Bispecific Antibody CDX-527 Enters Phase 1 Trial in Solid Tumors

The bispecific antibody CDX-527 is now under investigation in patients with advanced or metastatic solid tumors who have progressed during or following standard-of-care treatment with the recent initiation of a phase 1 trial (NCT04440943), according to an announcement from Celldex Therapeutics, Inc.¹

“CDX-527 builds on our prior clinical experience where the combination of CD27 activation and PD-1 blockade was well tolerated and demonstrated biological and clinical activity when the individual agents were dosed together,” Tibor Keler, PhD, executive vice president and chief scientific officer of Celldex Therapeutics, stated in a press release. “We believe this bodes well for the potential safety and activity profile of CDX-527, which incorporates the 2 mechanisms into 1 molecule.”

CDX-527 combines blockade of the PD-1 pathway with T-cell co-stimulation through CD27 into 1 molecule through the use of an IgG1-ScFv format, according to Celldex Therapeutics, Inc, the drug developer.

In the open-label, non-randomized, multicenter phase 1 trial, investigators will examine the safety, tolerability, and activity of CDX-527.² In the dose-escalation portion of the trial, participants will be assigned to different dose levels of the agent to establish its toxicity profile and which dose level will be examined in the expansion portion of the research. Up to 90 patients with select solid tumors will be enrolled to the expansion phase of the trial to receive the established dose. These patients will be closely monitored for response and adverse effects.

To be eligible for participation, patients had to have a recurrent, locally advanced, or metastatic solid tumor other than microsatellite instability–low colorectal cancer, glioblastoma multiforme, prostate cancer, pancreatic cancer, mucosal or ocular melanoma. Patients had to have received all standard options for their disease, have measurable disease per iRECIST criteria, and be willing to undergo a pre- and on-therapy biopsy, if needed.

If they had a history of severe hypersensitivity reactions to other monoclonal antibodies, previously received an anti-CD27 antibody, underwent major surgery within 4 weeks before study treatment, received immunosuppressive medications within 4 weeks or systemic corticosteroids within 2 weeks before study treatment, they were not permitted to enroll.

Additionally, if patients had a previous malignancy, other than treated basal or squamous skin cancer or in situ cancers, they could not participate. If they experienced any thrombotic events within the past 6 months before the study treatment, had active, untreated central nervous system metastases, or active autoimmune disease, they were excluded from the analysis.

The primary end point of the trial is safety and tolerability of the bispecific antibody, while key secondary end points included objective response rate, clinical benefit rate, duration of response, progression-free survival, and overall survival, as well as immunogenicity and pharmacokinetic evaluation of the agent.

Preclinical data have shown stronger T-cell activation and antitumor activity with the investigational agent compared with a PD-L1 antibody in combination with a CD27 antibody.³ Moreover, the agent has demonstrated direct antibody-dependent cellular cytotoxicity against tumor cells that express either CD27 or PD-L1. In preclinical models, the bispecific antibody has been found to have an antibody-like pharmacokinetic profile, without any concerning safety signals observed.

“Importantly, preclinical studies of CDX-527 also demonstrated greater activity than the combination of individual antibodies, adding to our enthusiasm that this next-generation checkpoint inhibitor could be an important addition to the Celldex pipeline,” added Keler.

References

1. Celldex Therapeutics initiates phase 1 study of new bispecific product candidate CDX-527 in solid tumors. News release. Celldex Therapeutics, Inc. August 24, 2020. Accessed September 16, 2020. https://bit.ly/2ZL58Of.
2. A study of PD-L1xCD27 bispecific antibody CDX-527 in patients with advanced malignancies. ClinicalTrials.gov. Updated August 26, 2020. Accessed September 16, 2020. https://clinicaltrials.gov/ct2/show/NCT04440943.​
3. Vitale LA, He L-Z, Thomas LJ, et al. Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy. Published online May 25, 2020. Cancer Immunol Immunother. doi:10.1007/s00262-020-02610-y