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A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
Ars2-containing bispecific, Fab- and IgG1-format BAR-bodies to target DLBCL cells
Maximilian Kiefer1, Lorenz Thurner1, Theresa Bock1
1Internal Medicine I Saarland University Medical Center Homburg Germany.
Abstract:
Despite recent advances in the therapy of diffuse large B-cell lymphoma, not otherwise specified (DLBCL), around 30% of patients develop refractory disease or relapse after first-line treatment. Recently, Ars2 was reported as the auto-antigenic target of the B-cell receptor (BCR) in approximately 25% of activated B-cell DLBCL cases. Ars2 could be used to specifically target B cells expressing Ars2-reactive BCRs. However, the optimal therapeutic format to integrate Ars2 into has yet to be determined. To mimic therapeutic antibody formats, Ars2-containing bispecific and IgG1-like constructs (BCR antigens for reverse [BAR]-bodies) were developed. Two bispecific BAR-bodies connecting single-chain antibodies against CD16 or CD3 to the BCR-binding epitope of Ars2 were constructed. Both constructs showed strong binding to U2932 cells and induced effector cell-dependent and selective cytotoxicity against U2932 cells of up to 44% at concentrations of 20 μg/ml. Additionally, IgG1-format Ars2 BAR-bodies were constructed by replacing the variable heavy- and light-chain regions of a full-length antibody with the Ars2 epitope. IgG1-format Ars2 BAR-bodies also bound selectively to U2932 and OCI-Ly3 cells and induced selective cytotoxicity of up to 60% at 10 μg/ml. In conclusion, Ars2-containing bispecific and IgG1-format BAR-bodies both are new therapeutic formats to target DLBCL cells.
Insights
New therapeutic antibody formats targeting Ars2 show promise for treating diffuse large B-cell lymphoma (DLBCL). These constructs effectively target cancer cells, offering potential new options for patients with refractory disease.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Diffuse large B-cell lymphoma (DLBCL) remains challenging, with ~30% of patients experiencing treatment failure.
- Ars2 is identified as a B-cell receptor (BCR) auto-antigen in ~25% of activated B-cell DLBCL cases.
- Targeting Ars2-reactive B cells presents a potential therapeutic strategy for DLBCL.
Purpose of the Study:
- To develop and evaluate novel therapeutic formats for targeting Ars2 in DLBCL.
- To investigate the efficacy of Ars2-containing bispecific and IgG1-format constructs (BAR-bodies).
Main Methods:
- Construction of bispecific BAR-bodies linking CD16 or CD3 single-chain antibodies to the Ars2 epitope.
- Development of IgG1-format BAR-bodies by engineering the Ars2 epitope into a full-length antibody.
- Assessment of binding affinity and selective cytotoxicity against DLBCL cell lines (U2932, OCI-Ly3).
Main Results:
- Bispecific BAR-bodies demonstrated strong binding and induced up to 44% selective cytotoxicity against U2932 cells.
- IgG1-format BAR-bodies showed selective binding and induced up to 60% selective cytotoxicity against U2932 and OCI-Ly3 cells.
- Both BAR-body formats effectively targeted DLBCL cells in vitro.
Conclusions:
- Ars2-containing bispecific and IgG1-format BAR-bodies represent novel therapeutic strategies for DLBCL.
- These constructs offer a targeted approach for DLBCL patients with Ars2-reactive BCRs.
- Further investigation into BAR-bodies could lead to improved DLBCL therapies.
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