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  1. Article ; Online: Development of a Novel DNA Mono-alkylator Platform for Antibody-Drug Conjugates.

    Thomas, Joshua D / Yurkovetskiy, Aleksandr V / Yin, Mao / Bodyak, Natalya D / Tang, Shuyi / Protopopova, Marina / Kelleher, Eugene / Jones, Brian / Yang, Liping / Custar, Daniel / Catcott, Kalli C / Demady, Damon R / Collins, Scott D / Xu, Ling / Bu, Charlie / Qin, LiuLiang / Ter-Ovanesyan, Elena / Damelin, Marc / Toader, Dorin /
    Lowinger, Timothy B

    Molecular cancer therapeutics

    2024  Volume 23, Issue 4, Page(s) 541–551

    Abstract: Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC ... ...

    Abstract Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.
    MeSH term(s) Humans ; Rats ; Animals ; Immunoconjugates/pharmacology ; Immunoconjugates/therapeutic use ; Alkylating Agents ; Neoplasms/drug therapy ; DNA/metabolism ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology
    Chemical Substances Immunoconjugates ; Alkylating Agents ; DNA (9007-49-2) ; Antineoplastic Agents
    Language English
    Publishing date 2024-02-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-23-0622
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Evolving Strategies for Target Selection for Antibody-Drug Conjugates.

    Damelin, Marc / Zhong, Wenyan / Myers, Jeremy / Sapra, Puja

    Pharmaceutical research

    2015  Volume 32, Issue 11, Page(s) 3494–3507

    Abstract: Antibody-drug conjugates (ADCs) represent a promising modality for the treatment of cancer. The therapeutic strategy is to deliver a potent drug preferentially to the tumor and not normal tissues by attaching the drug to an antibody that recognizes a ... ...

    Abstract Antibody-drug conjugates (ADCs) represent a promising modality for the treatment of cancer. The therapeutic strategy is to deliver a potent drug preferentially to the tumor and not normal tissues by attaching the drug to an antibody that recognizes a tumor antigen. The selection of antigen targets is critical to enabling a therapeutic window for the ADC and has proven to be surprisingly complex. We surveyed the tumor and normal tissue expression profiles of the targets of ADCs currently in clinical development. Our analysis demonstrates a surprisingly broad range of expression profiles and the inability to formalize any optimal parameters for an ADC target. In this context, we discuss additional considerations for ADC target selection, including interdependencies among biophysical properties of the drug, biological functions of the target and strategies for clinical development. The TPBG (5T4) oncofetal antigen and the anti-TPBG ADC A1-mcMMAF are highlighted to demonstrate the relevance of the target's biological function. Emerging platform technologies and novel biological insights are expanding ADC target space and transforming strategies for target selection.
    MeSH term(s) Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Databases, Genetic ; Drug Design ; Humans ; Immunoconjugates/chemistry ; Immunoconjugates/pharmacology ; Membrane Proteins/genetics ; Molecular Targeted Therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Proteome/genetics ; Transcriptome
    Chemical Substances Antibodies, Monoclonal ; Antineoplastic Agents ; Immunoconjugates ; Membrane Proteins ; Proteome
    Language English
    Publishing date 2015-01-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 843063-9
    ISSN 1573-904X ; 0724-8741 ; 0739-0742
    ISSN (online) 1573-904X
    ISSN 0724-8741 ; 0739-0742
    DOI 10.1007/s11095-015-1624-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Site-Specific Dolasynthen Antibody-Drug Conjugates Exhibit Consistent Pharmacokinetic Profiles across a Wide Range of Drug-to-Antibody Ratios.

    Clardy, Susan M / Uttard, Alex / Du, Bingfan / Catcott, Kalli C / Lancaster, Kelly L / Ditty, Elizabeth / Sadowsky, Jack / Zurita, Jeffrey / Malli, Naniye / Qin, LiuLiang / Bradley, Stephen P / Avocetien, Kenneth / Carter, Tyler / Kim, Dokyong / Nazzaro, Mark / Xu, Ling / Pillow, Thomas H / Zacharias, Neelie T / Lewis, Gail D /
    Rowntree, Rebecca K / Iyengar, Radha / Lee, David H / Damelin, Marc / Toader, Dorin / Lowinger, Timothy B

    Molecular cancer therapeutics

    2023  Volume 23, Issue 1, Page(s) 84–91

    Abstract: Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target ...

