CAR-T with Half CTLA-4

Currently, the main strategy for CTLA-4 is targeted inhibitors, such as CTLA-4 monoclonal antibody, CTLA-4 monoclonal antibody + PD-1 monoclonal antibody, CTL-4 + PD-1 dual-target monoclonal antibody, etc.

However, nowadays, drug development is becoming more and more open-minded, and instead of treating CTLA-4 only as a drug target, some researchers are trying to utilize its action characteristics as an engineered material for CAR-T. Creative Biolabs describes the emerging role of CTLA-4 in CAR-T drug development and offers to explore more possibilities.

Trans-endocytosis of CTLA-4

The minimal expression of CTLA-4 on the surface of T cells is due to its own highly endocytotic properties, which allow it to continuously circulate at the cell membrane and inside the cell. In addition to competing with CD28 for the binding of CD80/CD86 molecules, CTLA-4 swallows both molecules into the cell interior, resulting in a reduction of CD80/CD86 on the surface of APCs.

Fig. 1 Trans-endocytosis of CTLA-4.¹

The site that performs this function is the CTLA-4 cytoplasmic tail (CCT), which was initially thought to be the region that transmits immunosuppressive signals, and subsequent studies have revealed that the YVKM motif in the CCT interacts with the junction-activating protein 2 (AD-2) to mediate cell membrane-intracellular recycling.

CAR with Half of CTLA-4

Recently, some researchers have combined CCT with CAR C-terminal to construct three CARs targeting CD22: CAR-1CCT, CAR-2CCT, and CAR-3CCT, which also improved tumor therapeutic efficacy after gaining endocytosis.

Fig. 2 CCT combined with CAR-C end.²

The fusion CCT may have altered the CAR signaling, and in vitro studies found

• CCT-CAR-T has better durability to repetitive antigenic stimulation, lower levels of pro-inflammatory cytokine expression, enhanced cytotoxicity, and possesses a better tumor-killing function with weaker toxic side effects.
• Thanks to CCT-mediated endocytosis, the expression level of CCT-CAR-T on the membrane surface is also regulated by endocytosis, recycling and degradation mechanisms. Therefore, the reduced antigen phagocytosis of CCT-CAR-T on the surface of tumor cells can solve the problem of CAR-T consuming tumor antigen-mediated drug resistance to a certain extent. And the apoptosis level of cells with less antigen phagocytosis is lower.

Advantages of CAR-T with Half of CTLA-4

• Reduce phagocytic consumption of antigen and alter CAR signaling, resulting in lower toxicity and enhanced effector function, proliferation capacity, and durability.
• CTLA-4 partly outward and partly inward seems to reach just the right balance.

At Creative Biolabs, we are at the forefront of immune checkpoint drug development. Welcome your inquiries to discuss the latest development strategies with us.

References

1. Walker Lucy SK and David M. Sansom. "The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses." Nature Reviews Immunology 11.12 (2011): 852-863.
2. Zhou, Xiaoyu, et al. "CTLA-4 tail fusion enhances CAR-T anti-tumor immunity." bioRxiv (2023): 2023-03.

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