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Next-generation antibodies

Nature Reviews Drug Discovery volume 13, pages 413–414 (2014)Cite this article

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Antibody–drug conjugates

Antibody–drug conjugates (ADCs), the most prominent of the new antibody technology platforms, consist of a cytotoxic agent attached to a mAb via chemical linkers. By offering targeted delivery of chemotherapeutic agents directly to the cancerous tissue, ADCs may increase the clinical efficacy of mAbs and enable the deployment of cytotoxins that are too potent for systemic administration. The first ADC product, gemtuzumab ozogamicin (Mylotarg; Wyeth), a calicheamicin-linked CD33-specific mAb for the treatment of acute myeloid leukaemia (AML), was approved in 2000 but withdrawn in 2010 over safety concerns. New platforms for ADC development, such as the targeted antibody payload platform (TAP; Seattle Genetics and ImmunoGen), have emerged. In late 2011, brentuximab vedotin (Adcetris; Seattle Genetics), a CD30-specific mAb linked to the antimitotic agent monomethyl auristatin E (MMAE) for the treatment of non-Hodgkin's lymphoma (NHL), became the first of the new ADCs to gain approval from the US Food and Drug Administration (FDA). Its commercial impact to date has been muted, probably owing to problems with supply chains and the high cost of goods. The second approval was ado-trastuzumab-emtansine (Kadcyla; Genentech/Roche) in early 2013. Ado-trastuzumab-emtansine and the mAb pertuzumab (Perjeta; Roche (approved in 2012)) were developed as line-extensions of trastuzumab (Herceptin; Roche), targeting HER2 (also known as ERBB2) with different modes of action; Perjeta inhibits HER2–HER3 dimerization whereas ado-trastuzumab-emtansine delivers a cytotoxic payload to the cells. These agents can be used in combination with trastuzumab in metastatic, adjuvant and neoadjuvant settings, extending treatment opportunities. If successful, this strategy will offer a template for market life-cycle management. The next wave of products to enter the market will probably include CDX011 (glembatumumab vedotin; Celldex/Seattle Genetics), which targets glycoprotein non-metastatic melanoma protein B (GPNMB) and is in accelerated approval trials. Beyond this, Roche has two other ADCs in Phase II: pinatuzumab vedotin, targeting CD22 to treat lymphoma; and polatuzumab vedotin, targeting CD79b to treat NHL and diffuse large B cell lymphoma (DLBCL). Sanofi has a TAP-based CD19-binding antibody, SAR3419, in multiple Phase II studies in DLBCL and in B cell acute lymphoblastic leukaemia (B-ALL).

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Figure 1: Market potential for NGA products, 2013–2021.

Change history

  • 29 April 2014

    There was a small error in the Figure 1 title (it should refer to the 2013–2021 period, not 2012–2020). This has now been updated online.

References

  1. Reichert, J. M. Which are the antibodies to watch in 2013? MAbs 5, 1–4 (2013).

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  2. Visiongain. Next-Generation Antibody Therapeutics Market 2013–2023 (Visiongain, 2013).

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Authors and Affiliations

  1. Visiongain, BSG HOUSE, 230 City Road, London, EC1V 2QY, UK

    James B. Evans

  2. IMS Health, 210 Pentonville Road, London, N1 9JY, UK

    Basharut A. Syed

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  1. James B. Evans
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  2. Basharut A. Syed
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Correspondence to Basharut A. Syed.

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The authors declare no competing financial interests.

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Evans, J., Syed, B. Next-generation antibodies. Nat Rev Drug Discov 13, 413–414 (2014). https://doi.org/10.1038/nrd4255

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