    Abstract Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target characteristics. However, recent studies and modeling suggest that the optimal DAR can depend on target expression level and intratumoral heterogeneity, target internalization and trafficking, and characteristics of the linker and payload. An ADC platform that enables DAR optimization could improve the success rate of clinical candidates. Here we report a systematic exploration of DAR across a wide range, by combining THIOMAB protein engineering technology with Dolasynthen, an auristatin-based platform with monomeric and trimeric variants. This approach enabled the generation of homogeneous, site-specific ADCs spanning a discrete range of DARs 2, 4, 6, 12, and 18 by conjugation of trastuzumab IgG1 THIOMAB constructs with 1, 2, or 3 engineered cysteines to monomeric or trimeric Dolasynthen. All ADCs had physicochemical properties that translated to excellent in vivo pharmacology. Following a single dose of ADCs in a HER2 xenograft model with moderate antigen expression, our data demonstrated comparable pharmacokinetics for the conjugates across all DARs and dose-dependent efficacy of all test articles. These results demonstrate that the Dolasynthen platform enables the generation of ADCs with a broad range of DAR values and with comparable physiochemical, pharmacologic, and pharmacokinetics profiles; thus, the Dolasynthen platform enables the empirical determination of the optimal DAR for a clinical candidate for a given target.
    MeSH term(s) Humans ; Immunoconjugates/chemistry ; Xenograft Model Antitumor Assays ; Trastuzumab/pharmacology ; Trastuzumab/chemistry ; Receptor, ErbB-2/metabolism ; Cysteine
    Chemical Substances Immunoconjugates ; Trastuzumab (P188ANX8CK) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Cysteine (K848JZ4886)
    Language English
    Publishing date 2023-09-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-23-0262
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5750: Show issues Location:
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  4. Article ; Online: Discovery and Optimization of a STING Agonist Platform for Application in Antibody Drug Conjugates.

    Duvall, Jeremy R / Thomas, Joshua D / Bukhalid, Raghida A / Catcott, Kalli C / Bentley, Keith W / Collins, Scott D / Eitas, Timothy / Jones, Brian D / Kelleher, Eugene W / Lancaster, Kelly / Protopopova, Marina / Ray, Soumya S / Ter-Ovanesyan, Elena / Xu, Ling / Yang, Liping / Zurita, Jeffrey / Damelin, Marc / Toader, Dorin / Lowinger, Timothy B

    Journal of medicinal chemistry

    2023  Volume 66, Issue 15, Page(s) 10715–10733

    Abstract: While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor ... ...

    Abstract While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.
    MeSH term(s) Humans ; Immunoconjugates/pharmacokinetics ; Antibodies, Monoclonal ; Antineoplastic Agents/pharmacokinetics ; Neoplasms/drug therapy
    Chemical Substances Immunoconjugates ; Antibodies, Monoclonal ; Antineoplastic Agents
    Language English
    Publishing date 2023-07-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.3c00907
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Biological functions of DNA methyltransferase 1 require its methyltransferase activity.

    Damelin, Marc / Bestor, Timothy H

    Molecular and cellular biology

    2007  Volume 27, Issue 11, Page(s) 3891–3899

    Abstract: DNA methyltransferase 1 (DNMT1) has been reported to interact with a wide variety of factors and to contain intrinsic transcriptional repressor activity. When a conservative point mutation was introduced at the key catalytic residue, mutant DNMT1 failed ... ...

