Development and Optimization of Peptide-Based, Tumor-Associated Macrophage (TAM)-Targeting Therapeutics
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Cancer is one of the leading causes of death and is a subject of intense research worldwide. Within the past few decades, cancer immunotherapy has emerged as an important arm of cancer therapies following the prominent success of immune checkpoint blockade therapies and chimeric antigen receptor (CAR)-T cell therapies. While the first wave of cancer immunotherapy focuses on an adaptive immunity (T cells), a fruitful opportunity exists to modulate an innate immunity for anti-cancer therapies. Tumor-associated macrophages (TAMs) are one of the most studied innate immune populations due to their abundance in tumor microenvironment. In most tumors, the majority of TAMs expresses M2-like phenotypes and supports pro-tumoral functions, whereas the minority expresses M1-like phenotypes with anti-tumoral functions. Several investigational pre-clinical strategies to modulate TAMs, either depleting them or stimulating their tumoricidal functions, are delivering promising results with high translational potential. Chapter 1 provides a review on the current update in TAM-targeted therapeutics. To potentiate the reported TAM-modulating agents, several TAM-targeted drug delivery systems are being developed by us and others. This thesis focuses on optimization of the active targeting ligand (M2pep) previously shown to bind to M2 macrophages and M2-like TAMs. Chapter 2 explores synthesis and evaluation of targeting avidity of divalent and tetravalent M2pep, as well as the effect of ratiometric display of M2pep versus therapeutic cargo in regard to therapeutic selectivity. Chapter 3 and 4 report affinity and serum stability optimization of M2pep via amino acid sequence modifications and peptide macrocyclization. Rationalizing further M2pep optimization based on the context of acidic tumor microenvironment, Chapter 5 demonstrates the development of low pH-responsive M2pep. Chapter 6 further elaborates the development of multivalent M2pep utilizing a biocompatible polymer to confer both enhanced avidity and serum stability. Finally, chapter 7 concludes the major findings and provides recommendations for future optimization in regard to human translation.
- Bioengineering