Molecular mechanisms of heparin-induced modulation of human interleukin 12 bioactivity

Nguyen, Khue G.; Gillam, Francis B.; Hopkins, Jared; Jayanthi, Srinivas; Gundampati, Ravi Kumar; Su, Guowei; Bear, Jenifer; Pilkington, Guy R.; Jalah, Rashmi; Felber, Barbara K.; Liu, Jian; Thallapuranam, Suresh Kumar; Zaharoff, David A.

doi:10.1074/jbc.ra118.006193

Cited by 25 publications

(32 citation statements)

References 41 publications

(37 reference statements)

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“…A more recent study revealed that disruption of the heparin binding domain in the mscIL-12.her2.IgG3 immunocytokine, reduced IL-12 bioactivity (84). This result was consistent with recent studies showing that heparin and heparan sulfate bind to and enhance the activity of IL-12 (85)(86)(87)(88)(89). While eliminating heparin binding reduces IL-12 activity, we speculate that this reduction could be counterbalanced by an enhancement in tumor targeting as the IL-12 immunocytokine may no longer bind to ubiquitous sulfated glycosaminoglycans in non-targeted tissues.…”

Section: Targeting Tumor Antigenssupporting

confidence: 84%

Localized Interleukin-12 for Cancer Immunotherapy

et al. 2020

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Interleukin-12 (IL-12) is a potent, pro-inflammatory type 1 cytokine that has long been studied as a potential immunotherapy for cancer. Unfortunately, IL-12's remarkable antitumor efficacy in preclinical models has yet to be replicated in humans. Early clinical trials in the mid-1990's showed that systemic delivery of IL-12 incurred dose-limiting toxicities. Nevertheless, IL-12's pleiotropic activity, i.e., its ability to engage multiple effector mechanisms and reverse tumor-induced immunosuppression, continues to entice cancer researchers. The development of strategies which maximize IL-12 delivery to the tumor microenvironment while minimizing systemic exposure are of increasing interest. Diverse IL-12 delivery systems, from immunocytokine fusions to polymeric nanoparticles, have demonstrated robust antitumor immunity with reduced adverse events in preclinical studies. Several localized IL-12 delivery approaches have recently reached the clinical stage with several more at the precipice of translation. Taken together, localized delivery systems are supporting an IL-12 renaissance which may finally allow this potent cytokine to fulfill its considerable clinical potential. This review begins with a brief historical account of cytokine monotherapies and describes how IL-12 went from promising new cure to ostracized black sheep following multiple on-study deaths. The bulk of this comprehensive review focuses on developments in diverse localized delivery strategies for IL-12-based cancer immunotherapies. Advantages and limitations of different delivery technologies are highlighted. Finally, perspectives on how IL-12-based immunotherapies may be utilized for widespread clinical application in the very near future are offered.

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Section: Targeting Tumor Antigenssupporting

confidence: 84%

Localized Interleukin-12 for Cancer Immunotherapy

et al. 2020

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“…Indeed, the inhibiting effect of soluble heparin and HS on hIL-27 activity we describe here, contrasts with the positive effect of soluble GAGs on hIL-12 activity and the lack of soluble heparin effect on hIL-6 activity, observed in previous studies [22,23,40]. Two recent studies showed that LMWH and HS (purified from the same biological sources than the ones we used) bind to hIL-12, and increased its activity by several fold (1.5 to 12) by enhancing IL-12 binding to its cell surface receptor possibly through stabilization of IL-12/IL-12Rβ1 interaction [22,23]. The authors also observed that although heparin also binds mouse IL-12, it has no effect on its activity [23].…”

Section: Discussioncontrasting

confidence: 99%

“…Two recent studies showed that LMWH and HS (purified from the same biological sources than the ones we used) bind to hIL-12, and increased its activity by several fold (1.5 to 12) by enhancing IL-12 binding to its cell surface receptor possibly through stabilization of IL-12/IL-12Rβ1 interaction [22,23]. The authors also observed that although heparin also binds mouse IL-12, it has no effect on its activity [23]. In a similar manner, we observed that heparin and HS also bind to mIL-27, but had a less potent inhibiting effect on its activity.…”

