Preclinical pharmacokinetics, pharmacodynamics, and efficacy of RG7116: a novel humanized, glycoengineered anti-HER3 antibody.

Abstract

PURPOSE:

RG7116 is a novel anti-HER3 therapeutic antibody that inhibits HER3 signalling and induces antibody-dependent cellular cytotoxicity of tumor cells due to a glycoengineered antibody Fc moiety. We investigated the efficacy and pharmacokinetic/pharmacodynamic properties of HER3 signal inhibition by RG7116 in a murine xenograft model of human head and neck cancer.

METHODS:

SCID-beige mice bearing FaDu cells were treated with RG7116 at a weekly dose of 0.3-10 mg/kg, and tumor growth control and modulation of selected proteins (HER3 and AKT) were examined.

RESULTS:

Complete tumor stasis up to Day 46 was observed at a dose >3 mg/kg, and this dose down-modulated membrane HER3 expression and inhibited HER3 and AKT phosphorylation. Systemic RG7116 exposure was greater than dose-proportional and total clearance declined with increasing dose, indicating that RG7116 elimination is target-mediated. This is consistent with the better efficacy, and the HER3 and pAKT inhibition, that was observed at doses >1 mg/kg. Tumor regrowth occurred from Day 46 onwards and was associated with HER1 and HER2 upregulation, indicating the activation of alternative HER escape pathways. Modulation of HER3 and phospho-HER3 was also demonstrated in the skin and mucosa of an RG7116-treated cynomolgus monkey, suggesting that these may be useful surrogate tissues for monitoring RG7116 activity.

CONCLUSIONS:

These data confirm the promising efficacy of RG7116 and highlight the value of assessing the PK behavior of the antibody and measuring target protein modulation as a marker of biological activity. Clinical development of RG7116 has now begun, and phase I trials are ongoing.

• Authors: Georgina Meneses-Lorente, Thomas Friess, Irene Kolm, Gabriele Hölzlwimmer, Sabine Bader, Christophe Meille, Marlene Thomas, Birgit Bossenmaier
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 75 Issue 4 Pg. 837-50 (Apr 2015) ISSN: 1432-0843 [Electronic] Germany
• PMID: 25702049 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Glycoproteins
• ERBB3 protein, human
• Receptor, ErbB-3
• lumretuzumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacokinetics, pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Glycoproteins (pharmacokinetics, pharmacology, therapeutic use)
• Humans
• Hypopharyngeal Neoplasms (drug therapy, metabolism, pathology)
• Macaca fascicularis
• Mice, SCID
• Mouth Mucosa (drug effects, metabolism)
• Receptor, ErbB-3 (antagonists & inhibitors)
• Skin (drug effects, metabolism)
• Xenograft Model Antitumor Assays