Compstatin analogs with increased solubility and improved pharmacokinetic properties
AssigneeThe Trustees of the University of Pennsylvania
InventorJohn D. Lambris
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Abstract
Compounds comprising peptides capable of binding C3 protein and inhibiting complement activation are disclosed. The compounds comprise compstatin analogs in which the N-terminus and/or C-terminus contains an added component that improves (1) the peptide's solubility at physiological pH; (2) the peptide's plasma half-life; (3) the peptide's intraocular retention; and/or (4) the peptide's binding affinity to C3 or its fragments as compared to an unmodified compstatin peptide under equivalent conditions. Pharmaceutical compositions and methods of using the compounds are also disclosed.
Claims24
A compound comprising:
- (a) a compstatin or compstatin analog peptide having an amino acid sequence represented by SEQ ID NO:1, SEQ ID NO:2, SEQ NO:3, SEQ ID NO:4, SEQ ID NO:
- 5, SEQ ID NO:
- 6, or SEQ ID NO:7;
- and
- (b) a terminal modification comprising an added terminal component that improves (1) the peptide's C3, iC3b, C3b or C3c binding affinity, (2) the peptide's solubility at physiological pH, (3) the peptide's plasma stability and/or plasma residence time, and/or (4) the peptide's vitreous stability and/or vitreous residence time, as compared with an unmodified compstatin peptide under equivalent conditions;
- wherein the added terminal component:
- (i) is a C-terminal component comprising two or three lysine amino acid residues;
- or
- (ii) is an N-terminal component comprising polyethylene glycol (PEG) having an average molecular weight of about 1 kDa to about 3 kDa, or
- (iii) both (i) and (ii).
A compound comprising:
- (a) a compstatin analog peptide having an amino acid sequence:
- Xaa1-Xaa2-Cys-Val-Xaa3-Gin-Xaa4-Xaa5-Gly-Xaa6-His-Xaa7-Cys-Xaa8, in which Gly between Xaa5 and Xaa6 optionally is modified to constrain the backbone conformation;
- wherein:
- Xaa1 is absent or is Tyr, D-Tyr or Sar;
- Xaa2 is Ile, Gly or Ac-Trp;
- Xaa3 is Trp or an analog of Trp, wherein the analog of Trp has increased hydrophobic character as compared with Trp;
- Xaa4 is Asp or Asn;
- Xaa5 is Trp or an analog of Trp comprising a chemical modification to its indole ring wherein the chemical modification increases the hydrogen bond potential of the indole ring;
- Xaa6 is His, Ala, Phe or Trp;
- Xaa7 is Arg or Orn;
- Xaa8 is Thr, Ile, Leu, Nle, N-methyl Thr or N-methyl Ile, wherein a carboxy terminal —OH of any of the Thr, Ile, Leu, Nle, N-methyl Thr or N-methyl Ile optionally is replaced by —NH2;
- and
- the peptide is cyclic via a Cys-Cys or thioether bond;
- and
- (b) a terminal modification comprising an added terminal component that improves (1) the peptide's C3, iC3b, C3b or C3c binding affinity, (2) the peptide's solubility at physiological pH, and/or (3) the peptide's plasma stability and/or plasma residence time;
- and/or (4) the peptide's vitreous stability and/or vitreous residence time, as compared with an unmodified compstatin peptide under equivalent conditions;
- wherein the added terminal component:
- (i) is a C-terminal component comprising two or three lysine amino acid residues;
- or
- (ii) is an N-terminal component comprising polyethylene glycol (PEG) having an average molecular weight of about 1 kDa to about 3 kDa;
- or
- (iii) both (i) and (ii).
A compound comprising:
- (a) a compstatin or compstatin analog having an amino acid sequence represented by any one of SEQ ID NO:1 through SEQ ill NO:10;
- and
- (b) a polyethylene glycol (PEG) polymer having an average molecular weight of about 1 kDa to about 3 kDa linked to the N-terminus of the peptide.
Dependencies are inferred from the claim text.