Dutch Researcher Focuses on Fc Signaling in Targeting CD20

Jeanette H.W. Leusen, PhD

Associate Professor, Department of Immunology, University Medical Center Utrecht

Utrecht, the Netherlands

Jeanette H.W. Leusen, PhD, heads an Immunotherapy lab at University Medical Center Utrecht in the Netherlands, where her team focuses on studying the working mechanisms of therapeutic antibodies and the biology of fragment crystallizable (Fc) receptors, including the anti-CD20 monoclonal antibody rituximab in patients with non-Hodgkin lymphoma. The group has developed a transgenic mouse selectively deficient in Fc receptor signaling as a way of studying novel strategies for targeting the pathway.

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What is CD20?

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Please briefly describe your research and how it relates to CD20 anticancer therapy.

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How do newer anti-CD20 monoclonal antibodies compare with rituximab, and which is the most promising of these newer agents?

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How do genetic polymorphisms in FcγRIIIa impact CD20 immunotherapy?

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What is the most significant gap in our understanding of CD20 and its role as a target antigen?

She discussed several key questions involving CD20 research in this interview with OncologyLive.Cluster of differentiation 20, CD20 or MS4A1, is a member of the membrane-spanning 4A gene family. It is expressed on all stages of B lymphocyte development except on pro-B cells or plasma cells. It is a B-cell surface molecule, which plays a role in the development and differentiation of B cells into plasma cells. Defects in CD20 are the cause of common variable immunodeficiency type 5 (CVID5). CVID5 is a primary immunodeficiency characterized by hypogammaglobulinemia, recurrent bacterial infections, and an inability to mount an antibody response to antigen. The numbers of circulating B cells are usually in the normal range, but can be low.The research of my groups focuses on the biology of Fc receptors and the mechanisms of action of therapeutic antibodies. My laboratory has done many in vitro and in vivo studies on CD20 antibodies, studying the mechanism of action. Recently, we have generated a panel of 16 new CD20 antibodies that have different sequences and binding patterns compared with existing CD20 antibodies [unpublished work].Building on the success achieved with rituximab (RTX), other anti-CD20 monoclonal antibodies (mAbs) are being investigated. The fully human anti-CD20 mAb ofatumumab was approved by FDA in October 2009 for chronic lymphocytic leukemia (CLL). Novel bioengineering techniques have helped in the development of anti-CD20 mAbs. A glyco-engineered type II anti-CD20 mAb, obinutuzumab (GA101), is currently in clinical trials. AME-133v (LY2469298) and PRO131921 are both humanized type I CD20 mAbs with protein-engineered Fc regions that provide enhanced affinity for Fc gamma receptor IIIa (FcγRIIIa), and therefore induce better ADCC [antibody-dependent cellular cytotoxicity] activity compared with RTX. TRU-015 is a smaller CD20 mAb with retained Fc-mediated effector functions and is currently in development for rheumatoid arthritis. In my opinion, the most promising agents are the ones with different effector mechanisms, so we can combine treatments to get optimal responses in patients. Also, the induction of adaptive immunity would be a big advantage, so the patient’s immune system can recognize the cancer cells and clear them autonomously.It was already clear in the first studies from Cartron in 2000, and Weng and Levy in 2003, that the 158 valine/phenylalanine polymorphism is important for the outcome of treatment with RTX. The presence of a homozygous V158 allele in RTX-treated non-Hodgkin lymphoma patients was shown to be associated with longer progression-free survival. In CLL, however, FcγR polymorphisms did not associate with response to RTX treatment alone, or in combination with chemotherapy.Personally, it bothers me that it is still not known what the ligand of CD20 is, and what the exact function of CD20 is. It has been suggested that CD20 can operate as a calcium channel, but it is still unclear how targeting CD20 would interfere with this function in patients.