On April 19, 2023 Replicate Bioscience, a company pioneering novel self-replicating RNA (srRNA) technology for use in infectious disease, oncology, autoimmune disease, and more, reported new preclinical data underscoring the strength of Replicate’s srRNA platform and its potential for oncology applications at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, Replicate Bioscience, APR 19, 2023, View Source [SID1234630327]).
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"Taken together, the results of these studies demonstrate the activity, versatility, and durability of Replicate’s srRNA vectors and their potential for treating cancer," said Zelanna Goldberg, M.D., Chief Medical Officer at Replicate, and poster presenter. "Our srRNAs are designed to produce higher bioactivity at low doses compared to linear mRNA therapeutics. These unique characteristics enable flexible co-administration with existing therapies and better tolerability. We are pleased to share these promising results with the oncology community and look forward to advancing our programs towards clinical trials."
The poster presented today by Dr. Goldberg, titled "A self-replicating RNA precision medicine approach to overcoming resistance to endocrine therapy in ER+ breast cancer," underscores the therapeutic potential of Replicate’s lead immuno-oncology candidate, RBI-1000, to address acquired resistance mutations, a major factor behind the clinical failure of existing endocrine therapy.
RBI-1000 encodes high frequency, clinically characterized pervasive and predictable acquired resistance mutations found in estrogen-receptor expressing breast cancer, representing about 80% of all ER+ breast cancers. RBI-1000 primes T cells to respond to these mutations as they arise and is designed to act synergistically with standard of care treatments.
In a mouse model expressing the targeted acquired resistance mutations, RBI-1000 successfully primed CD4+ and CD8+ T cells leading to significant tumor growth inhibition and improved survival at a 100-fold lower dose than linear mRNA approaches in other tumor models.
"This study contributes to our growing body of preclinical data indicating that when coupled with a standard of care therapy, RBI-1000 forces tumors into a lose-lose situation and ultimately, destruction," said Parinaz Aliahmad, Ph.D., head of Research and Development at Replicate. "Our team is proud to pave the way in unlocking broader applications for RNA to realize therapeutic breakthroughs for large and diverse patient populations."
The second poster, titled "A self-replicating RNA precision medicine approach to therapeutic protein delivery of narrow therapeutic index biomolecules," was presented on April 17 by Dr. Goldberg. The study is the first demonstration of Replicate’s srRNAs to encode multiple biotherapeutic molecules in a single vector backbone for better bioactivity at lower doses than linear mRNA approaches. Multiple encoded proteins also allow for durable tumor immunotherapy, and applications such as the expression of cytokines, other biologics, protein replacement, or secreted proteins.
RBI-2000 encodes two distinct proteins on one RNA strand: one multimeric protein to promote generation of new immune cells, and another monomeric to prevent sterile inflammation, aberrant angiogenesis, and tumor invasiveness. RBI-2000 utilizes a novel self-replicating RNA vector with an enhanced pharmacokinetic profile and pharmacodynamic effects at very low doses capable of controlling tumors as a monotherapy or in combination with checkpoint inhibition.
Mice who had complete responses were rechallenged with tumor cells at 70 days post-treatment and successfully rejected the challenge, indicating robust immunological memory.