6 Aptamers for Targeted Therapy
141
DNA aptamer of IL-5 was obtained through 12 rounds of screening. Furthermore,
the inhibitory effect of aptamer on IL-5 will be compared with that of mepolizumab
in the following work.
6.4.1.3 Interleukin-6
Interleukin-6 (IL-6) is a member of the cytokine family of immunomodulatory
proteins, which is produced by B cells, T cells, monocytes, fibroblasts, and other
types of cells. IL-6 participates in pro-inflammatory and anti-inflammatory processes
[97, 98]. As a pleiotropic regulator, IL-6 plays an important role in host immune
defense mechanism, hematopoietic function and the proliferation and differentiation of various tumor cells [99]. IL-6 binds to the receptor protein (IL-6R α, gp80, or
CD126) on the cell membrane to form a complex, which binds to the signal transduction protein gp130 (CD130) and activates the JAK-STAT3-signal pathway [100]. At
present, the related proteins of IL-6 signal pathway have become important targets of
inflammatory therapy and intervention. Anti-IL-6R α antibody tocilizumab is the first
regulatory approved IL-6 signal pathway antagonist and is currently implemented in
the treatment of rheumatoid arthritis [101]. Several other antagonists of IL-6 pathway
are being developed, including direct inhibitors of IL-6 [102]. Hirota et al. [103]
screened two SOMAmer aptamers of IL-6, SL1026, and SL1033 (K D = ∼0.2 nM),
which can block IL-6 signal transduction by preventing the interaction between IL-6
and its receptors, and have the equivalent effect as tocilizumab in inhibiting the proliferation of tumor cells in vitro. In the arthritis model of cynomolgus, Q.I.D. administration of SL1026 (1, 10 mg/kg) delayed the development of arthritis. In addition,
SL1026 inhibited IL-6-induced STAT3 phosphorylation in human T lymphocytes
and the production of C-reactive protein and serum amyloid A in human primary
hepatocytes, and did not induce immune response. It is suggested that this new IL-6
aptamer inhibitor has the potential for the treatment of inflammatory diseases.
The 19 nt aptamer AIR-3A (K D = ∼20 nm) of IL-6 receptor (IL-6R) was screened
by Ulrich Hahn group [104–106]. In order to improve the nuclease resistance, the
pyrimidine base of AIR-3A was introduced 2
-fluorine modification, but did not
meet the expectation. Therefore, the aptamer FAIR-6 has the same functional motif
as AIR-3A with stronger nuclease resistance, which can trigger its uptake into cells
without affecting the interaction between IL-6R and ligands. The remarkable property
enables AIR-3A to act as a targeted element for accurately delivery of molecules,
for instance, tags or drugs, and so on to cells, which has been applied for targeted
delivery of gold nanoparticles [107].
6.4.1.4 Interleukin-8
Interleukin-8 (IL-8) is the first defined chemokine, also known as C-X-C motif ligand
8 (CXCL8) [108]. As a chemical attractant for neutrophils, IL-8 is produced by a
variety of cells, including monocytes, macrophages, and tumor cells, in response to
141
DNA aptamer of IL-5 was obtained through 12 rounds of screening. Furthermore,
the inhibitory effect of aptamer on IL-5 will be compared with that of mepolizumab
in the following work.
6.4.1.3 Interleukin-6
Interleukin-6 (IL-6) is a member of the cytokine family of immunomodulatory
proteins, which is produced by B cells, T cells, monocytes, fibroblasts, and other
types of cells. IL-6 participates in pro-inflammatory and anti-inflammatory processes
[97, 98]. As a pleiotropic regulator, IL-6 plays an important role in host immune
defense mechanism, hematopoietic function and the proliferation and differentiation of various tumor cells [99]. IL-6 binds to the receptor protein (IL-6R α, gp80, or
CD126) on the cell membrane to form a complex, which binds to the signal transduction protein gp130 (CD130) and activates the JAK-STAT3-signal pathway [100]. At
present, the related proteins of IL-6 signal pathway have become important targets of
inflammatory therapy and intervention. Anti-IL-6R α antibody tocilizumab is the first
regulatory approved IL-6 signal pathway antagonist and is currently implemented in
the treatment of rheumatoid arthritis [101]. Several other antagonists of IL-6 pathway
are being developed, including direct inhibitors of IL-6 [102]. Hirota et al. [103]
screened two SOMAmer aptamers of IL-6, SL1026, and SL1033 (K D = ∼0.2 nM),
which can block IL-6 signal transduction by preventing the interaction between IL-6
and its receptors, and have the equivalent effect as tocilizumab in inhibiting the proliferation of tumor cells in vitro. In the arthritis model of cynomolgus, Q.I.D. administration of SL1026 (1, 10 mg/kg) delayed the development of arthritis. In addition,
SL1026 inhibited IL-6-induced STAT3 phosphorylation in human T lymphocytes
and the production of C-reactive protein and serum amyloid A in human primary
hepatocytes, and did not induce immune response. It is suggested that this new IL-6
aptamer inhibitor has the potential for the treatment of inflammatory diseases.
The 19 nt aptamer AIR-3A (K D = ∼20 nm) of IL-6 receptor (IL-6R) was screened
by Ulrich Hahn group [104–106]. In order to improve the nuclease resistance, the
pyrimidine base of AIR-3A was introduced 2
-fluorine modification, but did not
meet the expectation. Therefore, the aptamer FAIR-6 has the same functional motif
as AIR-3A with stronger nuclease resistance, which can trigger its uptake into cells
without affecting the interaction between IL-6R and ligands. The remarkable property
enables AIR-3A to act as a targeted element for accurately delivery of molecules,
for instance, tags or drugs, and so on to cells, which has been applied for targeted
delivery of gold nanoparticles [107].
6.4.1.4 Interleukin-8
Interleukin-8 (IL-8) is the first defined chemokine, also known as C-X-C motif ligand
8 (CXCL8) [108]. As a chemical attractant for neutrophils, IL-8 is produced by a
variety of cells, including monocytes, macrophages, and tumor cells, in response to