YH010 is a fully human PD-L1 x IL-12 antibody-cytokine fusion protein developed for the treatment of solid tumors. This innovative therapy activates the IL-12 signaling pathway while simultaneously inhibiting PD-L1 binding to PD-1. Furthermore, YH010 has the potential to enhance the specific killing activity of T cells by tethering IL-12R positive T cells with PD-L1 positive tumor cells, providing an additional mechanism to attack cancer cells.

Preclinical studies have demonstrated the following findings:

1. In vivo experiments have demonstrated that the safety of YH010 is dependent on the targeting affinity of the anti-PD-L1 antibody. Low binding capacity of the PD-L1 antibody may result in weight loss and elevated serum ALT, leading to serious side effects.

Figure 1. Only PD-L1-dependent activation of IL-12R is safe

2. YH010 has shown a more potent anti-tumor response than anti-PD-L1 antibodies.

Figure 2. In the humanized PD-L1 syngeneic MC38 colorectal cancer model, YH010 demonstrated a stronger anti-tumor response than anti-PD-L1 antibodies.

Targets

PD-L1 immunosuppressants function to block the inhibitory binding of PD-L1 on tumor cells to PD-1 on T cells, which triggers programmed T cell death, leading to immune escape of tumor cells. By blocking this interaction, PD-L1 immunosuppressants can enhance T cell activity, enabling continuous recognition and elimination of tumor cells.

IL-12 is a multipotential cytokine composed of two independent proteins, IL-12A (p35) and IL-12B (p40), which form an active heterodimer (p70) or homodimer (p80) of p40. This cytokine is primarily produced by antigen-stimulated dendritic cells, macrophages, and neutrophils. IL-12 plays a critical role in innate resistance and adaptive immunity by inducing the differentiation of naive T cells into Th1 cells and stimulating T cell proliferation. Additionally, it enhances the activation of cytotoxic lymphocytes and natural killer cells (NK) and increases the production of interferon IFN-γ, turning "cold" tumors "hot" through its pro-inflammatory and immunomodulatory effects.

Although IL-12 is a promising anti-tumor drug, unmodified IL-12 may not accumulate specifically in the tumor microenvironment, limiting its efficacy and potentially causing immune-related side effects. Therefore, modifying IL-12 or using it in combination with other targeted drugs may improve its effectiveness and overcome safety concerns.