YH008 is an anti-PD-1 x CD40 bispecific antibody for the treatment of solid tumors. YH008 activates CD40 while simultaneously inhibiting PD-1. The results of in vitro and in vivo experiments show that the activation of the CD40 pathway by YH008 depends on the cross-linking effect of PD-1, avoiding non-specific activation outside the tumor microenvironment.
We received the U.S. FDA approval in December 2022 and NMPA approval in March 2023 for the Phase I clinical trial, which is a first-in-human study of YH008 in subjects with advanced solid malignant tumors, in order to assess the safety and tolerability of YH008, as well as to determine the MTD or the recommended.
Structure of YH008
Preclinical studies have shown the following findings:
1. YH008 demonstrated superior potency compared to parental monoclonal antibodies (mAbs) or combination therapy.
Figure 1. In the MC38 tumor model, YH008 has better anti-tumor activity than parental mAbs or combination therapy.
2. YH008 has stronger in vivo anti-tumor activity than the benchmark mAb and anti-PD-L1 x CD40 bispecific antibody in multiple syngenic models.
Figure 2. A) In the B16F10 tumor model, YH008 has better anti-tumor activity than the PD-1 benchmark mAb;
B) In the MC38 tumor model, YH008 has stronger anti-tumor activity than anti-PD-L1 x CD40 bispecific antibody.
3. YH008 showed no systemic toxicity or hepatotoxicity.
Figure 3. YH008 has a better safety profile than selicrelumab (CD40 monoclonal antibody) analogues. mAb: 20mg/kg, BsAb: 26mg/kg, i.p.
4. YH008 requires PD-1 expression to activate human CD40 signaling.
5. YH008 has high affinity to human PD-1 and CD40.
PD-1 (Programmed Death-1) is predominantly expressed on the surface of T cells and primary B cells, whereas its two ligands, PD-L1 and PD-L2, are widely expressed on antigen-presenting cells (APCs). The interaction between PD-1 and its ligands plays a crucial role in negative immune regulation. In a variety of solid tumors, PD-L1 is highly expressed and leads to tumor immune evasion by suppressing T cell activation. Anti-PD-1 or anti-PD-L1 antibodies can block the PD-1/PD-L1 signaling pathway, restore anti-tumor immune response, and eliminate tumors. Therefore, PD-1/PD-L1 is considered a fundamental target of tumor immunotherapy.
CD40, a member of the tumor necrosis factor receptor superfamily (TNFRSF), is expressed on immune cells' surface. This receptor promotes the activation of innate immune cells, such as dendritic antigen-presenting cells (DCs), and positively regulates the effector activity of anti-tumor T cells by activating the CD40 receptor signaling pathway. CD40 activation is a key regulatory point for tumor immunotherapy and can transform cold tumors lacking immune cell infiltration into hot tumors that respond well to immunotherapy. However, the toxicity of CD40 has long limited the development of CD40 antibody drugs. With YH008's PD-1-dependent CD40 activation, it is expected to enhance the efficacy through the synergistic effects of both targets while addressing CD40's safety issue.
AACR2022: YH008, a PD-1-CD40 Bispecific Antibody, Inhibits Tumor Growth In Vivo Through PD-1-Dependent Activation of CD40 Signaling