A fusion protein that can cure solid tumors was born!
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A fusion protein that can cure solid tumors was born!
INTRODUCTION: Interleukin-12 (IL-12) has become one of the most potent cytokines for tumor immunotherapy due to its ability to induce interferon gamma (IFN-γ) and polarize Th1 helper cell responses.
However, IL-12 is limited in clinical application due to its short half-life and narrow therapeutic index.
On April 13, an American research institution published an article titled “An optimized IL-12-Fc expands its therapeutic window, achieving strong activity against mouse tumors at tolerable drug doses” on Cell Press: Med. The researchers Said to have developed a fusion protein, and has carried out human experiments, this protein is expected to cure solid tumors.
https://www.cell.com/med/fulltext/S2666-6340(23)00103-4
Research Background
IL-12 has great potential in cancer therapy because of its ability to stimulate innate adaptive antitumor immune responses.
However, due to its short half-life, recombinant IL-12 requires frequent dosing and also produces a high-amplitude IFN-γ response, which ultimately produces dose-limiting toxicity in the clinic.
Dragonfly Therapeutics has developed an engineered IL-12 therapy that is well tolerated when administered systemically, can be used as a monotherapy or in combination with a checkpoint inhibitor and produces a potent anti-tumor response .
Currently, the research institution is conducting a phase 1/2 first-in-human clinical trial to test IL-12-Fc protein (DF6002) for the treatment of solid tumors.
Research methods
Over the past two decades, interleukin-12 (IL-12) has emerged as one of the most appreciable cytokines in cancer immunotherapy, with a powerful ability to stimulate innate adaptive immune responses.
IL-12 signaling also produces chemokines and cytokines, among which interferon gamma (IFN-γ) is the main mediator of IL-12 activity.
IFN-γ produced by T cells and NK cells further stimulates myeloid cells and tree IL-12 production by dendritic cells drives a feed-forward loop.
Recombinant IL-12 exhibited strong antitumor activity in animal models.
Based on these encouraging preclinical effects, recombinant human interleukin (rhIL-12) is being evaluated as a treatment for patients with advanced cancers, including kidney cancer, melanoma, and non-Hodgkin’s lymphoma.
However, systemic rhIL-12 administration is associated with severe dose-limiting toxicities. Due to the short half-life of rhIL-12, daily administration resulted in a gradual increase in serum IFN-γ concentrations, which eventually led to toxicity.
In order to overcome toxicity, reducing the frequency of dosing is often adopted, however, this approach will lead to reduced exposure and weakened pharmacodynamic response, which also reduces the efficacy.
Although signs of antitumor activity could be observed, clinical development of rhIL-12 was eventually discontinued due to safety concerns and the narrower therapeutic window of rhIL-12. Preclinically, direct tumor injection of IL-12 has shown significant efficacy, especially in improving tumor-retaining variants, suggesting that the duration of tumor exposure to IL-12 is a critical parameter for efficacy.
Taken together, the data suggest that enhancing the efficacy of IL-12 depends on extending its half-life, but retaining the native engagement of IL-12Rs.
Therefore, we generated an optimized, monovalent mouse IL-12-Fc, named mDF6006, and bound it to the disused Fcγ receptor to further increase the half-life of IL-12 and reduce non-native interactions, This results in greater intratumoral exposure and expands the therapeutic window of IL-12.
In addition, the research team synthesized a fully human IL-12-Fc therapeutic candidate , named DF6002 .
Prolonged exposure to IL-12 resulted in prolonged IFN-γ responses, which were well tolerated compared to IL-12, as demonstrated in studies in mice and cynomolgus monkeys.
These data support the team’s Phase 1/2 clinical study evaluating DF6002 as a monotherapy or in combination with the anti-PD-1 antibody nivolumab in the treatment of solid tumors.
image
https://www.cell.com/med/fulltext/S2666-6340(23)00103-4
Research application
The research team synthesized a monovalent, long-half-life IL-12-fc fusion protein mDF6006 , which can retain the high efficacy of natural IL-12 while significantly expanding its therapeutic window .
Mechanistically, mDF6006 can produce IFN-γ more sustainably without high toxicity. The researchers found that the expanded therapeutic window of mDF6006 was effective against tumors as a single agent.
In addition, mDF6006 can also be effectively combined with PD-1 blockers , which can be used as a new treatment method.
Reference:
https://www.cell.com/med/fulltext/S2666-6340(23)00103-
A fusion protein that can cure solid tumors was born!
(source:internet, reference only)
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