Heat Shock Protein 90 Inhibitor BIIB021 (CNF2024) Depletes NF-κB and Sensitizes Hodgkin's Lymphoma Cells for Natural Killer Cell–Mediated Cytotoxicity

2009 ◽  
Vol 15 (16) ◽  
pp. 5108-5116 ◽  
Author(s):  
Boris Böll ◽  
Farag Eltaib ◽  
Katrin S. Reiners ◽  
Bastian von Tresckow ◽  
Samir Tawadros ◽  
...  
2020 ◽  
Vol 80 (23) ◽  
pp. 5355-5366
Author(s):  
Munisha Smalley ◽  
Siva Kumar Natarajan ◽  
Jayanta Mondal ◽  
Douglas Best ◽  
David Goldman ◽  
...  

2015 ◽  
Vol 6 ◽  
Author(s):  
Michio Suzuki ◽  
Tadashi Takeda ◽  
Hikaru Nakagawa ◽  
Seiko Iwata ◽  
Takahiro Watanabe ◽  
...  

2021 ◽  
Vol 8 ◽  
Author(s):  
Tanmoy Saha ◽  
Amanda A. van Vliet ◽  
Chunxiao Cui ◽  
Jorge Jimenez Macias ◽  
Arpita Kulkarni ◽  
...  

Allogeneic natural killer (aNK) cell adoptive therapy has the potential to dramatically impact clinical outcomes of glioblastoma multiforme (GBM). However, in order to exert therapeutic activity, NK cells require tumor expression of ligands for activating receptors, such as MHC Class I peptide A/B (MICA/B) and ULBPs. Here, we describe the use of a blood–brain barrier (BBB) permissive supramolecular cationic drug vehicle comprising an inhibitor of the chaperone heat shock protein 90 (Hsp90), which sustains a cytotoxic effect on GBM cells, boosts the expression of MICA/B and ULBPs on the residual population, and augments the activity of clinical-grade aNK cells (GTA002). First, we identify Hsp90 mRNA transcription and gain of function as significantly upregulated in GBM compared to other central nervous system tumors. Through a rational chemical design, we optimize a radicicol supramolecular prodrug containing cationic excipients, SCI-101, which displays >2-fold increase in relative BBB penetration compared to less cationic formulations in organoids, in vitro. Using 2D and 3D biological models, we confirm SCI-101 sustains GBM cytotoxicity 72 h after drug removal and induces cell surface MICA/B protein and ULBP mRNA up to 200% in residual tumor cells compared to the naked drug alone without augmenting the shedding of MICA/B, in vitro. Finally, we generate and test the sequential administration of SCI-101 with a clinical aNK cell therapy, GTA002, differentiated and expanded from healthy umbilical cord blood CD34+ hematopoietic stem cells. Using a longitudinal in vitro model, we demonstrate >350% relative cell killing is achieved in SCI-101–treated cell lines compared to vehicle controls. In summary, these data provide a first-of-its-kind BBB-penetrating, long-acting inhibitor of Hsp90 with monotherapy efficacy, which improves response to aNK cells and thus may rapidly alter the treatment paradigm for patients with GBM.


Blood ◽  
1999 ◽  
Vol 94 (8) ◽  
pp. 2562-2568 ◽  
Author(s):  
Michaela A.E. Arndt ◽  
Jürgen Krauss ◽  
Sergey M. Kipriyanov ◽  
Michael Pfreundschuh ◽  
Melvyn Little

CD16/CD30 bispecific monoclonal antibodies can induce remissions of Hodgkin’s disease refractory to chemo- and radiotherapy. However, the development of human antimouse immunoglobulin antibodies and allergic reactions precludes repeated applications of the antibody. Moreover, problems of producing and purifying sufficient amounts of material limit the clinical practicability of this novel treatment approach. To overcome these obstacles, we have constructed a bispecific antibody in a diabody form that only employs the variable domains of the CD16/CD30 hybrid hybridoma. The diabody compared favorably with the parent CD16/CD30 bispecific antibody in its ability to activate and target natural killer cells in vitro. Its administration to mice bearing xenografted Hodgkin’s lymphoma resulted in a marked regression of tumor growth, thus proving for the first time the capability of a diabody for immune recruitment in vivo. The CD16/CD30 diabody is a novel reagent that should considerably facilitate the immunotherapy of patients with refractory Hodgkin’s lymphoma.


2012 ◽  
Vol 35 (5) ◽  
pp. 725-730 ◽  
Author(s):  
Chizuka Higashi ◽  
Chiaki Saji ◽  
Koji Yamada ◽  
Hiroki Kagawa ◽  
Rie Ohga ◽  
...  

2017 ◽  
Vol 187 (1) ◽  
pp. 163-175 ◽  
Author(s):  
Mariko Watanabe ◽  
Kazumi Nakano ◽  
Marshall E. Kadin ◽  
Masaaki Higashihara ◽  
Toshiki Watanabe ◽  
...  

2015 ◽  
Vol 5 (1) ◽  
pp. e1058459 ◽  
Author(s):  
Christian Kellner ◽  
Andreas Günther ◽  
Andreas Humpe ◽  
Roland Repp ◽  
Katja Klausz ◽  
...  

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