Multimeric elastin-like polypeptides
Inventors
MacKay, John Andrew • Shah, Mihir • Hamm-Alvarez, Sarah F. • Guo, Hao • Peddi, Santosh
Assignees
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Publication Number
US-12458704-B2
Publication Date
2025-11-04
Expiration Date
Abstract
This disclosure provides a novel compositions and methods to deliver cyclosporine A using genetically engineered protein polymers.
Core Innovation
The invention relates to genetically engineered multimeric elastin-like peptide (ELP) fusion agents for drug delivery. The disclosed ELPs comprise an amino acid sequence set forth in SEQ ID NO: 11 and are described as exhibiting a reversible inverse phase transition with coacervate formation, which is used to support purification and drug loading through coacervate formation.
Multimers of ELP, such as dimers to pentamers, are fused to drug-binding domains and/or targeting domains to sequester therapeutic agents and enhance solubility, bioavailability, and reduce clearance. The document describes drug-binding domain examples including cyclophilin A (CypA), FK506 binding protein (FKBP), and peptidyl-prolyl cis/trans isomerase (PIN1) that are used with corresponding therapeutic payloads.
Targeted delivery is supported by fusing multimeric ELP constructs with targeting ligands, including ICAM-1 targeting peptides, adenovirus knob domain, and pIgR/mIgA ligands. The document further describes therapeutic payloads including cyclosporin A, rapamycin and rapalogues, and all-trans retinoic acid, with co-localization and release behavior referenced for specific constructs.
Claims Coverage
The relevant independent claim is clm-00001, which defines an agent with a specific ELP sequence fused to an ICAM-1 targeting peptide chosen from two specified targeting peptides. The independent-claim coverage centers on the ELP fusion architecture and the selected ICAM-1 targeting peptide, with further inventive features added in dependent claims.
ICAM-1-targeted ELP fusion agent with SEQ ID NO: 11
An agent comprising an elastin-like peptide (ELP) that comprises the amino acid sequence set forth in SEQ ID NO: 11 fused to an intracellular adhesion molecule 1 (ICAM-1) targeting peptide selected from an ICAM-1 targeting peptide that comprises EWCEYLGGYLRCYA (SEQ ID NO: 29) or FEGFSFLAFEDFVSSI (SEQ ID NO: 28).
FK506 binding protein incorporation
The agent of the ELP fusion further comprises an FK506 binding protein (FKBP).
Selectable drug-binding domain fusion
The agent further includes a drug-binding domain selected from knob ligand (SEQ ID NO: 26), an mIgA ligand (SEQ ID NO: 27), or a peptidyl-prolyl cis/trans isomerase (PIN1) (SEQ ID NO: 31).
Rapamycin payload selection
The agent further comprises rapamycin or a rapamycin analog selected from Everolimus, Temsirolimus, Ridaforolimus, and Tacrolimus.
Across the identified independent claim and associated refinements, the core inventive architecture is an ICAM-1-targeted ELP fusion using the amino acid sequence set forth in SEQ ID NO: 11 fused to one of two specified ICAM-1 targeting peptides, with additional inventive features including incorporation of FKBP, selection of a named drug-binding domain, and selection of rapamycin or enumerated rapamycin analogs as a payload.
Stated Advantages
Enhance solubility.
Enhance bioavailability.
Reduce clearance.
Documented Applications
Autoimmune diseases including Sjögren’s syndrome and dry eye.
Transplant rejection.
Cancers including breast cancer.
CD20-related disorders.
In vitro and in vivo administration, including topical/ocular and parenteral delivery.
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