ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053

Abstract

Purpose

Multiple myeloma (MM) remains incurable and its diagnosis relies heavily on bone marrow aspiration and biopsy. CD38 is a glycoprotein highly specific for MM. Antibody therapeutics (e.g., daratumumab) targeting CD38 have shown encouraging efficacy in treating MM, either as a monotherapy agent or in combination with other regimens. However, efficient stratification of patients who might benefit from daratumumab therapy and timely monitoring of the therapeutic responses are still clinical challenges. This work aims to devise a CD38-targeted imaging strategy and assess its value in diagnosing MMs.

Methods

By labeling a CD38-specific single domain antibody (Nb1053) with 68Ga (t1/2 = 1.1 h), we developed a CD38-targeted immuno-positron emission tomography (immunoPET) imaging probe [68Ga]Ga-NOTA-Nb1053. The probe was developed with good radiochemical yield (> 50%), excellent radiochemical purity (> 99%), and immunoreactivity (> 95%). The diagnostic accuracy of the probe was thoroughly investigated in preclinical MM models.

Results

ImmunoPET imaging with [68Ga]Ga-NOTA-Nb1053 specifically depicted all the subcutaneous and orthotopic MM lesions, outperforming the traditional 18F-fluorodeoxyglucose PET and the nonspecific [68Ga]Ga-NOTA-NbGFP immunoPET. More importantly, daratumumab preloading significantly reduced [68Ga]Ga-NOTA-Nb1053 uptake in the disseminated bone lesions, indicating the overlapping targeting epitopes of [68Ga]Ga-NOTA-Nb1053 with that of daratumumab. Furthermore, premedication with sodium maleate or fructose significantly decreased kidney retention of [68Ga]Ga-NOTA-Nb1053 and improved the diagnostic value of the probe in lymphoma models.

Conclusion

This work successfully developed a novel CD38-targeted immunoPET imaging approach that enabled precise visualization of CD38 and diagnosis of MMs. Upon clinical translation, [68Ga]Ga-NOTA-Nb1053 immunoPET may serve as a valuable CD38-targeted molecular imaging toolbox, facilitating early diagnosis of MM and precise assessment of the therapeutic responses.

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Data availability

All the raw data and materials involved in the work can be obtained from Prof. Wei upon rational request.

Code availability

Not applicable.

References

  1. 1.

    Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International myeloma working group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48. https://doi.org/10.1016/S1470-2045(14)70442-5.

    Article  PubMed  Google Scholar 

  2. 2.

    Nooka AK, Kaufman JL, Hofmeister CC, Joseph NS, Heffner TL, Gupta VA, et al. Daratumumab in multiple myeloma. Cancer. 2019;125:2364–82. https://doi.org/10.1002/cncr.32065.

    Article  PubMed  Google Scholar 

  3. 3.

    van de Donk N, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131:13–29. https://doi.org/10.1182/blood-2017-06-740944.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328–e46. https://doi.org/10.1016/S1470-2045(16)30206-6.

    Article  PubMed  Google Scholar 

  5. 5.

    Wei W, Rosenkrans ZT, Liu J, Huang G, Luo QY, Cai W. ImmunoPET: concept, design, and applications. Chem Rev. 2020;120:3787–851. https://doi.org/10.1021/acs.chemrev.9b00738.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Wei W, Ni D, Ehlerding EB, Luo QY, Cai W. PET imaging of receptor tyrosine kinases in cancer. Mol Cancer Ther. 2018;17:1625–36. https://doi.org/10.1158/1535-7163.MCT-18-0087.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Wei W, Jiang D, Ehlerding EB, Luo Q, Cai W. Noninvasive PET imaging of T cells. Trends Cancer. 2018;4:359–73. https://doi.org/10.1016/j.trecan.2018.03.009.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Wei W, Jiang D, Lee HJ, Li M, Kutyreff CJ, Engle JW, et al. Development and characterization of CD54-targeted immunoPET imaging in solid tumors. Eur J Nucl Med Mol Imaging. 2020;47:2765–75. https://doi.org/10.1007/s00259-020-04784-0.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Wei W, Jiang D, Ehlerding EB, Barnhart TE, Yang Y, Engle JW, et al. CD146-targeted multimodal image-guided photoimmunotherapy of melanoma. Adv Sci (Weinh). 2019;6:1801237. https://doi.org/10.1002/advs.201801237.

