NGF antagonists for medical use
Provided are various embodiments relating to TrkA ECD polypeptides from companion animal species that bind to NGF. Such polypeptides can be used in methods to treat NGF-induced condition related to chronic pain and/or inflammatory pain in companion animals, such as canines, felines, and equines.
1 . A polypeptide comprising at least one extracellular domain of a TrkA polypeptide (TrkA ECD polypeptide) from a companion animal species and a fusion partner;
wherein the TrkA ECD polypeptide comprises SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, except that the TrkA ECD polypeptide comprises a pair of cysteine substitutions selected from the group consisting of:
a) a cysteine at a position corresponding to position 7 and position 89 of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4; or
b) a cysteine at a position corresponding to position 5 and position 87 of SEQ ID NO: 5; or
c) a cysteine at position 7 and position 89 of SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4; or
d) a cysteine at position 5 and position 87 of SEQ ID NO: 5.
2 . The polypeptide of claim 1 , wherein the polypeptide binds to an NGF polypeptide with a dissociation constant (Kd) of less than 5×10 −6 M, less than 1×10 −6 M, less than 5×10 −7 M, less than 1×10 −7 M, less than 5×10 −8 M, less than 1×10 −8 M, less than 5×10 −9 M, less than 1×10 −9 M, less than 5×10 −10 M, less than 1×10 −10 M, less than 5×10 −11 M, less than 1×10 −11 M, less than 5×10 −12 M, or less than 1×10 −12 M, as measured by biolayer interferometry.
3 . The polypeptide of claim 2 , wherein the NGF polypeptide is a human NGF polypeptide, a canine NGF polypeptide, a feline NGF polypeptide, or an equine polypeptide.
4 . The polypeptide of claim 1 , wherein the polypeptide reduces NGF signaling in the companion animal species, wherein the companion animal species is canine, feline, or equine.
5 . The polypeptide of claim 1 , wherein the polypeptide comprises a linker.
6 . The polypeptide of claim 1 , wherein the fusion partner is an Fc polypeptide.
7 . The polypeptide of claim 1 , wherein the fusion partner is a Fc polypeptide comprising a wild-type or a variant canine IgG-A, IgG-B, IgG-C, or IgG-D polypeptide.
8 . The polypeptide of claim 1 comprising the formula:
TrkA ECD 1-L1-Fc;
wherein TrkA ECD 1 is a TrkA ECD polypeptide, L1 is a linker, and Fc is a wild type or variant IgG Fc polypeptide of a companion animal species.
9 . The polypeptide of claim 1 further comprising at least one extracellular domain of an NGFR polypeptide (NGFR ECD polypeptide).
10 . A pharmaceutical composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier.
11 . A method of treating a companion animal species having an NGF-induced condition or pain, the method comprising administering to the companion animal species a therapeutically effective amount of the polypeptide of claim 1 .