Degron Therapeutics Co-Founder Provides New Strategy for Molecular Glue in Tumor Immunotherapy
Degron Therapeutics (“Degron”), a biotechnology company developing a new class of small-molecule medicines that target previously undruggable targets, today announced research suggesting lenalidomide, a molecular glue degrader of IKZF1 and IKZF3, can enhance the potential of the programmed cell death protein 1 (PD-1) antibody to treat cancer. The research was led by Yong Cang, Ph.D., Degron’s co-founder and chief scientific officer, and conducted by Dr. Cang’s research group at ShanghaiTech University’s School of Life Science and Technology.
Published in the journal Cell Chemical Biology, the study, “Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling,” found that the molecular glue drug lenalidomide could restore the tumor immunotherapy effect of the PD-1 antibody and inhibit tumor growth in mice lacking T-cell co-stimulatory signals. PD-1 is a checkpoint protein on T cells. It normally operates as a type of ‘off switch’ that helps keep T cells from attacking other cells in the body.
“Science-based innovation is core to Degron’s exploration into the mechanisms of molecular glue drugs and cancer immunity. The work performed in Dr. Cang’s lab reveals that degradation of IKZF1 and IKZF3, can reinvigorate T cells to attack cancers by modulating immune regulatory networks,” said Lily Zou, Ph.D., co-founder and CEO of Degron. “This discovery provides new ideas for Degron to dial in such activities into our molecular glue programs when appropriate.”
“Degron’s pipeline of molecular glue degraders against novel oncology targets can be chemically modified to selectively retain the ability to degrade IKZF1 and IKZF3. As a result, such drugs can kill cancer cells by two different mechanisms, directly inactivating oncogenesis and by inducing T cells to target the cancer cells,” said Dr. Cang.
Dr. Cang’s group constructed a humanized mouse model of cereblon (CRBN) that is sensitive to lenalidomide and proved that lenalidomide can co-stimulate CD8+ T cells in the absence of CD28 receptors. Using CD28-KO CRBN humanized mouse models and tumor samples from colorectal cancer patients, the researchers demonstrated that lenalidomide could restore the response of CD28-CD8+ T cells to PD-1 antibodies, thereby enabling the recovery of PD-1 antibody therapy failure due to CD28 deficiency.
Dr. Cang’s team demonstrated that lenalidomide could co-stimulate T cells by upregulating the secretion of the immune system signaling molecule, interleukin-2 (IL2). Through transcriptome sequencing, the researchers found that lenalidomide can also upregulate Notch targets. Simultaneously blocking both IL2 and Notch signaling pathways simultaneously limits the co-stimulatory effect of lenalidomide on T cells, rendering the combination therapy of lenalidomide and PD-1 antibody ineffective.
Approved for marketing in 2005 as an anti-myeloma drug, lenalidomide kills myeloma cells directly while enhancing T-cell anti-tumor activity to inhibiting tumor growth. Lenalidomide is approved for the treatment of multiple myeloma (MM), deletion 5q myelodysplastic syndrome (MDS), mantle cell lymphoma, and other hematological tumors. In addition, lenalidomide’s iterative product, pomalidomide, a third-generation immunomodulatory agent that acts as molecular glue, has also achieved great success as a treatment for relapsed and refractory MM.
The research was mainly supported by the National Natural Science Foundation of China, the Shanghai Science and Technology Commission, and ShanghaiTech University.