(6-Maleimidocaproyl)hydrazone of doxorubicin. A new derivative for the preparation of immunoconjugates of doxorubicin

Willner, David; Pa, Trail; Sj, Hofstead; Hd, King; Sj, Lasch; Gr, Braslawsky; Greenfield, RS; Kaneko, Takushi; Ra, Firestone

doi:10.1021/bc00024a015

Cited by 212 publications

(176 citation statements)

References 24 publications

(37 reference statements)

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“…IgG1 molecules contain 12 intrachain and 4 interchain disulfide bonds. However, it has been shown that the latter are significantly more susceptible to reduction by agents such as DTT than are the intrachain bonds (27,28). In fact, Willner et al (27) reported that reduction of a chimeric antibody with up to 100 molar equivalents of DTT could only generate eight sulfhydryls per antibody corresponding to reduction of the four interchain disulfide bonds.…”

Section: Discussionmentioning

confidence: 99%

Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate

Hamblett

Senter²,

Chace³

et al. 2004

Clinical Cancer Research

1,043

1,032

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Purpose: An antibody-drug conjugate consisting of monomethyl auristatin E (MMAE) conjugated to the anti-CD30 monoclonal antibody (mAb) cAC10, with eight drug moieties per mAb, was previously shown to have potent cytotoxic activity against CD30 ؉ malignant cells. To determine the effect of drug loading on antibody-drug conjugate therapeutic potential, we assessed cAC10 antibody-drug conjugates containing different drug-mAb ratios in vitro and in vivo.Experimental Design: Coupling MMAE to the cysteines that comprise the interchain disulfides of cAC10 created an antibody-drug conjugate population, which was purified using hydrophobic interaction chromatography to yield antibody-drug conjugates with two, four, and eight drugs per antibody (E2, E4, and E8, respectively). Antibody-drug conjugate potency was tested in vitro against CD30؉ lines followed by in vivo xenograft models. The maximum-tolerated dose and pharmacokinetic profiles of the antibody-drug conjugates were investigated in mice.Results: Although antibody-drug conjugate potency in vitro was directly dependent on drug loading (IC 50 values E8

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Section: Discussionmentioning

confidence: 99%

Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate

Hamblett

Senter²,

Chace³

et al. 2004

Clinical Cancer Research

1,043

1,032

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“…The resulting mixture was sonicated few minutes until complete dissolution. [6-(maleimido)hexanamido]azanium trifluoroacetate (7) [23] (0.306 g, 0.868 mmol) and 4 Å molecular sieves (200 mg) were then added and the reaction mixture was stirred for 1 h at room temperature under nitrogen. The formation of the desired product (9) was monitored by TLC (petroleum ether/ethyl acetate 1/1 v/v, R f : 0.65).…”

Section: Synthesis and Characterization Of 6-(maleimidyl)-hexanoic Acmentioning

confidence: 99%

Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor

Valetti¹,

Maione

Mura

et al. 2014

Journal of Controlled Release

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Chemotherapy for pancreatic cancer is hampered by the tumor physio-pathological complexity. Here we show a targeted nanomedicine using a new ligand, the CKAAKN peptide, which had been identified by phage display, as an efficient homing device within the pancreatic pathological microenvironment. Taking advantage of the squalenoylation platform, the CKAAKN peptide was conjugated to squalene (SQCKAAKN) and then co-nanoprecitated with the squalenoyl prodrug of gemcitabine (SQdFdC) giving near monodisperse nanoparticles (NPs) for safe intravenous injection. By interacting with a novel target pathway, the Wnt-2, the CKAAKN functionalization enabled nanoparticles: (i) to specifically interact with both tumor cells and angiogenic vessels and (ii) to simultaneously promote pericyte coverage, thus leading to the normalization of the vasculature likely improving the tumor accessibility for the therapy. All together, this approach represents a unique targeted nanoparticle design with remarkable selectivity towards pancreatic cancer and multiple mechanism of action. Graphical abstract

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“…Doxorubicin conjugated to mAb cBR96, by using a thiol linker to the mAb and acid-labile hydrazone linker to the drug, was produced as previously described, 11 to yield a molar ratio of 8 drugs per mAb. [Methyl 3 H]-thymidine was purchased from Amersham (Piscataway, NJ).…”

