Unbiased phenotypic combinatorial screening uncovers a bispecific antibody (bAb) targeting HER2 and HER3.

  • Major finding: Unbiased phenotypic combinatorial screening uncovers a bispecific antibody (bAb) targeting HER2 and HER3.

  • Mechanism: The HER2/HER3-targeted bAb blocks HRG/HER3 signaling through a “dock and block” mechanism.

  • Impact: This bAb design may allow therapeutic targeting in tumors resistant to monoclonal antibody therapies.


HER2 dimerizes with HER3 to activate PI3K/AKT signaling and promote tumor growth and survival. Resistance to HER2-targeted therapies can occur via upregulation of HER3 or its ligand HRG. These findings support therapeutic approaches aimed at inhibiting HER3 pathway activation, but these strategies have failed to provide meaningful clinical benefit. Geuijen and colleagues sought to identify bispecific antibodies (bAb) that can potently block PI3K/AKT signaling via HER3. An unbiased phenotypic combinatorial screen of 545 bAbs targeting both HER2 and HER3 identified bAbs that potently inhibited tumor growth. Subsequent humanization and optimization of the top hit yielded PB4188, a bispecific immunoglobulin G1 (IgG1) antibody against HER2 and HER3. PB4188 potently inhibited tumor cell growth, even under high levels of HRG where monoclonal antibodies (mAb) targeting HER2 and HER3 failed to suppress growth. Further, PB4188 inhibited HRG-mediated HER2–HER3 heterodimerization and downstream signaling. In vivo, PB4188 inhibited HRG-driven tumor growth in a dose-dependent manner in an ERBB2 (encoding HER2)-amplified breast cancer xenograft model, whereas the tumors were resistant to the HER2-targeted monoclonal antibody trastuzumab. Similar results were observed in other tumor xenograft and patient-derived xenograft models. PB4188 acted through a “dock and block” mechanism, with the HER2 antigen binding fragment (Fab) of PB4188 docking and saturating HER2 binding sites on tumor cells, thereby increasing the local concentration of HER3 Fab to block HRG binding to HER3 and abolish downstream signaling. These findings indicate that a IgG1-based bAb targeting HER2 and HER3 may be effective in tumors with hyperactive HRG/HER3 signaling even when mAb therapies have failed. Further, bAbs designed with this “dock and block” mode of action may allow for therapeutic targeting of a broad range of targets where clinical activity cannot be achieved using mAbs.

Geuijen CA, De Nardis C, Maussang D, Rovers E, Gallenne T, Hendriks LJ, et al. Unbiased combinatorial screening identifies a bispecific IgG1 that potently inhibits HER3 signaling via HER2-guided ligand blockade. Cancer Cell 2018;33:922–36.

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