Bispecific T-Cell Engaging Antibodies Against MUC16 Demonstrate Efficacy Against Ovarian Cancer in Monotherapy and in
Oladapo O Yeku1,2, Thapi Dharma Rao3, Ian Laster1
1Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, United States.
Abstract:
Immunotherapy for ovarian cancer is an area of intense investigation since the majority of women with relapsed disease develop resistance to conventional cytotoxic therapy. The paucity of safe and validated target antigens has limited the development of clinically relevant antibody-based immunotherapeutics for this disease. Although MUC16 expression is almost universal in High Grade Serous Ovarian Cancers, engagement of the shed circulating MUC16 antigen (CA-125) presents a theoretical risk of systemic activation and toxicity. We designed and evaluated a series of bispecific tandem single-chain variable fragments specific to the retained portion of human MUC16 ectodomain (MUC16ecto) and human CD3. These MUC16ecto- BiTEDs retain binding in the presence of soluble MUC16 (CA-125) and show cytotoxicity against a panel of ovarian cancer cells in vitro. MUC16ecto- BiTEDs delay tumor progression in vivo and significantly prolong survival in a xenograft model of ovarian peritoneal carcinomatosis. This effect was significantly enhanced by antiangiogenic (anti-VEGF) therapy and immune checkpoint inhibition (anti-PD1). However, the combination of BiTEDs with anti-VEGF was superior to combination with anti-PD1, based on findings of decreased peritoneal tumor burden and ascites with the former. This study shows the feasibility and efficacy of MUC16ecto- specific BiTEDs and provides a basis for the combination with anti-VEGF therapy for ovarian cancer.
Insights
New bispecific antibodies targeting MUC16 ectodomain (MUC16ecto) show promise for ovarian cancer immunotherapy. These MUC16ecto-BiTEs effectively kill cancer cells and delay tumor progression, especially when combined with anti-VEGF therapy.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Ovarian cancer often develops resistance to conventional therapies, necessitating novel treatment strategies.
- Limited availability of safe and validated target antigens hinders the development of effective antibody-based immunotherapeutics for ovarian cancer.
- While MUC16 is highly expressed in high-grade serous ovarian cancers, targeting the circulating form (CA-125) poses a risk of systemic toxicity.
Purpose of the Study:
- To design and evaluate bispecific tandem single-chain variable fragments (BiTEDs) targeting the retained MUC16 ectodomain (MUC16ecto) and CD3.
- To assess the efficacy of MUC16ecto-BiTEDs against ovarian cancer cells in vitro and in vivo.
- To investigate the synergistic effects of MUC16ecto-BiTEDs in combination with anti-VEGF or anti-PD1 therapies.
Main Methods:
- Development of bispecific tandem single-chain variable fragments (MUC16ecto-BiTEDs) targeting MUC16 ectodomain and CD3.
- In vitro cytotoxicity assays against a panel of ovarian cancer cell lines.
- In vivo evaluation in a xenograft model of ovarian peritoneal carcinomatosis, including combination studies with anti-VEGF and anti-PD1 therapies.
Main Results:
- MUC16ecto-BiTEDs demonstrated binding affinity even in the presence of soluble MUC16 (CA-125).
- Significant in vitro cytotoxicity against ovarian cancer cells was observed.
- In vivo studies showed delayed tumor progression and prolonged survival in a xenograft model.
- Combination therapy with anti-VEGF demonstrated superior efficacy over anti-PD1, evidenced by reduced tumor burden and ascites.
Conclusions:
- MUC16ecto-specific BiTEDs are feasible and effective for ovarian cancer immunotherapy.
- The combination of MUC16ecto-BiTEDs with anti-VEGF therapy shows significant therapeutic potential.
- This approach offers a promising strategy to overcome treatment resistance in ovarian cancer.
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