Human amylin analog polypeptides and methods of use
Inventors
Blackwell, William • Srivastava, Ved P. • Way, James M.
Assignees
Intarcia Assignment For Benefit Of Creditors LLC • I2O Therapeutics Inc
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Publication Number
US-12018059-B2
Publication Date
2024-06-25
Expiration Date
Abstract
This invention relates to isolated polypeptides that are analogs of human amylin. The disclosed amylin analog polypeptides have beneficial physicochemical properties relative to endogenous amylin, such as longer elimination half-lives (t1/2) and improved solubility and thermal stability. This invention also relates to methods of using presently disclosed amylin analog polypeptides in a variety of therapeutic indications, as well as methods of producing the same. The disclosed amylin analog polypeptides are particularly useful in methods of treating metabolic diseases or disorders, such as types 1 and 2 diabetes, and providing weight loss.
Core Innovation
The invention relates to isolated polypeptide variants of human amylin / islet amyloid polypeptide (IAPP), including amylin analog polypeptides defined using a consensus sequence framework with SEQ ID NO:203 and SEQ ID NO:211. The polypeptides include variable positions where selected amino acids can be varied within defined sets at positions such as X1, X5, X10, X15, X16, X17, X18, and X35.
The polypeptides optionally include lysine conjugation, where each K can independently represent an L-lysine optionally covalently bound to a lipophilic substituent optionally via a spacer, and each k can independently represent a D-lysine optionally covalently bound to a lipophilic substituent optionally via a spacer or a protecting group. The disclosed framework also supports optional formation of a disulfide bridge between two cysteine residues in a defined cysteine-containing motif, further characterizing the polypeptide structure.
The disclosed lipophilic substituent and spacer architecture includes Formula I and spacer/lipophilic conjugates of Formulas II-X, including Formula III and Formula VI, with spacer motifs including γGlu-related spacer structures. The resulting amylin analog polypeptides have improved physicochemical properties compared to endogenous amylin, including longer elimination half-life, improved solubility, and improved thermal stability.
Claims Coverage
The provided claim set includes two independent claims. Both independent claims focus on structurally defined isolated amylin analog polypeptides with defined sequence frameworks, optional lysine-to-lipophilic conjugation, and optional disulfide-bridged cysteine motifs.
Isolated amylin analog polypeptide with SEQ ID NO:203 sequence and defined variable residues
An isolated polypeptide comprising the amino acid sequence of SEQ ID NO:203 with X1 is k or K, X5 is S, X10 is Q or S, X15 is E or F, X16 is L, X17 is H, V, and Q, and X18 is K, H, or R; with each K being an L-lysine optionally covalently bound to a lipophilic substituent optionally via a spacer and each k being a D-lysine optionally covalently bound to a lipophilic substituent optionally via a spacer.
Optional disulfide bridge in the SEQ ID NO:308 cysteine motif for SEQ ID NO:203 polypeptides
The two cysteine residues of X1CNTX5TC (SEQ ID NO:308) are optionally further bound by a disulfide bridge, as part of the isolated polypeptide comprising SEQ ID NO:203.
Isolated amylin analog polypeptide with SEQ ID NO:211 sequence and defined variable residues
An isolated polypeptide comprising the amino acid sequence of SEQ ID NO:211 with X1 is K or k, X10 is Q or S, X15 is E or F, X16 is L, X17 is H, V or Q, and X35 is E; where each K independently represents an L-lysine optionally covalently bound to a protecting group or a spacer optionally bound to a protecting group, and each k independently represents a D-lysine optionally covalently bound to a protecting group or a spacer optionally bound to a protecting group.
Optional disulfide bridge in the SEQ ID NO:309 cysteine motif for SEQ ID NO:211 polypeptides
The two cysteine residues of X1CNTSTC (SEQ ID NO:309) are optionally further bound by a disulfide bridge, as part of the isolated polypeptide comprising SEQ ID NO:211.
Overall, the claim coverage centers on isolated human amylin/IAPP analog polypeptides defined by specified SEQ ID frameworks, with defined allowable substitutions at variable positions, optional lysine-based covalent conjugation, and optional disulfide-bridged cysteine motifs.
Stated Advantages
Longer elimination half-life versus endogenous amylin.
Improved solubility versus endogenous amylin.
Improved thermal stability versus endogenous amylin.
Documented Applications
Therapeutic use in metabolic diseases including type 1 and type 2 diabetes and obesity/weight loss.
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