Degron Therapeutics Co-Founders Reveal Novel Molecular Glue Strategy for Tumor Immunotherapy in IPO Prospectus
A study published in the journal Cell Chemical Biology, titled “Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling,” found that the molecular glue drug lenalidomide can restore the efficacy of PD-1 antibody-based cancer immunotherapy and inhibit tumor growth in mice lacking T-cell co-stimulatory signals. PD-1 is a checkpoint protein on T cells. It typically functions as an “immune off-switch,” helping to prevent T cells from attacking other cells in the body.
“Science-driven innovation is the core strategy behind Dage’s exploration of molecular glue therapeutics and cancer immunology mechanisms,” stated Dr. Zou Lihui, Co-founder and CEO of the company. “The work conducted in Professor Cang’s laboratory has revealed that degraders targeting IKZF1 and IKZF3 can reactivate T cells to attack cancer by modulating the immunoregulatory network. This discovery also provides Dage with new insights for incorporating this mechanism into its molecular glue programs.”
Professor Cang stated, “Molecular glue degraders in Dage’s pipeline that target novel oncology targets can be chemically modified to selectively retain their ability to degrade IKZF1 and IKZF3. Consequently, such drugs can kill cancer cells through two distinct mechanisms: direct inactivation of oncogenes and induction of T cell–mediated immune responses to control cancer.”
Professor Cang’s laboratory developed a CRBN-humanized mouse model sensitive to lenalidomide and demonstrated that lenalidomide can co-stimulate CD8+ T cells in the absence of the CD28 receptor. Using CD28-knockout (CD28-KO) CRBN-humanized mice and tumor samples from patients with colorectal cancer, the researchers showed that lenalidomide restores the responsiveness of CD28-deficient CD8+ T cells to anti-PD-1 antibodies, thereby overcoming resistance to anti-PD-1 antibody therapy caused by CD28 deficiency.
Professor Cang’s team demonstrated that lenalidomide can co-stimulate T cells by upregulating the secretion of interleukin-2 (IL-2), an immune system signaling molecule. Through transcriptome sequencing, the researchers found that lenalidomide also upregulates Notch targets. Simultaneous blockade of the IL-2 and Notch signaling pathways restricts the co-stimulatory effect of lenalidomide on T cells, thereby rendering the combination therapy of lenalidomide and PD-1 antibodies ineffective.
Lenalidomide, an anti-myeloma drug, was approved for market launch in 2005. It directly kills myeloma cells while enhancing T-cell anti-tumor activity to inhibit tumor growth. Lenalidomide is approved for the treatment of multiple myeloma (MM), myelodysplastic syndromes (MDS) with deletion 5q, mantle cell lymphoma, and other hematologic malignancies. Furthermore, pomalidomide, an iterative product of lenalidomide and a third-generation immunomodulatory agent, has achieved significant success as a molecular glue in the treatment of relapsed and refractory MM.
This study was supported by the National Natural Science Foundation of China, the Shanghai Municipal Science and Technology Commission, and ShanghaiTech University.
Dage Bio is a biotechnology company dedicated to the research and development of innovative drugs based on molecular glue-mediated targeted protein degradation. The company has established its proprietary GlueXplorer platform technology, which comprises a rapidly expanding, patent-protected library of unique compounds and a robust screening system, to develop novel small-molecule therapeutics targeting previously undruggable disease targets. The company’s product pipeline includes a growing number of preclinical candidates for oncology, immune-mediated diseases, metabolic disorders, and rare diseases.