Humanized multivalent protein conjugates
AssigneeValitor, Inc.
InventorsWesley M. JACKSON, Amy A. TWITE, Adam BARNEBEY, Livia Wilz BRIER, Jesse M. MCFARLAND
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Abstract
The present invention relates to peptide sequences having a high degree of humanness and/or the ability to be expressed in appreciable levels in culture media, such as in E. coli. The peptides can be covalently attached via an alpha-helical peptide linker to a polymer backbone. The invention further relates to methods of preparing the peptides, polymer conjugates comprising the peptides, and pharmaceutical compostions thereof.
Claims29
A peptide having Formula (I):
- FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 (I),
- CDR1, CDR2, and CDR3 are each independently complementarity-determining regions;
- FR1 has an amino acid sequence comprising
- (SEQ ID NO:
- 1)
- X10VQLX11EX12GGGX13X14QX15GX16SLRLSCX17X18SG,
- wherein
- X10 is Q, E, or D,
- X11 is V, Q, A, or E,
- X12 is S or T,
- X13 is L, S, or V,
- X14 is V or A,
- X15 is P, A, or T,
- X16 is G, D, or R,
- X17 is A, V, T, or E, and
- X18 is A or V;
- FR2 has an amino acid sequence comprising
- (SEQ ID NO:
- 2)
- X20X21WX22RQX23PGKX24X25EX26VX27x28I,
- wherein
- X20 is M, I, V, or L,
- X21 is G, S, or A,
- X22 is F, Y, or V,
- X23 is A, V, P, or T,
- X24 is E, G, A, or Q,
- X25 is R or L,
- X26 is F, G, W, or L,
- X27 is A, G, or S, and
- X28 is A, S, or G;
- FR3 has an amino acid sequence comprising
- (SEQ ID NO:
- 3)
- YX30DSVKGRFTISX31DX32X33KX34X35VX36LQMX37X38LRX39aEDTAX39b
- YYCAA,
- wherein
- X30 is A, G, S, or T,
- X31 is R or Q,
- X32 is N, S, or D,
- X33 is S, A, or D,
- X34 is N or K,
- X35 is T or M,
- X36 is Y, D, or S,
- X37 is N or D,
- X38 is S or N,
- X39a is P or A, and
- X39b is V, M, L, or I;
- and
- FR4 has an amino acid sequence comprising
- (SEQ ID NO:
- 4)
- YWGX40GTX41VTVSS,
- wherein
- X40 is Q or K, and
- X41 is L or Q.
-10. (canceled)
-13. (canceled)
A conjugate of Formula IIb:
- (X1—X2A—Y)n—Z (IIb)
- wherein
- each X1 is independently a peptide having a molecular weight of from about 5 kDa to about 200 kDa;
- each X2A is independently a peptide linker that comprises an alpha-helix;
- each Y is independently an organic linker;
- Z is a biocompatible polymer having a molecular weight of from about 0.1 MDa to about 3 MDa;
- and
- subscript n is an integer of from 1 to 1500.
-21. (canceled)
-27. (canceled)
(canceled)
(canceled)
A conjugate that is a random polymer of Formula Illa:
- (X1—X2—Y—Z1)n—(Z2)p—(Z3)q (IIIa),
- having a molecular weight of about 0.8 MDa;
- wherein
- each X1 is a peptide having an amino acid sequence comprising SEQ ID NO:
- 55;
- each X2 is a peptide linker having an amino acid sequence comprising
- (SEQ ID NO:
- 21)
- AEAAAKEAAAKEAAAKAGC;
- each Y is an organic linker having the structure:
- each X1—X2—Y—Z1 moiety has the structure:
- each Z2 has the structure:
- each Z3 independently has the structure:
- each Z3a is independently OH or Y′;
- each Y′ has the structure:
- each R1 and R2 is ethyl or —(CH2)3—NMe2;
- subscript n is an integer of from 10 to 300 and less than about 10% of the sum of subscripts n, p, and q;
- subscript p is an integer of from 1 to 15 and less than about 0.5% of the sum of subscripts n, p, and q;
- and
- subscript q is an integer of from 1000 to 3000.
A conjugate that is a random polymer of Formula Illa:
- (X1—X2—Y—Z1)n—(Z2)p—(Z3)q (IIIa),
- having a molecular weight of about 0.8 MDa;
- wherein
- each X1 is a peptide having an anti-VEGF amino acid sequence comprising SEQ ID NO:
- 67;
- each X2 is a peptide linker having an amino acid sequence comprising
- (SEQ ID NO:
- 21)
- AEAAAKEAAAKEAAAKAGC;
- each Y is an organic linker having the structure:
- each X1—X2—Y—Z1 moiety has the structure:
- each Z2 has the structure:
- each Z3 independently has the structure:
- each Z3a is independently OH or Y′;
- each Y′ has the structure:
- each R1 and R2 is ethyl or —(CH2)3—NMe2;
- subscript n is an integer of from 10 to 300 and less than about 10% of the sum of subscripts n, p, and q;
- subscript p is an integer of from 1 to 15 and less than about 0.5% of the sum of subscripts n, p, and q;
- and
- subscript q is an integer of from 1000 to 3000.
-42. (canceled)
-47. (canceled)
Dependencies are inferred from the claim text.