a-bw-reporter-system-for-studying-receptor-ligand-interactions

A BW Reporter System for Studying Receptor-Ligand Interactions

Interactions between receptors and ligands constitute a fundamental biological process. However, direct experiments with cells that express the native ...

Hadassah - Hebrew University Medical Center

The oncogenic fusion protein CBFB-SMMHC downregulates CD48 to evade NK cell recognition.

Treatment with monoclonal antibodies has revolutionized clinical medicine, especially in the fields of cancer and immunology. One of the oldest antibodies, which is widely used for the treatment of lymphomas and autoimmune diseases, is the anti-CD20 antibody rituximab. In recent years, new antibodies against CD20 have been developed including ofatumumab and obinutuzumab. An important mechanism of action of therapeutic monoclonal antibodies is activation of immune cells via Fc receptors (FcγRs). However, surprisingly, little is known about triggering of FcγRs by different therapeutic antibodies in general and anti-CD20 antibodies in particular. Here we establish a reporter assay to assess whether a particular antibody activates a certain Fc receptor. Using this assay we corroborated previous reports demonstrating obinutuzumab's ability to highly activate FcγRIIIa (CD16a). Importantly, we discovered that obinutuzumab also activates FcγRI (CD64) significantly more than rituximab and ofatumumab in response to chronic lymphocytic leukemia (CLL) cells obtained from patients. Mechanistically we show that this is due to the lack of FcγRIIb-mediated internalization of obinutuzumab following binding to CD20. Moreover, we show that obinutuzumab induces increased phagocytosis by primary macrophages in an FcγRI-dependent manner. Beyond the discovery of a new mechanism of obinutuzumab activity, the reporter assay can be applied to other therapeutic antibodies and may assist in developing antibodies with improved immunological properties.

Article	Year
The oncogenic fusion protein CBFB-SMMHC downregulates CD48 to evade NK cell recognition. Blood cancer journal\| PubMed ID: 29795444	2018
Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL). Oncoimmunology\| PubMed ID: 29872553	2018
Duodenal amyloid A depositions in a patient with refractory Hodgkin's lymphoma: an old complication in the modern treatment era. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis\| PubMed ID: 30350721	2018

Shlomo Elias

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