YH008 is an anti-PD-1 x CD40 bispecific antibody. With the PD-1-dependent agonistic activity of anti-CD40, YH008 has a good safety profile. YH008 can be used in solid tumors and hematologic tumors. YH008 has received FDA IND clearance in December 2022.
Structure of YH008
Preclinical studies have shown the following findings:
1. YH008 demonstrated superior potency than 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 has 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 mainly expressed on the surface of T cells and primary B cells. The two ligands of PD-1, PD-L1 and PD-L2, are widely expressed on antigen-presenting cells (APCs). PD-1 interacts with its ligands and plays an important role in the negative regulation of immune response. PD-L1 is highly expressed in a variety of solid tumors. The interaction between PD-1 and PD-L1 reduces T cell activation and promotes tumor immune escape. Blockade of the binding of PD-1 to PD-L1 by anti-PD-1 or anti-PD-L1 antibody can block the PD-1/PD-L1 signaling pathway, thereby restoring anti-tumor immune response and eliminating tumors. Therefore, PD-1/PD-L1 is considered the basic target of tumor immunotherapy.
CD40 is a member of the tumor necrosis factor receptor superfamily (TNFRSF) on the surface of immune cells. This drug 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 specifically activating the CD40 receptor signaling pathway. To date, studies have shown that CD40 activation is a key regulatory point for tumor immunotherapy, effectively transforming cold tumors lacking immune cell infiltration into hot tumors that respond well to tumor immunotherapy. However, the toxicity of this target has long limited the development of CD40 antibody drugs. With PD-1-dependent CD40 activation, YH008 is expected to further enhance the efficacy through the synergistic effects of both targets while addressing the safety issue of CD40.
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