Preclinical Data on Tumor-Selective Peptide-Drug Conjugates Presented at ESMO Targeted Anticancer Therapies Congress 2025

New preclinical data from Cybrexa Therapeutics alphalex™ technology were presented at the ESMO Targeted Anticancer Therapies (TAT) Congress 2025 being held March 3-5. 2025 in Paris, France.

The findings demonstrate that Cybrexa’s antigen-agnostic tumor-targeting peptide-drug conjugate (PDC) therapeutics platform technology* selectively delivers highly potent microtubule inhibitors to tumor cells, suppressing tumor growth while inducing a durable anti-tumor immune response.

PDC vs ADC
Unlike antibody-drug conjugates (ADCs), alphalex PDCs use a pH-driven targeting approach to enable broad tumor applicability and avoid the toxicities often associated with antigen-based drug targeting.

Preclinical Findings at ESMO TAT 2025
The poster presented during the ESMO TAT meeting highlighted preclinical results evaluating the efficacy, safety, and immune-modulating effects of alphalex conjugates across mouse and rat xenograft and syngeneic models, including colorectal, melanoma, renal, and breast cancers.

The data demonstrate that alphalex PDCs achieved tumor-selective delivery, long-term stability in plasma, and potent anti-tumor effects as both monotherapy and in combination with standard-of-care therapies.

“These data reinforce the potential of the alphalex platform to overcome the challenges of antigen-based therapies, while providing a powerful, tumor-selective approach to delivering cytotoxic agents,” said Vishwas Paralkar, Ph.D., Chief Scientific Officer of Cybrexa Therapeutics.

“In bypassing the limitations of antibody-drug conjugates, we are opening new therapeutic possibilities for patients with hard-to-treat solid tumors.”

Key findings:

• Tumor-selective drug delivery
  • Plasma stability and in vivo analyses confirmed that alphalex conjugates selectively deliver microtubule inhibitors to tumor tissue while sparing healthy immune cells.
• Potent efficacy in multiple tumor models
  • Monotherapy: alphalex conjugates led to complete tumor suppression in HCT116 human colorectal cancer models.
  • Combination therapy: In flank and metastatic models, alphalex PDCs demonstrated synergy with doxorubicin and anti-PD-L1 therapy, further enhancing tumor suppression.
• Induction of durable anti-tumor immunity
  • Immunogenic cell death following alphalex treatment-activated T- and B-cell responses, with evidence of tumor-binding IgG and long-term immune memory, support the potential for sustained anticancer effects.
• Potential following a topoisomerase-1 (TOP1)-based ADC
  • The antigen-agnostic delivery of auristatin and maytansinoid payloads potentially positions alphalex PDCs in patients who have progressed following TOP1-based ADCs.

Advancing alphalex in the Clinic
Cybrexa is actively advancing its alphalex platform into clinical development. In October 2024, the company dosed the first patient in its Phase 2 clinical trial of CBX-12 in platinum-resistant or refractory ovarian cancer.

CBX-12 is a first-in-class PDC that utilizes Cybrexa’s proprietary alphalex technology. The patyload is exatecan, which inhibits topoisomerase I, an enzyme that helps DNA unwind and replicate. By trapping topoisomerase I on DNA, exatecan prevents DNA from being repaired and leads to cell death.

This trial builds upon promising Phase 1 data (NCT04902872), which demonstrated broad activity across multiple tumor types, including ovarian, breast, non-small cell lung cancer (NSCLC), thymic, gallbladder, and colorectal cancers, alongside a manageable safety profile. In this study the pH sensitive peptide demonstrated an improved safety profile despite the administration of a 5-fold increase in the dose of exatecan compared to unconjugated exatecan.[2]

Overall, CBX-12 demonstrated broad activity with 5 confirmed responses in three malignancies.

Note: Alphalex™ technology is a novel antigen-independent, peptide-drug conjugate (PDC) platform that enables targeted delivery of highly potent anticancer treatments and aims to revolutionize the standard of care in oncology. The platform consists of a pH-Low Insertion Peptide (pHLIP^®), a linker, and a small molecule anticancer agent. pHLIP peptides are a family of pH-low insertion peptides that target acidic cell surfaces. pHLIP was developed at Yale University and the University of Rhode Island and is exclusively licensed to pHLIP, Inc., and Cybrexa is a sublicensee of pHLIP.

Clinical trials
CBX-12 for the Treatment of Metastatic Chemotherapy-Refractory Microsatellite Stable Colorectal Cancer ClinicalTrials.gov ID NCT06730100
A Study of CBX 12 in Subjects With Platinum Resistant or Refractory Ovarian Cancer ClinicalTrials.gov ID NCT06315491
Testing How the Body Responds to the Drug CBX-12 in Patients With Advanced Solid Cancers – ClinicalTrials.gov ID NCT05691517
Study of CBX-12 in Subjects with Advanced or Metastatic Refractory Solid Tumors – ClinicalTrials.gov ID NCT04902872

Reference
[1] Gayle S, Zhang Q, Hagen C, Paradis T, Tylaska L, Paralkar V Characterization of Antigen Agnostic Tumor Selective Delivery and Immunomodulatory Activities of Auristatin and Maytansinoid alphalexTM Peptide-Drug Conjugates. Presented during the European Society for Medical Oncology (ESMO) Targeted Anticancer Therapies (TAT) Congress 2025 being held March 3-5. 2025 in Paris, France.
[2] Lorusso PM, Meric-Bernstam F, Hafez N, Rodriguez Rivera II, Tripathy D, Wilks S, Pearson P, Needle MN, Tolcher AW. 669P – CBX-12-101: Final results of a phase I study of CBX-12, a peptide drug conjugate (PDC) in patients (pts) with metastatic solid tumors. Annals of Oncology (2024) 35 (suppl_2): S482-S535. 10.1016/annonc/annonc1589

Featured image: ESMO TAT, Match 2525 © 2025 European Society for Medical Oncology. Used with permission.

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