Crossbow Therapeutics Advances Second TCR-Mimetic Cancer Therapy Candidate, CBX-663, Targeting TERT Across Broad Range of Tumors
Crossbow Therapeutics, Inc., a biotechnology company pioneering a new class of T-cell receptor (TCR)-mimetic antibody therapeutics through its proprietary T-Bolt™ platform, has announced the nomination of its second development candidate, CBX-663. This investigational agent is a next-generation bispecific T-cell engager engineered to target telomerase reverse transcriptase (TERT)—a tumor-associated antigen expressed in up to 95% of cancers—positioning CBX-663 as a promising treatment for a wide array of solid tumors and hematologic malignancies.
CBX-663 exemplifies the innovative potential of Crossbow Therapeutics’s TCR-mimetic approach, which bridges the precision of T-cell receptor biology with the therapeutic advantages of antibody-based modalities. The candidate was unveiled alongside new preclinical data at the 2025 American Association for Cancer Research (AACR) Annual Meeting, highlighting its potent, selective antitumor activity, favorable safety profile, and pharmacokinetics comparable to traditional antibody therapies.
Targeting the Undruggable: A New Approach to TERT
One of the most challenging aspects of oncology drug development is identifying and reaching intracellular targets that play a fundamental role in cancer proliferation. TERT, an enzyme that maintains telomere length and promotes limitless replication in cancer cells, is one such elusive target. While TERT is located within the cell and thus inaccessible to conventional antibody therapeutics, Crossbow Therapeutics’s T-Bolt™ platform overcomes this barrier by exploiting peptide-human leukocyte antigen (pHLA) complexes—natural cellular processes that allow fragments of intracellular proteins to be displayed on the cell surface by HLA molecules.
CBX-663 is a bispecific antibody that binds with high affinity to the TERT540 peptide presented on HLA-A*02:01 molecules—a specific and well-characterized epitope derived from TERT. It simultaneously engages CD3 on T-cells, effectively redirecting immune cells to recognize and destroy tumor cells displaying the TERT epitope.
“CBX-663 illustrates how Crossbow’s TCR-mimetic platform can unlock new opportunities for antibody-based cancer therapies,” said Dr. Briggs Morrison, Chief Executive Officer of Crossbow Therapeutics. “With strong preclinical performance selectively targeting a pHLA expressed across a broad range of cancers, CBX-663 has the potential to offer a meaningful new treatment option for patients with limited therapeutic options.”
Preclinical Data Validates Selectivity and Potency
According to data presented by Crossbow Therapeutics at AACR 2025, CBX-663 has demonstrated potent antigen-specific cytotoxicity across a range of preclinical models, including multiple TERT-positive solid tumors and hematologic cancers. The molecule showed:
- Selective killing of tumor cells expressing the HLA-A*02:01–TERT540 complex
- Minimal off-target activity in TERT-negative or HLA-mismatched cells
- In vivo anti-tumor efficacy in several animal models
- A favorable safety profile in early toxicology studies
- Pharmacokinetics on par with conventional antibody therapeutics
The bispecific structure of CBX-663 includes two independent binding domains for TERT, enhancing its binding avidity and tumor cell engagement while minimizing non-specific activation. This dual-binding mechanism amplifies the immune activation effect, driving more efficient and targeted tumor cell elimination.
In vitro testing extended to primary human samples and cell lines across diverse cancer types, affirming the broad applicability of the candidate. Ex vivo experiments in TERT-positive, HLA-A*02:01-matched patient-derived samples mirrored the cytotoxic efficacy seen in cell lines. Importantly, CBX-663 was not active against mismatched or normal cells, underscoring its precision targeting capabilities.
TCR-Mimetic Innovation: The T-Bolt™ Platform
CBX-663 was discovered and optimized through Crossbow Therapeutics’s T-Bolt™ platform, which is designed to identify high-affinity antibodies that mimic the T-cell receptor’s natural ability to recognize pHLA complexes. The platform integrates sophisticated antibody libraries with precision screening technologies, enabling Crossbow to engineer bispecific T-cell engagers that are both selective and highly potent.
According to Dr. Dmitri Wiederschain, Chief Scientific Officer of Crossbow Therapeutics, CBX-663’s development reflects the company’s deep commitment to addressing previously intractable cancer targets. “CBX-663 reflects the depth of antibody discovery and protein engineering that underpins our T-Bolt™ platform and our ability to generate highly selective, potent molecules against difficult cancer targets,” said Wiederschain. “Its performance in preclinical models reinforces the promise of TCR-mimetic Crossbow Therapeutics, and we’re excited to continue advancing this program.”
The nomination of CBX-663 as the Crossbow Therapeutics company’s second development candidate—following its lead candidate, CBX-12—underscores the platform’s scalability and versatility. With pHLA targets representing a vast, largely untapped frontier in oncology, Crossbow is well-positioned to build a deep pipeline of bispecific T-cell engagers capable of addressing both common and rare malignancies.
Broad Implications for Oncology Treatment Paradigms
The development of CBX-663 is significant not only because of the molecule’s promising preclinical activity, but also because it represents a paradigm shift in how antibody therapies can be designed to engage intracellular cancer targets. While conventional monoclonal antibodies are limited to targeting extracellular proteins, TCR-mimetic antibodies like CBX-663 tap into a vast array of intracellular tumor antigens that are presented on the cell surface by HLA molecules—effectively expanding the universe of druggable targets.
TERT, in particular, represents an ideal proof-of-concept for this approach. As a universal cancer antigen expressed in the overwhelming majority of human tumors and largely absent from normal adult tissues, TERT provides an opportunity to achieve broad coverage of malignancies with a single, precisely targeted therapeutic. Crossbow’s focus on the HLA-A*02:01–TERT540 complex also enhances the specificity of CBX-663, potentially reducing the risk of off-target toxicity.
Importantly, the company’s platform is designed to identify additional HLA-peptide targets across different HLA haplotypes, which could broaden patient eligibility and increase the clinical impact of its therapeutics.
What’s Next for CBX-663?
With nomination as a formal development candidate, CBX-663 will now advance into IND-enabling studies, with the goal of initiating clinical trials in TERT-positive cancers. Crossbow expects to initially focus on solid tumors and hematologic malignancies with high unmet need, including cancers where TERT expression correlates with poor prognosis and limited treatment options.
The Crossbow Therapeutics company also continues to expand its pipeline of TCR-mimetic bispecifics, leveraging lessons from CBX-663 and other programs to refine its discovery and development engine.
“We believe our T-Bolt™ platform is uniquely suited to repeatedly generate potent T-cell engagers that go beyond conventional antibody approaches,” said Morrison. “CBX-663 is the latest example of how we can bring forward transformative new therapies against validated, yet previously inaccessible cancer targets.
Crossbow Therapeutics’ nomination of CBX-663 marks a significant milestone in the evolution of cancer immunotherapy. By harnessing the power of T-cell engagement against the widely expressed but historically undruggable TERT target, CBX-663 could open new doors for patients with treatment-resistant cancers.
Backed by robust preclinical data, a proprietary platform with broad discovery capabilities, and a clear strategic roadmap, Crossbow is rapidly emerging as a leader in the next wave of T-cell engager innovation—one that brings the precision of TCR biology to the scalability of antibody engineering.
As CBX-663 moves closer to the clinic, the oncology community will be watching closely for signs that this novel approach can deliver not just better outcomes—but new hope—for patients with few remaining options.
