A phase 1 dose-escalation study of a PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies.
Authors: Sanborn Rachel E. , Bordoni Rodolfo Eduardo , Fleming Gini F. , Khasraw Mustafa , Hawthorne Thomas , Thomas Lawrence J , Rawls Tracey , Young Diane C. , Golden Philip , Keler Tibor , Yellin Michael Jay 
Published: June 2021

2585

Background: CDX-527 is a bispecific antibody (BsAb) targeting PD-L1 and CD27 that is designed to block immune checkpoint PD-L1/PD-1 interactions while providing immune costimulation through CD27 signaling. CD27 is a key immunostimulatory molecule that enhances T cell activation, effector function, and survival. Combining anti-PD-L1 and anti-CD27 mAbs synergize in preclinical studies, activating complementary cytotoxic and proliferative gene expression profiles, respectively. Clinical studies demonstrated the safety and biological activity of combining varlilumab, an agonist anti-CD27 mAb, with nivolumab or atezolizumab, along with modest clinical activity of the combinations. CDX-527 is a novel human BsAb containing a neutralizing, high affinity IgG1k PD-L1 mAb and the single chain Fv fragment (scFv) of an agonist anti-CD27 mAb genetically attached to the C-terminus of each heavy chain, thereby making CDX-527 bivalent for each target. Pre-clinical studies demonstrated enhanced T cell activation by CDX-527 and anti-tumor activity of a surrogate bispecific compared to individual mAb combinations. Methods: CDX527-01 is a phase 1 first-in-human, open-label, multi-center, dose-escalation (DE) and expansion study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of CDX-527 in patient with advanced solid tumors that have progressed on standard-of-care therapy. The primary study objective is to characterize the safety and tolerability of CDX-527. CDX-527 is administered intravenously Q2W with doses ranging from 0.03 mg/kg up to 10.0 mg/kg or until the maximum tolerated dose. The first 2 cohorts of the DE phase initiate with single patients and subsequent DE cohorts will be conducted in 3+3 manner. Tumor-specific expansion cohorts may be enrolled to further characterize the safety, PK, PD, and efficacy of CDX-527. Tumor assessments are performed Q8W by the investigator per iRECIST. Biomarker assessments include characterizing the effects on peripheral blood immune cells and cytokines, and for the expansion cohorts, the impact of CDX-527 on the tumor microenvironment in paired tumor biopsies. Results: To date, 8 patients have received CDX-527 in doses ranging from 0.03 mg/kg to 1 mg/kg and 3 are still on treatment. There has been no drug related SAEs, DLTs or discontinuations due to an AE. Most common treatment related AEs were influenza-like illness, fatigue, and arthralgia (all at 25%). All drug related AEs have been grade 1 or 2. Conclusions: Preliminary results indicate that the novel anti-PD-L1xCD27 bispecific antibody CDX-527 up to and including the 1 mg/kg dose level has been well tolerated. Additional data will be presented, including the safety profile at higher dose levels along with clinical activity, as well as PK and PD data. Clinical trial information: NCT04440943.