Treatment parameters modulating regression of human melanoma xenografts by an antibody–drug conjugate (CR011-vcMMAE) targeting GPNMB

Pollack, Vincent A.; Alvarez, Enríque; Tse, Kam Fai; Torgov, Michael; Xie, Quan; Shenoy, Suresh; MacDougall, John R.; Arrol, Sharon; Zhong, Haihong; Gerwien, Robert; Hahne, William F.; Senter, Peter D.; Jeffers, Michael; Lichenstein, Henri S.; LaRochelle, William J.

doi:10.1007/s00280-007-0490-z

Cited by 74 publications

(51 citation statements)

References 41 publications

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“…To determine if GPNMB represents a feasible target for breast cancer therapy, we tested the effects of CDX-011, an antibody-drug conjugate that specifically targets GPNMB, on tumor cell growth and survival. This antibody conjugate can kill GPNMB-expressing melanoma cells (9,14). Breast cancer cells expressing low (MDA-MB-453-VC, BT549-VC), moderate (MDA-MB-361, MDA-MB-468), or high (MDA-MB-453-GPNMB, BT549 GPNMB) levels of cell surface GPNMB were incubated with increasing concentrations of CDX-011 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Given its role as a mediator of metastasis and its cell surface expression, GPNMB is an attractive candidate for cancer therapy. In this regard, a GPNMB-specific antibody conjugated to a cytotoxic drug, monomethylauristatin E, induces complete regression of GPNMB-expressing tumors derived from melanoma cell lines (14). This agent (formerly CR011-vcMMAE, CuraGen) has recently been assigned the generic name of glembatumumab vedotin, also known as CDX-011, by Celldex Therapeutics.…”

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confidence: 99%

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Glycoprotein Nonmetastatic B Is an Independent Prognostic Indicator of Recurrence and a Novel Therapeutic Target in Breast Cancer

Rose

Grosset

Dong

et al. 2010

Clinical Cancer Research

168

156

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Purpose: Although the murine orthologue of glycoprotein nonmetastatic B (GPNMB), Osteoactivin, promotes breast cancer metastasis in an in vivo mouse model, its importance in human breast cancer is unknown. We have examined the significance of GPNMB expression as a prognostic indicator of recurrence and assessed its potential as a novel therapeutic target in breast cancer.Experimental Design: The clinical significance of GPNMB expression in breast cancer was addressed by analyzing GPNMB levels in several published gene expression data sets and two independent tissue microarrays derived from human breast tumors. GPNMB-expressing human breast cancer cell lines were further used to validate a toxin-conjugated anti-GPNMB antibody as a novel therapeutic agent.Results: GPNMB expression correlates with shorter recurrence times and reduced overall survival of breast cancer patients. Epithelial-specific GPNMB staining is an independent prognostic indicator for breast cancer recurrence. GPNMB is highly expressed in basal and triple-negative breast cancers and is associated with increased risk of recurrence within this subtype. GPNMB expression confers a more migratory and invasive phenotype on breast cancer cells and sensitizes them to killing by CDX-011 (glembatumumab vedotin), a GPNMB-targeted antibody-drug conjugate.Conclusions: GPNMB expression is associated with the basal/triple-negative subtype and is a prognostic marker of poor outcome in patients with breast cancer. CDX-011 (glembatumumab vedotin) is a promising new targeted therapy for patients with metastatic triple-negative breast cancers, a patient population that currently lacks targeted-therapy options.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Glycoprotein Nonmetastatic B Is an Independent Prognostic Indicator of Recurrence and a Novel Therapeutic Target in Breast Cancer

Rose

Grosset

Dong

et al. 2010

Clinical Cancer Research

168

156

View full text Add to dashboard Cite

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“…Lorvotuzumab mertansine is a conjugate of the humanized monoclonal antibody huN901 and the maytansine derivative DM1 (65,66). It is currently in phase I/II (67,68). CR011-vc-auristatin antitumor activity was dose-dependent but not strongly schedule-dependent.…”

Section: Targetsmentioning

confidence: 99%

Antibody Conjugate Therapeutics: Challenges and Potential

Teicher

Chari²

2011

Clinical Cancer Research

373

281

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Antibody conjugates are a diverse class of therapeutics consisting of a cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody conjugates is marked by hurdles that have been identified and overcome. Early conjugates used mouse antibodies; cytotoxic agents that were immunogenic (proteins), too toxic, or not sufficiently potent; and linkers that were not sufficiently stable in circulation. Investigators have explored 4 main avenues using antibodies to target cytotoxic agents to malignant cells: antibody-protein toxin (or antibody fragment-protein toxin fusion) conjugates, antibody-chelated radionuclide conjugates, antibody-small-molecule drug conjugates, and antibody-enzyme conjugates administered along with small-molecule prodrugs that require metabolism by the conjugated enzyme to release the activated species. Only antibody-radionuclide conjugates and antibody-drug conjugates have reached the regulatory approval stage, and nearly 20 antibody conjugates are currently in clinical trials. The time may have come for this technology to become a major contributor to improving treatment for cancer patients.

