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A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell
Stefan Schönberger1,2, Daniela Kraft3, Daniel Nettersheim4
1Department of Pediatric Hematology and Oncology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany.
Abstract:
Outcome in high-risk patients with refractory or relapsed germ cell tumours (GCT) remains poor. Novel strategies enhancing therapeutic efficacy whilst limiting therapeutic burden are warranted, yet immunotherapy approaches geared towards activating endogenous antitumor responses have not been successful thus far. Redirection of cytotoxic effector cells by bispecific antibodies represents a promising approach in this setting. We demonstrate that the Epithelial Cell Adhesion Molecule (EpCAM) is broadly expressed in GCT cell lines of different histologic origin including seminoma, choriocarcinoma (CHC), and embryonal carcinoma (EC). In these GCT lines of variable EpCAM surface expression, targeting T cells by the prototypic bispecific EpCAM/CD3-antibody (bAb) Catumaxomab together with natural killer (NK) cell engagement via the Fc domain promotes profound cytotoxicity across a broad range of antibody dilutions. In contrast, tumor cell lysis mediated by either immune cell subset alone is influenced by surface density of the target antigen. In the CHC line JAR, NK cell-dependent cytotoxicity dominates, which may be attributed to differential surface expression of immunomodulatory proteins such as MHC-I, CD24, and Fas receptors on CHC and EC. In view of redirecting T cell therapy mediated by bispecific antibodies, such differences in GCT immunophenotype potentially favoring immune escape are worth further investigation.
Insights
Bispecific antibodies targeting EpCAM on germ cell tumors (GCT) show promise for treating refractory GCT. This approach redirects T cells and NK cells, enhancing anti-tumor activity in preclinical models.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- High-risk patients with refractory or relapsed germ cell tumors (GCT) have poor outcomes.
- Current immunotherapy strategies have not successfully activated endogenous anti-tumor responses.
- Bispecific antibodies offer a novel approach by redirecting cytotoxic effector cells.
Purpose of the Study:
- To investigate the efficacy of bispecific antibodies targeting Epithelial Cell Adhesion Molecule (EpCAM) in germ cell tumors (GCT).
- To evaluate the combined activity of T cells and natural killer (NK) cells mediated by bispecific antibodies against GCT.
- To explore the influence of GCT immunophenotype on bispecific antibody-mediated cytotoxicity.
Main Methods:
- Demonstrated broad EpCAM expression across various GCT cell lines (seminoma, choriocarcinoma, embryonal carcinoma).
- Utilized the bispecific EpCAM/CD3 antibody (Catumaxomab) to engage T cells and NK cells.
- Assessed GCT cell lysis mediated by T cells and NK cells at varying antibody concentrations.
Main Results:
- Bispecific antibody targeting EpCAM and CD3 induced profound GCT cytotoxicity by engaging both T cells and NK cells.
- Cytotoxicity mediated by individual immune cell subsets was dependent on EpCAM surface expression levels.
- Natural killer (NK) cell-dependent cytotoxicity was dominant in choriocarcinoma cell lines, potentially due to differential expression of immunomodulatory proteins.
Conclusions:
- Bispecific antibodies targeting EpCAM represent a promising strategy for refractory germ cell tumors.
- The immunophenotype of GCT, including expression of MHC-I, CD24, and Fas receptors, influences immune cell-mediated cytotoxicity.
- Further investigation into GCT immunophenotypic differences is warranted for optimizing bispecific antibody-based therapies.
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