Long-acting protein drugs for the treatment of ocular diseases.
Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye's vitreous, with therapeutic antibodies and proteins. When administered to rabbit and monkey eyes, the half-life of the modified proteins is increased ∼3-4-fold relative to unmodified proteins. We further show that prototype long-acting anti-VEGF drugs (LAVAs) that include this peptide attenuate VEGF-induced retinal changes in animal models of neovascular retinal disease ∼3-4-fold longer than unmodified drugs. This approach has the potential to reduce the dosing frequency associated with retinal disease treatments.
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Joy G
JG
Ghosh
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Andrew A
AA
Nguyen
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Chad E
CE
Bigelow
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Stephen
S
Poor
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Yubin
Y
Qiu
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Nalini
N
Rangaswamy
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Richard
R
Ornberg
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Brittany
B
Jackson
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Howard
H
Mak
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Tucker
T
Ezell
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Vania
V
Kenanova
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Elisa
E
de la Cruz
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Ana
A
Carrion
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Bijan
B
Etemad-Gilbertson
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Roxana Garcia
RG
Caro
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Kan
K
Zhu
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Vinney
V
George
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Jirong
J
Bai
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Radhika
R
Sharma-Nahar
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Siyuan
S
Shen
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Yiqin
Y
Wang
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Kulandayan K
KK
Subramanian
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Elizabeth
E
Fassbender
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Michael
M
Maker
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Shawn
S
Hanks
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Joanna
J
Vrouvlianis
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Barrett
B
Leehy
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Debby
D
Long
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Melissa
M
Prentiss
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Viral
V
Kansara
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Bruce
B
Jaffee
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Thaddeus P
TP
Dryja
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
Michael
M
Roguska
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005260:Female; D006207:Half-Life; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D058449:Intravitreal Injections; D008252:Macaca fascicularis; D008297:Male; D011817:Rabbits; D000069579:Ranibizumab / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage* / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D012164:Retinal Diseases / Q000188:drug therapy* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D000068258:Bevacizumab; D006820:Hyaluronic Acid; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab