Exelixis, Inc. (NASDAQ: EXEL) has initiated the dose-escalation stage of a first-in-human Phase 1 clinical trial evaluating XB628 in patients with recurrent advanced or metastatic solid tumors, according to an announcement from collaboration partner Invenra Inc. on May 13, 2025.
XB628 represents a novel approach to cancer immunotherapy as a first-in-class bispecific antibody natural killer (NK) cell engager. The investigational therapy simultaneously targets NK group 2 member A (NKG2A), an inhibitory receptor on NK cells, and programmed cell death-ligand 1 (PD-L1), a well-established immune checkpoint protein.
Novel Mechanism of Action
The dual-targeting mechanism of XB628 is designed to enhance anti-tumor immune responses through NK cell activation. By binding to NKG2A, the antibody aims to block inhibitory signals that normally restrain NK cell activity. Simultaneously, targeting PD-L1 addresses a key immune evasion pathway utilized by many cancer types.
This approach differs from conventional checkpoint inhibitors by specifically engaging NK cells, which are critical components of innate immunity and play important roles in tumor surveillance and elimination.
Clinical Trial Design
The Phase 1 study has now entered its dose-escalation stage, which typically aims to determine the maximum tolerated dose and preliminary safety profile of the investigational therapy. While specific details about the trial design were not disclosed, Phase 1 oncology trials generally enroll patients with advanced malignancies who have progressed on standard therapies.
The trial is recruiting participants with recurrent advanced or metastatic solid tumors, suggesting a basket trial approach that may include multiple tumor types rather than focusing on a specific cancer indication.
Collaborative Development
XB628 emerged from a collaboration between Exelixis and Invenra, combining Exelixis' expertise in oncology drug development with Invenra's specialized antibody discovery capabilities.
"The advancement of XB628 into clinical development represents an important milestone in our collaboration with Exelixis," said Bryan Glaser, Ph.D., Senior Vice President of Business Development at Invenra, in a statement accompanying the announcement.
Invenra's proprietary B-Body® platform was instrumental in the development of XB628. This platform is engineered to create bispecific antibody scaffolds with superior yield, purity, stability, and manufacturing compatibility—critical factors for successful clinical and commercial development of complex biologics.
Potential Clinical Significance
While still in early clinical development, XB628 could potentially address significant unmet needs in oncology. NK cell-based approaches represent an emerging area of cancer immunotherapy that may complement or provide alternatives to T-cell focused treatments like conventional PD-1/PD-L1 inhibitors.
The bispecific approach targeting both NKG2A and PD-L1 could potentially overcome resistance mechanisms observed with single-target immunotherapies. This may be particularly relevant for patients whose tumors have developed resistance to existing checkpoint inhibitors.
About the Companies
Exelixis is an established oncology-focused biopharmaceutical company with marketed products including cabozantinib (CABOMETYX®), a tyrosine kinase inhibitor approved for multiple cancer indications. The company has been expanding its pipeline through both internal research and strategic collaborations.
Invenra specializes in the discovery and development of multispecific antibodies addressing unmet therapeutic needs. The company's B-Body® platform enables the rapid generation of bispecific and multispecific antibodies with favorable biophysical properties. Invenra also offers the B-Body Express™ Antibody Expression service to accelerate antibody development for partners.
Market Context
The advancement of XB628 into clinical trials comes amid growing interest in NK cell-based cancer therapies and bispecific antibody platforms. Several bispecific antibodies have received regulatory approvals in recent years, primarily for hematological malignancies, while development programs for solid tumors continue to advance.
The global market for bispecific antibodies is projected to grow significantly over the coming years, driven by their potential to address complex disease mechanisms through dual-targeting approaches.
