Targeted therapy for Hodgkin lymphoma and systemic anaplastic large cell lymphoma: focus on brentuximab vedotin

Abstract

Despite the relative success of chemotherapy for Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), novel therapeutic agents are needed for refractory or relapsed patients. Targeted immunotherapy has emerged as a novel treatment option for these patients. Although unconjugated anti-cluster of differentiation (CD)30 antibodies showed minimal antitumor activity in early clinical trials, development of antibody-drug conjugates (ADCs) appears promising. Brentuximab vedotin is an ADC composed of an anti-CD30 antibody linked to a potent microtubule-disrupting agent monomethyl auristatin E (MMAE). It has the ability to target CD30-positive tumor cells and, once bound to CD30, brentuximab vedotin is internalized and MMAE is released to induce cell cycle arrest and apoptosis. In two Phase II trials, objective response was reported in 75% and 86% of patients with refractory or relapsed HL and systemic ALCL, respectively, with an acceptable toxicity profile. Based on these studies, the US Food and Drug Administration (FDA) granted accelerated approval of brentuximab vedotin in August 2011 for the treatment of refractory and relapsed HL and ALCL. We review the key characteristics of brentuximab vedotin, clinical data supporting its therapeutic efficacy, and current ongoing trials to explore its utility in other CD30-positive malignancies.

Keywords: CD30; SGN-35; brentuximab vedotin; classical Hodgkin lymphoma; systemic anaplastic large cell lymphoma.

Figure 1

Brentuximab vedotin mechanism of action. Notes: Brentuximab vedotin is an ADC composed of a chimeric anti-CD30 antibody, covalently linked via valine-citrulline dipeptides to four MMAE molecules (on average) (1). The ADC first binds to CD30 on the target cell surface (2) and is internalized by receptor-mediated endocytosis (3 and 4). Fusion with lysosomes (5) results in the proteolytic cleavage of the dipeptide linker, yielding free MMAE in the cytoplasm. MMAE then binds tubulin (6), inhibiting tubulin polymerization, and causing growth arrest. Abbreviations: ADC, antibody–drug conjugate; CD, cluster of differentiation; MMAE, monomethyl auristatin E.