Section: Discussionmentioning

confidence: 99%

“…While, for some cytokines, GAG binding has no effect on their in vitro activity, it also can act positively by increasing cytokine stability or enhancing its binding to its cognate receptor, or negatively by competitively inhibiting its interaction with its receptor [18][19][20]. Among cytokines of the IL-12 family, the binding and in vitro effects of GAGs have only been reported for IL-12 so far, with soluble heparin and HS increasing hIL-12 bioactivity [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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Glycosaminoglycans bind human IL‐27 and regulate its activity

et al. 2020

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IL-27 is a cytokine of the IL-12 family, composed of EBI3 and IL-27p28. IL-27 regulates immune responses and also other physiological processes including hematopoiesis, angiogenesis, and bone formation. Its receptor, composed of IL-27Rα and gp130, activates the STAT pathway. Here, we show that different glycosaminoglycans (GAGs) modulate human IL-27 activity in vitro. We find that soluble heparin and heparan sulfate efficiently inhibit human IL-27 activity as shown by decreased STAT signaling and downstream biological effects. In contrast, membrane-bound heparan sulfate seems to positively regulate IL-27 activity. Our biochemical studies demonstrate that soluble GAGs directly bind to human IL-27, consistent with in silico analyses, and prevent its binding to IL-27Rα. Although murine IL-27 also bound to GAGs in vitro, its activity was less efficiently inhibited by soluble GAGs. Lastly, we show that two heparin-derivatives, low molecular weight heparin and fondaparinux, that like unfractionated heparin are used in clinics, had weaker or no effect on human IL-27 activity. Together, our data identify GAGs as new players in the regulation of human IL-27 activity that might act under physiological conditions and may also have a clinical impact in heparin-treated patients.

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“…For example, the HS-fibroblast growth factor (FGF)-FGF receptor (FGFR) complex formation and HS binding specificity of FGF1 and FGF2 are further elucidated with chemoenzymatically synthesized HS [ 32 , 46 ]. Moreover, critical pro-inflammatory cytokine and regulator, IL-12 and Wnt are found to bind to HS that has a minimum of octasaccharide domain containing 3- O and 6- O sulfation, respectively [ 34 , 39 ]. A critical receptor for heparin/LMWH clearance in the liver, stabilin-2, is also shown to have significantly higher affinity to 3- O -sulfated HS by applying the customized HS [ 47 ].…”

Section: Biosynthesis and Chemoenzymatic Synthesis Of Hsmentioning

confidence: 99%

Potential Use of Anti-Inflammatory Synthetic Heparan Sulfate to Attenuate Liver Damage

Arnold

Liao

2020

Biomedicines

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Heparan sulfate is a highly sulfated polysaccharide abundant on the surface of hepatocytes and surrounding extracellular matrix. Emerging evidence demonstrates that heparan sulfate plays an important role in neutralizing the activities of proinflammatory damage associate molecular patterns (DAMPs) that are released from hepatocytes under pathological conditions. Unlike proteins and nucleic acids, isolation of homogenous heparan sulfate polysaccharides from biological sources is not possible, adding difficulty to study the functional role of heparan sulfate. Recent advancement in the development of a chemoenzymatic approach allows production of a large number of structurally defined oligosaccharides. These oligosaccharides are used to probe the physiological functions of heparan sulfate in liver damage under different pathological conditions. The findings provide a potential new therapeutic agent to treat liver diseases that are associated with excessive inflammation.

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Molecular mechanisms of heparin-induced modulation of human interleukin 12 bioactivity

Cited by 25 publications

References 41 publications

Localized Interleukin-12 for Cancer Immunotherapy

Localized Interleukin-12 for Cancer Immunotherapy

Glycosaminoglycans bind human IL‐27 and regulate its activity

Potential Use of Anti-Inflammatory Synthetic Heparan Sulfate to Attenuate Liver Damage

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