Synthetic multidomain peptide biomaterials that inhibit inducible nitric oxide synthase
Inventors
HARTGERINK, Jeffrey • Sikora, Andrew G. • Leach, David • Newton, Jared M. • Young, Simon
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Assignees
Baylor College of Medicine • William Marsh Rice University • University of Texas System
Member
Rice UniversityRice University is a leading research university in Houston, Texas, recognized for its emphasis on scientific discovery, innovation, and interdisciplinary collaboration. The institution is committed to academic excellence, impactful research, and community engagement, offering robust undergraduate and graduate programs in engineering, natural sciences, social sciences, humanities, business, and the arts. Rice is distinguished by its history of collaboration with organizations such as NASA, fostering advances in space science, biotechnology, energy research, and artificial intelligence.
Rice University is a leading research university in Houston, Texas, recognized for its emphasis on scientific discovery, innovation, and interdisciplinary collaboration. The institution is committed to academic excellence, impactful research, and community engagement, offering robust undergraduate and graduate programs in engineering, natural sciences, social sciences, humanities, business, and the arts. Rice is distinguished by its history of collaboration with organizations such as NASA, fostering advances in space science, biotechnology, energy research, and artificial intelligence.
Publication Number
US-12251449-B2
Publication Date
2025-03-18
Expiration Date
Abstract
Provided herein are compositions comprising multi domain peptide (MDP) hydrogels where the peptides that constitute the hydrogel have at least one N6-(1-iminoethyl)-lysine side chain. Also provided are hydrogels that further comprise a STING agonist, an immune checkpoint inhibitor, and/or an anti-cancer therapy. Also provided are methods of using such compositions in the treatment of cancer.
Core Innovation
Provided herein are compositions comprising multi domain peptide (MDP) hydrogels where the peptides that constitute the hydrogel have at least one N6-(1-iminoethyl)-lysine side chain. The hydrogels can further comprise a STING agonist, an immune checkpoint inhibitor, and/or an anti-cancer therapy, and methods of using such compositions in the treatment of cancer are provided.
The background identifies that N6-(1-iminoethyl)-L-lysine (L-NIL) and its derivatives selectively inhibit inducible nitric oxide synthase (iNOS) and that the use of L-NIL in preclinical research has been hindered by the need to repeatedly deliver large drug quantities over a long period of time, resulting in material waste, inconsistent treatment results with ad libitum administration, and issues of absorption, bioavailability, and incomplete drug distribution. The invention addresses this by providing an injectable, controlled and extended dose delivery system for L-NIL to increase localized dosage to tumor and tumor-infiltrating immune cells while minimizing systemic side-effects.
The summary discloses peptides comprising a first domain, a second domain, and a third domain, wherein the first and third domain are each Xm and m is 1-6 in some embodiments, wherein the second domain comprises alternating hydrophobic (H) and hydrophilic (p) amino acids and in certain aspects comprises (SerLeu)6, and wherein X is an amino acid having a side chain with nitric oxide synthase (NOS) inhibitory activity, including N6-(1-iminoethyl)-lysine (L-NIL). The compositions include hydrogels that are biocompatible, remain intact at pH 3-11 and at physiological pH, can be lyophilized, can load STING agonists (e.g., CDNs), immune checkpoint inhibitors, and/or anti-cancer drugs, and are described for use by intratumoral administration, administration to the tumor bed, or administration regional to the tumor for treating cancer, inhibiting iNOS, and reducing VEGF levels.
Claims Coverage
The claims include one independent claim defining a multidomain peptide with specified domain architecture and a defined X substituent. Two main inventive features are identified from the independent claim.
Multidomain peptide architecture
A peptide comprising a first domain, a second domain, and a third domain; wherein the first and third domain are each Xm and m is 1-3; wherein the first domain is positioned at the N-terminal end of the second domain; and wherein the third domain is positioned at the C-terminal end of the second domain.
Second domain composition and L-NIL substitution
The second domain comprises (SerLeu)6; and X is an amino acid having a side chain of N6-(1-iminoethyl)-lysine (L-NIL).
The independent claim covers a specific multidomain peptide architecture with N- and C-terminal Xm domains flanking a (SerLeu)6 central domain and specifies that X is an amino acid bearing an N6-(1-iminoethyl)-lysine (L-NIL) side chain.
Stated Advantages
Provides an injectable, controlled and extended dose delivery system for L-NIL that can reduce material waste and standardize drug intake compared to ad libitum oral administration.
Increases localized dosage to tumor and tumor-infiltrating immune cells while minimizing systemic side-effects.
Generates an extended systemic response and a durable, controlled biological effect not achievable with free L-NIL, with the hydrogel able to remain in its injected location for over three weeks.
Serves as a bioactive carrier material that can be combined with additional loaded agents to create extended release, multi-component combination therapies, including STING agonists and immune checkpoint inhibitors.
Methods using the compositions can improve survival of the patient and decrease tumor volume as stated in the summary of embodiments.
Administration of the compositions can reduce serum VEGF levels in tumor-bearing subjects.
Documented Applications
Methods of treating a cancer in a patient by administering a therapeutically effective amount of the described composition, including intratumoral administration, administration to the tumor bed, or administration regional to the tumor.
Methods of inhibiting inducible nitric oxide synthase (iNOS) in a patient by administering a therapeutically effective amount of the described composition.
Methods of reducing vascular endothelial growth factor (VEGF) levels in a patient by administering a therapeutically effective amount of the described composition; VEGF levels can be serum VEGF levels.
Hydrogels further comprising a STING agonist (e.g., a cyclic dinucleotide (CDN)), an immune checkpoint inhibitor, and/or an anti-cancer drug for use as an intratumoral delivery platform (exemplified as SynerGel: L-NIL-MDP loaded with CDN).
Use of the L-NIL-MDP hydrogel as a platform for controlled release of biologics and small molecules such as cyclic dinucleotides and IgG, and for combination immunotherapy with agents including anti-CTLA-4 and anti-PD-1 antibodies.
Kits containing peptides or hydrogels of the present invention and reagents required for formation or delivery of the hydrogel.
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