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Multiple myeloma gammopathies

Preclinical assessment of an antibody–PBD conjugate that targets BCMA on multiple myeloma and myeloma progenitor cells

Leukemia volume 33, pages 766–771 (2019)Cite this article

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Although current treatments are effective in controlling multiple myeloma (MM) and prolonging remission, the disease invariably recurs. A possible explanation for the recalcitrance of MM is that a subpopulation of chemoresistant cells with clonogenic potential, distinct from the bulk of myeloma cells, may be responsible for recurrence [1, 2]. Several studies have shown that some MM cells lack a mature plasma cell phenotype and that these less differentiated myeloma progenitor cells (MPCs) can transfer the disease, share immunoglobulin H (IgH) gene rearrangements with mature MM cells, show greater clonogenic growth, and predict a poorer patient response to both stem cell transplant and treatment with proteasome inhibitors [3,4,5,6].

B-cell maturation antigen (BCMA) is absent in non-hematopoietic tissues and is selectively expressed in plasmablasts, plasma cells, and plasmacytoid dendritic cells [7, 8]. BCMA expression has been linked to hematologic malignancies, most notably MM, where it is expressed in all stages of the disease. Although the expression and functional relevance of BCMA makes it an attractive target for the treatment of MM, its expression in MPCs is unknown. Herein, we characterize the MPC population present in MM patient bone marrow and examine expression of BCMA in these cells. In addition, we describe the preclinical development of MEDI2228, a novel BCMA-targeting antibody–drug conjugate (ADC) for the treatment of MM.

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Acknowledgements

We gratefully acknowledge Jeff Carrell (MedImmune) for his assistance with flow cytometry; Terrence O’Day (MedImmune) for statistical support; Deborah Shuman (MedImmune) for editorial assistance during the preparation of this manuscript; and Sepi Farshadi (MedImmune) for help with the preparation of figures. This study was funded by MedImmune, the global biologics R&D arm of AstraZeneca.

Author contributions

KK, EMH, SBT, MF and ND designed experiments, analyzed and interpreted data, and wrote the manuscript; KK, JM, RV, SB, SBT, MF, PGH, RF, BB, CC, LW, RC and Y-TT designed and performed experiments and interpreted data; XX and HZ designed experiments and interpreted data; KCA, RH, PWH and DAT provided guidance, intellectual input, and reviewed the paper; all authors participated in critical review and editing of the manuscript.

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Author notes

  1. Xiaodong Xiao

    Present address: Bristol-Myers Squibb, Redwood City, CA, USA

  2. Paul G. Hynes

    Present address: Cell Medica, London, UK

  3. Binyam Bezabeh

    Present address: Salubris Biotherapeutics, Gaithersburg, MD, USA

Authors and Affiliations

  1. MedImmune, Oncology Research, Gaithersburg, MD, USA

    Krista Kinneer, Matt Flynn, Suneetha B. Thomas, John Meekin, Haihong Zhong, Shannon Breen, Paul G. Hynes, Cui (Tracy) Chen, Leslie Wetzel, Ronald Herbst, Elaine M. Hurt & David A. Tice

  2. MedImmune, Antibody Discovery and Protein Engineering, Gaithersburg, MD, USA

    Reena Varkey, Xiaodong Xiao, Ryan Fleming, Binyam Bezabeh & Nazzareno Dimasi

  3. MedImmune, Biosuperiors, Gaithersburg, MD, USA

    Ruoyan Chen

  4. Dana-Farber Cancer Institute, Boston, MA, USA

    Yu-Tzu Tai & Kenneth C. Anderson

  5. Spirogen, London, UK

    Philip W. Howard

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  1. Krista Kinneer
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Corresponding author

Correspondence to Krista Kinneer.

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Conflict of interest

Y-TT declares that she has no conflict of interest. KCA is the scientific founder of Oncopep and C4 Therapeutics and serves on the advisory boards of MedImmune, Bristol-Myers Squibb, Gilead and Millenium Pharmaceuticals. PWH is an employee of Spirogen and has stock and/or stock interests in AstraZeneca. All other authors are employees of MedImmune or were employees of MedImmune while they were involved with this work and have stock and/or stock interests in AstraZeneca.

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Kinneer, K., Flynn, M., Thomas, S.B. et al. Preclinical assessment of an antibody–PBD conjugate that targets BCMA on multiple myeloma and myeloma progenitor cells. Leukemia 33, 766–771 (2019). https://doi.org/10.1038/s41375-018-0278-7

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