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

Georgina Meneses-Lorente,Birgit Bossenmaier,Marlene Thomas,Thomas Friess,Gabriele Hölzlwimmer,Irene Kolm,Christophe Meille,Sabine Bader

doi:10.1007/s00280-015-2697-8

Georgina Meneses-Lorente, Birgit Bossenmaier + Show 6 more

Open Access

https://doi.org/10.1007/s00280-015-2697-8

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Abstract

PurposeRG7116 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.MethodsSCID-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.ResultsComplete 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.ConclusionsThese 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.

Highlights

The human epidermal growth factor receptor 3 (HER3/ ERBB3) is a 185-kDa member of the evolutionary-conserved family of HER transmembrane receptors
RG7116 is a novel anti-HER3 antibody that can exert a therapeutic effect through both the inhibition of HER3 signaling and by recruiting immune effector cells for antibody-dependent cellular cytotoxicity (ADCC) [22]
In order to better understand the therapeutic potential of RG7116, we further assessed the anti-tumoral efficacy mediated by HER3-signaling inhibition in a FaDu cell line-based xenograft of human hypopharyngeal cancer and characterized the PK and PD changes occurring in response to treatment with RG7116 at different doses and dosing schedules

Summary

Introduction

The human epidermal growth factor receptor 3 (HER3/ ERBB3) is a 185-kDa member of the evolutionary-conserved family of HER transmembrane receptors. Together, these four receptor tyrosine kinases form a dynamic signaling network that transduces extracellular growth signals into the cell and activates multiple cellular pathways involved in proliferation, cell survival, and differentiation. HER receptors normally exist as inactive monomers [1] and only become activated in response to overexpression or ligand binding followed by receptor dimerization. The HER2(ERBB2)/HER3 heterodimer is among the most stable of HER dimers and is a potent initiator of phosphoinositide 3-kinase (PI3K) signaling [1]. PI3K triggers the translocation of AKT to the phospholipid membrane—through the second messenger PIP3—where AKT becomes phosphorylated and acts as a kinase for multiple substrates [2]

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