Section: Reagentsmentioning

confidence: 99%

“…Following binding to the Le y tumor antigen, cBR96-Dox is internalized via endocytosis, the hydrazone linkage of mAb to drug is cleaved within the acidic environment of the endocytic vesicle and free doxorubicin is released into the cytosol. 8,11 To examine the contribution of internalization to sensitivity, the rates of cBR96-Dox uptake, surface levels of Le y antigen and IC 50 for the conjugate were compared on four different Le y -positive tumor lines ( Fig. 1).…”

Section: Antigen Internalization Provides Sensitivity To Cbr96-doxmentioning

confidence: 99%

“…7 BR96 mAb was genetically engineered in chimeric form (cBR96) to reduce immunogenicity. 10 A chemical conjugate of cBR96 and the anti-cancer drug doxorubicin (cBR96-Dox) was prepared utilizing hydrazone linker chemistry 11 and was found to be highly active in regressing large human tumor xenografts implanted in mice or rats. 12,13 Multiple tumor models including lung, breast and colon were evaluated, and cBR96-Dox was found to have broad and potent anti-tumor activity, even in doxorubicinresistant tumors.…”

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confidence: 99%

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Selective tumor sensitization to taxanes with the mAb-drug conjugate cBR96-doxorubicin

et al. 2001

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The chimeric monoclonal antibody cBR96 conjugated to doxorubicin (cBR96-Dox) is selectively internalized by a wide variety of human carcinomas expressing an extended form of Lewis Y antigen (Le y ). Endocytosis is followed by cleavage and release of free doxorubicin from the endocytic vesicles and subsequent cytotoxicity. Combination studies with standard anti-cancer agents, undertaken to further increase the potency of this targeted therapy, identified significant synergistic anti-tumor activity of cBR96-Dox and either of the taxanes paclitaxel or docetaxel. Treatment with cBR96-Dox 24 hr prior to paclitaxel resulted in a steady increase in the percentage of G 2 tumor cells and corresponding increase in sensitivity to taxanes. Cell cycle analysis indicated the cBR96-delivered doxorubicin was most effective against S-phase cells, yet cells exposed to even subtoxic levels progressed to and arrested in G 2 , at a point of high sensitivity to the antitubulin agent paclitaxel. The synergy obtained by staged combination of cBR96-Dox and paclitaxel in vitro was reflected in significant anti-tumor efficacy in vivo against xenograft models of human lung and breast tumors that could not be achieved by either agent alone. The staged combination elicited significant or complete regressions of established human Le y -positive tumor xenografts using significantly reduced drug levels. Taken together, these data demonstrate a mechanistic approach to the selective elimination of Le ypositive tumors by using targeted doxorubicin followed by taxane treatment. © 2001 Wiley-Liss, Inc. Key words: doxorubicin; paclitaxel; immunoconjugate; antitumortargeting; antibody-mediatedMonoclonal antibodies (mAbs) directing drugs or toxins to tumor-specific antigens have held the promise of selective tumor cell elimination with reduced collateral damage to normal tissue. 1,2 In addition to mAb accessory functions that mobilize natural killer and complement-mediated cytotoxicity (antibody-dependent cellmediated cytotoxicity [ADCC] and complement-dependent cytotoxicity [CDC]) responses against the tumor, internalizing mAbs can direct delivery of cytotoxics to the tumor. Despite these qualities, and despite demonstrated efficacy in hematologic disease, 3 mAb-directed therapy as a single agent has not shown great success in eliminating established solid carcinomas in the clinic. The reasons for this shortcoming include the fact that most tumor antigens are preferentially expressed by, but not restricted to, tumor cells; thus, dose-limiting toxicity is still seen in normal tissues expressing significant levels of the antigen. Second, most solid tumors not amenable to surgical removal represent significant and well-established masses. The effectiveness of mAb-based therapeutics relative to small molecules in this setting may be reduced by poor tumor vascularization and increased internal pressure of the tumor compared with surrounding tissue, which reduces the ability of large molecules such as mAbs to penetrate a large tumor mass. 4 -6 Interestingl...

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(6-Maleimidocaproyl)hydrazone of doxorubicin. A new derivative for the preparation of immunoconjugates of doxorubicin

Cited by 212 publications

References 24 publications

Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate

Effects of Drug Loading on the Antitumor Activity of a Monoclonal Antibody Drug Conjugate

Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor

Selective tumor sensitization to taxanes with the mAb-drug conjugate cBR96-doxorubicin

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