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US-20260125446-A1 - RELAXIN ANALOGS AND METHODS OF USING THE SAME

US20260125446A1US 20260125446 A1US20260125446 A1US 20260125446A1US-20260125446-A1

Abstract

Relaxin (RLN) analogs are disclosed including modifications that increase half-life when compared to native, human RLN, that maintain selectivity to the RXFP1 receptor and that provide in vitro and in vivo stability for improved druggability properties and less immunogenicity. Pharmaceutical compositions also are disclosed that include one or more of the RLN analogs described herein in a pharmaceutically acceptable carrier. Methods of making and using the RLN analogs also are disclosed, especially for treating cardiovascular, pulmonary and/or renal conditions, diseases or disorders.

Inventors

  • Petra Verdino
  • Stacey Lynn Lee
  • Xiaojun Wang

Assignees

  • ELI LILLY AND COMPANY

Dates

Publication Date
20260507
Application Date
20250619

Claims (20)

  1. 1 . A compound comprising a structure of: wherein VHH comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:10, 11, 12 and 13 or a sequence having at least 90% sequence similarity thereto, wherein A is a relaxin A chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 5 and 8 or a sequence having at least 90% sequence similarity thereto, wherein B is a relaxin B chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:3, 6 and 9 or a sequence having at least 90% sequence similarity thereto, wherein L 1 is a first linker comprising an amino acid sequence selected from the group consisting of (GGGGQ) n (SEQ ID NO:14), (PGPQ) n (SEQ ID NO:17) and (PGPA) n (SEQ ID NO:18), and wherein n can be from 1 to 10, and wherein L 2 is a second linker comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:22, 23 and 67; or a pharmaceutically acceptable salt thereof.
  2. 2 . The compound of claim 1 , wherein A is SEQ ID NO:2.
  3. 3 . The compound of claim 1 , wherein B is SEQ ID NO:3.
  4. 4 . The compound of claim 1 , wherein A is SEQ ID NO:5.
  5. 5 . The compound of claim 1 , wherein B is SEQ ID NO:6.
  6. 6 . The compound of claim 1 , wherein A is SEQ ID NO:5 and lacks the first four amino acids (desA1-4).
  7. 7 . The compound of claim 1 , wherein B is SEQ ID NO:6 and lacks the first amino acid (desB1).
  8. 8 . The compound of claim 1 , wherein A is SEQ ID NO:5 and lacks the first four amino acids (desA1-4), and wherein B is SEQ ID NO:6 and lacks the first amino acid (desB1).
  9. 9 . The compound of claim 1 , wherein A is SEQ ID NO:8.
  10. 10 . The compound of claim 1 , wherein B is SEQ ID NO:9.
  11. 11 . The compound of claim 1 , wherein L 1 is SEQ ID NO:19.
  12. 12 . The compound of claim 1 , wherein L 1 is SEQ ID NO:20.
  13. 13 . The compound of claim 1 , wherein L 1 is SEQ ID NO:21.
  14. 14 . The compound of claim 1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:24 to 39 or a sequence having at least 90% sequence similarity thereto or a pharmaceutically acceptable salt thereof.
  15. 15 . The compound of claim 1 consisting essentially of an amino acid sequence selected from the group consisting of SEQ ID NOS:24 to 39 or a sequence having at least 90% sequence similarity thereto or a pharmaceutically acceptable salt thereof.
  16. 16 . The compound of claim 1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NOS:24 to 39 or a sequence having at least 90% sequence similarity thereto or a pharmaceutically acceptable salt thereof.
  17. 17 . A pharmaceutical composition comprising: a compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable buffer.
  18. 18 . A method of treating cardiac, pulmonary and/or renal conditions, diseases and/or disorders in an individual, the method comprising the step of: administering to the individual an effective amount of a compound of claim 1 .
  19. 19 - 21 . (canceled)
  20. 22 . A compound comprising an amino acid sequence of selected from the group consisting of SEQ ID NOS: 10-13 and 45-66 or a sequence having at least 90% sequence similarity thereto.

