Nutcracker Therapeutics Demonstrates Enhanced Functional Activity of Prostate Cancer Candidate NTX-470 at the 2024 AACR Annual Meeting

Of these, NTX-470 showed the strongest target cell killing activity – it was capable of engaging CD3 T cells, while displaying minimal activity in the absence of STEAP1- or PSMA-expressing target cells, retaining low bystander activity.

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Jeudi, avril 11, 2024
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Software, Research, Men, Pharmaceutical, Oncology, Consumer, Technology, Genetics, Clinical Trials, Science, Biotechnology, Health, PSMA, CD3, University, WT, STEAP1, RNA, Tumor microenvironment, Protein engineering, Prostate cancer, Engineering, HVEM, Patient, Cervical intraepithelial neoplasia, Toxicity, Messenger, Beauty, AACR, Therapy, Vaccine
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UNITED STATES, NORTH AMERICA, CALIFORNIA, SAN FRANCISCO
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Résumé
Key Points: 
  • Of these, NTX-470 showed the strongest target cell killing activity – it was capable of engaging CD3 T cells, while displaying minimal activity in the absence of STEAP1- or PSMA-expressing target cells, retaining low bystander activity.
  • LIGHT comes in two forms: membrane-bound or soluble, with the former generally having stronger activity, leading to the hypothesis that limiting membrane shedding would enhance advantageous activity.
  • Nutcracker’s scientists engineered multiple variants of LIGHT with either flexible or rigid linkers in place of protease-sensitive sites, to explore how membrane shedding susceptibility affects immunomodulatory activity.
  • Of the tested designs, membrane-stabilized variants of LIGHT enhanced HVEM stimulation over WT LIGHT and increased proinflammatory cytokines in the tumor microenvironment.


Nutcracker Therapeutics, Inc., a biotechnology company dedicated to developing transformative RNA therapies through its proprietary technology platform, recently presented two posters at the American Association for Cancer Research (AACR) Annual Meeting in San Diego: one showcasing the latest preclinical data for the company’s mRNA drug candidate for prostate cancer, NTX-470; and the other highlighting data on the immunomodulatory cytokine, LIGHT.

“Nutcracker is building a strong slate of drug candidates for oncology indications, with NTX-470 being one of the highlights of our pipeline,” said Chief Executive Officer Igor Khandros, Ph.D. “Through our technology platform, Nutcracker scientists were able to engineer multiple variants of LIGHT and NTX-470 to investigate the activities of each molecule, and determine which has the most potential to be a clinical product candidate. This type of discovery process was made possible by the nature of RNA, and I look forward to sharing more progress our team has made on other drug candidates in the near future.”

NTX-470

There are limited treatment options for the 10 percent to 20 percent of prostate cancer patients who develop castration resistance. Bispecific T cell engagers targeting prostate-specific membrane antigen (PSMA) and six transmembrane epithelial antigen of the prostate 1 (STEAP1) have demonstrated promising preliminary clinical activity, but have faced challenges with durability and toxicity, primarily due to erroneous on-target, off-tumor binding.

By building and iterating on RNA sequences through the proprietary CodonCrackerTM software and the Nutcracker Manufacturing Unit, Nutcracker’s scientists engineered a group of molecules with attenuated PSMA and CD3 (cluster of differentiation 3) binding to mitigate on-target, off-tumor binding and target-independent T cell activation. Of these, NTX-470 showed the strongest target cell killing activity – it was capable of engaging CD3 T cells, while displaying minimal activity in the absence of STEAP1- or PSMA-expressing target cells, retaining low bystander activity.

“The data on NTX-470, as a promising preclinical candidate, expands upon work described in a previous presentation by our partners at the University of California, San Francisco,” said Chief Scientific Officer Samuel Deutsch, Ph.D. “We’re hopeful that with our continued work, NTX-470 will prove itself as a viable treatment for prostate cancer, and serve as another example of the beauty of engineering RNA to encode for complex therapeutic proteins that would be difficult to obtain in the traditional protein engineering paradigm.”

LIGHT

Also at this year’s AACR annual meeting, Nutcracker presented data on its engineered version of the immunomodulatory cytokine, LIGHT, a component of NTX-250, the company’s lead candidate for cervical intraepithelial neoplasia. LIGHT comes in two forms: membrane-bound or soluble, with the former generally having stronger activity, leading to the hypothesis that limiting membrane shedding would enhance advantageous activity. Nutcracker’s scientists engineered multiple variants of LIGHT with either flexible or rigid linkers in place of protease-sensitive sites, to explore how membrane shedding susceptibility affects immunomodulatory activity. Of the tested designs, membrane-stabilized variants of LIGHT enhanced HVEM stimulation over WT LIGHT and increased proinflammatory cytokines in the tumor microenvironment.

About Nutcracker Therapeutics, Inc.

Nutcracker Therapeutics, Inc. is an RNA therapeutics company that has combined the power of advanced engineering with high-precision biosynthesis to deploy a complete RNA platform that encompasses the design, delivery, and manufacturing of RNA medicines. Armed with this high-tech advantage, the company has initiated multiple therapeutic programs with the support of clinical investigators at leading institutions. Nutcracker’s technology platform has the potential to significantly reduce costs and cycle times for RNA therapeutic development, with dramatic advantages in speed and capacity scaling over other RNA manufacturing approaches.

For more information, visit www.nutcrackerx.com.

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