    CAS  Article  Google Scholar 

  10. 10.

    Wei W, Jiang D, Rosenkrans ZT, Barnhart TE, Engle JW, Luo Q, et al. HER2-targeted multimodal imaging of anaplastic thyroid cancer. Am J Cancer Res. 2019;9:2413–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Wei W, Liu Q, Jiang D, Zhao H, Kutyreff CJ, Engle JW, et al. Tissue factor-targeted immunoPET imaging and radioimmunotherapy of anaplastic thyroid cancer. Adv Sci (Weinh). 2020;7:1903595. https://doi.org/10.1002/advs.201903595.

    CAS  Article  Google Scholar 

  12. 12.

    Caserta E, Chea J, Minnix M, Poku EK, Viola D, Vonderfecht S, et al. Copper 64-labeled daratumumab as a PET/CT imaging tracer for multiple myeloma. Blood. 2018;131:741–5. https://doi.org/10.1182/blood-2017-09-807263.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ghai A, Maji D, Cho N, Chanswangphuwana C, Rettig M, Shen D, et al. Preclinical development of CD38-targeted [(89)Zr]Zr-DFO-daratumumab for imaging multiple myeloma. J Nucl Med. 2018;59:216–22. https://doi.org/10.2967/jnumed.117.196063.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ulaner GA, Sobol NB, O'Donoghue JA, Kirov AS, Riedl CC, Min R, et al. CD38-targeted immuno-PET of multiple myeloma: from xenograft models to first-in-human imaging. Radiology. 2020;295:606–15. https://doi.org/10.1148/radiol.2020192621.

    Article  PubMed  Google Scholar 

  15. 15.

    Krishnan A, Adhikarla V, Poku EK, Palmer J, Chaudhry A, Biglang-Awa VE, et al. Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64-labeled daratumumab. Blood Adv. 2020;4:5194–202. https://doi.org/10.1182/bloodadvances.2020002603.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Chakravarty R, Goel S, Cai W. Nanobody: the “magic bullet” for molecular imaging? Theranostics. 2014;4:386–98. https://doi.org/10.7150/thno.8006.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Xing Y, Chand G, Liu C, Cook GJR, O'Doherty J, Zhao L, et al. Early phase I study of a (99m)Tc-labeled anti-programmed death ligand-1 (PD-L1) single-domain antibody in SPECT/CT assessment of PD-L1 expression in non-small cell lung cancer. J Nucl Med. 2019;60:1213–20. https://doi.org/10.2967/jnumed.118.224170.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Keyaerts M, Xavier C, Heemskerk J, Devoogdt N, Everaert H, Ackaert C, et al. Phase I study of 68Ga-HER2-nanobody for PET/CT assessment of HER2 expression in breast carcinoma. J Nucl Med. 2016;57:27–33. https://doi.org/10.2967/jnumed.115.162024.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Li T, Qi S, Unger M, Hou YN, Deng QW, Liu J, et al. Immuno-targeting the multifunctional CD38 using nanobody. Sci Rep. 2016;6:27055. https://doi.org/10.1038/srep27055.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    An N, Hou YN, Zhang QX, Li T, Zhang QL, Fang C, et al. Anti-multiple myeloma activity of nanobody-based anti-CD38 chimeric antigen receptor T cells. Mol Pharm. 2018;15:4577–88. https://doi.org/10.1021/acs.molpharmaceut.8b00584.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Deng QW, Zhang J, Li T, He WM, Fang L, Lee HC, et al. The transferrin receptor CD71 regulates type II CD38, revealing tight topological compartmentalization of intracellular cyclic ADP-ribose production. J Biol Chem. 2019;294:15293–303. https://doi.org/10.1074/jbc.RA119.010010.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Kubala MH, Kovtun O, Alexandrov K, Collins BM. Structural and thermodynamic analysis of the GFP:GFP-nanobody complex. Protein Sci. 2010;19:2389–401. https://doi.org/10.1002/pro.519.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Greenstein S, Krett NL, Kurosawa Y, Ma C, Chauhan D, Hideshima T, et al. Characterization of the MM.1 human multiple myeloma (MM) cell lines: a model system to elucidate the characteristics, behavior, and signaling of steroid-sensitive and -resistant MM cells. Exp Hematol. 2003;31:271–82. https://doi.org/10.1016/s0301-472x(03)00023-7.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Altai M, Garousi J, Rinne SS, Schulga A, Deyev S, Vorobyeva A. On the prevention of kidney uptake of radiolabeled DARPins. EJNMMI Res. 2020;10:7. https://doi.org/10.1186/s13550-020-0599-1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Ehlerding EB, England CG, Jiang D, Graves SA, Kang L, Lacognata S, et al. CD38 as a PET imaging target in lung cancer. Mol Pharm. 2017;14:2400–6. https://doi.org/10.1021/acs.molpharmaceut.7b00298.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    D'Huyvetter M, De Vos J, Caveliers V, Vaneycken I, Heemskerk J, Duhoux FP, et al. Phase I trial of (131)I-GMIB-Anti-HER2-VHH1, a new promising candidate for HER2-targeted radionuclide therapy in breast cancer patients. J Nucl Med. 2020:jnumed.120.255679. https://doi.org/10.2967/jnumed.120.255679.

