Crossbow Therapeutics Doses First Patient in Phase 1 Trial of CBX-663 for Multiple Cancers
Crossbow Therapeutics, Inc., a biotechnology company developing targeted antibody therapies designed to address a broad range of cancers, has announced the dosing of the first participant in its TelOscope-001 Phase 1 clinical trial evaluating CBX-663. The investigational therapy is being developed as a first-in-class T-cell engager (TCE) intended to target multiple hematologic malignancies and solid tumors.
The initiation of the Phase 1 study represents an important clinical development milestone for Crossbow Therapeutics as the company advances its pipeline of precision cancer immunotherapies. CBX-663 is the second therapeutic candidate generated through Crossbow’s proprietary T-Bolt™ platform, which is designed to identify tumor-associated peptide human leukocyte antigen (pHLA) complexes and develop antibody-based therapies capable of recognizing these targets.
Unlike conventional antibodies that primarily recognize proteins located directly on the surface of cancer cells, Crossbow’s T-Bolt platform is designed to expand the range of potentially druggable cancer targets by recognizing peptide fragments derived from intracellular proteins when they are presented on the cell surface by HLA molecules. CBX-663 applies this approach to telomerase reverse transcriptase (TERT), a protein associated with cancer cell survival and uncontrolled proliferation.
CBX-663 Targets TERT-Associated Tumor Cells
TERT is a central component of the telomerase enzyme and plays an important role in maintaining telomeres, the protective structures at the ends of chromosomes. In normal adult tissues, telomerase activity is generally limited. However, many cancer cells reactivate telomerase, enabling them to maintain their telomeres and continue dividing beyond normal cellular limits.
Crossbow Therapeutics estimates that TERT is overexpressed in approximately 90% of cancers, making it an attractive target for a broadly applicable cancer therapy. The company believes that targeting TERT-derived pHLA complexes could provide an opportunity to develop an immune-based treatment capable of addressing multiple cancer types.
“TERT is a priority target for anticancer therapy due to its widespread overexpression, which allows cancer cells to bypass cellular aging, promotes uncontrolled tumor proliferation, and correlates with disease severity,” said Briggs Morrison, M.D., Chief Executive Officer of Crossbow Therapeutics.
According to Morrison, CBX-663 is designed to selectively recognize a TERT-derived pHLA complex found on tumor cells across a range of hematologic and solid malignancies. This broad tumor-targeting potential could make the candidate particularly relevant for cancers where treatment options remain limited and where patients may have exhausted existing therapies.
Phase 1 TelOscope-001 Trial Begins
The first participant dosing in TelOscope-001 marks the transition of CBX-663 from preclinical development into human clinical testing. The study is an open-label, dose-escalation Phase 1 trial designed primarily to evaluate the safety and tolerability of the investigational therapy while also assessing preliminary signs of clinical activity.
The study is enrolling patients with several categories of difficult-to-treat cancer, including relapsed or refractory myeloid malignancies, advanced solid tumors, and recurrent or progressive glioblastoma multiforme (GBM).
Patients with relapsed or refractory disease represent a significant area of unmet medical need because their cancers have either returned following treatment or failed to respond adequately to available therapies. Similarly, advanced solid tumors and recurrent or progressive GBM can be particularly challenging to treat because of tumor heterogeneity, disease progression and resistance to existing treatment approaches.
The TelOscope-001 study is evaluating CBX-663 using a fixed step-up dosing schedule. This approach is commonly incorporated into early-stage development of T-cell-engaging therapies to help investigators characterize safety and tolerability as exposure to an immune-activating therapy increases.
Crossbow expects to report initial clinical data from the TelOscope-001 study around the end of 2027. These future results are expected to provide important information about the therapy’s safety profile, pharmacokinetics, dosing strategy and potential antitumor activity in patients.
A Bispecific T-Cell Engager
CBX-663 is a wholly owned bispecific antibody engineered to bring cancer cells and T cells together. One portion of the molecule recognizes a TERT-derived pHLA complex displayed on tumor cells, while another binding arm interacts with CD3, a protein associated with T cells.
By simultaneously engaging the tumor-associated target and CD3 on T cells, the therapy is designed to direct the patient’s immune cells toward cancer cells carrying the targeted pHLA complex.
CBX-663 contains two binding domains directed against TERT, according to Crossbow. The company believes this configuration can strengthen tumor-cell engagement and support immune activation.
The underlying concept is based on redirecting the body’s existing T-cell population toward cancer cells rather than relying solely on the immune system’s naturally occurring recognition mechanisms. T-cell engagers have become an increasingly important area of cancer immunotherapy research, particularly in hematologic malignancies.
