Bispecific T-cell engaging antibodies against MUC16 demonstrate efficacy against ovarian cancer in monotherapy and in combination with PD-1 and VEGF inhibition Journal Article


Authors: Yeku, O. O.; Rao, T. D.; Laster, I.; Kononenko, A.; Purdon, T. J.; Wang, P.; Cui, Z.; Liu, H.; Brentjens, R. J.; Spriggs, D.
Article Title: Bispecific T-cell engaging antibodies against MUC16 demonstrate efficacy against ovarian cancer in monotherapy and in combination with PD-1 and VEGF inhibition
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. © Copyright © 2021 Yeku, Rao, Laster, Kononenko, Purdon, Wang, Cui, Liu, Brentjens and Spriggs.
Keywords: ovarian cancer; angiogenesis; vegf; muc16; immune checkpoint blockade; bispecific antibodies; bispecific engagers; muc16ecto
Journal Title: Frontiers in Immunology
Volume: 12
ISSN: 1664-3224
Publisher: Frontiers Media S.A.  
Date Published: 2021-04-01
Start Page: 663379
Language: English
DOI: 10.3389/fimmu.2021.663379
PUBMED: 33936101
PROVIDER: scopus
PMCID: PMC8079980
DOI/URL:
Notes: Dharmarao Thapi's first and last names are reversed on the original publication -- Article -- Export Date: 1 June 2021 -- Source: Scopus
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  1. Renier J Brentjens
    286 Brentjens
  2. Dharmarao Thapi
    38 Thapi
  3. Terence John Purdon
    61 Purdon