mRNA prostate cancer drug successfully engaged CD3 T cells

Prostate cancer cells

Nutcracker Therapeutics’ prostate cancer mRNA drug candidate NTX-470 successfully engaged CD3 T cells, while retaining low bystander activity and reduced off-tumour binding, according to data presented at the 2024 AACR Annual Meeting.

There are limited treatment options for the 10-20% 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-tumour binding.

By building and iterating on RNA sequences through the CodonCracker software and the Nutcracker Manufacturing Unit, Nutcracker reported that its scientists engineered a group of molecules with attenuated PSMA and CD3 (cluster of differentiation 3) binding to mitigate on-target, off-tumour 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.

Chief Scientific Officer Samuel Deutsch, said: “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.”

Cervical intraepithelial neoplasia candidate

The company also 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-stabilised variants of LIGHT enhanced Herpesvirus-entry mediator (HVEM) stimulation over WT LIGHT and increased proinflammatory cytokines in the tumour microenvironment.

“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. “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.”

Diana Spencer, Senior Digital Content Editor, DDW

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