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<p>Immune checkpoint inhibitors, such as monoclonal antibodies or engineered small molecules, are a novel approach to cancer immunotherapy and are being used to treat several types of cancer. CTLA-4, an immune checkpoint, is expressed on the surface of activated T cells where it downregulates immune responses. CD80, also known as B7-1, is a common ligand for CTLA-4 and the T cell co-stimulatory protein CD28. In this study, to inhibit CTLA-4, a variant of the extracellular domain of CD80 (mCD80) carrying the R29Y, Y31R, and Q33K mutations to increase its binding affinity to CTLA-4 was recombinantly expressed in <i>Escherichia coli</i>. The equilibrium dissociation constant (K<sub>D</sub>) for the binding of mCD80 to both CD28 and CTLA-4 was also calculated using surface plasmon resonance (SPR) technology. The results showed a significant increase in the binding affinity of mCD80 to CTLA-4, with a 69.76-fold increase compared to wild-type CD80. In contrast, the binding affinity of mCD80 to CD28 showed a significant decrease compared to its wild-type counterpart. These findings suggest that mCD80 may serve as a promising candidate for inhibiting the CTLA-4 on the surface of T cells. Consequently, it may be developed in the future as a potential pharmaceutical agent for cancer immunotherapy.</p>

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Biophysical Characterization of an Engineered CD80 Variant for CTLA-4 Blockade in Cancer Immunotherapy

  • 期刊论文

  • 发表日期：

    2025年12月29日

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  • Zahra Hajihassan,
  • Amir Hossein Mosayebi,
  • Ramezan Ali Taheri,
  • Parisa Bazargannia

摘要

Immune checkpoint inhibitors, such as monoclonal antibodies or engineered small molecules, are a novel approach to cancer immunotherapy and are being used to treat several types of cancer. CTLA-4, an immune checkpoint, is expressed on the surface of activated T cells where it downregulates immune responses. CD80, also known as B7-1, is a common ligand for CTLA-4 and the T cell co-stimulatory protein CD28. In this study, to inhibit CTLA-4, a variant of the extracellular domain of CD80 (mCD80) carrying the R29Y, Y31R, and Q33K mutations to increase its binding affinity to CTLA-4 was recombinantly expressed in Escherichia coli. The equilibrium dissociation constant (KD) for the binding of mCD80 to both CD28 and CTLA-4 was also calculated using surface plasmon resonance (SPR) technology. The results showed a significant increase in the binding affinity of mCD80 to CTLA-4, with a 69.76-fold increase compared to wild-type CD80. In contrast, the binding affinity of mCD80 to CD28 showed a significant decrease compared to its wild-type counterpart. These findings suggest that mCD80 may serve as a promising candidate for inhibiting the CTLA-4 on the surface of T cells. Consequently, it may be developed in the future as a potential pharmaceutical agent for cancer immunotherapy.