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  1. Artikel: Novel Developments to Enable Treatment of CNS Diseases with Targeted Drug Delivery.

    Meyer, Axel H / Feldsien, Thomas M / Mezler, Mario / Untucht, Christopher / Venugopalan, Ramakrishna / Lefebvre, Didier R

    Pharmaceutics

    2023  Band 15, Heft 4

    Abstract: The blood-brain barrier (BBB) is a major hurdle for the development of systemically delivered drugs against diseases of the central nervous system (CNS). Because of this barrier there is still a huge unmet need for the treatment of these diseases, ... ...

    Abstract The blood-brain barrier (BBB) is a major hurdle for the development of systemically delivered drugs against diseases of the central nervous system (CNS). Because of this barrier there is still a huge unmet need for the treatment of these diseases, despite years of research efforts across the pharmaceutical industry. Novel therapeutic entities, such as gene therapy and degradomers, have become increasingly popular in recent years, but have not been the focus for CNS indications so far. To unfold their full potential for the treatment of CNS diseases, these therapeutic entities will most likely have to rely on innovative delivery technologies. Here we will describe and assess approaches, both invasive and non-invasive, that can enable, or at least increase, the probability of a successful drug development of such novel therapeutics for CNS indications.
    Sprache Englisch
    Erscheinungsdatum 2023-03-29
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics15041100
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Bystander effects, pharmacokinetics, and linker-payload stability of EGFR-targeting antibody-drug conjugates Losatuxizumab vedotin and Depatux-M in glioblastoma models.

    Jain, Sonia / Griffith, Jessica I / Porath, Kendra A / Rathi, Sneha / Le, Jiayan / Pasa, Tugce I / Decker, Paul A / Gupta, Shiv K / Hu, Zeng / Carlson, Brett L / Bakken, Katrina / Burgenske, Danielle M / Feldsien, Thomas M / Lefebvre, Didier R / Vaubel, Rachael A / Eckel-Passow, Jeanette E / Reilly, Edward B / Elmquist, William F / Sarkaria, Jann N

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2024  

    Abstract: Purpose: Antibody-drug conjugates (ADCs) are targeted therapies with robust efficacy in solid cancers, and there is intense interest in using EGFR-specific ADCs to target EGFR-amplified glioblastoma (GBM). Given the molecular heterogeneity of GBM, ... ...

    Abstract Purpose: Antibody-drug conjugates (ADCs) are targeted therapies with robust efficacy in solid cancers, and there is intense interest in using EGFR-specific ADCs to target EGFR-amplified glioblastoma (GBM). Given the molecular heterogeneity of GBM, bystander activity of ADCs may be important for determining treatment efficacy. In this study, the activity and toxicity of two EGFR-targeted ADCs, Losatuxizumab vedotin (ABBV-221) and Depatuxizumab mafodotin (Depatux-M), with similar auristatin toxins, were compared in GBM patient-derived xenografts (PDXs) and normal murine brain following direct infusion by convection enhanced delivery (CED).
    Methods: EGFRviii-amplified and non-amplified GBM PDXs were used to determine in vitro cytotoxicity, in vivo efficacy, and bystander activities of ABBV-221 and Depatux-M. Non-tumor bearing mice were used to evaluate pharmacokinetics and toxicity of ADCs using LC-MS/MS and immunohistochemistry.
    Results: CED improved intracranial efficacy of Depatux-M and ABBV-221 in three EGFRviii-amplified GBM PDX models (Median survival: 125 to >300 days vs 20-49 days with isotype-control AB095). Both ADCs had comparable in vitro and in vivo efficacy. However, neuronal toxicity and CD68+ microglia/macrophage infiltration were significantly higher in brains infused with ABBV-221, with the cell-permeable MMAE, as compared to Depatux-M, with the cell-impermeant MMAF. CED infusion of ABBV-221 into brain or incubation of ABBV-221 with normal brain homogenate resulted in significant release of MMAE, which is consistent with linker instability in the brain microenvironment.
    Conclusion: EGFR-targeting ADCs are promising therapeutic options for GBM when delivered intra-tumorally by CED. However, the linker and payload for the ADC must be carefully considered to maximize the therapeutic window.
    Sprache Englisch
    Erscheinungsdatum 2024-05-14
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-24-0426
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

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  3. Artikel ; Online: Convection enhanced delivery of EGFR targeting antibody-drug conjugates Serclutamab talirine and Depatux-M in glioblastoma patient-derived xenografts.

    Porath, Kendra A / Regan, Michael S / Griffith, Jessica I / Jain, Sonia / Stopka, Sylwia A / Burgenske, Danielle M / Bakken, Katrina K / Carlson, Brett L / Decker, Paul A / Vaubel, Rachael A / Dragojevic, Sonja / Mladek, Ann C / Connors, Margaret A / Hu, Zeng / He, Lihong / Kitange, Gaspar J / Gupta, Shiv K / Feldsien, Thomas M / Lefebvre, Didier R /
    Agar, Nathalie Y R / Eckel-Passow, Jeanette E / Reilly, Edward B / Elmquist, William F / Sarkaria, Jann N

    Neuro-oncology advances

    2022  Band 4, Heft 1, Seite(n) vdac130

    Abstract: Background: EGFR targeting antibody-drug conjugates (ADCs) are highly effective against EGFR-amplified tumors, but poor distribution across the blood-brain barrier (BBB) limits their efficacy in glioblastoma (GBM) when administered systemically. We ... ...

    Abstract Background: EGFR targeting antibody-drug conjugates (ADCs) are highly effective against EGFR-amplified tumors, but poor distribution across the blood-brain barrier (BBB) limits their efficacy in glioblastoma (GBM) when administered systemically. We studied whether convection-enhanced delivery (CED) can be used to safely infuse ADCs into orthotopic patient-derived xenograft (PDX) models of EGFRvIII mutant GBM.
    Methods: The efficacy of the EGFR-targeted ADCs depatuxizumab mafodotin (Depatux-M) and Serclutamab talirine (Ser-T) was evaluated
    Results: Dose-finding studies in orthotopic GBM6 identified single infusion of 2 μg Ser-T and 60 μg Depatux-M as safe and effective associated with extended survival prolongation (>300 days and 95 days, respectively). However, with serial infusions every 21 days, four Ser-T doses controlled tumor growth but was associated with lethal toxicity approximately 7 days after the final infusion. Limiting dosing to two infusions in GBM108 provided profound median survival extension of over 200 days. In contrast, four Depatux-M CED doses were well tolerated and significantly extended survival in both GBM6 (158 days) and GBM108 (310 days). In a toxicity analysis, Ser-T resulted in a profound loss in NeuN+ cells and markedly elevated GFAP staining, while Depatux-M was associated only with modest elevation in GFAP staining.
    Conclusion: CED of Depatux-M is well tolerated and results in extended survival in orthotopic GBM PDXs. In contrast, CED of Ser-T was associated with a much narrower therapeutic window.
    Sprache Englisch
    Erscheinungsdatum 2022-08-24
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 3009682-0
    ISSN 2632-2498 ; 2632-2498
    ISSN (online) 2632-2498
    ISSN 2632-2498
    DOI 10.1093/noajnl/vdac130
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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