Degron Therapeutics (“Degron”), a biotechnology company developing a new class of small-molecule medicines that target previously undruggable targets, 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.
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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.