexpresses on many cancer cells. A stepwise conjugation of c[RGDfK(Mal)] and maleimide-conjugated closo-dodecaborate (MID) to bovine serum albumin (BSA) afforded cRGD-MID-BSA, which was noncytotoxic toward bot...
journal_title：Molecular pharmaceutics
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更新日期：2020-10-05 00:00:00
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更新日期：2013-01-07 00:00:00
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更新日期：2016-11-07 00:00:00
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更新日期：2019-01-07 00:00:00
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更新日期：2013-03-04 00:00:00
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更新日期：2014-03-03 00:00:00
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doi：10.1021/acs.molpharmaceut.0c00729
更新日期：2020-12-07 00:00:00
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更新日期：2014-02-03 00:00:00
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pub_type： 杂志文章
doi：10.1021/acs.molpharmaceut.6b00102
更新日期：2016-07-05 00:00:00
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更新日期：2019-01-07 00:00:00
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更新日期：2019-03-04 00:00:00
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journal_title：Molecular pharmaceutics
pub_type： 杂志文章
doi：10.1021/mp400189j
更新日期：2014-01-06 00:00:00
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journal_title：Molecular pharmaceutics
pub_type： 杂志文章
doi：10.1021/mp300146m
更新日期：2012-07-02 00:00:00
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journal_title：Molecular pharmaceutics
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doi：10.1021/acs.molpharmaceut.0c00231
更新日期：2020-08-03 00:00:00
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journal_title：Molecular pharmaceutics
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更新日期：2015-03-02 00:00:00
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journal_title：Molecular pharmaceutics
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更新日期：2019-07-01 00:00:00
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更新日期：2015-09-08 00:00:00
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journal_title：Molecular pharmaceutics
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更新日期：2019-06-03 00:00:00
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journal_title：Molecular pharmaceutics
pub_type： 杂志文章
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更新日期：2019-12-02 00:00:00
abstract：:Recently, increased interest in drug transporters and research in this area has revealed that drug transporters play an important role in modulating drug absorption, distribution, and elimination. Acting alone or in concert with drug metabolizing enzymes they can affect the pharmacokinetics and pharmacodynamics of a d...
journal_title：Molecular pharmaceutics
pub_type： 杂志文章,评审
doi：10.1021/mp050095h
更新日期：2006-01-01 00:00:00
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更新日期：2020-09-08 00:00:00
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journal_title：Molecular pharmaceutics
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更新日期：2020-03-02 00:00:00
abstract：:Liposomes are representative lipid nanoparticles widely used for delivering anticancer drugs, DNA fragments, or siRNA to cancer cells. Upon targeting, various internal and external triggers have been used to increase the rate for contents release from the liposomes. Among the internal triggers, decreased pH within the...
journal_title：Molecular pharmaceutics
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doi：10.1021/mp500186a
更新日期：2014-11-03 00:00:00
