CD30 in Pathway Context
This figure illustrates the classical activation of the NF-κB pathway in Hodgkin lymphoma, in which CD30 is among the receptors (top row) that help promote events leading to the survival of cancerous cells.
Adapted from Horton TH, Sheehan AM, López-Terrada D, et al. Analysis of NFκ-B pathway proteins in pediatric Hodgkin lymphoma: correlations with EBV status and clinical outcome—a Children’s Oncology Group Study. Lymphoma. 2012;article ID 341629. http://dx.doi.org/10.1155/2012/341629.
The cytokine receptor CD30 was identified as an attractive anticancer target more than 30 years ago. Initial clinical trials using naked monoclonal antibodies (mAbs) directed against CD30 were disappointing, even when the antibodies were engineered to have enhanced activity. Conjugating CD30 mAbs to a cytotoxic agent resulted in the development of brentuximab vedotin (Adcetris), which has demonstrated remarkable responses in patients with relapsed and refractory Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL), for which it has now been approved in the United States and Europe.
Today, exploration of the CD30 pathway revolves around a substantial development program for brentuximab vedotin in HL, ALCL, and a number of other CD30-positive malignancies, in some cases in the front-line setting, both as monotherapy and in combination regimens.
Several experimental strategies for using genetically engineered T cells in CD30-positive lymphomas also are being explored.
Malignant Activity Stands Out
The CD30 protein is a member of the tumor necrosis factor (TNF) receptor superfamily of cytokine receptors. Although predominantly expressed as a type I transmembrane protein, it also is shed in a soluble form (sCD30).
In healthy individuals, CD30 is found mainly on activated B, T, and NK cells of the immune system and its expression elsewhere is limited. While its exact function is poorly understood, it has been shown to regulate a diverse range of important biological processes in these cells, including activation of mitogen-activated protein (MAP) kinases and nuclear factor-kappa B (NFκB). The outcome of CD30 signaling is context-dependent and can lead to promotion of cell proliferation and survival or, conversely, antiproliferative responses and cell death. A number of other functions for CD30 have been proposed, including regulation of memory cells, B-cell proliferation, and enhancement of immunoglobulin (Ig) production.
CD30 is highly expressed on malignant cells, particularly such lymphoid malignancies as HL and ALCL, which are defined by the presence of CD30 and show CD30 expression on all of the constituent cells of the tumor. It regulates the growth of these malignant lymphomas by promoting NFκB activation and driving cancer cell survival. sCD30 is also observed at elevated levels in patients with HL and ALCL, and has been shown to correlate with poor prognosis.
Given its limited expression in normal cells, high levels of expression in malignant cells, and its important role in driving the development of lymphomas and other malignancies, researchers set their sights on targeting CD30. Although most of the investigations have focused on T-cell and B-cell malignancies, researchers also have explored CD30 expression in testicular embryonal carcinomas.
First and Second-Generation Agents
Antibody-based cancer therapies that target specific antigens expressed on the cancer cell surface have shown remarkable activity in a variety of different tumor types and, in fact, the three top-selling cancer drugs in 2012 were mAbs. Unsurprisingly, therefore, the first CD30-targeting agents to be advanced into clinical trials were mAbs, including cAC10 (SGN-30), a chimeric antibody constructed from the mouse mAb AC10 and the human gamma 1 heavy chain and kappa light chain constant regions, and MDX-060, a fully human IgG1 mAb. However, these agents displayed only limited efficacy when administered as single agents, with low response rates and high production of nontherapeutic antibodies.