Date of Award
6-3-2025
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Pharmacology and Experimental Therapeutics
First Advisor
Jawed Fareed
Second Advisor
Ravi Durvasula
Abstract
Neuropathic pain, caused by damage to the somatosensory nervous system, remains a significant medical challenge due to limited efficacy and side effects of current treatments. The goal of this research was to develop a novel, non-opioid therapeutic strategy targeting the cholecystokinin B receptor (CCKBR), which is implicated in chronic pain propagation and opioid resistance. By designing a humanized single-chain variable fragment (scFv) antibody against CCKBR, this study aims to address the limitations of existing pain management approaches as CCKBR plays a critical role in modulating pain pathways by opposing μ-opioid receptor (MOR) signaling, contributing to persistent pain and reduced opioid efficacy. Immunohistochemical analyses confirmed the co-localization of CCKBR and MOR in pain-related regions of the brain, including dorsal root ganglia (DRG) and spinal cord tissues from rats, mice, and humans. Functional studies using live-cell calcium imaging demonstrated that CCKBR activation antagonizes MOR signaling by increasing intracellular calcium levels. To target this receptor, a murine anti-CCKBR scFv was generated using ribosomal display technology and subsequently humanized to reduce immunogenicity while preserving high specificity and affinity. The lead humanized scFv exhibited robust binding to CCKBR and functional assays confirmed its ability to inhibit CCKBR-mediated pronociceptive signaling in vitro. The findings highlight the potential of humanized anti-CCKBR scFv antibodies as a promising therapeutic approach for neuropathic pain. By specifically targeting CCKBR, these antibodies may restore MOR function and provide effective analgesia without the risks associated with opioids. Future directions include further preclinical development and clinical translation of this innovative treatment strategy.
Recommended Citation
Sandhu, Gurpreet, "Development of a Humanized SCFV Antibody: Step Towards Treatment of Neuropathic Pain" (2025). Dissertations. 4188.
https://ecommons.luc.edu/luc_diss/4188
