Cited by 219Multiple Myeloma Research and TreatmentsMonoclonal and Polyclonal Antibodies ResearchCell death mechanisms and regulation

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RETRACTED ARTICLE: SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide

Jiang, H, Acharya, C, An, G, Zhong, M, Feng, X, Wang, L, Dasilva, N, Song, Z, Yang, G, Adrian, F, Qiu, L, Richardson, P, Munshi, N C, Tai, Y-T, Anderson, K C·2016·Leukemia

DOI 10.1038/leu.2015.240

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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 Pom/Len. Taken together, SAR is the first therapeutic monoclonal antibody mediating direct cytotoxicity against MM cells via multiple mechanisms of action. Our data show that Pom augments both direct and effector cell-mediated MM cytotoxicity of SAR, providing the framework for combination clinical trials.

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Authors: Jiang, H., Acharya, C., An, G., Zhong, M., Feng, X., Wang, L., Dasilva, N., Song, Z., Yang, G., Adrian, F., Qiu, L., Richardson, P., Munshi, N. C., Tai, Y.-T., & Anderson, K. C.
Affiliations: Second Military Medical University (CN)
Dana-Farber Cancer Institute (US)
Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
Corresponding author: Tai, Y-T
ORCID: Jiang, H
Acharya, C
An, G
Feng, X
Wang, L
Song, Z
Yang, G
Qiu, L
Richardson, P
Munshi, N C
Anderson, K C
Venue: Leukemia
Publisher: Springer Science and Business Media LLC
Published: 2015-09-04
Volume: 30
Issue: 2
Pages: 399-408
ISSN: 0887-6924 (ISSN-L)
1476-5551
DOI: 10.1038/leu.2015.240
OpenAlex: W1916436059
Cited by: 219
References: 45
Citations by year: 2026: 1 · 2025: 3 · 2024: 17 · 2023: 25 · 2022: 45 · 2021: 33 · 2020: 31 · 2019: 20 · 2018: 11 · 2017: 16 · 2016: 16 · 2015: 1
FWCI: 10.59
Type: journal article
Language: en
Status: Retracted
Update notices: retraction (2024-10-22)
Open access: closed
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Leukemia (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5p01ca078378-15)
U.S. Public Health Service (R01-050947)
National Cancer Institute (P01-CA078378, P50CA100707)
Topics: Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords: pomalidomide, multiple myeloma, anti-CD38 monoclonal antibody, homotypic aggregation, lysosomal membrane permeabilization, cathepsin B, LAMP1, reactive oxygen species, F(ab')2 fragments, TP53 mutation, lenalidomide resistance, combination therapy, retracted article
MeSH terms: Actins, Humans, Lysosomes, Membrane Glycoproteins, Multiple Myeloma, Thalidomide, Genes, p53, Apoptosis, Reactive Oxygen Species, Membrane Microdomains, ADP-ribosyl Cyclase 1, Antibodies, Monoclonal, Humanized

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

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