Description

The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled “X22483A_US_000 Sequence Listing ST26” created Jun. 11, 2025, and is 94,208 bytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety. No new matter is added herewith. The disclosure relates generally to biology and medicine, and more particularly it relates to relaxin (RLN) analogs, especially long-acting, single-chain RLN analogs that can bind to a RLN/insulin-like family peptide (RXFP) receptor, such as the RXFP1 receptor, thereby functioning as RXFP receptor agonists. The disclosure further relates to compositions including the same and their use in treating cardiovascular, pulmonary and/or renal conditions, diseases or disorders. Relaxins (RLNs) are part of the insulin superfamily and, in humans, include seven peptides of high structural, but low sequence, similarity—RLN1 (H1RLX, RLXH1 or H1), RLN2 (H2RLX, RLXH2 or H2), RLN3 (RXN3, ZINS4 or H3), insulin-like (INSL) peptide 3 (INSL3), INSL4, INSL5 and INSL6. Of particular interest herein is RLN2, which is a heterodimer of two peptide chains of twenty-four and twenty-nine amino acids (A chain and B chain), respectively, linked by two disulfide bonds with the A chain further having one intramolecular disulfide bond (see, Schwabe & McDonald (1977) Science 197:914-915). RLN2 is produced from its prohormone, prorelaxin, by cleaving a C peptide therefrom. Physiologically, RLN2 exhibits a diverse array of functions that modulate cardiovascular, hepatic, neural, pancreatic, pulmonary and renal adaptations such as vasodilatory, anti-fibrotic and angiogenic effects, even though it initially was described as a pregnancy hormone. RLN2 signaling occurs through two different classes of G-protein-coupled receptors (GPCRs), namely, leucine-rich repeat-containing GPCRs LGR7 and LGR8, now referred to as the RXFP1 and RXFP2 receptors, respectively. Two other receptors in this family include the RXFP3 and RXFP4 receptors. RLN2 has a short half-life (t½), which presents challenges when using it as a therapeutic agent. In fact, native RLN2 has a t½ of minutes in vivo. Consequently, clinicians administer RLN2 by continuous intravenous infusion, which often results in inconvenience for individuals receiving the RLN compound and in short-term efficacy. A number of RLN2 analogs exist having an improved t½. For example, Intl. Patent Application Publication No. WO 2018/148419 describes analogs that include a non-native amino acid residue such as para-acetyl-phenylalanine to which linkers, polymers and/or pharmacokinetic enhancers can be attached to improve t½. Intl. Patent Application Publication No. WO 2018/138170 describes analogs that are fusions of the A chain and B chain having a linker of at least fifteen amino acids and a half-life extending moiety to improve t½. Intl. Patent Application Publication No. WO 2017/201340 describes analogs that are fusions of the A chain and B chain having a variable light chain fragment to improve t2. Intl. Patent Application Publication No. WO 2015/067791 describes analogs that are carrier-linked prodrugs, especially PEG-based carriers, to improve t½ (see also, WO 2012/024452 for additional PEG-linked analogs). Intl. Patent Application Publication No. WO 2014/102179 describes analogs that are fusions of the A chain and B chain having a Fc moiety of IgG2 or IgG4 to improve t½. Intl. Patent Application Publication No. WO 2013/004607 describes analogs that are fusions of the A chain and B chain having a linker of at least five amino acids but less than fifteen amino acids to improve t½ or that are fusions of the A chain and B chain having a Fc domain of antibodies to improve t½. In view of the increases in understanding the various physiological roles of RLNs, there remains a need for long-acting RLN analogs having an improved t½. To address this need, the disclosure first describes single-chain RLN analogs having principal activity at the RXFP1 receptor (i.e., act as RXFP1 receptor agonists). Such RXFP1 receptor agonists include a basic structure from an amino-terminus (N-terminus) to a carboxy-terminus (C-terminus) of: where VHH is a moiety that can act as a pharmacokinetic enhancer, A is a RLN A chain, B is a RLN B chain, L1 is a first linker, and L2 is a second linker. In some instances, the VHH moiety can have an amino acid sequence of SEQ ID NO:10, 11, 12 or 13, especially SEQ ID NO:10 or 12. In other instances, the VHH moiety can have one or more additions, deletions, insertions or substitutions such that the VHH moiety has an amino acid sequence having at least about 90% to about 99% sequence similarity to any one of SEQ ID NOS:10, 11, 12 or 13 (see, e.g., SEQ ID NOS:45-66). In some instances, the A chain can have an amino acid sequence of SEQ ID NO:2, 5 or 8, especially SEQ ID NO:5. In other instances, the A chain can have one or more