10D1F, an Anti-HER3 Antibody That Uniquely Blocks the Receptor Heterodimerization Interface, Potently Inhibits Tumor Growth Across a Broad Panel of Tumor Models

Abstract

In recent years, HER3 has increasingly been implicated in the progression of a variety of tumor types and in acquired resistance to EGFR and HER2 therapies. Whereas EGFR and HER2 primarily signal through the MAPK pathway, HER3, as a heterodimer with EGFR or HER2, potently activates the PI3K pathway. Despite its critical role, previous attempts to target HER3 with neutralizing antibodies have shown disappointing efficacy in the clinic, most likely due to suboptimal and indirect mechanisms of action that fail to completely block heterodimerization; for example, tumors can escape inhibition of ligand binding by upregulating ligandindependent mechanisms of HER3 activation. We therefore developed 10D1F, a picomolar affinity, highly specific anti-HER3 neutralizing antibody that binds the HER3 heterodimerization interface, a region that was hitherto challenging to raise antibodies against. We demonstrate that 10D1F potently inhibits both EGFR: HER3 and HER2:HER3 heterodimerization to durably suppress activation of the PI3K pathway in a broad panel of tumor models. Even as a monotherapy, 10D1F shows superior inhibition of tumor growth in the same cell lines both in vitro and in mouse xenograft experiments, when compared with other classes of anti-HER3 antibodies. This includes models demonstrating ligand-independent activation of heterodimerization as well as constitutively activating mutations in the MAPK pathway. Possessing favorable pharmacokinetic and toxicologic profiles, 10D1F uniquely represents a new class of anti-HER3 neutralizing antibodies with a novel mechanism of action that offers significant potential for broad clinical benefit.10D1F is a novel anti-HER3 antibody that uniquely binds the receptor dimerization interface to block ligand-dependent and independent heterodimerization with EGFR/HER2 and thus more potently inhibits tumor growth than existing anti-HER3 antibodies.

Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities

“…Ligand-bound EGFR, HER3 and HER4 tend to form heterodimers with HER2, as HER2 is the preferred dimerization partner when overexpressed. HER2 can form homodimers in a ligand-independent manner, and we also consider ligand-independent formation of HER2/HER3 heterodimers [ 16 ]. Dimerized receptors then undergo transphosphorylation, activating the downstream PI3K/AKT and Raf/MAPK cascades.…”

“…HER2 + BC is one such example. Overexpression of HER2 biases dimer formation toward HER2-containing homo- and heterodimers (particularly HER2/HER2 and HER2/HER3 complexes) [ 14 ], resulting in constitutive activation of downstream pathways in a ligand-independent manner [ 15 , 16 ]. In addition, HER2 heterodimers can also be activated in ligand-dependent manners during EGF and NRG1 stimulation [ 13 ].…”

AMT-562, a Novel HER3-targeting Antibody–Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors

“…1B ; ref. 28 ). Despite its moderate affinity, Ab562 showed specific binding to HER3-overexpressing HEK293T cells but not wild-type cells ( Fig.…”

“…Because of internalization, HER3-targeting antibodies have been shown to variably decrease cell surface HER3 protein expression in the absence or presence of endogenous HER3 ligand NRG1 ( 28–30 ). We examined the effect of Ab562 binding on cell surface HER3 expression.…”

DB-1310, an ADC comprised of a novel anti-HER3 antibody conjugated to a DNA topoisomerase I inhibitor, is highly effective for the treatment of HER3-positive solid tumors

“…It inhibits both ligand dependent and independent HER3 signaling activation with single-agent activity in tumor growth inhibition for both in vitro and in vivo. However, HER3 internalization was not observed after 10D1F binding [ 33 ]. DB-1310 binds HER3 via a new epitope, which is distinct from the epitope recognized by patritumab, inducing fast HER3 internalization.…”