Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) approved for the treatment of relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). Brentuximab vedotin is comprised of a chimeric IgG1-directed antibody against CD30 and the small molecule, MMAE, a microtubule-disrupting agent covalently attached to the antibody via a cleavable linker. The primary anticancer activity of BV is believed to be the binding of the ADC to CD30-expressing cells, followed by internalization, release of MMAE which results in microtubule network disruption, cell cycle arrest, and apoptotic death.
In addition to classical ADC activity, the antibody and auristatin drug payload components of BV have additional and distinct modalities that may contribute to its overall function and antitumor activity in the heterogeneous and complex immune microenvironment of lymphoma. In addition to classical ADC activity, recent evidence elucidates new functionality of BV including antibody-dependent cellular phagocytosis (ADCP); bystander-killing of nearby CD30-negative tumor cells in the tumor microenvironment due to MMAE release from CD30-expressing tumor cells and macrophages; and immunogenic cell death driven by endoplasmic reticulum (ER) stress that can promote an antigen specific T-cell response.
Decoration of CD30-expressing cells with BV mediates macrophage recognition and phagocytosis promoting the removal of tumor cells independent of antibody internalization and release of the auristatin payload (MMAE). This activity occurs in vitro and contributes to in vivo activity seen with the antibody backbone. Furthermore, cell-permeable MMAE released from proteolytic processing of BV by macrophages within the tumor microenvironment or CD30-expressing tumor cells is able to kill antigen-negative tumor cells in a variety of in vivo tumor models. Additionally, in vitro characterization has demonstrated that MMAE-mediated disruption of microtubules not only drives tumor cell apoptosis but results in ER stress leading to surface exposure of immune-activating molecules that can drive innate and adaptive immune response that may contribute to the overall and long-term antitumor activity of BV. Taken together, these data provide rationale for the activity of BV in tumors with low and heterogeneous CD30 expression and for ongoing combinatorial trial with immuno-oncology agents.