Past, Present, and Future of Rituximab—The World’s First Oncology Monoclonal Antibody Therapy

Abstract

Rituximab is a chimeric mouse/human monoclonal antibody (mAb) therapy with binding specificity to CD20. It was the first therapeutic antibody approved for oncology patients and was the top-selling oncology drug for nearly a decade with sales reaching $8.58 billion in 2016. Since its initial approval in 1997, it has improved outcomes in all B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. Despite widespread use, most mechanistic data have been gathered from in vitro studies while the roles of the various response mechanisms in humans are still largely undetermined. Polymorphisms in Fc gamma receptor and complement protein genes have been implicated as potential predictors of differential response to rituximab, but have not yet shown sufficient influence to impact clinical decisions. Unlike most targeted therapies developed today, no known biomarkers to indicate target engagement/tumor response have been identified, aside from reduced tumor burden. The lack of companion biomarkers beyond CD20 itself has made it difficult to predict which patients will respond to any given anti-CD20 antibody. In the past decade, two new anti-CD20 antibodies have been approved: ofatumumab, which binds a distinct epitope of CD20, and obinutuzumab, a mAb derived from rituximab with modifications to the Fc portion and to its glycosylation. Both are fully humanized and have biological activity that is distinct from that of rituximab. In addition to these new anti-CD20 antibodies, another imminent change in targeted lymphoma treatment is the multitude of biosimilars that are becoming available as rituximab’s patent expires. While the widespread use of rituximab itself will likely continue, its biosimilars will increase global access to the therapy. This review discusses current research into mechanisms and potential biomarkers of rituximab response, as well as its biosimilars and the newer CD20 binding mAb therapies. Increased ability to assess the effectiveness of rituximab in an individual patient, along with the availability of alternative anti-CD20 antibodies will likely lead to dramatic changes in how we use CD20 antibodies going forward.

Nanocarriers as Magic Bullets in the Treatment of Leukemia

“…Rituximab is a genetically engineered chimeric mouse-human antibody that binds to the transmembrane antigen CD20, involved in B-cell non-Hodgkin lymphoma. Since its initial approval in 1997, it has improved outcomes in all B-cell malignancies [83]. Nowadays, many drug-antibody conjugates are under development, in order to merge the advantages of monoclonal antibodies with chemotherapeutic drugs, while at the same time eluding drug resistance mechanisms.…”

Updates on CAR T‐cell therapy in B‐cell malignancies

“…Targeting CD20 with monoclonal and/or conjugated antibody‐based approaches represents one of the earliest forms of B‐cell targeting, currently serving an integral part of standard of care regimens for B‐cell mature lymphoma, CLL, and adult ALL, but its applicability has been limited by partial expression and/or an enrichment of CD20 expression in more mature B‐cell phenotypes. While the extent of antibody‐based therapies targeting CD20 is beyond the scope of this manuscript, several recent publications provide a nice review . In addition to CD20, CD19, CD22, and CD38 have gained recent attention for immunotherapy applications that go beyond naked antibodies.…”

“…The approximate position of progenitors and B-cell fractions is indicated. Image and legend courtesy of Kara Davis, Stanford University 9 targeting, 18,19 currently serving an integral part of standard of care regimens for B-cell mature lymphoma, CLL, and adult ALL, but its applicability has been limited by partial expression and/or an enrichment of CD20 expression in more mature B-cell phenotypes. While the extent of antibody-based therapies targeting CD20 is beyond the scope of this manuscript, several recent publications provide a nice review.…”

“…While the extent of antibody-based therapies targeting CD20 is beyond the scope of this manuscript, several recent publications provide a nice review. 19 In addition to CD20, CD19, CD22, and CD38 have gained recent attention for immunotherapy applications that go beyond naked antibodies.…”

Development of Therapeutic Antibody Technology And Recent Perspectives For Leukemia-Lymphoma Treatment

“…A humanized mAb (hUMG1) anti-CD43 showed high reactivity with T-ALL cells. In recently antibody technology, afucosylated of certain antibody showed increased its ADCC/ADCP therapeutic monoclonal antibody was used for all B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, and chronic diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia therapeutic applications [47]. However, its humanized version showed much better in its therapeutic efficacy on various hematological malignancies.…”