Lumretuzumab (alternative names: RG-7116; RO-5479599) is a humanized and glycoengineered monoclonal antibody directed against HER3 with potential immunostimulatory and anti-tumor activity. By preventing HRG from binding to HER3, lumretuzumab resulted in almost complete inhibition of HER3 heterodimers and phosphorylation and significantly inhibited tumor growth in a mouse xenograft model. Currently, the safety of lumretuzumab in clinical stage I is assessed for patients with advanced solid tumors. The safety and tolerability of Lumretuzumab has been evaluated in clinical phase 1/2 dose escalation studies in patients with advanced or metastatic squamous non-small cell lung cancer.
Lumretuzumab is a novel glycosylation engineered humanized anti-HER3 monoclonal antibody developed to meet the needs of new therapies with higher activity on HER3-positive cancers. The glycosylation process used to develop this agent is achieved by reducing the fucosylation in the Fc region of the mAb molecule, resulting in increased binding affinity of the agent for the FcyRIII receptor on immune effector cells.
Fig.1 Glycoengineering by defucosylation of immunoglobulin G oligosaccharides in the Fc region of Lumretuzumab.
HER3 belongs to the human epidermal growth factor receptor (HER) family. It often co-expresses and forms heterodimers with other receptor tyrosine kinases (RTKs) in cancer cells, thereby activating oncogenic signaling, particularly the PI-3K/Akt pathway and Src kinase. The figure below depicts the major signaling pathways for HER3 during cancer progression and the monospecific HER3 blocking antibodies currently in clinical use in cancer patients. Currently, several human or humanized anti-HER3 monospecific and bispecific Abs are clinically tested for their therapeutic activity to eliminate drug resistance and inhibit cancer metastasis. Lumretuzumab showed enhanced ADCC activity as a glycosyl engineered monoclonal antibody compared to a non-glycosyl engineered parent antibody.
Fig.2 Mechanisms of action of Her3 antibodies. (Hui Lyu, 2018)
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Creative Biolabs provides luciferase-based ADCC assay. This Jurkat cell based assay is pioneered by Creative Biolabs, and the methodology is very well accepted by the field. See attached ADCC Reporter Assay Protocol for further details.
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