On July 23, 2025 Crossbow Therapeutics, Inc., a biotechnology company developing T-Bolt therapies, a novel class of T-cell receptor (TCR)-mimetic antibody therapeutics, reported the nomination of its second development candidate, CBX-663, for the treatment of a broad range of solid tumor and hematologic malignancies (Press release, Crossbow Therapeutics, JUL 23, 2025, View Source [SID1234654494]). The next-generation T-cell engager targets telomerase reverse transcriptase (TERT), a protein that drives tumor growth and is expressed in up to 95% of cancers.1,2

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CBX-663, a bispecific antibody, binds to TERT-derived peptide human leukocyte antigen (pHLA) complexes on the surface of tumor cells and activates T-cells through a CD3-binding arm. The molecule includes two binding domains for TERT, which increase its ability to engage tumor cells and boost immune activation.

"CBX-663 illustrates how Crossbow’s TCR-mimetic platform can unlock new opportunities for antibody-based cancer therapies," said Briggs Morrison, MD, Chief Executive Officer of Crossbow. "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."

In preclinical studies, CBX-663 drove potent, antigen-specific tumor killing across multiple TERT-positive cancer models, with minimal activity against TERT-negative or HLA-mismatched cells. The candidate also demonstrated a favorable safety profile and pharmacokinetics comparable to conventional antibody therapies. Crossbow presented data summarizing the initial characterization of CBX-663 at the 2025 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

Although TERT resides inside the cell, HLA molecules can present fragments of the protein, known as peptides, on the tumor surface. CBX-663 recognizes one of those peptides, the HLA-A*02:01-restricted TERT540 peptide, and redirects T-cells to attack tumor cells. CBX-663 demonstrated broad cytotoxic activity in vitro in both solid and hematologic cancer cell lines, as well as in primary patient samples ex vivo. In vivo studies further confirmed its anti-tumor efficacy and tolerability.

"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 Dmitri Wiederschain, PhD, Chief Scientific Officer of Crossbow. "Its performance in preclinical models reinforces the promise of TCR-mimetic therapeutics, and we’re excited to continue advancing this program."

Crossbow discovered and developed CBX-663 through its proprietary T-Bolt platform, which uses optimized antibody libraries and precision screening to find high-affinity, specific binders to intracellular tumor antigens displayed as pHLA complexes.

The nomination of CBX-663 underscores the platform’s potential to deliver a scalable pipeline of T-cell engagers for difficult-to-treat cancers.