Synthesis and antitumor activity of the immunoconjugate BR96-Dox

Firestone, Raymond A.; Willner, David; Hofstead, Sandra J.; King, H. Dalton; Kaneko, Takushi; Braslawsky, Gary R.; Greenfield, Robert S.; Trail, Pamela A.; Lasch, Shirley J.; Henderson, Arris J.; Casazza, Anna Maria; Hellström, Ingegerd; Hellström, Karl Erik

doi:10.1016/0168-3659(95)00160-3

Cited by 32 publications

(21 citation statements)

References 7 publications

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“…On the basis of the IC 50 values, E4 was 3-fold less potent than E8, and the E2 was 2-fold less potent than E4 for both CD30 ϩ cell lines tested. Similar to doxorubicin-antibodydrug conjugates (20,26), the in vitro potency of the cAC10 -antibody-drug conjugates was directly dependent on drug loading and thus the total MMAE exposure.…”

Section: Discussionmentioning

confidence: 89%

“…For example, doxorubicin-antibody-drug conjugates displayed a correlation between drug loading and cell cytotoxicity in vitro (20,26). The use of branched linkers increased molar ratios as high as 16 doxorubicin molecules per mAb, which additionally improved the in vitro potency without affecting antigen binding (20).…”

Section: Discussionmentioning

confidence: 99%

“…Historically, augmenting the potency of an antibody-drug conjugate involved increasing the number of drugs on an antibody (20) or conjugating more potent drugs (12). Although previous reports describe how drug loading influences in vitro characteristics (16,20,26), the effects of drug multiplicity on in vivo parameters of antibody-drug conjugates has not been described. In the present work, we have evaluated the effect of drug loading on the in vitro and in vivo properties of cAC10 antibody-drug conjugates.…”

Section: Introductionmentioning

confidence: 99%

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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: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

View full text Add to dashboard Cite

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“…32,33 The ketone group on the C13 position of these drugs reacts with pendant hydrazide groups on the polymer backbone. A similar reaction was utilized in this paper to incorporate daunomycin into hydrogels for localized drug delivery.…”

Section: Daunomycin Incorporationmentioning

confidence: 99%

Sustained and controlled release of daunomycin from cross‐linked poly(aldehyde guluronate) hydrogels

et al. 2000

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“…It is, however an essential component of tumor cell sensitivity, as IC 50 s for antigen-negative cells treated with cBR96-Dox, or antigenpositive cells treated with irrelevant IgG-Dox, are approximately an order of magnitude less than that of antigen-positive cells (Table I). 20 …”

Section: Antigen Internalization Provides Sensitivity To Cbr96-doxmentioning

confidence: 99%

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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Synthesis and antitumor activity of the immunoconjugate BR96-Dox

Cited by 32 publications

References 7 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

Sustained and controlled release of daunomycin from cross‐linked poly(aldehyde guluronate) hydrogels

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

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