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    DRUG:

    MEDI2228

    i
    Other names: MEDI2228, MEDI 2228
    Associations

    News

    Trials
    Company:
    AstraZeneca
    Drug class:
    DNA replication inhibitor, BCMA-targeted antibody-drug conjugate
    Related drugs:
    Associations

    News

    Trials
    over1year
    ANTIBODY DRUG CONJUGATES (ADCS) (EMN 2023)
    Belantamab Mafodotin (belamaf) is the first approved anti-BCMA ADC for the treatment of relapsed/refractory multiple myeloma (RRMM)...Three-phase III studies evaluate the safety and efficacy of belamaf in combination with pomalidomide (NCT04162210; DREAMM-3), daratumumab plus bortezomib (NCT04246047; DREAMM-7), or pomalidomide plus bortezomib (NCT04484623: DREAMM-8)...MEDI2228 has shown potent antitumor activity in preclinical models, including cell lines resistant to lenalidomide. Phase 1 data in heavily pretreated patients were encouraging.
    IO biomarker
    |
    EGFR (Epidermal growth factor receptor) • TNFA (Tumor Necrosis Factor-Alpha)
    |
    lenalidomide • bortezomib • Darzalex (daratumumab) • pomalidomide • Blenrep (belantamab mafodotin-blmf) • MEDI2228
    over3years
    BCMA-specific ADC MEDI2228 and Daratumumab induce synergistic myeloma cytotoxicity via enhanced IFN-driven innate immune responses and expression of CD38 and NKG2D ligands (IMW 2021)
    It overcame CD38 downregulation triggered by IL6 and bone marrow stromal cell culture supernatant (BMSC- sup), via activation of STAT1-IRF1 without phosphorylation of STAT3 in immunomodulatory drugs (IMiDs)- and bortezomib-resistant MM cell lines. Taken together, our data showed that MEDI2228 restored MM sensitivity to CD38 targeting by Dara without depleting NK cells and potentiated immunogenic cell death of MM cells. These results therefore provide the mechanistic rationale for clinical evaluation of combination CD38- and BCMA-directed immunotherapies to further improve patient outcome in MM.
    IO biomarker
    |
    IL6 (Interleukin 6) • CD38 (CD38 Molecule) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CXCL9 (Chemokine (C-X-C motif) ligand 9) • STING (stimulator of interferon response cGAMP interactor 1) • CCR7 (Chemokine (C-C motif) receptor 7) • CCL2 (Chemokine (C-C motif) ligand 2) • CSF2 (Colony stimulating factor 2) • GZMB (Granzyme B) • SOCS1 (Suppressor Of Cytokine Signaling 1) • IFIT1 (Interferon Induced Protein With Tetratricopeptide Repeats 1) • RUNX3 (RUNX Family Transcription Factor 3) • STAT1 (Signal Transducer And Activator Of Transcription 1) • CCL22 (C-C Motif Chemokine Ligand 22) • CGAS (Cyclic GMP-AMP Synthase) • IKBKE (Inhibitor Of Nuclear Factor Kappa B Kinase Subunit Epsilon) • NKG2D (killer cell lectin like receptor K1)
    |
    CD38 expression • IRF1 expression
    |
    bortezomib • Darzalex (daratumumab) • MEDI2228
    over3years
    BCMA-specific ADC MEDI2228 and Daratumumab induce synergistic myeloma cytotoxicity via IFN-driven immune responses and enhanced CD38 expression. (PubMed, Clin Cancer Res)
    These results provide the basis for clinical evaluation of combination MEDI2228 with Dara to further improve patient outcome in MM.
    Journal • IO biomarker
    |
    IL6 (Interleukin 6) • CD38 (CD38 Molecule) • STING (stimulator of interferon response cGAMP interactor 1) • STAT1 (Signal Transducer And Activator Of Transcription 1) • NKG2D (killer cell lectin like receptor K1)
    |
    CD38 expression • IRF1 expression
    |
    bortezomib • Darzalex (daratumumab) • MEDI2228
    4years
    A novel BCMA PBD-ADC with ATM/ATR/WEE1 inhibitors or bortezomib induce synergistic lethality in multiple myeloma. (PubMed, Leukemia)
    To target mechanisms critical for multiple myeloma (MM) plasma cell adaptations to genomic instabilities and further sustain MM cell killing, we here specifically trigger DNA damage response (DDR) in MM cells by a novel BCMA antibody-drug conjugate (ADC) delivering the DNA cross-linking PBD dimer tesirine, MEDI2228. Such combination further induces superior in vivo efficacy than monotherapy via increased nuclear γH2AX-expressing foci, irreversible DNA damages,  and tumor cell death, leading to significantly prolonged host survival. These results indicate leveraging MEDI2228 with DDRi s or btz as novel combination strategies, further supporting ongoing clinical development of MEDI2228 in patients with relapsed and refractory MM.
    Journal
    |
    IL6 (Interleukin 6) • ATR (Ataxia telangiectasia and Rad3-related protein) • CHEK1 (Checkpoint kinase 1) • CDK1 (Cyclin-dependent kinase 1)
    |
    bortezomib • MEDI2228
    5years
    MEDI2228, a Novel Bcma Antibody-PBD Conjugate, Sensitizes Human Multiple Myeloma Cells to NK Cell-Mediated Cytotoxicity and Upregulates CD38 Expression in MM Cells (ASH 2019)
    MEDI2228 induces DNA damage responses (DDR) prior to apoptosis, as demonstrated by phosphorylation of ATM/ATR, CHK1/2, and gH2AX in MM cells regardless of p53 status and responsiveness to current MM therapies including bortezomib and IMiDs. Simultaneously, MEDI2228 induces IFN-stimulated genes, including CD38, resulting in enhanced MM cell lysis by daratumumab. These results indicate additional mechanisms of anti-MM activity for MEDI2228 and suggest that a combination of MEDI2228 and anti-CD38 mAbs may further improve outcome for MM patients.
    IO biomarker
    |
    CD38 (CD38 Molecule) • ATR (Ataxia telangiectasia and Rad3-related protein) • CHEK1 (Checkpoint kinase 1)
    |
    bortezomib • Darzalex (daratumumab) • MEDI2228
    5years
    Anti-Bcma PBD MEDI2228 Combats Drug Resistance and Synergizes with Bortezomib and Inhibitors to DNA Damage Response in Multiple Myeloma (ASH 2019)
    Significantly, MM cells with lower BCMA expression and resistance to bortezomib or immunomodulatory drugs (IMiDs, i.e., lenalidomide, pomalidomide) are more susceptible to MEDI2228 vs its MMAF ADC homolog. Moreover, DDR checkpoint inhibitors, i.e., AZD0156 (ATMi), AZD6738 (ATRi), AZD1775 (WEE1i), synergize with MEDI2228 to enhance MM cell cytotoxicity (combination index < 1). This study therefore further supports clinical development of MEDI2228 (NCT03489525) as an important next-generation immunotherapy to improve outcome of MM patients.
    IO biomarker
    |
    IL6 (Interleukin 6) • ATR (Ataxia telangiectasia and Rad3-related protein) • CHEK1 (Checkpoint kinase 1)
    |
    lenalidomide • bortezomib • adavosertib (AZD1775) • ceralasertib (AZD6738) • pomalidomide • AZD0156 • MEDI2228