Cell-penetrating compstatin analogs and uses thereof

• US 10,308,687 B2
• Filed: 03/14/2014
• Issued: 06/04/2019
• Est. Priority Date: 03/15/2013
• Status: Active Grant

• Current Assignee: Apellis Pharmaceuticals, Inc.
• Original Assignee: Apellis Pharmaceuticals, Inc.
• Inventors: Francois, Cedric, Deschatelets, Pascal, Gerber, Monica
• Primary Examiner(s): Ha, Julie
• Assistant Examiner(s): Hellman, Kristina M
• Application Number:
  US14/775,663
• Publication Number:
  US 20160215022A1
• Time in Patent Office: 1,908 Days
• Field of Search: None
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C07K 14/472 Complement proteins, e.g. anaphylatoxin, C3a, C5a
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators
• CPC Class Codes: C07K 2319/01 containing a localisation/targetting motif
• CPC Class Codes: C07K 2319/10 containing a tag for extracellular membrane crossing, e.g. TAT or VP22
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links
• CPC Class Codes: C12N 2740/16022 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2740/16033 Use of viral protein as therapeutic agent other than vaccine, e.g. apoptosis inducing or anti-inflammatory
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: G01N 2333/4716 Complement proteins, e.g. anaphylatoxin, C3a, C5a
• CPC Class Codes: G01N 33/564 for pre-existing immune complex or autoimmune disease , i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9

Abstract

In some aspects, the present invention cell-penetrating compstatin analog and compositions comprising cell-penetrating compstatin analog. In some aspects, the invention further provides methods of using cell-penetrating compstatin analogs treat a complement-mediated disorder, e.g., to inhibit complement-mediated damage to a cell, tissue, or organ, to inhibit production or release of biologically active C3 cleavage products.

Claims

1. A compound comprising:

(i) a compstatin analog moiety comprising a peptide comprising an amino acid sequence of one of SEQ ID NOs;

3-6 and 9-36; and

(ii) a cell penetrating moiety (CPM) comprising a cell penetrating peptide comprising an amino acid sequence of one of SEQ ID NOs;

77-136,

wherein the compstatin analog moiety is covalently linked to the CPM.

2. The compound of claim 1, wherein the compstatin analog moiety is linked to the CPM via a linker.

3. The compound of claim 1, wherein the compstatin analog moiety comprises a cyclic peptide having a core sequence of

4. The compound of claim 1, wherein the compstatin analog moiety comprises a cyclic peptide having a core sequence of

5. The compound of claim 1, wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence of

6. The compound of claim 1, wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence:

7. The compound of claim 6, wherein

Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile or Ac-Gly-Ile;

Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp;

Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp;

Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —

OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by —

NH₂.

8. The compound of claim 6, wherein Xaa2 is an analog of Trp comprising a substituted or unsubstituted bicyclic aromatic ring component or two or more substituted or unsubstituted monocyclic aromatic ring components.

9. The compound of claim 6, wherein Xaa2 is an analog of Trp comprising a lower alkoxy or lower alkyl substituent at the 1 or 5 position of tryptophan or a halogen substituent at the 5 or 6 position of tryptophan.

10. The compound of claim 9, wherein Xaa2 is an analog of Trp comprising a lower alkoxy or lower alkyl substituent at the 1 or 5 position of tryptophan or a halogen substituent at the 5 or 6 position of tryptophan and Xaa2* is Trp.

11. The compound of claim 1, wherein the compstatin analog comprises a cyclic peptide having a sequence selected from the group consisting of SEQ ID NOs:

14, 21, 28, 29, 32, 33, 34, or 36.

12. A composition comprising (a) an isolated cell;

and (b) a compound comprising;

(i) a compstatin analog moiety comprising a peptide comprising an amino acid sequence of one of SEQ ID NOs;

3-6 and 9-36; and

(ii) a cell penetrating moiety (CPM) comprising a cell penetrating peptide comprising an amino acid sequence of one of SEQ ID NOs;

77-136,

wherein the compstatin analog moiety is covalently linked to the CPM.

13. The composition of claim 12, wherein the isolated cell is a liver cell, endothelial cell, epithelial cell, or immune system cell.