Armed Antibodies Targeting the Mucin Repeats of the Ovarian Cancer Antigen, MUC16, Are Highly Efficacious in Animal Tumor Models

Chen, Youjun; Clark, Suzanna; Wong, Terence; Chen, Yongmei; Chen, Yvonne; Dennis, Mark S.; Luis, Elizabeth; Zhong, Fiona; Bheddah, Sheila; Koeppen, Hartmut; Gogineni, Alvin; Ross, Sarajane; Polakis, Paul; Mallet, William

doi:10.1158/0008-5472.can-06-4512

Cited by 81 publications

(72 citation statements)

References 23 publications

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“…Nonetheless, in all lines, aMSLN accumulation in lysosomes was far slower than most other ADC targets (25,36,42), likely explaining the higher activity with cleavable vcMMAE than mc-or vc-MMAF, and also the lower (by an order of magnitude) in vitro potency on OVCAR3 cells (20 nmol/L) compared with other vcMMAE conjugates to similarly expressed endogenous targets in other adherent cell lines. Our efficacy data in OVCAR3 cells and xenografts are similar to those of aMuc16-auristatin conjugates, which also internalize slowly (27,43). Unexpectedly, endogenous (but not exogenous) mesothelin was upregulated up to 10-fold in vivo by an unknown mechanism in all the lines tested (including others not shown).…”

Section: Discussionsupporting

confidence: 69%

“…Scatchard analysis was as described (27) except 125 Ih7D9.v3 was incubated for 2 hours at room temperature.…”

Section: Scatchard Analysismentioning

confidence: 99%

“…In vitro efficacy was assayed with CellTiterGlo II (Promega) as described (27), except with 2,000 gD-MSLN-HT1080 cells per well.…”

Section: In Vitro Efficacymentioning

confidence: 99%

“…Cells or tumor fragments were implanted subcutaneously into female mice as summarized in Supplementary Table S2, except OVCAR3 were in the mammary fat pad (27). Mice were randomized into groups of 8 to 11 with tumors averaging approximately 150 mm 3 .…”

Section: In Vivo Efficacymentioning

confidence: 99%

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An Antimesothelin-Monomethyl Auristatin E Conjugate with Potent Antitumor Activity in Ovarian, Pancreatic, and Mesothelioma Models

Scales¹,

Gupta²,

Pacheco³

et al. 2014

Molecular Cancer Therapeutics

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Mesothelin (MSLN) is an attractive target for antibody-drug conjugate therapy because it is highly expressed in various epithelial cancers, with normal expression limited to nondividing mesothelia. We generated novel antimesothelin antibodies and conjugated an internalizing one (7D9) to the microtubuledisrupting drugs monomethyl auristatin E (MMAE) and MMAF, finding the most effective to be MMAE with a lysosomal protease-cleavable valine-citrulline linker. The humanized (h7D9.v3) version, aMSLN-MMAE, specifically targeted mesothelin-expressing cells and inhibited their proliferation with an IC 50 of 0.3 nmol/L. Because the antitumor activity of an antimesothelin immunotoxin (SS1P) in transfected mesothelin models did not translate to the clinic, we carefully selected in vivo efficacy models endogenously expressing clinically relevant levels of mesothelin, after scoring mesothelin levels in ovarian, pancreatic, and mesothelioma tumors by immunohistochemistry. We found that endogenous mesothelin in cancer cells is upregulated in vivo and identified two suitable xenograft models for each of these three indications. A single dose of aMSLN-MMAE profoundly inhibited or regressed tumor growth in a dosedependent manner in all six models, including two patient-derived tumor xenografts. The robust and durable efficacy of aMSLN-MMAE in preclinical models of ovarian, mesothelioma, and pancreatic cancers justifies the ongoing phase I clinical trial. Mol Cancer Ther; 13(11); 2630-40. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 69%

“…Scatchard analysis was as described (27) except 125 Ih7D9.v3 was incubated for 2 hours at room temperature.…”

Section: Scatchard Analysismentioning

confidence: 99%

“…In vitro efficacy was assayed with CellTiterGlo II (Promega) as described (27), except with 2,000 gD-MSLN-HT1080 cells per well.…”

Section: In Vitro Efficacymentioning

confidence: 99%

Section: In Vivo Efficacymentioning

confidence: 99%

See 2 more Smart Citations

An Antimesothelin-Monomethyl Auristatin E Conjugate with Potent Antitumor Activity in Ovarian, Pancreatic, and Mesothelioma Models

Scales¹,

Gupta²,

Pacheco³

et al. 2014

Molecular Cancer Therapeutics

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“…3A5 was previously found to bind more sites per cell than an antibody that binds to a single epitope (Chen et al, 2007). This property is hypothesized to enhance the therapeutic effectiveness of 3A5 and explains why 3A5 is currently a component of an antibody-drug conjugate strategy (Trail et al, 2003;Polakis, 2005;Wu and Senter, 2005;Chen et al, 2007;Junutula et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Effect of Immune Complex Formation on the Distribution of a Novel Antibody to the Ovarian Tumor Antigen CA125

Pastuskovas¹,

Mallet²,

Clark³

et al. 2010

Drug Metab Dispos

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ABSTRACT:3A5 is a novel antibody that binds repeated epitopes within CA125, an ovarian tumor antigen that is shed into the circulation. Binding to shed antigen may limit the effectiveness of therapeutic antibodies because of unproductive immune complex (IC) formation and/or altered antibody distribution. To evaluate this possibility, we characterized the impact of shed CA125 on the in vivo distribution of 3A5. In vitro, 3A5 and CA125 were found to form ICs in a concentration-dependent manner. This phenomenon was then evaluated in vivo using quantitative whole-body autoradiography to assess the tissue distribution of 125 I-3A5 in an orthotopic OVCAR-3 tumor mouse model at different stages of tumor burden. Low doses of 3A5 (75 g/kg) and pathophysiological levels of shed CA125 led to the formation of ICs in vivo that were rapidly distributed to the liver. Under these conditions, increased clearance of 3A5 from normal tissues was observed in mice bearing CA125-expressing tumors. Of importance, despite IC formation, 3A5 uptake by tumors was sustained over time. At a therapeutically relevant dose of 3A5 (3.5 mg/kg), IC formation was undetectable and distribution to normal tissues followed that of blood. In contrast, increased levels of radioactivity were observed in the tumors. These data demonstrate that CA125 and 3A5 do form ICs in vivo and that the liver is involved in their uptake. However, at therapeutic doses of 3A5 and clinically relevant CA125 levels, IC formation consumes only a minor fraction of 3A5, and tumor targeting seems to be unaffected.

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Antibody‐Drug Conjugate Therapy

Alley

Benjamin

Law

2009

Therapeutic Monoclonal Antibodies

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Armed Antibodies Targeting the Mucin Repeats of the Ovarian Cancer Antigen, MUC16, Are Highly Efficacious in Animal Tumor Models

Cited by 81 publications

References 23 publications

An Antimesothelin-Monomethyl Auristatin E Conjugate with Potent Antitumor Activity in Ovarian, Pancreatic, and Mesothelioma Models

An Antimesothelin-Monomethyl Auristatin E Conjugate with Potent Antitumor Activity in Ovarian, Pancreatic, and Mesothelioma Models

Effect of Immune Complex Formation on the Distribution of a Novel Antibody to the Ovarian Tumor Antigen CA125

Antibody‐Drug Conjugate Therapy

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