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Immunotherapy

A novel BCMA PBD-ADC with ATM/ATR/WEE1 inhibitors or bortezomib induce synergistic lethality in multiple myeloma

Leukemia volume 34, pages 2150–2162 (2020)Cite this article

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Abstract

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. MEDI2228, more effectively than its anti-tubulin MMAF-ADC homolog, induces cytotoxicity against MM cells regardless of drug resistance, BCMA levels, p53 status, and the protection conferred by bone marrow stromal cells and IL-6. Distinctly, prior to apoptosis, MEDI2228 activates DDRs in MM cells via phosphorylation of ATM/ATR kinases, CHK1/2, CDK1/2, and H2AX, associated with expression of DDR-related genes. Significantly, MEDI2228 synergizes with DDR inhibitors (DDRi s) targeting ATM/ATR/WEE1 checkpoints to induce MM cell lethality. Moreover, suboptimal doses of MEDI2228 and bortezomib (btz) synergistically trigger apoptosis of even drug-resistant MM cells partly via modulation of RAD51 and accumulation of impaired DNA. 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.

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Fig. 1: MEDI2228 (M2) induces more potent cytotoxicity against MM cells than its MMAF-ADC homolog (M3).
Fig. 2: M2, more potently than M3, inhibits BMSC-induced MM cell viability and MM cells from patients.
Fig. 3: M2 significantly induces phosphorylation of DNA damage response (DDR)-signaling pathways in MM cells, regardless of p53 status and drug resistance.
Fig. 4: M2 treatment induces DDR-related gene expression including RAD51.
Fig. 5: Combined treatments with M2 and DDR inhibitors (DDRi s) cause synthetic lethality in drug-sensitive and -resistant MM cells.
Fig. 6: M2 co-treated with bortezomib synergistically induces MM cell death.
Fig. 7: M2 combined with bortezomib induces more potent in vivo anti-MM activity and prolonged survival in mice, when compared with individual drug alone.

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Acknowledgements

The authors thank the flow cytometry assistance from the flow cytometry facility at Dana-Farber Cancer Institute. We thank all lab members and the clinical research coordinators of the Jerome Lipper Multiple Myeloma Center and the LeBow Institute for Myeloma Therapeutics of the Dana-Farber Cancer Institute for support and help in providing primary tumor specimens for this study. We would also like to acknowledge Ryan Fleming of AstraZeneca for the preparation and characterization of ADCs used in this study.

Funding

This work was supported in part by grants from the National Institutes of Health Specialized Programs of Research Excellence (SPORE) P50 CA100707, P01CA155258, and RO1 CA 207237. This work was supported in part by Dr Miriam and Sheldon G Adelson Medical Research Foundation. KCA is an American Cancer Society Clinical Research Professor. This study was funded by AstraZeneca.

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Authors and Affiliations

  1. Jerome Lipper Multiple Myeloma Center, LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Lijie Xing, Liang Lin, Tengteng Yu, Yuyin Li, Shih-Feng Cho, Jiye Liu, Kenneth Wen, Phillip A. Hsieh, Nikhil Munshi, Kenneth C. Anderson & Yu-Tzu Tai

  2. Department of Hematology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, 250021, Shandong, PR China

    Lijie Xing

  3. School of Biotechnology, Tianjin University of Science and Technology, Key Lab of Industrial Fermentation Microbiology of the Ministry of Education, State Key Laboratory of Food Nutrition and Safety, Tianjin, 300457, PR China

    Yuyin Li

  4. Division of Hematology & Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

    Shih-Feng Cho

  5. Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Shih-Feng Cho

  6. Oncology Discovery, AstraZeneca, Gaithersburg, MD, USA

    Krista Kinneer

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  1. Lijie Xing
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Contributions

Conception and design: Y-TT, KK, KCA; Development of methodology: LX, LL, TY, YL, JL, S-FC. Acquisition of data (provided reagents, facilities, etc.): LX, LLin, T Yu, Y Li, J Liu, S-FC, KW, PAH. Reagents and Materials: KK. Analysis and interpretation of data (statistical analysis, biostatistics analysis): LX, LL, TY, YL, S-FC, JL, KW, PAH, Y-TT. Provided and managed patients: NM, KCA. Writing, review, and/or revision of the paper: LX, KK, Y-TT, KCA. Study supervision: KCA, Y-TT

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Correspondence to Kenneth C. Anderson or Yu-Tzu Tai.

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KK is an employee of AstraZeneca and has stock and/or stock interests in AstraZeneca. NM serves on advisory boards to Millennium-Takeda, Celgene, and Novartis. KCA serves on advisory boards Celgene, Millennium-Takeda, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Sanofi-Aventis and is a Scientific founder of OncoPep and C4 Therapeutics. All other authors declare no competing financial interests.

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Xing, L., Lin, L., Yu, T. et al. A novel BCMA PBD-ADC with ATM/ATR/WEE1 inhibitors or bortezomib induce synergistic lethality in multiple myeloma. Leukemia 34, 2150–2162 (2020). https://doi.org/10.1038/s41375-020-0745-9

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