Human epidermal growth factor receptor 2 (HER2) overexpression has
been demonstrated in a variety of cancers. Targeted therapy with
anti-HER2 monoclonal antibodies (mAbs) has been approved as a
therapeutic modality. Despite the efficacy of mAbs in tumor treatment,
many patients do not benefit from this therapeutic platform. Fragment
crystallizable (Fc) engineering is a common approach to improve the
efficacy of therapeutic mAbs. Five Fc-engineered mAbs have so far been
approved by FDA. We have recently developed an anti-HER2 bispecific mAb,
BiHT, constructed from variable domains of trastuzumab, and our novel
humanized anti-HER2 mAb, hersintuzumab. BiHT displayed promising
antitumor activity as potently as the combination of the parental mAbs.
Here, we aimed to modify the Fc of BiHT to improve its therapeutic
efficacy. The Fc-engineered BiHT (MBiHT) bound to recombinant HER2 and
its subdomains with an affinity similar to BiHT. It also recognized
native HER2 on different cell lines, inhibited their proliferation,
downregulated HER2 expression, and suppressed downstream signaling
pathways similar to BiHT. Compared with BiHT, MBiHT displayed enhanced
antibody-dependent cellular cytotoxicity activity against various tumor
cell lines. It also inhibited the growth of ovarian xenograft tumors in
nude mice more potently than BiHT. Our findings suggest that MBiHT could
be a potent therapeutic candidate for the treatment of
HER2-overexpressing cancer types.