• NTX-471 had similar activity to conjugates of existing anti-CD47 therapeutics, without anemic side effects
• Mice treated with mNTX-250 for HPV-16-transformed tumors became tumor-free and remained so after tumor rechallenge

Nutcracker Therapeutics, Inc., a biotechnology company dedicated to developing transformative RNA therapies through its proprietary technology platform, today presented preclinical data for two of its therapeutic candidates: its latest therapeutic candidate, NTX-471, which targets CD47; and the company’s lead mRNA candidate targeting human papillomavirus (HPV)-driven tumors, NTX-250. These data were presented at the Society for Immunotherapy of Cancer’s (SITC’s) 38th Annual Meeting.

CD47 molecules are transmembrane glycoproteins that signal macrophages not to eat the cells on which they are expressed by binding to signal regulatory protein alpha (SIRPa). Anemia is the most common adverse effect of CD47-targeting molecules, since red blood cells also express CD47. NTX-471 is being developed to specifically target CD47 on cancerous cells with unique mRNA-encoded compositions.

Nutcracker’s scientists engineered bivalent, tetravalent, hexavalent, and octavalent RNA-encoded SIRPa proteins and bispecific SIRPa-antiCCR4 molecules. The performance of these molecules were then assessed in vivo and in vitro. Key highlights of the data include:

• The octavalent variant’s cytotoxic activity was similar to that of anti-CD47 molecules currently in clinical trials. But, most importantly, the Nutcracker molecules showed little-to-no binding to red blood cells in vitro
• Administering mice with formulated mRNA molecules encoding the tetravalent, octavalent, and bispecific SIRPa fully eradicated established subcutaneous tumors, and resulted in robust protein expression (~10-100ug/ml) with high purity/homogeneity similar to, or better than, DNA-expressed proteins

“We’re excited to share our first set of data on NTX-471 with the scientific community,” said Executive Vice President of Research and Early Development Samuel Deutsch, Ph.D. “It’s no secret that anti-CD47 therapeutics have recently hit many roadblocks, and have often struggled to address anemic side effects in patients. Using our proprietary platform and the Nutcracker Manufacturing Unit, our team was able to design and quickly produce multiple RNA molecules to assess in vivo. Through our continued work, we are hopeful that NTX-471 will prove to be a viable solution in using CD47 to eradicate tumor cells, while leaving red blood cells untouched.”

Further, Nutcracker presented data on a murine version of its lead candidate, NTX-250, labelled mNTX-250. The lead indication for NTX-250 is cervical intraepithelial neoplasia CIN, a precancerous condition caused by HPV infection, which can progress to cervical cancer if left untreated. HPV-16 is the most prevalent high-risk HPV strain.

Nutcracker compared the activity of mNTX-250 to NTX-010. NTX-010 contains IL-12 and LIGHT components found in NTX-250, but lacks HPV antigens (the components of NTX-250 are detailed in previous communications). Key highlights of the data include:

• Two doses of mNTX-250 treatment eradicated well-established HPV16-transformed tumors, and improved overall survival in mice. The treated animals also generated significant numbers of HPV-16 E7 antigen-specific T cells
• All treated mice with eradicated tumors showed complete rejection when rechallenged
• Mice treated with NTX-010 generated fewer HPV16 antigen-specific T cells. When rechallenged, 6 out of 11 NTX-010-treated mice showed tumor growth

“We developed our platform, including the Nutcracker Manufacturing Unit, specifically to fast track early R&D work for RNA therapies, and to efficiently produce them once ready for patients," said Chief Executive Officer Igor Khandros, Ph.D. "The data we presented at SITC are a testament to the power of RNA, but also what a solution designed specifically for this modality can enable for drug developers. For example, with NTX-471, delivering mRNA, which encodes anti-CD47 proteins, offers a more straightforward method versus producing the complex proteins using a traditional cell line paradigm. Moreover, modifying the RNA sequence of the prospective anti-CD47 molecule is far more efficient than engineering the final protein product. Our platform has made it possible for Nutcracker to lay a strong and early foundation for our future therapeutic work.”

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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