Intracellular Activation of SGN-35, a Potent Anti-CD30 Antibody-Drug Conjugate

Okeley, Nicole M.; Miyamoto, Jamie B.; Zhang, Xinqun; Sanderson, Russell J.; Benjamin, Dennis R.; Sievers, Eric L.; Senter, Peter D.; Alley, Stephen C.

doi:10.1158/1078-0432.ccr-09-2069

Cited by 345 publications

(250 citation statements)

References 37 publications

Supporting

Mentioning

237

Contrasting

Unclassified

Order By: Relevance

“…Maytansinoid and auristatin ADCs with cleavable linkers generate intracellular catabolites that can diffuse out of the targeted cells into proximal antigen-negative cells, to induce killing of these "bystander" cells (27,28). To understand the possible cause of the improved antitumor activity of the IGN ADC with a disulfide linker relative to that observed with the noncleavable linker, we compared the in vitro bystander killing activities of the two ADCs.…”

Section: Bystander Cell Killingmentioning

confidence: 99%

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

Miller

Fishkin

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The promise of tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADC) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, for cancer therapy. An ongoing challenge remains in identifying potent agents with alternative mechanisms of cell killing that can provide ADCs with high therapeutic indices and favorable tolerability. Here, we describe the development of a new class of potent DNA alkylating agents that meets these objectives. Through chemical design, we changed the mechanism of action of our novel DNA cross-linking agent to a monofunctional DNA alkylator. This modification, coupled with linker optimization, generated ADCs that were well tolerated in mice and demonstrated robust antitumor activity in multiple tumor models at doses 1.5% to 3.5% of maximally tolerated levels. These properties underscore the considerable potential of these purpose-created, unique DNAinteracting conjugates for broadening the clinical application of ADC technology. Mol Cancer Ther; 15(8); 1870-8. Ó2016 AACR.

show abstract

Section: Bystander Cell Killingmentioning

confidence: 99%

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

Miller

Fishkin

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…The intermediate activity of the mc-vc-PAB-MMAF conjugate (110% inhibition) probably reflects more efficient diffusion of free MMAF (than cys-mc-MMAF) following val-cit cleavage and PAB self-immolation, but lack of a bystander effect (the ability to intoxicate neighboring cells; ref. 38) compared with free MMAE; MMAF has poor membrane permeability unless protonated in lowpH environments such as lysosomes (24). Humanized 7D9 (h7D9.v3) was, therefore, conjugated to mc-vc-PAB-MMAE, henceforth called aMSLN-MMAE, and characterized in detail.…”

Section: Antibody Linker and Drug Selectionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

“…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

View full text Add to dashboard Cite

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).

show abstract

Intracellular Activation of SGN-35, a Potent Anti-CD30 Antibody-Drug Conjugate

Cited by 345 publications

References 37 publications

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

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

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

Contact Info

Product

Resources

About

Intracellular Activation of SGN-35, a Potent Anti-CD30 Antibody-Drug Conjugate

Cited by 345 publications

References 37 publications

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

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

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