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Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells

  • Authors:
    • Liu Yang
    • Xin Chen
    • Qian Wang
    • Yuankui Zhu
    • Changfa Wu
    • Xuqian  Ma
    • Dianbao Zuo
    • Huixia He
    • Le Huang
    • Jingwen Li
    • Chunjiao  Xia
    • Sheng Hu
    • Xiaoqing Yang
    • Mingqian Feng
  • View Affiliations / Copyright

    Affiliations: College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, P.R. China, Clinical Testing Branch, Hongshan District Chinese Medicine Hospital, Wuhan, Hubei 430000, P.R. China, Department of Internal Medicine‑Oncology, Hubei Cancer Hospital, Wuhan, Hubei 430079, P.R. China, Clinical Laboratory, Hospital of Huazhong Agricultural University, Wuhan, Hubei 430070, P.R. China
    Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 542
    |
    Published online on: May 20, 2021
       https://doi.org/10.3892/ol.2021.12803
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Abstract

Targeting inhibitory immune checkpoint molecules has significantly altered cancer treatment regimens. T cell immunoglobulin and mucin domain 3 (TIM3) is one of the major inhibitory immune checkpoints expressed on T cells. Blocking the engagement of TIM3 and its inhibitory ligand galectin‑9 may potentiate the effects of immunotherapy or overcome the adaptive resistance to the therapeutic blockade of programmed cell death protein 1, cytotoxic T‑lymphocyte‑associated protein 4, B‑ and T‑lymphocyte attenuator and lymphocyte‑activation gene 3, amongst others, as each of these immune checkpoints harbors unique properties that set it apart from the rest. Heavy chain variable fragment (VH)‑derived single‑domain antibodies (sdAbs) represent a class of expanding drug candidates. These sdAbs have unique advantages, including their minimal size in the antibody class, ease of expression, broad scope for modular structure design and re‑engineering, and excellent tumor penetration. In the present study, two sdAbs, TIM3‑R23 and TIM3‑R53, were generated by immunizing rabbits with the recombinant extracellular domain of TIM3 and applying phage display technology. These sdAbs were easily expressed in mammalian cells. The purified sdAbs were able to bind to both recombinant and cell surface TIM3, and blocked it from binding to the ligand galectin‑9. In vivo studies demonstrated that TIM3‑R53 was able to potentiate the antitumor activity of chimeric antigen receptor T cells that targeted mesothelin. In conclusion, the results of the present study suggested that TIM3‑R53 may be a novel and attractive immune checkpoint inhibitor against TIM3, which is worthy of further investigation.
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Copy and paste a formatted citation
Spandidos Publications style
Yang L, Chen X, Wang Q, Zhu Y, Wu C, Ma X, Zuo D, He H, Huang L, Li J, Li J, et al: Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells. Oncol Lett 22: 542, 2021.
APA
Yang, L., Chen, X., Wang, Q., Zhu, Y., Wu, C., Ma, X. ... Feng, M. (2021). Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells. Oncology Letters, 22, 542. https://doi.org/10.3892/ol.2021.12803
MLA
Yang, L., Chen, X., Wang, Q., Zhu, Y., Wu, C., Ma, X., Zuo, D., He, H., Huang, L., Li, J., Xia, C., Hu, S., Yang, X., Feng, M."Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells". Oncology Letters 22.1 (2021): 542.
Chicago
Yang, L., Chen, X., Wang, Q., Zhu, Y., Wu, C., Ma, X., Zuo, D., He, H., Huang, L., Li, J., Xia, C., Hu, S., Yang, X., Feng, M."Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells". Oncology Letters 22, no. 1 (2021): 542. https://doi.org/10.3892/ol.2021.12803
Copy and paste a formatted citation
x
Spandidos Publications style
Yang L, Chen X, Wang Q, Zhu Y, Wu C, Ma X, Zuo D, He H, Huang L, Li J, Li J, et al: Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells. Oncol Lett 22: 542, 2021.
APA
Yang, L., Chen, X., Wang, Q., Zhu, Y., Wu, C., Ma, X. ... Feng, M. (2021). Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells. Oncology Letters, 22, 542. https://doi.org/10.3892/ol.2021.12803
MLA
Yang, L., Chen, X., Wang, Q., Zhu, Y., Wu, C., Ma, X., Zuo, D., He, H., Huang, L., Li, J., Xia, C., Hu, S., Yang, X., Feng, M."Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells". Oncology Letters 22.1 (2021): 542.
Chicago
Yang, L., Chen, X., Wang, Q., Zhu, Y., Wu, C., Ma, X., Zuo, D., He, H., Huang, L., Li, J., Xia, C., Hu, S., Yang, X., Feng, M."Generation of TIM3 inhibitory single‑domain antibodies to boost the antitumor activity of chimeric antigen receptor T cells". Oncology Letters 22, no. 1 (2021): 542. https://doi.org/10.3892/ol.2021.12803
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