Immune tolerant elastin-like peptide tetramer guided nanoparticles and methods of use
Inventors
Assignees
University of Utah • University of Utah Research Foundation Inc
Publication Number
US-12162923-B2
Publication Date
2024-12-10
Expiration Date
2038-10-05
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Abstract
Disclosed herein, are nanoparticles comprising one or more immune-tolerant elastin-like polypeptide tetramers and one or more immune-tolerant elastin-like fusion molecules. Also, disclosed herein are pharmaceutical compositions including the nanoparticles; methods of administering the nanoparticles to patients for the treatment of cancer; and methods of making the nanoparticles.
Core Innovation
The invention relates to nanoparticles composed of immune-tolerant elastin-like polypeptide (iTEP) tetramers and iTEP-fusion molecules, which can self-assemble into stable particles. The tetramers include four MHC class I monomers, one or two iTEP sequences, and a cysteine-containing tag, while the fusion molecules comprise a HisTag, linker, therapeutic agent (such as a single-chain variable fragment of anti-CTLA-4 or anti-PD-1 antibody), iTEP sequences, and a cysteine-containing tag. The assembly features crosslinking through disulfide bonds between the cysteine tags for added stability.
This technology addresses the problem that current immune checkpoint inhibitors, like anti-PD-1 or anti-CTLA-4 antibodies, non-selectively block immune checkpoints on all relevant and irrelevant immune cells, leading to limited efficacy and autoimmune toxicity. There is a need for therapeutic approaches that target these inhibitors specifically to cancer-reactive immune cells, reducing side effects and improving clinical outcomes in cancer therapy.
The nanoparticles designed herein utilize MHC class I tetramer-guided targeting to deliver checkpoint inhibitors directly to defined clones of tumor-reactive cytotoxic T lymphocytes (CTLs). This strategy allows for cell clone-specific checkpoint inhibition, concentrating therapeutic effect on the cells needed for anti-cancer response and decreasing unwanted activity elsewhere. Methods for making, using, and pharmaceutical compositions of these nanoparticles, as well as kits containing their components, are also disclosed.
Claims Coverage
The patent includes multiple independent claims covering the structure of the nanoparticles, methods of use, methods of making these nanoparticles and their components, pharmaceutical compositions, and kits. There are several main inventive features described.
Nanoparticle comprising iTEP-tetramers and iTEP-fusion molecules
A nanoparticle consisting of: - One or more immune-tolerant elastin-like polypeptide (iTEP)-tetramers, each having: - Four MHC class I monomers selected from H2-Db/gp100 epitope, H2-Kb/TRP-1 epitope, H2-Kb/TRP-2 epitope, or MHC class I tumor-associated epitopes; - A first and second iTEP sequence, specified as Gly-(Val-Pro-Gly-Phe-Gly-Ala-Gly-Ala-Gly)21-Gly-Gly (SEQ ID NO: 25) or Gly-(Val-Pro-Gly-Leu-Gly-Ala-Gly-Ala-Gly)96-Gly-Gly (SEQ ID NO: 26); - A cysteine containing tag. - One or more iTEP-fusion molecules, each comprising: - A HisTag; - A linker; - A therapeutic agent that is a single chain variable fragment of an anti-CTLA-4 or anti-PD-1 antibody; - First and second iTEP sequences as described above; - A cysteine containing tag.
Pharmaceutical composition including the nanoparticle
A pharmaceutical composition comprising the above-described nanoparticle and a pharmaceutically acceptable carrier, optionally formulated for intravenous administration.
Method of treating a patient with cancer using the nanoparticle
A method of treating a patient with cancer by: 1. Identifying a patient in need of treatment; 2. Administering a therapeutically effective amount of the pharmaceutical composition containing the above-described nanoparticle, wherein the MHC class I monomer contains an epitope expressed by the patient's cancer. The method includes use in human patients, patients with autoimmune diseases or disorders, treatment of primary or secondary tumors (including those in breast, lung, skin, kidneys, bladder, head, neck, lymphatic system, liver, brain, esophagus, digestion system, stomach, or ovaries), and specifically melanoma.
