A novel bispecific antibody for HER2+ breast cancer: The BEAT GBR 1302

While the idea of bispecific drugs was brought up over 30 years ago, the development of formats mature enough for the clinic remained for a long time a challenge. The whole field has been hampered by major problems of manufacturability (e.g. product purity and yields) and immunogenicity. With the recent arrival of new bispecific formats, either as antibody–like molecules (containing an Fc) or scFv fragments, at least 18 bispecific molecules have entered clinical trials showing very promising results. The BEAT® format has been developed as bispecific antibodies maintaining the pharmacokinetics and the low immunogenicity of human IgG with excellent manufacturability properties. In brief, the molecule is asymmetric consisting of a Hc, a Lc and a Fc-scFv. A proprietary engineered CH3 interface mimics the natural association of the heterodimeric TCRα β chains driving heterodimerization of the Hc and Fc-scFv. CHO cell lines are generated with a volumetric productivity of several g/L and a high product purity (e.g. \u3e90% of bispecific product). Based on a built-in purification approach the BEAT molecules can be purified using a standard DSP process with yield and purity comparable to standard mAbs. The presentation will highlight a new bispecific drug targeting HER2 on tumor cellsand CD3 on cytotoxic T-cells: the GBR 1302-BEAT molecule. GBR 1302-BEAT effectively recruits cytotoxic T cells against HER2 positive breast cancer cells including the trastuzumab-resistant breast cancer cell line JIMT-1. It shows strong tumor cell lysis activity with a better in vitro potential than current HER2-targeting therapies including the ADC TDM-1. The differential killing efficacy both in vitro and in vivo of HER2 overexpressing (3+) and normal, HER2 (0) cells reveals a large therapeutic window. In addition GBR 1302 does not trigger non-specific T cell activation. The excellent manufacturing attributes and the pre-clinical efficacy and safety of GBR1302 justify further clinical development as a treatment for HER2 positive cancers

The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell-Mediated Killing of AML Leukemic Stem Cells.

The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging DARPin (designed ankyrin repeat protein) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell-mediated killing of AML cells co-expressing at least two of the antigens. In vitro, MP0533 induced selective T cell-mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen-targeting T-cell engagers. In xenograft AML mouse models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity towards LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057)