SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide

Leukemia
H JiangKenneth C Anderson

Abstract

The anti-CD38 monoclonal antibody SAR650984 (SAR) is showing promising clinical activity in treatment of relapsed and refractory multiple myeloma (MM). Besides effector-mediated antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, we here define molecular mechanisms of SAR-directed MM cell death and enhanced anti-MM activity triggered by SAR with Pomalidomide (Pom). Without Fc-cross-linking agents or effector cells, SAR specifically induces homotypic aggregation (HA)-associated cell death in MM cells dependent on the level of cell surface CD38 expression, actin cytoskeleton and membrane lipid raft. SAR and its F(ab)'2 fragments trigger caspase 3/7-dependent apoptosis in MM cells highly expressing CD38, even with p53 mutation. Importantly, SAR specifically induces lysosome-dependent cell death (LCD) by enlarging lysosomes and increasing lysosomal membrane permeabilization associated with leakage of cathepsin B and LAMP-1, regardless of the presence of interleukin-6 or bone marrow stromal cells. Conversely, the lysosomal vacuolar H+-ATPase inhibitor blocks SAR-induced LCD. SAR further upregulates reactive oxygen species. Pom enhances SAR-induced direct and indirect killing even in MM cells resistant to P...Continue Reading

References

Oct 18, 2002·Immunology·Julie P DeansMaria J Polyak
Dec 25, 2004·Proceedings of the National Academy of Sciences of the United States of America·Hamdiye ErdalStig Linder
Jan 14, 2005·Journal of Leukocyte Biology·Bernard DrénouNuala Mooney
Mar 1, 2007·Blood·Silvia DeaglioFabio Malavasi
Sep 18, 2007·Medical Oncology·Vladimir JurisicMilica Colovic
Feb 27, 2008·The Journal of Experimental Medicine·Sébastien ConusHans-Uwe Simon
May 13, 2008·The Journal of Biological Chemistry·Gabriela Droga-MazovecBoris Turk
Jul 6, 2010·Cancer Letters·Line Groth-Pedersen, Marja Jäättelä
Dec 29, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Michel de WeersPaul W H I Parren
Nov 3, 2011·Bone Marrow Research·Yu-Tzu Tai, Kenneth C Anderson
May 2, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Hervé Avet-LoiseauPhilippe Moreau
May 31, 2013·Journal of Cell Science·Sonja Aits, Marja Jäättelä
Dec 18, 2013·Expert Review of Anticancer Therapy·Roberto CastelliMassimo Cugno
Jan 7, 2014·Frontiers in Bioscience (Landmark Edition)·Jesus G Berdeja
Feb 22, 2014·Expert Opinion on Investigational Drugs·Jacob P LaubachKenneth C Anderson
Apr 16, 2014·Journal of Hematology & Oncology·Caroline S BretonJonathan Back
Jun 20, 2014·Future Oncology·Philippe Moreau, Cyrille Touzeau
Jul 6, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jutta DeckertVéronique Blanc
Sep 19, 2014·Biochemical Society Transactions·Ana M Villamil GiraldoKarin Öllinger
Sep 23, 2014·Frontiers in Oncology·Alessandro GozzettiMonica Bocchia
Oct 9, 2014·Blood Reviews·Daniel W SherbenouBin Liu
Nov 26, 2014·Nature Reviews. Clinical Oncology·Meletios A DimopoulosKenneth C Anderson

❮ Previous
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Citations

Feb 24, 2016·Current Hematologic Malignancy Reports·Hans C LeeJatin J Shah
Nov 26, 2015·Annals of the New York Academy of Sciences·Ana Serrano-Puebla, Patricia Boya
Jun 29, 2016·Expert Opinion on Drug Safety·Stefania Oliva, Antonio Palumbo
Jul 23, 2016·Blood·Yu-Tzu Tai, Kenneth C Anderson
Nov 9, 2016·Best Practice & Research. Clinical Haematology·Aneel PaulusAsher Chanan-Khan
Nov 9, 2016·Best Practice & Research. Clinical Haematology·Jorge J CastilloSteven P Treon
Jan 7, 2017·Expert Opinion on Drug Safety·Maria GavriatopoulouMeletios A Dimopoulos
Jan 25, 2017·Expert Review of Hematology·Annamaria BrioliMarie Von Lilienfeld-Toal
Feb 18, 2017·Leukemia·C TouzeauC Dumontet
Jun 13, 2017·Expert Opinion on Pharmacotherapy·Klaus Podar, Martin Pecherstorfer
Nov 16, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lihua SongNinghua Tan
Nov 6, 2018·Expert Opinion on Biological Therapy·Francesca BonelloFrancesca Gay
Jan 30, 2019·The Cancer Journal·Raphaël Szalat, Nikhil C Munshi
Aug 26, 2017·Blood·Efstathios Kastritis, Meletios A Dimopoulos
Jul 7, 2019·Expert Opinion on Biological Therapy·Yu-Tzu Tai, Kenneth C Anderson
Nov 10, 2017·Blood·Niels W C J van de DonkFabio Malavasi
Nov 30, 2019·Cells·Thomas G MartinKenneth C Anderson
Jan 7, 2020·Médecine sciences : M/S·Jérôme Moreaux
Feb 14, 2020·Cancers·Vanessa PintoM Helena Vasconcelos
Apr 26, 2020·Journal of Clinical Medicine·Laurens E FranssenInger S Nijhof
Apr 30, 2020·Drugs·Sohita Dhillon
Aug 22, 2020·Expert Opinion on Investigational Drugs·Ying JiaoKongming Wu
May 28, 2019·Expert Review of Hematology·Nicola GiulianiFabio Malavasi
Jun 19, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Marije B OverdijkPeter Boross
Dec 31, 2016·Human Antibodies·Alberto L HorensteinFabio Malavasi
May 10, 2019·EMBO Molecular Medicine·Vadim Le JoncourPirjo Laakkonen
Feb 22, 2018·Expert Review of Clinical Immunology·Kristine A FrerichsNiels W C J van de Donk
Oct 18, 2018·Japanese Journal of Clinical Oncology·Tadao Ishida
Aug 4, 2018·International Journal of Molecular Sciences·Antoni DomagalaMalgorzata Firczuk
Nov 14, 2017·Antibodies·Shih-Feng ChoYu-Tzu Tai
Dec 22, 2016·Oncoimmunology·Djordje AtanackovicTim Luetkens
Aug 28, 2018·Frontiers in Immunology·Yu-Tzu TaiKenneth C Anderson
Sep 21, 2018·American Society of Clinical Oncology Educational Book·Jacob P LaubachJoseph Mikhael

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