Crossbow is attempting to extend this therapeutic strategy to intracellular cancer-associated proteins through pHLA targeting. If successful, the approach could potentially increase the number of cancer-associated proteins that can be addressed using antibody-based therapies.
Preclinical Data Support Further Development
Before entering clinical development, CBX-663 demonstrated antitumor activity in multiple preclinical models, according to Crossbow Therapeutics.
The company reported that CBX-663 produced potent and antigen-specific tumor-cell killing across several TERT-positive cancer models. Importantly, the molecule showed minimal activity against TERT-negative cells or cells carrying an HLA mismatch.
This selectivity is an important characteristic for a targeted immune therapy. By preferentially recognizing the intended TERT-derived pHLA complex, CBX-663 is designed to distinguish tumor cells carrying the target from cells that do not display the appropriate antigen-HLA combination.
Crossbow also reported favorable preclinical safety findings and pharmacokinetic characteristics comparable to those observed with conventional antibody therapies. However, these findings remain based on preclinical research, and the ongoing Phase 1 study will determine whether the observed characteristics translate into humans.
The safety and tolerability profile will be a major focus of TelOscope-001 as investigators determine appropriate dosing and assess potential treatment-related adverse events.
T-Bolt Platform Expands Targeting Opportunities
CBX-663 is the second candidate produced through Crossbow’s T-Bolt platform. The platform is intended to discover antibodies capable of recognizing pHLA complexes associated with intracellular tumor antigens.
Many proteins that play important roles in cancer biology are located inside cells and therefore cannot be directly targeted by conventional antibody therapies. Crossbow’s strategy is to identify peptide fragments from these intracellular proteins that are naturally presented on the tumor-cell surface in association with HLA molecules.
The company uses optimized antibody libraries and precision screening technologies to identify high-affinity binders against these pHLA complexes. These binders can then serve as the tumor-recognition components of engineered T-cell-engaging therapies.
Through this approach, Crossbow aims to combine the target specificity of antibodies with the cancer-killing capabilities of T cells.
The company’s focus on TERT is particularly significant because of the protein’s prevalence across cancer types. Rather than limiting development to a single tumor indication, CBX-663 is being evaluated across both hematologic and solid malignancies.
Potential for Broad Cancer Applications
One of the central objectives of the CBX-663 program is to determine whether a single TERT-directed therapy can demonstrate activity across multiple cancer types.
TERT expression has been associated with a wide range of malignancies, and the company believes targeting a TERT-derived pHLA complex could potentially overcome some limitations associated with therapies that depend on tumor-specific surface proteins.
The inclusion of myeloid malignancies, advanced solid tumors and GBM in the initial Phase 1 program reflects this broad development strategy.
Nevertheless, the ability of CBX-663 to produce meaningful clinical responses across these cancers will need to be established through clinical testing. Factors such as HLA expression, presentation of the targeted peptide, TERT-derived pHLA abundance, tumor biology and immune-cell activity may influence how individual patients respond.
The TelOscope-001 trial will therefore provide an early assessment of whether the mechanism demonstrated in laboratory models can translate into clinical benefit.
Next Steps for Crossbow Therapeutics
With the first patient now dosed, Crossbow Therapeutics is entering an important stage in the development of CBX-663. The Phase 1 study is expected to generate the first human clinical experience with the company’s TERT-directed T-cell engager and provide information needed to guide subsequent development.
As dose escalation progresses, investigators will evaluate safety, tolerability, pharmacokinetics and preliminary evidence of antitumor activity. The resulting data will help determine the potential therapeutic window and inform future clinical studies.
Crossbow expects initial TelOscope-001 clinical data around the end of 2027. Positive findings could support further evaluation of CBX-663 in selected tumor types and potentially broader clinical development across TERT-positive malignancies.
The program also represents an important test of the broader T-Bolt platform. If CBX-663 successfully demonstrates the ability to selectively recognize tumor-associated pHLA complexes and activate T cells in patients, the results could help validate Crossbow’s strategy for targeting intracellular cancer proteins that have historically been difficult to address with antibody therapeutics.
Additional information about the TelOscope-001 study, registered as NCT07779798, is available through ClinicalTrials.gov.
About Crossbow Therapeutics, Inc.
Crossbow Therapeutics, Inc., is a biotechnology company determined to improve the lives of people with cancer by unlocking the therapeutic potential of T-cell receptor (TCR)-mimetic antibodies. The company’s T-Bolt™ therapies are next-generation, easily assembled immunotherapies directed with high precision at previously unreachable cancer cell targets. Crossbow’s efficient and selective approach is designed to target the entire universe of cancer proteins, dramatically expanding the potential of antibody therapy to address many types of cancer.