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Background <p>Single-chain antibody-based CAR-T cells targeting BAFF-R have demonstrated antitumor effects against human B-cell malignancies and can overcome CD19 antigen loss. However, CARs built on antigen-specific single-chain antibody variable fragments may have limitations, e.g., large CAR binding domain size. To improve the function of BAFF-R CAR-T cells, we designed CARs with only a fully human heavy-chain variable domain.</p> Methods <p>A fully human antibody phage display library was used to select anti- BAFF- R clones using protein/cell alternate panning. The screened clones were grafted into a second-generation CAR to generate CAR-T cells. CD107a degranulation, luciferase-based cytolysis, repeat antigen stimulation, activation markers, and exhaustion markers were used to detect the function of CAR-T cells in vitro. Xenografts were established in NPG mice following intravenous injection of Jeko-1 cells. Tumor burden and survival of mice were recorded weekly.</p> Results <p>Three single-domain heavy chain antibodies, namely Clone #5, Clone #77, and Clone #80, were selected for further evaluation. CAR-T cells constructed with these three candidate clones demonstrated specific target cell activation and effective cytotoxicity in vitro. Clone #5 and Clone #77 CAR-T cells exhibited superior cytotoxic capacity and expansion ability. No significant difference was observed in the expression levels of exhaustion markers on the surface of the three CAR-T cell types. In vivo studies revealed that Clone #5 CAR-T cells displayed enhanced antitumor efficacy compared to other groups, resulting in prolonged survival.</p> Conclusion <p>We developed a novel BAFF-R CAR-T cell product structured on a fully human single-domain antibody. This product demonstrated promising preclinical activity and may provide a potential alternative treatment for patients with B-cell malignancies.</p>

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Human single domain antibody-based CAR-T cells targeting BAFF-R demonstrate promising preclinical activity in B-cell malignancies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Cuiling Zhang,
  • Qian Luo,
  • Sungui Wu,
  • Le Xu,
  • Qiaoe Wei,
  • Yanying Zhang,
  • Chaoyang Guan,
  • Xiaoqing Dong,
  • Yang Hong,
  • Taochao Tan,
  • Bing Chen

摘要

Background

Single-chain antibody-based CAR-T cells targeting BAFF-R have demonstrated antitumor effects against human B-cell malignancies and can overcome CD19 antigen loss. However, CARs built on antigen-specific single-chain antibody variable fragments may have limitations, e.g., large CAR binding domain size. To improve the function of BAFF-R CAR-T cells, we designed CARs with only a fully human heavy-chain variable domain.

Methods

A fully human antibody phage display library was used to select anti- BAFF- R clones using protein/cell alternate panning. The screened clones were grafted into a second-generation CAR to generate CAR-T cells. CD107a degranulation, luciferase-based cytolysis, repeat antigen stimulation, activation markers, and exhaustion markers were used to detect the function of CAR-T cells in vitro. Xenografts were established in NPG mice following intravenous injection of Jeko-1 cells. Tumor burden and survival of mice were recorded weekly.

Results

Three single-domain heavy chain antibodies, namely Clone #5, Clone #77, and Clone #80, were selected for further evaluation. CAR-T cells constructed with these three candidate clones demonstrated specific target cell activation and effective cytotoxicity in vitro. Clone #5 and Clone #77 CAR-T cells exhibited superior cytotoxic capacity and expansion ability. No significant difference was observed in the expression levels of exhaustion markers on the surface of the three CAR-T cell types. In vivo studies revealed that Clone #5 CAR-T cells displayed enhanced antitumor efficacy compared to other groups, resulting in prolonged survival.

Conclusion

We developed a novel BAFF-R CAR-T cell product structured on a fully human single-domain antibody. This product demonstrated promising preclinical activity and may provide a potential alternative treatment for patients with B-cell malignancies.