Antengene Publishes Preclinical Research on CD73 Inhibitor ATG-037 Combined with Selinexor for Multiple Myeloma

Antengene Corporation Limited, a global biotech company focused on developing first-in-class and best-in-class medicines, has announced the publication of a preclinical research paper that explores the potential of combining its CD73 small molecule inhibitor ATG-037 with selinexor for the treatment of multiple myeloma (MM). The study, conducted in collaboration with the Department of Hematology at Peking University Third Hospital, was published in the international journal Cancer Gene Therapy.

The research aimed to address a key resistance mechanism observed in MM treatment, where selinexor, a selective inhibitor of nuclear export (SINE) drug, upregulates CD73 expression, leading to adenosine accumulation and an immunosuppressive state. This immunosuppressive environment hinders the activation of CD8+ T cells, which are crucial for tumor cell killing. The combination therapy of ATG-037 and selinexor was designed to counteract this resistance mechanism by suppressing CD73-dependent adenosine synthesis, thereby restoring CD8+ T cell activation and enhancing their cytotoxicity.

In the preclinical study, the research team first analyzed the expression of CD73 in various tumor cell lines following selinexor treatment. They then tested the combination therapy in vivo using a J558-inoculated BALB/c mouse model. The mice were divided into four groups: a vehicle group, an ATG-037 monotherapy group, a selinexor monotherapy group, and a combination-therapy group. Single-cell RNA sequencing was used to characterize immune cell subtypes and tumor-immune crosstalk, while immunofluorescence staining was performed on tumor tissue. Co-culture experiments of CD8+ T cells and multiple myeloma cell lines further confirmed the mechanism behind the combination's antitumor effect.

The results showed that the combination therapy significantly suppressed tumor growth, with an inhibition rate of 62%, compared to 31% for ATG-037 monotherapy and 43% for selinexor monotherapy. Single-cell RNA sequencing revealed that the combination synergistically potentiated CD8+ T cell activation by enhancing the interaction between CD8+ T cells and Enpp1+ cells via the CD80, CD28 signaling pathway. This interaction led to an increase in CD8+ T cell infiltration into tumor tissue, as confirmed by immunofluorescence staining. Co-culture experiments demonstrated that CD73 inhibition strengthened selinexor-mediated tumor cell killing by activating CD8+ T cells, with significantly elevated levels of Granzyme B (P=0.0252) and IFN-γ (P=0.0067) observed in the combination group.

These findings establish a novel, clinically feasible therapeutic paradigm for addressing drug resistance and refractory MM. By leveraging the synergistic potential of combining selinexor with a CD73 inhibitor, Antengene aims to enhance CD8+ T cell-mediated tumor cytotoxicity, offering a promising approach for the treatment of MM.

Antengene's pipeline includes several investigational candidates, including ATG-022 (CLDN18.2 ADC), ATG-037 (oral CD73 inhibitor), ATG-101 (PD-L1 x 4-1BB bispecific antibody), ATG-125 (B7-H3 × PD-L1 bispecific ADC), ATG-207 (αCD3-TGF-β bifunctional fusion protein), and T cell engager (TCE) programs developed using Antengene's proprietary AnTenGager® platform. To date, the company has obtained 34 investigational new drug (IND) approvals in the U.S. and Asia and has secured new drug application (NDA) approvals in 10 Asia Pacific markets.