Enhancing Cancer Immunotherapy with CDX-527: Targeting CD27 and PD-L1 for Synergistic T Cell Activation

CD27, a costimulatory molecule on T cells, represents an alternative target to the PD-1/PD-L1 pathway for enhancing immune responses against cancer. The combination of varlilumab, a CD27 agonist monoclonal antibody (mAb), with nivolumab, a PD-1 mAb, has shown promising clinical responses in patients with advanced cancer. Building on this, CDX-527 has been developed as a tetravalent bispecific antibody (bsAb) targeting both CD27 and PD-L1, with the hypothesis that it may offer superior immune activation through enhanced CD27 stimulation via crosslinking.

CDX-527 has been shown to effectively inhibit PD-1 signaling and to stimulate T cells more potently than individual antibodies or their combination, as evidenced by increased cytokine production and cell proliferation. In assays, CDX-527 demonstrated greater potency than the parent antibodies, suggesting that the cross-linking of CD27 by CDX-527 leads to enhanced agonist activity. In human CD27 transgenic mice, the bsAb significantly boosted antigen-specific T cell responses to vaccination and exhibited superior antitumor effects compared to the individual antibodies.

These findings indicate that CDX-527, through its dual targeting approach, can achieve more efficient T cell activation and effective PD-1/PD-L1 blockade, offering a new strategy in cancer immunotherapy. Development activities for CDX-527 are underway, including a pilot study in cynomolgus macaques to evaluate pharmacokinetics and pharmacodynamics, which will inform the design of a GLP toxicology study.