Women are disproportionally impacted by functional pain syndromes (FPS), a large subgroup ofpain conditions defined by the absence of a clear etiology or tissue injury. These syndromes have a highfemale:male prevalence ratio and include, but are not limited to, temporomandibular joint and muscle disorders(TMJD) (9:1 ratio), fibromyalgia (9:1 ratio), irritable bowel syndrome (IBS) (3:1 ratio), and migraine (3:1 ratio), aswell as female exclusive FPS such as dysmenorrhea, endometriosis and vulvodynia.Reasons for the sexually dimorphic prevalence in FPS remain uncertain but emerging evidence suggests thatprolactin (PRL) elicits sensitization of female nociceptors. PRL selectively promotes hyperalgesia and pain infemale mice with minimal effects in male animals. PRL signals through mutually inhibitory long- and short-formPRL receptor (PRLR) isoforms that are expressed at higher levels in female nociceptors. Female animals andhumans have higher circulating PRL than males. A role for circulating PRL was demonstrated by prevention ofopioid-induced hyperalgesia (OIH) selectively in female mice by cabergoline, a dopaminergic D2 agonist whichinhibits PRL release from the pituitary. Similarly, migraines associated with PRL-secreting tumors are treatedwith D2 agonists. Collectively, these data support that PRL selectively promotes female hyperalgesia.Our team now wishes to translate these breakthrough findings into novel and transformative therapeutics forfemale-prevalent pain conditions. We propose to develop PRL monoclonal antibodies (PRL-mAbs) as first-in-class therapeutics for female FPS, targeting migraine as the primary indication.The specific goals of this SBIR Phase I application are to (i) assess the technical feasibility of the program (i.e.,identification of neutralizing PRL-mAb leads) and (ii) validate the working hypothesis (i.e., demonstration thatsystemic administration of a neutralizing PRL-mAb selectively prevents PRL-induced female hyperalgesia in amigraine relevant model).Impact and
Public Health Relevance Statement: Project narrative: Peptide Logic is developing prolactin monoclonal antibodies (PRL-mAbs) as first-in- class therapeutics for the treatment of female-prevalent functional pain syndromes (FPS), targeting migraine as the primary indication. PRL-mAbs are designed to prevent PRL-induced sexually-dimorphic hyperalgesia in injury-free pain conditions, an emerging but still untapped nociceptive mechanism. If successful, PRL-mAbs have the potential to profoundly transform the standard of care for the treatment of female-prevalent FPS and improve the quality of life for many women.
Project Terms: Animals ; Antibodies ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Cells ; Cell Body ; Dysmenorrhea ; Menstrual Pain ; Painful Menstruation ; endometriosis ; Exhibits ; Female ; Fibromyalgia ; Diffuse Myofascial Pain Syndrome ; Fibromyositis-Fibromyalgia Syndrome ; Fibrositis ; MPD syndrome ; Muscular Rheumatism ; fibromyalgia syndrome ; myofascial pain dysfunction syndrome ; Freedom ; Liberty ; Goals ; Human ; Modern Man ; Hyperalgesia ; Hyperalgesic Sensations ; hyperalgia ; Immunization ; Immunologic Sensitization ; Immunologic Stimulation ; Immunological Sensitization ; Immunological Stimulation ; Immunostimulation ; In Vitro ; Irritable Bowel Syndrome ; Irritable Colon ; Mucous Colitis ; spastic colon ; Logic ; male ; Mus ; Mice ; Mice Mammals ; Murine ; Nociceptors ; Pain ; Painful ; Peptides ; Phosphorylation ; Protein Phosphorylation ; Pituitary Gland ; Hypophysis ; Hypophysis Cerebri ; Pituitary ; Pituitary Nervous System ; Human Placental Lactogen ; Human Chorionic Somatomammotropin ; Prolactin ; Mammotropin ; Pituitary Lactogenic Hormone ; Pituitary Mammotropic Hormone ; luteotropic hormone ; luteotropin ; Quality of life ; QOL ; Prolactin Receptor ; PRL Receptors ; Research ; Research Personnel ; Investigators ; Researchers ; Role ; social role ; Safety ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Somatotropin ; Growth Hormone ; Growth Hormone 1 ; Pituitary Growth Hormone ; somatotropic hormone ; Syndrome ; Tail ; Temporomandibular Joint Disorders ; TMJ Diseases ; TMJ Disorders ; TMJD ; Temporomandibular Disorders ; Temporomandibular Joint Diseases ; Temporomandibular Joint and Muscle Disorder ; Testing ; Translating ; Veins ; Woman ; cabergoline ; Migraine ; Migraine Headache ; Injury ; injuries ; base ; improved ; Peripheral ; Phase ; Nociception ; nociceptive ; Opioid ; Opiates ; Agonist ; Antibody Therapy ; antibody based therapies ; antibody treatment ; antibody-based therapeutics ; antibody-based treatment ; Therapeutic ; tool ; Intravenous ; programs ; Burning vulva ; Vulval discomfort ; Vulvar discomfort ; vulva discomfort ; Vulvodynia ; Tactile ; subdermal ; subcutaneous ; Route ; allodynia ; Isoforms ; Protein Isoforms ; success ; stable cell line ; sex dimorphism ; sexually dimorphic ; sexual dimorphism ; novel ; Prevention ; Reporting ; Modeling ; response ; cross reactivity ; Proteomics ; Adverse effects ; Pain-Free ; MGF protein ; MGSNF protein ; STAT5 ; STAT5A ; STAT5A gene ; STAT5a Transcription Factor ; Signal Transducer and Activator of Transcription 5A ; Stat5a protein ; Stat5alpha protein ; mammary gland factor ; mammary gland-specific nuclear factor ; signal tranducer and activator of transcription 5 ; Stat5 protein ; preventing ; prevent ; Causality ; causation ; disease causation ; Etiology ; Dose ; Adherence ; Control Animal ; Data ; randomisation ; randomization ; randomly assigned ; Randomized ; Recombinants ; Subgroup ; in vitro Assay ; in vivo ; Filament ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; follow-up ; Active Follow-up ; active followup ; follow up ; followed up ; followup ; digital ; design ; designing ; blind ; Prevalence ; tumor ; public health relevance ; standard of care ; experimental study ; experiment ; experimental research ; efficacy study ; clinical development ; tissue injury ; injury to tissue ;