    Abstract DNA methyltransferase 1 (DNMT1) has been reported to interact with a wide variety of factors and to contain intrinsic transcriptional repressor activity. When a conservative point mutation was introduced at the key catalytic residue, mutant DNMT1 failed to rescue any of the phenotypes of Dnmt1-null embryonic stem (ES) cells, which indicated that the biological functions of DNMT1 are exerted through the methylation of DNA. ES cells that expressed the mutant protein did not survive differentiation. Intracisternal A-particle family retrotransposons were no longer methylated and were transcribed at high levels. The proper localization of DNMT1 depended on normal genomic methylation, and we discuss the implications of this finding for epigenetic dysregulation in cancer.
    MeSH term(s) Animals ; Cell Differentiation ; Cells, Cultured ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methylation ; Embryonic Stem Cells/cytology ; Embryonic Stem Cells/physiology ; Epigenesis, Genetic ; Gene Expression Regulation ; Heterochromatin/genetics ; Heterochromatin/metabolism ; Histones/metabolism ; Humans ; Mice ; Mice, Knockout ; Phenotype ; Point Mutation ; Retroelements/genetics
    Chemical Substances Heterochromatin ; Histones ; Retroelements ; DNA (Cytosine-5-)-Methyltransferase 1 (EC 2.1.1.37) ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNMT1 protein, human (EC 2.1.1.37) ; Dnmt1 protein, mouse (EC 2.1.1.37)
    Language English
    Publishing date 2007-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00036-07
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1666: Show issues Location:
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  6. Article: Analysis of Protein Interactions In Vivo with Fluorescence Resonance Energy Transfer (FRET).

    Damelin, Marc / Silver, Pamela

    CSH protocols

    2006  Volume 2006, Issue 5

    Abstract: INTRODUCTIONThe protocol presented here focuses on a standard microscope-based fluorescence resonance energy transfer (FRET) assay for budding yeast, but many aspects are applicable to other systems and assays. It provides information on experimental ... ...

    Abstract INTRODUCTIONThe protocol presented here focuses on a standard microscope-based fluorescence resonance energy transfer (FRET) assay for budding yeast, but many aspects are applicable to other systems and assays. It provides information on experimental design and data analysis procedures that can be extended to FRET experiments in any system, including mammalian cell lines and other model organisms. The steps describing strain construction can be applied to studies in yeast using fluorimetry instead of microscopy. Although the data acquisition and analysis described in this protocol can be a daunting task, careful quantitative analysis is absolutely necessary because of a high degree of cross-talk and many unknown parameters that vary from cell to cell.
    Language English
    Publishing date 2006-10-01
    Publishing country United States
    Document type Journal Article
    DOI 10.1101/pdb.prot4581
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Equipment for In Vivo FRET Analysis.

    Damelin, Marc / Silver, Pamela

    CSH protocols

    2006  Volume 2006, Issue 5

    Language English
    Publishing date 2006-10-01
    Publishing country United States
    Document type Journal Article
    DOI 10.1101/pdb.ip8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Experimental Design for In Vivo FRET Analysis.

    Damelin, Marc / Silver, Pamela

    CSH protocols

    2006  Volume 2006, Issue 5

    Language English
    Publishing date 2006-10-01
    Publishing country United States
    Document type Journal Article
    DOI 10.1101/pdb.ip10
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: An Explanation of Symbols Used for Analysis of FRET Data.

    Damelin, Marc / Silver, Pamela

    CSH protocols

    2006  Volume 2006, Issue 5

    Language English
    Publishing date 2006-10-01
    Publishing country United States
    Document type Journal Article
    DOI 10.1101/pdb.ip9
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  10. Article ; Online: Decatenation checkpoint deficiency destabilizes the stem cell genome.

    Damelin, Marc / Bestor, Timothy H

    Cell cycle (Georgetown, Tex.)

    2006  Volume 5, Issue 4, Page(s) 345–346

    MeSH term(s) Animals ; Cell Cycle/genetics ; Chromosome Aberrations ; Genomic Instability/genetics ; Humans ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Stem Cells/metabolism ; Stem Cells/pathology
    Language English
    Publishing date 2006-02-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.5.4.2480
    Database MEDical Literature Analysis and Retrieval System OnLINE

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