Lumretuzumab

Overview

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.

ADCC Enhancement Technology for Lumretuzumab

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.

Mechanism of Action 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)

ADCC Activity

• Glycoengineered RG7116 has higher in vitro ADCC efficacy (E:T ratio of 5:1) compared to non-glycoengineered wild-type RG7116 using recombinant NK92 cells as effector cells and T-47D cells as target cells.

Antitumor Activity in Preclinical

• RG7116 inhibits proliferation of MDA-MB-175 cells grown in culture in vitro.

• In vivo efficacy of RG7116 in human pancreatic cancer subcutaneous xenograft mice.

Antitumor Activity in Clinical

• A Phase Ib study evaluated the safety and clinical activity of the anti-HER3 antibody raltuzumab in combination with the anti-HER2 antibody patozumab and paclitaxel in HER3 positive, HER2 low metastatic breast cancer. The figure below shows the results of clinical activities.

• A Phase Ib study of Lumretuzumab plus Cetuximab or Erlotinib in patients with solid tumors. The figure below shows the antitumor clinical activity of HER3 as a potential biomarker in sqNSCLC patients.

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References

1. Mirschberger C.; et al. RG7116, a Therapeutic Antibody That Binds the Inactive HER3 Receptor and Is Optimized for Immune Effector Activation. Cancer Research. 2013, 73(16):5183-5194.
2. Schneeweiss A.; et al. Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer. Invest New Drugs. 2018,1-12.
3. Meulendijks D.; et al. Phase Ib study of lumretuzumab plus cetuximab or erlotinib in solid tumor patients and evaluation of HER3 and heregulin as potential biomarkers of clinical activity. Clinical Cancer Research An Official Journal of the American Association for Cancer Research. 2017, 23(18):clincanres.0812.2017.