Rituximab for Non‐Hodgkin's Lymphoma: A Story of Rapid Success in Translation

Abstract

Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non-Hodgkin’s lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation.

Efficacy and safety of rituximab therapy in patients with pemphigus vulgaris: first report from Turkey

“…Rituximab therapy facilitates the reappearance of naive B cells characterized by a normal repertoire, which may explain this long‐term recovery and the dramatic decreases in anti‐Dsg1 and anti‐Dsg3 IgG antibodies observed after rituximab therapy . This B cell kinetic is similar to that described previously in patients with B cell lymphoma and autoimmune diseases . B cells have been shown to undergo different processes in autoimmune diseases and lymphoma, although they demonstrate an overall response …”

Rituximab treatment of myasthenia gravis: A systematic review

“…The Fab domain of rituximab binds to CD20, and the Fc domain recruits immune effector cells for B‐cell lysis. Rituximab produces a substantial reduction in circulating CD20 + B‐cells for up to 6 months after a cycle of infusions and is used as targeted therapy for the treatment of non‐Hodgkin B‐cell lymphoma, rheumatoid arthritis, Wegener granulomatosis, and microangiopathic vasculitis, indications for which it is approved by regulatory agencies in many countries. Recently, rituximab has been found to be effective in several other autoimmune diseases, including immune thrombocytopenia, autoimmune hemolytic anemia, type 1 diabetes mellitus, renal disorders, pemphigus, and several neurological diseases .…”

A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematologic malignancies

“…Moreover, the Fc-effector activity of PF-06747143 in vitro was comparable to that of rituximab, an anti-CD20 monoclonal Ab, whose main mechanism of action in the clinic relies largely on effector function. 34 The importance of effector function for antitumor activity was demonstrated comparing the in vivo activities of PF-06747143 parent Ab, m15-IgG1, to that of its IgG4 version, m15-IgG4, which is deprived of Fc-effector function. The m15-IgG1 Ab had superior TGI, associated with a significant increase in cell death in tumors.…”

“…Rituximab, a component of the SOC treatment regimen for NHL, was used as positive control because its clinical activity depends on both ADCC and CDC. 34 In the ADCC assay in the Ramos NHL cell line, in the presence of NK92 158V effector cells, m15-IgG1 showed strong cytotoxicity, with an IC 50 of 124 pM, when compared with no significant activity with m15-IgG4 (Figure 2A). This is in agreement with the expected diminished ADCC activity of the IgG4 Ab.…”