We’ve found Cancer’s "Achilles' Heel"
When tumor cells replicate, they prioritize quantity over quality. This means mistakes are made by tumors that are not made by healthy host cells. We’ve discovered that this is especially rampant during RNA processing. At the molecular level, this translates to many abnormal, tumor peptides. The tumor peptides are seen by the immune system as foreign, setting them apart from normal host cells. This class of tumor peptides had been untapped; their discovery provides the opportunity for a new class of targeted attacks on tumors.
Just as the mythological Achilles seemed invulnerable, his enemy discovered his unprotected heel and killed him. We will use tumors’ previously unexposed mistakes in RNA processing to end cancer.
Our Technology
Mistakes are rarely made in genomic DNA, even with the more relaxed checks and balances of tumor cells. However, mistakes are very common during tumor cells’ RNA synthesis and processing. We discovered that these mistakes are a plentiful, powerful source of immunogenic tumor antigens. These RNA-Error Derived Neoantigens (REDNs) had not been previously tapped as a resource for novel diagnostics and vaccines cancer.
We build peptides representing these REDNs on semiconductor chips, then query an individual’s blood for antibody responses to the arrayed peptides. Since specific antibodies are vastly amplified when a REDN is recognized by the immune system, antibodies serve as very sensitive biomarkers of cancer. The specific binding activities that are shared across cancers have strong diagnostic value.
The antibodies also serve to inform us which neoantigens are being made by which tumors. Those neoantigens that are shared across different tumors become valuable components for therapeutic and preventative vaccines against cancer.
Semiconductor Chips
Biology
Calviri's Products
The Biology
Healthy Cell
Central Dogma refers to the transcription of genomic DNA’s information into messenger RNA (mRNA) and then its translation into proteins- the major actors in biology.
Very effective DNA proofreading and repair processes have evolved to maintain the integrity of a cell’s genomic DNA.
Though less stringent, there are also quality control systems for its processing into mRNA and protein. Mistakes are more common than in DNA synthesis, but still relatively rare.
Tumor Cell
The accuracy of Central Dogma’s information flow is compromised in tumor cells to support rapid, uncontrolled growth. While DNA integrity is somewhat still maintained, RNA and protein processing run largely unchecked.
Consequently, many abnormal RNAs are generated by tumor cells and translated into peptide variants. Many of these peptide variants are created by a shift in the ribosome’s coding frame, and result in large changes in the protein sequence. These frameshifted sequences are recognized by the immune system as foreign, non-self “neoantigens”, leading to strong responses.
How It Works
We Build Biology on Microchips to Identify Cancer Activity
We have shown that frameshift peptides generated from errors in tumor cell RNA processing steps are presented on the tumor’s surface or released by it as neoantigens. These are called RNA-Error Derived Neoantigens (REDNs).
The REDNs are recognized by the host immune system, activating both T and B cells to proliferate. Each activated plasma B cell secretes highly amplified levels of antibodies that specifically recognize a REDN.
The Biology:
Identifying Frameshifted Peptides Tails on Protein Sequences
If antibodies to REDNs can be detected and measured in patients, then they could be the basis for developing a new class of cancer diagnostics and vaccines.
The Chip:
Identifying Frameshifted Peptides Tails on Protein Sequences
We learned to detect and measure REDN-specific antibodies in patient blood samples by building high density microchips that display 10 to 10 REDN-like ligands.
We developed a competitive immunoassay that captures these biologically important binding activities.
Specific antibody binding activities associated with cancer patients, but not healthy individuals, serve as sensitive biomarkers for detecting cancer on our diagnostic chips. The REDN-like peptides bound by antibodies in cancer patients’ blood, but not antibodies of healthy individuals on our Discovery chips, define components for both therapeutic and preventative vaccines.
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Calviri announced the successful completion of the Vaccine Against Canine Cancer Study (VACCS) on May 4, 2024. Promising results led an additional year’s extension. This is a six-year, 800+ dog clinical trial investigating a novel preventative cancer vaccine in dogs. The collective results are currently being statistically analyzed. This multi-center, double-blind, placebo-controlled study, the largest of its kind in veterinary oncology, represents a significant milestone in the fight against canine cancer.
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