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“…7,[26][27][28][29][30]35,40 Discussion A small spectrum of molecular platforms has been applied to facilitate selective ''targeted'' delivery of a variety of biological agents and conventional chemotherapeutics that can exert significant cytotoxic anti-neoplastic properties. Biological agents utilized in this regard include various immunotoxin preparations synthesized to enhance selective ''targeted'' delivery of Pseudomonas exotoxin, 64 84 and monomethyl auristatin E. [86][87][88][89] Several different chemical characteristics of the anthracycline class of chemotherapeutics can be utilized to develop multiple molecular designs and synthesis strategies allowing their covalent incorporation into immunoglobulin fractions or receptor ligands applying a variety of organic chemistry reactions. One method entails the reaction of both the carbohydrate C 3 monoamine group of anthracyclines and the e-amine of lysine residues within the amino acid sequence of immunoglobulin with the aldehyde groups found in sodium periodate oxidized dextran.…”

Section: Cytotoxic Anti-neoplastic Potencymentioning

confidence: 99%

Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

Coyne

Jones²,

Bear³

2012

Cancer Biotherapy and Radiopharmaceuticals

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The C 3 -monoamine on the carbohydrate moiety (daunosamine -NH 2 -3¢) of epirubicin was reacted under anhydrous conditions with succinimidyl 4,4-azipentanoate to create a covalent UV-photoactivated epirubicin-(C 3 -amide) intermediate with primary amine-reactive properties. A synthetic covalent bond between the UV-photoactivated epirubicin-(C 3 -amide) intermediate and the e-amine of lysine residues within the amino acid sequence of anti-HER2/neu monoclonal immunoglobulin was subsequently created by exposure to UV light (354 nm) for 15 minutes. Size-separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis combined with immunodetection analysis and chemiluminescent autoradiographic imaging revealed a lack of IgG-IgG polymerization or degradative protein fragmentation of the covalent epirubicin-(C 3 -amide)-[anti-HER2/neu] immunochemotherapeutic. Retained binding-avidity of epirubicin-(C 3 -amide)-[anti-HER2/neu] was validated by cell-ELISA utilizing monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma SKBr-3 which highly overexpress membrane-associated HER2/neu complexes. Between epirubicin-equivalent concentrations of 10 -10 to 10 -6 M the covalent epirubicin-(C 3 -amide)-[anti-HER2/neu] immunochemotherapeutic consistently evoked levels of cytotoxic anti-neoplastic potency that were highly analogous to chemotherapeuticequivalent concentrations of epirubicin. Cytotoxic anti-neoplastic potency of epirubicin-(C 3 -amide)-[anti-HER2/ neu] against chemotherapeutic-resistant mammary adenocarcinoma SKBr-3 challenged with epirubicin-(C 3 -amide)-[anti-HER2/neu] at an epirubicin-equivalent concentration of 10 -6 M was 88.5% (e.g., 11.5% residual survival). Between final epirubicin-equivalent concentrations of 10 -8 and 10 -7 M there was a marked threshold increase in the mean cytotoxic anti-neoplastic activity for epirubicin-(C 3 -amide)-[anti-HER2/neu] from 9.9% to 66.9% (90.2% to 33.1% residual survival).

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Treatment parameters modulating regression of human melanoma xenografts by an antibody–drug conjugate (CR011-vcMMAE) targeting GPNMB

Abstract: Short-term anti-tumor effects and long-term effects (complete regression) were observed with CR011-vcMMAE, but not with the reference agents. These results suggest that CR011-vcMMAE may provide therapeutic benefit in malignant melanoma.

Cited by 74 publications

References 41 publications

Glycoprotein Nonmetastatic B Is an Independent Prognostic Indicator of Recurrence and a Novel Therapeutic Target in Breast Cancer

Glycoprotein Nonmetastatic B Is an Independent Prognostic Indicator of Recurrence and a Novel Therapeutic Target in Breast Cancer

Antibody Conjugate Therapeutics: Challenges and Potential

Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

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Treatment parameters modulating regression of human melanoma xenografts by an antibody–drug conjugate (CR011-vcMMAE) targeting GPNMB

Abstract: Short-term anti-tumor effects and long-term effects (complete regression) were observed with CR011-vcMMAE, but not with the reference agents. These results suggest that CR011-vcMMAE may provide therapeutic benefit in malignant melanoma.

Cited by 74 publications

References 41 publications

Glycoprotein Nonmetastatic B Is an Independent Prognostic Indicator of Recurrence and a Novel Therapeutic Target in Breast Cancer

Glycoprotein Nonmetastatic B Is an Independent Prognostic Indicator of Recurrence and a Novel Therapeutic Target in Breast Cancer

Antibody Conjugate Therapeutics: Challenges and Potential

Synthesis of a Covalent Epirubicin-(C3-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

Contact Info

Product

Resources

About

Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate