Clinical success with CAR-T therapy highlights the value of engaging cytotoxic T cells (CTLs) to treat cancer. Bispecific antibodies that link CTLs to tumor cells in an MHC-independent manner offer an off-the-shelf solution to T cell therapy that is accessible and scalable. Most bispecific antibodies are built as heterodimers, with monovalent binding to a highly expressed antigen on the tumor cell and to CD3 on the T cell. Here, we describe ABP-100, a HER2-specific T-cell engaging antibody built using a tetravalent bispecific (TetraBi) format that provides several significant advantages over the traditional format of bi-specific antibodies
ABP-100 was constructed by fusing a CD3-binding scFv to the light chain of an aglycosylated anti-HER2 IgG1, resulting in two binding sites each for HER2 and CD3. This TetraBi format was compared with a clinical-stage heterodimeric antibody that is monovalent for HER2 and CD3. The biophysical features of the two formats were compared, along with functional characteristics associated with both efficacy and safety.
We observed that bivalent binding to HER2 provides a stronger association with HER2+ tumor cells than monovalent binding, but that locating the CD3-binding domains in the hinge regions of ABP-100 results in functionally monovalent binding to CD3. ABP-100 showed a similar safety profile (cytokine release) to the heterodimer molecule both in vitro and in vivo. In models of HER2+ cancer, however, ABP-100 showed highly potent antitumor activity, resulting in complete responses in mice at doses as low as 0.1 mg/kg with no evidence of tumor regrowth after treatments were stopped. Overall, the efficacy of ABP-100 was strongly dependent on HER2 levels and synergistic effects were observed when ABP-100 was combined with a PD-L1 inhibitor.
The TetraBi format of ABP-100 provides a potentially larger therapeutic index than more traditional bispecific formats that feature monovalent recognition of HER2. Moreover, because ABP-100 is designed to engage CTLs, it provides a novel mechanism for treating HER2+ disease relative to current therapies. These data support the clinical development of ABP-100 in HER2+ solid tumors.
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Legal entity responsible for the study
A. Boudot, X. Huang, S. Murphy, V. Appleman, G. Macbeath: A. Boudot, X. Huang, S. Murphy, V. Appleman, and G. MacBeath: Employee: Abpro. H. Xu: Employee: Abpro; Research conducted funded in part: Abpro. N.-K. Cheung: Employee: Abpro; Member: SAB of Abpro; Research conducted funded in part: Abpro.