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<p>Bispecific protein engagers (BIPEs) are an emerging class of immunotherapeutics with substantial clinical promise. Blinatumomab is currently the only approved Bispecific T cell Engager (BiTE®) and is limited to acute lymphoblastic leukemia, however, efficacy and target selectivity must improve to fully extend this modality to solid tumors. We engineered dual BIPEs as an off-the-shelf, non-cell alternative to chimeric antigen receptor (CAR)-T cell therapy that avoids apheresis, conditioning, and genomic modification. We analyzed MSLN and NECTIN2 expression in colorectal cancer (CRC) using GEPIA. Guided by highly expression of MSLN and NECTIN2 CRC expression, we built a stable cell line that produces αMSLN × αCD3 and αNECTIN2 × αCD28 BIPEs. We then tested whether these BIPEs activate T cells and drive selective killing of MSLN/NECTIN2 double-positive CRC patient-derived organoids. αMSLN × αCD3 and αNECTIN2 × αCD28 BIPEs specifically bound CD3 or CD28 on T cells and MSLN or NECTIN2 on CRC cells. Compared with T cells without BIPEs, they mediated significantly greater cytotoxicity against MSLN<sup>High</sup>/NECTIN2<sup>High</sup> CRC cells and organoids. In BIPEs-activated T cells, co-culture with CRC cells triggered robust T cell activation and cytokine release (TNF-α, IFN-γ, granzyme A, granzyme B, perforin, and granulysin) without elevating IL-6. These data support dual-targeting, bispecific protein engager strategies that activate T cells through 2 tumor-associated antigens. Dual αMSLN × αCD3 and αNECTIN2 × αCD28 BIPEs merit further translational value for development to improve outcomes for patients with CRC. </p>

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Dual bispecific protein engagers targeting mesothelin and NECTIN2 deliver CD3/CD28 signals to activate cytotoxic T cells against colorectal cancer patient-derived organoids

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Suyanee Thongchot,
  • Kamonlapat Supimon,
  • Nattaporn Phanthaphol,
  • Pattara Kanoksing,
  • Titaporn Mitchasin,
  • Thaweesak Chieochansin,
  • Woramin Riansuwan,
  • Siriluck Prapasrivorakul,
  • Pornraksa Ovartchaiyapong,
  • Aitsariya Mongkhonsupphawan,
  • Surat Phumphuang,
  • Mutita Junking,
  • Pa-thai Yenchitsomanus,
  • Peti Thuwajit,
  • Chanitra Thuwajit

摘要

Bispecific protein engagers (BIPEs) are an emerging class of immunotherapeutics with substantial clinical promise. Blinatumomab is currently the only approved Bispecific T cell Engager (BiTE®) and is limited to acute lymphoblastic leukemia, however, efficacy and target selectivity must improve to fully extend this modality to solid tumors. We engineered dual BIPEs as an off-the-shelf, non-cell alternative to chimeric antigen receptor (CAR)-T cell therapy that avoids apheresis, conditioning, and genomic modification. We analyzed MSLN and NECTIN2 expression in colorectal cancer (CRC) using GEPIA. Guided by highly expression of MSLN and NECTIN2 CRC expression, we built a stable cell line that produces αMSLN × αCD3 and αNECTIN2 × αCD28 BIPEs. We then tested whether these BIPEs activate T cells and drive selective killing of MSLN/NECTIN2 double-positive CRC patient-derived organoids. αMSLN × αCD3 and αNECTIN2 × αCD28 BIPEs specifically bound CD3 or CD28 on T cells and MSLN or NECTIN2 on CRC cells. Compared with T cells without BIPEs, they mediated significantly greater cytotoxicity against MSLNHigh/NECTIN2High CRC cells and organoids. In BIPEs-activated T cells, co-culture with CRC cells triggered robust T cell activation and cytokine release (TNF-α, IFN-γ, granzyme A, granzyme B, perforin, and granulysin) without elevating IL-6. These data support dual-targeting, bispecific protein engager strategies that activate T cells through 2 tumor-associated antigens. Dual αMSLN × αCD3 and αNECTIN2 × αCD28 BIPEs merit further translational value for development to improve outcomes for patients with CRC.