Obinutuzumab may activate Fcγ receptors (FcγRs) more effectively than other monoclonal antibodies and may accordingly have increased anti-cancer activity in patients with chronic lymphocytic leukemia (CLL), according to a study published in OncoImmunology.1
Although the development of monoclonal antibodies has improved CLL outcomes, an important drug mechanism — immune activation via FcγRs — is not fully understood.
For this study, researchers used a reporter assay to determine which immune-mediating receptors were activated by rituximab, obinutuzumab, and ofatumumab; this was done by transfecting mouse BW5147 cells with chimeric FcγRs.
Obinutuzumab led to increased activation of FcγRIIIa and FcγRI in mouse cells compared with rituximab or ofatumumab; no significant differences were noted for FcγRIIA. When assessed in CLL cells from human patients, a similar increase in activation of FcγRIIIa and FcγRI with obinutuzumab vs other monoclonal antibodies was observed.
Exposure to obinutuzumab translated to efficient antibody-dependent cellular cytotoxicity by primary natural killer cells activated by FcγRIIIa, and increased FcγRI activation enhanced phagocytic activity of primary macrophages, leading to increased elimination of CLL cells.
The authors concluded that “obinutuzumab leads to enhanced activation of FcγRI compared to both rituximab and ofatumumab. We suggest that this assay will enable better evaluation of new therapeutic antibodies against CD20 or against other targets in general.”
- Elias S, Kahlon S, Kotzur R, Kaynan N, Mandelboim O. Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL). OncoImmunology. 2018 Jan 16. doi: 10.1080/2162402X.2018.1428158 [Epub ahead of print]