  27. 27.

    Chatalic KL, Veldhoven-Zweistra J, Bolkestein M, Hoeben S, Koning GA, Boerman OC, et al. A novel (1)(1)(1)in-labeled anti-prostate-specific membrane antigen nanobody for targeted SPECT/CT imaging of prostate cancer. J Nucl Med. 2015;56:1094–9. https://doi.org/10.2967/jnumed.115.156729.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Kang L, Jiang D, England CG, Barnhart TE, Yu B, Rosenkrans ZT, et al. ImmunoPET imaging of CD38 in murine lymphoma models using (89)Zr-labeled daratumumab. Eur J Nucl Med Mol Imaging. 2018;45:1372–81. https://doi.org/10.1007/s00259-018-3941-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Zamagni E, Tacchetti P, Cavo M. Imaging in multiple myeloma: how? when? Blood. 2019;133:644–51. https://doi.org/10.1182/blood-2018-08-825356.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Cavo M, Terpos E, Nanni C, Moreau P, Lentzsch S, Zweegman S, et al. Role of (18)F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group. Lancet Oncol. 2017;18:e206–e17. https://doi.org/10.1016/S1470-2045(17)30189-4.

    Article  PubMed  Google Scholar 

  31. 31.

    Kumar S, Glazebrook KN, Broski SM. Fludeoxyglucose F 18 PET/computed tomography evaluation of therapeutic response in multiple myeloma. PET Clin. 2019;14:391–403. https://doi.org/10.1016/j.cpet.2019.03.006.

    Article  PubMed  Google Scholar 

  32. 32.

    Rasche L, Angtuaco E, McDonald JE, Buros A, Stein C, Pawlyn C, et al. Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood. 2017;130:30–4. https://doi.org/10.1182/blood-2017-03-774422.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Bailly C, Chalopin B, Gouard S, Carlier T, Saëc PR-L, Marionneau-Lambot S, et al. ImmunoPET in multiple myeloma—what? so what? now what? Cancers (Basel). 2020;12:1467. https://doi.org/10.3390/cancers12061467.

    CAS  Article  Google Scholar 

  34. 34.

