Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

CD30-targeting immunoconjugates and bystander effects

Nature Reviews Clinical Oncology volume 12, page 245 (2015)Cite this article

Subjects

Access through your institution
Buy or subscribe

Immunoconjugates, also known as antibody-drug conjugates (ADCs), consist of monocloncal antibodies and cytotoxic drugs (for example, monomethyl auristatin E [MMAE], a potent mitotic spindle formation inhibitor), which are connected by a linker. The elegant Review by Smaglo and colleagues (The development of immunoconjugates for targeted cancer therapy. Nat. Rev. Clin. Oncol. 11, 637–648; 2014)1 explains the details of ADCs, including brentuximab vedotin, an anti-CD30–MMAE immunoconjugate that received FDA approval for the treatment of patients with Hodgkin lymphoma or anaplastic large-cell lymphoma in 2011. Other forms of lymphoma have been intensively investigated to explore whether brentuximab vedotin is an effective treatment for tumours containing cells that present CD30. The high clinical response rates achieved using brentuximab vedotin in patients with lymphoma suggest that this agent is one of the most promising drugs currently available for targeted lymphoma treatment. However, we would like to highlight interesting, and potentially important, findings on the mechanism of action of this targeted therapy, and discuss possible future perspectives.

According to reports, a 'paradoxical lack of correlation' exists between tumour CD30 expression and clinical response to brentuximab vedotin;2 even in tumours in which the percentage of CD30-positive cells is low, the response rate is sometimes high. Although the precise mechanisms underlying this phenomenon remain unknown, some evidence indicates a 'bystander effect', whereby free MMAE is released from dying cells in concentrations sufficient to kill neighbouring tumour cells3 either directly or indirectly by altering the tumour microenvironment. This bystander effect might explain the favourable clinical responses associated with brentuximab vedotin. Tumour heterogeneity is increasingly recognized as a key determinant of treatment outcome, and bystander effects of targeted therapy that overcome heterogeneous expression of the target antigen might have important clinical consequences. The bystander effect itself has been demonstrated elsewhere, in a study using BAY 94-9343, a novel ADC targeting mesothelin.4 Other ADCs include auristatin-based immunoconjugates targeting tumour necrosis factor receptor superfamily member 17 (also known as B-cell maturation protein; GSK2857916),5 CD70 (SGN-75),6 CXC-motif chemokine receptor 4,7 prostate-specific membrane antigen,8 and LIV-1 (also known as ZIP6; SGN-LIV1A),9 as well as an anti-CD37–maytansinoid immunoconjugate (IMGN529).10 Whether or not these agents have the same bystander effects on surrounding cells would be interesting to know.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Smaglo, B. G., Aldeghaither, D. & Weiner, L. M. The development of immunoconjugates for targeted cancer therapy. Nat. Rev. Clin. Oncol. 11, 637–648 (2014).

    Article  CAS  Google Scholar 

  2. Horwitz, S. M. et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood 123, 3095–3100 (2014).

    Article  CAS  Google Scholar 

  3. Okeley, N. M. et al. Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin. Cancer Res. 16, 888–897 (2010).

    Article  CAS  Google Scholar 

  4. Golfier, S. et al. Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol. Cancer Ther. 13, 1537–1548 (2014).

    Article  CAS  Google Scholar 

  5. Tai, Y. T. et al. Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood 123, 3128–3138 (2014).

    Article  CAS  Google Scholar 

  6. Tannir, N. M. et al. Novel Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma. Invest. New Drugs 32, 1246–1257 (2014).

    Article  CAS  Google Scholar 

  7. Kularatne, S. A. et al. A CXCR4-targeted site-specific antibody-drug conjugate. Angew. Chem. Int. Ed. Engl. 53, 11863–11867 (2014).

    Article  CAS  Google Scholar 

  8. DiPippo, V. A. et al. Efficacy studies of an antibody-drug conjugate PSMA–ADC in patient-derived prostate cancer xenografts. Prostate 75, 303–313 (2015).

    Article  CAS  Google Scholar 

  9. Sussman, D. et al. SGN-LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer. Mol. Cancer Ther. 13, 2991–3000 (2014).

    Article  CAS  Google Scholar 

  10. Beckwith, K. A. et al. The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model. Leukemia 28, 1501–1510 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors express their appreciation to Drs Kaori Okimoto, Satsuki Fukushima and Atsuhiro Saito for their assistance with this correspondence.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Shigeo Masuda, Shigeru Miyagawa, Nagako Sougawa & Yoshiki Sawa

Authors
  1. Shigeo Masuda
    View author publications

    Search author on:PubMed Google Scholar

  2. Shigeru Miyagawa
    View author publications

    Search author on:PubMed Google Scholar

  3. Nagako Sougawa
    View author publications

    Search author on:PubMed Google Scholar

  4. Yoshiki Sawa
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Yoshiki Sawa.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Masuda, S., Miyagawa, S., Sougawa, N. et al. CD30-targeting immunoconjugates and bystander effects. Nat Rev Clin Oncol 12, 245 (2015). https://doi.org/10.1038/nrclinonc.2014.159-c1

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nrclinonc.2014.159-c1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing