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Characterization of the D8P1C1 Anti-ADAM17 Inhibitory Monoclonal Antibody and Generation of Its Bispecific T-Cell
Nayanendu Saha1, Sang Gyu Lee2, Elisa de Stanchina3
1Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
EGFR signaling, which requires ligand shedding by ADAM proteases, drives the progression of a variety of cancers, including breast, ovarian and lung. We previously reported the generation and characterization of a fully human, affinity-matured anti-ADAM17 monoclonal antibody, D8P1C1, which inhibits both the proliferation of an array of cancer cell lines in vitro as well as breast cancer growth in a mouse xenograft model. Here, we show that the mAb inhibits the shedding of EGFR ligands and EGFR phosphorylation in cancer cell lines, thus explaining its anti-tumor effects. In a xenograft model with a high-grade serous ovarian cancer (HGSOC) cell line, D8P1C1 showed only modest therapeutic effect, without any discernible toxicity. These results suggest that ovarian cancers are less susceptible than breast cancers to therapeutic targeting of ADAM17- or EGFR-dependent signaling. Radioimmuno PET imaging with 89Zr-DFO-D8P1C1 confirmed tumoral accumulation of the mAb in high-grade and non-high-grade serous ovarian tumor xenografts. Furthermore, we report the generation and preliminary characterization of a bispecific T cell engager derivative of D8P1C1 with improved anti-tumor efficacy in vitro.
Insights
An anti-ADAM17 antibody, D8P1C1, effectively targets breast cancer by inhibiting EGFR signaling. However, ovarian cancers show less response, suggesting differential therapeutic susceptibility.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Epidermal Growth Factor Receptor (EGFR) signaling is crucial for various cancers.
- ADAM proteases mediate ligand shedding, activating EGFR signaling.
- ADAM17 is a key protease in this pathway.
Purpose of the Study:
- To evaluate the therapeutic potential of the anti-ADAM17 monoclonal antibody (mAb) D8P1C1.
- To investigate the anti-tumor mechanisms of D8P1C1 in breast and ovarian cancers.
- To assess the efficacy of D8P1C1 and its derivatives in preclinical cancer models.
Main Methods:
- In vitro proliferation assays with cancer cell lines.
- In vivo efficacy studies using mouse xenograft models (breast and ovarian cancer).
- Radioimmuno Positron Emission Tomography (PET) imaging with 89Zr-labeled D8P1C1.
- Generation and characterization of a bispecific T cell engager derivative.
Main Results:
- D8P1C1 inhibited EGFR ligand shedding and phosphorylation in cancer cells.
- D8P1C1 demonstrated significant anti-tumor effects in breast cancer xenografts.
- Ovarian cancer xenografts showed modest response to D8P1C1, with no observed toxicity.
- 89Zr-DFO-D8P1C1 confirmed antibody accumulation in ovarian tumors.
- A bispecific T cell engager derivative showed enhanced in vitro anti-tumor efficacy.
Conclusions:
- Targeting ADAM17 with D8P1C1 is a viable strategy for breast cancer treatment.
- Ovarian cancers may be less sensitive to ADAM17 or EGFR-targeted therapies compared to breast cancers.
- D8P1C1 demonstrates potential for diagnostic imaging in ovarian cancer.
- Bispecific T cell engagers represent a promising advancement for enhanced anti-cancer activity.
