SCIENTIFIC OVERVIEW
Forward progress.
We are developing novel small molecules that engage an anti-cancer immune response.
Small-molecule immunotherapy has finally arrived.
Our lead candidate, PT-112, is the first ever conjugate of pyrophosphate in clinical development in oncology. PT-112 has numerous advantages — including its tolerability, osteotropism (the tendency to target mineralized bone), and inhibition of ribosomal biogenesis (RiBi) which leads to immunogenic cell death (ICD).
PT-112 promotes an anti-cancer immune response.
RIBOSOMAL BIOGENESIS (RiBi) INHIBITION
Cancer cells require high levels of ribosomal activity to survive and promote malignancy. Ribosomes are manufactured in the nucleolus through a process called RiBi. Inhibition of RiBi with PT-112 promotes immunogenic cell death.
IMMUNOGENIC CELL DEATH (ICD)
PT-112 induces a rare form of cancer cell death called ICD, a process that elicits an anti-cancer immune response related to the specific way in which a cancer cell dies.
The induction of ICD can be a critical factor in response to therapy, whether alone or in combination with other immunotherapy agents. Based upon pre-clinical models, PT-112 represents the potential best-in-class ICD inducing agent.
HOW IT WORKS
RiBi inhibition causes cancer cell stress and the release of damaged-associated molecular patterns, or “DAMPs”, from dying cancer cells. These DAMPs, hallmarks of ICD, include calreticulin translocation, ATP secretion, and release of HMGB1 and immunostimulatory cytokines, such as type I interferons.
The DAMPs bind to specific pattern-recognition receptors on dendritic cells, which are the sentinels for the adaptive immune response.
This binding stimulates dendritic cells to recognize the cancer cell antigens. The dendritic cells present these antigens to naïve T cells, thereby initiating the adaptive immune response, and the infiltration of activated lymphocytes into the tumor microenvironment (TME).
Published in OncoImmunology, we showed in vivo that PT-112 treatment, alone or in combination with established checkpoint inhibitors, increased cytotoxic T-cells (CTLs) in the TME. This results in a favorable shift in immune cell population towards an anti-cancer environment.
This may explain the durable responses in some cancer patients treated with PT-112, as published in The Lancet’s eClinical Medicine.
Activity in cancers related to the bone.
In addition to soft tissue responses, PT-112’s unique biodistribution profile allows it to be effective in cancers that originate in, or metastasize, to the bone. PT-112 is the first known pyrophosphate containing new chemical entity (NCE) in oncology. This allows for the ability to target certain solid and liquid tumor with bone involvement.
