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A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells
Nadine Aschmoneit1, Sophia Steinlein1, Lennart Kühl1
1Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
Abstract:
HER3 is a member of the EGF receptor family and elevated expression is associated with cancer progression and therapy resistance. HER3-specific T-cell engagers might be a suitable treatment option to circumvent the limited efficacy observed for HER3-blocking antibodies in clinical trials. In this study, we developed bispecific antibodies for T-cell retargeting to HER3-expressing tumor cells, utilizing either a single-chain diabody format (scDb) with one binding site for HER3 and one for CD3 on T-cells or a trivalent bispecific scDb-scFv fusion protein exhibiting an additional binding site for HER3. The scDb-scFv showed increased binding to HER3-expressing cancer cell lines compared to the scDb and consequently more effective T-cell activation and T-cell proliferation. Furthermore, the bivalent binding mode of the scDb-scFv for HER3 translated into more potent T-cell mediated cancer cell killing, and allowed to discriminate between moderate and low HER3-expressing target cells. Thus, our study demonstrated the applicability of HER3 for T-cell retargeting with bispecific antibodies, even at moderate expression levels, and the increased potency of an avidity-mediated specificity gain, potentially resulting in a wider safety window of bispecific T-cell engaging antibodies targeting HER3.
Insights
Bispecific antibodies targeting HER3 (Human Epidermal growth factor Receptor 3) show promise for cancer therapy. A novel trivalent bispecific antibody demonstrated enhanced T-cell activation and tumor cell killing compared to a diabody format.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Human Epidermal growth factor Receptor 3 (HER3) is implicated in cancer progression and resistance to therapies.
- HER3-targeting T-cell engagers offer a potential therapeutic strategy to overcome limitations of current HER3-blocking antibodies.
Purpose of the Study:
- To develop and evaluate bispecific antibodies for T-cell retargeting against HER3-expressing tumor cells.
- To compare the efficacy of a single-chain diabody (scDb) and a trivalent bispecific scDb-scFv fusion protein targeting HER3.
Main Methods:
- Development of two bispecific antibody formats: a single-chain diabody (scDb) and a trivalent bispecific scDb-scFv fusion protein.
- Assessment of antibody binding affinity to HER3-expressing cancer cell lines.
- Evaluation of T-cell activation, proliferation, and tumor cell killing in vitro.
Main Results:
- The trivalent bispecific scDb-scFv exhibited enhanced binding to HER3-expressing cells compared to the scDb.
- The scDb-scFv demonstrated superior T-cell activation, proliferation, and potent cancer cell killing.
- The trivalent format effectively discriminated between moderate and low HER3-expressing target cells.
Conclusions:
- HER3 is a viable target for T-cell retargeting using bispecific antibodies, even at moderate expression levels.
- Increased avidity through bivalent HER3 binding enhances bispecific T-cell engager potency and specificity.
- This approach may lead to improved therapeutic windows for HER3-targeted immunotherapies.
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