Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes Tumor Heterogeneity and Plasticity

Abstract

Purpose: 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.Experimental Design/Results: 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.Conclusions: 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.

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

“…Pan-HER exhibited superior tumor growth delay in H226 lung xenograft models with downmodulation of three HER family receptors as compared to cetuximab ( Figure 4A, 4B). Our data is consistent with other investigators indicating that Pan-HER is an effective treatment for pancreatic, squamous, and gastric tumors (19,42). Next, we utilized two different model systems; de novo acquired cetuximab-resistant and intrinsically cetuximab-resistant PDX xenograft models ( Figure 5A, 7A).…”

Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

“…HER3 is transcriptionally regulated by PI3K/AKT signaling, and inhibition of AKT activity has been shown to induce HER3 transcription in a FOXO-dependent manner (47)(48)(49). Multiple studies have confirmed a role of HER-3 in acquired resistance to EGFR inhibition (35,45,50). Increased IGF1R activity is another well-described mechanism of resistance to EGFR inhibition.…”

“…The two anti-EGFR antibodies (1565, 1277) and the two anti-HER3 antibodies (5038, 5082) are described by Koefoed and colleagues. (30) and Jacobsen and colleagues (35). Antibody mixtures were generated freshly prior to the individual experiments and mixed in ratios of 1:1 or 1:1:1 (w/w).…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…168 Sym013 (Pan-HER) is a mixture of 6 mAbs, comprising 3 pairs of synergistic mAbs, each targeting EGFR, HER2 and HER3. 169 The mixture has been reported to effectively inhibit growth of lung (NSCLC) and head and neck (HNSCC) cancer models in vitro and in vivo. Sym013 triggers degradation of EGFR, HER2 and HER3, prevents ligand binding to EGFR and HER3, and strongly inhibits subsequent activation of the AKT and MAPK/ERK pathways.…”