PSMA x CD3 x STEAP1

Data showed NTX-470 successfully engaged CD3 T cells, while retaining low bystander activity and reduced off-tumor binding Another set of data detailed the design of LIGHT, an immunomodulatory cytokine that is a component of lead drug candidate NTX-250 Company scientists engineered and iterated multiple RNA sequences for NTX-470 and LIGHT through its technology platform EMERYVILLE, Calif.--(BUSINESS WIRE)-- 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 .

The discontinuation of AMG 340 is the latest in a series of rethinks regarding bispecific T-cell engagers, BiTEs, for short. Amgen’s Teneobio misadventure has taken a $650 million BiTE out of its earnings. The Big Biotech took the hit after stopping a phase 1 trial of the PSMA bispecific it picked up in the $900 million acquisition of Teneobio two years ago. Buying Teneobio gave Amgen control of AMG 340, a PSMAxCD3 bispecific designed to turn T cells against metastatic castrate-resistant prostate cancer (mCRPC). Amgen already had a PSMA bispecific, acapatamab, when it bought Teneobio. The decision to double up reflected a belief that the drug candidates used “a different approach.” A little more than two years later, both approaches have been found wanting. Amgen stopped developing acapatamab in the summer of 2022. AMG 340 hung on longer, but the ax was brought down Tuesday. The company disclosed the discontinuation of a phase 1 dose-escalation study of the asset as part of its financial update for the third quarter. The statement lacks details of the thinking behind the action but does contain information about how it will affect Amgen’s finances. Amgen took a $650 million net impairment charge in relation to the axing of AMG 340, dragging down its earnings per share. The discontinuation of AMG 340 is the latest in a series of rethinks regarding bispecific T-cell engagers, or BiTEs for short. Amgen dropped candidates aimed at BCMA and PSMA last summer. Amid the changes, the biotech has remained committed to tarlatamab, a DLL3 therapy that recently impressed in a phase 2 trial. Amgen is testing tarlatamab in a form of prostate cancer and has another mCRPC project on the go. Xaluritamig, a bispecific that binds to STEAP1, is in phase 1b development in mCRPC. Amgen plans to start two more phase 1 trials of the candidate in patients with early prostate cancer. Paul Burton, M.D., Ph.D., chief medical officer at Amgen, recently told Fierce Biotech how xaluritamig illustrates one of two approaches it can take to validate oncology candidates.  “I think there are two options. One is we can go after cancer by cancer. We're doing that. We're looking at … xaluritamig in prostate. Where we see receptors that are expressed in a variety of different cancer cells, then I think we would also go after a strategy of a basket trial design,” Burton said. Amgen disclosed the discontinuation of AMG 340 alongside news that it is stopping a phase 1b study of bemarituzumab in squamous non-small cell lung cancer with FGFR2b overexpression. The clinical trial was evaluating the anti-FGFR2b antibody as a monotherapy and in combination with standard of care therapy. Amgen is continuing to study the candidate in a clutch of other phase 1 to phase 3 trials.