The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index.
RETRACTED ARTICLE: SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide
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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“Isatuximab has been shown to directly induce apoptosis in MM cells without the need for crosslinking agents or effector cells. This unique ability contributes to its effectiveness in killing MM cells [167, 168].”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [168]
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Self-citationLysosomal cell death at a glance
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Immunotherapy in Lung and Thoracic Cancer
Muğlu, H., & Ölmez, Ö. F. (2024) · doi:10.69860/nobel.9786053359388.12
Immunothearpy for the Treatment of Multiple Myeloma
Okumus, N., Hatipoglu, U., & Ulaş, T. (2024) · doi:10.69860/nobel.9786053359388.9
Mechanism of action of isatuximab in multiple myeloma. Literature review and clinical observation
Soloveva, M. V., Solovev, M. V., & Mendeleeva, L. P. (2026) · Oncohematology · doi:10.17650/1818-8346-2026-21-1-59-65
Metadata
- 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
- Venue
- Leukemia
- Published
- 2015-09-04
- Volume
- 30
- Issue
- 2
- Pages
- 399-408
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- 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
- 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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