Dual Checkpoint Blockade

Bispecific antibodies (BsAbs) are artificial molecules that can simultaneously bind to two different antigens or epitopes, thereby enabling novel modes of action and therapeutic applications. BsAbs have been explored for various purposes, such as targeting multiple pathways, recruiting immune cells, enhancing effector functions, and delivering drugs or toxins. Among these, one of the most promising and attractive applications of BsAbs is cancer immunotherapy, which aims to harness the power of the immune system to fight against tumors. Cancer immunotherapy has been revolutionized by the discovery and development of checkpoint inhibitors, which are monoclonal antibodies (mAbs) that block the inhibitory signals that suppress the anti-tumor activity of T cells. However, checkpoint inhibitors have several limitations, such as low response rates, resistance mechanisms, toxicity issues, and high costs. To overcome these challenges, BsAbs have been developed to achieve dual checkpoint blockade, which is a strategy that simultaneously targets two inhibitory receptors or ligands on T cells or tumor cells, such as PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, etc. Dual checkpoint blockade can potentially enhance the efficacy and safety of cancer immunotherapy by overcoming the immune suppression and resistance mediated by multiple checkpoints.

Principle of Dual Checkpoint Blockade

The immune system is composed of various cells and molecules that work together to protect the body from foreign invaders and eliminate abnormal or damaged cells. Among these, T cells are the key players of adaptive immunity, which can recognize and kill specific antigens, such as tumor-associated antigens (TAAs). However, T cells are also regulated by various signals that modulate their activation, proliferation, differentiation, and function. These signals can be classified into two categories: co-stimulatory signals and co-inhibitory signals. Co-stimulatory signals enhance the T cell response, while co-inhibitory signals suppress the T cell response. Co-inhibitory signals are also known as checkpoints, which are essential for maintaining immune tolerance and preventing autoimmunity. However, tumors can exploit these checkpoints to evade immune surveillance and resistance by expressing or inducing the expression of inhibitory receptors or ligands on T cells or tumor cells, such as PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, etc. These checkpoints can inhibit the T cell activation, proliferation, survival, effector function, and memory formation, resulting in T cell exhaustion and dysfunction.

To overcome immune suppression and resistance mediated by multiple checkpoints, a strategy called dual checkpoint blockade has been developed. Dual checkpoint blockade uses bispecific antibodies (BsAbs) to simultaneously target two inhibitory receptors or ligands on T cells or tumor cells. This blocks their interaction and restores the T cell response. Dual checkpoint blockade has the potential to enhance the efficacy and safety of cancer immunotherapy by achieving synergistic effects, overcoming heterogeneity, reducing toxicity, and improving pharmacokinetics.

For example, dual checkpoint blockade can target PD-1 and CTLA-4, which are two major checkpoints that regulate T cell activation at different stages. PD-1 inhibits the T cell response in peripheral tissues, while CTLA-4 inhibits the T cell response in lymph nodes. By blocking both PD-1 and CTLA-4, dual checkpoint blockade can enhance the priming and effector phases of the T cell response.

Similarly, dual checkpoint blockade can target PD-1 and LAG-3, which are two co-expressed checkpoints that induce T cell exhaustion in chronic infections and cancers. By blocking both PD-1 and LAG-3, dual checkpoint blockade can reverse T cell exhaustion and restore T cell function.

Moreover, dual checkpoint blockade can target PD-L1 and 4-1BB, which are two ligands expressed on tumor cells and activated T cells, respectively. By blocking PD-L1 and engaging 4-1BB, dual checkpoint blockade can not only inhibit tumor-induced immune suppression but also stimulate T cell activation and survival. These are some examples of how dual checkpoint blockade can achieve superior outcomes compared to monospecific checkpoint blockade or combination therapy in cancer immunotherapy.

Application Scenarios of Dual Checkpoint Blockade by Bispecific Antibodies

Application scenarios of dual checkpoint blockade using bispecific antibodies have been seen in various types of cancers, such as melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), head and neck squamous cell carcinoma (HNSCC), and colorectal cancer (CRC). These cancers are characterized by high immunogenicity, high expression of inhibitory checkpoints, and low response to monospecific checkpoint inhibitors. By simultaneously blocking two inhibitory checkpoints, bispecific antibodies can enhance anti-tumor immunity and overcome resistance mechanisms in these cancers.

Table 1. Examples of bispecific antibodies for dual checkpoint blockade in different types of cancers

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