Abstract
Accumulating evidence indicates a high degree of plasticity and compensatory signaling within the human epidermal growth factor receptor (HER) family, leading to resistance upon therapeutic intervention with HER family members. We have generated Pan-HER, a mixture of six antibodies targeting each of the HER family members EGFR, HER2, and HER3 with synergistic pairs of antibodies, which simultaneously remove all three targets, thereby preventing compensatory tumor promoting mechanisms within the HER family. Pan-HER induces potent growth inhibition in a range of cancer cell lines and xenograft models, including cell lines with acquired resistance to therapeutic antibodies. Pan-HER is also highly efficacious in the presence of HER family ligands, indicating that it is capable of overcoming acquired resistance due to increased ligand production. All three target specificities contribute to the enhanced efficacy, demonstrating a distinct benefit of combined HER family targeting when compared with single-receptor targeting. Our data show that simultaneous targeting of three receptors provides broader efficacy than targeting a single receptor or any combination of two receptors in the HER family, especially in the presence of HER family ligands. Pan-HER represents a novel strategy to deal with primary and acquired resistance due to tumor heterogeneity and plasticity in terms of HER family dependency and as such may be a viable alternative in the clinic.
Highlights
The human epidermal growth factor receptor (HER) family consists of four members: EGFR/HER1, ErbB-2/HER2, ErbB-3/ HER3, and ErbB-4/HER4
EGFR and HER2 are clinically validated targets in squamous cell carcinoma of the head and neck, colorectal, breast, gastric, and non–small cell lung cancers, and growing evidence suggests that HER3 will prove to be a clinically relevant target as well [2, 4,5,6]
Pairs of antibodies against EGFR, HER2, and HER3 for inclusion in the Pan-HER antibody mixture were identified by screening panels of approximately 50 antibodies against each receptor for synergistic in vitro inhibition of cancer cell growth and induction of target downmodulation in multiple cancer cell lines (28, 29 and data not shown)
Summary
The human epidermal growth factor receptor (HER) family consists of four members: EGFR/HER1, ErbB-2/HER2, ErbB-3/ HER3, and ErbB-4/HER4. These receptors play an important role in normal cell growth, metabolism, proliferation, survival, and differentiation. Deregulation through mutation, overexpression, or gene amplification of the HER family is commonly associated with development, progression, or acquired resistance of many human cancers [1]. Homo- or hetero- dimerization induced by binding of ligands within the EGF family of growth factors results in cross-phosphorylation of the dimerization partners, triggering intracellular signaling [2, 3]. EGFR and HER2 are clinically validated targets in squamous cell carcinoma of the head and neck, colorectal, breast, gastric, and non–small cell lung cancers, and growing evidence suggests that HER3 will prove to be a clinically relevant target as well [2, 4,5,6].
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