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Editor's note iNature is China's largest academic public account.
It is jointly created by doctoral teams from Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature talent public account is now launched, focusing on talent recruitment, academic progress, and scientific research information.
Long press or scan the QR code below to follow us
.
It is a challenge for iNature to efficiently reactivate pre-existing tumor-infiltrating lymphocytes (TILs) without causing severe toxicity
.
Interleukin 12 (IL-12) can effectively activate lymphocytes, but its clinical application is limited by its short half-life and dose-related toxicity
.
On January 7, 2022, Peng Hua from the Institute of Biophysics, Chinese Academy of Sciences and Fu Yangxin from the University of Texas Southwestern Medical Center/Tsinghua University published a joint communication online in Science Immunology (IF=18) entitled "A tumor-specific pro-IL- 12 "activates preexisting cytotoxic T cells to control established tumors", which developed a tumor-conditioned IL-12 (pro-IL-12) that binds with a selective extracellular receptor for the IL-12 receptor The domain masks IL-12 while preferentially and persistently activating TIL metalloproteinases expressed by tumors
.
Compared with IL-12-Fc, systemic delivery of pro-IL-12 demonstrated reduced toxicity but better control of established tumors
.
Mechanistically, the antitumor response induced by pro-IL-12 was dependent on TIL and IFNγ
.
Furthermore, direct binding of IL-12 to IL-12R on CD8+ (but not CD4+) T cells is critical for maximum potency
.
Pro-IL-12 improves the efficacy of immune checkpoint blockade and targeted therapy when used in combination
.
Thus, this study shows that pro-IL-12 can rejuvenate TILs, which can then be combined with current treatment modalities, while limiting the side effects of treating established tumors
.
Interleukin 12 (IL-12) plays a key role in regulating the tumor immune milieu, including activation and expansion of tumor-infiltrating lymphocytes (TILs)
.
IL-12 is a heterodimeric cytokine (75 kDa) composed of two distinct polypeptide chains, an α chain (p35 subunit) and a β chain (p40 subunit), which are co-linked by disulfide bonds.
price connection
.
The functional IL-12 receptor complex consists of two beta-cytokine receptor subunits
.
The mouse IL-12 receptor β1 is the subunit mainly responsible for high-affinity binding to IL-12, and the expression of IL-12 receptor β2 alone is not sufficient to mediate IL-12 responsiveness
.
Systemic administration of recombinant mouse IL-12 (rmIL-12) elicits potent antitumor effects in a variety of mouse models
.
IL-12 is a key cytokine for T helper (TH) cell differentiation and antibody production
.
In addition, IL-12 stimulates the effector functions of activated T cells and natural killer (NK) cells by inducing cytotoxic enzymes and cytokines, primarily interferon gamma (IFNγ)
.
Local expression of IL-12 in tumors can lead to faster tumor rejection and the generation of antitumor memory immune responses
.
Unfortunately, systemic administration of therapeutic doses of IL-12 is limited due to its short half-life in vivo and lethal on-target, non-tumor side effects
.
Significant effort has been devoted to developing IL-12 that can be preferentially delivered to the tumor microenvironment (TME), eg, immunocytokines that couple IL-12 to antibodies against tumor-associated antigens
.
However, in these designs, extremely high or specific tumor antigen expression is required
.
Furthermore, due to interactions with high-affinity receptors on various immune cells, some cytokines are always bound and consumed unintentionally before reaching the TME
.
Therefore, systemic administration of IL-12 to treat mature tumors without causing severe toxicity remains a challenge
.
There is a clear need to develop next-generation cytokines that are designed to activate preferentially within tumors, giving them greater efficacy and less toxicity
.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade extracellular matrix (ECM) proteins to break down barriers to cancer invasion and metastasis
.
Clinical studies and mouse models have shown that MMPs are highly expressed in both primary and metastatic tumors, as well as in tumor-associated myeloid cells
.
Some groups have used tumor-specific MMP expression by designing protease-activated antibodies (pre-antibodies) that link the masking peptide to the antibody through an MMP-sensitive linker
.
However, assessing the potency and persistence of pro-antibodies is challenging due to the difficulty of completely blocking antibodies with short peptides and their strong immunogenicity
.
This study proposes that the use of high-affinity subdomains in endogenous receptors can overcome both of these limitations
.
In this study, a novel pro-IL-12, consisting of IL-12 masked by the extracellular receptor-binding domain of IL-12, was designed and released using an MMP-cleavable linker
.
It appears that this pro-IL-12 can be preferentially activated within the TME with limited systemic sequelae
.
Therefore, pro-IL-12 may be more effective than existing IL-12 designs in targeting and treating tumors while limiting side effects
.