Reduced toxicity of nanoparticle-delivered checkpoint inhibitor
The method wherein the nanoparticle comprising the single chain variable fragment of an anti-CTLA-4 antibody or anti-PD-1 antibody yields reduced toxicity or reduced side effects when administered as part of the nanoparticle, compared to the single chain variable fragment administered alone or not as part of the nanoparticle.
Method of making iTEP-tetramers
A method for making immune-tolerant elastin-like polypeptide (iTEP)-tetramers by: 1. Mixing one or more iTEP fusion peptides (containing HisTag, linker, four or more streptavidin moieties, first and second specified iTEP sequences, and a cysteine containing tag) with four or more biotinylated MHC class I monomers (specific epitope choices stated); 2. Allowing binding to form the iTEP-tetramer.
Method of making the nanoparticle
A method for making the above nanoparticle comprising: 1. Mixing iTEP fusion peptides as described with biotinylated MHC class I monomers to produce iTEP-tetramer; 2. Mixing the iTEP-tetramer with an iTEP-fusion molecule (containing a HisTag, linker, single chain variable fragment of an anti-CTLA-4 or anti-PD-1 antibody, first and second specified iTEP sequences, and a cysteine tag), at a 10:1 ratio; 3. Crosslinking the cysteine containing tags via disulfide bonds; 4. Oxidizing to form a stable nanoparticle.
Kit containing components for nanoparticle assembly
A kit comprising: - One or more iTEP-tetramers (with four MHC class I monomers, specified iTEP sequences, and a cysteine containing tag); - One or more iTEP-fusion molecules (HisTag, linker, single chain variable fragment of anti-CTLA-4 or anti-PD-1 antibody, specified iTEP sequences, cysteine tag); - Optionally, a reducing or oxidizing agent and protected thiol groups.
Collectively, these inventive features define structural, functional, and methodological aspects of iTEP-based nanoparticles for cell-targeted delivery of immune checkpoint inhibitors, including their pharmaceutical compositions, use in cancer treatment, preparation methods, and kits.
Stated Advantages
Reduces the toxicity and side effects associated with immune checkpoint inhibitors by targeting inhibitors specifically to cancer-reactive immune cells rather than all checkpoint-expressing cells.
Improves the efficacy of checkpoint inhibitor therapy by concentrating the inhibitor at the relevant tumor-reactive CTLs, thereby enhancing the anti-cancer response.
Permits cell clone-specific immune checkpoint therapy, enabling targeted delivery to specific T cell clones through MHC class I tetramer guidance.
May broaden the patient population benefiting from checkpoint inhibitor therapy, including patients with pre-existing autoimmune disorders.
Provides stable, reproducible, and purifiable nanoparticle carriers that are immune-tolerant and biodegradable.
Facilitates rational combinational regimens by synchronizing CTL vaccine-induced responses with peak concentrations of checkpoint inhibition, providing greater efficacy and safety.
Allows for easy and consistent assembly and purification due to properties of the iTEP polypeptide system.
Documented Applications
Treatment of cancer in patients, including but not limited to melanoma, breast cancer, ovarian cancer, lung cancer (non-small cell), kidney cancer, bladder cancer, head and neck cancers, lymphomas, stomach cancer, brain cancer, esophageal cancer, multiple myeloma, skin cancer, or gastric cancer.
Treatment of cancer in patients with comorbid autoimmune diseases or disorders (e.g., type I diabetes mellitus, multiple sclerosis, rheumatoid arthritis, Sjögren's syndrome, Graves' disease ophthalmopathy, etc.).
Reduction of toxicity and side effects in immune checkpoint inhibitor regimens by directing inhibitors to tumor-reactive CTLs.
Preparation and use of pharmaceutical compositions containing the nanoparticles for intravenous or other parenteral, oral, or topical administration.
Cell clone-specific targeting of immune checkpoint inhibition using MHC class I tetramer-guided nanoparticles.
Use in combination with cancer vaccines, chemotherapeutic agents, or other immune checkpoint inhibitors for combinational cancer therapy.
Amplification of melanoma-reactive CTLs using multifunctional vaccine nanoparticles for enhanced immunotherapy.
Preparation and use of kits containing iTEP-tetramers and iTEP-fusion molecules for nanoparticle assembly and therapeutic administration.
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