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YH006


YH006 is a fully human CTLA-4 x OX40 IgG1 bispecific antibody produced by RenLite mice of fully human antibodies with a common light chain and very close to monoclonal antibody in the structural style. YH006 reduces the CTLA-4 toxicity and treat tumors mainly by more specifically removing tumor-infiltrating Treg cells.


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The structure of YH006


Preclinical studies have shown the following findings:
1. CTLA-4 and OX40 are co-expressed and highly expressed in tumor-infiltrating Tregs. The dual targets enable more specific identification of tumor-infiltrating Tregs. YH006 has stronger in vivo anti-tumor activity.

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Figure 1. In the MC38 syngeneic mouse tumor model, YH006 better inhibited tumor growth than ipilimumab analogs and Fc-enhanced parental IgG1 monoclonal antibody


2. YH006 addresses the double-antibody mismatch with a common light chain and provides good stability and druggability.

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Figure 2. The fully human bispecific antibody YH006 with high purity and good stability is obtained in one step


Targets
CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4), also known as CD152, plays an important regulatory role in the activation of T cells. CTLA-4 is expressed on the surface of regulatory T cells (Tregs), and when bound to B7-1 (CD80) and B7-2 (CD86) on the surface of antigen-presenting cells (APCs), competitively inhibits the binding of B7 to CD28 on the surface of effector T cells, thereby inhibiting the activation of T cells. Therefore, inhibition of CTLA-4 by inhibitory antibodies can block this mechanism, thereby enhancing T cell activity.

Currently, the marketed antibody drugs targeting CTLA-4 include CTLA-4 mAb ipilimumab (Yervoy) from BMS and PD-1 x CTLA-4 bispecific antibody cadonilimab (trade name: Kaitanni; AK104) from Akeso.

OX40 is a type I transmembrane glycoprotein, a member of the tumor necrosis factor receptor superfamily (TNFRSF), and an important costimulator of T cell response. OX40 is not expressed on naïve T cells, but is transiently expressed on CD4+ and CD8+ T cells after TCR engagement, enhancing the TCR signaling, promoting the proliferation and survival, as well as the release of effector cytokines, and preventing T-cell tolerance. In addition, activation of OX40 inhibits the production and secretion of inhibitory cytokines including IL-10 and TGF-b by Treg cells. Moreover, OX40 plays an important role in the formation of memory T cells.

There are currently no marketed OX40 drugs.