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A unique aptamer-drug conjugate for targeted therapy of multiple myeloma

Leukemia volume 30, pages 987–991 (2016)Cite this article

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Despite recent advances in cancer therapeutics, multiple myeloma (MM) remains incurable1 and new targeted treatments are critically needed. CD38, a 46-kDa type II transmembrane glycoprotein, has been widely used for detection of plasma cells and diagnosis of MM (Supplementary Figure 1A), and is an attractive biomarker for targeted MM therapy.2 Therapeutic anti-CD38 monoclonal antibodies are currently undergoing clinical evaluation.2, 3 In addition, antibody-drug conjugates have been developed that combine a targeting antibody with cytotoxic agents, which significantly enhances the therapeutic potential by preferentially targeting cancer cells and avoiding healthy tissues.4, 5 However, manufacture of antibody-drug conjugates is costly and time- and labor-intensive. Aptamers are a new class of small molecule ligands composed of short, single-stranded oligonucleotides that are developed from RNA or ssDNA libraries via systematic evolution of ligands by exponential enrichment.6, 7 Similar to protein antibodies, aptamers specifically recognize and bind to their targets with high affinity on the basis of their unique three-dimensional structures.8 However, compared with protein antibodies, aptamers offer a number of advantages: they (i) exhibit higher tissue-penetrating potential due to their small size; (ii) appear to have negligible immunogenicity in vivo; (iii) can be easily conjugated to various functional agents; and (iv) can be simply generated through chemical synthesis at a low cost.8 In this study, we fabricated CD38-specific aptamer-drug conjugates (ApDCs) and demonstrated that the synthetic ApDCs provide a new avenue for targeted MM therapy.

To develop CD38-specific ssDNA aptamers that are also able to target MM cells, a hybrid systematic evolution of ligands by exponential enrichment process including MM cell-based selection and CD38 protein-based enrichment was performed (Supplementary Figure 2A). The 20 most abundant sequences were determined by next generation sequencing were comprised of three groups identified by clustal analysis (Supplementary Figures 2B and C). Among them, aptamer #1 had the highest binding affinity and specificity (Supplementary Figure 3) and was therefore chosen for subsequent studies. To determine minimal functional sequences, aptamer #1 was truncated based on the structure predicted by software and subsequent cell binding analysis demonstrated that aptamer #1 and #1S had similar binding affinities (Supplementary Figure 4A). The specificity of aptamer #1S was confirmed in additional MM and control cells (Supplementary Figure 4B). Western blots and siRNA-induced gene silencing studies showed that both aptamer #1 and #1S specifically recognized cellular CD38 proteins and CD38-expressing cells (Supplementary Figures 4C and D). As aptamer #1S is smaller in size and may have higher potential for in vivo tissue penetration, it was selected for further studies. MM cells (MM1S) and CD38-negative cells were mixed and fluorescence microscopy revealed that aptamer #1S selectively bound to MM1S cells and did not react to the negative control cells (Supplementary Figure 4E).

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Acknowledgements

The authors thank Drs Zheng-Zheng Shi, Kemi Cui and David Haviland at the Houston Methodist Research Institute for their technical support, and Dr Kathryn Stockbauer for editorial assistance. This study was partially supported by NIH grants R01CA151955, R33CA173382 and CPRIT grant (RP140315) to YZ.

Author contributions

JW, SPI and YZ designed the experiments. JW, WT and SH performed the experiments. JW and YZ prepared the manuscript. All authors read the manuscript and provided critical input.

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Authors and Affiliations

  1. Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA

    J Wen, S Hao & Y Zu

  2. Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    W Tao

  3. Houston Methodist Cancer Center, Houston, TX, USA

    S P Iyer

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  1. J Wen
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Correspondence to Y Zu.

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Wen, J., Tao, W., Hao, S. et al. A unique aptamer-drug conjugate for targeted therapy of multiple myeloma. Leukemia 30, 987–991 (2016). https://doi.org/10.1038/leu.2015.216

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