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G. Yang and Y. Huang
combination therapy was superior to monotherapy in both prevention and treatment
of CNV, which indicated that PDGF is another potentially important target in the
treatment of AMD [18, 19]. In 1995, the DNA aptamer of PDGF-AB with the affinity
of pmol level (K D = ∼93–147 pM) was obtained through SELEX for the first time,
and the sequence 36t was truncated from 39 nt to 29 nt [20–22]. By introducing 2
-F,
2
-OMe and 40 kDa-PEG modification, the original sequence NX1975 of Fovista
(Ophthotech) was formed, and its affinity for PDGF-B was maintained with a 2 h
half-life in rat serum. Furthermore, NX1975 showed inhibitory effect on PDGFB in a variety of disease models including the rat model of complement-mediated
kidney injury (induced with anti-thy 1.1 antibody), mice restenosis model, rat colon
carcinoma model, and fetal sheep pulmonary arterial hypertension model. According
to the results of Akiyama et al., the half-life of PEG-modified NX1975 in the vitreous
of BD rabbits was 96 h, while that of PEG-free NX1975 was reduced to 48 h [23]. In
a transgenic mice model with human PDGF-BB photoreceptor overexpression, both
PEG and non-PEG modified NX1975 inhibited the formation of retinal epimembrane
and retinal detachment when injected into the vitreous cavity.
The NX1975 was subsequently renamed ARC127, E10030, and Fovista
(Ophthotech) by several companies. Fovista was given in combination with Lucentis
in phase 1 clinical trials. After 12 weeks, 59% of patients had an increase of three
lines in best-corrected visual acuity (BVCA) [24]. Significant angiogenesis regression was observed for the first time, and the CNV area decreased by an average of 86%
[15, 16]. In phase 2b clinical trials, Fovista was administered in combination with
Ranibizumab, showing good safety and BVCA improvements [20]. At present, phase
3 clinical trials had been launched to evaluate the safety and efficacy of united medication of Fovista with Bevacizumab, Ranibizumab, or Aflibercept compared with
the sole therapy against vascular endothelial growth factor (VEGF) [20, 22, 25].
6.2.3 Zimura (ARC1905) TargetingComplement-5 (C5)
The complement system is a key component of the innate and adaptive immune
response, mediating the processes of phagocytosis, inflammation, chemotaxis of
immune cells, and pathogen cytolysis [26]. The activation pathways of complement
system include classical pathway, lectin pathway, and alternative pathway, all of
which are activated by serine protease successively. The above pathways converge at
the activation of complement component 3 (C3), and then complement component
5 (C5) invertase is assembled. The C5 protein was hydrolyzed by the C5 invertase,
and the C5a fragment (9 kDa) and C5b fragment (200 kDa) were produced. C5a is
the most effective allergenic toxin in the complement system, mediating a variety
of biological activities, including immune cell chemotaxis, cytokine release and
regulation, oxidant production, and increased vascular permeability.
C5b induces the assembly of the membrane attack complex (MAC), which
destroys the cellular pathogen or the lipid bilayer of the damaged host cell,
leading to cytolysis. A series of complement proteins have been identified as AMD
G. Yang and Y. Huang
combination therapy was superior to monotherapy in both prevention and treatment
of CNV, which indicated that PDGF is another potentially important target in the
treatment of AMD [18, 19]. In 1995, the DNA aptamer of PDGF-AB with the affinity
of pmol level (K D = ∼93–147 pM) was obtained through SELEX for the first time,
and the sequence 36t was truncated from 39 nt to 29 nt [20–22]. By introducing 2
-F,
2
-OMe and 40 kDa-PEG modification, the original sequence NX1975 of Fovista
(Ophthotech) was formed, and its affinity for PDGF-B was maintained with a 2 h
half-life in rat serum. Furthermore, NX1975 showed inhibitory effect on PDGFB in a variety of disease models including the rat model of complement-mediated
kidney injury (induced with anti-thy 1.1 antibody), mice restenosis model, rat colon
carcinoma model, and fetal sheep pulmonary arterial hypertension model. According
to the results of Akiyama et al., the half-life of PEG-modified NX1975 in the vitreous
of BD rabbits was 96 h, while that of PEG-free NX1975 was reduced to 48 h [23]. In
a transgenic mice model with human PDGF-BB photoreceptor overexpression, both
PEG and non-PEG modified NX1975 inhibited the formation of retinal epimembrane
and retinal detachment when injected into the vitreous cavity.
The NX1975 was subsequently renamed ARC127, E10030, and Fovista
(Ophthotech) by several companies. Fovista was given in combination with Lucentis
in phase 1 clinical trials. After 12 weeks, 59% of patients had an increase of three
lines in best-corrected visual acuity (BVCA) [24]. Significant angiogenesis regression was observed for the first time, and the CNV area decreased by an average of 86%
[15, 16]. In phase 2b clinical trials, Fovista was administered in combination with
Ranibizumab, showing good safety and BVCA improvements [20]. At present, phase
3 clinical trials had been launched to evaluate the safety and efficacy of united medication of Fovista with Bevacizumab, Ranibizumab, or Aflibercept compared with
the sole therapy against vascular endothelial growth factor (VEGF) [20, 22, 25].
6.2.3 Zimura (ARC1905) TargetingComplement-5 (C5)
The complement system is a key component of the innate and adaptive immune
response, mediating the processes of phagocytosis, inflammation, chemotaxis of
immune cells, and pathogen cytolysis [26]. The activation pathways of complement
system include classical pathway, lectin pathway, and alternative pathway, all of
which are activated by serine protease successively. The above pathways converge at
the activation of complement component 3 (C3), and then complement component
5 (C5) invertase is assembled. The C5 protein was hydrolyzed by the C5 invertase,
and the C5a fragment (9 kDa) and C5b fragment (200 kDa) were produced. C5a is
the most effective allergenic toxin in the complement system, mediating a variety
of biological activities, including immune cell chemotaxis, cytokine release and
regulation, oxidant production, and increased vascular permeability.
C5b induces the assembly of the membrane attack complex (MAC), which
destroys the cellular pathogen or the lipid bilayer of the damaged host cell,
leading to cytolysis. A series of complement proteins have been identified as AMD