SAR3419: An Anti-CD19-Maytansinoid Immunoconjugate for the Treatment of B-Cell Malignancies

Blanc, Véronique; Bousseau, A.; Caron, Anne; Carrez, Chantal; Lutz, Robert J.; Lambert, John M.

doi:10.1158/1078-0432.ccr-11-0485

Cited by 151 publications

(127 citation statements)

References 55 publications

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“…The tumor uptake and activation of SAR3419 and IMGN901 in mice were found to be similar to that described for T-DM1 conjugates (49,50). The major catabolites of IMGN901 were lysine-SPP-DM1 and DM1 (50).…”

Section: Tumor Localizaton and Activation Of Sar3419 And Imgn901supporting

confidence: 70%

ADME of Antibody–Maytansinoid Conjugates

Erickson

Lambert

2012

AAPS J

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114

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Abstract. The concept of treating cancer with antibody-drug conjugates (ADCs) has gained momentum with the favorable activity and safety of trastuzumab emtansine (T-DM1), SAR3419, and lorvotuzumab mertansine (IMGN901). All three ADCs utilize maytansinoid cell-killing agents which target tubulin and suppress microtubule dynamics. Each ADC utilizes a different optimized chemical linker to attach the maytansinoid to the antibody. Characterizing the absorption, distribution, metabolism, and excretion (ADME) of these ADCs in preclinical animal models is important to understanding their efficacy and safety profiles. The ADME properties of these ADCs in rodents were inferred from studies with radiolabeled ADCs prepared with nonbinding antibodies since T-DM1, SAR3419, IMGN901 all lack crossreactivity with rodent antigens. For studies exploring tumor localization and activation in tumor-bearing mice, tritium-labeled T-DM1, SAR3419, and IMGN901 were utilized. The chemical nature of the linker was found to have a significant impact on the ADME properties of these ADCs-particularly on the plasma pharmacokinetics and observed catabolites in tumor and liver tissues. Despite these differences, T-DM1, SAR3419, and IMGN901 were all found to facilitate efficient deliveries of active maytansinoid catabolites to the tumor tissue in mouse xenograft models. In addition, all three ADCs were effectively detoxified during hepatobiliary elimination in rodents.

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Section: Tumor Localizaton and Activation Of Sar3419 And Imgn901supporting

confidence: 70%

ADME of Antibody–Maytansinoid Conjugates

Erickson

Lambert

2012

AAPS J

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114

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“…Antibodies conjugated to various toxophores have shown potent antitumor activity in preclinical animal models (23). Recently, encouraging clinical efficacy has been observed with SAR3419 targeting CD19 (24). Furthermore, approvals of brentuximab vedotin targeting CD30 (25,26) and trastuzumab-DM1 in HER2-positive breast cancer (27)(28)(29) support the development of ADCs for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

Golfier

Kopitz

Kahnert

et al. 2014

Molecular Cancer Therapeutics

199

166

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Mesothelin is a tumor differentiation antigen frequently overexpressed in tumors such as mesothelioma, ovarian, pancreatic, and lung adenocarcinomas while showing limited expression in nonmalignant tissues. Mesothelin is therefore an attractive target for cancer therapy using antibody-drug conjugates (ADC). This study describes the detailed characterization of anetumab ravtansine, here referred to as BAY 94-9343, a novel ADC consisting of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker. Binding properties of the anti-mesothelin antibody were analyzed using surface plasmon resonance, immunohistochemistry, flow cytometry, and fluorescence microscopy. Effects of BAY 94-9343 on cell proliferation were first studied in vitro and subsequently in vivo using subcutaneous, orthotopic, and patient-derived xenograft tumor models. The antibody binds to human mesothelin with high affinity and selectivity, thereby inducing efficient antigen internalization. In vitro, BAY 94-9343 demonstrated potent and selective cytotoxicity of mesothelin-expressing cells with an IC 50 of 0.72 nmol/L, without affecting mesothelin-negative or nonproliferating cells. In vivo, BAY 94-9343 localized specifically to mesothelin-positive tumors and inhibited tumor growth in both subcutaneous and orthotopic xenograft models. In addition, BAY 94-9343 was able to induce a bystander effect on neighboring mesothelin-negative tumor cells. Antitumor efficacy of BAY 94-9343 correlated with the amount of mesothelin expressed and was generally superior to that of standard-of-care regimen resulting in complete tumor eradication in most of the models. BAY 94-9343 is a selective and highly potent ADC, and our data support its development for the treatment of patients with mesothelin-expressing tumors. Mol Cancer Ther; 13(6); 1537-48. Ó2014 AACR.

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“…[16][17][18]. Attachment of potent maytansinoids to an antibody via an optimized hindered disulfide bond provides a stable linkage in the bloodstream while keeping the potential to release active drug inside target cells (9,19). Thus, ADCs can be considered tumoractivated prodrugs (TAP; refs.…”

Section: Introductionmentioning

confidence: 99%

A Dose-Escalation Study of SAR3419, an Anti-CD19 Antibody Maytansinoid Conjugate, Administered by Intravenous Infusion Once Weekly in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma

Ribrag

Dupuis

Tilly

et al. 2014

Clinical Cancer Research

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Purpose: To determine recommended dose, dose-limiting toxicity, safety profile, pharmacokinetics, preliminary antitumor activity, and exploratory pharmacodynamics of SAR3419, an antibody-drug conjugate targeting CD19, administered alone by intravenous infusion weekly (qw), in a dose-escalation phase I study in patients with refractory/relapsed (R/R) non-Hodgkin lymphoma (NHL).Experimental Design: Patients with R/R CD19 þ B-NHL were treated with escalating doses of SAR3419 repeated qw for eight to 12 doses. On the basis of clinical evidence of late or cumulative toxicities, the study protocol was amended to test an "optimized" administration schedule consisting of four qw doses followed by four biweekly (q2w) doses (qw/q2w) at the recommended dose with the intent of reducing drug accumulation.Results: Forty-four patients were treated on seven dose levels ranging from 5 to 70 mg/m 2 . SAR3419 recommended dose was determined as 55 mg/m 2 qw. Twenty-five patients received the qw/q2w schedule at 55 mg/m 2 , which showed an improved safety profile compared with the qw schedule. Antilymphoma activity was observed with both schedules in around 30% of patients with either indolent or aggressive diseases. SAR3419 displayed a long terminal half-life (approximately 7 days) and a low clearance (approximately 0.6 L/d), with no dose effect. The qw/q2w schedule allowed limiting accumulation with a decrease in SAR3419 plasma trough and average concentrations by around 1.4-fold compared with the qw schedule.Conclusion: While administered weekly, SAR3419 is well tolerated and active. The qw/q2w schedule that shows an improved safety profile and preserves antilymphoma activity is selected for clinical phase II studies.

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SAR3419: An Anti-CD19-Maytansinoid Immunoconjugate for the Treatment of B-Cell Malignancies

Cited by 151 publications

References 55 publications

ADME of Antibody–Maytansinoid Conjugates

ADME of Antibody–Maytansinoid Conjugates

Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody–Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect

A Dose-Escalation Study of SAR3419, an Anti-CD19 Antibody Maytansinoid Conjugate, Administered by Intravenous Infusion Once Weekly in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma

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