    Minnix M, Adhikarla V, Caserta E, Poku E, Rockne R, Shively JE, et al. Comparison of CD38 targeted alpha- vs beta-radionuclide therapy of disseminated multiple myeloma in an animal model. J Nucl Med. 2020. https://doi.org/10.2967/jnumed.120.251983.

  35. 35.

    Li S, England CG, Ehlerding EB, Kutyreff CJ, Engle JW, Jiang D, et al. ImmunoPET imaging of CD38 expression in hepatocellular carcinoma using 64Cu-labeled daratumumab. Am J Transl Res. 2019;11:6007–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Nielsen R, Christensen EI, Birn H. Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease. Kidney Int. 2016;89:58–67. https://doi.org/10.1016/j.kint.2015.11.007.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Gainkam LO, Caveliers V, Devoogdt N, Vanhove C, Xavier C, Boerman O, et al. Localization, mechanism and reduction of renal retention of technetium-99m labeled epidermal growth factor receptor-specific nanobody in mice. Contrast Media Mol Imaging. 2011;6:85–92. https://doi.org/10.1002/cmmi.408.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Rashidian M, Ingram JR, Dougan M, Dongre A, Whang KA, LeGall C, et al. Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. J Exp Med. 2017;214:2243–55. https://doi.org/10.1084/jem.20161950.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Fumey W, Koenigsdorf J, Kunick V, Menzel S, Schutze K, Unger M, et al. Nanobodies effectively modulate the enzymatic activity of CD38 and allow specific imaging of CD38(+) tumors in mouse models in vivo. Sci Rep. 2017;7:14289. https://doi.org/10.1038/s41598-017-14112-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Xu J, Chen LJ, Yang SS, Sun Y, Wu W, Liu YF, et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci U S A. 2019;116:9543–51. https://doi.org/10.1073/pnas.1819745116.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors want to thank all the clinical and research staff at the Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University for their technical assistance and helpful discussions.

Funding

This work was supported in part by the National Key Research and Development Program of China (Grant No. 2020YFA0909000), National Natural Science Foundation of China (Grant Nos. 81771858, 81830052, 81530053, 31871403, and 82001878), Shanghai Key Laboratory of Molecular Imaging (Grant No. 18DZ2260400), Shanghai Rising-Star Program (Grant No. 20QA1406100), Foundation for Basic Research of Science and Technology Project in Shenzhen (Grant No. JCYJ20190808163411340), Construction Project of Shanghai Key Laboratory of Molecular Imaging (Grant No. 18DZ2260400), and Shanghai Municipal Education Commission (Class II Plateau Disciplinary Construction Program of Medical Technology of SUMHS, 2018–2020).

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Contributions

W. Wei, J. Liu, and Y. J. Zhao collaboratively conceived and designed the project. C. Wang, Y. Chen, W. Wei, Q. Liu, and D. Zhang performed the experiments and wrote most of the manuscript. Y. N. Hou produced the sdAbs and contributed to the writing. S. An, Y. Zhang, and H. Zhao helped in the radiolabeling and characterization of the radiotracers. J. Hou and G. Huang provided inputs in the initial design of the project and revised the manuscript. W. Wei, J. Liu, and Y. J. Zhao supervised the study, revised, and finalized the manuscript.

Corresponding authors

Correspondence to Jianjun Liu or Yong Juan Zhao or Weijun Wei.

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Conflict of interest

W. Wei and J. Liu are co-inventors on a provisional patent application (Application No. 202011131233.7) encompassing the technology described in this manuscript.

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Wang, C., Chen, Y., Hou, Y.N. et al. ImmunoPET imaging of multiple myeloma with [68Ga]Ga-NOTA-Nb1053. Eur J Nucl Med Mol Imaging (2021). https://doi.org/10.1007/s00259-021-05218-1

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Keywords

  • ImmunoPET
  • Multiple myeloma
  • Nanobody
  • CD38
  • Daratumumab