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The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma

Abstract

Progress has been made recently in developing antibody-drug conjugates (ADCs) that can selectively deliver cancer drugs to tumor cells. In principle, the idea is simple: by attaching drugs to tumor-seeking antibodies, target cells will be killed and nontarget cells will be spared. In practice, many parameters needed to be addressed to develop safe and effective ADCs, including the expression profiles of tumor versus normal tissues, the potency of the drug, the linker attaching the drug and placement of the drug on the antibody, and the pharmacokinetic and stability profiles of the resulting ADC. All these issues had been taken into account in developing brentuximab vedotin (Adcetris), an ADC that recently received accelerated approval by the US Food and Drug Administration for the treatment of relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL). Research is under way to extend the applications of brentuximab vedotin and to advance the field by developing other ADCs with new linker and conjugation strategies.

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Figure 1: Some of the key players that helped advance ADC technology.
Figure 2: Mechanisms of drug delivery mediated by ADCs.

Katie Vicari

Figure 3: Structures of highly potent antimitotic drugs.
Figure 4: Drug-conjugation strategies.

Katie Vicari

Figure 5: Some important milestones that led to accelerated approval of brentuximab vedotin.

Katie Vicari

Figure 6: Maximum percentage reduction in the sum of the product of tumor diameters in individual patients (n = 98) per Cheson et al.65

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Acknowledgements

We are grateful for meaningful and enduring contributions by our colleagues at Seattle Genetics and various international cancer centers, our corporate partner, Millennium, the Takeda Oncology Company and to patients with life-threatening lymphoma, who collectively participated in clinical trials of brentuximab vedotin —ultimately leading to its approval by the FDA.

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Correspondence to Peter D Senter.

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P.D.S. and E.L.S. are paid employees and shareholders of Seattle Genetics.

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Senter, P., Sievers, E. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol 30, 631–637 (2012). https://doi.org/10.1038/nbt.2289

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