Figure 1. CD19 as a Regulator in BCR Signaling
BCR indicates B-cell receptor; BTK, Bruton tyrosine kinase.
Source: GeneCards, www.genecards.org./p>
For the past two decades, researchers have been exploring B-cell specific antigens in hopes of developing a new anticancer target that would mirror the success of the CD20-targeting rituximab (Rituxan). Now, strategies aimed at CD19 are proving particularly promising.
CD19 is serving as the target not only of antibody-based therapies but also in a potentially paradigm-altering approach to cancer immunotherapy that continues to yield impressive clinical outcomes. The complexities of developing CD19-targeting immunotherapy were highlighted recently when several clinical trials were suspended for a safety review in response to the deaths of two patients during a study.
CD19 Makes an Attractive Target
CD19 is a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily, which plays a critical role in establishing an optimal immune response by regulating both B-cell receptor (BCR)- dependent and BCR–independent signaling pathways. It regulates both antigen-independent development and immunoglobulin- induced activation of B cells. (Figure 1
CD19 makes an attractive target for cancer therapy since its expression on normal cells is limited to those of B-cell lineage. Furthermore, it is expressed on the vast majority of B-cell malignancies, including 80% of acute lymphoblastic leukemias (ALLs), 88% of B-cell lymphomas, and 100% of B-cell leukemias.
Thus, CD19 is a suitable tumor-associated antigen (TAA) against which to target anticancer agents. In contrast to CD20, CD19 is expressed throughout B-cell development, from B-cell precursors through to mature B cells, before expression is lost when they become plasma cells.
This wider range of expression potentially gives CD19-targeted agents an advantage over their CD20 counterparts, since they could be more useful in treating early B-cell neoplasms like ALL, which cannot be treated with rituximab.
Antibody-Based Strategies Under Study
A number of monoclonal antibodies (mAbs) targeting the CD19 protein are in various stages of development for the treatment of B-cell malignancies. The murine B4 antibody was one of the earliest CD19-targeted agents and was subsequently humanized to form HuB4. In order to boost efficacy and reduce toxicity, several novel CD19 antibody designs that build upon HuB4 are currently being explored, including both engineered and conjugated antibodies.Engineered Antibodies
MEDI-551 and MOR-208 are antibodies that have been genetically engineered so that they have optimized fragment crystallizable (Fc) regions to enhance binding to the Fc-gamma receptor on the surface of target cells and, ultimately, the cytotoxic efficacy of the antibody.
Phase I data for MEDI-551 demonstrated an objective response rate of 26.5% among 34 evaluable patients with advanced B-cell malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), who were treated with doses of 0.5 to 12 mg/kg. In early clinical trial results for MOR208, an 11% overall response rate (ORR), all of which were partial responses (PRs), was observed among 27 evaluable patients with CLL or small lymphocytic leukemia who participated in the phase I study.
Blinatumomab (AMG103) is a bispecific T-cell engaging antibody (BiTE), an artificial bispecific antibody generated through the fusion of the single-chain variable fragments of two different antibodies: one that binds to T cells through the CD3 receptor and one that binds to CD19 on the surface of tumor cells. It is designed to bring cytotoxic T cells into close proximity with tumor cells expressing CD19.
The first trial of blinatumomab was a doseescalation study in 38 patients with indolent NHL, and an overall response rate (ORR) of 28.9% was observed. The focus has subsequently switched to B-cell ALL. In a phase II study of patients with persistent or relapsed minimal residual disease, 80% of patients experienced complete molecular remission. Two phase III studies and various phase II studies of blinatumomab are currently ongoing.
Preliminary results from part one of a phase II study of blinatumomab in patients with relapsed/refractory NHL were presented at the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans in December 2013. Among the 7 patients evaluable for response, the ORR was 57%. A recommended stepwise dosage of 9, 28, and 112 μg/day will be evaluated in the second part of the trial.Conjugated Antibodies
Conjugation of monoclonal antibodies to toxins, radionuclides, and cytotoxic drugs has proved to be a successful strategy for combining the potent cytotoxicity of traditional anticancer agents and the specificity of monoclonal antibodies. The FDA has approved several conjugated antibodies targeting CD20 and CD30 for the treatment of hematologic malignancies.