6 Aptamers for Targeted Therapy
143
6.4.1.7 Interleukin-17
Interleukin-17 (IL-17) is a pro-inflammatory cytokine mainly produced by Th17 cells
in CD4+T cell subsets, which is associated with a variety of autoimmune diseases,
including psoriasis [123], rheumatoid arthritis [124], multiple sclerosis [125], inflammatory bowel disease [126], type I diabetes [127], and asthma [128]. The IL-17
cytokine family consists of six structure-related proteins (IL-17A, B, C, D, E, and
F), among which IL-17A is the most bioactive cytokine [129].
Studies have shown that antibody inhibitors of interleukin-17A can prevent inflammation and bone erosion in RA rats [130, 131], and reduce the inflammatory damage
of experimental autoimmune encephalomyelitis (EAE) [132, 133]; for instance,
AIN457 has been undergoing clinical trials [134, 135]. Therefore, IL-17A inhibitors
may play an important role in the treatment of autoimmune diseases. Ishiguro et al.
[136] screened an RNA aptamer Apt21-2 (K D = ∼48.5 pm) for human interleukin17A (hIL-17A), which can block the interaction between IL-17A and IL-17R in vitro.
Meanwhile, the production of downstream cytokine IL-6 induced by IL-17A was also
restrained by Apt21-2 in mice and human cells. In EAE mouse model (simulating
human inflammatory demyelinating disease multiple sclerosis), the time of EAE in
PEG21-2idT (PEG modification of Apt21-2) group (3 and 10 mg/kg every day) was
significantly delayed, while the incidence and symptoms were significantly decreased
in a dose-dependent manner. Similarly, in the RA mice arthritis model induced by
glucose-6-phosphate isomerase (GPI), the development of arthritis in PEG21-2idT
group was significantly delayed, indicating that PEG21-2idT blocking IL-17A has a
protective and therapeutic effect on GPI-induced arthritis.
Among the members of the IL-7 family, IL-17A has the closest evolutional relationship with IL-17F, sharing 55% homology in amino acid sequence and four
conserved cysteine residues at the C-terminal. IL-17A and IL-17F combined to form
homodimer (IL-17A/A, IL-17F/F) and heterodimer (IL-17A/F) complexes. Studies
have shown that the probability of IL-17A/F heterodimers formed by differentiated
Th17 cells is higher than that of homodimers, and IL-17A/F plays a main role in
regulating airway inflammation [137, 138].
In addition, genetic analysis using IL-17A and/or IL-17F-deficient mice showed
that IL-17A and IL-17F had overlapping and specific functions [139] (Fig. 6.4). In
the mouse model of EAE, both IL-17A and IL-17F contribute to the occurrence
of chronic inflammation [140]. However, the mechanism of IL-17A/F is unknown
due to the lack of experimental systems or reagents specifically for the inhibition of
heterodimer IL-17A/F.
Chen et al. [141] screened an RNA aptamer AptAF42 targeting human IL-17A/F,
which can specifically bind to IL-17A/F, but not to IL-17A/A and IL-17F/F. Further
studies showed that AptAF42 could block the interaction between IL-17A/F and
IL-17 receptor and inhibit the activation of pro-inflammatory cytokine GRO-A
production pathway in human cells. Similarly, the DNA aptamer of IL-17RA (IL-17
receptor) has also been screened to block the binding of IL-17 to IL-17RA, control
the expression of IL-6 mediated by IL-17, and then inhibit synovitis. At present,
more than ten monoclonal antibody inhibitors of IL-17 have entered the clinical
143
6.4.1.7 Interleukin-17
Interleukin-17 (IL-17) is a pro-inflammatory cytokine mainly produced by Th17 cells
in CD4+T cell subsets, which is associated with a variety of autoimmune diseases,
including psoriasis [123], rheumatoid arthritis [124], multiple sclerosis [125], inflammatory bowel disease [126], type I diabetes [127], and asthma [128]. The IL-17
cytokine family consists of six structure-related proteins (IL-17A, B, C, D, E, and
F), among which IL-17A is the most bioactive cytokine [129].
Studies have shown that antibody inhibitors of interleukin-17A can prevent inflammation and bone erosion in RA rats [130, 131], and reduce the inflammatory damage
of experimental autoimmune encephalomyelitis (EAE) [132, 133]; for instance,
AIN457 has been undergoing clinical trials [134, 135]. Therefore, IL-17A inhibitors
may play an important role in the treatment of autoimmune diseases. Ishiguro et al.
[136] screened an RNA aptamer Apt21-2 (K D = ∼48.5 pm) for human interleukin17A (hIL-17A), which can block the interaction between IL-17A and IL-17R in vitro.
Meanwhile, the production of downstream cytokine IL-6 induced by IL-17A was also
restrained by Apt21-2 in mice and human cells. In EAE mouse model (simulating
human inflammatory demyelinating disease multiple sclerosis), the time of EAE in
PEG21-2idT (PEG modification of Apt21-2) group (3 and 10 mg/kg every day) was
significantly delayed, while the incidence and symptoms were significantly decreased
in a dose-dependent manner. Similarly, in the RA mice arthritis model induced by
glucose-6-phosphate isomerase (GPI), the development of arthritis in PEG21-2idT
group was significantly delayed, indicating that PEG21-2idT blocking IL-17A has a
protective and therapeutic effect on GPI-induced arthritis.
Among the members of the IL-7 family, IL-17A has the closest evolutional relationship with IL-17F, sharing 55% homology in amino acid sequence and four
conserved cysteine residues at the C-terminal. IL-17A and IL-17F combined to form
homodimer (IL-17A/A, IL-17F/F) and heterodimer (IL-17A/F) complexes. Studies
have shown that the probability of IL-17A/F heterodimers formed by differentiated
Th17 cells is higher than that of homodimers, and IL-17A/F plays a main role in
regulating airway inflammation [137, 138].
In addition, genetic analysis using IL-17A and/or IL-17F-deficient mice showed
that IL-17A and IL-17F had overlapping and specific functions [139] (Fig. 6.4). In
the mouse model of EAE, both IL-17A and IL-17F contribute to the occurrence
of chronic inflammation [140]. However, the mechanism of IL-17A/F is unknown
due to the lack of experimental systems or reagents specifically for the inhibition of
heterodimer IL-17A/F.
Chen et al. [141] screened an RNA aptamer AptAF42 targeting human IL-17A/F,
which can specifically bind to IL-17A/F, but not to IL-17A/A and IL-17F/F. Further
studies showed that AptAF42 could block the interaction between IL-17A/F and
IL-17 receptor and inhibit the activation of pro-inflammatory cytokine GRO-A
production pathway in human cells. Similarly, the DNA aptamer of IL-17RA (IL-17
receptor) has also been screened to block the binding of IL-17 to IL-17RA, control
the expression of IL-6 mediated by IL-17, and then inhibit synovitis. At present,
more than ten monoclonal antibody inhibitors of IL-17 have entered the clinical