RO5083945

Overview

RO5083945 (or GA201, RG7160) is the first glycosylation-modified monoclonal antibody (mAb) directed against the epidermal growth factor receptor (EGFR) for the treatment of cancer and autoimmune diseases. RO5083945 has a fully human glycosylation pattern and is optimized for glycosylation in its Fc domain to promote antibody-dependent cell-mediated cytotoxicity (ADCC). EGFR is overexpressed on the cell surface in a variety of tumor types and acts under several anti-tumor mechanisms: strong ADCC, inhibition of proliferation by receptor blockade, and induction of apoptosis. A clinical phase I dose escalation study involving RO5083945 is ongoing to investigate the efficacy of this antibody in the treatment of solid tumors, including KRAS mutant CRC.

ADCC Enhancement Technology for RO5083945

RO5083945 is derived by glycosylation of the parental cetuximab. The glycosylation process used to develop this agent is achieved by altering the glycosylation profile in the Fc region of the mAb molecule, resulting in a significant enhancement of immunogenicity and thus, a stronger ADCC response.

Fig.1 Site-specific glycoengineering of cetuximab for enhanced ADCC activity.

Mechanism of Action of RO5083945

Glyco-engineered RO5083945 is thought to have therapeutic activity against EGFR-positive tumors because of:

• Regulating EGFR signaling, leading to growth retardation or induction of apoptosis or cell death.
• Binding to Fc gamma receptor on improved immune cells to enhance the destruction of EGFR-positive tumor cells.
• Reaction with tumor antigens, which are presented by cells such as macrophage. When taking up antigen, it displays to other cells of the immune system, including T cells.

Fig.2 Mechanism of action of RO5083945.

Glycan Analysis of RO5083945

• The glycosylation pattern of glycosylated modified cetuximab (RO5083945) was verified by LC-MS analysis.

Antigen Binding Characteriztion

• SPR analysis of FcγRIIIa binding with commercial cetuximab and the glycosylation-modified cetuximab (RO5083945)

ADCC Activity

• RO5083945 showed superior in vitro ADCC activity compared with cetuximab in a variety of scenarios.

Preclinical Anti-tumor Activity

• RO5083945 showed superior efficacy when comparing with cetuximab in xenograft models.

• GA201 showed enhanced efficacy when combined with irinotecan in an in situ EGFR-positive HT29 tumor model.

Clinical Anti-tumor Activity

• The efficacy of imgatuzumab in patients with KRAS-mutant colorectal cancer (CRC) is shown.

Clinical Development Status

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References

1. Gerdes CA.; et al. GA201 (RG7160): A Novel, Humanized, Glycoengineered Anti-EGFR Antibody with Enhanced ADCC and Superior In Vivo Efficacy Compared with Cetuximab. Clinical Cancer Research. 2013, 19(5):1126-1138.
2. Open-label, multicentre expansion cohort to evaluate imgatuzumab in pre-treated patients with KRAS-mutant advanced colorectal carcinoma. European Journal of Cancer. 2014, 50(3):496-505.