Drug design strategies for modulating immune activity for the treatment of autoimmune diseases and cancer

The immune system plays an important role in protecting the body from foreign pathogens and damaged cells. Self-tolerance mechanisms exist to prevent the immune system from attacking normal cells. However, malfunctions in the self-tolerance mechanisms can result in the inability of the immune system of distinguishing self and non-self, cause damage to normal tissue, and lead to the development of autoimmune diseases. Moreover, damaged cells may utilize these self-tolerance mechanisms to avoid detection and suppress the immune response, resulting in the development of cancer. In this dissertation, we considered the physiochemical properties of various immune-modifying therapeutics to improve their delivery to their intended biological destination. In chapter 2, we used a small molecule inhibitor of N-linked glycosylation, kifunensine, to demonstrate the role of glycosylation in affecting B-cell receptor signaling. Moreover, we demonstrated that more hydrophobic analogs of the inhibitory molecule resulted in better cell permeability and higher potency. These glycosylation-modifying molecules may have applications in the treatment of diseases (e.g., ERAD-related diseases, cancer, and viral infections), and for the production of other glycoprotein therapeutics. In chapter 3, we developed a yeast surface display platform that can be used to screen for anti-AQP4 autoantibodies found in patients with neuromyelitis optica (NMO). This platform may be used to help develop targeted therapeutics that selectively suppress disease-related immune cells for the treatment of autoimmune diseases such as NMO. Due to their more-limited effects on the immune system, these targeted therapeutics may be a safer treatment option than traditional immunosuppressant therapies that suppress many parts of the immune system. In chapter 4, we used a cationic polypeptide, glatiramer acetate (Copaxone®), as a vehicle to help deliver CpG, a negatively-charged immunostimulant. We previously demonstrated that this polyplex formulation can help increase tumor retention and limit systemic toxicity. Here, we investigated whether this polyplex formulation can be used in combination with anti-PD-1 therapy to instigate further anti-tumor effects. Together, each chapter demonstrates examples of the utilization of drug design strategies for applications in modulating immune function.

Grantor dc:publisher

University of Kansas

Year dc:date.issued

2022

Author dc:creator

• Huang, Aric

Advisor dc:contributor.advisor

• Berkland, Cory J

• Pharmaceutical sciences

Statement dc:rights

• Copyright held by the author.

Language dc:language.iso

en

Dc Identifier Other

http://dissertations.umi.com/ku:18608

OAI identifier oai:identifier

oai:kuscholarworks.ku.edu:1808/36565