Reference message: https://
It is jointly created by doctoral teams from Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature talent public account is now launched, focusing on talent recruitment, academic progress, and scientific research information.
Long press or scan the QR code below to follow us
.
It is a challenge for iNature to efficiently reactivate pre-existing tumor-infiltrating lymphocytes (TILs) without causing severe toxicity
.
Interleukin 12 (IL-12) can effectively activate lymphocytes, but its clinical application is limited by its short half-life and dose-related toxicity
.
On January 7, 2022, Peng Hua from the Institute of Biophysics, Chinese Academy of Sciences and Fu Yangxin from the University of Texas Southwestern Medical Center/Tsinghua University published a joint communication online in Science Immunology (IF=18) entitled "A tumor-specific pro-IL- 12 "activates preexisting cytotoxic T cells to control established tumors", which developed a tumor-conditioned IL-12 (pro-IL-12) that binds with a selective extracellular receptor for the IL-12 receptor The domain masks IL-12 while preferentially and persistently activating TIL metalloproteinases expressed by tumors
.
Compared with IL-12-Fc, systemic delivery of pro-IL-12 demonstrated reduced toxicity but better control of established tumors
.
Mechanistically, the antitumor response induced by pro-IL-12 was dependent on TIL and IFNγ
.
Furthermore, direct binding of IL-12 to IL-12R on CD8+ (but not CD4+) T cells is critical for maximum potency
.
Pro-IL-12 improves the efficacy of immune checkpoint blockade and targeted therapy when used in combination
.
Thus, this study shows that pro-IL-12 can rejuvenate TILs, which can then be combined with current treatment modalities, while limiting the side effects of treating established tumors
.
Interleukin 12 (IL-12) plays a key role in regulating the tumor immune milieu, including activation and expansion of tumor-infiltrating lymphocytes (TILs)
.
IL-12 is a heterodimeric cytokine (75 kDa) composed of two distinct polypeptide chains, an α chain (p35 subunit) and a β chain (p40 subunit), which are co-linked by disulfide bonds.
price connection
.
The functional IL-12 receptor complex consists of two beta-cytokine receptor subunits
.
The mouse IL-12 receptor β1 is the subunit mainly responsible for high-affinity binding to IL-12, and the expression of IL-12 receptor β2 alone is not sufficient to mediate IL-12 responsiveness
.
Systemic administration of recombinant mouse IL-12 (rmIL-12) elicits potent antitumor effects in a variety of mouse models
.
IL-12 is a key cytokine for T helper (TH) cell differentiation and antibody production
.
In addition, IL-12 stimulates the effector functions of activated T cells and natural killer (NK) cells by inducing cytotoxic enzymes and cytokines, primarily interferon gamma (IFNγ)
.
Local expression of IL-12 in tumors can lead to faster tumor rejection and the generation of antitumor memory immune responses
.
Unfortunately, systemic administration of therapeutic doses of IL-12 is limited due to its short half-life in vivo and lethal on-target, non-tumor side effects
.
Significant effort has been devoted to developing IL-12 that can be preferentially delivered to the tumor microenvironment (TME), eg, immunocytokines that couple IL-12 to antibodies against tumor-associated antigens
.
However, in these designs, extremely high or specific tumor antigen expression is required
.
Furthermore, due to interactions with high-affinity receptors on various immune cells, some cytokines are always bound and consumed unintentionally before reaching the TME
.
Therefore, systemic administration of IL-12 to treat mature tumors without causing severe toxicity remains a challenge
.
There is a clear need to develop next-generation cytokines that are designed to activate preferentially within tumors, giving them greater efficacy and less toxicity
.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade extracellular matrix (ECM) proteins to break down barriers to cancer invasion and metastasis
.
Clinical studies and mouse models have shown that MMPs are highly expressed in both primary and metastatic tumors, as well as in tumor-associated myeloid cells
.
Some groups have used tumor-specific MMP expression by designing protease-activated antibodies (pre-antibodies) that link the masking peptide to the antibody through an MMP-sensitive linker
.
However, assessing the potency and persistence of pro-antibodies is challenging due to the difficulty of completely blocking antibodies with short peptides and their strong immunogenicity
.
This study proposes that the use of high-affinity subdomains in endogenous receptors can overcome both of these limitations
.
In this study, a novel pro-IL-12, consisting of IL-12 masked by the extracellular receptor-binding domain of IL-12, was designed and released using an MMP-cleavable linker
.
It appears that this pro-IL-12 can be preferentially activated within the TME with limited systemic sequelae
.
Therefore, pro-IL-12 may be more effective than existing IL-12 designs in targeting and treating tumors while limiting side effects
.
Reference message: https://
