Therapeutic antibody fragments, methods of making, and methods of use
Inventors
Westlund High, Karin • Durvasula, Ravi Venkata • Kunamneni, Adinarayana
Assignees
Loyola University Chicago • US Department of Veterans Affairs • UNM Rainforest Innovations
Publication Number
US-12145991-B2
Publication Date
2024-11-19
Expiration Date
2039-11-01
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Abstract
A pharmaceutical composition generally includes a therapeutic antibody, or fragment thereof, and a pharmaceutically acceptable carrier. The therapeutic antibody specifically binds to a target peptide that mediates pain in a subject. The composition may be administered to a subject experiencing pain to at least partially alleviate the pain.
Core Innovation
This invention provides a pharmaceutical composition including a therapeutic antibody or fragment thereof, specifically binding to a target peptide that mediates pain in a subject, combined with a pharmaceutically acceptable carrier. The therapeutic antibody can be an scFv including amino acid sequences of SEQ ID NOs:3-10, targeted especially to an extracellular binding portion of the cholecystokinin B (CCK-B) receptor. The composition is designed to relieve acute or chronic orofacial pain and reduce anxiety-related behaviors associated with pain.
The problem addressed is the poor therapeutic response rate in managing chronic orofacial pain, which is often unrelenting, excruciating, and difficult to treat with conventional analgesics like opioids, NSAIDS, and others. Chronic orofacial pain involves neuroplasticity, remodeling of brain circuitry, and gene expression changes linked to nociceptive and anxiety-related pathways. Existing treatments are often ineffective, particularly for neuropathic pain of the trigeminal nerve. Thus, there is a need for non-addictive, non-opioid therapeutics that can alleviate both pain and associated anxiety or depression.
The disclosed solution involves generating brain-penetrant, non-opioid, single-chain variable fragment (scFv) antibodies that specifically block the CCK-B receptor activation linked to pain and anxiety. These scFv antibodies reduce mechanical hypersensitivity and anxiety-like behaviors in animal models, lowering mRNA and protein expression associated with pain and neural pathology. The use of cell-free ribosome display enables rapid generation of high-affinity scFv antibodies with improved tissue penetration and therapeutic efficacy. This approach offers the potential to modulate pain and mood simultaneously in chronic orofacial pain and other pain syndromes.
Claims Coverage
The patent includes two independent claims focusing on a pharmaceutical composition and a method for relieving pain. The main inventive features center on specific antibodies and their use against pain.
Pharmaceutical composition comprising specific antibodies
A pharmaceutical composition comprising an antibody or fragment thereof that specifically binds to a target peptide mediating pain in a subject, including at least one of SEQ ID NOs:3-10, and combined with a pharmaceutically acceptable carrier.
Use of scFv antibodies to relieve pain
The composition wherein the antibody is a single-chain variable fragment (scFv) designed to relieve acute or chronic orofacial pain and reduce anxiety-related behaviors, optionally including a fluorescent tag (e.g., monomeric red fluorescent protein RFP1) and/or an affinity tag (e.g., 6×His tag).
Method for alleviating pain using the antibody composition
A method for relieving pain comprising administering a sufficient amount of the pharmaceutical composition containing the specified antibody to a subject experiencing pain, including neuropathic orofacial pain, in an amount effective to alleviate the pain.
The claims cover compositions of specific scFv antibodies targeting pain-mediating peptides, their pharmaceutical formulations, and methods of administration for treating pain and associated behavioral symptoms.
Stated Advantages
The therapeutic antibodies are effective, non-addictive, and non-opioid alternatives to conventional analgesics.
The scFv antibodies demonstrate brain penetration, enabling modulation of central pain and anxiety pathways.
The compositions relieve acute and chronic orofacial neuropathic pain and reduce anxiety-related and depression-related behaviors in animal models.
The use of cell-free ribosome display technology enables rapid production of highly specific, high-affinity antibodies with small size for better tissue penetration.
Potential additional benefits include reduction of pathological tau phosphorylation and related neuropathology associated with chronic pain.
Documented Applications
Therapeutic treatment of acute or chronic orofacial pain, including neuropathic pain of the trigeminal nerve.
Reduction of anxiety-related and depression-related behaviors associated with chronic pain.
Potential applicability for other pain syndromes involving CCK-B receptor or related pain-mediating targets.
Possible adjunctive use to improve low dose opioid effectiveness and treatment of withdrawal symptoms related to opioid dependence.
Applications in palliative care for cachexic patients with intractable chronic pain, including terminal cancer pain.
Potential use to reduce growth and metastases of gastrointestinal cancers expressing CCK-B receptors.
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