CTLA-4: A Key Target in Immunotherapy and Future Directions I. How Does CTLA-4 Regulate Immune Responses?

CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4), also known as CD152, is a crucial transmembrane protein encoded by the *CTLA-4* gene. Belonging to the Immunoglobulin Superfamily (IgSF), its structure comprises an extracellular immunoglobulin variable (IgV) domain, a transmembrane region, and an intracellular domain. CTLA-4 is primarily expressed on the surface of activated CD4⁺ and CD8⁺ T cells, with negligible expression on naïve T cells. Additionally, Regulatory T cells (Tregs) constitutively express high levels of CTLA-4, a characteristic closely associated with their immunosuppressive function.

Notably, CTLA-4 shares high structural homology with the T cell co-stimulatory receptor CD28. Both competitively bind the same ligands – CD80 (B7-1) and CD86 (B7-2). However, they exhibit significant functional antagonism: CD28 transmits a co-stimulatory signal, promoting T cell activation, proliferation, and cytokine secretion; whereas CTLA-4 acts as an inhibitory receptor, negatively regulating T cell immune responses.

II. Through Which Mechanisms Does CTLA-4 Suppress Immune Reactions?

CTLA-4 plays a central role in maintaining immune homeostasis and preventing autoimmunity. Its immunosuppressive mechanisms primarily include the following aspects:

1. Competitive Ligand Binding: CTLA-4 has a significantly higher affinity for CD80/CD86 than CD28, enabling it to effectively compete for and bind B7 molecules on the surface of Antigen-Presenting Cells (APCs). This blocks the CD28-mediated co-stimulatory signal, thereby inhibiting full T cell activation.
2. Signal Transduction Interference: The intracellular segment of CTLA-4 contains an Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) and an Immunoreceptor Tyrosine-Based Switch Motif (ITSM). Upon binding B7 molecules, the intracellular tail becomes phosphorylated, recruiting and activating protein phosphatases such as SHP-2 (SH2-containing protein tyrosine phosphatase-2) and PP2A (Protein Phosphatase 2A). These phosphatases dephosphorylate key molecules in the T cell receptor (TCR) signaling pathway, inhibiting downstream signal propagation.
3. Ligand Deprivation and Transendocytosis: CTLA-4 can internalize and degrade CD80/CD86 from the APC surface via "transendocytosis." This reduces the expression level of B7 molecules on APCs, further limiting CD28 activation.
4. Modulation of Dendritic Cell Function: Recent research has found that the binding of CTLA-4 to CD80/CD86 on Dendritic Cells (DCs) can induce the expression of the tryptophan-catabolizing enzyme IDO (Indoleamine 2,3-dioxygenase). IDO, by degrading local tryptophan, activates stress response pathways, subsequently inhibiting T cell proliferation and function.
5. Enhancement of Treg Suppressive Activity: High expression of CTLA-4 in Regulatory T cells enhances their ability to suppress effector T cells. Studies indicate that Tregs suppress DC antigen presentation function and promote the secretion of immunosuppressive cytokines in a CTLA-4-dependent manner.

III. What Progress Has Been Made in Antibody Drug Development Targeting CTLA-4?

Given the pivotal role of CTLA-4 in immune negative regulation, blocking the CTLA-4 signal has become a major strategy in cancer immunotherapy. Using anti-CTLA-4 monoclonal antibodies can relieve its suppression of T cells, thereby enhancing anti-tumor immune responses.

Currently, the approved CTLA-4 antibody is Ipilimumab (trade name Yervoy®), developed by Bristol-Myers Squibb (BMS). It was approved by the US FDA in 2011 for the treatment of unresectable or metastatic melanoma. Ipilimumab is a humanized IgG1κ monoclonal antibody that binds CTLA-4 with high affinity, blocking its interaction with B7 ligands, thus restoring T cell activation and proliferation capacity. Clinical studies have shown that Ipilimumab significantly improves overall survival in patients with advanced melanoma, but it is also associated with a high incidence of immune-related adverse events (irAEs), such as colitis, dermatitis, and hepatitis.

Another notable CTLA-4 antibody is Tremelimumab, initially developed by Pfizer and now owned by MedImmune (part of AstraZeneca). Tremelimumab is an IgG2 antibody that has been evaluated in numerous clinical trials for cancers including melanoma, non-small cell lung cancer, and hepatocellular carcinoma.

IV. Can CTLA-4 Antibodies Deliver Greater Value in Combination Therapies?

With the deepening of immunotherapy research, the combination of CTLA-4 antibodies with other immune checkpoint inhibitors (such as PD-1/PD-L1 antibodies) has demonstrated synergistic anti-tumor effects. For example, the combination therapy of Ipilimumab and Nivolumab (an anti-PD-1 antibody) has been approved for several indications, including melanoma, renal cell carcinoma, and non-small cell lung cancer. This combination simultaneously relieves T cell inhibition mediated by both the CTLA-4 and PD-1 pathways, significantly enhancing T cell activation and tumor infiltration, albeit with an increased risk of toxicity.

Furthermore, combination strategies involving CTLA-4 antibodies with chemotherapy, radiotherapy, targeted therapy, and cancer vaccines are actively being explored, holding promise for expanding their application in treating various solid tumors.

V. Which Manufacturers Provide CTLA-4 Antibodies?

Hangzhou Starter Bio-tech possesses over fifteen years of experience in monoclonal antibody research and development and is committed to providing high-quality, highly specific CTLA-4 antibodies for global researchers. Our CTLA-4 antibody products undergo rigorous validation, offering excellent specificity, high affinity, and good batch-to-batch consistency. They are suitable for various experimental platforms such as Flow Cytometry, Immunohistochemistry (IHC), and Western Blot. These reagents provide reliable tools for in-depth studies of CTLA-4's biological function, signaling regulation mechanisms, and drug screening.

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