ArticleClinical cancer research : an official journal of the American Association for Cancer Research2021
BCMA-Specific ADC MEDI2228 and Daratumumab Induce Synergistic Myeloma Cytotoxicity via IFN-Driven Immune Responses and Enhanced CD38 Expression.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
27 citing papers in PubMed, 1 synthesis or guideline pooled it, 27 citations in OpenAlex.
- The Efficacy and Safety of B-Cell Maturation Antigen (BCMA) Antibody-Drug Conjugates (ADC) in Development against Cancer: A Systematic Review.Oncology research · 2025Pooled it
- Decoding immunotherapy resistance in multiple myeloma: genetic insights and approaches to counter resistance.Science China. Life sciences · 2026Review
- Endothelial NADAlzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Frontiers in Antibody-Drug Conjugates: Mechanisms, Design Innovations, and Clinical Applications in Targeted Cancer Therapy.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Identification of CD38Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- BCMA-targeted therapies in multiple myeloma: advances, challenges and future prospects.Medical oncology (Northwood, London, England) · 2025Review
- Clinical updates of B‑cell maturation antigen‑targeted therapy in multiple myeloma (MM) and relapsed/refractory MM (Review).International journal of molecular medicine · 2025Review
- The multiple roles of interferon regulatory factor family in health and disease.Signal transduction and targeted therapy · 2024Review
- Disruption of DNA-PKcs-mediated cGAS retention on damaged chromatin potentiates DNA damage-inducing agent-induced anti-multiple myeloma activity.British journal of cancer · 2024Article
- Targeted Delivery Strategies for Multiple Myeloma and Their Adverse Drug Reactions.Pharmaceuticals (Basel, Switzerland) · 2024Review
- An Antibody-Drug Conjugate for Multiple Myeloma Prepared by Multi-Arm Linkers.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Article
- A B7-H4-Targeting Antibody-Drug Conjugate Shows Antitumor Activity in PARPi and Platinum-Resistant Cancers with B7-H4 Expression.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth.Nature communications · 2024Article
- Targeting B-cell maturation antigen for treatment and monitoring of relapsed/refractory multiple myeloma patients: a comprehensive review.Therapeutic advances in hematology · 2024Review
- TBK1 is paradoxical in tumor development: a focus on the pathway mediating IFN-I expression.Frontiers in immunology · 2024Review
- Adverse events of antibody-drug conjugates on the ocular surface in cancer therapy.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2023Review
- Characterization and application of a lactate and branched chain amino acid metabolism related gene signature in a prognosis risk model for multiple myeloma.Cancer cell international · 2023Article
- Antibody-Drug Conjugates for Multiple Myeloma: Just the Beginning, or the Beginning of the End?Pharmaceuticals (Basel, Switzerland) · 2023Review
- Review
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 4 countries.
Funding
Abstract
purposeEfforts are required to improve the potency and durability of CD38- and BCMA-based immunotherapies in human multiple myeloma. We here delineated the molecular and cellular mechanisms underlying novel immunomodulatory effects triggered by BCMA pyrrolobenzodiazepine (PBD) antibody drug conjugate (ADC) MEDI2228 which can augment efficacy of these immunotherapies. EXPERIMENTAL
designMEDI2228-induced transcriptional and protein changes were investigated to define significantly impacted genes and signaling cascades in multiple myeloma cells. Mechanisms whereby MEDI2228 combination therapies can enhance cytotoxicity or overcome drug resistance in multiple myeloma cell lines and patient multiple myeloma cells were defined using in vitro models of tumor in the bone marrow (BM) microenvironment, as well as in human natural killer (NK)-reconstituted NOD/SCID gamma (NSG) mice bearing MM1S tumors.
resultsMEDI2228 enriched IFN I signaling and enhanced expression of IFN-stimulated genes in multiple myeloma cell lines following the induction of DNA damage-ATM/ATR-CHK1/2 pathways. It activated cGAS-STING-TBK1-IRF3 and STAT1-IRF1-signaling cascades and increased CD38 expression in multiple myeloma cells but did not increase CD38 expression in BCMA-negative NK effector cells. It overcame CD38 downregulation on multiple myeloma cells triggered by IL6 and patient BM stromal cell-culture supernatant via activation of STAT1-IRF1, even in immunomodulatory drug (IMiD)- and bortezomib-resistant multiple myeloma cells. In vitro and in vivo upregulation of NKG2D ligands and CD38 in MEDI2228-treated multiple myeloma cells was further associated with synergistic daratumumab (Dara) CD38 MoAb-triggered NK-mediated cytotoxicity of both cell lines and autologous drug-resistant patient multiple myeloma cells.
conclusionsThese results provide the basis for clinical evaluation of combination MEDI2228 with Dara to further improve patient outcome in multiple myeloma.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.